U.S. patent application number 11/828446 was filed with the patent office on 2009-03-05 for peroxisome proliferator activated receptor alpha agonists.
Invention is credited to Ivan Collado Cano, David Scott Coffey, Samuel James Dominianni, Garret Jay Etgen, JR., Cristina Garcia-Paredes, Richard Duane Johnston, Michael Edward Letourneau, Nathan Bryan Mantlo, Michael John Martinelli, Daniel Ray Mayhugh, Ashraf Saeed, Christopher Randall Schmid, Richard Craig Thompson, Jeffrey Thomas Vicenzi, Xiaodong Wang, Yanping Xu.
Application Number | 20090062358 11/828446 |
Document ID | / |
Family ID | 22934453 |
Filed Date | 2009-03-05 |
United States Patent
Application |
20090062358 |
Kind Code |
A1 |
Cano; Ivan Collado ; et
al. |
March 5, 2009 |
PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONISTS
Abstract
The present invention is directed to compounds represented by
the following structural formula, and pharmaceutically acceptable
salts, solvates and hydrates thereof, ##STR00001## R1 is a
substituted or unsubstituted group selected from C.sub.1-C.sub.8
alkyl, aryl-C.sub.0-2-alkyl, heteroaryl-C.sub.0-2-alkyl, C3-C6
cycloalkylaryl-C.sub.0-2-alkyl or phenyl. W is O or S. R2 is H or a
substituted or unsubstituted group selected from C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl and heteroaryl. X is a
C.sub.2-C.sub.5 alkylene linker wherein one carbon atom of the
linker may be replaced with O, NH or S. Y is C, O, S, NH or a
single bond. Furthermore, E is (CH.sub.2).sub.nCOOH, wherein n is
0, 1, 2 or 3, or C(R3)(R4)A, wherein A is an acidic functional
group such as carboxyl, carboxamide substituted or unsubstituted
sulfonamide, or substituted or unsubstituted tetrazole. R3 is H,
saturated or unsaturated C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5
alkoxy. Additionally, R4 is H, halo, a substituted or unsubstituted
group selected from C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy,
C.sub.3-C.sub.6 cycloalkyl, arylC.sub.0-C.sub.4alkyl and phenyl, or
R3 and R4 are combined to form a C.sub.3-C.sub.4 cycloalkyl.
Inventors: |
Cano; Ivan Collado;
(Alcobendas, ES) ; Dominianni; Samuel James;
(Indianapolis, IN) ; Etgen, JR.; Garret Jay;
(Carmel, IN) ; Garcia-Paredes; Cristina;
(Alcobendas, ES) ; Johnston; Richard Duane;
(Greenfield, IN) ; Letourneau; Michael Edward;
(Indianapolis, IN) ; Mantlo; Nathan Bryan;
(Brownsburg, IN) ; Martinelli; Michael John;
(Zionsville, IN) ; Mayhugh; Daniel Ray; (Carmel,
IN) ; Saeed; Ashraf; (Framingham, MA) ;
Thompson; Richard Craig; (Frankfort, IN) ; Wang;
Xiaodong; (Carmel, IN) ; Coffey; David Scott;
(Indianapolis, IN) ; Schmid; Christopher Randall;
(Indianapolis, IN) ; Vicenzi; Jeffrey Thomas;
(Brownsburg, IN) ; Xu; Yanping; (Fishers,
IN) |
Correspondence
Address: |
ELI LILLY & COMPANY
PATENT DIVISION, P.O. BOX 6288
INDIANAPOLIS
IN
46206-6288
US
|
Family ID: |
22934453 |
Appl. No.: |
11/828446 |
Filed: |
July 26, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10415673 |
Sep 11, 2003 |
7304062 |
|
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PCT/US01/42928 |
Nov 9, 2001 |
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11828446 |
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60247317 |
Nov 10, 2000 |
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Current U.S.
Class: |
514/384 ;
548/263.2 |
Current CPC
Class: |
A61P 9/10 20180101; C07D
249/12 20130101; A61P 3/10 20180101; C07D 413/06 20130101; A61P
43/00 20180101; C07D 409/12 20130101; C07C 281/04 20130101; A61P
9/00 20180101; A61P 9/12 20180101; C07D 405/06 20130101; C07D
417/12 20130101; A61P 3/06 20180101; C07C 257/22 20130101; C07D
409/06 20130101; A61P 3/00 20180101; A61P 3/04 20180101; C07D
401/06 20130101; C07C 281/06 20130101 |
Class at
Publication: |
514/384 ;
548/263.2 |
International
Class: |
A61K 31/4196 20060101
A61K031/4196; C07D 249/12 20060101 C07D249/12; C07D 405/02 20060101
C07D405/02 |
Claims
1. A compound represented by the following structural Formula I:
##STR00434## and pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein: (a) R1 is selected from the group
consisting of hydrogen, substituted or unsubstituted group selected
from C.sub.1-C.sub.8 alkyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl, and --CH.sub.2--C(O)--R17-R18,
wherein R17 is O or NH and R18 is optionally substituted benzyl;
(b) W is O or S; (c) R2 is H or a substituted or unsubstituted
group selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 allyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, sulfonamide, amide, OR10 and
C.sub.3-C.sub.6 cycloalkyl; (d) X is an optionally substituted
C.sub.1-C.sub.5 alkylene linker wherein one carbon atom of the
linker may be replaced with O, NH or S; (e) Y is C, O, S, NH or a
single bond; and (f) E is selected from the group consisting of
hydrogen, C(R3)(R4)A, A, substituted or unsubstituted selected from
the group consisting of (CH.sub.2).sub.n COOR19, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 allyl, aryl-C.sub.0-4-alkyl,
thio-C.sub.1-4-alkyl, thioaryl, C.sub.1-4alkoxyaryl,
C.sub.1-4alkoxy C.sub.1-4alkyl, aminoaryl, and aminoC.sub.1-4alkyl,
and wherein (i) n is 0, 1, 2 or 3, (ii) A is an functional group
selected from the group consisting of carboxyl,
C.sub.1-C.sub.3alkylnitrile, carboxamide, substituted or
unsubstituted sulfonamide, substituted or unsubstituted
acylsulfonamide and substituted or unsubstituted tetrazole; (iii)
R3 is H, saturated or unsaturated C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, and (iv) R4 is H, halo, a substituted or
unsubstituted group selected from C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6 cycloalkyl, aryl
C.sub.0-C.sub.4 alkyl and phenyl, or R3 and R4 are combined to form
a C.sub.3-C.sub.4 cycloalkyl; (v) R19 is selected from the group
consisting of hydrogen, optionally substituted arylmethyl and
optionally substituted C.sub.1-C.sub.4alkyl; (g) R8 is
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylenyl, and halo; (h) R9
is independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylenyl, halo, substituted
or unsubstituted aryl, substituted or unsubstituted
aryl-C.sub.1-C.sub.4 alkyl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.6 allyl, and OR10; and (i) R10 is
independently selected from the group consisting of hydrogen and
C.sub.1-C.sub.4 alkyl.
2. (canceled)
3. A compound as claimed by any one of claims 1 or 2 wherein W is
O.
4. A compound as claimed by any one of claims 1, 2 or 3 wherein E
is A.
5. A compound as claimed by any one of claims 1, 2, 3 or 4 wherein
A is COOH.
6. A compound as claimed by any one of claims 1, 2, 3, 4 or 5
wherein Y is O.
7. A compound as claimed by any one of claims 1, 2, 3, 4 or 5
wherein Y is C.
8. A compound of claim 7 wherein E is selected from the group
consisting of aryl-C.sub.0-4-alkyl, thio-C.sub.1-4-alkyl, thioaryl,
C.sub.1-4alkoxyaryl, C.sub.1-4alkoxyalkyl, aminoaryl, and
aminoC.sub.1-4alkyl.
9. A compound as claimed by any one of claims 1, 2, 3, 6, or 7
wherein E is a group of the formula: ##STR00435## wherein R14 is
selected from the group consisting of CF.sub.3, substituted or
unsubstituted phenyl, substituted or unsubstituted
aryl-C.sub.0-4-alkyl, and C.sub.1-6-alkyl.
10. A compound as claimed by any one of claims 1, 2, 3, 6, or 7
wherein E is a group of the formula: ##STR00436## wherein R14 is
selected from the group consisting of CF.sub.3, substituted or
unsubstituted phenyl, substituted or unsubstituted
aryl-C.sub.0-4-alkyl, and C.sub.1-6-alkyl.
11. A compound as claimed by any one of claims 1, 2, 3, 4, 5, 6, 7,
8, 9, or 10 wherein X is optionally substituted C.sub.2-C.sub.5
alkylene.
12. A compound as claimed by any one of claims 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, or 11 wherein X is propylene.
13. A compound of claim 1 which is Propanoic Acid,
2-[4-[3-[2,5-dihydro-1-[(4-methylphenyl)methyl]-5-oxo-1H-1,2,4-triazol-3--
yl]propyl]phenoxy]-2-methyl-.
14. A compound of claim 13 which is Crystalline Propanoic Acid,
2-[4-[3-[2,5-dihydro-1-[(4-methylphenyl)methyl]-5-oxo-1H-1,2,4-triazol-3--
yl]propyl]phenoxy]-2-methyl- having an X-ray diffraction pattern
which comprises at least one of the following peaks: 13.2+/-0.2,
15.9+/-0.2, 20.7+/-0.2, and 24.1+/-0.2 in 20 when obtained from a
copper radiation source.
15. A compound as claimed by any one of claims 1, 2, 5, 11 or 12
that is represented by the following structural formula:
##STR00437## and pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein: (a) R1 is selected from the group
consisting of hydrogen, substituted or unsubstituted group selected
from C.sub.1-C.sub.8 alkyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl, and --CH.sub.2--C(O)--R17-R18,
wherein R17 is O or NH and R18 is optionally substituted benzyl;
(b) R2 is H or a substituted or unsubstituted group selected from
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl and heteroaryl;
(c) X is a C.sub.2-C.sub.5 alkylene linker wherein one carbon atom
of the linker may be replaced with O, NH or S; (d) Q is C, O or S;
(e) A is a functional group selected from the group consisting of
carboxyl, C.sub.1-C.sub.3alkylnitrile, carboxamide, substituted or
unsubstituted sulfonamide, substituted or unsubstituted
acylsulfonamide and substituted or unsubstituted tetrazole; (f) R3
is H, saturated or unsaturated C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy; and (g) R4 is H, halo, a substituted or
unsubstituted group selected from C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6 cycloalkyl and phenyl, or
R3 and R4 are combined to form a C.sub.3-C.sub.4 cycloalkyl.
16. A compound as claimed by claim 15 wherein A is COOH.
17. A compound as claimed by any one of claims 15, or 16 wherein R3
is methyl.
18. A compound as claimed by any one of claims 15, 16 or 17 wherein
R4 is methyl.
19. A compound as claimed by any one of claims 1, 2, 11 or 12 that
is represented by the following structural formula: ##STR00438##
and pharmaceutically acceptable salts, solvates and hydrates
thereof, wherein: (a) R1 is selected from the group consisting of
hydrogen, substituted or unsubstituted group selected from
C.sub.1-C.sub.8 alkyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl, and --CH.sub.2--C(O)--R17-R18,
wherein R17 is O or NH and R18 is optionally substituted benzyl;
(b) R2 is H or a substituted or unsubstituted group selected from
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl and heteroaryl;
(c) X is an optionally substituted C.sub.1-C.sub.5 alkylene linker
wherein one carbon atom of the linker may be replaced with O, NH or
S; (d) Q is C, O or S; (e) R3 is H, saturated or unsaturated
C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy; and (f) R4 is H,
halo, a substituted or unsubstituted group selected from
C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6
cycloalkyl and phenyl, or R3 and R4 are combined to form a
C.sub.3-C.sub.4 cycloalkyl.
20. A compound as claimed by any one of claims 1-12, 15, 16, 17,
18, or 19 wherein R1 selected from the group consisting of a
substituted or unsubstituted C.sub.1-C.sub.8 alkyl,
aryl-C.sub.0-4-alkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl.
21. A compound as claimed by any one of claims 1-12, 15, 16, 17,
18, 19 or 20 wherein R1 is substituted aryl.
22. A compound as claimed by any one of claims 1, 2, 11, or 12 that
is represented by the following structural formula: ##STR00439##
and pharmaceutically acceptable salts, solvates and hydrates
thereof, wherein: (a) R2 is H or a substituted or unsubstituted
group selected from C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl and heteroaryl; (b) X is an optionally substituted
C.sub.1-C.sub.5 alkylene linker wherein one carbon atom of the
linker may be replaced with O, NH or S; (c) R3 is H, saturated or
unsaturated C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy; (d) R4
is H, halo, a substituted or unsubstituted group selected from
C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6
cycloalkyl and phenyl, or R3 and R4 are combined to form a
C.sub.3-C.sub.4 cycloalkyl; (e) V is a bond or a unsubstituted or
substituted C.sub.1-C.sub.3 alkylene group; and (f) R5 is
substituted or unsubstituted group selected from aryl, heteroaryl
and cycloalkyl groups.
23. A compound as claimed by any one of claims 1, 2, 11 or 12 that
is represented by the following structural formula: ##STR00440##
and pharmaceutically acceptable salts, solvates and hydrates
thereof, wherein: (a) R2 is H or a substituted or unsubstituted
group selected from C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl and heteroaryl (delete heteroaryl); (b) X is an
optionally substituted C.sub.1-C.sub.5 alkylene linker wherein one
carbon atom of the linker may be replaced with O, NH or S; (c) R3
is H, saturated or unsaturated C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy; (d) R4 is H, halo, a substituted or
unsubstituted group selected from C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6 cycloalkyl and phenyl, or
R3 and R4 are combined to form a C.sub.3-C.sub.4 cycloalkyl; (e) V
is a bond or a unsubstituted or substituted C.sub.1-C.sub.3
alkylene group; and (f) R6 is H, OH, C.sub.1-C.sub.5 alkyl, alkoxy,
halo, haloalkyl, haloalkoxy, nitro, phenyl, aryloxy, SO.sub.2R7,
SR7, cyano, benzyloxy, phenoxy, alkylcarboxamido or COOH wherein R7
is an alkyl or a haloalkyl.
24. A compound of claim 23 wherein V is methylene.
25. A compound as claimed by any one of claims 23 or 24 wherein X
is propylene.
26. A compound as claimed by any one of claims 23, 24 or 25 wherein
R3 is methyl.
27. A compound as claimed by any one of claims 23, 24, 25 or 26
wherein R4 is methyl.
28. A compound as claimed by any one of claims 1 or 2 that is
represented by the following structural formula: ##STR00441## and
pharmaceutically acceptable salts, solvates and hydrates thereof,
wherein: (a) R2 is H or a substituted or unsubstituted group
selected from C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl and
heteroaryl (delete heteroaryl); (b) R3 is H, saturated or
unsaturated C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy; (c) R4
is H, halo, a substituted or unsubstituted group selected from
C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6
cycloalkyl and phenyl, or R3 and R4 are combined to form a
C.sub.3-C.sub.4 cycloalkyl; and (d) R6 is independently selected
from the group consisting of H, OH, C1-C5 alkyl, alkoxy, halo,
haloalkyl, haloalkoxy, nitro, phenyl, aryloxy, SO2R7, SR7, cyano,
benzyloxy, phenoxy, alkylcarboxamido or COOH wherein R7 is an alkyl
or a haloalkyl.
29. A compound as claimed by any one of claims 1, 2, or 4-28, that
is represented by the following structure: ##STR00442## wherein R6
is independently selected from the group consisting of H, OH,
C.sub.1-C.sub.5 alkyl, alkoxy, halo, haloalkyl, haloalkoxy, nitro,
phenyl, aryloxy, SO2R7, SR7, cyano, benzyloxy, phenoxy,
alkylcarboxamido or COOH wherein R7 is an alkyl or a haloalkyl.
30. A compound as claimed by any one of claims 1, 2, or 4-29
wherein there are two R6 substituents independently selected from
the group consisting of hydrogen, C.sub.1-C.sub.5 alkyl, Cl, F,
OCH.sub.3, CF.sub.3, and SCF.sub.3.
31. A compound as claimed by any one of claims 1, 2, or 4-30
wherein EY is ##STR00443##
32. A compound represented by the following structural formula:
##STR00444## and pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein: (a) R1 is selected from the group
consisting of hydrogen, substituted or unsubstituted group selected
from C.sub.1-C.sub.8 alkyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl, and --CH.sub.2--C(O)--R17-R18,
wherein R17 is O or NH and R18 is optionally substituted benzyl;
(b) W is O or S; (c) R2 is H or a substituted or unsubstituted
group selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, sulfonamide, amide, OR10 and
C.sub.3-C.sub.6 cycloalkyl; (d) X is an optionally substituted
C.sub.1-C.sub.5 alkylene linker wherein one carbon atom of the
linker may be replaced with O, NH or S; (e) Y is C, O, S, NH or a
single bond; and (f) E is selected from the group consisting of
hydrogen, C(R3)(R4)A, A, substituted or unsubstituted selected from
the group consisting of (CH.sub.2).sub.n COOR19, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 allyl, aryl-C.sub.0-4-alkyl,
thio-C.sub.1-4-alkyl, thioaryl, C.sub.1-4alkoxyaryl,
C.sub.1-4alkoxy C.sub.1-4alkyl, aminoaryl, and aminoC.sub.1-4alkyl,
and wherein (i) n is 0, 1, 2 or 3, (ii) A is a functional group
selected from the group consisting of carboxyl,
C.sub.1-C.sub.3alkylnitrile, carboxamide, substituted or
unsubstituted sulfonamide, substituted or unsubstituted
acylsulfonamide and substituted or unsubstituted tetrazole; (iii)
R3 is H, saturated or unsaturated C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, and (iv) R4 is H, halo, a substituted or
unsubstituted group selected from C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6 cycloalkyl, aryl
C.sub.0-C.sub.4 alkyl and phenyl, or R3 and R4 are combined to form
a C.sub.3-C.sub.4 cycloalkyl; (v) R19 is selected from the group
consisting of hydrogen, optionally substituted arylmethyl and
optionally substituted C.sub.1-C.sub.4 alkyl; (g) R8 is
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylenyl, and halo; (h) R9
is independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylenyl, halo, substituted
or unsubstituted aryl, substituted or unsubstituted
aryl-C.sub.1-C.sub.4 alkyl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.6 allyl, and OR10; (i) R10 is
independently selected from the group consisting of hydrogen and
C.sub.1-C.sub.4 alkyl; (j) Z is C.sub.0-C.sub.3 alkylene, O, S, N,
O--(C.sub.0-C.sub.2 alkylene), S--(C.sub.0-C.sub.2 alkylene), and
N--(C.sub.0-C.sub.2 alkylene); and (k) -- is an optional bond to
form a double bond.
33. A compound of claim 32 having the formula: ##STR00445##
34. A compound of 33 represented by the structural formula:
##STR00446##
35. A compound of claim 32 represented by the structural formula:
##STR00447##
36. A compound of claim 32 represented by the following structure:
##STR00448##
37. A compound of claim 32 represented by the following structure:
##STR00449##
38. A compound as claimed by 32 wherein A is COOH.
39. A compound as claimed by claim 32 wherein W is O.
40. A compound as claimed by claim 39 wherein R2 is C.sub.1-C.sub.4
alkyl.
41. A compound as claimed by claim 40, wherein X is C.sub.2-C.sub.3
alkylene.
42. A compound as claimed by claim 41 wherein R1 is optionally
substituted phenyl or benzyl.
43. A compound as claimed by claim 32, wherein R1 is a substituted
or unsubstituted group selected from the group consisting of
C.sub.1-C.sub.8 alkyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl and phenyl.
44. A compound as claimed by claim 32 wherein said compound is
radiolabeled.
45. A compound as claimed by claim 44 wherein said compound is
tritiated.
46. A pharmaceutical composition, comprising a pharmaceutically
acceptable carrier and at least one compound as claimed by any one
of claim 42, or a pharmaceutically acceptable salt, solvate or
hydrate thereof.
47. A method of modulating a peroxisome proliferator activated
receptor, comprising the step of contacting the receptor with at
least one compound as claimed by any one of claims 1-43, or a
pharmaceutically acceptable salt, solvate or hydrate thereof.
48. The method of claim 47, wherein the peroxisome proliferator
activated receptor is an .alpha. receptor.
49. A method of treating diabetes mellitus in a mammal, comprising
the step of administering to the mammal a therapeutically effective
amount of at least one compound of claims 1-43, or a
pharmaceutically acceptable salt, solvate or hydrate thereof.
50. A method of preventing diabetes mellitus in a mammal,
comprising the step of administering to the mammal an effective
amount of at least one compound of claims 1-43, or a
pharmaceutically acceptable salt, solvate or hydrate thereof.
51. The method of any one of claims 49 or 50 wherein the compound
lowers blood glucose levels.
52. A method of treating cardiovascular disease in a mammal,
comprising the step of administering to the mammal a
therapeutically effective amount of at least one compound of claims
1-43, or a pharmaceutically acceptable salt, solvate or hydrate
thereof.
53. A method of preventing cardiovascular disease in a mammal,
comprising the step of administering to the mammal an effective
amount of at least one compound of claims 1-43, or a
pharmaceutically acceptable salt, solvate or hydrate thereof.
54. The method of any one of claims 52 or 53 wherein the compound
lowers triglycerides in the mammal.
55. The method of any one of claims 52, 53, or 54 wherein the
compound lowers low density lipoproteins in the mammal.
56. The method of claims 52, 53 or 54 wherein the compound
increases high density lipoproteins in a mammal.
57. A method of treating Syndrome X in a mammal, comprising the
step of administering to the mammal a therapeutically effective
amount of at least one compound of claims 1-43, or a
pharmaceutically acceptable salt, solvate or hydrate thereof.
58. A method of preventing Syndrome X in a mammal, comprising the
step of administering to the mammal an effective amount of at least
one compound of claims 1-43, or a pharmaceutically acceptable salt,
solvate or hydrate thereof.
59. The method of claim 58 wherein the compound lowers blood
glucose levels.
60. The method of any one of claims 58 or 59 wherein the compound
lowers serum concentration of triglycerides in the mammal.
61. The method of any one of claims 58, 59 or 60 wherein the
compound lowers serum concentration of low density lipoproteins in
the mammal.
62. The method of any one of claims 58, 59, 60 or 61 wherein the
compound increases serum concentration of high density lipoproteins
in a mammal.
63. A method of treating obesity in a mammal, comprising the step
of administering to the mammal a therapeutically effective amount
of at least one compound of claims 1-43, or a pharmaceutically
acceptable salt, solvate or hydrate thereof.
64. A method of preventing obesity in a mammal, comprising the step
of administering to the mammal an effective amount of at least one
compound of claims 1-43, or a pharmaceutically acceptable salt,
solvate or hydrate thereof.
65. The method of any one of claims 47-64 wherein the mammal is a
human.
66. A compound for use in therapy for a disorder modulated by a
peroxisome proliferator activated receptor, wherein the compound,
or pharmaceutically acceptable salt, solvate or hydrate thereof, is
a compound of claims 1-43.
67. Use of a compound for the manufacture of a medicament for the
treatment of a condition modulated by a peroxisome proliferator
activated receptor, wherein the compound, or pharmaceutically
acceptable salt, solvate or hydrate thereof, is a compound of
claims 1-43.
68. (canceled)
69. A process for preparing a triazolone from an acyl semicarbazide
comprising contacting said acyl semicarbazide with an acid.
70. A process as claimed by claim 69 wherein the acid is a sulfonic
acid.
71. A process as claimed by claim 69 wherein the acid is pyridinium
hydrochloride.
72. A process as claimed by any one of claims 69, 70, or 71 wherein
the triazalone is represented by Formula I.
73. A compound of the formula: ##STR00450## wherein (a) R1 is
hydrogen or is selected from the group consisting of a substituted
or unsubstituted group selected from C.sub.1-C.sub.8 alkyl,
aryl-C.sub.0-4-alkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl; (b) R2 is H or a
substituted or unsubstituted group selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 allyl,
aryl-C.sub.0-4-alkyl, heteroaryl-C.sub.0-4-alkyl, sulfonamide,
amide, OR10 and C.sub.3-C.sub.6 cycloalkyl; (c) X is an optionally
substituted C.sub.1-C.sub.5 alkylene linker wherein one carbon atom
of the linker may be replaced with O, NH or S; (d) Y is C, O, S, NH
or a single bond; and (e) E is selected from the group consisting
of hydrogen, (CH.sub.2).sub.nCOOR19, C(R3)(R4)A, substituted or
unsubstituted selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 allyl, aryl-C.sub.0-4-alkyl,
thio-C.sub.1-4-alkyl, thioaryl, C.sub.1-4alkoxyaryl,
C.sub.1-4alkoxy C.sub.1-4alkyl, aminoaryl, and aminoC.sub.1-4alkyl,
and wherein (i) n is 0, 1, 2 or 3, (ii) A is a functional group
selected from the group consisting of carboxyl,
C.sub.1-C.sub.3alkylnitrile, carboxamide, substituted or
unsubstituted sulfonamide, substituted or unsubstituted
acylsulfonamide and substituted or unsubstituted tetrazole; (iii)
R3 is H, saturated or unsaturated C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, and (iv) R4 is H, halo, a substituted or
unsubstituted group selected from C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6 cycloalkyl, aryl
C.sub.0-C.sub.4 alkyl and phenyl, or R3 and R4 are combined to form
a C.sub.3-C.sub.4 cycloalkyl; (v) R19 is selected from the group
consisting of hydrogen, optionally substituted C.sub.1-C.sub.4alkyl
and optionally substituted arylmethyl; (f) R8 is independently
selected from the group consisting of hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkylenyl, and halo; (g) R9 is independently
selected from the group consisting of hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkylenyl, halo, substituted or
unsubstituted aryl, substituted or unsubstituted
aryl-C.sub.1-C.sub.4 alkyl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.6 allyl, and OR10; and (h) R10 is
independently selected from the group consisting of hydrogen and
C.sub.1-C.sub.4 alkyl; and (i) R15 is selected from the group
consisting of hydrogen and an optionally substituted substituent
selected from the group consisting of C.sub.1-C.sub.4 alkyl, aryl,
and benzyl.
74. A compound of claim 73 having the formula: ##STR00451##
75. A compound as claimed by any one of claims 73 and 74 wherein X
is C.sub.2-C.sub.5 alkylene.
76. A compound as claimed by any one of claims 73, 74, or 75
wherein A is selected from the group consisting of COOH, and
C.sub.1-C.sub.3alkylnitrile.
77. A compound as claimed by any one of claims 73, 74, 75, or 76
wherein R2 is C.sub.1-C.sub.4 alkyl.
78. A compound as claimed by any one of claims 73, 74, 75, 76 or
77, wherein X is C.sub.2-C.sub.3 alkylene.
79. A compound as claimed by any one of claims 73, 74, 75, 76, 77,
or 78 wherein R1 is optionally substituted phenyl or benzyl.
80. A compound as claimed by any one of claims 73, 74, 75, 76, 77,
78, or 79 wherein R1 is a substituted or unsubstituted group
selected from the group consisting of C.sub.1-C.sub.8 alkyl,
aryl-C.sub.0-4-alkyl, heteroaryl-C.sub.0-4-alkyl, C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl and phenyl.
81. A compound of the formula: ##STR00452## wherein (a) R1 is
hydrogen or is selected from the group consisting of a substituted
or unsubstituted group selected from C.sub.1-C.sub.8 alkyl,
aryl-C.sub.0-4-alkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl; (b) R2 is H or a
substituted or unsubstituted group selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 allyl,
aryl-C.sub.0-4-alkyl, heteroaryl-C.sub.0-4-alkyl, sulfonamide,
amide, OR10 and C.sub.3-C.sub.6 cycloalkyl; (c) X is an optionally
substituted C.sub.1-C.sub.5 alkylene linker wherein one carbon atom
of the linker may be replaced with O, NH or S; (d) Y is C, O, S, NH
or a single bond; and (e) E is selected from the group consisting
of hydrogen, substituted or unsubstituted selected from the group
consisting of (CH.sub.2).sub.nCOOR19, C(R3)(R4)A, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 allyl, aryl-C.sub.0-4-alkyl,
thio-C.sub.1-4-alkyl, thioaryl, C.sub.1-4alkoxyaryl,
C.sub.1-4alkoxy C.sub.1-4alkyl, aminoaryl, and aminoC.sub.1-4alkyl,
and wherein (i) n is 0, 1, 2 or 3, (ii) A is an acidic functional
group selected from the group consisting of carboxyl,
C.sub.1-C.sub.3alkylnitrile, carboxamide, substituted or
unsubstituted sulfonamide, substituted or unsubstituted
acylsulfonamide and substituted or unsubstituted tetrazole; (iii)
R3 is H, saturated or unsaturated C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, and (iv) R4 is H, halo, a substituted or
unsubstituted group selected from C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6 cycloalkyl, aryl
C.sub.0-C.sub.4 alkyl and phenyl, or R3 and R4 are combined to form
a C.sub.3-C.sub.4 cycloalkyl; (v) R19 is selected from the group
consisting of hydrogen, optionally substituted C.sub.1-C.sub.4alkyl
and optionally substituted arylmethyl; (f) R8 is independently
selected from the group consisting of hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkylenyl, and halo; (g) R9 is independently
selected from the group consisting of hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkylenyl, halo, substituted or
unsubstituted aryl, substituted or unsubstituted
aryl-C.sub.1-C.sub.4 alkyl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.6 allyl, and OR10; and (h) R10 is
independently selected from the group consisting of hydrogen and
C.sub.1-C.sub.4 alkyl.
82. A compound as claimed by claim 81 wherein X is C.sub.2-C.sub.5
alkylene.
83. A compound as claimed by any one of claims 81 or 82 wherein A
is selected from the group consisting of COOH, and
C.sub.1-C.sub.3alkylnitrile.
84. A compound as claimed by any one of claims 81, 82, or 83
wherein R2 is C.sub.1-C.sub.4 alkyl.
85. A compound as claimed by any one of claims 81, 82, 83, or 84,
wherein X is C.sub.2-C.sub.3 alkylene.
86. A compound as claimed by any one of claims 81, 82, 83, 84, or
85 wherein R1 is optionally substituted phenyl or benzyl.
87. A compound of the formula: ##STR00453## wherein (a) R1 is
hydrogen or is selected from the group consisting of a substituted
or unsubstituted group selected from C.sub.1-C.sub.8 alkyl,
aryl-C.sub.0-4-alkyl, heteroaryl-C.sub.0-4-alkyl, and
C.sub.3-C.sub.6 cycloalkylaryl-C.sub.0-2-alkyl; (b) R2 is H or a
substituted or unsubstituted group selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 allyl,
aryl-C.sub.0-4-alkyl, heteroaryl-C.sub.0-4-alkyl, sulfonamide,
amide, OR10 and C.sub.3-C.sub.6 cycloalkyl; (c) X is an optionally
substituted C.sub.1-C.sub.5 alkylene linker wherein one carbon atom
of the linker may be replaced with O, NH or S; (d) Y is C, O, S, NH
or a single bond; and (e) E is selected from the group consisting
of hydrogen, substituted or unsubstituted selected from the group
consisting of (CH.sub.2).sub.nCOOR19, C(R3)(R4)A, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 allyl, aryl-C.sub.0-4-alkyl,
thio-C.sub.1-4-alkyl, thioaryl, C.sub.1-4alkoxyaryl,
C.sub.1-4alkoxy C.sub.1-4alkyl, aminoaryl, and aminoC.sub.1-4alkyl,
and wherein (i) n is 0, 1, 2 or 3, (ii) A is an acidic functional
group selected from the group consisting of carboxyl,
C.sub.1-C.sub.3alkylnitrile, carboxamide, substituted or
unsubstituted sulfonamide, substituted or unsubstituted
acylsulfonamide and substituted or unsubstituted tetrazole; (iii)
R3 is H, saturated or unsaturated C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, and (iv) R4 is H, halo, a substituted or
unsubstituted group selected from C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6 cycloalkyl, aryl
C.sub.0-C.sub.4 alkyl and phenyl, or R3 and R4 are combined to form
a C.sub.3-C.sub.4 cycloalkyl; (v) R19 is selected from the group
consisting of hydrogen, optionally substituted C.sub.1-C.sub.4
alkyl and optionally substituted arylmethyl; (f) R8 is
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylenyl, and halo; (g) R9
is independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylenyl, halo, substituted
or unsubstituted aryl, substituted or unsubstituted
aryl-C.sub.1-C.sub.4 alkyl, substituted or unsubstituted
heteroaryl, C.sub.1-C.sub.6 allyl, and OR10; and (h) R10 is
independently selected from the group consisting of hydrogen and
C.sub.1-C.sub.4 alkyl.
88. A compound as claimed by claim 87 wherein X is C.sub.2-C.sub.5
alkylene.
89. A compound as claimed by any one of claims 87 or 88 wherein A
is selected from the group consisting of COOH, and
C.sub.1-C.sub.3alkylnitrile.
90. A compound as claimed by any one of claims 87, 88, or 89
wherein R2 is C.sub.1-C.sub.4 alkyl.
91. A compound as claimed by any one of claims 87, 88, 89, or 90,
wherein X is C.sub.2-C.sub.3 alkylene.
92. A compound as claimed by any one of claims 87, 88, 89, 90, or
91 wherein R1 is optionally substituted phenyl or benzyl.
93. A compound as claimed by claim 32 wherein E is selected from
the group consisting of hydrogen, C(R3)(R4)A, substituted or
unsubstituted selected from the group consisting of
(CH.sub.2).sub.n COOH, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
allyl, aryl-C.sub.0-4-alkyl, thio-C.sub.1-4-alkyl, thioaryl,
C.sub.1-14alkoxyaryl, C.sub.1-4alkoxy C.sub.1-4alkyl, aminoaryl,
and aminoC.sub.1-4-alkyl.
94. (canceled)
Description
BACKGROUND OF THE INVENTION
[0001] Peroxisome Proliferator Activated Receptors (PPARS) are
members of the nuclear hormone receptor super family, which are
ligand-activated transcription factors regulating gene expression.
Various subtypes of PPARs have been discovered. These include
PPAR.alpha., NUC1, PPAR.gamma. and PPAR.delta..
[0002] The PPAR.alpha. receptor subtypes are reported to be
activated by medium and long-chain fatty acids. They are involved
in stimulating beta-oxidation of fatty acids and with the activity
of fibrates which reportedly produce a substantial reduction in
plasma triglycerides and moderate reduction in low density
lipoprotein (LDL) cholesterol.
[0003] PPAR.alpha., PPAR.gamma. and PPAR.delta. receptors have been
implicated in diabetes mellitus, cardiovascular disease, obesity,
Syndrome X and gastrointestinal disease, such as, inflammatory
bowel disease. Syndrome X is the combination of symptoms which
include hyperinsulemia combined with hypertension, elevated body
weight, elevated triglycerides and elevated LDL.
[0004] Current PPAR agonist treatment for Syndrome X relates to the
use of thiazolidinediones (TZDs) or other insulin sensitivity
enhancers (ISEs). TZDs are a class of PPAR gamma agonists which
have been shown to increase the sensitivity of insulin sensitive
cells. Increasing insulin sensitivity rather than the amount of
insulin in the blood reduces the likelihood of hypoglycemic coma.
However, TZDs and ISEs typically have little effect in preventing
the cardiovascular part of Syndrome X in that their administration
usually dose not result in the lowering of triglycerides and
LDL-cholesterol while raising HDL-cholesterol. Furthermore, side
effects commonly associated with treatment with TZDs include
significant weight gain, and, for troglitazone, liver toxicity.
Therefore, a need exists for new pharmaceutical agents which affect
treat or prevent cardiovascular disease, particularly that
associated with Syndrome X, while preventing or minimizing weight
gain, and more preferably while improving insulin sensitivity.
SUMMARY OF THE INVENTION
[0005] The present invention is directed to compounds represented
by the following structural Formula I:
##STR00002## [0006] and pharmaceutically acceptable salts, solvates
and hydrates thereof, wherein: [0007] (a) R1 is selected from the
group consisting of hydrogen, substituted or unsubstituted group
selected from C.sub.1-C.sub.8 alkyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl, and --CH.sub.2--C(O)--R17-R18,
wherein R17 is O or NH and R18 is optionally substituted benzyl;
[0008] (b) W is O or S; [0009] (c) R2 is H or a substituted or
unsubstituted group selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 allyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, sulfonamide, amide, OR10 and
C.sub.3-C.sub.6 cycloalkyl; [0010] (d) X is an optionally
substituted C.sub.1-C.sub.5 alkylene linker wherein one carbon atom
of the linker may be replaced with O, NH or S; [0011] (e) Y is C,
O, S, NH or a single bond; and [0012] (f) E is selected from the
group consisting of hydrogen, C(R3)(R4)A, A, substituted or
unsubstituted selected from the group consisting of
(CH.sub.2).sub.nCOOR19, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
allyl, aryl-C.sub.0-4-alkyl, thio-C.sub.1-4-alkyl, thioaryl,
C.sub.1-4alkoxyaryl, C.sub.1-4alkoxy C.sub.1-4alkyl, aminoaryl, and
aminoC.sub.1-4alkyl, and wherein [0013] (i) n is 0, 1, 2 or 3,
[0014] (ii) A is an functional group selected from the group
consisting of carboxyl, C.sub.1-C.sub.3alkylnitrile, carboxamide,
substituted or unsubstituted sulfonamide, substituted or
unsubstituted acylsulfonamide and substituted or unsubstituted
tetrazole; [0015] (iii) R3 is H, saturated or unsaturated
C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, and [0016] (iv) R4
is H, halo, a substituted or unsubstituted group selected from
C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6
cycloalkyl, aryl C.sub.0-C.sub.4 alkyl and phenyl, or R3 and R4 are
combined to form a C.sub.3-C.sub.4 cycloalkyl; [0017] (v) R19 is
selected from the group consisting of hydrogen, optionally
substituted C.sub.1-C.sub.4alkyl and optionally substituted
arylmethyl; [0018] (g) R8 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkylenyl, and halo; [0019] (h) R9 is independently selected from
the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkylenyl, halo, substituted or unsubstituted aryl,
substituted or unsubstituted aryl-C.sub.1-C.sub.4 alkyl,
substituted or unsubstituted heteroaryl, C.sub.1-C.sub.6 allyl, and
OR10; and [0020] R10 is independently selected from the group
consisting of hydrogen and C.sub.1-C.sub.4 alkyl. [0021] An
additional embodiment is a compound of Structural Formula I' and
pharmaceutically acceptable salts, solvates and hydrates
thereof:
##STR00003##
[0022] In Structural Formula I', R1 is a substituted or
unsubstituted group selected from C.sub.1-C.sub.8 alkyl,
aryl-C.sub.0-2-alkyl, heteroaryl-C.sub.0-2-alkyl, C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl or phenyl. W is O or S. R2 is H or a
substituted or unsubstituted group selected from C.sub.1-C.sub.6
alkyl and C.sub.3-C.sub.6 cycloalkyl. X is a C.sub.2-C.sub.5
alkylene linker wherein one carbon atom of the linker may be
replaced with O, NH or S. Y is C, O, S, NH or a single bond.
Furthermore, E is (CH.sub.2).sub.nCOOH, wherein n is 0, 1, 2 or 3,
or C(R3)(R4)A, wherein A is an acidic functional group such as
carboxyl, carboxamide substituted or unsubstituted sulfonamide, or
substituted or unsubstituted tetrazole. R3 is H, saturated or
unsaturated C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy.
Additionally, R4 is H, halo, a substituted or unsubstituted group
selected from C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy,
C.sub.3-C.sub.6 cycloalkyl and phenyl, or R3 and R4 are combined to
form a C.sub.3-C.sub.4 cycloalkyl.
[0023] A further embodiment of the present invention is a compound
represented by the following structural formula:
##STR00004## [0024] and pharmaceutically acceptable salts, solvates
and hydrates thereof, wherein: [0025] (a) R1 is selected from the
group consisting of hydrogen, substituted or unsubstituted group
selected from CL-CB alkyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl, and --CH.sub.2--C(O)--R17-R18,
wherein R17 is O or NH and R18 is optionally substituted benzyl;
[0026] (b) W is O or S; [0027] (c) R2 is H or a substituted or
unsubstituted group selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 allyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, sulfonamide, amide, OR10 and
C.sub.3-C.sub.6 cycloalkyl; [0028] (d) X is an optionally
substituted C.sub.1-C.sub.5 alkylene linker wherein one carbon atom
of the linker may be replaced with O, NH or S; [0029] (e) Y is C,
O, S, NH or a single bond; and [0030] (f) E is selected from the
group consisting of hydrogen, C(R3)(R4)A, A, substituted or
unsubstituted selected from the group consisting of
(CH.sub.2).sub.nCOOR19, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
allyl, aryl-C.sub.0-4-alkyl, thio-C.sub.1-4-alkyl, thioaryl,
C.sub.1-4alkoxyaryl, C.sub.1-4alkoxy C.sub.1-4alkyl, aminoaryl, and
aminoC.sub.1-4alkyl, and wherein [0031] (i) n is 0, 1, 2 or 3,
[0032] (ii) A is a functional group selected from the group
consisting of carboxyl, C.sub.1-C.sub.3alkylnitrile, carboxamide,
substituted or unsubstituted sulfonamide, substituted or
unsubstituted acylsulfonamide and substituted or unsubstituted
tetrazole; [0033] (iii) R3 is H, saturated or unsaturated
C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, and [0034] (iv) R4
is H, halo, a substituted or unsubstituted group selected from
C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6
cycloalkyl, aryl C.sub.0-C.sub.4 alkyl and phenyl, or R3 and R4 are
combined to form a C.sub.3-C.sub.4 cycloalkyl; [0035] (v) R19 is
selected from the group consisting of hydrogen, optionally
substituted C.sub.1-C.sub.4alkyl, and optionally substituted
arylmethyl; [0036] (g) R8 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkylenyl, and halo; [0037] (h) R9 is independently selected from
the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkylenyl, halo, substituted or unsubstituted aryl,
substituted or unsubstituted aryl-C.sub.1-C.sub.4 alkyl,
substituted or unsubstituted heteroaryl, C.sub.1-C.sub.6 allyl, and
OR10; [0038] (i) R10 is independently selected from the group
consisting of hydrogen and C.sub.1-C.sub.4 alkyl; [0039] (j) Z is
C.sub.0-C.sub.3 alkylene, O, S, N, O--(C.sub.0-C.sub.2 alkylene),
S--(C.sub.0-C.sub.2 alkylene), and N--(C.sub.0-C.sub.2 alkylene);
and [0040] (k) -- is an optional bond to form a double bond.
[0041] Another claimed embodiment of the present invention is a
compound of the formula:
##STR00005##
[0042] Another embodiment of this invention is compounds of the
following formula, which may be preferred:
##STR00006##
[0043] In another embodiment of the present invention, compounds
represented the following structure may be preferred:
##STR00007##
[0044] In a further embodiment of this invention, a compound the
following structural formula may be preferred:
##STR00008##
[0045] Another compound claimed by this invention that may be
preferred is shown by the following structure:
##STR00009##
[0046] In another feature of this invention, a compound claimed
herein is radiolabeled.
[0047] The present invention additionally provides a process for
preparing a triazolone from an acyl semicarbazide comprising
contacting said acyl semicarbazide with an acid. Preferred acids
for said process are sulfonic acid and pyridinium hydrochloride. It
is a preferred embodiment of this invention when the triazole
prepared by said process is a compound of Formula I.
[0048] Another embodiment of the present invention is a compound of
the formula:
##STR00010##
wherein [0049] (a) R1 is hydrogen or is selected from the group
consisting of a substituted or unsubstituted group selected from
C.sub.1-C.sub.8 alkyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, and C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl; [0050] (b) R2 is H or a substituted
or unsubstituted group selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 allyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, sulfonamide, amide, OR10 and
C.sub.3-C.sub.6 cycloalkyl; [0051] (c) X is an optionally
substituted C.sub.1-C.sub.5 alkylene linker wherein one carbon atom
of the linker may be replaced with O, NH or S; [0052] (d) Y is C,
O, S, NH or a single bond; and [0053] (e) E is selected from the
group consisting of hydrogen, (CH.sub.2).sub.nCOOR19, C(R3)(R4)A,
substituted or unsubstituted selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 allyl, aryl-C.sub.0-4-alkyl,
thio-C.sub.1-4-alkyl, thioaryl, C.sub.1-4alkoxyaryl,
C.sub.1-4alkoxy C.sub.1-4alkyl, aminoaryl, and aminoC.sub.1-4alkyl,
and wherein [0054] (i) n is 0, 1, 2 or 3, [0055] (ii) A is a
functional group selected from the group consisting of carboxyl,
C.sub.1-C.sub.3alkylnitrile, carboxamide, substituted or
unsubstituted sulfonamide, substituted or unsubstituted
acylsulfonamide and substituted or unsubstituted tetrazole; [0056]
(iii) R3 is H, saturated or unsaturated C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.5 alkoxy, and [0057] (iv) R4 is H, halo, a
substituted or unsubstituted group selected from C.sub.1-C.sub.5
alkyl, C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6 cycloalkyl, aryl
C.sub.0-C.sub.4 alkyl and phenyl, or R3 and R4 are combined to form
a C.sub.3-C.sub.4 cycloalkyl; [0058] (v) R19 is selected from the
group consisting of hydrogen, optionally substituted
C.sub.1-C.sub.4alkyl and optionally substituted arylmethyl; [0059]
(f) R8 is independently selected from the group consisting of
hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylenyl, and
halo; [0060] (g) R9 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkylenyl, halo, substituted or unsubstituted aryl, substituted or
unsubstituted aryl-C.sub.1-C.sub.4 alkyl, substituted or
unsubstituted heteroaryl, C.sub.1-C.sub.6 allyl, and OR10; and
[0061] (h) R10 is independently selected from the group consisting
of hydrogen and C.sub.1-C.sub.4 alkyl; and [0062] (i) R15 is
selected from the group consisting of hydrogen and an optionally
substituted substituent selected from the group consisting of
C.sub.1-C.sub.4 alkyl, aryl, and benzyl. Such compounds are
particularly useful as intermediates for the preparation of
compounds claimed herein.
[0063] Another embodiment of the present invention is a compound of
the formula:
##STR00011##
wherein [0064] (a) R1 is hydrogen or is selected from the group
consisting of a substituted or unsubstituted group selected from
C.sub.1-C.sub.8 alkyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, and C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl; [0065] (b) R2 is H or a substituted
or unsubstituted group selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 allyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, sulfonamide, amide, OR10 and
C.sub.3-C.sub.6 cycloalkyl; [0066] (c) X is an optionally
substituted C.sub.1-C.sub.5 alkylene linker wherein one carbon atom
of the linker may be replaced with O, NH or S; [0067] (d) Y is C,
O, S, NH or a single bond; and [0068] (e) E is selected from the
group consisting of hydrogen, substituted or unsubstituted selected
from the group consisting of (CH.sub.2).sub.nCOOR19, C(R3) (R4)A,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 allyl, aryl-C.sub.0-4-alkyl,
thio-C.sub.1-4-alkyl, thioaryl, C.sub.1-4alkoxyaryl,
C.sub.1-4alkoxy C.sub.1-4alkyl, aminoaryl, and aminoC.sub.1-4alkyl,
and wherein [0069] (i) n is 0, 1, 2 or 3, [0070] (ii) A is an
acidic functional group selected from the group consisting of
carboxyl, C.sub.1-C.sub.3alkylnitrile, carboxamide, substituted or
unsubstituted sulfonamide, substituted or unsubstituted
acylsulfonamide and substituted or unsubstituted tetrazole; [0071]
(iii) R3 is H, saturated or unsaturated C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.5 alkoxy, and [0072] (iv) R4 is H, halo, a
substituted or unsubstituted group selected from C.sub.1-C.sub.5
alkyl, C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6 cycloalkyl, aryl
C.sub.0-C.sub.4 alkyl and phenyl, or R3 and R4 are combined to form
a C.sub.3-C.sub.4 cycloalkyl; [0073] (v) R19 is selected from the
group consisting of hydrogen, optionally substituted
C.sub.1-C.sub.4alkyl and optionally substituted arylmethyl; [0074]
(f) R8 is independently selected from the group consisting of
hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylenyl, and
halo; [0075] (g) R9 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkylenyl, halo, substituted or unsubstituted aryl, substituted or
unsubstituted aryl-C.sub.1-C.sub.4 alkyl, substituted or
unsubstituted heteroaryl, C.sub.1-C.sub.6 allyl, and OR10; and
[0076] (h) R10 is independently selected from the group consisting
of hydrogen and C.sub.1-C.sub.4 alkyl. Such compounds are
particularly useful as intermediates for the preparation of
compounds of Formula I.
[0077] Another embodiment of the invention claimed herein is a
compound of the formula:
##STR00012##
wherein [0078] (a) R1 is hydrogen or is selected from the group
consisting of a substituted or unsubstituted group selected from
C.sub.1-C.sub.8 alkyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, and C.sub.3-C.sub.6
cycloalkylaryl-C.sub.0-2-alkyl; [0079] (b) R2 is H or a substituted
or unsubstituted group selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 allyl, aryl-C.sub.0-4-alkyl,
heteroaryl-C.sub.0-4-alkyl, sulfonamide, amide, OR10 and
C.sub.3-C.sub.6 cycloalkyl; [0080] (c) X is an optionally
substituted C.sub.1-C.sub.5 alkylene linker wherein one carbon atom
of the linker may be replaced with O, NH or S; [0081] (d) Y is C,
O, S, NH or a single bond; and [0082] (e) E is selected from the
group consisting of hydrogen, substituted or unsubstituted selected
from the group consisting of (CH.sub.2).sub.nCOOR19, C(R3) (R4)A,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 allyl, aryl-C.sub.0-4-alkyl,
thio-C.sub.1-4-alkyl, thioaryl, C.sub.1-4alkoxyaryl,
C.sub.1-4alkoxy C.sub.1-4alkyl, aminoaryl, and aminoC.sub.1-4alkyl,
and wherein [0083] (i) n is 0, 1, 2 or 3, [0084] (ii) A is an
acidic functional group selected from the group consisting of
carboxyl, C.sub.1-C.sub.3alkylnitrile, carboxamide, substituted or
unsubstituted sulfonamide, substituted or unsubstituted
acylsulfonamide and substituted or unsubstituted tetrazole; [0085]
(iii) R3 is H, saturated or unsaturated C.sub.1-C.sub.5 alkyl,
C.sub.1-C.sub.5 alkoxy, and [0086] (iv) R4 is H, halo, a
substituted or unsubstituted group selected from C.sub.1-C.sub.5
alkyl, C.sub.1-C.sub.5 alkoxy, C.sub.3-C.sub.6 cycloalkyl, aryl
C.sub.0-C.sub.4 alkyl and phenyl, or R3 and R4 are combined to form
a C.sub.3-C.sub.4 cycloalkyl; [0087] (v) R19 is selected from the
group consisting of hydrogen, optionally substituted
C.sub.1-C.sub.4alkyl and optionally substituted arylmethyl; [0088]
(f) R8 is independently selected from the group consisting of
hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylenyl, and
halo; [0089] (g) R9 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkylenyl, halo, substituted or unsubstituted aryl, substituted or
unsubstituted aryl-C.sub.1-C.sub.4 alkyl, substituted or
unsubstituted heteroaryl, C.sub.1-C.sub.6 allyl, and OR10; and
[0090] (h) R10 is independently selected from the group consisting
of hydrogen and C.sub.1-C.sub.4 alkyl. Such compounds are
especially useful as intermediates for the manufacture of compounds
of Formula I.
[0091] For compounds having Structural Formula I, it is preferred
that E is C(R3)(R4)A. It is more preferred that A is a carboxyl
group. It is even more preferred that E is C(R3)(R4)COOH and
R.sub.3 is H or CH.sub.3.
[0092] The present invention further provides a crystalline
Propanoic Acid,
2-[4-[3-[2,5-dihydro-1-[(4-methylphenyl)methyl]-5-oxo-1H-1,2,4-tria-
zol-3-yl]propyl]phenoxy]-2-methyl-compound of Formula I or a
pharmaceutically acceptable salt, solvate, hydrate or prodrug
thereof.
[0093] In one embodiment, the present invention also relates to
pharmaceutical compositions which comprising at least one compound
of the present invention, or a pharmaceutically acceptable salt,
solvate, hydrate or prodrug thereof, and a pharmaceutically
acceptable carrier.
[0094] In another embodiment, the present invention relates to a
method of modulating a PPAR alpha receptor by contacting the
receptor with at least one compound represented by Structural
Formula I, and pharmaceutically acceptable salts, solvates and
hydrates thereof.
[0095] In a further embodiment, the present invention relates to a
method of making a compound represented by Structural Formula
I.
[0096] The compounds of the present invention and pharmaceutically
acceptable salts, solvates and hydrates thereof are believed to be
effective in treating and preventing Syndrome X, Type II diabetes,
hyperglycemia, hyperlipidemia, obesity, coagaulopathy,
hypertension, atherosclerosis, and other disorders related to
Syndrome X and cardiovascular diseases. In addition, the compounds
exhibit fewer side effects than compounds currently used to treat
these conditions. Further, compounds of this invention can be
useful for lowering fibrinogen, increasing HDL levels, treating
renal disease, controlling desirable weight, treating demyelinating
diseases, treating certain viral infections, and treating liver
disease.
DETAILED DESCRIPTION OF THE INVENTION
[0097] The terms used to describe the instant invention have the
following meanings herein.
[0098] As used herein, alkyl groups include straight chained or
branched hydrocarbons, which are completely saturated.
[0099] As used herein, alkylene linker is an optionally unsaturated
C.sub.1-C.sub.5 straight or branched chain hydrocarbon group.
[0100] Cycloalkyl groups, as used herein, include cyclic
hydrocarbons, which are partially or completely saturated.
[0101] As used herein, aryl groups include carbocyclic aromatic
ring systems (e.g. phenyl), fused polycyclic aromatic ring systems
(e.g. naphthyl and anthracenyl) and aromatic ring systems fused to
carbocyclic non-aromatic ring systems (e.g.,
1,2,3,4-tetrahydronaphthyl and benzodioxyl).
[0102] Heterocyclic group, as used herein, is a ring system having
at least one heteroatom such as nitrogen, sulfur or oxygen.
Heterocyclic groups include benzoturanyl, benzothiazolyl,
benzothienyl, isoquinolyl, isoxazolyl, morpholino, oxadiazolyl,
pyridyl, pyrimidinyl, pyrrolyl, quinolyl, tetrahydropyranyl and
thienyl.
[0103] Examples of R1, R5, E, R4, R19 and R9 suitable substituents
when said R1, E, R4, R5, R19 or R9 are one or more independently
selected from the group consisting of C.sub.1-C.sub.8alkyl, aryl,
(CH.sub.2).sub.nCOOR19, C.sub.1-C.sub.6 allyl,
thio-C.sub.1-C.sub.4alkyl, thioaryl, C.sub.1-C.sub.4alkoxyaryl,
C.sub.1-C.sub.4alkoxy C.sub.1-C.sub.4alkyl, aminoaryl and
aminoC.sub.1-C.sub.4alkyl, aryl-C.sub.0-4alkyl,
heteroarylC.sub.0-4alkyl, heterocyclic, --CH.sub.2--C(O)--R17-R18,
(C.sub.3-C.sub.6)cycloalkylaryl-C.sub.0-2-alkyl and cycloalkyl,
then suitable substituted groups include, for example, C1-C5 alkyl,
C1-C5 alkoxy, C1-C5 haloalkyl, C1-C5 haloalkoxy, nitro, cyano, CHO,
hydroxyl, C1-C4 alkanoic acid phenyl, aryloxy, SO2R7, SR7,
benzyloxy, alkylcarboxamido or COOH. R7 is an alkyl or a haloalkyl.
When R1, R5, E, R4, R19 or R9 is substituted, it is preferred that
there are from 1-3 substitutions on said R1, R5, E, R4, R19 or R9
group.
[0104] Examples of suitable substituents for an "optionally
substituted C.sub.2-C.sub.5 alkylene linker", include one or more
independently selected from the group consisting of
C.sub.1-C.sub.6alkyl, oxo, substituted or unsubstituted
arylC.sub.0-C.sub.3alkyl, C.sub.1-C.sub.3alkoxy, hydroxy,
C.sub.3-C.sub.6cycloalkyl and halo. When the alkylene linker is
substituted, it is preferred that there are from one to three
independent substitutions.
[0105] Examples of suitable substituents for a substituted
C.sub.1-C.sub.3 alkylene, include one or more independently
selected from C.sub.1-C.sub.6alkyl, oxo, aryl C.sub.0-C.sub.3alkyl,
C.sub.1-C.sub.3alkoxy, hydroxy, and halo. When the alkylene is
substituted it is preferred that there are from 1-3 independent
substitutions.
[0106] Suitable substituents for substituted R2 groups wherein R2
is C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6allyl,
arylC.sub.0-C.sub.4alkyl, arylC.sub.0-C.sub.4alkyl, sulfonamide,
amide, OR10, or C.sub.3-C.sub.6cycloalkyl, include for example, one
or more independently selected from the group consisting of OH,
alkoxy, haloalkyl, amino, COOH, heteroaryl-O--, heteroaryl-C(O)--,
alkyl-O--, alkyl-C(O)--, C.sub.3-C.sub.6 cycloalkyl, aryl-O--,
aryl-C(O)--, heteroaryl, aryl, heterocycloalkyl,
heterocycloalkyl-O--, and heterocycloalkyl-C(O)--. When R2 is
substituted it is preferred that there are from 1-3 independent
substitutions on the R2 group.
[0107] Examples of suitable substituents for A groups, wherein the
A is a sulfonamide, include one or more independently selected from
C1-C4 alkyl, C1-C4 haloalkyl, substituted or unsubstituted
heteroaryl, or substituted or unsubstituted aryl. When the A group
is substituted, it is preferred that there are from 1-3 independent
substitutions on the A group.
[0108] Examples of suitable substituents for A groups, wherein
[0109] A is acylsulfonamide and tetrazole include, for example, one
or more independently selected from C1-C4 alkyl, C1-C4 haloalkyl,
substituted or unsubstituted heteroaryl, or substituted or
unsubstituted aryl.
[0110] Suitable substitutents for R4 wherein R4 is C.sub.1-C.sub.5
alkyl, C.sub.1-C.sub.5alkoxy, C.sub.1-C.sub.6cycloalkyl,
arylC.sub.0-C.sub.4alkyl or phenyl, include, for example phenyl,
C.sub.1-C.sub.4 alkoxy, hydroxy and alkoxy. When R4 is substituted,
it is preferred that there are from 1-4 independent substitutions
on the R4 group.
[0111] Preferably, for the compounds of the present invention,
represented by Structural Formula I, and with their respective
pharmaceutical compositions, W is an oxygen.
[0112] More preferably, the compounds of the present invention, and
with their respective pharmaceutical compositions, have a structure
represented by Structural Formula II:
##STR00013##
[0113] In Structural Formula II, R1, R2, X, R3, R4 and A are as
defined for Structural Formula I. Q is C, O or S.
[0114] For compounds having Structural Formula I, it is preferred
that R.sub.3 is H or CH.sub.3.
[0115] Compounds that may be especially preferred are Compounds of
Formula III, and with their respective pharmaceutical compositions.
Such compounds have a structure represented by Structural Formula
III:
##STR00014##
[0116] In Structural Formula III, R1, R2, X, Q, R3 and R4 are as
defined for Structural Formulas I and II.
[0117] A further preferred embodiment is the compounds of the
present invention having Formula IV, and their respective
pharmaceutical compositions, have a structure represented by
Structural Formula IV.
##STR00015##
[0118] In Structural Formula IV, R2, X, R3 and R4 are as defined
for Structural Formulas I and II. V is a bond, C.sub.1-C.sub.3
alkylene which is unsubstituted or substituted with oxo or alkyl)
group. R5 is substituted or unsubstituted group selected from aryl,
heteroaryl and cycloalkyl groups.
[0119] Another preferred embodiment is the compounds of the present
invention, and with their respective pharmaceutical compositions,
having a structure represented by Structural Formula V.
##STR00016##
[0120] In Structural Formula V, R2, X, R3, R4 and V are as defined
for Structural Formulas I, II and IV. R6 is H, OH, C.sub.1-C.sub.5
alkyl, alkoxy, halo, haloalkyl, haloalkoxy, nitro, phenyl, aryloxy,
SO.sub.2R7, SR7, cyano, benzyloxy, phenoxy, alkylcarboxamido or
COOH. R7 is an alkyl or a haloalkyl.
[0121] For, the compounds of the present invention, and their
respective pharmaceutical compositions, having a structure
represented by Structural Formula V, it is preferred that V is
methylene. It is more preferred that V is methylene and X is
propylene. It is even further preferred that V is methylene, X is
propylene, R3 is methyl, and R4 is methyl.
[0122] Another preferred embodiment is the compounds of the present
invention, and with their respective pharmaceutical compositions,
have a structure represented by Structural Formula VI.
##STR00017##
[0123] In Structural Formula VI, R2, R3, R4 and R6 are as defined
for Structural Formulas I, II, IV and V. For the compounds of
Structural Formula VI, it is preferred that, independently, each R6
group is H or methyl.
[0124] The present invention further provides a desired crystalline
Propanoic Acid,
2-[4-[3-[2,5-dihydro-1-[(4-methylphenyl)methyl]-5-oxo-1H-1,2,4-triazol-3--
yl]propyl]phenoxy]-2-methyl- having an X-ray diffraction pattern
which comprises at least one of the following peaks: 13.2+/-0.2,
15.9+/-0.2, 20.7+/-0.2, and 24.1+/-0.2 in 2.theta. when obtained
from a copper radiation source.
[0125] The compounds of Structural Formula I may contain one or
more chiral centers, and exist in different optically active forms.
When compounds of Structural Formula I contain one chiral center,
the compounds exist in two enantiomeric forms and the present
invention includes both enantiomers and mixtures of enantiomers,
such as racemic mixtures. The enantiomers may be resolved by
methods known to those skilled in the art, for example by formation
of diastereoisomeric salts which may be separated, for example, by
crystallization; formation of diastereoisomeric derivatives or
complexes which may be separated, for example, by crystallization,
gas-liquid or liquid chromatography; selective reaction of one
enantiomer with an enantiomer-specific reagent, for example
enzymatic esterification; or gas-liquid or liquid chromatography in
a chiral environment, for example on a chiral support for example
silica with a bound chiral ligand or in the presence of a chiral
solvent. It will be appreciated that where the desired enantiomer
is converted into another chemical entity by one of the separation
procedures described above, a further step is required to liberate
the desired enantiomeric form. Alternatively, specific enantiomers
may be synthesized by asymmetric synthesis using optically active
reagents, substrates, catalysts or solvents, or by converting one
enantiomer into the other by asymmetric transformation.
[0126] When a compound represented by Structural Formula I has more
than one chiral substituent it may exist in diastereoisomeric
forms. The diastereoisomeric pairs may be separated by methods
known to those skilled in the art, for example chromatography or
crystallization and the individual enantiomers within each pair may
be separated as described above. The present invention includes
each diastereoisomer of compounds of Structural Formula I and
mixtures thereof.
[0127] Certain compounds of Structural Formula I may exist in
different stable conformational forms which may be separable.
Torsional asymmetry due to restricted rotation about an asymmetric
single bond, for example because of steric hindrance or ring
strain, may permit separation of different conformers. The present
invention includes each conformational isomer of compounds of
Structural Formula I and mixtures thereof.
[0128] Certain compounds of Structural Formula I may exist in
zwitterionic form and the present invention includes each
zwitterionic form of compounds of Structural Formula I and mixtures
thereof.
[0129] Certain compounds of Structural Formula I and their salts
may also exist in the form of solvates, for example hydrates, and
the present invention includes each solvate and mixtures
thereof.
[0130] "Pharmaceutically-acceptable salt" refers to salts of the
compounds of the Structural Formula I which are substantially
non-toxic to mammals. Typical pharmaceutically-acceptable salts
include those salts prepared by reaction of the compounds of the
present invention with a mineral or organic acid or an organic or
inorganic base. Such salts are known as base addition salts,
respectively. It should be recognized that the particular
counterion forming a part of any salt of this invention is not of a
critical nature, so long as the salt as a whole is
pharmaceutically-acceptable and as long as the counterion does not
contribute undesired qualities to the salt as a whole.
[0131] By virtue of its acidic moiety, a compound of Structural
Formula I forms salts with pharmaceutically acceptable bases. Some
examples of base addition salts include metal salts such as
aluminum; alkali metal salts such as lithium, sodium or potassium;
and alkaline earth metal salts such as calcium and magnesium; and
ammonium or substituted ammonium salts. Examples of substituted
ammonium salts include, for instance, those with lower alkylamines
such as trimethylamine, triethylamine; hydroxyalkylamines such as
2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or
tri-(2-hydroxyethyl)-amine, cycloalkylamines such as
bicyclohexylamine or dibenzylpiperidine,
N-benzyl-.beta.-phenethylamine, dehydroabietylamine,
N,N'-bisdehydro-abietylamine, glucamine, N-methylglucamine; bases
of the pyridine type such as pyridine, collidine, quinine or
quinoline; and salts of basic amino acids such as lysine and
arginine.
[0132] Examples of inorganic bases include, without limitation,
sodium hydroxide, potassium hydroxide, potassium carbonate, sodium
carbonate, sodium bicarbonate, potassium bicarbonate, calcium
hydroxide, calcium carbonate, and the like.
[0133] Compounds of Structural Formula I, which are substituted
with a basic group, may exist as salts with pharmaceutically
acceptable acids. The present invention includes such salts.
Examples of such salts include hydrochlorides, hydrobromides,
sulfates, methanesulfonates, nitrates, maleates, acetates,
citrates, fumarates, tartrates [e.g. (+)-tartrates, (-)-tartrates
or mixtures thereof including racemic mixtures], succinates,
benzoates and salts with amino acids such as glutamic acid.
[0134] These salts may be prepared by methods known to those
skilled in the art.
[0135] Certain compounds of Structural Formula I and their salts
may also exist in the form of solvates, for example hydrates, and
the present invention includes each solvate and mixtures
thereof.
[0136] Poorly crystalline and/or amorphous materials are typically
less desirable than highly crystalline materials for formulation
processing. Amorphous compounds are chemically and physically less
stable as they tend to adsorb significant amounts of water. The
adsorption of water by an amorphous material in a gelatin capsule,
for example, may cause the capsule to shrink or buckle as moisture
is transferred from the capsule to the amorphous component. In
addition, amorphous compounds have a tendency to precipitate out of
solutions containing them. If an amorphous drug substance
precipitates from a delivery solution, the dissolution and
bioavailability properties of the drug may be negatively
affected.
[0137] In addition, it is generally not desirable to formulate
pharmaceuticals containing substantial amounts of organic solvent
(e.g., ethyl acetate) due to potential solvent toxicity to the
recipient thereof and changes in potency of the pharmaceutical as a
function of the solvent. In addition, from a manufacturing
perspective, it is also generally less desirable to prepare
non-crystalline materials whenever said preparation involves a
collection of the final product via filtration. Such filtrations
are often more difficult to perform when the material collected is
non-crystalline. Moreover, it is also generally less desirable,
from a manufacturing perspective, to formulate pharmaceuticals
containing substantial amounts of water (hydrates) because the
level of hydration will typically be some function of the relative
humidity at which the pharmaceutical is produced and stored. In
other words, potency variability is typically more problematic with
a hydrate relative to its anhydrous form. The present invention
provides a desired crystalline form.
[0138] Prodrugs are compounds of the present invention, which have
chemically or metabolically cleavable groups and become by
solvolysis or under physiological conditions the compounds of the
invention which are pharmaceutically active in vivo. Prodrugs
include acid derivatives well known to practitioners of the art,
such as, for example, esters prepared by reaction of the parent
acidic compound with a suitable alcohol, or amides prepared by
reaction of the parent acid compound with a suitable amine. Simple
aliphatic or aromatic esters derived from acidic groups pendent on
the compounds of this invention are preferred prodrugs. In some
cases it is desirable to prepare double ester type prodrugs such as
(acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.
Particularly preferred esters as prodrugs are methyl, ethyl,
propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl,
and N,N-diethylglycolamido.
[0139] Methyl ester prodrugs may be prepared by reaction of the
acid form of a compound of Formula I in a medium such as methanol
with an acid or base esterification catalyst (e.g., NaOH,
H.sub.2SO.sub.4). Ethyl ester prodrugs are prepared in similar
fashion using ethanol in place of methanol. Morpholinylethyl ester
prodrugs may be prepared by reaction of the sodium salt of a
compound of Structural Formula I (in a medium such as
dimethylformamide) 4-(2-chloroethyl)morphine hydrochloride
(available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No.
C4, 220-3).
Characterization of Propanoic Acid,
2-[4-[3-[2,5-dihydro-1-[(4-methylphenyl)methyl]-5-oxo-1H-1,2,4-triazol-3--
yl]propyl]phenoxy]-2-methyl-crystalline Form
[0140] Differential scanning calorimetry/thermogravimetric analysis
(DSC/TGA), moisture sorption/desorption, and X-ray powder
diffraction (XRD) methods were used to characterize Propanoic Acid,
2-[4-[3-[2,5-dihydro-1-[(4-methylphenyl)methyl]-5-oxo-1H-1,2,4-triazol-3--
yl]propyl]phenoxy]-2-methyl-. TGA is a measure of the thermally
induced weight loss of the material as a function of temperature.
It is most commonly used to study desolvation processes and
quantatively determine the total volatile content of a solid. DSC
is a technique that is often used to screen compounds for
polymorphism because the temperatures(s) at which a physical change
in a material occurs is usually characteristic of that material.
Moisture sorption isotherms provide evaluation of the degree of
hydroscopicity associated with a given material and)
characterization of non-hydrates and hydrates. Lastly, XRD is a
technique that detects long-range order in a crystalline
material.
[0141] The thermodynamically favorable crystalline Propanoic Acid,
2-[4-[3-[2,5-dihydro-1-[(4-methylphenyl)methyl]-5-oxo-1H-1,2,4-triazol-3--
yl]propyl]phenoxy]-2-methyl-polymorph was characterized using a
Siemens D5000 diffractometer equipped with a CuK.alpha. radiation
source (.lamda.=1.54056 Angstroms) and a solid state detector.
[0142] It is well known in the crystallography art that, for any
given crystal form, the relative intensities of the diffraction
peaks may vary due to preferred orientation resulting from factors
such as crystal morphology and habit. Where the effects of
preferred orientation are present, peak intensities are altered,
but the characteristic peak positions of the polymorph are
unchanged. See, e.g., The United States Pharmacopeia #23, National
Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well
known in the crystallography art that, for any given crystal form,
the angular peak positions may vary slightly. For example, peak
positions can shift due to a variation in the temperature at which
a sample is analyzed, sample displacement, or the presence or
absence of an internal standard. In the present case, a peak
position variability of .+-.0.2 in 2.theta. will take into account
these potential variations without hindering the unequivocal
identification of the desired crystalline form.
[0143] A well known and accepted method for searching crystal forms
in the literature is the "Fink" method. The Fink method uses the
four most intense lines for the initial search followed by the next
four most intense lines. In accord with the Fink method, based on
peak intensities as well as peak position, the desired crystalline
form of Propanoic Acid,
2-[4-[3-[2,5-dihydro-1-[(4-methylphenyl)methyl]-5-oxo-1H-1,2,4-triazol-3--
yl]propyl]phenoxy]-2-methyl- may be identified by the presence of
peaks at 13.2+/-0.2, 15.9 +/-0.2, 20.7+/-0.2, and 24.1+/-0.2 in
2.theta.; when the pattern is obtained from a copper radiation
source. The presence of desired Propanoic Acid,
2-[4-[3-[2,5-dihydro-1-[(4-methylphenyl)methyl]-5-oxo-1H-1,2,4-triazol-3--
yl]propyl]phenoxy]-2-methyl-crystalline form may be further
verified by peaks at 7.9+/-0.2, 17.37+/-0.2, and 19.57 +/-0.2 in
2.theta.; when the pattern is obtained from a copper radiation
source.
[0144] The term, "active ingredient" means the compounds
generically described by Structural Formula I as well as the salts,
solvates, and prodrugs of such compounds.
[0145] The term "pharmaceutically acceptable" means that the
carrier, diluent, excipients and salt must be compatible with the
other ingredients of the composition, and not deleterious to the
recipient thereof. Pharmaceutical compositions of the present
invention are prepared by procedures known in the art using well
known and readily available ingredients.
[0146] "Preventing" refers to reducing the likelihood that the
recipient will incur or develop any of the pathological conditions
described herein.
[0147] "Treating" refers to mediating a disease or condition and
preventing, or mitigating, its further progression or ameliorate
the symptoms associated with the disease or condition.
[0148] "Pharmaceutically-effective amount" means that amount of a
compound, or of its salt, solvate, hydrate or prodrug thereof, that
will elicit the biological or medical response of a tissue, system,
or mammal. Such an amount can be administered prophylactically to a
patient thought to be susceptible to development of a disease or
condition. Such amount when administered prophylactically to a
patient can also be effective to prevent or lessen the severity of
the mediated condition. Such an amount is intended to include an
amount which is sufficient to modulate a PPAR alpha receptor or to
prevent or mediate a disease or condition. Conditions prevented or
treated by PPAR.alpha. receptors include diabetes mellitus,
cardiovascular disease, Syndrome X, obesity and gastrointestinal
disease.
[0149] A "mammal" is an individual animal that is a member of the
taxonomic class Mammalia. The class Mammalia includes humans,
monkeys, chimpanzees, gorillas, cattle, swine, horses, sheep, dogs,
cats, mice, and rats.
[0150] Administration to a human is most preferred. The compounds
and compositions of the present invention are useful for the
treatment and/or prophylaxis of cardiovascular disease, for raising
serum HDL cholesterol levels, for lowering serum triglyceride
levels and for lower serum LDL cholesterol levels. Elevated
triglyceride and LDL levels, and low HDL levels, are risk factors
for the development of heart disease, stroke, and circulatory
system disorders and diseases.
[0151] The compounds and compositions of the present invention are
also useful for treating and/or preventing obesity.
[0152] Further, these compounds and compositions are useful for the
treatment and/or prophylaxis of non-insulin dependent diabetes
mellitus (NIDDM) with reduced or no body weight gains by the
patients. Furthermore, the compounds and compositions of the
present invention are useful to treat or prevent acute or transient
disorders in insulin sensitivity, such as sometimes occur following
surgery, trauma, myocardial infarction, and the like. The physician
of ordinary skill will know how to identify humans who will benefit
from administration of the compounds and compositions of the
present invention.
[0153] The present invention further provides a method for the
treatment and/or prophylaxis of hyperglycemia in a human or
non-human mammal which comprises administering an effective,
non-toxic amount of a compound of the general formula (I), or a
tautomeric form thereof and/or a pharmaceutically acceptable salt
thereof and/or a pharmaceutically acceptable solvate thereof to a
hyperglycemic human or non-human mammal in need thereof.
[0154] They are useful as therapeutic substances in preventing or
treating Syndrome X, diabetes mellitus and related endocrine and
cardiovascular disorders and diseases in human or non-human
animals.
[0155] The invention also relates to the use of a compound of
Formula I as described above, for the manufacture of a medicament
for treating a PPARC mediated condition.
[0156] A therapeutically effective amount of a compound of
Structural Formula I can be used for the preparation of a
medicament useful for treating Syndrome X, diabetes, treating
obesity, lowering tryglyceride levels, lowering serum LDL levels,
raising the plasma level of high density lipoprotein, and for
treating, preventing or reducing the risk of developing
atherosclerosis, and for preventing or reducing the risk of having
a first or subsequent atherosclerotic disease event in mammals,
particularly in humans. In general, a therapeutically effective
amount of a compound of the present invention typically reduces
serum triglyceride levels of a patient by about 20% or more, and
increases serum HDL levels in a patient. Preferably, HDL levels
will be increased by about 30% or more. In addition, a
therapeutically effective amount of a compound, used to prevent or
treat NIDDM, typically reduces serum glucose levels, or more
specifically HbA1c, of a patient by about 0.7% or more.
[0157] Advantageously, compositions containing the compound of
Structural Formula I or the salts thereof may be provided in dosage
unit form, preferably each dosage unit containing from about 1 to
about 500 mg be administered although it will, of course, readily
be understood that the amount of the compound or compounds of
Structural Formula I actually to be administered will be determined
by a physician, in the light of all the relevant circumstances.
[0158] When used herein Syndrome X includes pre-diabetic insulin
resistance syndrome and the resulting complications thereof,
insulin resistance, non-insulin dependent diabetes, dyslipidemia,
hyperglycemia obesity, coagulopathy, hypertension and other
complications associated with diabetes. The methods and treatments
mentioned herein include the above and encompass the treatment
and/or prophylaxis of any one of or any combination of the
following: pre-diabetic insulin resistance syndrome, the resulting
complications thereof, insulin resistance, Type II or non-insulin
dependent diabetes, dyslipidemia, hyperglycemia, obesity and the
complications associated with diabetes including cardiovascular
disease, especially atherosclerosis.
[0159] The compositions are formulated and administered in the same
general manner as detailed herein. The compounds of the instant
invention may be used effectively alone or in combination with one
or more additional active agents depending on the desired target
therapy. Combination therapy includes administration of a single
pharmaceutical dosage composition which contains a compound of
Structural Formula I and one or more additional active agents, as
well as administration of a compound of Structural Formula I and
each active agent in its own separate pharmaceutical dosage
formulation. For example, a compound of Structural Formula I or
thereof and an insulin secretogogue such as biguanides,
thiazolidinediones, sulfonylureas, insulin, or .alpha.-glucosidose
inhibitors can be administered to the patient together in a single
oral dosage composition such as a tablet or capsule, or each agent
administered in separate oral dosage formulations. Where separate
dosage formulations are used, a compound of Structural Formula I
and one or more additional active agents can be administered at
essentially the same time, i.e., concurrently, or at separately
staggered times, i.e., sequentially; combination therapy is
understood to include all these regimens.
[0160] An example of combination treatment or prevention of
atherosclerosis may be wherein a compound of Structural Formula I
or salts thereof is administered in combination with one or more of
the following active agents: antihyperlipidemic agents; plasma
HDL-raising agents; antihypercholesterolemic agents, fibrates,
vitamins, aspirin, and the like. As noted above, the compounds of
Structural Formula I can be administered in combination with more
than one additional active agent.
[0161] Another example of combination therapy can be seen in
treating diabetes and related disorders wherein the compounds of
Structural Formula I, salts thereof can be effectively used in
combination with, for example, sulfonylureas, biguanides,
thiazolidinediones, .alpha.-glucosidase inhibitors, other insulin
secretogogues, insulin as well as the active agents discussed above
for treating atherosclerosis.
[0162] The compounds of the present invention, and the
pharmaceutically acceptable salts, solvates and hydrates thereof,
have valuable pharmacological properties and can be used in
pharmaceutical compositions containing a therapeutically effective
amount of a compound of the present invention, or pharmaceutically
acceptable salts, esters or prodrugs thereof, in combination with
one or more pharmaceutically acceptable excipients. Excipients are
inert substances such as, without limitation carriers, diluents,
fillers, flavoring agents, sweeteners, lubricants, solubilizers,
suspending agents, wetting agents, binders, disintegrating agents,
encapsulating material and other conventional adjuvants. Proper
formulation is dependent upon the route of administration chosen.
Pharmaceutical compositions typically contain from about 1 to about
99 weight percent of the active ingredient which is a compound of
the present invention.
[0163] Preferably, the pharmaceutical formulation is in unit dosage
form. A "unit dosage form" is a physically discrete unit containing
a unit dose, suitable for administration in human subjects or other
mammals. For example, a unit dosage form can be a capsule or
tablet, or a number of capsules or tablets. A "unit dose" is a
predetermined quantity of the active compound of the present
invention, calculated to produce the desired therapeutic effect, in
association with one or more pharmaceutically-acceptable
excipients. The quantity of active ingredient in a unit dose may be
varied or adjusted from about 0.1 to about 1000 milligrams or more
according to the particular treatment involved.
[0164] The dosage regimen utilizing the compounds of the present
invention is selected by one of ordinary skill in the medical or
veterinary arts, in view of a variety of factors, including,
without limitation, the species, age, weight, sex, and medical
condition of the recipient, the severity of the condition to be
treated, the route of administration, the level of metabolic and
excretory function of the recipient, the dosage form employed, the
particular compound and salt thereof employed, and the like.
[0165] Preferably, the compounds of the present invention are
administered in a single daily dose, or the total daily dose may be
administered in divided doses, two, three, or more times per day.
Where delivery is via transdermal forms, of course, administration
is continuous.
[0166] Suitable routes of administration of pharmaceutical
compositions of the present invention include, for example, oral,
eyedrop, rectal, transmucosal, topical, or intestinal
administration; parenteral delivery (bolus or infusion), including
intramuscular, subcutaneous, intramedullary injections, as well as
intrathecal, direct intraventricular, intravenous, intraperitoneal,
intranasal, or intraocular injections. The compounds of the
invention can also be administered in a targeted drug delivery
system, such as, for example, in a liposome coated with endothelial
cell-specific antibody.
[0167] For oral administration, the compounds can be formulated
readily by combining the active compounds with pharmaceutically
acceptable carriers well known in the art. Such carriers enable the
compounds of the invention to be formulated as tablets, pills,
powders, sachets, granules, dragees, capsules, liquids, elixers,
tinctures, gels, emulsions, syrups, slurries, suspensions and the
like, for oral ingestion by a patient to be treated. Pharmaceutical
preparations for oral use can be obtained by combining the active
compound with a solid excipient, optionally grinding a resulting
mixture, and processing the mixture of granules, after adding
suitable auxiliaries, if desired, to obtain tablets or dragee
cores.
[0168] For oral administration in the form of a tablet or capsule,
the active ingredient may be combined with an oral, non-toxic,
pharmaceutically-acceptable carrier, such as, without limitation,
lactose, starch, sucrose, glucose, methyl cellulose, calcium
carbonate, calcium phosphate, calcium sulfate, sodium carbonate,
mannitol, sorbitol, and the like; together with, optionally,
disintegrating agents, such as, without limitation, cross-linked
polyvinyl pyrrolidone, maize, starch, methyl cellulose, agar,
bentonite, xanthan gum, alginic acid, or a salt thereof such as
sodium alginate, and the like; and, optionally, binding agents, for
example, without limitation, gelatin, acacia, natural sugars,
beta-lactose, corn sweeteners, natural and synthetic gums, acacia,
tragacanth, sodium alginate, carboxymethyl-cellulose, polyethylene
glycol, waxes, and the like; and, optionally, lubricating agents,
for example, without limitation, magnesium stearate, sodium
stearate, stearic acid, sodium oleate, sodium benzoate, sodium
acetate, sodium chloride, talc, and the like. When a dosage unit
form is a capsule, it may contain, in addition to materials of the
above type, a liquid carrier such as a fatty oil.
[0169] Solid form formulations include powders, tablets and
capsules. A solid carrier can be one or more substance which may
also act as flavoring agents, lubricants, solubilisers, suspending
agents, binders, tablet disintegrating agents and encapsulating
material.
[0170] In powders, the carrier is a finely divided solid which is
in admixture with the finely divided active ingredient. In tablets,
the active ingredient is mixed with a carrier having the necessary
binding properties in suitable proportions and compacted in the
shape and size desired.
[0171] Various other materials may be present as coatings or to
modify the physical form of the dosage unit. For instance, tablets
may be coated with shellac, sugar or both. A syrup or elixir may
contain, in addition to the active ingredient, sucrose as a
sweetening agent, methyl and propylparabens as preservatives, a dye
and a flavoring such as cherry or orange flavor.
[0172] Sterile liquid formulations include suspensions, emulsions,
syrups, and elixirs. The active ingredient can be dissolved or
suspended in a pharmaceutically acceptable carrier, such as sterile
water, sterile organic solvent, or a mixture of both sterile water
and sterile organic solvent.
[0173] The active ingredient can also be dissolved in a suitable
organic solvent, for example, aqueous propylene glycol. Other
compositions can be made by dispersing the finely divided active
ingredient in aqueous starch or sodium carboxymethyl cellulose
solution or in a suitable oil.
[0174] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0175] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added.
[0176] All formulations for oral administration should be in
dosages suitable for such administration. Particularly suitable
compositions for oral administration are unit dosage forms such as
tablets and capsules.
[0177] For parental administration the compounds of the present
invention, or salts thereof, can be combined with sterile aqueous
or organic media to form injectable solutions or suspensions.
Formulations for injection may be presented in unit dosage form,
such as in ampoules or in multi-dose containers, with an added
preservative. The compositions may take such forms as suspensions,
solutions or emulsions in oily or aqueous vehicles, and may contain
formulatory agents such as suspending, stabilizing and/or
dispersing agents. The pharmaceutical forms suitable for injectable
use include sterile aqueous solutions or dispersions and sterile
powders for the extemporaneous preparation of sterile injectable
solutions or dispersions. In all cases, the form must be sterile
and must be fluid to the extent that each syringability exists. It
must be stable under the conditions of manufacture and storage and
must be preserved against any contamination. The carrier can be
solvent or dispersion medium containing, for example, water,
preferably in physiologically compatible buffers such as Hanks's
solution, Ringer's solution, or physiological saline buffer,
ethanol, polyol (e.g. glycerol, propylene glycol and liquid
polyethylene glycol), propylene glycol and liquid polyethylene
glycol), suitable mixtures thereof, and vegetable oils. Under
ordinary conditions of storage and use, these preparations contain
a preservative to prevent the growth of microorganisms.
[0178] The injectable solutions prepared in this manner can then be
administered intravenously, intraperitoneally, subcutaneously, or
intramuscularly, with intramuscular administration being preferred
in humans.
[0179] For transmucosal administration, penetrants appropriate to
the barrier to be permeated are used in the formulation. Such
penetrants are generally known in the art. The active compounds can
also be administered intranasally as, for example, liquid drops or
spray.
[0180] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in a conventional
manner.
[0181] For administration by inhalation, the compounds for use
according to the present invention are conveniently delivered in
the form of a dry powder inhaler, or an aerosol spray presentation
from pressurized packs or a nebuliser, with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of pressurized aerosol the dosage unit may be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of gelatin for use in an inhaler or insufflator may be
formulated containing a powder mix of the compound and a suitable
powder base such as lactose or starch.
[0182] Pharmaceutical compositions of the present invention can be
manufactured in a manner that is itself known, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or lyophilizing
processes.
[0183] In making the compositions of the present invention, the
active ingredient will usually be admixed with a carrier, or
diluted by a carrier, or enclosed within a carrier which may be in
the form of a capsule, sachet, paper or other container. When the
carrier serves as a diluent, it may be a solid, lyophilized solid
or paste, semi-solid, or liquid material which acts as a vehicle,
or can be in the form of tablets, pills, powders, lozenges,
elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a
solid or in a liquid medium), or ointment, containing, for example,
up to 10% by weight of the active compound. The compounds of the
present invention are preferably formulated prior to
administration.
[0184] The following pharmaceutical formulations 1 through 8 are
illustrative only and are not intended to limit the scope of the
invention in any way. "Active Ingredient", refers to a compound
according to Structural Formula I or salts thereof.
Formulation 1
[0185] Hard gelatin capsules are prepared using the following
ingredients:
TABLE-US-00001 Quantity (mg/capsule) Active Ingredient 250 Starch,
dried 200 Magnesium stearate 10 Total 460 mg
Formulation 2
[0186] A tablet is prepared using the ingredients below:
TABLE-US-00002 Quantity (mg/tablet) Active Ingredient 250
Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic
acid 5 Total 665 mg
[0187] The components are blended and compressed to form tablets
each weighing 665 mg
Formulation 3
[0188] An aerosol solution is prepared containing the following
components:
TABLE-US-00003 Weight Active Ingredient 0.25 Ethanol 25.75
Propellant 22 (Chlorodifluoromethane) 74.00 Total 100.00
[0189] The Active Ingredient is mixed with ethanol and the mixture
added to a portion of the propellant 22, cooled to 30.degree. C.
and transferred to a filling device. The required amount is then
fed to a stainless steel container and diluted with the remainder
of the propellant. The valve units are then fitted to the
container.
Formulation 4
[0190] Tablets, each containing 60 mg of Active ingredient, are
made as follows:
TABLE-US-00004 Active Ingredient 60 mg Starch 45 mg
Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as 10%
solution in water) 4 mg Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg
[0191] The Active Ingredient, starch and cellulose are passed
through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous
solution containing polyvinylpyrrolidone is mixed with the
resultant powder, and the mixture then is passed through a No. 14
mesh U.S. sieve. The granules so produced are dried at 50.degree.
C. and passed through a No. 18 mesh U.S. sieve. The sodium
carboxymethyl starch, magnesium stearate and talc, previously
passed through a No. 60 mesh U.S. sieve, are then added to the
granules which, after mixing, are compressed on a tablet machine to
yield tablets each weighing 150 mg.
Formulation 5
[0192] Capsules, each containing 80 mg of Active Ingredient, are
made as follows:
TABLE-US-00005 Active Ingredient 80 mg Starch 59 mg
Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 200
mg
[0193] The Active Ingredient, cellulose, starch, and magnesium
stearate are blended, passed through a No. 45 mesh U.S. sieve, and
filled into hard gelatin capsules in 200 mg quantities.
Formulation 6
[0194] Suppositories, each containing 225 mg of Active Ingredient,
are made as follows:
TABLE-US-00006 Active Ingredient 225 mg Saturated fatty acid
glycerides 2,000 mg Total 2,225 mg
[0195] The Active Ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides
previously melted using the minimum heat necessary. The mixture is
then poured into a suppository mold of nominal 2 g capacity and
allowed to cool.
Formulation 7
[0196] Suspensions, each containing 50 mg of Active Ingredient per
5 ml dose, are made as follows:
TABLE-US-00007 Active Ingredient 50 mg Sodium carboxymethyl
cellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor
q.v. Color q.v. Purified water to total 5 ml
[0197] The Active Ingredient is passed through a No. 45 mesh U.S.
sieve and mixed with the sodium carboxymethyl cellulose and syrup
to form a smooth paste. The benzoic acid solution, flavor and color
are diluted with a portion of the water and added, with stirring.
Sufficient water is then added to produce the required volume.
Formulation 8
[0198] An intravenous formulation may be prepared as follows:
TABLE-US-00008 Active Ingredient 100 mg Isotonic saline 1,000
ml
[0199] The solution of the above materials generally is
administered intravenously to a subject at a rate of 1 ml per
minute.
[0200] In yet another embodiment of the compounds of the present
invention, the compound is radiolabelled, such as with carbon-14,
or tritiated. Said radiolabelled or tritiated compounds are useful
as reference standards for in vitro assays to identify new
PPAR.alpha. agonists.
Synthesis
[0201] Compounds of the present invention have been formed as
specifically described in the examples. Further, many compounds
were prepared as more generally as shown in the following
schematic. Alternative synthesis methods may also be effective and
known to the skilled artisan.
[0202] Certain compounds of this invention were prepared as shown
in scheme 1. Intermediates 1, 2 were obtained from commercially
available p-bromo salicyl aldehyde and alpha-bromo esters.
Intermediates A and B were obtained following the reaction sequence
shown in scheme 2. The final compounds were obtained through a
palladium catalized coupling reaction between land 2 with A or B,
followed by basic hydrolysis of the ester to the acid.
##STR00018## ##STR00019##
PPAR Alpha Agonist 518674 DSR 10-00
##STR00020##
[0204] The Examples provided herein are illustrative of the
invention claimed herein and are not intended to limit the scope of
the claimed invention in any way.
EXEMPLIFICATION
Instrumental Analysis
[0205] Infrared spectra were recorded on a Perkin Elmer 781
spectrometer. .sup.1H NMR spectra were recorded on a Varian 400 MHz
spectrometer at ambient temperature. Data are reported as follows:
chemical shift in ppm from internal standard tetramethylsilane on
the .delta. scale, multiplicity (b=broad, s=singlet, d doublet,
t=triplet, q=quartet, qn=quintet and m=multiplet), integration,
coupling constant (Hz) and assignment. .sup.13C NMR were recorded
on a Varian 400 MHz spectrometer at ambient temperature. Chemical
shifts are reported in ppm from tetramethylsilane on the .delta.
scale, with the solvent resonance employed as the internal standard
(CDCl.sub.3 at 77.0 ppm and DMSO-d.sub.6 at 39.5 ppm). Combustion
analyses were performed by Eli Lilly & Company Microanalytical
Laboratory. High resolution mass spectra were obtained on VG ZAB 3F
or VG 70 SE spectrometers. Analytical thin layer chromatography was
performed on EM Reagent 0.25 mm silica gel 60-F plates.
Visualization was accomplished with UV light.
Exemplified Compounds
Example 1
Compound 1(1)
[0206] Compound 1, shown below, was prepared according to the Steps
outlined below:
##STR00021##
Step A: Preparation of
##STR00022##
[0208] To a suspension of 4-(4-hydroxyphenyl)butyrylhydrazide (0.5
g, 2.58 mmol) in isopropanol (5 mL) was added 3-chloro-benzaldehyde
(Aldrich, 420 mg, 3 mmol), followed by p-toluenesulphonic acid (25
mg). The reaction mixture was stirred at room temperature for 20 h.
A solid separated, which was filtered, washed with isopropanol
(0.25 mL), and dried to give the product as a solid. MS: m/z
(M.sup.++1): 317 Additional compounds, shown below, were prepared
by substituting the appropriate benzaldehyde for
3-chloro-benzaldehyde.
TABLE-US-00009 ##STR00023## R MS: m/z (M.sup.+ + 1) 3-Methylphenyl
297 Phenyl 283 2,4-Difluorophenyl 319 2-Methylphenyl 297
3-Methoxyphenyl 313
Step B: Preparation of
##STR00024##
[0210] To a solution of the Step A product (650 mg, 2.05 mmol,
Example 1) in a mixture of 5 mL of isopropanol, tetrahydrofuran,
and acetic acid (1:1:0.3) was added sodium cyanoborohydride (1.25
g, 20 mmol). The reaction mixture was stirred at room temperature
for 30 h. Reaction mixture was diluted with ethyl acetate (50 mL)
and washed with water 2.times.75 mL). The organic phase was dried
(Na.sub.2SO.sub.4) and concentrated to dryness to give the product
as syrup. MS: m/z (M.sup.++1): 319
[0211] Additional compounds, shown below, were also prepared.
TABLE-US-00010 ##STR00025## R MS: m/z (M.sup.+ + 1) 3-Methylphenyl
299 Phenyl 285 2,4-Difluorophenyl 321 2-Methylphenyl 299
3-Methoxyphenyl 315
Step C: Preparation of
##STR00026##
[0213] To a solution of the Step B product (400 mg, 1.26 mmol) in
anhydrous THF (5 mL) was added n-propylisocyanate (213 mg, 2.52
mmol). The reaction mixture was stirred for 16 h. Methanol (1 mL)
was added to the reaction mixture and the stirring was continued
for an additional 30 min. The solvent was removed on a rotary
evaporator to give the product as an oily residue. MS: m/z
(M.sup.++1): 404
[0214] Additional compounds, shown below, were also prepared.
TABLE-US-00011 ##STR00027## R MS: m/z (M.sup.+ + 1) 3-Methylphenyl
384 Phenyl 370 2,4-Difluorophenyl 406 2-Methylphenyl 384
3-Methoxyphenyl 400
Step D: Preparation of
2-(3-chlorobenzyl)-5-(3-(4-hydroxyphenyl)propyl)-4-n-propyltriazolin-3H-3-
-one
##STR00028##
[0215] The Step C product,
[1-(4-(4-hydroxyphenyl))butyryl-2-(3-chlorobenzyl)-4-n-propylcarbazate],
(200 mg) was dissolved in methanol (20 mL). To this solution was
added solid potassium hydroxide (0.50 g) and the reaction mixture
was heated at reflux for 24 h with stirring. The reaction mixture
was concentrated to a small volume (5 mL) and diluted with water
(50 mL) and the aqueous layer was then acidified with 5N
hydrochloric acid (pH .about.2). The aqueous layer was extracted
with ethyl acetate (2.times.50 mL), the organic layer was dried
(Na.sub.2SO.sub.4), and the solvent was removed on a rotary
evaporator to give the product as an oily residue. MS: m/z
(M.sup.++1): 386
[0216] Additional compounds, shown below, were also prepared.
TABLE-US-00012 ##STR00029## R MS: m/z (M.sup.+ + 1) 3-Methylphenyl
366 Phenyl 352 2,4-Difluorophenyl 388 2-Methylphenyl 366
3-Methoxyphenyl 382
Step E: Preparation of
##STR00030##
[0218] To a solution of the Step D product
[2-(3-chlorobenzyl)-5-(3-(4-hydroxyphenyl)propyl)-4-n-propyltriazolin-3H--
3-one] (0.17 g, 0.45 mmol) in anhydrous DMF (5 mL) was added
tert-butyl bromoisobutyrate (0.70 gm, 3.14 mmol) followed by
anhydrous K.sub.2CO.sub.3 (1.0 gm, powdered). The reaction mixture
was stirred at 50.degree. C. for 64 h. The reaction mixture was
diluted with water (30 mL) and extracted with ethyl acetate
(2.times.25 mL). The ethyl acetate layer was dried
(Na.sub.2SO.sub.4) and concentrated on a rotary evaporaor to give
an oily residue which was further purified on a silica gel column
(1 cm.times.7 in.) eluting with ethyl acetate-hexane mixture
(20-30% v/v) to give the product as an oil. MS: m/z (M.sup.++1):
530
[0219] Additional compounds, shown below, were also prepared.
TABLE-US-00013 ##STR00031## R MS: m/z (M.sup.+ + 1) 3-Methylphenyl
466 Phenyl 452 2,4-Difluorophenyl 530 2-Methylphenyl 466
3-Methoxyphenyl
Step F: Preparation of
##STR00032##
[0221] The Step E product (180 mg) was treated a mixture of
trifluoroacetic acid and dichloromethane (10 mL, 50% v/v) with
stirring for 3 h. The solvent was removed on a rotary evaporator
and the residue dried under high vacuum to give the title compound
as an oil. MS: m/z (M.sup.++1): 472.9
[0222] Additional compounds, shown below, were also prepared.
TABLE-US-00014 ##STR00033## Example Number R MS: m/z (M.sup.+ + 1)
1(2) 3-Methylphenyl 452 1(3) Phenyl 438 1(4) 2,4-Difluorophenyl 473
1(5) 2-Methylphenyl 452 1(6) 3-Methoxyphenyl 468
Example 2
Compound 2(1)
[0223] The compound shown below was prepared as follows:
##STR00034##
Step A: Preparation of:
##STR00035##
[0225] To a cooled (0.degree. C.) solution of boron tribromide (50
g, 200 mmol) in CH.sub.2Cl.sub.2 (50 mL) was added a solution of
methyl 4-(4-methoxyphenyl)butyrate (15.5 g, 74.4 mmol) in
CH.sub.2Cl.sub.2 (100 mL) dropwise over one hour. After stirring
for an additional hour at 0.degree. C., the reaction mixture was
treated with 1:1 CH.sub.3OH:CH.sub.2Cl.sub.2 (120 mL) with cooling
and stirred overnight at ambient temperature. Concentration of the
mixture gave an oil which was partitioned between ethyl acetate
(150 mL) and water (150 mL). The aqueous layer was extracted with
ethyl acetate (2.times.50 mL), and the combined organic extracts
washed with water (50 mL), brine (50 mL), dried (Na.sub.2SO.sub.4),
then concentrated to give the desired phenol as an oil.
C.sub.11H.sub.14O.sub.3 (MW=194.23); MS: m/z (M.sup.++1)=195
Step B: Preparation of:
##STR00036##
[0227] The phenol from Step A (18.6 g, 96 mmol) was dissolved in
DMF (300 mL) and treated with t-butyl 2-bromoisobutyrate (50 mL,
288 mmol), powdered K.sub.2CO.sub.3 (53.0 g, 384 mmol) and
MgSO.sub.4 (1.6 g, 96 mmol), and the resulting mixture heated at
75.degree. C. overnight. After cooling to ambient temperature, the
reaction mixture was decanted into 1N aqueous HCl (300 ml) and
extracted with diethyl ether (3.times.150 ml). The remaining solids
from the decantation were washed several times with diethyl ether.
The diethyl ether extracts and washes were combined and washed with
1N aqueous HCl (150 ml), dried (Na.sub.2SO.sub.4), and concentrated
to a dark oil. Purification by flash chromatography (gradient
elution, hexanes to 95:5 hexanes:ethyl acetate) gave the desired
ether as an oil. C.sub.19H.sub.28O.sub.5 (MW=336.43); MS: m/z
(M.sup.++1)=337
Step C: Preparation of:
##STR00037##
[0229] A solution of the ether from Step B (21.8 g, 64 mmol) in
methanol (250 mL) was treated with hydrazine hydrate (32.0 g, 650
mmol) and the mixture stirred overnight at ambient temperature. The
reaction mixture was concentrated and the residue partitioned
between ethyl acetate (250 mL) and water (100 mL). The aqueous
layer was extracted with ethyl acetate (2.times.100 mL), and the
combined organic extracts washed with brine (100 mL), dried
(Na.sub.2SO.sub.4), and concentrated to give the desired
acylhydrazide as an oil. C.sub.18H.sub.28N.sub.2O.sub.4
(MW=336.43); MS: m/z (M.sup.++1)=337
Step D: Preparation of:
##STR00038##
[0231] To a solution of the acylhydrazide from Step C (6.6 g, 19.6
mmol) in anhydrous THF (150 mL) was added methyl isocyanate (1.51
mL, 25.5 mmol) in one portion. The reaction mixture was stirred
overnight at ambient temperature, then concentrated to give the
desired acylsemicarbazate as an oil. C.sub.20H.sub.31N.sub.3O.sub.5
(MW=393.49); MS: m/z (M.sup.++1)=394
[0232] The compounds shown below were also prepared by substituting
an appropriate alkylisocyanate or arylisocyanate for
methylisocyanate.
TABLE-US-00015 ##STR00039## R MS: m/z (M.sup.+ + 1) Ethyl 408
n-Propyl 422 n-Butyl 436 n-Pentyl 450 n-Hexyl 464
2,4-Dimethoxybenzyl 530 2,4,6-Trimethoxybenzyl 664 Allyl
Step E: Preparation of
##STR00040##
[0234] To a solution of the acylsemicarbazide from Step D in
methanol (175 mL) was added solid potassium hydroxide (13 g, 231
mmol) and the reaction mixture heated at reflux for 48 hours. After
cooling to ambient temperature, the reaction mixture was diluted
with water (50 mLl) and methylene chloride (200 mL), then acidified
to pH 2 with 5N hydrochloric acid. The aqueous layer was extracted
with methylene chloride (2.times.40 mL). The combined organic
extracts were washed with water (75 mL), brine (75 mL), dried
(Na.sub.2SO.sub.4), and concentrated to give the desired
triazolinone as an oil. C.sub.16H.sub.21N.sub.3O.sub.4 (MW=319.36);
MS: m/z (M.sup.++1)=320
[0235] The compounds listed below were also prepared by this
cyclization procedure.
TABLE-US-00016 ##STR00041## R MS: m/z (M + 1) Ethyl 334 n-Propyl
348 n-Butyl 362 n-Pentyl 376 n-Hexyl 390 2,4-Dimethoxybenzyl 456
2,4,6-Trimethoxybenzyl 590 Allyl
Step F: Preparation of:
##STR00042##
[0237] To a solution of the triazolinone from Step E in methanol
(150 mL) was added concentrated sulfuric acid (1 mL) and the
reaction mixture stirred at room temperature for 18 hours. After
concentration to remove methanol, the oil was dissolved in ethyl
acetate (125 mL), washed with water (50 ml), saturated aqueous
NaHCO.sub.3 (50 ml), and (brine 50 ml). The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated to give the methyl ester as a
solid. C.sub.17H.sub.23N.sub.3O.sub.4 (MW=333.39); MS: m/z
(M.sup.++1)=334
[0238] The compounds listed below were also prepared by Fisher
esterification of the appropriate carboxylic acids above.
TABLE-US-00017 ##STR00043## Example Number R MS: m/z (M.sup.+ + 1)
2(2) Ethyl 348 2(3) n-Propyl 362 2(4) n-Butyl 376 2(5) n-Pentyl 390
2(6) n-Hexyl 404 2(7) 2,4-Dimethoxybenzyl 470 2(8) 2,4,6- 604
Trimethoxybenzyl 2(9) Allyl
Example 3
##STR00044##
[0239] Step A: Preparation of:
##STR00045##
[0241] To a solution of the methyl ester, specifically Compound
2(1) (100 mg, 0.29 mmol) in DMF (2 mL), was added
3,4,5-trimethoxybenzyl chloride (129 mg, 0.6 mmol) and powdered
potassium carbonate (350 mg, 2.53 mmol) and the resulting mixture
heated at 45.degree. C. for 24 hours. After cooling to ambient
temperature, the reaction mixture was diluted with water (10 mL)
and extracted with ethyl acetate (3.times.3 mL). The combined
organic extracts were concentrated to an oil which was purified by
flash chromatography (gradient elution, 1:4 ethyl acetate:hexanes
to 4:1 ethyl acetate:hexanes) to give the desired product as an
oil. C.sub.27H.sub.35N.sub.3O.sub.7 (MW=513.60); MS: m/z
(M.sup.++1)=514
[0242] The compounds listed below were also prepared by alkylation
of N-methyltriazolinone using appropriate alkylhalides in the place
of 3,4,5-trimethoxybenzyl chloride.
TABLE-US-00018 ##STR00046## R MS: m/z (M.sup.+ + 1)
3,5-Dimethoxyphenyl 484 4-Biphenyl 500 3-Chlorophenyl 458
3-Chloro-4-methylphenyl 472 Bis-trifluoromethylphenyl 560
3,4-Diflourophenyl 460 3-Phenoxyphenyl 516 4-Isopropylphenyl 468
3-triflouromethoxyphenyl 508 4-Methoxyphenyl 454
4-Trifluoromethoxyphenyl 508 4-Methylsulphonylphenyl 502
3-(triflouromethylthio)phenyl 524 4-Ethylphenyl 452
3,4-Dimethylphenyl 452 4-tert-Butylphenyl 480 2-Naphthyl 474
3-Methylphenyl 438 Phenmethyl 438 3-(5-Chloro)benzothiophene 515
4-Methylphenyl 438 3,5-Difluorophenyl 460 3-Trifluorophenyl 492
3,4-Dichlorophenyl 493 Phenyl 424 3,5-Dimethylphenyl 452
4-Chlorophenyl 458
Step B: Preparation of:
##STR00047##
[0244] A solution of the methyl ester from Step A (125 mg, 0.24
mmol) in methanol (3 mL) was treated with 5N aqueous NaOH (0.30 mL)
and the mixture stirred overnight at ambient temperature. After
concentration to dryness, the residue was dissolved in water (5
mL), the solution acidified to pH 3 with concentrated hydrochloric
acid, then extracted into methylene chloride (3.times.2 mL). The
combined organic extracts were dried by eluting through a cartridge
packed with diatomaceous earth, then concentrated to provide the
carboxylic acid as a waxy solid. C.sub.26H.sub.33N.sub.3O.sub.7
(MW=499.57); MS: m/z (M.sup.++1)=500
[0245] The compounds listed below were also prepared by hydrolysis
of appropriate methyl ester listed above.
TABLE-US-00019 ##STR00048## Example Number R MS: m/z (M.sup.+ + 1)
3(2) 3,5-Dimethoxyphenyl 470 3(3) 4-Biphenyl 486 3(4)
3-Chlorophenyl 444 3(5) 3-Chloro-4-methylphenyl 458 3(6)
2,4-Diflouromethylphenyl 546 3(7) 3,4-Difluorophenyl 446 3(8)
3-Phenoxyphenyl 502 3(9) 4-Isopropylphenyl 452 3(10)
3-triflouromethoxyphenyl 494 3(11) 4-Methoxyphenyl 440 3(12)
4-Trifluoromethoxy 494 3(13) 4-Methylsulphonylphenyl 488 3(14)
3-(triflouromethylthio)phenyl 510 3(15) 4-Ethylphenyl 438 3(16)
3,4-Dimethylphenyl 438 3(17) 4-tert-Butylphenyl 466 3(18)
2-Naphthyl 460 3(19) 3-Methylphenyl 424 3(20) Phenmethyl 424 3(21)
3-(5-Chloro)benzothiophene 501 3(22) 4-Methylphenyl 424 3(23)
3,5-Difluorophenyl 446 3(24) 3-Trifluorophenyl 478 3(25)
3,4-Dichlorophenyl 479 3(26) Phenyl 410 3(27) 3,5-Dimethylphenyl
438 3(28) 4-Chlorophenyl 444
Example 4
##STR00049##
[0246] Step A: Preparation of:
##STR00050##
[0248] To a solution of Compound 2(2) (100 mg, 0.28 mmol) in DMF (2
mL), was added m-chlorobenzyl bromide (119 mg, 0.58 mmol) and
powdered potassium carbonate (350 mg, 2.53 mmol) and the resulting
mixture heated at 45.degree. C. for 24 hours. After cooling to
ambient temperature, the reaction mixture was diluted with water
(10 mL) and extracted with ethyl acetate (3.times.3 mL). The
combined organic extracts were concentrated to an oil which was
purified by flash chromatography (gradient elution, 1:4 ethyl
acetate:hexanes to 4:1 ethyl acetate:hexanes) to give the desired
product as an oil. C.sub.25H.sub.30ClN.sub.3O.sub.4 (MW=471.99);
MS: m/z (M.sup.++1)=473.
[0249] The compounds listed below were also prepared by alkylation
of Compound 2(2) using the appropriate alkylhalide in the place of
m-chlorobenzyl bromide.
TABLE-US-00020 ##STR00051## R MS: m/z (M.sup.+ + 1) n-propyl
3-chlorophenyl 472 3-methylphenyl 452 phenyl 438 2,4-difluorophenyl
3-trifluoromethylphenyl 506 4-methylphenyl 452 2-methylphenyl
3-nitrophenyl 4-carboxyphenyl 2-phenylethyl 3,5-difluorophenyl 474
2-pyridyl 4-pyridyl 3-pyridyl 2-quinolinoyl 489 6-(4-methoxy-2-
trifluoromethyl)quinolinoyl 3-(5-chloro)benzo[b]thienyl
4-tert-butylphenyl 494 .beta.-naphthyl 488 .alpha.-methylbenzyl
3,5-dimethylphenyl 2,6-dichlorophenyl 3-cyanophenyl 463
5-(6-chloro)piperonyl 4-cyanophenyl 463 5-piperonyl 482
3-trifluoromethoxyphenyl 522 bis-2,4-trifluoromethylphenyl
Cyclohexyl 4-ethylphenyl 3,4-dimethylphenyl 466
4-trifluoromethylthiophenyl 4-isopropylphenyl 480 4-methoxyphenyl
466 4-trifluoromethoxyphenyl 522 3,4-dichlorophenyl 507
4-chlorophenyl 3,4-difluorophenyl 474 4-methylsulfonylphenyl
2-methoxyphenyl 3,5-dimethoxyphenyl 498 3,4,5-trimethoxyphenyl 528
4-tert-pentylphenyl 2-(6-methyl)naphthyl 502 2-naphthoyl 516
5-(tert-butyl)1,2,4-oxadiazol- 486 3-yl 3-methyl-4-methoxyphenyl
482 4-benzyloxyphenyl 544 3-chloro-4-methylphenyl 487
3-phenoxyphenyl 530 4-acetamidophenyl 495 4-trifluoromethylphenyl
506 p-biphenyl 514 3,5-dimethylisoxazol-4-yl 457
Step B: Preparation of
##STR00052##
[0251] A solution of the product (125 mg, 0.24 mmol) from Step A in
methanol (3 mL) was treated with 5N aqueous NaOH (0.30 mL) and the
mixture stirred overnight at ambient temperature. After
concentration to dryness, the residue was dissolved in water (5
mL), the solution acidified to pH 3 with concentrated hydrochloric
acid, then extracted into methylene chloride (3.times.2 mL). The
combined organic extracts were dried by eluting through a cartridge
packed with diatomaceous earth, then concentrated to provide the
carboxylic acid as a waxy solid. C.sub.26H.sub.33N.sub.3O.sub.7
(MW=457.96); MS: m/z (M.sup.++1)=458.
[0252] The compounds listed below were also prepared by hydrolysis
of appropriate methyl ester listed above.
TABLE-US-00021 ##STR00053## Example MS: m/z Number R (M.sup.+ + 1)
4(2) n-propyl 4(3) 3-methylphenyl 438 4(4) phenyl 424 4(5)
2,4-difluorophenyl 4(6) 3-trifluoromethylphenyl 492 4(7)
4-methylphenyl 438 4(8) 2-methylphenyl 4(9) 3-nitrophenyl 4(10)
4-carboxyphenyl 4(11) 2-phenylethyl 4(12) 3,5-difluorophenyl 460
4(13) 2-pyridyl 4(14) 4-pyridyl 4(15) 3-pyridyl 4(16) 2-quinolinoyl
475 4(17) 6-(4-methoxy2- trifluoromethyl)quinolinoyl 4(18)
3-(5-chloro)benzo[b]thiophenyl 515 4(19) 4-tert-butylphenyl 480
4(20) .beta.-naphthyl 474 4(21) .alpha.-methylbenzyl 4(22)
3,5-dimethylphenyl 4(23) 2,6-dichlorophenyl 4(24) 3-cyanophenyl 449
4(25) 5-(6-chloro)piperonyl 4(26) 4-cyanophenyl 449 4(27)
5-piperonyl 468 4(28) 3-trifluoromethoxyphenyl 508 4(29)
bis-2,4-trifluoromethylphenyl 4(30) Cyclohexyl 4(31) 4-ethylphenyl
4(32) 3,4-dimethylphenyl 452 4(33) 4-trifluoromethylthiophenyl
4(34) 4-isopropylphenyl 466 4(35) 4-methoxyphenyl 454 4(36)
4-trifluoromethoxyphenyl 508 4(37) 3,4-dichlorophenyl 493 4(38)
4-chlorophenyl 4(39) 3,4-difluorophenyl 460 4(40)
4-methylsulfonylphenyl 4(41) 2-methoxyphenyl 4(42)
3,5-dimethoxyphenyl 484 4(43) 3,4,5-trimethoxyphenyl 514 4(44)
4-tert-pentylphenyl 4(45) 2-(6-methyl)naphthyl 488 4(46)
2-naphthoyl 502 4(47) 5-(tert-butyl)1,2,4-oxadiazol-3- 472 yl 4(48)
3-methyl-4-methoxyphenyl 468 4(49) 4-benzyloxyphenyl 530 4(50)
3-chloro-4-methylphenyl 473 4(51) 3-phenoxyphenyl 516 4(52)
4-acetamidophenyl 481 4(53) 4-trifluoromethylphenyl 492 4(54)
p-biphenyl 500 4(55) 3,5-dimethylisoxazol-4-yl 443
Example 5
##STR00054##
[0253] Step A: Preparation of
##STR00055##
[0255] To a solution of triazolinone, Compound 2(3) (0.4 mmol) in
anhydrous DMF (2 mL), was added the 2-bromomethyl-naphthalene (0.8
mmol), followed by anhydrous K.sub.2CO.sub.3 (500 mg, powdered).
The reaction was stirred at 40 to 45.degree. C. for 18 h. The
reaction mixture was diluted with water (20 mL) and extracted with
ethylacetate (3.times.20 mL). The combined organic layer was dried
(Na.sub.2SO.sub.4) and concentrated to give an oily residue. The
crude was further purified on pre-packed silica column (Biotage,
Quad 3) eluting with ethyl acetate-hexane mixture to give the
product. MS: m/z (M.sup.++1)=502.
[0256] The compounds below were also prepared by alkylation of
Compound 2(3) using appropriate alkylhalides in the place of
2-bromomethylnaphthalene.
TABLE-US-00022 ##STR00056## R MS: m/z (M.sup.+ + 1) n-ethyl 404
3-chlorophenyl 486 3-methylphenyl 466 Phenyl 452 2,4-difluorophenyl
488 3-trifluoromethylphenyl 520 4-methylphenyl 466 2-methylphenyl
466 3-nltrophenyl 497 4-carboxyphenyl 496 2-phenylmethyl 466
3,5-difluorophenyl 488 2-pyridyl 443 4-pyridyl 443 3-pyridyl 443
2-quinolinoyl 503 6-(4-methoxy-2- 601 trifluoromethyl)quinolinoyl
3-(5-chloro)benzo[b]thienyl 543 4-tert-butylphenyl 508
.beta.-naphthyl 502 .alpha.-methylbenzyl 466 3,5-dimethylphenyl 480
2,6-dichlorophenyl 521 3-cyanophenyl 477 5-(6-chloro)piperonyl 531
4-cyanophenyl 477 5-piperonyl 496 3-trifluoromethoxyphenyl 536
Bis-2,4-trifluoromethylphenyl 588 Cyclohexyl 458 4-ethylphenyl 480
3,4-dimethylphenyl 480 4-trifluoromethylthiophenyl 552
4-isopropylphenyl 494 4-methoxyphenyl 482 4-trifluoromethoxyphenyl
536 3,4-dichlorophenyl 521 4-chlorophenyl 486 3,4-difluorophenyl
488 4-methylsulfonylphenyl 530 2-methoxyphenyl 482
3,5-dimethoxyphenyl 512 3,4,5-trimethoxyphenyl 542
4-tert-pentylphenyl 522 2-(6-methyl)naphthyl 516 2-naphthoyl 530
5-(tert-butyl)1,2,4-oxadiazol-3-yl 500
Step B: Preparation of:
##STR00057##
[0258] To a solution of the methyl ester of Step A (150 mg) in
methanol (2 mL) was added 1N aqueous KOH solution (2 mL). The
reaction mixture was stirred at room temp for 4 h. Methanol was
removed on a rotary evaporator and the aqueous layer diluted with
water (1 mL). This was then acidified with 5 N aqueous HCl (pH
.about.2). The aqueous layer was extracted with dichloromethane
(3.times.20 mL), dried (Na.sub.2SO.sub.4) and concentrated to
dryness to give the product as a foam. MS: m/z (M.sup.++1)=488.
[0259] The compounds below were also prepared by hydrolysis of the
appropriate methyl ester.
TABLE-US-00023 ##STR00058## Example MS: m/z Number R (M.sup.+ + 1)
5(2) n-Ethyl 390 5(3) 3-chlorophenyl 472 5(4) 3-methylphenyl 452
5(5) Phenyl 438 5(6) 2,4-difluorophenyl 474 5(7)
3-trifluoromethylphenyl 506 5(8) 4-methylphenyl 452 5(9)
2-methylphenyl 452 5(10) 3-nitrophenyl 483 5(11) 4-carboxyphenyl
482 5(12) phenylmethyl 452 5(13) 3,5-difluorophenyl 474 5(14)
2-pyridyl 439 5(15) 4-pyridyl 439 5(16) 3-pyridyl 439 5(17)
2-quinolinoyl 489 5(18) 6-(4-methoxy-2- 587
trifluoromethyl)quinolinoyl 5(19) 3-(5-chloro)benzo[b]thienyl 529
5(20) 4-tert-butylphenyl 494 5(21) .alpha.-methylbenzyl 452 5(22)
3,5-dimethylphenyl 466 5(23) 2,6-dichlorophenyl 507 5(24)
3-cyanophenyl 463 5(25) 5-(6-chloro)piperonyl 517 5(26)
4-cyanophenyl 463 5(27) 5-piperonyl 482 5(28)
3-trifluoromethoxyphenyl 522 5(29) Bis-2,4-trifluoromethylphenyl
574 5(30) Cyclohexyl 444 5(31) 4-ethylphenyl 466 5(32)
3,4-dimethylphenyl 466 5(33) 4-trifluoromethylthiophenyl 538 5(34)
4-isopropylphenyl 480 5(35) 4-methoxyphenyl 468 5(36)
4-trifluoromethoxyphenyl 522 5(37) 3,4-dichlorophenyl 507 5(38)
4-chlorophenyl 472 5(39) 3,4-difluorophenyl 474 5(40)
4-methylsulfonylphenyl 516 5(41) 2-methoxyphenyl 468 5(42)
3,5-dimethoxyphenyl 498 5(43) 3,4,5-trimethoxyphenyl 528
4-tert-pentylphenyl 508 5(45) 2-(6-methyl)naphthyl 502 5(46)
2-naphthoyl 516 5(47) 5-(tert-butyl)1,2,4-oxadiazol-3-yl 486
Example 6
##STR00059##
[0260] Step A: Preparation of:
##STR00060##
[0262] To a solution of 4-butyltriazolinone derivative, Compound
2(4) (188 mg, 0.4 mmol) in anhydrous DMF (3 mL), was added the
2-bromethylnaphthalene (265 mg, 1.2 mmol), followed by anhydrous
K.sub.2CO.sub.3 (500 mg, powdered) The reaction was stirred at 40
to 45.degree. C. for 18 h. The reaction mixture was diluted with
water (20 mL) and extracted with ethylacetate (3.times.20 mL). The
combined organic layers were concentrated to give an oily residue.
The crude was purified on pre-packed silica column (Biotag, Quad 3)
eluting with ethyl acetate-hexane mixture to give the product. MS:
m/z (M.sup.++1)=516.
[0263] The compounds below were also prepared by alkylation of the
4-butyltriazolinone derivative using the appropriate alkylhalide in
place of 2-bromethylnaphthalene.
TABLE-US-00024 ##STR00061## R MS: m/z (M.sup.+ + 1)
3-Trifluoromethylphenyl 534 3-Cyanophenyl 491
3,5-Bistrifluoromethylphenyl 502 Phenyl 466 4-Cyanophenyl 491
3,5-Dimethylphenyl 494 4-tert-Butylphenyl 522 4-Methylphenyl 480
2-Biphenyl 542 3,5-Diflourophenyl 502 Piperonyl 510 Phenylmethyl
480
Step B: Preparation of
##STR00062##
[0265] To a solution of ester from Step A (150 mg) in 2 mL of
methanol was added 2N aqueous NaOH solution (2 mL). The reaction
mixture was stirred at room temperature for 2 h. Methanol was
removed on the rotary evaporator. The reaction mixture was
acidified with 5N aqueous HCl (pH .about.3) and extracted with
dichloromethane (2.times.25 mL). The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated to dryness to give the product as
an oily residue. MS: m/z (M.sup.++1)=502.
[0266] The compounds below were also prepared by hydrolysis of
appropriate methyl ester.
TABLE-US-00025 ##STR00063## Example Number R MS: m/z (M.sup.+ + 1)
6(2) 3-Trifluoromethylphenyl 520 6(3) 3-Cyanophenyl 477 6(4)
3,5-Bistrifluoromethylphenyl 588 6(5) Phenyl 452 6(6) 4-Cyanophenyl
477 6(7) 3,5-Dimethylphenyl 480 6(8) 4-tert-Butylphenyl 508 6(9)
4-Methylphenyl 466 6(10) 2-Biphenyl 528 6(11) 3,5-Diflourophenyl
488 6(12) Piperonyl 496 6(13) Phenylmethyl 466
Example 7
##STR00064##
[0267] Step A: Preparation of
##STR00065##
[0269] To a solution of the 4-n-pentyltriazolinone derivative,
Compound 2(5) (150 mg, 0.39 mmol) in anhydrous DMF (3 mL), was
added the 3-trifluoromethylbenzyl bromide (286 mg, 1.2 mmol),
followed by anhydrous K.sub.2CO.sub.3 (500 mg, powdered). The
reaction was stirred at 40 to 45.degree. C. for 18 h. The reaction
mixture was diluted with water (20 mL) and extracted with ethyl
acetate (3.times.20 mL). The combined organic layers were
concentrated to give an oily residue. The crude was purified on
pre-packed silica column (Biotage, Quad 3) eluting with ethyl
acetate-hexane mixture to give the product. MS: m/z
(M.sup.++1)=548.
[0270] The compounds below were also prepared in the same manner by
alkylation of the 4-n-pentyltriazolinone derivative using the
appropriate alkylhalide in the place of 3-trifluoromethylbenzyl
bromide.
TABLE-US-00026 ##STR00066## R MS: m/z (M.sup.+ + 1)
3,5-bis-triflouromethylphenyl 616 phenyl 480 4-cyanophenyl 505
3,5-dimethylphenyl 508 4-tert-butylphenyl 536 4-methylphenyl 494
2-biphenyl 556 3,5-difluorophenyl 516 piperanyl 524 3-heptyl 502
2-naphthyl 3-cyanophenyl
Step B: Preparation of:
##STR00067##
[0272] To a solution of the Step A ester (170 mg) in 2 mL of
methanol was added 2N aqueous NaOH solution (2.5 mL). The reaction
mixture was stirred at room temperature for 2 h. Methanol was
removed on the rotary evaporator. The reaction mixture was
acidified with 5N aqueous HCl (pH .about.3) and extracted with
dichloromethane (2.times.25 mL). The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated to dryness to give the product as
an oily residue. MS: m/z (M.sup.++1) 534.
[0273] The compounds below were also prepared by hydrolysis of the
appropriate methyl ester.
TABLE-US-00027 ##STR00068## Example Number R MS: m/z (M.sup.+ + 1)
7(2) 3,5-bis-triflouromethylphenyl 602 7(3) phenyl 466 7(4)
4-cyanophenyl 491 7(5) 3,5-dimethylphenyl 494 7(6)
4-tert-butylphenyl 522 7(7) 4-methylphenyl 480 7(8) 2-biphenyl 542
7(9) 3,5-difluorophenyl 502 7(10) piperanyl 510 7(11) 3-heptyl 488
7(12) 2-naphthyl 516 7(13) 3-cyanophenyl 491
Example 8
##STR00069##
[0274] Step A: Preparation of
##STR00070##
[0276] To a solution of the 4-hextyltriazolinone derivative,
Compound 2(6) (150 mg, 0.39 mmol) in anhydrous DMF (3 mL), was
added the 3-trifluoromethylbenzyl bromide (286 mg, 1.2 mmol),
followed by anhydrous K.sub.2CO.sub.3 (500 mg, powdered). The
reaction was stirred at 40 to 45.degree. C. for 18 h. The reaction
mixture was diluted with water (20 mL) and extracted with ethyl
acetate (3.times.20 mL). The combined organic layers were
concentrated to give an oily residue. The crude product was further
purified on pre-packed silica column (Biotage, Quad 3) eluting with
ethyl acetate-hexane mixture to give the products as oils.
[0277] The compounds listed below were prepared by alkylation of
Compound 2(6) and using the appropriate alkylhalide in the place of
3-trifluoro-methylbenzyl bromide.
TABLE-US-00028 R MS: m/z (M.sup.+ + 1) 2-naphthyl 3-cyanophenyl
3,5-bis-trifluoromethylphenyl
Step B: Preparation of:
##STR00071##
[0279] To a solution of the Step A ester (204 mg) in 2 mL of
methanol was added 2N aqueous NaOH solution (2.5 mL). The reaction
mixture was stirred at room temperature for 2 h. Methanol was
removed on the rotary evaporator. The reaction mixture was
acidified with 5N aqueous HCl (pH .about.3) and extracted with
dichloromethane (2.times.25 mL). The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated to dryness to give the product as
an oily residue. MS: m/z (M+1) 548.
[0280] The compounds listed below were prepared by hydrolysis of
appropriate methyl ester.
TABLE-US-00029 ##STR00072## Example Number R MS: m/z (M.sup.+ + 1)
8(2) 2-naphthyl 530 8(3) 3-cyanophenyl 505 8(4)
3,5-bis-trifluoromethylphenyl 616
Example 9
##STR00073##
[0281] Step A: Preparation of:
##STR00074##
[0283] To a solution of the 4-(2,4-dimethoxybenzyl)-triazolinone
derivative from Compound 2(7) (190 mg, 0.40 mmol) in DMF (2 mL),
was added 3,5-dimethylbenzyl bromide (159 mg, 0.80 mmol) and
powdered potassium carbonate (350 mg, 2.53 mmol), and the resulting
mixture heated at 45.degree. C. for 24 hours. After cooling to
ambient temperature, the reaction mixture was diluted with water
(10 mL) and extracted with ethyl acetate (3.times.3 mL). The
combined organic extracts were concentrated to an oil which was
purified by flash chromatography (gradient elution, 1:4 ethyl
acetate:hexanes to 4:1 ethyl acetate:hexanes) to give the desired
product as an oil. C.sub.34H.sub.41N.sub.3O.sub.6 (MW=587.72); MS:
m/z (M.sup.++1)=588.
[0284] The following compounds were prepared utilizing the
appropriate bromide in the place of 3,5-dimethylbenzyl bromide, as
shown in the table.
TABLE-US-00030 ##STR00075## R MS: m/z (M.sup.+ + 1) 4-t-butylphenyl
616 3-phenoxyphenyl 652 3-methylphenyl 574 3-trifluoromethylphenyl
628 2-naphthyl 610 3,5-dimethylphenyl 588
Step B: Preparation of:
##STR00076##
[0286] A solution of the Step A product (157 mg, 0.26 mmol) in 33%
(wt) hydrogen bromide in acetic acid (3 ml) was stirred at ambient
temperature for 24 hours. The reaction mixture was treated with ice
(30 g) and the mixture extracted with ethyl acetate (2.times.15
mL). The combined ethyl acetate extracts were washed with water,
brine, dried and concentrated to an oil. The oil was dissolved in
methanol (3 mL), treated with 5N aqueous NaOH (0.5 mL), and the
resulting solution was stirred at ambient temperature for 18 hours.
Concentration to remove methanol gave a residue which was dissolved
in water (10 mL) and the resulting solution acidified to pH3 with
concentrated hydrochloric acid. The suspension was extracted with
methylene chloride (3.times.4 mL). The combined organic extracts
were purified by reverse phase HPLC to give the desired product as
a foam after lyophilization. C.sub.24H.sub.29N.sub.3O.sub.4
(MW=423.52); mass spectroscopy (MH.sup.+)=424.
[0287] The compounds listed below were prepared from the
corresponding methyl esters.
TABLE-US-00031 ##STR00077## Example Number R MS: m/z (M.sup.+ + 1)
9(2) 4-t-butylphenyl 452 9(3) 3-phenoxyphenyl 488 9(4)
3-methylphenyl 410 9(5) 3-trifluoromethylphenyl 464 9(6) 2-naphthyl
446
Example 10
##STR00078##
[0288] Step A: Preparation of:
##STR00079##
[0290] To a solution of the 4-(2,4-dimethoxybenzyl)-triazolinone
derivative from Compound 2(7) (9.0, 21.3 mmol) in DMF (25 mL), was
added 3,4-dimethylbenzyl bromide (4.62 g, 25 mmol) and powdered
potassium carbonate (10 g), and the resulting mixture stirred at
ambient temperature for 24 hours. The reaction mixture was diluted
with water (100 mL) and extracted with ethyl acetate (3.times.75
mL). The combined organic extracts were concentrated to an oil.
Alternatively the product could be further purified by flash
chromatography (gradient elution, 1:4 ethyl acetate:hexanes to 4:1
ethyl acetate:hexanes) to give the desired product as an oil. MS:
m/z (M.sup.++1)=588.
Step B: Preparation of:
##STR00080##
[0292] A solution of the Step A product (9.5 gm) in 33% (wt)
hydrogen bromide in acetic acid (50 mL) was stirred at ambient
temperature for 24 hours. The reaction mixture was treated with ice
(100 g) and the mixture extracted with ethyl acetate (2.times.100
mL). The combined ethyl acetate extracts were washed with water,
brine, dried and concentrated to an oil. The oil was dissolved in
methanol (200 mL), treated with 2 mL of concentrated
H.sub.2SO.sub.4, and the resulting solution was stirred at ambient
temperature for 18 hours. Concentration to remove methanol gave a
residue which was dissolved in methylene chloride (200 mL) and
washed with water (2.times.100 mL) followed by saturated aqueous
NaHCO.sub.3. The combined organic extracts were dried
(Na.sub.2SO.sub.4), concentrated, and purified by flash
chromatography (SiO.sub.2, EtOAc/Heanes) to give the desired
product as a solid. MS: m/z (M.sup.++1)=438.
Step C: Preparation of:
##STR00081##
[0294] A solution of the Step B product (150 mg) in methanol (3 mL)
was added 2N NaOH (2 mL) and the mixture was stirred at ambient
temperature for 4 hours. The reaction mixture concentrated, diluted
with methylene chloride (25 mL), water (5 mL) was added, and the
mixture was acidified with concentrated HCl to pH .about.2. The
layers were separated, and the aqueous layer was extracted
(2.times.25 mL) methylene chloride. The combined organic extracts
were dried (Na.sub.2SO.sub.4) and concentrated, to give the desired
product as a solid.
[0295] MS: m/z (M.sup.++1)=424.
Example 11
##STR00082##
[0296] Step A: Preparation of:
##STR00083##
[0298] To the acyl hydrazide product of Example 2, Step C (5.4079
g, 16.07 mmol) in ethyl acetate (15 mL) was added p-methyl
benzaldehyde (1.90 mL, 1.936 g, 16.11 mmol) via syringe. The
resulting solution was stirred at room temperature and hexanes (30
mL) was added. Precipitate began to form and the resulting slurry
was stirred for 16 h, then cooled to 0.degree. C. and filtered. The
filter cake was rinsed with cold hexanes and air dried to afford
the desired imine (6.49 g, 92.1%) as a white solid. Anal. Calcd.
for C.sub.26H.sub.34N.sub.2O.sub.4: C, 71.21; H, 7.81; N, 6.39.
Found: C, 70.90; H, 7.79; N, 6.45.
Step B: Preparation of:
##STR00084##
[0300] To the product of Step A (4.0 g, 9.12 mmol) in THF (40 mL)
was added platinum oxide (0.2012 g) and the resulting slurry
hydrogenated at room temperature and 40 psi for 3 h. The solution
was filtered and an additional charge of platinum oxide (0.303 g)
was added, and the resulting slurry was hydrogenated at room
temperature and 40 psi for 16 h. The slurry was filtered and
concentrated in vacuo at 60.degree. C. to afford the desired acyl
hydrazide (3.88 g, 96.6%) as a viscous oil.
C.sub.26H.sub.36N.sub.2O.sub.4 (MW=440.58); MS: m/z
(M.sup.++1)=441.
Step C: Preparation of:
##STR00085##
[0302] Acyl hydrazide from Step B (287 g, 0.65 mol, 1 equiv) and
isopropanol (1.7 L) were combined and heated to 50.degree. C.
Trimethylsilylisocyanate (85%, 112 g, 0.98 mol, 1.5 equiv) was
added rapidly. The reaction was stirred for 45 min, then cooled to
0.degree. C. and stirred for 30 min. Colorless crystalline solid
was collected by filtration and dried to provide product acyl
semicarbazide (253.7 g, 81%). C.sub.27H.sub.37N.sub.3O.sub.5
(MW=483.60); MS: m/z (M.sup.++1)=484.
Step D: Preparation of:
##STR00086##
[0304] Acylsemicarbazide product from Step C (25.0 g, 0.0517 mol,
1.0 equiv), toluene (250 mL) and methanesulfonic acid (1.68 mL,
0.0258 mol, 0.5 equiv) were combined and the resulting solution was
heated at reflux with azeotropic removal of water for 4 hrs. The
reaction was concentrated in vacuo and the residue partitioned
between CH.sub.2Cl.sub.2 (250 mL) and water (50 mL). The layers
were separated and the organic phase was washed with 1N HCl
(3.times.50 mL), dried (Na.sub.2SO.sub.4), filtered and the filter
cake washed with CH.sub.2Cl.sub.2 (3.times.30 mL). The filtrate was
concentrated to a white foamy film, dissolved in CH.sub.2Cl.sub.2
(200 mL) and washed with 1 N HCl (4.times.100 mL, then 5.times.200
mL), dried (Na.sub.2SO.sub.4) and concentrated to a white foam.
Crude product was dissolved in warm ethyl acetate (75 mL) and
seeded with authentic product. The resulting slurry was allowed to
stand at rt for 1 h, then refrigerated overnight. Colorless
crystals were collected by filtration, washed with a minimal amount
of cold ethyl acetate and dried to afford desired triazolone (12.5
g, 59%). C.sub.23H.sub.27N.sub.3O.sub.4 (MW=409.48); MS: m/z
(M.sup.++1)=410.
Example 12
Compound 12(1)
Step A: Preparation of:
##STR00087##
[0306] To a solution of the 4-(2,4-dimethoxybenzyl)-triazolinone
derivative from Compound 2(7) (9.0, 21.3 mmol) in DMF (25 mL), was
added 4-methylbenzyl bromide (4.62 g, 25 mmol) and powdered
potassium carbonate (10 g), and the resulting mixture stirred at
ambient temperature for 24 hours. The reaction mixture was diluted
with water (100 mL) and extracted with ethyl acetate (3.times.75
mL). The combined organic extracts were concentrated to an oil.
Alternatively the product could be further purified by flash
chromatography (gradient elution, 1:4 ethyl acetate:hexanes to 4:1
ethyl acetate:hexanes) to give the desired product as an oil. MS:
m/z (M.sup.++1)=588.
Step B. Preparation of:
##STR00088##
[0308] A mixture of 4-(2,4-dimethoxylbenzyl)triazolinone
derivative, from Step A, (12.6 gm, 21.9 mmol) and HBr solution (50
mL, 32% w/v in glacial acetic acid) was stirred at room temp. for
24 h. Crushed ice (50 gm) was added to the reaction mixture and
diluted with water (100 mL). The aqueous layer was extracted with
ethyl acetate (400 mL). Wash ethyl acetate layer with water
(2.times.250 mL), brine (100 mL), and dry over Na.sub.2SO.sub.4.
The ethyl acetate layer was concentrated to dryness on a rotary
evaporator to give an oily residue. The residue was taken up in
methanol (300 mL). To this solution was added conc. Sulfuric acid
(5 mL) with stirring. The reaction mixture was stirred at room
temperature for 18 h. Methanol was removed to a small volume (25
mL) and the residue was diluted with ethyl acetate (200 mL), washed
with water (2.times.200 mL), saturated NaHCO.sub.3 solution
(2.times.100 mL), brine (100 mL) and dried over Na.sub.2SO.sub.4.
The ethyl acetate layer was concentrated to dryness to give a
residue which was purified on a flash silica column to give the
product as an oily residue. MS: m/z (M+1) 424.
Step C: Preparation of:
##STR00089##
[0310] To a solution of the Step B product (50 mg, 0.12 mmol) in
DMF (1 mL) was added isopropylmethyliodide followed by anhydrous
(250 mg, powdered). The reaction mixture was stirred at
40-45.degree. C. for 18 h. The reaction mixture was diluted with
water (10 mL) and extracted with ethyl acetate (3.times.15 mL).
Combined organic layer was concentrated to dryness on a rotary
evaporator and then under high vacuum for 2 h. The crude was
chromatographed on a prepacked silica column using Biotage Quad3
parallel chromatographic system eluting with ethyl acetate-hexane
mixture (30-40% v/v) to give the product as an oily residue. MS:
m/z (M+1) 480
[0311] The compounds below were prepared by alkylation of the Step
B product, using the appropriate alkylhalide listed in the
table.
TABLE-US-00032 ##STR00090## MS: m/z Alkyl halide R (M + 1)
1-Iodo-2-methylpropane Isobutyl 480 2-bromoethyl methyl ether
2-Methoxyethyl 482 2-Bromoethyl ethyl ether 2-Ethoxyethyl 496
1-bromobutan-2-one 2-Oxobutyl 494 4-bromobutyl benzoate
4-Hydroxybutyl 496 2-bromoethyl acetate 2-Hydroxyethyl 468 2-(N,N-
523 Diethyl)ethyl 1-bromo-3,3- 3,3-Dimethyl-2- 522
dimethylbutan-2-one oxobutyl Bromomethylcyclopropane
Cyclopropylmethyl 478 1- 593 Morpholinocarbonyl- 2-isopropylmethyl
Methyl bromopropanoate 2- 510 methoxycarbonylethyl 3-(2-tetrahydro-
566 pyranyloxy)prop-1- yl 1-bromo-3-hydroxypropane 3-Hydroxypropyl
482 Methyl bromoacetate 2- 496 methoxycarbonylmethyl
Isopropyliodide Isopropyl 466 methoxyethoxyethyl 526 3-Methoxy-2-
512 hydroxypropyl 2-chloromethylpyridien 2-Pyridylmethyl 515
4-chloromethyl pyridine 4-Pyridylmethyl 515 Benzyl bromide Benzyl
514 2,2,2-trifluroethyl 3,3,3- trifluropropyl
4,4,4-triflurobutyl
Step D: Preparation of:
##STR00091##
[0313] To a solution of the Step C product (15 mg,) in MeOH (1 mL)
was added 2N NaOH (2 mL) and the mixture was stirred at ambient
temperature for 16 hrs. The reaction mixture was concentrated,
diluted with 15 mL water, and acidified to pH 2 with concentrated
HCl and extracted with methylene-chloride (3.times.10 mL). The
combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated to give the product as an oil. MS: m/z (M+1) 466.
[0314] The compounds below were prepared from the corresponding
methyl esters.
TABLE-US-00033 ##STR00092## Example MS: m/z Number R (M + 1) 12(2)
2-Methoxyethyl 468 12(3) 2-Ethoxyethyl 482 12(4) 2-Oxobutyl 480
12(5) 4-Hydroxybutyl 482 12(6) 2-Hydroxyethyl 454 12(7)
2-(N,N-Diethyl)ethyl 509 12(8) 3,3-Dimethyl-2-oxobutyl 508 12(9)
Cyclopropylmethyl 464 12(10) 1-Morpholinocarbonyl-2- 579
methylpropyl 12(11) 2-Carboxyethyl 482 12(12) THPether 552 12(13)
3-Hydroxypropyl 468 12(14) Carboxymethyl 468 12(15) Isopropyl 452
12(16) methoxyethyloxyethyl 512 12(17) 3-Methoxy-2-hydroxypropyl
498 12(18) 2-Pyridylmethyl 501 12(19) 4-Pyridylmethyl 501 12(20)
Benzyl 500 12(21) 2,2,2-trafluoroethyl 492 12(22)
3,3,3-trifluoropropyl 506 12(23) 4,4,4-trifluorobutyl 520
Example 13
##STR00093##
[0315] Step A: Preparation of
##STR00094##
[0317] To a solution of hydrazide, specifically the 3-methoxyphenyl
compound of Example 1, Step B (250 mg, 0.79 mmol) in anhydrous THF
(5 mL) was added n-hexylisocyanate (202 mg, 1.59 mmol). The
reaction mixture was stirred at room temp for 18 h. Methanol (1 mL)
was added to the reaction mixture and it was stirred for an
additional 30 min. The solvent was evaporated on a rotary
evaporator to give the semicarbazate. MS: m/z (M+1) 442
[0318] Step B: Preparation of
##STR00095##
[0319] To a solution of the Step A product, in methanol (20 mL) and
water (0.5 mL) was added KOH (500 mg). The reaction mixture was
heated at reflux with stirring for 48 h. The reaction mixture was
cooled to room temp and concentrated on a rotary evaporator to a
small volume (5 mL). The reaction mixture was diluted with water
(30 mL) and acidified with 5N HCl (pH 2-3) and extracted with ethyl
acetate (2.times.35 mL). The combined organic layers were dried
over Na.sub.2SO.sub.4 and concentrated on a rotary evaporator to
give product as a colorless oily residue. MS: m/z (M+1) 424.
Step C: Preparation of
##STR00096##
[0321] To a solution of the Step B product (300 mg, 0.71 mmol) in
anhydrous DMF (5 mL) was added tert-butyl bromoiso-butyrate (1 gm,
4.48 mmol) followed by powdered anhydrous K.sub.2CO.sub.3 (20
mmol). The reaction mixture was heated at 50.degree. C. with
stirring for 64 h. The reaction mixture was diluted with water (30
mL) and extracted with ethyl acetate (2.times.30 mL). Combined
ethyl acetate layer dried (Na.sub.2SO.sub.4) and concentrated to
dryness on rotary evaporator to give an oily residue. The crude was
purified on a flash silica column eluting with 20% ethyl
acetate-hexane mixture giving the product as a colorless oil. MS:
m/z (M+1) 566
Step D: Preparation of
##STR00097##
[0323] The Step C product (225 mg) was treated with a 50:50 mixture
of TFA and dichloromethane (10 mL). The reaction was stirred at
room temperature for 2 h. The solvent was removed on a rotary
evaporator and the residue was dried under high vacuum to give the
product as a colorless oil. MS: m/z (M+1) 510.
Example 14
##STR00098##
[0324] Step A: Preparation of
##STR00099##
[0326] To a solution of 4-(4-hydroxyphenyl)butyrylhydrazine (200
mg, 1.03 mmol) in THF (5 mL) was added benzylisocyanate (200 mg,
1.5 mmol). The reaction mixture was stirred at room temperature for
48 h. Methanol (1 mL) was added to the reaction mixture and stirred
for and additional 30 minutes. Solvent was removed on rotary
evaporator to give the product as a white solid. MS: m/z (M+1)
328
Step B: Preparation of
##STR00100##
[0328] To a solution of the Step A semicarbazate (315 mg) in
methanol (20 mL) was added solid KOH (1 gm). The reaction was
heated at reflux with stirring for 20 h. The reaction mixture was
concentrated to small volume (5 mL), acidified with 5N HCl to pH 3.
It was then extracted with ethyl acetate (2.times.30 mL). Ethyl
acetate layer was dried (Na.sub.2SO.sub.4) and concentrated to
dryness to give the product as gummy solid. MS: m/z (M+1) 310
Step C: Preparation of
##STR00101##
[0330] To a solution of the Step B benzyl triazolinone (270 mg) in
DMF (7.5 mL) was added tert-butyl isobutyrate (1.1 g) followed by
solid powdered anhydrous K.sub.2CO.sub.3 (500 mg). The reaction
mixture was heated at 50.degree. C. with stirring for 3 days. The
reaction mixture was diluted with water (40 mL) and extracted with
ethyl acetate (2.times.40 mL). Ethyl acetate layer dried
(Na.sub.2SO.sub.4) and concentrated on a rotary evaporator to give
a crude residue. The crude was purified on a flash silica column
eluting with 60% ethyl acetate-hexane to give the product. MS: m/z
(M+1) 452
Step D: Preparation of
##STR00102##
[0332] To a solution of the Step C benzyltriazolinone (30 mg) in
anhydrous THF (1 mL) was added 1-iodoproapane followed by 1M
methanolic KOH solution (1 mL). Reaction initially stirred at room
temp for 24 h. The reaction was then heated at 50.degree. C. for
and 18 h. The reaction mixture was diluted with water 920 mL) and
extracted with ethyl acetate (2.times.20 mL). Ethyl acetate layer
was dried (Na.sub.2SO.sub.4) and concentrated to dryness to give a
residue. The residue was purified on flash silica column eluting
with 40% ethyl acetate-hexane mixture to give the product.
[0333] MS: m/z (M+1)=494.
##STR00103##
Step E: Preparation of
##STR00104##
[0335] The Step D tert-butyl ester, described (16 mg) was treated
with a 50% mixture of trifluoroacetic acid and dichloromethane (2
mL) for 2 h with stirring. The solvent was removed on a rotary
evaporator and the residue dried under high vacuum to give the
product as an oil.
[0336] MS: m/z (M+1) 438
[0337] The compounds below were synthesized by alkylating
benzyltriazolinone, using appropriate bromides to give the
corresponding products.
TABLE-US-00034 Example MS: m/z Number R (M + 1) 14(2) H 14(3)
Benzyl 14(4) 4-tert-butylbenzyl
Example 15
##STR00105##
[0339] To a solution of the compound described in Example 4,
Compound 4(19) (120 mg, 0.25 mmol), trifluoromethane-sulfonamide
(37 mg, 0.25 mmol), and 4-dimethylaminopyridine (31 mg, 0.25 mmol)
in methylene chloride (2 mL) at ambient temperature was added
N,N-diisopropylethylamine (65 mg, 0.50 mmol) and
1-[3-(dimethylamino)propyl]-3-ethylcarbo-diimide hydrochloride (77
mg, 0.40 mmol). After stirring for 24 hours, the reaction mixture
was concentrated in vacuo to give a residue which was partitioned
between ethyl acetate and 1N hydrochloric acid. The organic layer
was washed with water, brine, dried (Na.sub.2SO.sub.4) and
concentrated to an oil which was purified by flash chromatography
(gradient elution, 1:4 ethyl acetate:hexanes to 100% ethyl acetate)
to give the desired product as a white solid.
C.sub.29H.sub.37N.sub.4O.sub.5SF.sub.3 (MW=610.70); mass
spectroscopy (MH.sup.+)=611.
[0340] The following compounds were also prepared utilizing the
appropriate sulfonamide (listed in the table) by the procedure of
Compound 15(1).
TABLE-US-00035 ##STR00106## Example Number RSO.sub.2NH.sub.2 R
(MH).sup.+ 15(2) benzenesulfonamide phenyl 619 15(3) .alpha.-
benzyl 633 toluenesulfonamide 15(4) 4- 4-methoxyphenyl 649
methoxybenzenesulfonamide 15(5) naphthalene-2- .beta.-naphthyl 669
sulfonamide 15(6) Methanesulfonamide Methyl 557 15(7)
5-bromothiophene-2- 5-bromo-2- 704 sulfonamide thienyl 15(8) 3-
3-chlorophenyl 654 chlorobenzenesulfonamide 15(9) 6-ethoxy-2-
6-ethoxy-2- 720 benzothiazolesulfonamide benzothiazolyl
Example 16
##STR00107##
[0341] Step A: Preparation of methyl
4-(4-methoxyphenyl)-butyrate
##STR00108##
[0342] To a solution of 4-(4-methoxyphenyl)-butyric acid (25.1 g,
0.129 mol) in methanol (130 mL), was added sulfuric acid
(concentrated, 1.0 mL) dropwise and it was stirred at room
temperature overnight under nitrogen. The reaction mixture was
concentrated on a rota-vapor, the residue was then partitioned
between ethyl acetate (200 mL) and saturated sodium bicarbonate
aqueous solution (200 mL). The organic phase was separated, washed
with brine (3.times.200 mL), then dried over Na.sub.2SO.sub.4 and
filtered. Evaporation of solvent gave the titled compound as an oil
(26.8 g, 99%). Mass (MH.sup.+)=209.
Step B: Preparation of
##STR00109##
[0344] A mixture of methyl 4-(4-methoxyphenyl)-butyrate (10.4 g,
0.0500 mol) from Step A and hydrazine hydrate (25.0 g, 0.500 mol)
in methanol (250 mL) was heated under reflux for an hour. It was
then cooled down to room temperature and stirred overnight. The
solvent was evaporated and the residue was partitioned between
ethyl acetate (200 mL) and water (200 mL). The organic layer was
washed with brine (3.times.200 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated to dryness to give the titled compound as
a white crystal (8.79 g, 85%). Mass (MH.sup.+)=209.
Step C: Preparation of
##STR00110##
[0346] To a solution of the Step B product (8.76 g, 0.0421 mol) in
THF (200 mL), was added n-propyl isocyanate (Aldrich, 4.34 mL,
0.0463 mol) dropwise and the mixture was stirred at room
temperature for an hour. Evaporation of solvent gave the titled
compound as an off-white powder (12.4 g, 100%). Mass
(MH.sup.+)=294.
Step D: Preparation of
##STR00111##
[0348] To a solution of the Step C product (12.4 g, 0.0421 mol) in
methanol (200 mL), was added potassium hydroxide in one portion
(35.4 g, 0.632 mol). The reaction mixture was heated at 70.degree.
C. for 36 hours. It was then concentrated on a rota-vapor, the
residue was then partitioned between methylene chloride (150 mL)
and water (150 mL), it was brought to pH=7 by concentrated HCl
before the two layers was separated. The aqueous layer was
extracted with more methylene chloride (150 mL). The combined
organic layers was dried over Na.sub.2SO.sub.4 and filtered.
Evaporation of solvent gave the titled compound as a off-white
solid (11.2 g, 97%). Mass (MH.sup.+)=276.
[0349] Step E: Preparation of
##STR00112##
[0350] To a solution of the Step D product (5.51 g, 0.0200 mol) in
DMF (100 mL), was added .alpha.-bromo-p-xylene (8.30 g, 0.0440)
followed by potassium carbonate powder (13.8 g, 0.100 mol). It was
heated to 70.degree. C. under nitrogen overnight. The reaction
mixture was partitioned between ethyl acetate (200 mL) and water
(200 mL), the aqueous layer was extracted with ethyl acetate (200
mL) one more time. The organic phase was combined, washed with
brine (4.times.200 mL), then dried over Na.sub.2SO.sub.4 and
filtered. Evaporation of solvent gave a crude product, which was
purified on a silica gel column eluting with 20-60% ethyl acetate
in hexane to give the titled compound as colorless oil (6.59 g,
87%). Mass (MH.sup.+)=380.
Step F: Preparation of
##STR00113##
[0352] To a solution of the Step E product (6.55 g, 0.0173 mol) in
DCM (100 mL) at 0.degree. C., was added dropwise the solution of
BBr.sub.3 (4.91 mL, 0.0519 mL) in methylene chloride (25 mL). The
reaction was kept at 0.degree. C. and stirred for an hour. It was
then quenched by 1:1 MeOH/DCM (20 mL), stirred for another hour at
0.degree. C., then room temperature overnight. The reaction mixture
was washed with water (3.times.100 mL), and the organic layer was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated
to an yellow oil, which was purified by chromatography on a silica
gel column eluting with 20-60% ethyl acetate in hexane to give the
titled compound as a white solid (2.39 g, 39%). Alternatively, the
titled compound can also be made at -78.degree. C. instead of
0.degree. C. on the same scale, white solid (4.89 g, 78%). Mass
(MH.sup.+)=366.
Step G: Preparation of
##STR00114##
[0354] The Step F product (0.100 g, 0.000274 mol) was dissolved in
DMF (1.0 mL), to it was added methyl bromoacetate (0.103 g,
0.000548 mol) followed by potassium carbonate (0.189 g, 0.00137
mol). After heated at 50.degree. C. over weekend, the reaction
mixture was diluted with ethyl acetate (2 mL), washed with water (2
mL), the separated organic layer was pass through a chem elut 1005
tube, and the tube was washed with more ethyl acetate (50 mL).
Evaporation of solvent gave the methyl ester as an oil, which was
purified on Biotage Quad3 (silica gel, 20-60% ethylacetate in
hexane). Mass (MH.sup.+) 438.
Step H: Preparation of
##STR00115##
[0356] The methyl ester obtained from Step G was treated with 1:1
MeOH/5.0N NaOH (6 mL) at room temperature overnight, and then
concentrated. The resulting residue was diluted with water (2 mL),
cooled down to 0.degree. C., acidified to pH=2 by adding
concentrated HCl dropwise. The aqueous suspension was loaded on a
Chem elut 1005 tube, eluted with DCM (50 mL). Evaporation of
methylene chloride gave the titled compound as an oil (0.103 g,
89%). Mass (MH.sup.+)=424.
[0357] The compounds listed below were prepared according to the
procedure outlined above by using the appropriate methyl or ethyl
.alpha.-substituted-.alpha.-bromo ester in Step G.
TABLE-US-00036 ##STR00116## Example Number R1 R2 MS (m/z) 16(2)
Methyl H 438 16(3) Ethyl H 452 16(4) Isopropyl H 466 16(5) F F 460
16(6) --(CH.sub.2).sub.3-- 464 16(7) Cyclohexyl H 506 16(8) Phenyl
H 500 16(9) Hydroxyethyl H 468 16(10) F H 442 16(11) n-Butyl H 480
16(12) n-Pentyl H 494 16(13) 4-fluoro phenyl H 518
Example 17
##STR00117##
[0359] To a solution of the compound described in Example 16,
**clarify, please . . . (45 mg, 0.10 mmol),
trifluoromethanesulfonamide (15 mg, 0.10 mmol), and
4-dimethylaminopyridine (12 mg, 0.10 mmol) in methylene chloride (1
mL) at ambient temperature was added N,N-diisopropylethylamine (26
mg, 0.20 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (31 mg, 0.16 mmol). After stirring for 24 hours, the
reaction mixture was concentrated in vacuo to give a residue which
was partitioned between ethyl acetate and 1N hydrochloric acid. The
organic layer was washed with water, brine, dried
(Na.sub.2SO.sub.4) and concentrated to an oil which was purified by
flash chromatography (gradient elution, 1:4 ethyl acetate:hexanes
to 100% ethyl acetate) to give the desired product as a white
solid. C.sub.25H.sub.29F.sub.3N.sub.4O.sub.5S (MW=554.59); mass
spectroscopy (MH.sup.+)=555.
Example 18
##STR00118##
[0361] The title compound was prepared utilizing the Example 16
product and 4-methoxybenzenesulfonamide according to the procedure
described in Example 17. C.sub.31H.sub.36N.sub.4O.sub.6S
(MW=592.72); mass spectroscopy (MH.sup.+)=593.
Example 19
##STR00119##
[0363] The title compound was prepared utilizing the compound
described in Example 5, Compound 5(8), and methane sulfonamide
according to the procedure described in Example 17.
C.sub.27H.sub.36N.sub.4O.sub.5S (MW=528.68); mass spectroscopy
(MH.sup.+)=529
Example 20
##STR00120##
[0365] To a cooled (0.degree. C.) solution of the compound
described in Example 4, Compound 4(19)(164 mg, 0.34 mmol) in
methylene chloride (3 mL) was added oxalyl chloride (178 .mu.L, 2.0
mmol) followed by N,N-dimethylformamide (1 drop). After stirring in
cold bath for 0.25 hour, the reaction mixture was stirred at room
temperature for one hour, then concentrated to dryness. The residue
was dissolved in tetrahydrofuran (15 mL) and the resulting solution
added dropwise to chilled (0.degree. C.) concentrated ammonium
hydroxide (30 mL) with vigorous stirring. The mixture was stirred
at 0.degree. C. for one hour, then stirred at room temperature for
20 hours. Concentration gave a residue which was partitioned
between ethyl acetate and saturated aqueous sodium bicarbonate. The
ethyl acetate layer was washed with water, brine, dried
(Na.sub.2SO.sub.4), and concentrated to give the desired product as
a foam. C.sub.28H.sub.38N.sub.4O.sub.3 (MW=478.64); mass
spectroscopy (MH.sup.+)=479.
Example 21
##STR00121##
[0366] Step A: Preparation of:
##STR00122##
[0368] To a solution of 4-(4-methoxyphenyl)-butyric acid (2.13 g,
11 mmol), cyclopropylamine (1.14 mL, 16 mmol), HOAt (1.49 g, 11
mmol) and DMAP (134 mg, 1 mmol) in 70 mL of dry DMF, 3.07 g of EDC
(16 mmol) was added in one portion. The resulting mixture was
allowed to stand under N.sub.2 for 8 h. Then the mixture was
diluted with 50 mL of Et.sub.2O. Organic layer was washed with 1N
HCl (3.times.20 mL), brine (3.times.20 mL) and dried over
Na.sub.2SO.sub.4, filtered. The organic solvent was then removed
under vacuum. Residue was purified by column chromatography to give
the title compound. MS (M+1.sup.+) m/z 234.
Step B: Preparation of:
##STR00123##
[0370] To a solution of the Step A product (1.72 g, 7.37 mmol) in 9
mL of dry CH.sub.2Cl.sub.2, 2.18 g of trimethyl-oxonium
tetrafluoroborate (14.7 mmol) was added in one portion. The mixture
was allowed to stand at r.t. for 4 h. Organic solvent was then
removed under vacuum. Residue was redissolved in 50 mL of Et.sub.2O
and washed with cold sat aq. K.sub.2CO.sub.3 (3.times.10 mL), brine
(3.times.10 mL). The ether layer was then dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
dissolved in 30 mL of dry toluene. To the solution, 0.79 g of
ethylcarbazate was added. The mixture was heated to reflux for 38
h. Organic solvent was then removed under vacuum. Residue was
purified by chromatography to give the title compound. MS
(M+1.sup.+) m/z 274.
Step C: Preparation of
##STR00124##
[0372] A mixture of the Step B product (1.53 g, 5.6 mmol),
4-methylbenzyl bromide (2.1 g, 11.2 mmol) and K.sub.2CO.sub.3 (7.7
g, 56 mmol) in 25 mL of dry DMF was heated at 60.degree. C. for 12
h. The mixture was then diluted with 75 mL of Et.sub.2O and
filtered. Organic layer was washed with 1N HCl (3.times.15 mL),
brine (3.times.15 mL), dried over MgSO.sub.4, filtered and
concentrated. Residue was purified by chromatography to give the
title compound. MS (M+1.sup.+) m/z 377.
Step D: Preparation of
##STR00125##
[0374] To a solution of the Step C product (1.01 g, 2.7 mmol) in 50
mL of dry CH.sub.2Cl.sub.2 at -78.degree. C., 0.8 mL of BBr.sub.3
(8.1 mmol) was added dropwise. The resulting solution was warmed up
to 0.degree. C. in 10 min. and maintained at same temperature for 2
h. The mixture was then diluted with 200 mL of Et.sub.2O. Organic
layer was washed with H.sub.2O (3.times.20 mL), brine (3.times.20
mL) and dried over Na.sub.2SO.sub.4, filtered. Organic solvent was
removed under vacuum. Residue was dissolved in 25 mL of absolute
EtOH. To the solution, 3.1 mL of 2-bromo-ethylbutyrate (21.2 mmol),
1.26 g of K.sub.2CO.sub.3 (9.1 mmol) and 365 mg of MgSO.sub.4 (3.03
mmol) were added. The resulting mixture was heated to 70.degree. C.
for 12 h. Solid was filtered off and organic solvent was removed
under vacuum. The residue was then dissolved in 75 mL of
CH.sub.2Cl.sub.2. The organic layer was washed with 1N HCl
(3.times.10 mL), brine (3.times.10 mL), dried over
Na.sub.2SO.sub.4, filtered and then concentrated. Residue was
purified by chromatography to give the title compound. MS
(M+1.sup.+) m/z 478.
Step E: Preparation of
##STR00126##
[0376] To a solution of the Step D product (490 mg, 1.03 mmol) in
20 mL of EtOH, 1.0 mL of 5N NaOH was added. The resulting solution
was heated to reflux for 30 min. Organic solvent was removed under
vacuum. Residue was dissolved in 30 mL of CH.sub.2Cl.sub.2 and
washed with 1N HCl (2.times.10 mL), brine (2.times.10 mL). Organic
layer was then dried over Na.sub.2SO.sub.4, filtered and
concentrated. Residue was purified by chromatography to give the
title compound. MS (M+1.sup.+) m/z 450.
Example 22
##STR00127##
[0377] Step A: Preparation of
##STR00128##
[0379] A methanol solution (500 mL) of 3-(4-methoxyphenyl)propionic
acid (Aldrich, 10.15 g, 0.056 mol) was treated with H.sub.2SO.sub.4
(concentrated, 3 mL) and stirred at room temperature overnight. The
solvent was evaporated and the residue diluted with
CH.sub.2Cl.sub.2 (150 mL). The resulting solution was extracted
with saturated aqueous sodium bicarbonate (1.times.150 mL) followed
by brine (1.times.150 mL), then dried over Na.sub.2SO.sub.4. Upon
evaporation of the solvent the desired methyl ester was obtained as
a colorless oil. C.sub.11H.sub.l4O.sub.3 (MW=194.23); mass
spectroscopy (MH.sup.+)=195.1
Step B: Preparation of
##STR00129##
[0381] A methanol solution (60 mL) of methyl ester from Step A
(10.6 g, 0.055 mol) was treated with hydrazine hydrate (30 g, 0.60
mol) and stirred overnight. The solvent was evaporated and the
residue dissolved in ethyl acetate (300 mL). The resulting solution
was extracted with H.sub.2O (300 mL). The aqueous extract was back
extracted with ethyl acetate (300 mL) then the combined organic
extracts were dried over Na.sub.2SO.sub.4 and concentrated to give
a white solid. The product was suspended in hexane (100 mL) then
filtered to give the desired acyl hydrizide as a white solid.
[0382] C.sub.10H.sub.14N.sub.2O.sub.2 (MW=194.23); mass
spectroscopy (MH.sup.+)=195.1
Step C: Preparation of
##STR00130##
[0384] A THF solution (125 mL) of the acyl hydrizide from Step B
(9.2 g, 0.047 mol) was treated with a THF solution (50 mL) of
n-propyl isocyanate (Aldrich, 5.3 mL, 0.057 mol)--added dropwise
over 15 minutes. The mixture was stirred overnight during which a
thick precipitate formed. The resulting suspension was treated with
methanol (100 mL) and stirred approximately 2 hours. The solvent
was then concentrated to give the desired acyl semicarbazide as a
white solid which was used without further purification.
Step D: Preparation of
##STR00131##
[0386] The acyl semicarbazide from Step C (13.4 g, 0.048 mol) was
dissolved in methanol (100 mL), treated with KOH (27 g, 0.48 mol),
then heated to 60.degree. C. for 16 hr and 85.degree. C. for an
additional 6 hr. The reaction mixture was cooled to room
temperature, poured into H.sub.2O, then extracted with ethyl
acetate (3.times.500 mL). The combined organic extracts were dried
over Na.sub.2SO.sub.4 then concentrated to give the desired
N4-propyl triazolinone as a slightly yellow solid.
[0387] C.sub.14H.sub.19N.sub.3O.sub.2 (MW=261.33); mass
spectroscopy (MH.sup.+) 262.1
Step E: Preparation of
##STR00132##
[0389] The N4-propyl triazolinone from Step D (1.05 g, 4.0 mmol)
was dissolved in DMF (25 mL) and treated with c-bromo-p-xylene
(1.17 g, 6.3 mmol) and powdered K.sub.2CO.sub.3 (3.17 g, 0.023
mol). The resulting mixture was heated to 50.degree. C. under a
drying tube overnight. The reaction mixture was cooled to room
temperature, poured into aqueous HCl (1N, 75 mL) and extracted into
ethyl acetate (75 mL). The organic extract was washed with brine,
dried over Na.sub.2SO.sub.4, then concentrated to give the crude
product. Purification by flash chromatography (1:1 hexanes:ethyl
acetate) gave the desired N2-p-methylbenzyl triazolinone as a
slightly yellow oil. C.sub.22H.sub.27N.sub.3O.sub.2 (MW=365.48);
mass spectroscopy (MH.sup.+) 366.1.
Step F: Preparation of
##STR00133##
[0391] The N2-p-methylbenzyl triazolinone from Step E (0.95 g, 2.6
mmol) was dissolved in CH.sub.2Cl.sub.2 and cooled to 0.degree. C.
under N.sub.2. To this solution was added, dropwise, a
CH.sub.2Cl.sub.2 solution (10 mL) of BBr.sub.3 (1.0 mL, 10.6 mmol).
After stirring for 2 hr at 0.degree. C., the reaction mixture was
quenched by the dropwise addition of methanol/CH.sub.2Cl.sub.2. The
resulting mixture was poured into H.sub.2O and extracted with
additional CH.sub.2Cl.sub.2 (50 mL). The organic extract was washed
with brine, dried over Na.sub.2SO.sub.4, then concentrated to give
the desired phenol as a slightly yellow oil.
C.sub.21H.sub.25N.sub.3O.sub.2 (MW=351.45); mass spectroscopy
(MH.sup.+)=352.2.
Step G: Preparation of
##STR00134##
[0393] The phenol from Step F (0.81 g, 2.3 mmol) was dissolved in
ethanol (absolute, 15 mL) and treated with ethyl 2-bromoisobutyrate
(1.2 mL, 8.2 mmol), powdered K.sub.2CO.sub.3 (1.4 g, 10.1 mmol),
and MgSO.sub.4 (1.0 g, 8.3 mmol). The resulting mixture was heated
to 60.degree. C. under a drying tube overnight. After cooling to
room temperature, the reaction mixture was filtered through a pad
of celite and the filtrate was concentrated. The resulting residue
was dissolved in CH.sub.2Cl.sub.2 (100 mL) and washed with aqueous
HCl (1N, 100 mL) followed by brine. The organic extract was dried
over Na.sub.2SO.sub.4 then concentrated to give the crude product.
Purification by flash chromatography (1:1 hexanes:ethyl acetate)
gave the desired ethyl ester as an oil.
C.sub.27H.sub.35N.sub.3O.sub.4 (MW=465.60); mass spectroscopy
(MH.sup.+)=466.2.
Step H: Preparation of
##STR00135##
[0395] The ethyl ester from Step G (277.3 mg, 0.60 mmol) was
dissolved in dioxane/H.sub.2O (10 mL/3 mL) and treated with LiOH
(44 mg, 1.8 mmol). The resulting mixture was stirred overnight then
concentrated. The resulting residue was diluted with
CH.sub.2Cl.sub.2 (25 mL) and extracted with aqueous NaOH (1N,
2.times.25 mL). The combined aqueous extracts were acidified by the
careful addition of aqueous HCl (5N) then extracted into
CH.sub.2Cl.sub.2 (2.times.25 mL). The combined organic extracts
were dried over Na.sub.2SO.sub.4 and concentrated to give the
desired carboxylic acid an a colorless oil.
C.sub.25H.sub.31N.sub.3O.sub.4 (MW=437.54); Mass spectroscopy
(MH.sup.+)=438.2 (MH.sup.-)=436.3
Example 23
##STR00136##
[0396] Step A: Preparation of
##STR00137##
[0398] The N4-propyl triazolinone from Example 22, Step D (1.13 g,
4.3 mmol) was dissolved in DMF (25 mL) and treated with
phenethylbromide (710 .quadrature.L, 5.2 mmol) and powdered
K.sub.2CO.sub.3 (1.25 g, 9.0 mmol). The resulting mixture was
heated to 50-60.degree. C. under a drying tube overnight. The
reaction mixture was cooled to room temperature, poured into
aqueous HCl (1N, 75 mL) and extracted into ethyl acetate (100 mL).
The organic extract was washed with brine, dried over
Na.sub.2SO.sub.4, then concentrated to give the crude product.
Purification by flash chromatography (gradient 2:1 to 1:1
hexanes:ethyl acetate) gave the desired N2-phenethyl triazolinone
as an oil. C.sub.22H.sub.27N.sub.3O.sub.2 (MW=365.48); mass
spectroscopy (MH.sup.+)=366.1.
Step B: Preparation of
##STR00138##
[0400] The N2-phenethyl triazolinone from Step A (0.83 g, 2.3 mmol)
was dissolved in CH.sub.2Cl.sub.2 and cooled to 0.degree. C. under
N.sub.2. To this solution was added, dropwise, a CH.sub.2Cl.sub.2
solution (10 mL) of BBr.sub.3 (1.0 mL, 10.6 mmol). After stirring
for 2 hr at 0.degree. C., the reaction mixture was quenched by the
dropwise addition of methanol/CH.sub.2Cl.sub.2. The resulting
mixture was poured into H.sub.2O and extracted with additional
CH.sub.2Cl.sub.2 (50 mL). The organic extract was washed with
brine, dried over Na.sub.2SO.sub.4, then concentrated to give the
desired phenol as a slightly yellow oil.
C.sub.21H.sub.25N.sub.3O.sub.2 (MW=351.45); mass spectroscopy
(MH.sup.+)=352.2.
Step C: Preparation of
##STR00139##
[0402] The phenol from Step B (0.78 g, 2.2 mmol) was dissolved in
ethanol (absolute, 15 mL) and treated with ethyl 2-bromoisobutyrate
(1.2 mL, 8.2 mmol), powdered K.sub.2CO.sub.3 (1.4 g, 10.1 mmol),
and MgSO.sub.4 (1.0 g, 8.3 mmol). The resulting mixture was heated
to 60.degree. C. under a drying tube overnight. After cooling to
room temperature, the reaction mixture was filtered through a pad
of celite and the filtrate was concentrated. The resulting residue
was dissolved in CH.sub.2Cl.sub.2 (100 mL) and washed with aqueous
HCl (1N, 100 mL) followed by brine. The organic extract was dried
over Na.sub.2SO.sub.4 then concentrated to give the crude product.
Purification by flash chromatography (1:1 hexanes:ethyl acetate)
gave the desired ethyl ester as an oil.
C.sub.27H.sub.35N.sub.3O.sub.4 (MW=465.60); mass spectroscopy
(MH.sup.+)=466.3.
Step D: Preparation of
##STR00140##
[0404] The ethyl ester from Step C (0.78 g, 1.7 mmol) was dissolved
in dioxane/H.sub.2O (20 mL, 3/1) and treated with LiOH (122 mg, 5.1
mmol). The resulting mixture was stirred overnight then
concentrated. The resulting residue was diluted with ethyl acetate
(50 mL) and extracted with aqueous HCl (1N, 50 mL). The organic
extract was reextracted with aqueous NaOH (1N, 1.times.50 mL). The
resulting aqueous washing was acidified by the addition of aqueous
HCl (5N) then extracted with ethyl acetate (2.times.50 mL). The
organic extracts were washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated to give the desired carboxylic
acid an a colorless oil. C.sub.25H.sub.31N.sub.3O.sub.4
(MW=437.54); mass spectroscopy (MH.sup.+)=438.2;
(MH.sup.-)=436.3
Example 24
##STR00141##
[0405] Step A: Preparation of
##STR00142##
[0407] The N4-propyl triazolinone from Example 22, Step D (1.07 g,
4.1 mmol) was dissolved in DMF (25 mL) and treated with
3-phenylpropyl bromide (750 .mu.L, 4.9 mmol) and powdered
K.sub.2CO.sub.3 (1.2 g, 8.7 mmol). The resulting mixture was heated
to 50-60.degree. C. under a drying tube overnight. The reaction
mixture was cooled to room temperature, poured into aqueous HCl
(1N, 75 mL) and extracted into ethyl acetate (100 mL). The organic
extract was washed with brine, dried over Na.sub.2SO.sub.4, then
concentrated to give the crude product. Purification by flash
chromatography (1:1 hexanes:ethyl acetate) gave the desired
N2-(3-phenylpropyl) triazolinone as a slightly yellow oil.
C.sub.23H.sub.29N.sub.3O.sub.2 (MW=379.51); mass spectroscopy
(MH.sup.+)=380.1
Step B: Preparation of
##STR00143##
[0409] The N2-(3-phenylpropyl) triazolinone from Step A (0.92 g,
2.4 mmol) was dissolved in CH.sub.2Cl.sub.2 and cooled to 0.degree.
C. under N.sub.2. To this solution was added, dropwise, a
CH.sub.2Cl.sub.2 solution (10 mL) of BBr.sub.3 (0.60 mL, 5.6 mmol).
After stirring for approximately 1.5 hr at 0.degree. C., the
reaction mixture was quenched by the dropwise addition of
methanol/CH.sub.2Cl.sub.2. The resulting mixture was poured into
H.sub.2O and extracted with additional CH.sub.2Cl.sub.2 (2.times.50
mL). The combined organic extracts were washed with brine, dried
over Na.sub.2SO.sub.4, then concentrated to give the crude phenol
as a colorless oil (used without further purification).
C.sub.22H.sub.27N.sub.3O.sub.2 (MW 365.48); mass spectroscopy
(MH.sup.+)=366.2.
Step C: Preparation of
##STR00144##
[0411] The phenol from Step B (0.91 g, 2.5 mmol) was dissolved in
ethanol (absolute, 15 mL) and treated with ethyl 2-bromoisobutyrate
(1.2 mL, 8.2 mmol), powdered K.sub.2CO.sub.3 (1.4 g, 10.1 mmol),
and MgSO.sub.4 (0.62 g, 5.2 mmol). The resulting mixture was heated
to 60.degree. C. under a drying tube overnight. After cooling to
room temperature, the reaction mixture was filtered through a pad
of celite and the filtrate was concentrated. The resulting residue
was diluted with aqueous HCl (0.5N, 75 mL) and extracted with
CH.sub.2Cl.sub.2 (2.times.75 mL). The combined organic extracts
were washed with brine, dried over Na.sub.2SO.sub.4 then
concentrated to give the crude product. Purification by flash
chromatography (gradient 5:1 to 1:1 hexanes:ethyl acetate) gave the
desired ethyl ester as a colorless oil.
C.sub.28H.sub.37N.sub.3O.sub.4 (MW=479.62); mass spectroscopy
(MH.sup.+)=480.2.
Step D: Preparation of
##STR00145##
[0413] The ethyl ester from Step C (0.82 g, 1.7 mmol) was dissolved
in dioxane/H.sub.2O (16 mL, 3/1) and treated with LiOH (140 mg, 5.8
mmol). The resulting mixture was stirred at room temperature for 2
hr then 45.degree. C. for an additional 2 hr. The mixture was
concentrated and the resulting residue was diluted with ethyl
acetate (50 mL) and extracted with aqueous HCl. The organic extract
was reextracted with aqueous NaOH (1N, 1.times.50 ml). The
resulting aqueous washing was acidified by the addition of aqueous
HCl (5N) then extracted with ethyl acetate (1.times.50 mL). The
organic extract was dried over Na.sub.2SO.sub.4 and concentrated to
give the desired carboxylic acid an a colorless oil.
C.sub.26H.sub.33N.sub.3O.sub.4 (MW=451.25); mass spectroscopy
(MH.sup.+)=452.3; (MH.sup.-)=450.3.
Example 25
##STR00146##
[0414] Step A: Preparation of
##STR00147##
[0416] A methylene chloride solution (300 mL) of
3-(4-methoxyphenyl)-1-propanol (Aldrich, 15.0 g, 0.090 mol) was
cooled to 0.degree. C. and stirred. Pyridinium chlorochromate
(Aldrich, 23.4 g, 0.108 mol) was slowly added to the solution which
was then warmed to room temperature, placed under a drying tube and
stirred over a weekend (approx. 72 hrs.). The reaction mixture was
filtered through a pad of Florisil (Aldrich) and the filtrate was
concentrated to give the crude product as a dark oil. Purification
by flash chromatography (6:1 hexanes:ethyl acetate) gave the
desired 3-(4-methoxyphenyl)propionaldehyde as a pale yellow
oil.
Step B: Preparation of
##STR00148##
[0418] An aqueous (18 mL) solution of the aldehyde from Step A (8.5
g, 0.052 mol) was treated with triethylphosphonoacetate (Aldrich,
14.0 g, 0.062 mol) and potassium carbonate (14.4 g, 0.104 mol). The
bi-phasic solution is stirred at room temperature overnight.
Additional water (60 mL) was added to the mixture which was
extracted with hexanes (3.times.). The combined organic layers were
washed with brine then dried over sodium sulfate. Evaporation of
the solvent gave the crude product as an oil. Purification by flash
chromatography (10:1 hexanes:ethyl acetate) gave the desired
unsaturated ethyl ester.
Step C: Preparation of
##STR00149##
[0420] An ethyl acetate solution (100 mL) of the unsaturated ethyl
ester from Step B (6.2 g, 0.026 mol) was stirred in a 3-neck flask.
The atmosphere of the flask was replaced with nitrogen by
alternating vacuum and nitrogen into the flask. Palladium on carbon
(5%) was added, the atmosphere purged again then introduced to a
balloon of hydrogen while stirring overnight. The hydrogen
atmosphere was replaced with nitrogen as above, the resulting
mixture was filtered through a pad of Celite and the filter cake
washed with ethyl acetate. The filtrate was concentrated to give
the desired saturated product as a clear oil.
Step D: Preparation of
##STR00150##
[0422] An ethanol solution of the ester from Step C (6.0 g, 0.025
mol) and hydrazine hydrate (EM Sciences, 12.7 g, 0.254 mol) was
stirred and heated to 60.degree. C. for 4 hours then cooled to room
temperature and stirred over the weekend (about 72 hrs.). The
resulting solution was concentrated, added to water and extracted
with ethyl acetate (2.times.). The organic layers were combined and
washed with brine then dried over sodium sulfate. Evaporation of
the solvent gave a solid product which was washed with hexanes and
filtered to give the desired acyl hydrazide as a white solid.
C.sub.12H.sub.18O.sub.2N.sub.2 (MW=222.29); mass spectroscopy
(MH.sup.+)=223.2.
[0423] Step E: Preparation of
##STR00151##
[0424] A tetrahydrofuran solution (25 mL) of the acyl hydrazide
from Step D (2.6 g, 0.012 mol) was treated with propyl isocyanate
(Aldrich, 1.2 g, 0.014 mol) and stirred at room temperature
overnight, during which a precipitate forms. The resulting
suspension was treated with methanol and stirred for an additional
30 minutes. The solvent was then evaporated to give the desired
acyl semicarbazide as a white solid, which was used without further
purification.
Step F: Preparation of
##STR00152##
[0426] A methanol solution (50 mL) of the acyl semicarbazide from
Step E (3.4 g, 0.011 mol) was stirred and treated with solid
potassium hydroxide (6.2 g, 0.110 mol). The mixture was heated at
60.degree. C. for 48 hrs. The resulting mixture was cooled, added
to water (150 mL) and extracted with ethyl acetate (3.times.). The
organic layers were combined, washed with brine and dried over
sodium sulfate. Evaporation of the solvent gave a solid which was
washed with hexane to give the desired N4-propyl triazolinone as a
white solid. C.sub.16H.sub.23N.sub.3O.sub.2 (MW=289); mass
spectroscopy (MH.sup.+)=290.2.
Step G: Preparation of
##STR00153##
[0428] The N4-propyl triazolinone from Step F (1.2 g, 0.0042 mol)
was dissolved in DMF (25 mL) and treated with
.alpha.-bromo-p-xylene (Aldrich, 1.2 g, 0.0063 mol) and powdered
potassium carbonate (Aldrich, 2.3 g, 0.0168 mol). The resulting
mixture was heated to 45.degree. C. for 2 hrs and then allowed to
cool to room temperature and stir overnight. The reaction mixture
was added to aqueous HCl (1N, 75 mL) and extracted with ethyl
acetate (3.times.). The combined organic layers were washed with
brine, dried over sodium sulfate and concentrated to give the crude
product as an oil. Purification by flash chromatography (gradient:
hexanes to 1:1 hexanes:ethyl acetate) gave the desired
N2-p-methyl-benzyl triazolinone.
Step H: Preparation of
##STR00154##
[0430] The N2-p-methylbenzyl triazolinone from Step G (1.2 g,
0.0031 mol) was dissolved in methylene chloride (25 mL) and cooled
to 0.degree. C. under a drying tube. A solution of boron tribromide
(0.6 mL, 0.006 mol) in methylene chloride (5 mL) was added
dropwise. The reaction mixture was stirred at 0.degree. C. for 1
hr. An additional two equivalents of boron tribromide (0.6 mL,
0.006 mol) was added and stirring continued for an additional 0.5
hr. The reaction was quenched by the dropwise addition of methanol
(4 mL) in methylene chloride (4 mL). The reaction was added to an
additional 60 mL of methylene chloride and washed with water. The
organic layer was then dried over sodium sulfate and concentrated
to give the desired phenol as a yellow solid.
C.sub.23H.sub.29N.sub.3O.sub.2 (MW=379.5); mass spectroscopy
(MH.sup.+) 380.3.
Step I: Preparation of
##STR00155##
[0432] The phenol from Step H (1.0 g, 0.0026 mol) was dissolved in
ethanol (absolute, 25 mL) and treated with ethyl 2-bromoisobutyrate
(Aldrich, 1.5 g, 1.1 mL, 0.0078 mol), powdered potassium carbonate
(Aldrich, 1.4 g, 0.010 mol) and magnesium sulfate (0.3 g, 0.0026
mol). The resulting mixture was stirred and heated to 60.degree.
C., under a drying tube, for 16 hrs. The reaction mixture was
filtered through a pad of Celite and the filtrate was concentrated.
The resulting residue was dissolved in ethyl acetate and washed
with HCl (IN) and brine. The organic layer was then dried over
sodium sulfate and concentrated to give the crude product.
Purification by flash chromatography (1:1 hexanes:ethyl acetate)
gave the desired ethyl ester. C.sub.29H.sub.39N.sub.3O.sub.4
(MW=493.6); mass spectroscopy (MH.sup.+)=494.3.
Step J: Preparation of
##STR00156##
[0434] The ethyl ester from Step I (0.6 g, 0.0012 mol) was
dissolved in methanol (6 mL) and an aqueous solution of lithium
hydroxide (0.06 g, 0.0024 mol) in water (6 mL) added. The resulting
mixture was heated to 60.degree. C. for 2 hrs. After cooling to
room temperature, the reaction mixture was added to ethyl acetate
(70 mL) and washed with water, resulting in an emulsion, which was
broken up by the addition of HCl (1N). This was extracted with
ethyl acetate (2.times.). These two layers were combined and
extracted with NaOH (1N), the aqueous layer was acidified with HCl
(5N) and extracted with ethyl acetate (2.times.). These two organic
layers were combined, dried over sodium sulfate and concentrated to
give the desired carboxylic acid as an oil.
C.sub.27H.sub.35N.sub.3O.sub.4 (MW=465.6); mass spectroscopy
(MH.sup.+)=466.3; (MH.sup.-)=464.3.
Example 26
##STR00157##
[0435] Step A: Preparation of
##STR00158##
[0437] The acyl hydrazide from Example 25, Step D (2.6 g, 0.012
mol) was dissolved in tetrahydrofuran (25 mL) and treated with
ethyl isocyanate (Aldrich, 1.2 g, 0.014 mol). The resulting mixture
was stirred at room temperature overnight. The resulting suspension
was treated with methanol and stirred for an additional 30 minutes.
The solvent was then evaporated to give the desired acyl
semicarbazide as a white solid which was used without further
purification.
Step B: Preparation of
##STR00159##
[0439] A methanol solution (50 mL) of the acyl semicarbazide from
Step A (3.3 g, 0.011 mol) was stirred and treated with solid
potassium hydroxide (6.2 g, 0.11 mol). The mixture was heated at
60.degree. C. overnight. The resulting mixture was cooled, added to
water (125 mL) and extracted with ethyl acetate (3.times.). The
organic layers were combined, washed with brine and dried over
sodium sulfate. Evaporation of the solvent gave the desired
N4-ethyl triazolinone as a white solid.
C.sub.15H.sub.21N.sub.3O.sub.2 (MW=275.35); mass spectroscopy
(MH.sup.+) 276.1.
Step C: Preparation of
##STR00160##
[0441] The N4-ethyl triazolinone from Step B (1.2 g, 0.0044 mol)
was slowly added to a slurry of sodium hydride (60% dispersion in
mineral oil, 0.3 g, 0.009 mol), under a stream of nitrogen. The
resulting slurry was stirred for 45 min. and then treated with
.alpha.-bromo-p-xylene (Aldrich, 1.2 g, 0.006 mol). The resulting
mixture was stirred at room temperature overnight. The reaction
mixture was added slowly to aqueous HCl (1N, 100 mL) and extracted
with ethyl acetate (3.times.). The combined organic layers were
washed with brine, dried over sodium sulfate and concentrated to
give the crude product as an oil. Purification by flash
chromatography (gradient: 1:1 hexanes:ethyl acetate to 4:1 ethyl
acetate:hexanes) gave the desired N2-p-methylbenzyl
triazolinone.
Step D: Preparation of
##STR00161##
[0443] The N2-p-methylbenzyl triazolinone from Step C (1.1 g,
0.0029 mol) was dissolved in methylene chloride (25 mL) and cooled
to 0.degree. C. under a drying tube. A solution of boron tribromide
(0.4 mL, 0.004 mol) in methylene chloride was added dropwise over 5
min. The reaction mixture was stirred at 0.degree. C. for 10 min.
then an additional solution of boron tribromide (0.4 mL, 0.004 mol)
in methylene chloride was added and stirring continued for 1 hr.
The reaction was quenched by the dropwise addition of methanol (2
mL). The reaction was added to an additional 100 mL water and
extracted with methylene chloride (3.times.). The organic layers
were combined, washed with brine and dried over sodium sulfate.
Evaporation of the solvent gave the desired phenol as a white
solid. C.sub.22H.sub.27N.sub.3O.sub.2 (MW 365.48); mass
spectroscopy (MH.sup.+)=366.2.
Step E: Preparation of
##STR00162##
[0445] The phenol from Step D (0.8 g, 0.0022 mol) was dissolved in
ethanol (absolute, 20 mL) and treated with ethyl
2-bromo-isobutyrate (Aldrich, 1.3 g, 0.0066 mol), powdered
potassium carbonate (Aldrich, 1.2 g, 0.0088 mol) and magnesium
sulfate (0.2 g, 0.002 mol). The resulting mixture was stirred and
heated to 65.degree. C., under a drying tube, for 48 hrs. The
reaction mixture was filtered through a pad of Celite and the
filtrate was concentrated to give the crude product. Purification
by flash chromatography (gradient: 3:2 hexanes:ethyl acetate to 1:1
hexanes:ethyl acetate) gave the desired ethyl ester.
C.sub.28H.sub.37N.sub.3O.sub.4 (MW=479.62); mass spectroscopy
(MH.sup.+)=480.3.
Step F: Preparation of:
##STR00163##
[0447] The ethyl ester from Step E (0.75 g, 0.0016 mol) was
dissolved in methanol (7 mL) and an aqueous solution of lithium
hydroxide (0.08 g, 0.0032 mol) in water (7 mL) added. The resulting
mixture was heated to 60.degree. C. for 1 hr. The reaction mixture
was added to water (60 mL) and washed with ether. The aqueous layer
was acidified with aqueous HCl (conc.) to a pH of 4 and extracted
with ethyl acetate (2.times.). These two layers were combined,
washed with brine and dried over sodium sulfate. The solvent was
evaporated to give the desired carboxylic acid as an oil.
C.sub.26H.sub.33N.sub.3O.sub.4 (MW=451.57); mass spectroscopy
(MH.sup.+)=452.2; (MH.sup.-)=450.3.
Example 27
##STR00164##
[0448] Step A: Preparation of
##STR00165##
[0450] A methanol solution (75 mL) of benzyloxyacetic acid
(Aldrich, 15.0 g, 0.090 mol) was treated with H.sub.2SO.sub.4
(concentrated, 1 mL) and stirred at room temperature overnight. The
solvent was evaporated and the residue diluted with
CH.sub.2Cl.sub.2 (150 mL). The resulting solution was extracted
with saturated aqueous sodium bicarbonate (1.times.150 mL) followed
by brine (1.times.150 mL), then dried over Na.sub.2SO.sub.4. Upon
evaporation of the solvent the desired methyl ester was obtained as
a colorless oil. C.sub.10H.sub.12O.sub.3 (MW=180.21); mass
spectroscopy (MH.sup.+)=195.1.
Step B: Preparation of
##STR00166##
[0452] A methanol solution (100 mL) of methyl ester from Step A
(6.45 g, 0.036 mol) was treated with hydrazine hydrate (20 mL, 0.41
mol) and stirred at room temperature several days. The solvent was
evaporated and the residue dissolved in ethyl acetate (200 mL). The
resulting solution was extracted with H.sub.2O (200 mL). The
organic extract was dried over Na.sub.2SO.sub.4 and concentrated to
give the desired acyl hydrizide as an oil.
Step C: Preparation of
##STR00167##
[0454] A THF solution (50 mL) of the acyl hydrizide from Step B
(3.56 g, 0.020 mol) cooled to 0.degree. C. and treated with a THF
solution (25 mL) of n-propyl isocyanate (Aldrich, 2.3 mL, 0.024
mol)--added dropwise over 15 minutes. The mixture was warmed to
room temperature and stirred overnight during which a thick
precipitate formed. The resulting suspension was treated with
methanol (25 mL) and stirred approximately 1 hour. The solvent was
then concentrated to give the desired acyl semicarbazide as a white
solid which was used without further purification.
C.sub.13H.sub.19N.sub.3O.sub.3 (MW=265.31); mass spectroscopy
(MH.sup.+)=266.1.
Step D: Preparation of
##STR00168##
[0456] The acyl semicarbazide from Step C (5.02 g, 18.9 mmol) was
dissolved in methanol (75 mL), treated with KOH (10.2 g, 18.2
mmol), then heated to reflux overnight. The reaction mixture was
cooled to room temperature, poured into H.sub.2O (300 mL), then
extracted with ethyl acetate (3.times.300 mL). The combined organic
extracts were washed with brine (1.times.300 mL), dried over
Na.sub.2SO.sub.4 then concentrated to give the desired N4-propyl
triazolinone as a slightly yellow solid.
[0457] C.sub.13H.sub.17N.sub.3O.sub.2 (MW=247.30); mass
spectroscopy (MH.sup.+)=248.1.
Step E: Preparation of
##STR00169##
[0459] The N4-propyl triazolinone from Step D (4.32 g, 17.5 mmol)
was dissolved in DMF (100 mL) and treated with
.alpha.-bromo-p-xylene (4.0 g, 21.6 mmol) and powdered
K.sub.2CO.sub.3 (5.2 g, 38 mmol). The resulting mixture was heated
to 50.degree. C. under a drying tube overnight. The reaction
mixture was cooled to room temperature, poured into aqueous HCl
(1N, 200 mL) and extracted into ethyl acetate (200 mL). The organic
extract was washed with brine, dried over Na.sub.2SO.sub.4, then
concentrated to give the crude product. Purification by flash
chromatography gave the desired N2-p-methylbenzyl triazolinone as a
slightly yellow oil. C.sub.21H.sub.25N.sub.3O.sub.2 (MW=351.45);
mass spectroscopy (MH.sup.+)=352.2.
Step F: Preparation of
##STR00170##
[0461] To a slurry containing 5% Pd/C (320 mg) in ethanol (50 mL)
was added the benzyl ether from Step E (2.9 gm, 8.25 mmol) as a THF
solution (50 mL). The resulting mixture was purged with nitrogen
and then with hydrogen. An atmosphere of hydrogen was maintained
over the reaction mixture by means of a balloon. After 48 hours,
the reaction was judged (TLC and MS) to be only 50% complete. The
catalyst was removed via filtration through a pad of celite. The
resulting filtrate was concentrated to an oil and redissolved in
CH.sub.3OH (50 mL). A slurry containing 5% Pd/C (210 mg) in
CH.sub.3OH (10 mL) was added and the mixture was purged with
nitrogen. An atmosphere of hydrogen was established as before and
maintained for 5 days. Again the catalyst was removed via
filtration through a pad of celite. Concentration of the filtrate
gave the crude product which was purified by flash chromatography
(gradient: 5:1 to 1:2 hexanes:ethyl acetate) to provide the desired
alcohol as a white solid. C.sub.14H.sub.19N.sub.3O.sub.2
(MW=261.33); mass spectroscopy (MH.sup.+)=262.0.
Step G: Preparation of
##STR00171##
[0463] To a suspension of NaH (60% in oil, 130 mg, 3.25 mmol) in
DMF (10 mL) at 0.degree. C. was added a DMF solution (5 mL) of the
alcohol from Step F (383.7 mg, 1.47 mmol). The resulting mixture
was stirred 5 minutes then treated with a DMF solution (5 mL) of
ethyl 2-[4-(bromomethyl)phenoxy]-2-methyl-propionate (registry
58336-71-3, 457.2 mg, 1.52 mmol). The reaction mixture was warmed
to room temperature and stirred overnight. The mixture was then
poured into aqueous HCl (1 N, 100 mL) and extracted into
CH.sub.2Cl.sub.2 (100 mL). The organic extract was washed a second
time with aqueous HCl (1 N) followed by brine, dried over
Na.sub.2SO.sub.4, and concentrated. Flash chromatography (3:1
hexanes:ethyl acetate) gave the desired product as a yellow oil.
NMR analysis indicated the presence of DMF so the oil was dissolved
in Et.sub.2O (50 mL) and washed with aqueous HCl (1 N, 50 mL)
followed by brine (1.times.50 mL). The organic solution was dried
over Na.sub.2SO.sub.4 then concentrated. Purification by flash
chromatography (3:1 hexanes:ethyl acetate) gave the desired ethyl
ester. C.sub.27H.sub.35N.sub.3O.sub.5 (NW=481.60); mass
spectroscopy (MH.sup.+)=482.2.
Step H: Preparation of
##STR00172##
[0465] The ethyl ester from Step G (252.9 mg, 0.53 mmol) was
dissolved in dioxane/H.sub.2O (15 mL/5 mL) and treated with LiCH
(50 mg, 2.1 mmol). The resulting mixture was stirred overnight then
concentrated. The resulting residue was diluted with H.sub.2O (70
mL) and washed with Et.sub.2O (1.times.75 mL). The aqueous extract
was acidified with aqueous HCl then extracted with ethyl acetate
(2.times.70 mL). The combined organic extracts were dried over
Na.sub.2SO.sub.4 then concentrated to give the desired carboxylic
acid as a thick, colorless oil. C.sub.25H.sub.31N.sub.3O.sub.5
(NW=453.54); mass spectroscopy (MH.sup.+)=454.2;
(MH.sup.-)=452.2.
Example 28
##STR00173##
[0466] Step A: Preparation of
##STR00174##
[0468] A solution of 4-methoxy benzyl alcohol (11 mL, 0.088 mol) in
methylene chloride (865 mL) was cooled to 0.degree. C. then treated
with triethyl amine (18 mL, 0.129 mol). Acetyl chloride (7.2 mL,
0.101 mol) was added to the mixture. The reaction was allowed to
stir for an hour. The solution was washed with 1N HCl, saturated
NaHCO.sub.3, and brine then dried over Na.sub.2SO.sub.4. The
organic layer was concentrated to give the desired compound as a
brown oil.
Step B: Preparation of
##STR00175##
[0470] The acetate from Step A (13 g, 0.072 mol) was dissolved in
methylene chloride (600 mL) and treated with 1-methoxy-1-trimethyl
siloxy-2-methyl-1-propene (Aldrich, 29 mL, 0.193 mol) followed by
Mg(ClO.sub.4).sub.2 (1.7 g, 0.0073 mol). The mixture was stirred
overnight at room temperature. The solution was washed with water
then brine. The organic layer was concentrated to yield to a yellow
oil. The material was carried forth without further
purification.
Step C: Preparation of
##STR00176##
[0472] A solution of BBr.sub.3 (9 mL, 0.048 mol) in methylene
chloride (180 mL) was cooled to 0.degree. C. and treated with a
solution of the methyl ester from Step B (10.56 g, 0.095 mol) in
methylene chloride (180 mL). The reaction was allowed to stir for
thirty minutes. Methylene chloride and methanol (1:1, 70 ml) was
added to quench the reaction. The solvent was concentrated.
Purification of the residue by flash chromatography (3:1
hexanes:ethyl acetate) afforded the phenol as a colorless oil.
Step D: Preparation of
##STR00177##
[0474] A THF solution of the phenol from Step C (173.3 mg, 0.83
mmol) and the alcohol from Example 27, Step F (204.5 mg, 0.78 mmol)
was treated with triphenylphosphine (218.5 mg, 0.83 mmol) and
diethyl azodicarboxylate (145 .mu.L, 0.92 mmol). The resulting
mixture was stirred overnight at room temperature under N.sub.2.
The mixture was concentrated and the residue dissolved in
CH.sub.2Cl.sub.2 (50 mL). The organic solution was washed with
H.sub.2O (1.times.50 mL) and brine (1.times.50 mL), dried over
Na.sub.2SO.sub.4, and then concentrated to give the crude product.
Purification by flash chromatography (4:1 hexanes:ethyl acetate)
gave the desired methyl ester as an oil.
C.sub.26H.sub.33N.sub.3O.sub.4 (MW=451.57); mass spectroscopy
(MH.sup.+)=452.2.
Step E: Preparation of
##STR00178##
[0476] The methyl ester from Step D (190 mg, 0.42 mmol) was
dissolved in dioxane/H.sub.2O (6 mL/3 mL) and treated with LiOH (50
mg, 2.1 mmol). The resulting mixture was stirred overnight then
concentrated. The resulting residue was diluted with H.sub.2O (50
mL) and washed with Et.sub.2O (1.times.50 mL). The aqueous extract
was acidified with aqueous HCl then extracted with ethyl acetate
(1.times.50 mL). The organic extract was washed with brine
(1.times.50 mL), dried over Na.sub.2SO.sub.4 then concentrated to
give the crude product. Purification by flash chromatography
(gradient 1:1 to 1:2 hexanes:ethyl acetate) gave the desired
carboxylic acid as a colorless oil. C.sub.25H.sub.31N.sub.3O.sub.4
(MW=437.54); mass spectroscopy (MH.sup.+)=438.1;
(MH.sup.-)=436.1.
Example 29
##STR00179##
[0477] Step A: Preparation of
##STR00180##
[0479] A DMF solution (65 mL) of the phenol from Example 28, Step C
(2.1 g, 0.010 mol) and methyl 4-bromobutyrate (2.2 g, 0.012 mol)
was treated with powdered K.sub.2CO.sub.3, (4.0 g, 0.030 mol) and
MgSO.sub.4 (4.0 g, 0.033 mol). The resulting mixture was heated to
60-70.degree. C. under a drying tube. After heating overnight the
mixture was cooled to room temperature and filtered through a pad
of celite. The filtrate was diluted with aqueous HCl (1 N, 150 mL)
and extracted with Et.sub.2O. The organic solution was washed with
brine, dried over Na.sub.2SO.sub.4, and concentrated. Purification
by flash chromatography (10:1 hexanes:ethyl acetate) provided the
desired methyl ester as a slightly yellow oil.
C.sub.17H.sub.24O.sub.5 (MW=308.38); mass spectroscopy
(MH.sup.+)=309.1.
Step B: Preparation of
##STR00181##
[0481] A methanol solution (76 mL) of the methyl ester from Step A
(2 g, 0.0065 mol) was treated with hydrazine hydrate (0.95 mL,
0.019 mol) and stirred overnight. Additional hydrazine hydrate
(0.95 mL, 0.019 mol) was added to drive the reaction to completion.
The solvent was concentrated and the resulting residue was diluted
with ethyl acetate. The organic layer was washed with water
followed by brine then evaporated to yield the desired acyl
hydrizide as a yellow oil. C.sub.16H.sub.24N.sub.2O.sub.4 (MW
308.38); mass spectroscopy (MH.sup.+)=309.2.
Step C: Preparation of
##STR00182##
[0483] A THF solution (20 mL) of the acyl hydrizide from Step B (2
g, 0.006 mol) was treated with a THF solution (20 mL) of n-propyl
isocyanate (Aldrich, 0.791 ml, 0.0084 mol), added dropwise. The
mixture was stirred overnight. The solvent was concentrated to give
a quantitative yield of the desired acyl semicarbazide which was
carried forth without further purification.
Step D: Preparation of
##STR00183##
[0485] The acyl semicarbazide from Step C (2.68 g, 0.0068 mol) was
dissolved in methanol and treated with KOH (3.82 g, 0.068 mol). The
reaction was refluxed overnight. Upon cooling, water was added to
the reaction mixture and the solution was then acidified using 1N
HCl to pH=3. The acidified layer was then extracted with ethyl
acetate. The organic layer was washed with brine, dried, and
concentrated. The resulting material was diluted with methanol and
treated with a catalytic amount of conc. H.sub.2SO.sub.4. The
solution stirred overnight. The solvent was evaporated then the
residue was diluted with methylene chloride and washed with water.
The organic layer was concentrated to give the methyl ester.
C.sub.20H.sub.29N.sub.3O.sub.4 (MW=375.47); mass spectroscopy
(MH.sup.+)=376.2.
Step E: Preparation of
##STR00184##
[0487] The N4-propyl triazolinone from Step D (1.5 g, 0.004 mol)
was dissolved in DMF (7 ml) and treated with .alpha.-bromo-p-xylene
(1.11 g, 0.006 mol) and powdered K.sub.2CO.sub.3. The resulting
mixture was stirred overnight at 67.degree. C. The heating source
was removed and ethyl acetate was added to the reaction mixture.
The organic layer was extracted with water followed by brine, dried
then concentrated. Purification of the yellow oil by flash
chromatography (4:1 hexanes:ethyl acetate) yielded the desired
N4-p-methyl benzyl triazolinone. C.sub.28H.sub.37N.sub.3O.sub.4
(MW=479.62); mass spectroscopy (MH.sup.+)=480.3.
Step F:
##STR00185##
[0489] The methyl ester from Step E (0.160 g, 0.00033 mol) was
dissolved in ethanol (6 mL) and treated with 2N NaOH (3 mL). The
reaction was refluxed for one hour. The reaction was cooled and
water (20 mL) was added to the solution. The solution was then
acidified using 1N HCl to pH=3 then extracted with ethyl acetate.
The organic layer was concentrated to afford the desired carboxylic
acid as a colorless oil. C.sub.27H.sub.35N.sub.3O.sub.4
(MW=465.60); mass spectroscopy (MH.sup.+)=466.3.
Example 30
##STR00186##
[0490] Step A: Preparation of
##STR00187##
[0492] Methyl-4-bromo butyrate (3 g, 0.0166 mol) and
2-(4-hydroxyphenyl)-2-methyl propanoic acid ethyl ester (American
Home Products U.S. Pat. No 3,795,691, 3.13 g, 0.014 mol) were
combined in a flask and heated to 70.degree. C. The reaction was
stirred overnight. Upon cooling, the reaction mixture was filtered
through celite. The filtrate was diluted with water and extracted
with ethyl ether. The organic layer was washed with brine then
concentrated. Purification by flash chromatography (4:1
hexanes:ethyl acetate) provided the desired diester as a yellow
oil. C.sub.17H.sub.24O.sub.6 (MW=324.38); mass spectroscopy
(MH.sup.+)=325.2.
Step B: Preparation of
##STR00188##
[0494] A methanol solution (60 mL) of the diester from Step A (1.64
g, 0.005 mol) was treated with hydrazine hydrate (1.23 mL, 0.025
mol) and stirred overnight. Additional hydrazine hydrate (2.46 mL,
0.050 mol) was added and the reaction was stirred overnight. The
solvent was evaporated. The resulting residue was diluted with
ethyl acetate and washed with water followed by brine.
Concentration of the organic layer gave the acyl hydrizide.
Step C: Preparation of
##STR00189##
[0496] A THF solution (10 mL) of the acyl hydrizide from Step B
(0.860 g, 0.00265 mol) was treated with a THF solution (10 mL) of
n-propyl isocyanate (Aldrich, 0.323 ml, 0.00345 mol) added
dropwise. The mixture was stirred overnight. The solvent was
concentrated to give a quantitative yield of the desired acyl
semicarbazide which was carried forth without further
purification.
Step D: Preparation of
##STR00190##
[0498] The acyl semicarbazide from Step C (1 g, 0.0026 mol) was
dissolved in methanol and treated with KOH (1.48 g, 0.026 mol). The
reaction was refluxed overnight. Upon cooling, water was added to
the reaction mixture and the solution was then acidified using 1N
HCl to pH=3. The acidified layer was then extracted with ethyl
acetate. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated. The resulting material was
diluted with methanol and treated with a catalytic amount of conc.
H.sub.2SO.sub.4. The solution was stirred overnight. The solvent
was evaporated then the residue was diluted with methylene chloride
and washed with water. The organic layer was concentrated to give
the desired N4-propyl-triazolinone. C.sub.19H.sub.27N.sub.3O.sub.5
(MW=377.44); mass spectroscopy (MH.sup.+)=378.2.
Step E: Preparation of
##STR00191##
[0500] The N4-propyl triazolinone from Step D (0.92 g, 0.0024 mol)
was dissolved in DMF (7 mL) and treated with .alpha.-bromo-p-xylene
(0.476 mL, 0.0036 mol) and powdered K.sub.2CO.sub.3 (1.68 g, 0.012
mol). The resulting mixture was stirred for two hours at 67.degree.
C. The heating source was removed and ethyl acetate was added to
the reaction mixture. The organic layer was extracted with water
followed by brine, dried over Na.sub.2SO.sub.4, then concentrated.
Purification of the yellow oil by flash chromatography (1:1
hexanes:ethyl acetate) yielded the desired N2-p-methyl benzyl
triazolinone as a yellow oil. C.sub.27H.sub.35N.sub.3O.sub.5
(MW=481.60); mass spectroscopy (MH.sup.+)=482.3.
Step F: Preparation of
##STR00192##
[0502] The methyl ester from Step E (0.250 g, 0.0005 mol) was
dissolved in ethanol (8 mL) and treated with 2N NaOH (4 mL). The
reaction was refluxed for thirty minutes. The reaction was cooled
and water (10 mL) was added to the solution. The solution was then
acidified using 1N HCl to pH=3 then extracted with ethyl acetate.
The organic layer was concentrated to afford the desired carboxylic
acid. C.sub.26H.sub.33N.sub.3O.sub.5 (MW=467.57); mass
spectroscopy. (MH.sup.+)=468.2.
Example 31
##STR00193##
[0503] Step A: Preparation of
##STR00194##
[0505] Pyridinium chlorochromate (14.2 g, 0.066 mol) was added
slowly to a solution of 4-(4-methoxyphenyl)-1-butanol (10 g, 0.055
mol) in methylene chloride at 0.degree. C. The reaction was warmed
to room temperature and stirred overnight. The reaction mixture was
filtered through a pad of Florisil and the solvent was evaporated.
Purification by flash chromatography (4:1 hexanes:ethyl acetate)
yielded the desired aldehyde as a colorless oil.
Step B: Preparation of
##STR00195##
[0507] The aldehyde from Step A (6.28 g, 0.035 mol) was combined
with triethyl phosphonoacetate (Aldrich, 8.39 mL, 0.042 mol) and
potassium carbonate (9.66 g, 0.07 mol) in water (120 mL) and
stirred overnight. Dioxane (120 mL) was added and the reaction was
stirred for several days. The solution was extracted with hexanes.
The organic layer was evaporated. The resulting material was
purified by flash chromatography (4:1 hexanes:ethyl acetate) to
give the olefin.
Step C: Preparation of
##STR00196##
[0509] The olefin from Step B (2.5 g, 0.010 mol) was dissolved in
ethyl acetate (40 mL) and purged with nitrogen. Upon the addition
of the 5% Pd/C (0.40 g), the solution was purged with nitrogen and
then H.sub.2 gas was released across the system. The reaction was
stirred overnight. The solution was filtered through a pad of
celite. The solvent was concentrated to give the desired methy
ether which was used without further purification.
Step D: Preparation of
##STR00197##
[0511] The methy ether, prepared as described in Step C (3.92 g,
0.016 mol), was dissolved in methylene chloride (50 mL) and cooled
to 0.degree. C. To this solution was added, dropwise, a solution of
BBr.sub.3 (4.5 mL, 0.48 mol) in methylene chloride. (20 mL). After
stirring for about 45 minutes at room temperature, the reaction
mixture was cooled to 0.degree. C. and quenched by the dropwise
addition of methanol/methylene chloride. During quenching,
transesterification from the ethyl ester to the methyl ester
occurred. The solvent was concentrated to give a dark oil.
Purification by flash chromatography (4:1 hexanes:ethyl acetate)
gave the desired phenol.
Step E: Preparation of
##STR00198##
[0513] The phenol from Step D (2.5 g, 0.011 mol) was dissolved in
ethanol (absolute, 40 mL) and treated with ethyl 2-bromoisobutyrate
(11.56 mL. 0.079 mol), powdered K.sub.2CO.sub.3 (4.55 g, 0.033
mol), and MgSO.sub.4. The reaction was stirred overnight at
75.degree. C. Upon cooling, the reaction mixture was filtered and
the filtrate was concentrated. The resulting residue was diluted
with ethyl acetate and extracted with water followed by brine. The
organic layer was concentrated to dryness. Purification by flashed
chromatography (9:1 hexanes:ethyl acetate) gave the desired
diester.
Step F: Preparation of
##STR00199##
[0515] A methanol solution (76 mL) of the diester from Step E (2.65
g, 0.0076 mol) was treated with hydrazine hydrate (1.84 mL, 0.038
mol) and stirred overnight. After about six hours, additional
hydrazine hydrate (1.84 mL, 0.038 mol) was added and the reaction
was stirred overnight. Again, additional hydrazine hydrate (1.84
mL, 0.038 mol) was added. After several hours, the reaction was
stopped and the solvent was evaporated. The resulting mixture was
purified by flash chromatography (gradient 100% ethyl acetate to
6:1 ethyl acetate:methanol) to give the desired acyl hydrizide.
Step G: Preparation of
##STR00200##
[0517] A THF solution (7 mL) of the acyl hydrizide from Step F (0.5
g, 0.0015 mol) was treated with a THF solution (7 mL) of n-propyl
isocyanate (Aldrich, 0.181 mL, 0.0019 mol) added dropwise. The
mixture was stirred overnight. The solvent was concentrated to give
a quantitative yield of the desired acyl semicarbazide which was
carried forth without further purification.
Step H: Preparation of
##STR00201##
[0519] The acyl semicarbazide from Step G (1 g, 0.0024 mol) was
dissolved in methanol and treated with KOH (1.34 g, 0.024 mol). The
reaction was refluxed overnight. Upon cooling, water was added to
the reaction mixture and the solution was then acidified using 1N
HCl to pH=3. The acidified layer was then extracted with ethyl
acetate. The organic layer was washed with brine, dried, and
concentrated. The resulting material was diluted with methanol and
treated with a catalytic amount of conc. H.sub.2SO.sub.4. The
solution stirred overnight. The solvent was evaporated then the
residue was diluted with methylene chloride and washed with water.
The organic layer was concentrated to give the desired N4-propyl
triazolinone. C.sub.21H.sub.31N.sub.3O.sub.4 (MW=389.50); mass
spectroscopy (MH.sup.+)=390.3.
Step I: Preparation of
##STR00202##
[0521] The N4-propyl triazolinone from Step H (0.5 g, 0.0013 mol)
was dissolved in DMF (7 mL) and treated with .alpha.-bromo-p-xylene
(0.885 g, 0.0064 mol) and powdered K.sub.2CO.sub.3 (0.885 g, 0.0064
mol). The resulting mixture was stirred for ninety minutes at
67.degree. C. The heating source was removed and ethyl acetate was
added to the reaction mixture. The organic layer was extracted with
water followed by brine, dried then concentrated. Purification of
the yellow oil by flash chromatography (2:1 hexanes:ethyl acetate)
yielded the desired N2-p-methyl benzyl triazolinone.
C.sub.29H.sub.39N.sub.3O.sub.4 (MW=493.65); mass spectroscopy
(MH.sup.+)=494.3.
Step J: Preparation of
##STR00203##
[0523] The methyl ester from Step I (0.129 g, 0.00026 mol) was
dissolved in ethanol (4 mL) and treated with 2N NaOH (2 mL). The
reaction was refluxed for forty-five minutes. The reaction was
cooled and water (10 mL) was added to the solution. The solution
was then acidified using 1N HCl to pH=3 then extracted with ethyl
acetate. The organic layer was concentrated to afford the desired
carboxylic acid as a colorless oil. C.sub.28H.sub.37N.sub.3O.sub.2
(MW=479.62); mass spectroscopy (MH.sup.+)=480.3.
Example 32
##STR00204##
[0524] Step A: Preparation of
##STR00205##
[0526] A methanol solution (75 mL) of 3-(3-methoxyphenyl)-propionic
acid (Aldrich, 10.0 g, 0.055 mol) was treated with H.sub.2SO.sub.4
(concentrated, 2 mL) and stirred at room temperature for 2 days.
The solvent was evaporated and the residue diluted with
CH.sub.2Cl.sub.2 (150 mL). The resulting solution was extracted
with saturated aqueous sodium bicarbonate (1.times.150 mL) followed
by brine (1.times.150 mL), then dried over Na.sub.2SO.sub.4. Upon
evaporation of the solvent the desired methyl ester was obtained as
a yellowish oil. Cl.sub.11H.sub.14O.sub.3 (MW=194.23); mass
spectroscopy (MH.sup.+)=195.0.
Step B: Preparation of
##STR00206##
[0528] A methanol solution (100 mL) of methyl ester from Step A
(10.3 g, 0.053 mol) was treated with hydrazine hydrate (30 mL, 0.60
mol) and stirred overnight. The solvent was evaporated and the
residue dissolved in ethyl acetate (200 mL). The resulting solution
was washed with H.sub.2O (200 mL), dried over Na.sub.2SO.sub.4 and
concentrated to give the desired acyl hydrizide as a white solid.
C.sub.10H.sub.14N.sub.2O.sub.2 (MW=194.23); mass spectroscopy
(MH.sup.+)=195.1.
Step C: Preparation of
##STR00207##
[0530] A THF solution (125 mL) of the acyl hydrizide from Step B
(7.3 g, 0.038 mol) was treated with a THF solution (25 mL) of
n-propyl isocyanate (Aldrich, 4.5 mL, 0.048 mol)--added dropwise
over 15 minutes. The mixture was stirred overnight during which a
thick precipitate formed. The resulting suspension was treated with
methanol (100 mL) and stirred approximately 2 hours. The solvent
was then concentrated to give the desired acyl semicarbazide as a
white solid which was used without further purification.
C.sub.14H.sub.21N.sub.3O.sub.3 (MW=279.34); mass spectroscopy
(MH.sup.+)=280.2.
Step D: Preparation of
##STR00208##
[0532] The acyl semicarbazide from Step C (10.0 g, 0.036 mol) was
dissolved in methanol (200 mL), treated with KOH (20 g, 0.36 mol),
then heated reflux overnight. The reaction mixture was cooled to
room temperature, poured into H.sub.2O (500 mL) and extracted with
ethyl acetate (2.times.500 mL). The combined organic extracts were
washed with brine (1.times.500 mL), dried over Na.sub.2SO.sub.4
then concentrated to give the desired N4-propyl triazolinone as a
yellow oil. C.sub.14H.sub.19N.sub.3O.sub.2 (MW=261.33); mass
spectroscopy (MH.sup.+)=262.1.
Step E: Preparation of
##STR00209##
[0534] The N4-propyl triazolinone from Step D (1.25 g, 4.8 mmol)
was dissolved in DMF (25 mL) and treated with
.alpha.-bromo-p-xylene (1.36 g, 7.3 mmol) and powdered
K.sub.2CO.sub.3 (4.2 g, 0.030 mol). The resulting mixture was
heated to 50.degree. C. under a drying tube overnight. The reaction
mixture was cooled to room temperature, poured into aqueous HCl
(1N, 200 mL) and extracted into ethyl acetate (200 mL). The organic
extract was washed with brine (1.times.200 mL), dried over
Na.sub.2SO.sub.4, then concentrated to give the crude product.
Purification by flash chromatography (gradient 2:1 to 1:1
hexanes:ethyl acetate) gave the desired N2-p-methylbenzyl
triazolinone as a colorless oil. C.sub.22H.sub.27N.sub.3O.sub.2
(MW=365.48); mass spectroscopy (MH.sup.+)=366.1.
Step F: Preparation of
##STR00210##
[0536] The N2-p-methylbenzyl triazolinone from Step E (1.06 g,
0.0029 mol) was dissolved in methylene chloride (15 mL) and cooled
to 0.degree. C. To this solution was added, dropwise, a solution of
BBr.sub.3 (0.548 mL, 0.0058 mol) in methylene chloride. (5 mL).
After stirring for two hours, the reaction mixture was cooled to
0.degree. C. and quenched by the dropwise addition of
methanol/methylene chloride. The solvent was concentrated and the
resulting material was dissolved in methylene chloride. The organic
layer was extracted with water followed by brine. Upon evaporation
of the solvent, the desired phenol was obtained.
C.sub.21H.sub.25N.sub.3O.sub.2 (MW=351.45); mass spectroscopy
(MH+)=352.19.
Step G: Preparation of
##STR00211##
[0538] The phenol from Step F (1 g, 0.0028 mol) was dissolved in
ethanol (absolute, 15 mL) and treated with ethyl 2-bromoisobutyrate
(2.88 mL, 0.0196 mol), powdered K.sub.2CO.sub.3 (1.157 g, 0.0084
mol), and MgSO.sub.4. The reaction was stirred overnight at
71.degree. C. Upon cooling, the reaction mixture was filtered and
the filtrate was concentrated. The resulting residue was diluted
with methylene chloride and extracted with water followed by brine.
An emulsion occurred. The organic layer was separated by the
addition of brine then concentrated to dryness. Purification by
flashed chromatography (gradient: 3:1 hexanes:ethyl acetate to 2:1
hexanes:ethyl acetate) gave the desired ester.
C.sub.27H.sub.35N.sub.3O.sub.4 (MW=465.60); mass spectroscopy
(MH.sup.+) 466.3.
Step H: Preparation of
##STR00212##
[0540] The ester from Step G (0.600 g, 0.0013 mol) was dissolved in
methanol (6 mL) and treated with an aqueous solution of LiCH (0.062
g, 0.0026 mol). The reaction was stirred overnight at room
temperature. Water (20 mL) was added to the reaction mixture and
the solution was extracted with ethyl acetate. The aqueous layer
was then acidified using 1N HCl to pH=3 then extracted with ethyl
acetate. The organic layer was concentrated to afford the desired
carboxylic acid. C.sub.25H.sub.31N.sub.3O.sub.4 (MW=437.54); mass
spectroscopy (MH.sup.+)=438.2.
Example 33
##STR00213##
[0541] Step A: Preparation of
##STR00214##
[0543] An ethanol solution of 3-hydroxybenzyl alcohol (Aldrich, 5
g, 0.040 mol) was combined with potassium carbonate (powdered, 18
g, 0.130 mol), ethyl 2-bromoisobutyrate (17 mL, 0.116 mol), and
magnesium sulfate (15 g). The reaction was stirred overnight at
50.degree. C. The reaction mixture was filtered and the filtrate
was concentrated. The resulting residue was dissolved in methylene
chloride and extracted with water followed by brine. Purification
by flash chromatography (gradient 5:1 hexanes:ethyl acetate to 2:1
hexanes:ethyl acetate) gave the desired alcohol as a yellow
oil.
Step B: Preparation of
##STR00215##
[0545] The alcohol from Step A (8.68 g, 0.036 mol) was dissolved in
methylene chloride (150 mL) and cooled to 0.degree. C. Carbon
tetrabromide (14.5 g, 0.044 mol) was added to the solution followed
by the slow addition of triphenylphosphine (11.5 g, 0.044 mol). The
solvent was evaporated and the resulting material was diluted with
ethyl ether causing the triphenylphosphine oxide by-product to
precipitate from the solution. The by-product was filtered and
filtrate was concentrated. The resulting material was dissolved in
hexane causing additional by-product to precipitate. A second
filtration was performed and the filtrate was concentrated. A 5 g
portion of the crude material was purified by flash chromatography
(gradient 95:5 hexanes:ethyl acetate to 9:1 hexanes:ethyl acetate)
to afford the ester. C.sub.13H.sub.17BrO.sub.3 (MW=301.18); mass
spectroscopy (MH.sup.+)=302.0.
Step C: Preparation of
##STR00216##
[0547] To a dry three-neck round bottom flask was added sodium
hydride (60% oil dispersion, 0.134 g, 0.0033 mol) in THF (12 mL)
and cooled to 0.degree. C. A solution of the alcohol (0.4 g, 0.0015
mol) from Example 27, Step F in THF (12 mL) was added and the
mixture was stirred for 5 minutes. The bromide from Step B was then
added as a solution in THF (12 mL) and the resulting mixture was
stirred overnight. The reaction mixture was poured into 1N HCl and
extracted with methylene chloride. The organic layer was washed
with water then brine. Purification by flash chromatography (1:1
hexanes:ethyl acetate) yielded the desired product.
[0548] C.sub.27H.sub.35N.sub.3O.sub.5 (MW=481.60); mass
spectroscopy (MH.sup.+)=482.1.
Step D: Preparation of
##STR00217##
[0550] The ethyl ester from Step C (0.270 g, 0.00056 mol) was
dissolved in ethanol (12 mL) and treated with 2N NaOH (6 mL). The
reaction was refluxed for one hour. The reaction was cooled and
water (25 mL) was added to the solution. The solution was then
acidified using 1N HCl to pH=3 then extracted with ethyl acetate.
The organic layer was concentrated to afford the desired carboxylic
acid as a thick oil. C.sub.25H.sub.31N.sub.3O.sub.5 (MW=453.54);
mass spectroscopy (MH.sup.+)=454.2.
Example 34
##STR00218##
[0551] Step A: Preparation of
##STR00219##
[0553] A methanol solution (15 mL) of ethyl
3-(3-methoxy-phenyl)butyrate (Registry 57816-01-0, 1.91 g, 0.0086
mol) was treated with hydrazine hydrate (4.2 mL, 0.086 mol) and
stirred overnight. The solvent was evaporated and the residue
dissolved in ethyl acetate (50 mL). The resulting solution was
washed with H.sub.2O (50 mL) and brine (50 mL), then dried over
Na.sub.2SO.sub.4 and concentrated to give the desired acyl
hydrizide as a white solid. C.sub.11H.sub.6N.sub.2O.sub.2
(MW=208.26); mass spectroscopy (MH.sup.+)=209.0.
Step B: Preparation of
##STR00220##
[0555] A THF solution (20 mL) of the acyl hydrizide from Step A
(1.03 g, 0.0050 mol) was treated with a THF solution of n-propyl
isocyanate (Aldrich, 0.60 mL, 0.0064 mol)--added dropwise over 15
minutes. The mixture was stirred then treated with H.sub.2O (50 mL)
and stirred approximately 2 hours. The mixture was concentrated to
an aqueous solution which was extracted with CH.sub.2Cl.sub.2
(2.times.75 mL). The combined organic extracts were dried over
Na.sub.2SO.sub.4 then concentrated to give the desired acyl
semicarbazide as a white solid, which was used without further
purification. C.sub.15H.sub.23N.sub.3O.sub.3 (MW=293.37) mass
spectroscopy (MH.sup.-)=292.2.
Step C: Preparation of
##STR00221##
[0557] The acyl semicarbazide from Step B was dissolved in methanol
(60 mL), treated with KOH (3.0 g, 0.053 mol), then heated to reflux
for 48 hours. The reaction mixture was cooled to room temperature,
poured into H.sub.2O (200 mL), then extracted with ethyl acetate
(2.times.200 mL). The combined organic extracts were washed with
brine (250 mL), dried over Na.sub.2SO.sub.4 then concentrated to
give the desired N4-propyl triazolinone as a solid.
C.sub.15H.sub.21N.sub.3O.sub.2 (MW=275.35); mass spectroscopy
(MH.sup.+)=276.1.
Step D: Preparation of
##STR00222##
[0559] The N4-propyl triazolinone from Step C (1.20 g, 4.4 mmol)
was dissolved in DMF (20 mL) and treated with p-methylbenzyl
bromide (1.60 g, 8.6 mmol), powdered K.sub.2CO.sub.3 (3.2 g, 0.023
mol), and MgSO.sub.4 (1.2 g, 0.010 mol). The resulting mixture was
heated to 80.degree. C. under a drying tube overnight. The reaction
mixture was cooled to room temperature, poured into aqueous HCl
(1N, 100 mL) and extracted into Et.sub.2O (2.times.100 mL). The
combined organic extracts were washed with brine (1.times.200 mL),
dried over Na.sub.2SO.sub.4, then concentrated to give the crude
product. Purification by flash chromatography (2:1 hexanes:ethyl
acetate) gave the desired N2-p-methylbenzyl triazolinone as a
colorless oil.
[0560] C.sub.23H.sub.29N.sub.3O.sub.2 (MW=379.51); mass
spectroscopy (MH.sup.+) 380.2.
Step E: Preparation of
##STR00223##
[0562] The N2-p-methylbenzyl triazolinone from Step D (0.7879 g,
0.002 mol) was dissolved in methylene chloride (15 mL) and cooled
to 0.degree. C. To this solution was added, dropwise, a solution of
BBr.sub.3 (0.392 mL, 0.004 mol) in methylene chloride (5 mL). After
stirring for about 90 minutes, the reaction mixture was cooled to
0.degree. C. and quenched by the dropwise addition of
methanol/methylene chloride. The solvent was concentrated and the
resulting material was dissolved in methylene chloride. The organic
layer was extracted with water followed by brine. Upon evaporation
of the solvent, the desired phenol was obtained.
C.sub.22H.sub.27N.sub.3O.sub.2 (MW=365.48); mass spectroscopy
(MH.sup.+)=366.3.
Step F: Preparation of
##STR00224##
[0564] The phenol from Step E (0.70 g, 0.0019 mol) was dissolved in
DMF (40 mL) and treated with ethyl 2-bromoisobutyrate (1.97 mL,
0.013 mol), powdered K.sub.2CO.sub.3 (0.797 g, 0.0057 mol), and
MgSO.sub.4. The reaction was stirred overnight at 75.degree. C.
Upon cooling, the reaction mixture was filtered and the filtrate
was concentrated. The resulting residue was diluted with ethyl
acetate and extracted with water followed by brine. The organic
layer was concentrated to dryness. Purification by flashed
chromatography (1:1 hexanes:ethyl acetate) gave the desired ester.
C.sub.28H.sub.37N.sub.3O.sub.4 (MW=479.62); mass spectroscopy
(MH.sup.+)=480.3.
[0565] Step G: Preparation of
##STR00225##
[0566] The ester from Step F (0.250 g, 0.00052 mol) was dissolved
in ethanol (8 mL) and treated with 2N NaOH (4 mL). The reaction was
refluxed for thirty minutes. The reaction was cooled and water (20
mL) was added to the solution. The solution was then acidified
using 1N HCl to pH=3 then extracted with ethyl acetate. The organic
layer was concentrated to afford the desired carboxylic acid.
[0567] C.sub.26H.sub.33N.sub.3O.sub.4 (MW=451.57); mass
spectroscopy (MH.sup.+)=452.3.
Example 35
##STR00226##
[0569] Step A: Preparation of
##STR00227##
[0570] A methanol solution (75 mL) of 3-(3-methoxyphenyl)-propionic
acid (Aldrich, 10 g, 0.055 mol) was treated with a catalytic amount
of concentrated H.sub.2SO.sub.4 and stirred at room temperature
overnight. The solvent was concentrated and the residue was diluted
with methylene chloride (150 mL). The resulting solution was
extracted with saturated aqueous sodium bicarbonate (1.times.150
mL) followed by brine (1.times.150 mL), then dried over
Na.sub.2SO.sub.4. Upon evaporation of the solvent, the desired
methyl ester was obtained as a colorless oil.
C.sub.11H.sub.14O.sub.3 (MW=194.23); mass spectroscopy
(MH.sup.+)=195.1.
Step B: Preparation of
##STR00228##
[0572] The ester from Step A (5 g, 0.0257 mol) was dissolved in
toluene (100 mL) and cooled to 0.degree. C. An excess of DIBAL (1M,
50 mL, 0.050 mol) was slowly added to the solution. The reaction
stirred for 1 hour. An aqueous solution of Rochelle's salt
(saturated) was added and the mixture was stirred over the weekend.
The resulting biphasic solution was diluted with water and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, then concentrated. Purification
by flash chromatography (gradient 4:1 to 3:1 hexanes:ethyl acetate)
gave the desired alcohol.
Step C: Preparation of
##STR00229##
[0574] The alcohol, prepared as described in Step B (5.5 g, 0.033
mol), was dissolved in methylene chloride (165 mL) and cooled to
0.degree. C. Pyridinium chlorochromate (8.57 g, 0.040 mol) was
added slowly to the solution. The reaction was warmed to room
temperature and stirred overnight. The reaction mixture was
filtered through a pad of celite then concentrated. Purification by
flash chromatography (4:1 hexanes:ethyl acetate) yielded the
desired aldehyde.
Step D: Preparation of
##STR00230##
[0576] The aldehyde (3.73 g, 0.023 mol) from Step C was combined
with triethyl phosphonoacetate (Aldrich, 6.12 g, 0.027 mol) and
potassium carbonate (6.26 g, 0.045 mol) in water and stirred
overnight. Dioxane was added and the reaction was stirred overnight
again. The reaction solution was diluted with hexanes and
extracted. The organic layer was concentrated. Purification by
flash chromatography (15:1 hexanes:ethyl acetate) gave the desired
olefin.
Step E: Preparation of
##STR00231##
[0578] The olefin from Step D (2.5 g, 0.010 mol) was dissolved in
ethyl acetate and purged with nitrogen. Upon the addition of 5%
Pd/C (0.250 g), the solution was purged with nitrogen then
subjected to H.sub.2 gas. The reaction was stirred overnight. The
solution was filtered through a pad of celite. The solvent was
concentrated to give the saturated ester which was used without
further purification.
Step F: Preparation of
##STR00232##
[0580] A methanol solution (60 mL) of the ester from Step E (2.5 g,
0.0105 mol) was treated with hydrazine hydrate (5.14 mL, 0.105 mol)
and stirred for three days. The solvent was evaporated. The
resulting mixture was dissolved in ethyl acetate and the solution
was extracted with water then brine. The organic layer was
concentrated to give the desired acyl hydrizide.
C.sub.12H.sub.18N.sub.2O.sub.2 (MW=222.29); mass spectroscopy
(MH.sup.+)=223.
Step G: Preparation of
##STR00233##
[0582] A THF solution (20 mL) of the acyl hydrizide from Step F
(2.1 g, 0.0095 mol) was treated with a THF solution (20 mL) of
n-propyl isocyanate (Aldrich, 1.15 mL, 0.012 mol) added dropwise.
The mixture was stirred overnight. The solvent was concentrated to
give the desired acyl semicarbazide which was carried forth without
further purification. C.sub.16H.sub.25N.sub.3O.sub.3
Step H: Preparation of
##STR00234##
[0584] The acyl semicarbazide from Step G (2.95 g, 0.0096 mol) was
dissolved in methanol and treated with KOH (5.39 g, 0.096 mol). The
reaction was refluxed overnight. Upon cooling, water was added to
the reaction mixture and the solution was then acidified using 1N
HCl to pH=3. The acidified layer was then extracted with ethyl
acetate. The organic layer was washed with brine, dried, and
concentrated. Purification by flash chromatography (1:1
hexanes:ethyl acetate) gave the desired N4-propyl triazolinone.
C.sub.16H.sub.23N.sub.3O.sub.2 (MW=289.38); mass spectroscopy
(MH.sup.+)=290.2.
Step I: Preparation of
##STR00235##
[0586] The N4-propyl triazolinone from Step H (2.13 g, 0.0073 mol)
was dissolved in DMF (75 mL) and treated with
.alpha.-chloro-p-xylene (1.54, 0.0110 mol) and powdered
K.sub.2CO.sub.3 (5.09 g, 0.037 mol) The resulting mixture was
stirred overnight at 67.degree. C. The heating source was removed
and ethyl acetate was added to the reaction mixture. The organic
layer was extracted with water followed by brine, dried over
Na.sub.2SO.sub.4 then concentrated. Purification of the residue by
flash chromatography (2:1 hexanes:ethyl acetate) yielded the
desired N2-p-methyl benzyl triazolinone.
C.sub.24H.sub.31N.sub.3O.sub.2 (MW=393.53); mass spectroscopy
(MH.sup.+)=394.3.
Step J: Preparation of
##STR00236##
[0588] The N2-p-methyl benzyl triazolinone from Step I (1.96 g,
0.005 mol) was dissolved in methylene chloride (30 mL) and cooled
to 0.degree. C. To this solution was added, dropwise, a solution of
BBr.sub.3 (0.942 mL, 0.010 mol) in methylene chloride (10 mL).
After stirring for about one hour, two additional equivalents of
BBr.sub.3 was added. The reaction mixture was cooled to 0.degree.
C. and quenched by the dropwise addition of methanol/methylene
chloride. The solvent was concentrated to give the desired phenol
which was used without further purification.
C.sub.23H.sub.29N.sub.3O.sub.2 (MW=379.51); mass spectroscopy
(MH.sup.+)=380.3.
Step K: Preparation of
##STR00237##
[0590] The phenol from Step J (1.75 g, 0.0046 mol) was dissolved in
ethanol (absolute, 20 mL) and treated with ethyl 2-bromoisobutyrate
(4.74 mL, 0.032 mol), powdered K.sub.2CO.sub.3 (1.90 g, 0.014 mol),
and MgSO.sub.4. The reaction was stirred overnight at 77.degree. C.
Upon cooling, the reaction mixture was filtered and the filtrate
was concentrated. The resulting residue was diluted with ethyl
acetate and extracted with water followed by brine. The organic
layer was concentrated to dryness. Purification by flashed
chromatography (1:1 hexanes:ethyl acetate) gave the ester as a
colorless oil. C.sub.29H.sub.39N.sub.3O.sub.4 (MW=493.65); mass
spectroscopy (MH.sup.+)=494.3.
Step L: Preparation of
##STR00238##
[0592] The ethyl ester from Step K (1 g, 0.002 mol) was dissolved
in ethanol (24 mL) and treated with 2N NaOH (12 mL). The reaction
was refluxed for one hour. The reaction was cooled and water (25
mL) was added to the solution. The solution was then acidified
using 1N HCl to pH=3 then extracted with ethyl acetate. The organic
layer was concentrated to afford the desired carboxylic acid as a
colorless oil. C.sub.27H.sub.35N.sub.3O.sub.4 (MW=465.6); mass
spectroscopy (MH.sup.+)=466.7.
Example 36
##STR00239##
[0593] Step A: Preparation of
##STR00240##
[0595] The phenol (2.1 g, 0.0060 mol), prepared as in Example 22,
Step F, was dissolved in DMF (25 mL) and treated with ethyl
4-bromobutyrate (Aldrich, 1.4 g, 0.0072 mol), powdered potassium
carbonate (Aldrich, 3.3 g, 0.0240 mol) and small amount of
magnesium sulfate. The resulting mixture was stirred and heated to
65.degree. C. for 18 hrs. The resulting reaction mixture was added
slowly to HCl (1N, 100 mL) and extracted with ether (3.times.). the
ether layers were combined, washed with water and dried over sodium
sulfate. Evaporation of the solvent gave the crude product.
Purification by flash chromatography (1:1 hexanes:ethyl acetate)
gave the desired ethyl ester as a clear oil.
Step B: Preparation of
##STR00241##
[0597] The ethyl ester from Step A (0.1 g, 0.0002 mol) was
dissolved in methanol (2 mL) and treated with an aqueous solution
of lithium hydroxide (0.01 g, 0.0004 mol) in water (2 mL). The
resulting mixture was heated to 50.degree. C. for 2 hrs., then
stirred at room temperature overnight. The reaction mixture was
added to water and acidified with aqueous HCl (conc.) to a pH of 3
and extracted with ethyl acetate (2.times.). These two layers were
combined, washed with brine and dried over sodium sulfate. The
solvent was evaporated to give the desired carboxylic acid as an
oil. C.sub.25H.sub.31N.sub.3O.sub.4 (MW=437.54); mass spectroscopy
(MH.sup.+)=438.1.
Example 37
##STR00242##
[0598] Step A: Preparation of methyl 4-(4-iodophenyl)-butyrate
##STR00243##
[0599] To a solution of 4-(p-iodophenyl)-butyric acid (45.0 g,
0.155 mol) in methanol (1.3 L), was added sulfuric acid
(concentrated, 8.4 mL) dropwise and it was stirred at room
temperature under nitrogen for 3 hours. The reaction mixture was
concentrated on a rota-vapor, the residue was then partitioned
between ethyl acetate (700 mL) and saturated sodium bicarbonate
aqueous solution (500 mL). The organic phase was separated, washed
with brine (2.times.200 mL), then dried over Na.sub.2SO.sub.4 and
filtered. Evaporation of solvent gave the titled compound as an oil
that was used in step B without further purification.
Step B: Preparation of
##STR00244##
[0601] A mixture of methyl 4-(4-iodophenyl)-butyrate (47.0 g, 0.155
mol) from Step A and hydrazine hydrate (38.8 g, 0.775 mol) in
methanol (200 mL) at room temperature was stirred overnight. The
solvent was evaporated and the residue was partitioned between
ethyl acetate (500 mL) and water (100 mL). The organic layer was
washed water (3.times.100 mL) and brine (2.times.100 mL), dried
over Na.sub.2SO.sub.4, filtered and concentrated to dryness to give
the titled compound as a white crystal that was used in step C
without further purification.
Step C: Preparation of
##STR00245##
[0603] To a solution of the Step B product (47.0 g, 0.155 mol) in
THF (500 mL), was added a solution of ethyl isocyanate (Aldrich,
14.7 mL, 0.186 mol) in THF (200 mL) dropwise and the mixture was
stirred at room temperature for an hour. Evaporation of solvent
gave the titled compound as an off-white powder that was used in
step D without further purification.
Step D: Preparation of
##STR00246##
[0605] To a solution of the Step C product (58 g, 0.155 mol) in
methanol (775 mL), was added potassium hydroxide in one portion
(43.5 g, 0.775 mol). The reaction mixture was heated at 85.degree.
C. for 48 hours. Half of the volume was then evaporated on a
rota-vapor, the residue was then partitioned between ethyl acetate
(1.0 L) and water (500 mL), and the two layers were separated. The
aqueous layer was extracted with ethyl acetate (2.times.200 mL).
The combined organic layers was dried over Na.sub.2SO.sub.4 and
filtered. Evaporation of solvent gave the titled compound as a
white solid.
Step E: Preparation of
##STR00247##
[0607] To a solution of the Step D product (2.05 g, 0.00574 mol) in
methyl ethyl ketone (60 mL), was added 4-(tert-butyl)benzyl bromide
(1.93 mL, 0.00861 mol) followed by potassium carbonate powder (4.75
g, 0.0344 mol). The resulting mixture was stirred under reflux
under a drying tube for 24 hours. The reaction mixture was cooled
to room temperature and then partitioned between ethyl acetate (100
mL) and NH.sub.4Cl saturated aqueous solution (100 mL). The aqueous
layer was extracted with ethyl acete (100 mL) and the combined
organic phase dried over Na.sub.2SO.sub.4 and filtered. Evaporation
of solvent gave a crude product, which was purified on a silica gel
column eluting with 50% ethyl acetate in hexane to give the titled
compound as colorless oil.
Step F: Preparation of
##STR00248##
[0609] To a solution of the Step E product (2.4 g, 0.0048 mol) in
benzene (5 mL) at room temperature, a solution of KOH (5.35 g,
0.0953 mol) in water (8.9 mL), chloroform (19.2 mL) and
Pd(Ph.sub.3P).sub.2Cl.sub.2 (0.34 g, 0.00048 mol) were added and
mixture stirred for 24 hours. Then, mixture was diluted with
diethyl ether (20 mL) and pH adjusted to pH=1-2 by addition of 1N
HCl. Layers were separated and the aqueous layer extracted with
diethyl ether (3.times.100 mL). The combined organic layers, were
dried over Na.sub.2SO.sub.4, filtered and evaporated to give a
crude product, which was purified on a silica gel column eluting,
first with 70% ethyl acetate in hexane and then with ethyl acetate.
The titled compound was obtained as white solid. Mass
(MH+=422.5).
Example 38
##STR00249##
[0610] Step A: Preparation of methyl 4-benzyloxybutyrate
##STR00250##
[0611] To a solution of 4-benzyloxybutyric acid (54.8 g, 0.282 mol)
in methanol (1.4 L), was added sulfuric acid (concentrated, 1.4 mL)
dropwise and it was stirred at room temperature under nitrogen
overnight. The reaction mixture was concentrated on a rota-vapor,
the residue was then partitioned between ethyl acetate (700 mL) and
saturated sodium bicarbonate aqueous solution (200 mL). The organic
phase was separated, washed with brine (2.times.100 mL), then dried
over Na.sub.2SO.sub.4 and filtered. Evaporation of solvent gave the
titled compound as an oil that was used in step B without further
purification.
Step B: Preparation of
##STR00251##
[0613] A mixture of methyl 4-benzyloxybutyrate (58.7 g, 0.282 mol)
from Step A and hydrazine hydrate (56.4 g, 1.13 mol) in methanol
(300 mL) at room temperature was stirred overnight. The solvent was
evaporated and the residue was partitioned between ethyl acetate (1
L) and water (100 mL). The organic layer was washed water
(3.times.100 mL) and brine (2.times.100 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated to dryness to give the
titled compound as a white crystal that was used in step C without
further purification.
Step C: Preparation of
##STR00252##
[0615] To a solution of the Step B product (58.7 g, 0.282 mol) in
THF (600 mL), was added a solution of ethyl isocyanate (Aldrich,
26.8 mL, 0.338 mol) in THF (300 mL) dropwise and the mixture was
stirred at room temperature for an hour. Evaporation of solvent
gave the titled compound as an off-white powder that was used in
step D without further purification.
Step D: Preparation of
##STR00253##
[0617] A suspension of the Step C product (78.6 g, 0.282 mol) in a
solution of KOH (19.0 g, 0.339 mol) in water (380 mL) (1.2 eq of 5%
KOH aqueous solution) was heated at 110.degree. C. for 1 hour (as
soon as the temperature is increased, suspension disappear). At
that time, TLC showed no starting material remained and reaction
was cooled to room temperature. Then, pH was adjusted to pH=6-7 by
addition of 1N HCl, and extracted with AcOEt (3.times.500 mL). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and evaporated to give the titled compound as white solid.
Step E: Preparation of
##STR00254##
[0619] To a solution of the Step D product (9.7 g, 0.00374 mol) in
methyl ethyl ketone (400 mL), was added 4-(tert-butyl)benzyl
bromide (17.2 mL, 0.00935 mol) followed by potassium carbonate
powder (25.8 g, 0.187 mol). The resulting mixture was stirred at
80-85.degree. C. under a drying tube for 24 hours. The reaction
mixture was cooled to room temperature and then partitioned between
ethyl acetate (300 mL) and NH.sub.4Cl saturated aqueous solution
(300 mL). The aqueous layer was extracted with ethyl acetate (200
mL) and the combined organic phase dried over Na.sub.2SO.sub.4 and
filtered. Evaporation of solvent gave a crude product, which was
purified on a silica gel column eluting with 50% ethyl acetate in
hexane to give the titled compound as colorless oil.
Step F: Preparation of
##STR00255##
[0621] To a solution of the Step E product (4.2 g, 0.0103 mol) in
ethanol (100 mL) at room temperature, palladium, 10% on activated
carbon (1.03 g) was added. Mixture was stirred under hydrogen
atmosphere (balloon) for 3 hours and then filtered through a plug
of celite. Evaporation of the solvent gave the titled compound as
white solid that was used in Step G without further
purification.
Step G: Preparation of
##STR00256##
[0623] To a solution of triphenylphosphine (1.23 g, 4.68 mmol) and
imidazole (0.32 g, 4.68 mmol) in a 3:1 mixture of
Et.sub.2O--CH.sub.3CN (20 mL) at 0.degree. C. under nitrogen
atmosphere, iodine (1.19 g, 4.68 mmol) was added in small portions
with vigorous stirring. The resulting mixture was warmed at room
temperature and stirred for 30 minutes. Then, mixture was cooled to
0.degree. C. and a solution of the Step F product (1.35 g, 4.25
mmol) in a 1:1 mixture of Et.sub.2O--CH.sub.3CN (5 mL) was added.
Reaction was stirred at 0.degree. C. for 15 min and at room
temperature for 30 minutes and then poured onto 0.5N HCl (50 mL).
The aqueous layer was extracted twice with a 1:1 mixture of
Et.sub.2O-hexanes (100 mL) and the combined organic phase dried
over Na.sub.2SO.sub.4 and filtered. Evaporation of solvent gave a
crude product, which was purified on a silica gel column eluting
with 50% ethyl acetate in hexane to give the titled compound as
yellow oil.
Step H: Preparation of
##STR00257##
[0625] To a stirred slurry of zinc dust (0.21 g, 3.22 mmol) in
anhydrous THF (0.5 mL) under nitrogen atmosphere at 60.degree. C.
was added 1,2-dibromoethane (13.9 .mu.L, 0.16 mmol). After 15
minutes of vigorous stirring, the slurry was allowed to cool to
room temperature and chlorotrimethylsilane (17.1 .mu.L, 0.135 mmol)
was added. Mixture was stirred for 30 minutes and then was reheated
to 60.degree. C. Then, a solution of the Step G product (0.23 g,
0.54 mmol) in anhydrous THF (1 mL) was added dropwise and mixture
stirred for 30 minutes. A solution of tert-butyl
2-(4-bromophenylsulfanyl)-2-methylpropionate (0.36 g, 1.08 mmol),
Pd(dba).sub.2 (0.0155 g, 0.027 mmol) and tri-o-tolylphosphine
(0.0164 g, 0.054 mmol) in anhydrous THF (1 mL) was added and the
resulting solution maintained at 60.degree. C. for 2 h. Reaction
was then cooled at room temperature and poured onto saturated
NH.sub.4Cl aqueous solution (20 mL). The aqueous layer was
extracted with ethyl acetate (50 mL) and the organic layer washed
with saturated NH.sub.4Cl aqueous solution (2.times.10 mL). The
combined aqueous phase was extracted with ethyl acetate (50 mL) and
the combined organic phase dried over Na.sub.2SO.sub.4 and
filtered. Evaporation of solvent gave a crude product, which was
purified on a silica gel column eluting with 40% ethyl acetate in
hexane to give the titled compound as colorless oil. MS: m/z
(M.sup.++1): 552.4.
Step I: Preparation of
##STR00258##
[0627] The Step I product (180 mg) was treated a mixture of
trifluoroacetic acid and dichloromethane (10 mL, 50% v/v) with
stirring for 3 h. The solvent was removed on a rotary evaporator
and the residue dried under high vacuum to give the titled
compound.
Example 39
Compound 39
2-(4-{3-[1-(4-tert-Butylbenzyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]triaz-
ol-3-yl]propyl}phenoxy)-2-methyl-3-phenylpropionic acid
##STR00259##
[0628] Step A: Preparation of 4-(4-Hydroxyphenyl)butyric acid
hydrazide
##STR00260##
[0629] A mixture of methyl 4-(4-hydroxyphenyl)butyrate (4.93 g,
0.025 mol) and hydrazine hydrate (25.4 g, 0.254 mol) in methanol
(64 mL) was heated under reflux for an hour. It was then cooled
down to room temperature and stirred overnight. The solvent was
evaporated and the residue was partitioned between ethyl acetate
(100 mL) and water (100 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated to dryness to give the
titled compound as a white crystal (3.30 g, 67%). 400 MHz .sup.1H
NMR (DMSO-d.sup.6) .delta. 9.10 (s, 1H), 8.89 (s, 1H), 6.93 (d,
J=8.8 Hz, 2H), 6.63 (d, J=8.8 Hz, 2H), 3.32 (s, 2H), 2.40 (t, J=7.6
Hz, 2H), 1.97 (t, J=7.2 Hz, 2H), 1.71-1.67 (m, 2H); Mass
(M-H.sup.-) 193.27.
Step B: Preparation of
##STR00261##
[0631] To a solution of the Step A product (3.49 g, 0.0180 mol) in
THF (900 mL), was added methyl isocyanate (Aldrich, 1.17 mL, 0.0198
mol) dropwise and the mixture was stirred at room temperature for
an hour. Evaporation of solvent gave the titled compound as an
off-white powder (3.2 g, 71%). Mass (M-H--)=250.30.
Step C: Preparation of
5-[3-(4-hydroxyphenyl)propyl]-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one
##STR00262##
[0632] To a solution of the Step B product (3.21 g, 0.0128 mol) in
methanol (64 mL), was added potassium hydroxide in one portion
(10.8 g, 0.181 mol). The reaction mixture was heated at 70.degree.
C. for 36 hours. The residue was concentrated under reduced
pressure and dissolved in water (80 mL). The aqueous solution was
acidified to pH=2 by concentrated HCl, resulting in product
precipitation. The heterogeneous mixture was stirred for 18 h, and
the product was collected by filtration, yielding the titled
compound as an off-white solid (4.5 g, in excess of theoretical
yield). 400 MHz .sup.1H NMR (DMSO-d.sup.6) .delta. 11.37 (s, 1H),
6.97 (d, J=8.0 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 3.01 (s, 3H), 2.50
(t, J=7.6 Hz, 2H), 2.42 (t, J=7.6 Hz, 2H), 1.80-1.77 (m, 2H); Mass
(M+H.sup.+)=234.21, (M-H--)=232.29.
Step D: Preparation of
2-(4-tert-Butylbenzyl)-5-{3-[4-(4-tertbutylbenzyloxy)-phenyl]propyl}-4-me-
thyl-2,4-dihydro[1,2,4]triazol-3-one
##STR00263##
[0633] To a solution of the Step C product (1.00 g, 4.3 mmol) in
DMF (21.2 mL), was added 4-t-butylbenzyl bromide (3.86 g, 17 mmol)
followed by potassium carbonate powder (2.92 g, 22 mmol). The
mixture was stirred at rt under nitrogen overnight. The reaction
mixture was partitioned between ethyl acetate (20 mL) and water (20
ml). The organic phase was dried over Na.sub.2SO.sub.4 and
filtered. Evaporation of solvent gave a crude product, which was
purified on a silica gel column eluting with 20% ethyl acetate in
hexane to give the titled compound as colorless oil (1.12 g, 59%).
400 MHz .sup.1H NMR (CDCl.sub.3) .delta. 7.42-7.26 (m, 8H), 7.06
(d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 5.00 (s, 2H), 4.89 (s,
2H), 3.15 (s, 3H), 2.63 (t, J=7.2 Hz, 2H), 2.46 (t, J=7.6 Hz, 2H),
1.95 (quintet, J=7.6 Hz, 2H); 1.29 (m, 18H); Mass
(M+H.sup.+)=526.43.
[0634] Step E: Preparation of
2-(4-tert-butylbenzyl)-5-[3-(4-hydroxyphenyl)propyl]-4-methyl-2,4-dihydro-
-[1,2,4]triazol-3-one
##STR00264##
[0635] To a solution of the Step D product (1.12 g, 2.1 mmol) in
EtOH (21 mL) was added 5% Pd/C (22 mg) and a hydrogen balloon. The
reaction was stirred for 18 h. After filtering away the catalyst on
celite, the filtrate was concentrated to produce the titled
compound as a white solid (0.746 mg, 92%). 400 MHz .sup.1H NMR
(CDCl.sub.3) .delta. 7.33 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz,
2H), .delta. 6.99 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.4 Hz, 2H), 4.89
(s, 2H), 3.15 (s, 3H), 2.61 (t, J=7.6 Hz, 2H), 2.46 (t, J=7.2 Hz,
2H), 1.97-1.92 (m, 2H); 1.28 (s, 9H); Mass (M+H.sup.+)=380.26.
[0636] Step F: Preparation of
2-(4-{3-[1-(4-tert-Butylbenzyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]tria-
zol-3-yl]propyl}phenoxy)propionic acid ethyl ester
##STR00265##
[0637] To a solution of the Step E product (0.746 g, 1.97 mmol) in
DMF (7.9 mL) was added ethyl bromopropionate (0.713 g, 3.94 mmol)
followed by powdered potassium carbonate (1.36 g, 9.85 mmol). The
reaction was stirred at rt overnight, then diluted with ethyl
acetate (20 mL) and washed with water (10 mL). The aqueous layer
was back-extracted with ethyl acetate (20 mL), then the combined
organics were dried over Na.sub.2SO.sub.4 and concentrated. The
product was purified by column chromatography (90 g SiO.sub.2, 50%
ethyl acetate in hexane to 100% ethyl acetate) providing the ethyl
ester as an oil (0.754 g, 80%). 400 MHz .sup.1H NMR (CDCl.sub.3)
.delta. 7.33 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.04 (d,
J=8.4 Hz, 2H), 6.79 (d, J=8.4 Hz, 2H), 4.89 (s, 2H), 4.70 (q, J=6.8
Hz, 2H), 4.21 (q, J=7.2 Hz, 2H), 3.15 (s, 3H), 2.62 (t, J=7.6 Hz,
2H), 2.45 (t, J=7.2 Hz, 2H), 1.94 (quintet, J=7.2 Hz, 2H), 1.60 (d,
J=6.8 Hz, 3H), 1.28-1.23 (m, 12H); Mass (M+H.sup.+)=480.2.
Step G: Preparation of
2-(4-{3-[1-(4-tert-Butylbenzyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]tria-
zol-3-yl]propyl}phenoxy)-2-methyl-3-phenyl-propionic acid ethyl
ester
##STR00266##
[0638] A magnetically stirred solution of the Step F product (0.752
g, 1.6 mmol) in THF (12 mL) was cooled to -78.degree. C. under
nitrogen. LHMDS (1M solution in THF, 1.96 mL) was added dropwise
via syringe, followed by syringe addition of a mixture of benzyl
bromide (0.992 g, 5.8 mmol) and tetrabutyl ammonium iodide (57 mg,
0.15 mmol). The reaction proceeded for 1 h at -78.degree. C., then
for 4 h at -20.degree. C., and finally for 1 h at rt. The reaction
was quenched with saturated aqueous ammonium chloride, and ethyl
acetate was added. Layers were separated, and the organic phase was
washed with brine, dried over Na.sub.2SO.sub.4, then concentrated.
The product was purified by column chromatography (50 g SiO.sub.2,
50% ethyl acetate in hexane to 100% ethyl acetate) providing the
ethyl ester as an oil (0.224 g, 25%). 400 MHz .sup.1H NMR
(CDCl.sub.3) .delta. 7.34-7.25 (m, 9H), 6.99 (d, J=8.8 Hz, 2H),
6.75 (d, J=8.8 Hz, 2H), 4.88 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.31
(d, J=9.6 Hz, 2H), 3.16 (d, J=9.6 Hz, 2H), 3.14 (s, 3H), 2.60 (t,
J=7.6 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H), 1.95-1.91 (m, 2H), 1.34 (s,
3H), 1.27-1.20 (m, 12H); Mass (M+H.sup.+)=570.3,
(M+NH.sub.4.sup.+)=587.3.
Step H: Preparation of
2-(4-{3-[1-(4-tert-Butylbenzyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]tria-
zol-3-yl]propyl}phenoxy)-2-methyl-3-phenyl-propionic acid
##STR00267##
[0639] A magnetically stirred solution of the Step G product (0.073
g, 0.13 mmol) in EtOH (1.3 mL) was treated with NaOH (5M aqueous
solution, 0.128 mL) and heated at reflux for 18 h. The reaction
mixture was acidified to pH=1 using 1M HCl, and cooled to rt. Ethyl
acetate was added (10 mL), layers were separated, and the aqueous
phase was back-extracted with EtOAc (3.times.10 mL). Combined
organic phases were dried over Na.sub.2SO.sub.4, and concentrated
to provide the product as a tacky solid (0.054 g, 77%). Mass
(M+H.sup.+) 542.2, (M-H--)=540.2.
Example 40
Compound 40
2-(4-{3-[1-(4-tert-Butylbenzyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]triaz-
ol-3-yl]propyl}phenoxy)-3-(4-fluorophenyl)-2-methylpropionic acid
ethyl ester
##STR00268##
[0640] Step A: Preparation of
2-(4-{3-[1-(4-tert-Butylbenzyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]tria-
zol-3-yl]propyl}phenoxy)-3-(4-fluorophenyl)-2-methylpropionic acid
ethyl ester
##STR00269##
[0641] A magnetically stirred solution of the
2-(4-{3-[1-(4-tert-butylbenzyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]tria-
zol-3-yl]propyl}phenoxy)propionic acid ethyl ester (Example 1, step
F)(0.119 g, 0.25 mmol) in THF (1.7 mL) was cooled to -78.degree. C.
under nitrogen. LHMDS (1M solution in THF, 0.31 mL) was added
dropwise via syringe, followed by syringe addition of a mixture of
4-fluorobenzyl bromide (0.173 g, 0.91 mmol) and tetrabutyl ammonium
iodide (10 mg, 0.03 mmol). The reaction proceeded for 1 h at
-78.degree. C., then for 4 h at -20.degree. C., and finally for 1 h
at rt. The reaction was quenched with saturated aqueous ammonium
chloride, and ethyl acetate was added. Layers were separated, and
the organic phase was washed with brine, dried over
Na.sub.2SO.sub.4, then concentrated. The product was purified by
column chromatography (30 g SiO.sub.2, 50% ethyl acetate in hexane)
providing the ethyl ester as an oil (0.051 g, 35%). 400 MHz .sup.1H
NMR (CDCl.sub.3) .delta. 7.34-7.22 (m, 8H), 7.00 (d, J=8.4 Hz, 2H),
6.74 (d, J=8.4 Hz, 2H), 4.88 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 3.28
(d, J=14.0 Hz, 2H), 3.14 (s, 3H), 3.12 (d, J=14.0 Hz, 2H), 2.61 (t,
J=7.6 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H), 1.95-1.91 (m, 2H), 1.28-1.22
(m, 18H).
Step B: Preparation of
2-(4-{3-[1-(4-tert-Butylbenzyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]tria-
zol-3-yl]propyl}-phenoxy)-3-(4-fluorophenyl)-2-methylpropionic
acid
##STR00270##
[0642] A magnetically stirred solution of the Step A product (54
mg, 0.09 mmol) in EtOH (0.9 mL) was treated with NaOH (5M aqueous
solution, 0.091 mL) and heated at reflux for 18 h. The reaction
mixture was acidified to pH=1 using 1M HCl, and cooled to rt. Ethyl
acetate was added (10 mL), layers were separated, and the aqueous
phase was back-extracted with EtOAc (3.times.10 mL). Combined
organic phases were dried over Na.sub.2SO.sub.4, and concentrated
to provide the product as a tacky solid (0.029 g, 57%). 400 MHz
.sup.1H NMR (DMSO-d.sup.6) .delta. 7.15 (d, J=8.0 Hz, 2H), 7.26 (d,
J=8.4 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 7.05
(d, J=8.4 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 4.76 (s, 2H), 3.08 (s,
2H), 2.53-2.45 (m, 4H), 1.82-1.78 (m, 2H), 1.25 (s, 3H), 1.22 (s,
9H); Mass (M+H.sup.+)=560.3, (M-H--)=558.3.
Example 41
Compound 41
2-Methyl-2-(4-{3-[4-methyl-5-oxo-1-(3-trifluoromethyl-benzyl)-4,5-dihydro--
1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-3-phenyl-propionic
acid
##STR00271##
[0643] Step A: Preparation of
4-Methyl-2-(3-trifluoromethyl-benzyl)-5-{3-[4-(3-trifluoromethyl-benzylox-
y)-phenyl]-propyl}-2,4-dihydro-[1,2,4]triazol-3-one
##STR00272##
[0644] To a solution of
5-[3-(4-hydroxyphenyl)propyl]-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one
(Example 1, step C) (0.350 g, 1.50 mmol) in DMF (5 mL), was added
3-trifluorobenzyl bromide (1.03 g, 4.29 mmol) followed by potassium
carbonate powder (0.74 g, 5.35 mmol). The mixture was stirred at rt
under nitrogen overnight. The reaction mixture was partitioned
between ethyl acetate (20 mL) and water (20 mL). The organic phase
was dried over MgSO.sub.4 and filtered. Evaporation of solvent gave
a crude product, which was purified on a silica gel column (125 mL
SiO.sub.2) eluting with 50% EtOAc/hexanes to give the titled
compound as colorless oil (0.675 g, 82%). 400 MHz .sup.1H NMR
(CDCl.sub.3) .delta. 7.70 (s, 1H), 7.63-7.42 (m, 7H), 7.08 (d,
J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 5.09 (s, 2H), 4.98 (s, 2H),
3.18 (s, 3H), 2.64 (t, J=7.2 Hz, 2H), 2.48 (t, J=7.6 Hz, 2H), 1.97
(quintet, J=7.6 Hz, 2H); Mass (M+H.sup.+)=550.3.
Step B: Preparation of
5-[3-(4-Hydroxy-phenyl)-propyl]-4-methyl-2-(3-trifluoromethyl-benzyl)-2,4-
-dihydro-[1,2,4]triazol-3-one
##STR00273##
[0645] To a solution of the Step A product (0.67 g, 1.22 mmol) in
EtOH (50 mL) was added 5% Pd/C (85 mg) and a hydrogen balloon. The
reaction was stirred for 18 h. After filtering away the catalyst on
celite, the filtrate was concentrated to produce the titled
compound (oil, 0.29 g, 60%). Mass (M+H.sup.+)=392.2.
Step C: Preparation of
2-Methyl-3-(4-{3-[4-methyl-5-oxo-1-(3-trifluoromethyl-benzyl)-4,5-dihydro-
-1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-propionic acid ethyl
ester
##STR00274##
[0646] To a solution of the Step B product (0.29 g, 0.74 mmol) in
DMF (3 mL) was added ethyl bromopropionate (0.27 g, 1.47 mmol, 0.19
mL) followed by powdered potassium carbonate (0.51 g, 3.7 mmol).
The reaction was stirred at rt overnight, then diluted with ethyl
acetate (20 mL) and washed with water (10 mL). The aqueous layer
was back-extracted with ethyl acetate (20 mL), then the combined
organics were dried over MgSO.sub.4 and concentrated. The product
was purified by column chromatography (100 mL SiO.sub.2, 50% ethyl
acetate in hexane to 100% ethyl acetate) providing the ethyl ester
as an oil (0.754 g, 80%). 400 MHz .sup.1H NMR (CDCl.sub.3) .delta.
7.57 (s, 1H), 7.51-7.49 (m, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.02 (d,
J=8.6 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 4.95 (s, 2H), 4.68 (q, J=7.2
Hz, 2H), 4.19 (q, J=7.2 Hz, 2H), 3.15 (s, 3H), 2.60 (t, J=7.6 Hz,
2H), 2.44 (t, J=7.2 Hz, 2H), 1.93 (quintet, J=7.6 Hz, 2H), 1.58 (d,
J=6.8 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H); Mass (M+H.sup.+)=492.1.
Step D: Preparation
2-Methyl-2-(4-{3-[4-methyl-5-oxo-1-(3-trifluoromethyl-benzyl)-4,5-dihydro-
-1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-3-phenyl-propionic acid
ethyl ester
##STR00275##
[0647] A magnetically stirred solution of the part C product (0.22
g, 0.45 mmol) in THF (2.8 mL) was cooled to -78.degree. C. under
nitrogen. LHMDS (1M solution in THF, 0.56 mL) was added dropwise
via syringe, followed by syringe addition of a mixture of benzyl
bromide (0.27 g, 1.6 mmol) and tetrabutyl ammonium iodide (16 mg,
0.045 mmol). The reaction proceeded for 1 h at -78.degree. C., then
for 4 h at -20.degree. C., and finally for 1 h at rt. The reaction
was quenched with saturated aqueous ammonium chloride, and ethyl
acetate was added. Layers were separated, and the organic phase was
washed with brine, dried over Na.sub.2SO.sub.4, then concentrated.
The product was purified by column chromatography (100 mL
SiO.sub.2, 15% EtOAc/hexanes to 70% EtOAc/hexanes) providing the
ethyl ester as an oil (23 mg, 9%). 400 MHz .sup.1H NMR (CDCl.sub.3)
.delta. 7.34-7.22 (m, 9H), 7.00 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.4
Hz, 2H), 4.97 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 3.28 (d, J=14.0 Hz,
2H), 3.14 (s, 3H), 3.12 (d, J=14.0 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H),
2.44 (t, J=7.6 Hz, 2H), 1.95-1.91 (m, 2H), 1.38 (s, 3H), 1.28 (s,
3H), 1.21 (t, J=7.2 Hz, 3H); Mass (M+H.sup.+)=582.4;
(M+NH.sub.4.sup.+)=599.4.
Step E: Preparation of
2-Methyl-2-(4-{3-[4-methyl-5-oxo-1-(3-trifluoromethyl-benzyl)-4,5-dihydro-
-1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-3-phenyl-propionic
acid
##STR00276##
[0648] A magnetically stirred solution of the Step D product (20
mg, 0.034 mmol) in EtOH (2 mL) was treated with NaOH (5M aqueous
solution, 40 .mu.L) and heated at reflux for 18 h. The reaction
mixture was acidified to pH=1 using 1M HCl, and cooled to rt. Ethyl
acetate was added (10 mL), layers were separated, and the aqueous
phase was back-extracted with EtOAc (3.times.10 mL). Combined
organic phases were dried over MgSO.sub.4, and concentrated to
provide the product as a tacky solid (10.3 mg, 54%). Mass
(M+H.sup.+)=554.3, (M-H--)=552.3.
Example 42
Compound 42
2-Methyl-2-(4-{3-[4-methyl-5-oxo-1-(3-phenoxybenzyl)-4,5-dihydro-1H-[1,2,4-
]triazol-3-yl]propyl}phenoxy)-3-phenylpropionic acid
##STR00277##
[0649] Step A: Preparation of
4-Methyl-2-(3-phenoxy-benzyl)-5-{3-[4-(3-phenoxy-benzyloxy)-phenyl]-propy-
l}-2,4-dihydro-[1,2,4]triazol-3-one
##STR00278##
[0650] To a solution of
5-[3-(4-hydroxyphenyl)propyl]-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one
(Example 1, step C) (0.350 g, 1.50 mmol) in DMF (5 mL), was added
3-phenoxybenzyl chloride (0.94 g, 4.29 mmol) followed by potassium
carbonate powder (0.74 g, 5.35 mmol). The mixture was stirred at rt
under nitrogen overnight. The reaction mixture was partitioned
between ethyl acetate (20 mL) and water (20 mL). The organic phase
was dried over MgSO.sub.4 and filtered. Evaporation of solvent gave
a crude product, which was purified on a silica gel column (125 mL
SiO.sub.2) eluting with 50% EtOAc/hexanes to give the titled
compound as colorless oil (0.0.78 g, 87%). 400 MHz .sup.1H NMR
(CDCl.sub.3) .delta. 7.32 (q, J=7.6 Hz, 4H), 7.30-7.25 (m, 3H),
7.20-6.90 (m, 10H), 6.97 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H),
5.01 (s, 2H), 4.91 (s, 2H), 3.16 (s, 3H), 2.63 (t, J=7.2 Hz, 2H),
2.46 (t, J=7.6 Hz, 2H), 1.94 (quintet, J=7.6 Hz, 2H); Mass
(M+H.sup.+)=598.4.
Step B: Preparation of
5-[3-(4-Hydroxy-phenyl)-propyl]-4-methyl-2-(3-phenoxy-benzyl)-2,4-dihydro-
-[1,2,4]triazol-3-one
##STR00279##
[0651] To a solution of the Step A product (0.78 g, 1.30 mmol) in
EtOH (10 mL) and EtOAc (2 mL) was added 5% Pd/C (85 mg) and a
hydrogen balloon. The reaction was stirred for 72 h. After
filtering away the catalyst on celite, the filtrate was
concentrated to produce the titled compound as a oil (0.138 g,
25%). Mass (M+H.sup.+)=416.1.
Step C: Preparation of
2-(4-{3-[4-Methyl-5-oxo-1-(3-phenoxybenzyl)-4,5-dihydro-1H-[1,2,4]triazol-
-3-yl]propyl}phenoxy)propionic acid ethyl ester
##STR00280##
[0652] To a solution of the Step B product (0.138 g, 0.33 mmol) in
DMF (1.3 mL) was added ethyl bromopropionate (0.120 g, 0.66 mmol)
followed by powdered potassium carbonate (0.23 g, 0.0017 mol). The
reaction was stirred at rt overnight, then diluted with ethyl
acetate (20 mL) and washed with water (10 mL). The aqueous layer
was back-extracted with ethyl acetate (20 mL), then the combined
organics were dried over Na.sub.2SO.sub.4 and concentrated. The
product was purified by column chromatography (20 g SiO.sub.2, 50%
ethyl acetate in hexane) providing the ethyl ester as an oil (0.144
g, 84%). 400 MHz .sup.1H NMR (CDCl.sub.3) .delta. 7.22-7.15 (m,
4H), 7.00-6.69 (m, 9H), 4.81 (s, 2H), 4.61 (q, J=6.8 Hz, 2H), 4.12
(q, J=7.2 Hz, 2H), 3.07 (s, 3H), 2.52 (t, J=7.2 Hz, 2H), 2.36 (t,
J=7.2 Hz, 2H), 1.86-1.82 (m, 2H), 1.51 (d, j=6.8 Hz, 3H), 1.16 (d,
J=7.2 Hz, 3H); Mass (M+H.sup.+)=516.3,
(M+NH.sub.4.sup.+)=533.3.
Step D: Preparation of
2-Methyl-2-(4-{3-[4-methyl-5-oxo-1-(3-phenoxybenzyl)-4,5-dihydro-1H-[1,2,-
4]triazol-3-yl]propyl}phenoxy)-3-phenylpropionic acid ethyl
ester
##STR00281##
[0653] A magnetically stirred solution of the Step C product (0.144
g, 0.00028 mol) in THF (2-mL) was cooled to -78.degree. C. under
nitrogen. LHMDS (1M solution in THF, 0.348 mL) was added dropwise
via syringe, followed by syringe addition of a mixture of benzyl
bromide (0.176 g, 0.00103 mol) and tetrabutyl ammonium iodide
(0.010 g, 0.00003 mol). The reaction proceeded for 1 h at
-78.degree. C., then for 4 h at -20.degree. C., and finally for 1 h
at rt. The reaction was quenched with saturated aqueous ammonium
chloride, and ethyl acetate was added. Layers were separated, and
the organic phase was washed with brine, dried over
Na.sub.2SO.sub.4, then concentrated. The product was purified by
column chromatography (50 g Sio.sub.2, 50% ethyl acetate in hexane)
providing the ethyl ester as an oil (0.146 g, 87%). 400 MHz .sup.1H
NMR (CDCl.sub.3) .delta. 7.31-7.24 (m, 8H), 7.09-6.74 (m, 10H),
4.90 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 3.30-3.15 (m, 5H), 2.60 (t,
J=7.2 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H), 1.94-1.91 (m, 2H), 1.38 (s,
3H), 1.27-1.20 (m, 3H); Mass (M+H.sup.+)=606.2,
(M+NH.sub.4.sup.+)=623.2.
Step E: Preparation of
2-Methyl-2-(4-{3-[4-methyl-5-oxo-1-(3-phenoxybenzyl)-4,5-dihydro-1H-[1,2,-
4]triazol-3-yl]propyl}phenoxy)-3-phenylpropionic acid
##STR00282##
[0654] A magnetically stirred solution of the Step D product (0.120
g, 0.00020 mol) in EtOH (2.0 mL) was treated with NaOH (5M aqueous
solution, 0.198 mL) and heated at reflux for 48 h. The reaction
mixture was acidified to pH=1 using 1M HCl, and cooled to rt. Ethyl
acetate was added (10 mL), layers were separated, and the aqueous
phase was back-extracted with EtOAc (3.times.10 mL). Combined
organic phases were dried over Na.sub.2SO.sub.4, and concentrated
to provide the product as a tacky solid (0.097 g, 85%). 400 MHz
.sup.1H NMR (DMSO-d.sup.6) .delta. 7.38-7.24 (m, 8H), 7.14-6.73 (m,
10H), 4.81 (s, 2H), 3.25-3.07 (m, 5H), 2.52 (m, 4H), 1.82-1.76 (m,
2H), 1.26 (s, 3H); Mass (M+H.sup.+)=578.3, (M-H--)=576.3.
[0655] Additional compounds of the present invention, having the
structural formula shown below, were synthesized by methods similar
to those described in the previous examples.
##STR00283##
[0656] These additional compounds are further exemplified in the
following table.
TABLE-US-00037 TABLE I Example Number R4 R3 R2 R20 R21 R22 43 CH3
CH3 propyl OH H H 44 CH3 CH3 butyl H H OCH3 45 CH3 CH3 CH3 H H OCH3
46 CH3 CH3 propyl H NO2 H 47 CH3 CH3 ethyl H H OCH3 48 ethyl CH3
propyl H CH3 H 49 benzyl CH3 propyl H CH3 H 50 H H propyl CH3 CH3 H
51 CH3 H propyl CH3 CH3 H 52 ethyl H propyl CH3 CH3 H 53 isopropyl
H propyl CH3 CH3 H 54 F F propyl CH3 CH3 H 55 cyclohexyl H propyl
CH3 CH3 H 56 phenyl H propyl CH3 CH3 H 57 2-hydroxy H propyl CH3
CH3 H ethyl 58 F H propyl CH3 CH3 H 59 butyl H propyl CH3 CH3 H 60
pentyl H propyl CH3 CH3 H 61 H H propyl H t-butyl H 62 CH3 H propyl
H t-butyl H 63 ethyl H propyl H t-butyl H 64 isopropyl H propyl H
t-butyl H 65 F F propyl H t-butyl H 66 cyclohexyl H propyl H
t-butyl H 67 phenyl H propyl H t-butyl H 68 2-hydroxy H propyl H
t-butyl H ethyl 69 butyl H propyl H t-butyl H 70 pentyl H propyl H
t-butyl H 71 CH3 CH3 2-methoxy CH3 CH3 H ethyl 72 H H ethyl H CH3 H
73 CH3 H ethyl H CH3 H 74 ethyl H ethyl H CH3 H 75 isopropyl H
ethyl H CH3 H 76 cyclohexyl H ethyl H CH3 H 77 phenyl H ethyl H CH3
H 78 CH3 CH3 t-butyl CH3 CH3 H 79 CH3 CH3 i-propyl CH3 CH3 H 80 CH3
CH3 H H H Cl 81 CH3 CH3 H CF3 H CF3 82 CH3 CH3 H H Cl Cl 83 CH3 CH3
H H F F 84 OCH3 H propyl H t-butyl H 85 CH3 CH3 H H t-amyl H 86 CH3
CH3 H H CF3 H 87 CH3 CH3 H H OCF3 H 88 CH3 CH3 H H CF3 F 89 CH3 CH3
2-phenoxy CH3 CH3 H ethyl 90 CH3 CH3 cyclo- CH3 CH3 H propyl-
methyl 91 CH3 CH3 propyl H amino H 92 CH3 CH3 2,4- H CH3 H
dimethoxy- benzyl 93 CH3 CH3 2,4- CH3 H CH3 dimethoxy- benzyl 94
CH3 CH3 2,4- H t-butyl H dimethoxy- benzyl 95 CH3 CH3 2,4- H H
phenoxy dimethoxy- benzyl 96 CH3 CH3 2,4- H H CH3 dimethoxy- benzyl
97 CH3 CH3 2,4- H H CF3 dimethoxy- benzyl 98 CH3 CH3 2,4- CH3 CH3 H
dimethoxy- benzyl 99 CH3 CH3 2,4,6- H CH3 H trimethoxy- benzyl
[0657] Other compounds of the present invention, having the
structural formula shown below, were also synthesized by methods
similar to those described in the previous examples.
TABLE-US-00038 ##STR00284## Example R2 R20 R21 R22 100 propyl CH3
CH3 H 101 propyl H t-butyl H 102 ethyl H CH3 H 103 methyl H CH3
H
TABLE-US-00039 ##STR00285## Example E Y X R1 R2 104 2(2-methyl) 0
butylene 4-methyl ethyl propanoic benzyl acid 105 2(2-methyl) 0
butylene 4-methyl propyl propanoic benzyl acid 106 ethanoic 0
propylene phenyl propyl acid 107 2(2-methyl) 0 propylene phenyl
propyl propanoic acid 108 2(2-methyl) 0 propylene .beta.-naphthyl
CH3 propanoic methyl acid 109 2(2- 0 proplyene 4-t-butyl propyl
tetrazole) benzyl ethyl 110 2(2-methyl) 0 ethylene 3-methoxy hexyl
propanoic benzyl acid 111 COOH -- propylene 4-t-butyl ethyl benzyl
112 2(2-methyl- 0 propylene 3,4- CH3 3- dimethoxy tetrazole) benzyl
ethyl
TABLE-US-00040 ##STR00286## Example R4 X R2 R21 113 CH3 propylene
CH3 t-butyl 114 benzyl propylene CH3 t-butyl 115 CH3 butylene
propyl methyl
Example 116
##STR00287##
[0658] (3-methoxyphenyl)methylenehydrazinecarboxylic Acid,
1,1-dimethylethyl Ester
[0659] To a solution of t-butyl carbazate (5.59 g, 42.3 mmol) in
ethyl acetate (15 mL) was added with stirring m-anisaldehyde (5.17
mL, 5.76 g, 42.3 mmol). Hexanes (70 mL) was added slowly and
crystallization occurred. The resulting slurry was stirred at rt
for 45 min and then cooled to 0.degree. C. The slurry was stirred
at 0.degree. C. for 60 min, then filtered and rinsed with cold
hexanes (20 mL), and dried in vacuo at 40.degree. C. to afford the
title compound as a solid (9.68 g, 91.4%): mp 135.6-137.4.degree.
C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 10.93 (s, 1H), 7.29 (t, 1H,
J=8 Hz), 7.14 (d, 2H, J=7 Hz), 6.92 (q, 1H, J=7 Hz), 3.75 (s, 3H),
1.45 (s, 9H); .sup.13C NMR (DMSO-d.sub.6) .delta. 160.2, 153.1,
143.7, 136.8, 130.5, 120.0, 116.2, 111.3, 80.1, 55.7, 28.7; IR (KBr
mull): 3360, 3010, 2982, 2838, 1510, 1487 cm.sup.-1; A portion was
recrystallized from ethyl acetate and submitted for elemental
analysis. Anal. Calcd. for C.sub.13H.sub.18N.sub.2O.sub.3: C,
62.38; H, 7.25; N, 11.19. Found: C, 62.34; H, 7.46; N, 11.19.
##STR00288##
(3-methoxybenzyl)hydrazinecarboxylic acid, 1,1-dimethylethyl ester
(3-methoxyphenyl)methylenehydrazinecarboxilic Acid,
1,1-dimethylethyl Ester
[0660] (7.03 g, 28.1 mmol) and Pt/C (5%, dry, 5.07 g) were slurried
in THF (80 mL) and hydrogenated at rt and 50 psig for 8 hr. The
slurry was then filtered through celite and concentrated in vacuo
at 50.degree. C. to afford the title compound as a clear oil (6.68
g, 94.0%): .sup.1H NMR (DMSO-d.sub.6) .delta. 8.22 (s, 1H), 7.19
(t, 1H, J=8 Hz), 6.85 (d, 1H, J=7 Hz), 6.77 (d, 1H, J=7 Hz), 3.84
(s, 2H), 3.72 (s, 3H), 1.37 (s, 9H); .sup.13C NMR (DMSO-d.sub.6)
.delta. 159.9, 157.1, 141.1, 129.7, 121.1, 114.1, 113.1, 78.9,
55.5, 54.9, 28.9; IR (CHCl.sub.3): 3008, 2982, 2935, 1712
cm.sup.-1; Exact Mass: Calc'd. m/z for
C.sub.13H.sub.20N.sub.2O.sub.3Na: 275.1372, Found: 275.1381.
##STR00289##
3-(aminocarbonyl)-2-(3-methoxyphenylmethyl)hydrazine carboxylic
Acid, 1,1-dimethylethyl Ester
[0661] (3-methoxybenzyl) hydrazinecarboxilic acid,
1,1-dimethylethyl ester (6.30 g, 25.0 mmol) was dissolved in
isopropyl alcohol (IPA, 65 mL). Trimethylsilyl isocyanate (4.73 g,
34.9 mmol) was added in one portion via syringe and the solution
was allowed to stir at ambient temperature for 7 h. The slurry was
cooled to 0-5.degree. C., filtered, and the solids rinsed with cold
IPA. The solids were dried in vacuo at 40.degree. C. overnight to
afford the title compound as a white solid (4.71 g, 63.9%). The
filtrate was concentrated and purified by column chromatography
(SiO.sub.2, EtOAc) to afford additional compound (0.91 g, 12.3%).
These two portions were combined to yield 5.82 g (76.2%) of the
title compound: mp 136.3-138.5.degree. C.; .sup.1H NMR
(DMSO-d.sub.6, 60.degree. C.) .delta. 8.70 (s, 1H), 7.20 (t, 1H,
J=8 Hz), 6.80 (m, 3H), 5.90 (s, 2H), 4.50 (s, 2H), 3.74 (s, 3H),
1.36 (s, 9H); .sup.13C NMR (DMSO-d.sub.6, 20.degree. C.) .delta.
159.9, 159.6, 155.0, 140.2, 129.8, 120.9, 114.0, 113.2, 80.2, 55.6,
51.1, 28.7; IR (CHCl.sub.3): 3003, 2984, 2938, 1745, 1680
cm.sup.-1; Anal. Calcd. for C.sub.14H.sub.21N.sub.3O.sub.4: C,
56.94; H, 7.17; N, 14.23. Found: C, 56.54; H, 7.17; N, 13.98.
##STR00290##
1-(3-methoxyphenylmethyl)hydrazine Carboxamide Methanesulfonate
[0662] 3-(aminocarbonyl)-2-(3-methoxyphenylmethyl)hydrazine
carboxylic acid, 1,1-dimethylethyl ester (5.30 g, 17.9 mmol) was
dissolved in dichloromethane (60 mL). Methanesulfonic acid (1.93 g,
19.9 mmol) was added in one portion and the solution was allowed to
stir at rt overnight. The resulting slurry was cooled to
0-5.degree. C., filtered, and the solids rinsed with cold
dichloromethane. The solids were dried in vacuo at 40.degree. C.
overnight to afford the title compound as a white solid (5.05 g,
96.6%). mp 130.3-132.1.degree. C.; .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.7 (broad s, 3H), 7.30 (t, 1H, J=8 Hz), 7.05 (broad s,
2H), 6.88 (s, 3H), 4.69 (s, 2H), 3.74 (s, 3H), 3.34 (s, 3H);
.sup.13C NMR (DMSO-d.sub.6) .delta. 160.1, 158.2, 137.3, 130.5,
120.7, 114.3, 114.0, 55.7, 52.7, 40.4; IR (KBr mull): 3186, 2939,
1719, 1707, 1168 cm.sup.-1; Anal. Calcd. for
C.sub.9H.sub.13N.sub.3O.sub.2: C, 41.23; H, 5.88; N, 14.42. Found:
C, 40.86; H, 5.92; N, 14.61.
##STR00291##
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(3-methoxyphen-
ylmethyl)semicarbazide
[0663] 4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)-phenyl]butyric acid
(4.86 g, 16.5 mmol) was dissolved in ethyl acetate (40 mL). Oxalyl
chloride (2.43 g, 19.14 mmol) was added to this solution dropwise
in the presence of a catalytic amount of N,N-dimethylformamide (100
mg, 1.37 mmol). Completion of acid chloride formation was verified
by HPLC. This solution was then added dropwise to a suspension of
1-(3-methoxyphenylmethyl)hydrazine carboxamide methanesulfonate
(4.80 g, 16.5 mmol) and pyridine (1.30 g, 16.5 mmol) in ethyl
acetate (55 mL) at 0-5.degree. C. After stirring at 0-5.degree. C.
for 6 h, an additional charge of pyridine was added (1.30 g, 16.5
mmol) and the solution was stirred at 0-5.degree. C. for 1 h at
which time the reaction was complete. The solution was warmed to rt
and washed twice with 1N HCl (80 mL) and twice with 5% aq.
NaHCO.sub.3 (80 mL). The organic layer was dried (MgSO.sub.4),
filtered and concentrated to a waxy solid. The solids were
recrystallized from a mixture of toluene (17 mL) and n-heptane (7
mL) at 60.degree. C., cooled to 0-5.degree. C. and filtered. The
solids were dried in vacuo at 40.degree. C. overnight, affording
the title compound as a white solid (5.05 g, 65%): .sup.1H NMR
(DMSO-d.sub.6, 60.degree. C.) .delta. 9.60 (s, 1H), 7.19 (t, 1H,
J=8 Hz), 7.00 (d, 2H), 6.80 (m, 3H), 6.71 (d, 2 H, J=8 Hz), 5.92
(s, 2H), 4.52 (s, 2H), 4.15 (q, J=7 Hz), 3.71 (s, 3H), 2.45 (t, 2H,
J=7 Hz), 2.07 (t, 2H, J=7 Hz), 1.73 (quint, 2H, J=7 Hz), 1.48 (s,
6H), 1.17 (t, 3H, J=7 Hz); .sup.13C NMR (DMSO-d.sub.6) .delta.
174.0, 171.9, 159.9, 159.3, 153.7, 140.5, 135.9, 129.9, 129.7,
120.9, 119.4, 114.1, 113.1, 79.2, 61.6, 55.5, 50.9, 34.3, 33.4,
27.2, 25.7, 14.6; IR (KBr mull): 3450, 3320, 3275, 3202, 2997,
2940, 1730, 1646, 1511 cm.sup.-3; Anal. Calcd. for
C.sub.25H.sub.33N.sub.3O.sub.6: C, 63.68; H, 7.05; N, 8.91. Found:
63.49; H, 7.02; N, 8.99.
##STR00292##
2-(4-{3-[-(3-Methoxy-benzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-pr-
opyl}-phenoxy)-2-methyl-propionic Acid Ethyl Ester
[0664]
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(3-metho-
xyphenylmethyl)semicarbazide (4.08 g, 8.65 mmol) was dissolved in
ethyl acetate (7.5 mL). IS (+)-10-camphorsulfonic acid (2.21 g,
9.51 mmol) was added in one portion and the solution was heated to
reflux overnight. The solution was cooled to rt and washed with
sat'd aq. NaHCO.sub.3 (40 mL.times.2) followed by 1N HCl (40
mL.times.2). The organic was concentrated to an orange oil. This
oil was redissolved in ethyl acetate (40 mL). Amberlyst-15 resin
(4.41 g) was added and the mixture was heated to 50.degree. C. and
stirred for 4 hours to remove de-ureated impurity. The mixture was
then cooled to ambient temperature, filtered, concentrated, and
purified by column chromatography (SiO.sub.2, 9:1 ethyl
acetate:hexanes) to afford the title compound as an orange oil
(1.93 g, 49.2%). .sup.1H NMR (DMSO-d.sub.6) .delta. 11.47 (s, 1H),
7.22 (t, 1H, J=8 Hz), 7.04 (d, 2H, J=8 Hz), 6.82 (d, 1H, J=2 Hz),
6.76 (m, 2H), 6.68 (d, 2H, J=2 Hz), 4.73 (s, 2H), 4.13 (q, 2H, J=7
Hz), 3.69 (s, 3H), 2.48 (t, 2H, J=8 Hz), 2.36 (t, 2H, J=8 Hz), 1.80
(quint, 2H, J=7 Hz), 1.47 (s, 6H), 1.14 (t, 3H, J=7 Hz); .sup.13C
NMR (DMSO-d.sub.6) .delta. 174.0, 160.0, 155.0, 153.8, 146.7,
139.8, 135.5, 130.2, 129.8, 120.1, 119.5, 113.8, 113.2, 79.2, 61.6,
55.6, 47.8, 34.0, 28.4, 26.2, 25.7, 14.6; IR (CHCl.sub.3) 2940,
1692, 1508, 1467 cm.sup.-1; Anal. Calcd. for
C.sub.25H.sub.31N.sub.3O.sub.5: C, 66.21; H, 6.89; N, 9.26. Found:
C, 66.29; H, 6.75; N, 9.19.
##STR00293##
2-(4-(3-[1-(3-Methoxy-benzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-p-
ropyl)-phenoxy)-2-methyl-propionic Acid
[0665]
2-(4-{3-[1-(3-Methoxy-benzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-
-yl]-propyl}-phenoxy)-2-methyl-propionic acid ethyl ester (1.55 g,
3.42 mmol) was dissolved in a mixture of ethanol (7.5 mL) and
deionized water (7.5 mL). Solid sodium hydroxide (0.36 g, 8.73
mmol) was added in one portion and the solution was warmed to
70.degree. C. and stirred for one hour. The solution was cooled to
ambient temperature and the pH adjusted to 7 with 6N HCl. The
solution was concentrated to a hazy yellow oil. This oil was
partitioned between 1N HCl (10 mL) and ethyl acetate (15 mL). The
aqueous layer was then re-extracted with ethyl acetate (15 mL) and
the organic layers combined, dried (MgSO.sub.4), filtered and
concentrated in vacuo at 50.degree. C. overnight to afford the
title compound as a clear oil (1.41 g, 97.0%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 13.0 (broad s, 1H), 11.47 (s, 1H), 7.23 (t,
1H, J=8 Hz), 7.03 (d, 2H, J=8 Hz), 6.82 (d, 1H, J=2 Hz), 6.75 (m,
5H), 4.73 (s, 2H), 3.70 (s, 3H), 3.35 (broad s, 1H), 2.48 (t, 2H,
J=8 Hz), 2.36 (t, 2H, J=8 Hz), 1.80 (quint, 2H, J=7 Hz), 1.46 (s,
6H); .sup.13C NMR (DMSO-d.sub.6, 20.degree. C.) .delta. 175.8,
160.0, 155.0, 154.1, 146.8, 139.8, 135.0, 130.3, 129.7, 120.1,
119.1, 113.8, 113.2, 78.9, 55.6, 47.8, 40.6, 40.5, 34.0, 28.4,
27.5, 26.2, 25.7; IR (CHCl.sub.3) 1707, 1603, 1509, 1159 cm.sup.-1;
Anal. Calcd. for C.sub.23H.sub.27N.sub.3O.sub.5: C, 64.93; H, 6.40;
N, 9.88. Found: C, 65.02; H, 6.65; N, 9.57.
Example 117
##STR00294##
[0666] Step A:
##STR00295##
[0668] A methanol solution of methyl 4-methoxyphenylacetate
(Aldrich, 10.0 g, 0.056 mol) and hydrazine hydrate (EM Sciences,
27.8 g, 0.556 mol) was stirred at ambient temperature overnight.
The resulting solution was concentrated, added to water and
extracted with ethyl acetate (2.times.). The organic layers were
combined and washed with aqueous brine then dried over sodium
sulfate. Evaporation of the solvent gives a solid product which is
washed with hexanes/ether and filtered to give the desired acyl
hydrazide as a white solid.
[0669] C.sub.9H.sub.12O.sub.2N.sub.2 (MW=180.21); mass spectroscopy
(MH.sup.+)=181.0
Step B:
##STR00296##
[0671] A tetrahydrofuran solution (150 mL) of the acyl hydrazide
from Step A (8.0 g, 0.044 mol) was treated with propyl isocyanate
(Aldrich, 1.2 g, 0.014 mol) and stirred at room temperature
overnight, during which a precipitate forms. The resulting
suspension was treated with methanol (20 ml) and stirred for an
additional 30 minutes. Hexane was then added and the mixture was
filtered to give the desired acyl semicarbazide as a white solid
which was used without further purification.
[0672] C.sub.13H.sub.19N.sub.3O.sub.3 (MW=265.31)
Step C:
##STR00297##
[0674] A methanol solution (150 mL) of the acyl semicarbazide from
Step B (10.0 g, 0.038 mol) was stirred and treated with solid
potassium hydroxide (21.1 g, 0.377 mol). The mixture was heated at
60.degree. C. for 24 hrs then cooled to ambient temperature and
stirred for 48 hrs. The solvent was reduced to about 75 ml, added
to water, acidified to pH 6 with conc. HCl and extracted with ethyl
acetate (3.times.). The organic layers were combined, washed with
aqueous brine and dried over sodium sulfate. Evaporation of the
solvent gives a solid that was washed with hexane/ether to give the
desired N4-propyl triazolinone as a white solid.
[0675] C.sub.13H.sub.17N.sub.3O.sub.2 (MW 247.30); mass
spectroscopy (MH.sup.+)=248.1
Step D:
##STR00298##
[0677] The N4-propyl triazolinone from Step C (7.0 g, 0.028 mol) is
dissolved in DMF (75 mL) and treated with chloro-p-xylene (Aldrich,
6.0 g, 0.043 mol) and powdered potassium carbonate (Aldrich, 15.6
g, 0.113 mol). The resulting mixture was heated to 60.degree. C.
overnight. The cooled reaction mixture was added to aqueous HCl
(1N, 200 mL) and extracted with ethyl acetate (3.times.). The
combined organic layers were washed with aqueous brine, dried over
sodium sulfate and concentrated to give the crude product as an
oil. Purification by flash chromatography (gradient: 100% hexanes
to 2:1 hexanes:ethyl acetate) gives the desired N2-p-methylbenzyl
triazolinone.
[0678] C.sub.21H.sub.25N.sub.3O.sub.2 (MW=351.45); mass
spectroscopy (MH+)=352.2
Step E:
##STR00299##
[0680] The N2-p-methylbenzyl triazolinone from Step D (1.5 g, 0.004
mol) was dissolved in methylene chloride (25 mL) and cooled under a
drying tube. A solution of boron tribromide (3.1 g, 1.2 mL, 0.013
mol) was added dropwise. The reaction mixture was then allowed to
warm to ambient temperature and stirred for 2 hrs. The reaction was
quenched by the dropwise addition of methanol (5 mL), added to
water and extracted with methylene chloride (2.times.). The organic
layers were combined, dried over sodium sulfate and concentrated to
give the desired phenol as an oil which is used without
purification.
[0681] C.sub.20H.sub.23N.sub.3O.sub.2 (MW=337.4); mass spectroscopy
(MH.sup.+)=338.3
Step F:
##STR00300##
[0683] The phenol from Step E (1.3 g, 0.004 mol) was dissolved in
ethanol (50 mL) and treated with ethyl 2-bromoisobutyrate (Aldrich,
2.3 g, 1.7 mL, 0.012 mol), powdered potassium carbonate (Aldrich,
2.2 g, 0.016 mol) and magnesium sulfate (0.6 g, 0.005 mol). The
resulting mixture was stirred and heated to 55.degree. C., under a
drying tube, overnight. The cooled reaction mixture was added to
HCl (5N. 70 ml) and extracted with ethyl acetate (2.times.). The
combined organic layers were dried over sodium sulfate and
concentrated to give the crude product. Purification by flash
chromatography (gradient: 100% hexanes to 3:2 ethyl
acetate:hexanes) gives the desired ethyl ester.
C.sub.26H.sub.33N.sub.3O.sub.4 (MW=451.6); mass spectroscopy
(MH.sup.+)=452.3
Step G:
##STR00301##
[0685] The ethyl ester from Step F (0.8 g, 0.002 mol) was dissolved
in methanol (12 mL) and sodium hydroxide (2N, 3.0 ml, 0.006 mol)
added. The resulting mixture was stirred at ambient temperature
overnight. The reaction mixture was added to HCl (5N, 15 ml) and
extracted with ethyl acetate (2.times.). The organic layers were
combined, dried over sodium sulfate and concentrated to give the
crude product. Purification by flash chromatography (gradient: 100%
hexanes to 1:1 ethyl acetate/hexane then 10% methanol in
ethylacetate) gives the desired carboxylic acid as a white
foam.
[0686] C.sub.24H.sub.29N.sub.3O.sub.4 (MW=423.5); mass spectroscopy
(MH.sup.+)=424.3; (MH.sup.+)=422.1
##STR00302##
Example 118
2-(n-Propylaminocarbonyl)-2-(4-methylphenylmethyl)hydrazine
Carboxylic Acid, 1,1-dimethylethyl Ester
[0687] 4-Methylphenylmethyl hydrazine carboxylic acid,
1,1-dimethylethyl ester (5.02 g, 21.2 mmol) was dissolved in
isopropanol (50 mL). Propyl isocyanate (2.71 g, 31.9 mmol) was
added in one portion via syringe and the solution was allowed to
stir at ambient temperature for 1 h. The solution was concentrated
to a clear yellow oil, and purified by column chromatography
(SiO.sub.2, 2:3 ethyl acetate:hexanes) to afford the title compound
as a white solid (5.58 g, 82%): mp 87.8-89.4.degree. C.; .sup.1H
NMR (DMSO-d.sub.6, 60.degree. C.) .delta. 8.45 (s, 1H), 7.10 (d-d,
4H, J=8.2 Hz), 6.21 (s, 1H), 4.43 (s, 1H), 3.01 (q, 2H, J=6.4 Hz),
2.27 (s, 3H), 1.41 (sext., 2H, J=7.3 Hz), 1.35 (s, 9H), 0.82 (t,
3H, J=7.4 Hz); .sup.13C NMR (DMSO-d.sub.6, 20.degree. C.) .delta.
158.6, 155.1, 136.6, 135.5, 129.3, 129.0, 80.2, 51.0, 42.2, 28.6,
23.7, 21.4, 11.8; Anal. Calcd. for C.sub.17H.sub.27N.sub.3O.sub.3:
C, 63.53; H, 8.47; N, 13.07.
##STR00303##
N-Propyl-1-(4-methylphenylmethyl)hydrazinecarboxamide
Methanesulfonate
[0688] To a solution of
2-(propylaminocarbonyl)-2-(4-methylphenylmethyl)hydrazinecarboxylic
acid, 1,1-dimethylethyl ester (3.0204 g, 9.397 mmol) in
dichloromethane (25 mL) was added methanesulfonic acid (762 .mu.L,
11.7 mmol) and the mixture stirred for 21 h. The mixture was then
concentrated in vacuo to an oil and recrystallized (ethyl acetate)
to afford the title compound as a white solid (2.0639 g, 6.502
mmol, 69%): mp 108.5-111.4.degree. C.; .sup.1H NMR (DMSO-d.sub.6)
.delta. 7.56 (s, 1H), 7.18 (s, 4H), 4.67 (s, 2H), 3.06 (t, 2H,
J=7.0 Hz), 2.35 (s, 3H), 2.81 (s, 3H), 1.44 (m, 2H), 0.82 (t, 3H,
J=7.5 Hz); .sup.13C NMR (DMSO-d.sub.6) .delta. 157.7, 138.0, 132.5,
129.9, 128.8, 52.7, 42.7, 40.6, 23.3, 21.4, 11.9; IR (CHCl.sub.3)
3416, 3009, 2967, 2936, 2877, 1691, 1543 cm.sup.-1. Anal. Calcd.
for C.sub.12H.sub.19N.sub.3O.CH.sub.4O.sub.3S: C, 49.19; H, 7.30;
N, 13.24. Found: C, 48.87; H, 7.32; N, 13.28.
##STR00304##
1-[(4-Methoxyphenyl)butyryl]-2-(4-methylphenylmethyl)-4-propyl)semicarbaz-
ide
[0689] To a solution of 4-(4-methoxyphenyl)butyric acid (2.0207 g,
10.42 mmol) and N,N-dimethylformamide (2 drops) in ethyl acetate
(25 mL) was added dropwise over 5 min oxalyl chloride (1.13 mL,
13.02 mmol). The resulting mixture was stirred for 30 min and then
concentrated in vacuo to remove excess oxalyl chloride. The
resulting oil was redissolved in ethyl acetate (15 mL) and then
added in one portion to a solution of
N-Propyl-2-(4-methylphenylmethyl)hydrazinecarboxamide
methanesulfonate (3.1578 g, 9.95 mmol,) and pyridine (2 mL, 24
mmol) in ethyl acetate (10 mL) at 0-5.degree. C. The reaction was
stirred for 1 hour at room temperature, then washed with 1N HCl
(2.times.50 mL), saturated aq. NaHCO.sub.3 (2.times.50 mL), and
saturated aq. NaCl (25 mL). The organic layer was dried
(MgSO.sub.4), filtered, concentrated and purified by silica gel
chromatography (3:1 ethyl acetate:hexanes) to afford the title
compound as a white solid (3.76 g, 9.47 mmol, 95%): mp
86.5-88.2.degree. C.; .sup.1H NMR (DMSO-d.sub.6, 60.degree. C.)
.delta. 9.45 (s, 1H), 7.10 (m, 4H), 6.92 (AB, 4H, J=8.0 Hz), 6.25
(s, 1H), 4.50 (s, 1H), 3.71 (2, 3H), 2.99 (m, 2H), 2.45 (t, 2H,
J=8.0 Hz), 2.26 (s, 3H), 2.06 (t, 2H, J=7.5 Hz), 1.72 (t, 2H, J=7.5
Hz), 1.40 (m, 2H), 0.81 (t, 3H, J=8.0 Hz); .sup.13C NMR
(DMSO-d.sub.6) .delta. 172.0, 158.2, 158.1, 136.7, 135.8, 134.1,
129.9, 129.4, 128.9, 114.3, 55.6, 50.8, 42.3, 34.3, 33.4, 27.3,
23.7, 21.4, 11.9; IR (CHCl.sub.3) 3456, 2996, 2963, 2936, 2876,
1708, 1669 cm.sup.-1. Anal. Calcd. for
C.sub.23H.sub.31N.sub.3O.sub.3: C, 69.49; H, 7.86; N, 10.57. Found:
C, 69.36; H, 7.71; N, 10.54.
##STR00305##
5-[3-(4-Methoxyphenyl)-propyl]-2-(4-methylbenzyl)-4-propyl-2,4-dihydro[1,-
2,4]tria-zol-3-one
[0690] To a solution of
1-[(4-methoxyphenyl)butyryl]-2-(4-methylphenylmethyl)-4-propyl)semicarbaz-
ide (1.24 g, 3.12 mmol) in ethyl acetate (25 mL) was added
camphorsulfonic acid (0.80 g, 3.43 mmol) and the resulting mixture
stirred at reflux for 2 hours. The organic layer was washed with
saturated aq. NaHCO.sub.3 (2.times.25 mL) and 1 N HCl (2.times.25
mL) followed by saturated aq. NaCl (25 mL). The organic layer was
then dried (MgSO.sub.4), filtered, and concentrated to afford the
title compound as an oil (1.14 g, 3.00 mmol, 96%): .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.10 (S, 4H), 7.06 (d, 2H, J=8.5 Hz), 6.81
(q, 2H, J=5.0 Hz), 4.77 (s, 2H), 3.69 (s, 3H), 3.46 (t, 2H, J=7.5
Hz), 2.54 (t, 2H, J=7.5 Hz), 2.47 (t, 2H, J=7.5 Hz), 2.23, (s, 3H),
1.82 (m, 2H), 1.52 (m, 2H), 0.79 (t, 3H, J=7.5 Hz); .sup.13C NMR
(DMSO-d.sub.6) .delta. 158.2, 154.1, 146.8, 137.2, 135.1, 133.9,
129.9, 129.7, 128.1, 114.4, 55.6, 48.3, 42.8, 34.0, 28.1, 24.8,
22.5, 21.3, 11.5; IR (CHCl.sub.3) 1691, 1513, 1465, 1247, 1225
cm.sup.-1. Anal. Calcd. for C.sub.23H.sub.29N.sub.3O.sub.2: C,
72.79; H, 7.70; N, 11.07. Found: C, 72.82; H, 7.87; N, 11.11.
##STR00306##
Example 119
5-[3-(4-Hydroxyphenyl)-propyl]-2-(4-methylbenzyl)-4-propyl-2,4-dihydro-[1,-
2,4]triazol-3-one
[0691]
5-[3-(4-Methoxyphenyl)-propyl]-2-(4-methylbenzyl)-4-propyl-2,4-dihy-
dro[1,2,4]triazol-3-one (0.770 g, 2.03 mmol) and excess pyridine
hydrochloride were melted together for 2 hours with stirring at
180.degree. C. After cooling to room temperature, the contents were
diluted in ethyl acetate (50 mL) and water (50 mL). The aqueous
layer was extracted with ethyl acetate (2.times.25 mL). The
combined organics were washed with 5 N HCl (50 mL), saturated aq.
NaCl (25 mL), dried (MgSO.sub.4), filtered and concentrated to
afford the title compound as a yellow oil (0.670 g, 1.83 mmol,
90%): .sup.1H NMR (DMSO-d.sub.6) .delta. 9.13 (s, 1H), 7.10 (q, 4H,
J=3.0 Hz), 6.79 (AB, 4H, J=8.5 Hz), 4.77 (s, 2H), 2.5 (t, 2H, J=7.5
Hz), 2.46 (t, 2H, J=7.5 Hz), 2.24 (s, 3H), 1.79 (m, 2H), 1.51 (m,
2H), 0.79 (t, 3H, J=7.5 Hz); .sup.13C NMR (DMSO-d.sub.6) .delta.
156.1, 154.1, 146.8, 137.2, 135.1, 132.1, 129.9, 129.7, 128.1,
115.7, 48.3, 42.8, 34.1, 28.2, 24.7, 22.5, 21.3, 11.5; IR
(CHCl.sub.3) 3007, 2937, 1690, 1515, 1463 cm.sup.-1. Exact Mass
Calcd. for C.sub.22H.sub.28N.sub.3O.sub.2: 366.2182. Found:
366.2191.
Example 120
##STR00307##
[0692]
2-Methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4-propyl-4,5-dihydro-1H--
[1,2,4]triazol-3-yl]-propyl}-phenoxy)-propionic Acid Ethyl
Ester
[0693] To a mixture of sodium ethoxide (1.22 mL, 3.28 mmol) and
ethyl acetate (322 .mu.L, 3.28 mmol) was added
5-[3-(4-hydroxyphenyl)-propyl]-2-(4-methylbenzyl)-4-propyl-2,4-dihydro-[1-
,2,4]triazol-3-one (1.2 g, 3.28 mmol) in ethanol (10 mL) and the
resulting mixture stirred at reflux for 1 hour. Then ethyl-2-butyl
isobutyrate (1.08 mL, 7.38 mmol) was added and the reaction
continued at reflux for 1 hour. Then sodium ethoxide (1.22 mL, 3.28
mmol) was added dropwise over 5 min and the reaction continued at
reflux for 4.5 hour. Additional sodium ethoxide (520 .mu.L, 1.4
mmol) and ethyl-2-butyl isobutyrate (205 .mu.L, 1.4 mmol) were
added and reaction continued at reflux for 4 hour. Additional
sodium ethoxide (336 .mu.L, 0.903 mmol) and ethyl-2-butyl
isobutyrate (132 .mu.L, 0.903 mmol) were added and the reaction
continued at reflux for 3 hours. Finally, additional sodium
ethoxide (200 .mu.L, 0.54 mmol) and ethyl-2-butyl isobutyrate (100
.mu.L, 0.133 mmol) were added and the reaction continued at reflux
for 1.5 hours. The mixture was allowed to cool to room temperature
and is then quenched into a solution of conc. HCl (1.5 g, 41 mmol)
in water (50 mL). The resulting solution was then concentrated in
vacuo, taken up in ethyl acetate (100 mL) and the aqueous layer was
discarded. The organic layer was washed with saturated aq.
NaHCO.sub.3 (2.times.50 mL) followed by saturated aq. NaCl
(2.times.25 mL). The organic layer was dried (MgSO.sub.4),
filtered, concentrated, and purified by silica gel chromatography
(1:1 ethyl acetate:hexanes) to afford the title compound as a
yellow oil (990 mg, 2.06 mmol, 63%):
[0694] .sup.1H NMR (DMSO-d.sub.6) .delta. 7.10 (s, 4H), 6.87 (AB,
4H, J=8.0 Hz), 4.77 (s, 2H), 4.14 (q, 2H, J=7.0 Hz), 3.46 (t, 2H,
J=6.5 Hz), 2.54 (t, 2H, J=7.5 Hz), 2.47 (t, 2H, J=7.5 Hz), 2.24 (s,
3H), 1.82 (m, 2H), 1.51 (m, 2H), 1.47 (s, 6H), 1.14 (t, 3H, J=7.5
Hz), 0.79 (t, 3H, J=7.0 Hz); .sup.13C NMR (DMSO-d.sub.6) .delta.
174.0, 154.1, 153.8, 146.7, 137.2, 135.6, 135.1, 129.75, 129.66,
128.1, 119.6, 79.2, 61.6, 48.3, 42.8, 34.0, 27.8, 25.7, 24.8, 22.5,
21.3, 14.5, 11.5; IR (CHCl.sub.3) 3005, 2939, 2878, 1729, 1692,
1509 cm.sup.-1. Anal. Calcd. for C.sub.28H.sub.37N.sub.3O.sub.4: C,
70.12; H, 7.78; N, 8.76. Found: C, 69.92; H, 7.84; N, 8.77.
Example 121
##STR00308##
[0696] To a solution of
2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4-propyl-4,5-dihydro-1H-[1,2,4-
]triazol-3-yl]-propyl}-phenoxy)-propionic acid ethyl ester (0.45 g,
0.938 mmol) in methanol (7 mL) was added with stirring aq. 1N NaOH
(2 mL, 2 mmol) at room temperature for 18 hours. The reaction
mixture was concentrated to a thin film and partitioned between
ethyl acetate (25 mL) and 1N HCl (25 mL). The organic layer was
washed with saturated aq. NaCl (25 mL), dried (MgSO.sub.4),
filtered, and concentrated to afford the title compound as a yellow
solid (0.400 g, 0.886 mmol, 94%): mp 94.0-96.5.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta. 12.92 (br. s, 1H), 7.10 (s, 4H), 6.88
(AB, 4H, J=8.5 Hz), 4.77 (s, 2H), 3.46 (t, 2H, J=7.5 Hz), 2.54 (t,
2H, J=7.5 Hz), 2.48 (m, 2H), 2.24 (s, 3H), 1.82 (m, 2H), 1.52 (t,
2H, J=7.5 Hz), 1.46 (s, 6H), 0.79 (t, 3H, J=8.0 Hz); .sup.13C NMR
(DMSO-d.sub.6) .delta. 175.8, 154.1, 146.8, 137.2, 135.2, 135.1,
129.7, 128.1, 119.3, 79.0, 60.4, 48.3, 42.8, 34.0, 27.9, 25.7,
24.8, 22.5, 21.3, 14.8, 11.5; IR (CHCl.sub.3) 3007, 2939, 2878,
1692, 1573, 1508 cm.sup.-1; Anal. Calcd. for
C.sub.26H.sub.33N.sub.3O.sub.4: C, 69.16; H, 7.37; N, 9.31. Found:
C, 68.90; H, 7.55; N, 9.14.
Example 122
##STR00309##
[0697] 4-(4-Hydroxyphenyl)butyric Acid
[0698] A 22-L 4-necked round bottom flask was equipped with a
condenser, nitrogen inlet, thermometer lead and overhead stirring
apparatus. The flask was charged with 4-(4-methoxyphenyl)butyric
acid (2250 g, 11.58 moles) followed by pyridine hydrochloride (5360
g, 46.34 moles, 4 eq). The resulting mixture of the two solids was
heated under nitrogen to 185-195.degree. C., with stirring
commencing by 50.degree. C. The flask contents were held at
185-195.degree. C., and reaction progress was monitored by TLC
(50/50 v/v hexanes/ethyl acetate+1% v/v acetic acid, p-anisaldehyde
stain for visualization). After two hours, TLC analysis indicated
complete consumption of starting material. The heat source was
removed and the mixture allowed to cool to 90.degree. C., after
which 5N HCl (2900 mL, 14.47 moles, 1.25 eq) and H.sub.2O (2700 mL)
were added sequentially. Stirring was continued until the pot
temperature reached 35.degree. C. The mixture was transferred to a
22-L bottom-outlet flask and diluted with t-butyl methyl ether
(MTBE, 6000 mL). The layers were separated and the aqueous portion
was reextracted with MTBE (3.times.4000 mL). The organic portions
were combined and back-washed with 5N HCl (750 mL). After drying
(Na.sub.2SO.sub.4) and filtration, the solution was concentrated in
vacuo to afford the title compound as a white solid (2020 g,
96.7%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 1.70 (m, 2H),
2.15 (t, 2H), 2.45 (t, 2H), 3.33 (s, 1H), 6.65 (d, 2H), 6.95 (d,
2H). .sup.13C NMR (DMSO-d.sub.6) .delta. 26.5, 32.5, 33.5, 114.6,
129.0, 131.2, 155.3, 174.2.
##STR00310##
4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyric Acid
[0699] A 12-L 3-neck round-bottom flask was equipped with an
overhead air-driven stirrer apparatus, condenser, nitrogen inlet,
thermometer/thermocouple, and heating mantle. The flask was charged
with ethyl acetate (450 mL) and 21% (wt.) sodium ethoxide in
ethanol solution (3318 mL, 8.87 moles, 2 eq). The resulting mixture
was heated to reflux under a nitrogen atmosphere and maintained at
reflux for 30 min. The mixture was then allowed to cool slightly
below reflux, and 4-(4-hydroxyphenyl)butyric acid (800 g, 4.43
moles) was added. The flask contents were re-heated to reflux for
30 min, at which point ethyl 2-bromoisobutyrate (EBIB, 1954 mL,
13.32 moles, 3.0 eqs.) was added. After 1 h at reflux, the flask
was equipped with a 2-L addition funnel, which was charged sodium
ethoxide in ethanol solution (1660 mL, 4.43 moles, 1 eq.). The
sodium ethoxide solution was added dropwise to the refluxing
reaction over 1 h. After an additional 30 min at reflux, HPLC
analysis showed the reaction was complete. The heat source was
removed and the flask contents were cooled to 5-10.degree. C. and
then transferred to a 22-L bottom-outlet flask. While stirring, the
mixture was quenched with dilute phosphoric acid (6000 mL),
transferred to a 20-L Buchi flask, and concentrated in vacuo to
remove ethanol. The resulting aqueous mixture of crystals and
excess EBIB was refrigerated overnight. The crystals were then
filtered and washed with water (2000 mL). The solids were removed
from the funnel and placed in a 20-L Buchi flask equipped with an
overhead stirring apparatus. After the addition of water (2000 mL),
the solids were stirred at ambient temperature for 30 min, then
filtered and washed with heptane (2.times.2500 mL). The solids were
then placed in the vacuum oven and dried at 45.degree. C. to afford
the title compound as an off-white solid (1247 g, 95.5%). .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 1.25 (t, 3H), 1.57 (s, 6H), 1.92
(m, 2H), 2.35 (t, 2H), 2.60 (t, 2H), 4.23 (q, 2H), 6.76 (d, 2H),
7.03 (d, 2H). .sup.13C NMR (CDCl.sub.3) .delta. 14.1, 25.4, 26.3,
33.3, 34.2, 61.4, 119.4, 129.1, 134.9, 153.7, 174.4, 179.7.
##STR00311##
(4-Methylbenzyl)hydrazinecarboxylic acid, 1,1-dimethylethyl
Ester
[0700] To a 10-gal stainless steel autoclave containing isopropanol
(10 L) under nitrogen was charged t-butyl carbazate (1.25 kg, 9.46
mol) followed by isopropanol (2 L). The contents were stirred and
heated at 35.degree. C. for 30 min, then 4-methylbenzaldehyde
(1.142 kg, 9.51 mol) was added, followed by isopropanol (0.3 L).
The contents were heated to 45.degree. C., and a slurry of 5% Pd/C
(0.3 kg) in water (0.3 L) and isopropanol (4 L) was added, followed
by rinses of isopropanol (2.times.1 L). The contents were
hydrogenated at 40 psig and 45.degree. C. for 4 h, then a second
charge of 5% Pd/C (0.3 kg) in water (0.3 L) and isopropanol (4 L)
was added, followed by rinses of isopropanol (2.times.1 L).
Hydrogenation was continued at 40 psig and 45.degree. C. for 14 h,
at which the reaction was determined to be complete by HPLC. The
contents were then cooled to 15.degree. C. and filtered, and the
filter cake rinsed with isopropanol (15 L). The filtrate was
concentrated in vacuo to afford the title compound (1.97 kg, 88.2%)
as a 33.8 wt-% solution in isopropanol.
##STR00312##
[0701] 2-(Aminocarbonyl)-2-(4-methylphenylmethyl)hydrazine
carboxylic acid, 1,1-dimethylethyl ester A 22-L 4-neck flask was
equipped with an overhead stirring apparatus, cooling bath,
thermometer probe, and 2-L addition funnel. The flask was charged
with a solution of (4-methylbenzyl)hydrazinecarboxylic acid,
1,1-dimethyl-ethyl ester in isopropanol (4988 g of a 31.73% wt/wt
solution, 1583 g, 6.70 moles). Additional isopropanol (3130 mL) was
added to dilute the solution to a total volume of 8933 mL.
Trimethylsilyl isocyanate (1179 mL, 8.71 mol, 1.3 eq) was charged
to the 2-L addition funnel and was added dropwise to the stirring
reaction solution over 45 minutes, while the temperature was
maintained between 15-25.degree. C. using a cool water bath.
Reaction progress was monitored by TLC (50/50 v/v hexane/ethyl
acetate, 12; Rf(sm)=0.6, Rf(prod)=0.1). After overnight stir at
room temperature, TLC indicated the reaction was essentially
complete. The reaction mixture was treated with heptane (7800 mL),
cooled to 5-10.degree. C. and stirred for 0.5 hr. The mixture was
filtered and the cake was washed with heptane (2.times.1000 mL).
The material was dried in a vacuum oven at 30-35.degree. C. to
yield the title compound as a white solid (1423 g, 96%). .sup.1H
NMR (DMSO-d.sub.6, 300 MHz): .quadrature. 1.35 (s, 9H), 2.26 (s,
1H), 4.45 (br s, 2H), 6.06 (s, 2H), 7.10 (s, 4H), 8.88 (br s, 1H);
Anal. Calcd. for C.sub.14H.sub.21N.sub.3O.sub.3: C, 60.20; H, 7.58;
N, 15.04. Found: C, 59.65; H, 7.34; N, 14.87.
##STR00313##
1-(4-Methylphenylmethyl)hydrazinecarboxamide methanesulfonate
[0702] A 22-L 4-neck flask was equipped with an overhead stirring
apparatus, warming/cooling bath, thermometer probe, condenser, and
500-mL addition funnel. The flask was charged with
2-(Aminocarbonyl)-2-(4-methylphenylmethyl)-hydrazine carboxylic
acid, 1,1-dimethylethyl ester (1100 g, 3.94 moles) and
dichloromethane (12 L). The mixture was warmed to 30-35.degree. C.
to completely dissolve all solids, then cooled to 25-30.degree. C.
and methanesulfonic acid (MsOH) (398 g, 4.14 moles) was added over
30 min. The water bath was replaced with a heating mantle and the
reaction solution was heated at reflux for 12-20 hours, and
monitored by TLC analysis (Ethyl Acetate 100%; 12, Rf(sm)=0.3,
Rf(prod)=0.1) When complete, the reaction mixture was diluted with
heptane (4000 mL), cooled to 10-20.degree. C., and stirred for 30
min. After filtration, the cake was washed with heptane
(2.times.1000 mL) and dried in vacuo at 35-45.degree. C., to afford
the title compound as a white solid (1070 g, 98.6%). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz): .delta. 1.35 (S, 9H), 2.26 (s, 1H), 4.45
(br s, 2H), 6.06 (s, 2H), 7.10 (s, 4H), 8.88 (br s, 1H); Anal.
Calcd. for C.sub.10H.sub.17N.sub.3O.sub.4S,: C, 43.62; H, 6.22; N,
15.26; S, 11.64. Found: C, 43.33; H, 6.21; N, 14.97.
##STR00314##
2-(4-{3-[1-(4-Methylphenylmethyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]tr-
iazol-3-yl]propyl}phenoxy)-2-methylpropionic Acid Ethyl Ester
[0703] A 22-L 4-neck flask was equipped with a
thermometer/thermocouple, addition funnel, overhead stirring
apparatus, nitrogen inlet, and cooling bath. The flask was charged
with 4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyric acid
(1250 g, 4.247 moles), ethyl acetate (11.250 mL) and DMF (16.4 mL),
and the resulting mixture was stirred to dissolve solids. Oxalyl
chloride (426 mL, 4.88 moles, 1.15 eq) was added dropwise to the
reaction mixture over 45 min, using a water bath to keep the
temperature below 30.degree. C. The reaction mixture was then
concentrated in vacuo to remove both the solvent and excess oxalyl
chloride to afford crude
4-[4-(1-ethoxycarbonyl-1-methylethoxy)phenyl]butyric acid chloride.
A separate 22-L 4-neck flask was equipped with a
thermometer/thermocouple, addition funnel, nitrogen inlet, overhead
stirring apparatus, and cooling bath. The flask was charged with
1-(4-methylphenylmethyl)hydrazine-carboxamide methanesulfonate
(1169 g, 4.247 moles, 1 eq.), ethyl acetate (8750 mL), and pyridine
(790 mL, 9.77 moles, 2.3 eqs.). The contents of the flask were
cooled to 0-5.degree. C. The crude acid chloride was dissolved in
ethyl acetate (1000 mL) and added dropwise to the mixture
containing 1-(4-methylphenylmethyl)hydrazinecarboxamide
methanesulfonate over 20 min, while maintaining the pot temperature
below 25.degree. C. The resulting mixture was stirred at ambient
temperature for 1 h, then (.+-.)-camphorsulfonic acid (1973 g,
8.494 moles, 2 eq) was added. The flask contents were then heated
to reflux for 16 h. The reaction was cooled to 20.degree. C. and
transferred into a flask containing 1N HCl (7500 mL). After
stirring, the layers were separated and the organic layer was
washed with saturated Na.sub.2CO.sub.3 solution (7500 mL) and water
(1000 mL), then dried over MgSO.sub.4. The ethyl acetate solution
was transferred to a 4-neck flask equipped with a condenser,
nitrogen inlet, thermometer/thermocouple, and a heating mantle. The
flask was charged with Amberlyst-15 resin (1975 g) and the mixture
was heated to reflux for 1 h. After cooling to 20.degree. C., the
material was filtered to remove the resin and the resin was washed
with ethyl acetate (2.times.2000 mL). The filtrate was concentrated
in vacuo to afford a tan solid. MTBE (5000 mL) was added to the
crude material and the mixture warmed to 45-50.degree. C. until all
solids were dissolved. While slowly rotating the flask, the
solution was allowed to cool, whereupon crystallization occurred.
The slurry was cooled to 0-5.degree. C. for 1 hour, filtered,
rinsed with cold MTBE (1500 mL) and dried in vacuo at 45.degree. C.
to afford the title compound as a white solid (1027 g, 55.2%).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 1.14 (t, 3H), 1.47 (s,
6H), 1.76, (m, 2H), 2.26 (t, 2H), 2.49 (t, 2H), 3.55 (s, 3H), 4.15
(q, 2H), 6.69 (d, 2H), 7.05 (d, 2H).).
[0704] .sup.13C NMR (CDCl.sub.3) .delta. 14.0, 21.0, 25.3, 26.1,
28.1, 34.1, 48.3, 61.2, 79.0, 119.3, 127.8, 128.1, 129.0, 129.3,
133.2, 134.8, 137.5, 147.2, 148.3, 153.6, 155.8, 174.3.
##STR00315##
2-[4-[3-[2,5-dihydro-1-[(4-Methylphenyl)methyl]-5-oxo-1H-1,2,4-triazol-3--
yl]propyl]phenoxy]-2-methyl-propanoic Acid
[0705] A 4-neck flask was equipped with overhead stirring apparatus
and thermometer probe. The flask was charged with
2-(4-{3-[1-(4-Methylphenylmethyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]tr-
iazol-3-yl]-propyl}phenoxy)-2-methyl-propionic acid, ethyl ester
(800 g, 1.828 moles), and toluene (4000 mL) followed by 1N NaOH
(4023 mL, 2.194 mol, 1.2 eq). The resulting mixture was stirred at
ambient temperature for 5 h. The mixture was transferred to a 22-L
bottom outlet flask and layers separated. The aqueous layer from
the above layer separation was charged to the flask and acidified
to pH 2 with concentrated HCl (337 mL). Ethyl acetate was added
(8000 mL) and the mixture was transferred to a 22-L bottom-outlet
flask. The layers were separated and the organic solution was
transferred to a 22-L 3-neck round-bottom flask equipped with a
distillation head and overhead stirring apparatus. The mixture was
concentrated by distillation of the ethyl acetate to approximately
4000 mL, and fresh ethyl acetate (3600 mL) was added to the
reaction vessel. Distillation was continued until 3600 mL of
distillate were recovered. Heating was stopped and the mixture was
allowed to cool slowly to 60-65.degree. C., at which point seed
crystals (0.8 g) of the desired product were added. The flask
contents were allowed to cool slowly until crystallization
initiated (55-57.degree. C.), then the mixture was cooled to
0-5.degree. C. and stirred for 1 h. The product was filtered,
washed with cold ethyl acetate, and dried in vacuo at 55.degree. C.
to afford the title compound as a white solid (713.6 g, 95.3%).
.sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. 1.46 (s, 6H), 1.79 (m,
2H), 2.25 (s, 3H), 2.35 (t, 2H), 2.47 (t, 2H), 4.70 (s, 2H), 6.71
(d, 2H), 7.03 (d, 2H), 7.10 (m, 4H). .sup.13C NMR (DMSO-d.sub.6),
.delta. 20.6, 25.0, 25.5, 27.7, 47.0, 78.3, 118.6, 127.4, 127.7,
128.9, 128.9, 134.4, 134.5, 136.4, 145.9, 153.4, 154.3, 175.0.
Example 123
##STR00316##
[0706] (3,5-Difluorophenyl)methylenehydrazinecarboxylic acid,
1,1-dimethylethyl Ester
[0707] To a solution of t-butyl carbazate (4.99 g, 37.76 mmol) in
ethyl acetate (10 mL) was added with stirring
3,5-difluorobenzaldehyde (5.50 g, 38.7 mmol) followed by hexanes
(50 mL). Crystallization occurred and the resulting slurry was
stirred at rt for 15 min, then cooled to 0.degree. C. and held at
that temperature for 45 min. The solids were filtered, rinsed with
cold hexanes and dried in vacuo at 60.degree. C. to afford the
title compound as a solid (9.04 g, 93.3%): mp 196.4-196.8.degree.
C. (dec); .sup.1H NMR (DMSO-d.sub.6) .delta. 11.16 (br s, 1H), 7.96
(s, 1H), 7.28 (m, 2H), 7.21 (t, 1H, J=2.2 Hz), 1.45 (s, 9H);
.sup.13C NMR (DMSO-d.sub.6) .delta. 163.3 (dd, J=246.1, 13.5 Hz),
152.9, 141.2, 139.2 (t, J=9.6 Hz), 109.9 (dd, J=20.2, 5.8 Hz),
105.1 (t, J=25.9 Hz), 80.5, 28.7; IR (KBr mull) 3263, 2987, 1709,
1584, 1536 cm.sup.-1. A portion was recrystallized (ethyl acetate)
for analysis. Anal. Calcd. for
C.sub.12H.sub.14F.sub.2N.sub.2O.sub.2: C, 56.25; H, 5.51; F, 14.83;
N, 10.93. Found: C, 56.11; H, 5.49; N, 10.86.
##STR00317##
2-(3,5-Difluorophenylmethyl)hydrazinecarboxylic acid,
1,1-dimethylethyl Ester
[0708] To substrate imine (7.00 g, 27.3 mmol) and 5% Pt/C (5.05 g)
was added tetrahydrofuran (70 mL) and the resulting suspension
hydrogenated at rt and 50 psi. After 4 h, an additional charge of
5% Pt/C (5.00 g) was added and hydrogenation continued for 12 h.
The contents were filtered and concentrated to an oil, then
reconstituted in THF (70 mL) along with 5% Pt/C (5.00 g) and
hydrogenation continued for 60 h at rt and 50 psi. The contents
were then filtered and concentrated. SiO.sub.2 gel chromatography
(20% ethyl acetate in hexanes) gave the title compound as an oil
(4.96 g, 19.2 mmol, 70%). .sup.1H NMR (DMSO-d.sub.6) .delta. 8.28
(br s, 1H), 7.03 (m, 3H), 5.03 (br s, 1H), 3.88 (s, 2H), 1.35 (s,
9H); .sup.13C NMR (DMSO-d.sub.6) .delta. 162.9 (dd, J=243.6, 12.4
Hz), 144.9 (t, J=9.6 Hz), 111.5 (d, J=23.0 Hz), 102.5 (t, J=25.9
Hz), 79.0, 53.9, 28.8; IR (CHCl.sub.3) 3444, 2982, 2933, 1712,
1628, 1597 cm.sup.-1; HRMS calcd for
C.sub.12H.sub.16F.sub.2N.sub.2O.sub.2 (M+H).sup.+: 259.1258. Found:
259.1252.
##STR00318##
2-(Aminocarbonyl)-2-(3,5-Difluorophenylmethyl)hydrazinecarboxylic
Acid, 1,1-dimethylethyl Ester
[0709] To substrate difluorobenzyl hydrazine (2.5649 g, 9.93 mmol)
in isopropanol (20 mL) at rt was added trimethylsilyl isocyanate
(1.808 g, 15.7 mmol) in one portion. The reaction was stirred at rt
for 36 h, then concentrated to a solid. Recrystallization (1:1
ethyl acetate:hexanes) followed by dilution with hexanes (100 mL)
to facilitate stirring gave the title compound as a solid (2.84 g,
9.43 mmol, 95%): mp 128.7-129.9.degree. C.; .sup.1H NMR
(DMSO-d.sub.6, 60.degree. C.) 88.86 (br s, 1H), 6.97 (m, 3H), 6.00
(s, 2H), 4.52 (s, 2H), 1.36 (s, 9H); .sup.13C NMR (DMSO-d.sub.6,)
.delta. 162.7 (dd, J=245, 13 Hz), 159.5, 155.1, 143.7 (t, J=9 Hz),
111.4 (d, J=23 Hz), 102.8 (t, J=26 Hz), 80.4, 51.4, 28.6; IR (KBr
mull) 3540, 3227, 3004, 2988, 1744, 1682 cm.sup.-1. Anal. Calcd.
for C.sub.13H.sub.17F.sub.2N.sub.3O.sub.3: C, 51.82; H, 5.69; N.
13.95. Found: C, 51.59; H, 5.61; N, 13.81.
##STR00319##
1-(3,5-Difluorophenylmethyl)hydrazinecarboxamide
Methanesulfonate
[0710] To substrate Boc semicarbazide (1.81 g, 6.00 mmol) in
tetrahydrofuran (25 mL) at rt was added methanesulfonic acid (0.725
g, 6.3 mmol, 1.05 equiv) in one portion. The reaction was stirred
at rt for 24 h, then heated to reflux for 22 h. The reaction
mixture was cooled to rt, filtered and the filter cake rinsed with
dichloromethane. The solids were dried in vacuo overnight at
60.degree. C. to afford title compound as a solid (1.32 g, 4.44
mmol, 74%): mp 138.4-139.5.degree. C. (dec); .sup.1H NMR
(DMSO-d.sub.6, 60.degree. C.) 67.94 (br s, 4H), 7.10 (m, 1H), 6.98
(m, 2H), 4.70, 4.06 (s, s, 2H total, pair of rotamers), 2.48, 2.41
(s, s, 3H total, pair of rotamers); .sup.13C NMR (DMSO-d.sub.6,)
.delta. 163.6 (dd, J=246, 13 Hz), 158.0, 140.9, 111.6 (dd, J=20, 6
Hz), 104.0 (t, J=26 Hz), 52.1; IR (KBr mull) 3411, 3281, 3211,
1706, 1685, 1457, 1209 cm.sup.-1. HRMS calcd. for
C.sub.8H.sub.9F.sub.2N.sub.3O (M+H).sup.+: 202.0792. Found:
202.0797.
##STR00320##
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(3,5-difluorop-
henyl-methyl)semicarbazide
[0711] To 4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyric acid
(1.0072 g, 3.42 mmol) in ethyl acetate (10 mL) at rt was added DMF
(1 pipette drop), followed by oxalyl chloride (0.728 g, 5.73 mmol)
dropwise over 5 min. The resulting solution was stirred for 30 min
at rt, then concentrated to an oil. The oil was twice reconstituted
into toluene (20 mL) and concentrated to an oil, then dissolved in
ethyl acetate (3 mL). 1-(3,5-Difluorophenylmethyl)hydrazine
carboxamide methanesulfonate (1.025 g, 3.45 mmol) was suspended in
ethyl acetate (10 mL) at 0.degree. C., and pyridine (0.65 mL, 636
mg, 8.04 mmol) was added. The solution of acid chloride in ethyl
acetate was then added dropwise over 15 min, and the resulting
mixture stirred for 30 min at 0.degree. C. The mixture was then
diluted with ethyl acetate and washed with 1 N HCl (2.times.)
followed by sat'd aq. NaCl. It was then dried (MgSO.sub.4),
filtered and concentrated to an oil, which was chromatographed on
silica gel (ethyl acetate) to afford the title compound as a solid
(1.1436 g, 70%): mp 108.1-109.4.degree. C.; .sup.1H NMR
(DMSO-d.sub.6, 60.degree. C.) .delta. 9.73 (s, 1H), 7.00 (m, 5H),
6.70 (d, 2H, J=6.5 Hz), 6.03 (s, 2H), 4.54 (br s, 2H), 4.15 (q, 2H,
J=7 Hz), 2.45 (m, 2H), 2.09 (m, 2H), 1.74 (m, 2H), 1.48 (s, 6H),
1.17 (t, 3H, J=7 Hz); .sup.13C NMR (DMSO-d.sub.6) .delta. 174.0,
172.0, 162.5 (dd, J=244, 13 Hz), 159.2, 153.8, 144.1, 135.8, 129.7,
119.4, 111.3 (d, J=25 Hz), 102.8 (t, J=26 Hz), 79.2, 51.1, 47.3,
34.3, 33.1, 27.0, 25.7, 14.6; IR (KBr) 3456, 3324, 1726, 1643,
1509, 1445 cm.sup.-1; Anal. Calcd. for
C.sub.24H.sub.29N.sub.3O.sub.5F.sub.2: C, 60.37; H, 6.12; N, 8.80;
F, 7.96. Found: C, 60.48; H, 6.28; N, 8.67; F, 7.75.
##STR00321##
2-(4-{3-[1-(3,5-Difluorobenzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-
-propyl}-phenoxy)-2-methylpropionic Acid, Ethyl Ester
[0712] To substrate
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(3,4-dichloror-
ophenylmethyl)-4-(n-propyl)semicarb-azide (1.06 g, 2.26 mmol) and
camphorsulfonic acid (0.5283 g, 2.27 mmol) was added ethyl acetate
(12 mL) and the resulting solution heated to reflux for 22 h. The
solution was diluted with ethyl acetate, then washed with sat'd aq.
NaHCO.sub.3 followed by sat'd aq. NaCl. It was then dried
(MgSO.sub.4), filtered and concentrated to an oil, which was
chromatographed on silica gel (1:1 ethyl acetate:hexanes) to afford
the title compound as an oil (0.3836 g, 37%): .sup.1H NMR
(DMSO-d.sub.6) .delta. 11.54 (s, 1H), 7.13 (t, 1H, J=9.3 Hz), 7.04
(d, 2H, J=8.5 Hz), 6.91 (d, 2H, J=6.5 Hz), 6.68 (d, 2H, J=8.5 Hz),
4.81 (s, 2H), 4.13 (q, 2H, J=7.0 Hz), 2.49 (t, 2H, J=7.5 Hz), 2.38
(t, 2H, J=7.5 Hz), 1.81 (m, 2H), 1.47 (s, 6H), 1.14 (t, 3H, J=7.0
Hz); .sup.13C NMR (DMSO-d.sub.6) .delta. 174.0, 162.6 (dd, J=245,
13 Hz), 155.0, 153.8, 147.3, 142.9 (d, J=9 Hz), 135.5, 129.8,
119.5, 111.1 (t, J=26, 6 Hz), 103.5 (t, J=26 Hz), 79.2, 61.6, 47.1,
34.0, 28.3, 26.2, 25.7; IR (CHCl.sub.3) 3004, 1727, 1695, 1601,
1509, 1464 cm.sup.-1; Anal. Calcd. for
C.sub.24H.sub.27F.sub.2N.sub.3O.sub.4: C, 62.74; H, 5.92; N, 9.14.
Found: C, 62.65; H, 5.99; N, 8.98.
##STR00322##
2-(4-{3-[1-(3,5-Difluorobenzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-
-propyl}-phenoxy)-2-methylpropionic Acid
[0713] To substrate triazolone ethyl ester (0.2971 g, 0.647 mmol)
in methanol (3 mL) at rt was added 1 N NaOH (2 mL, 2.0 mmol) and
the resulting mixture stirred at rt for 16 h. The mixture was then
acidified by addition of 1 N HCl and concentrated to an oil, which
was partitioned between ethyl acetate (35 mL) and water (25 mL).
The layers were separated and the organic phase washed with sat'd
aq. NaCl, then dried (Mg SO.sub.4), filtered and concentrated to
afford the title compound as an oil (0.2643 g, 95%): .sup.1H NMR
(DMSO-d.sub.6, 60.degree. C.) .delta. 12.96 (br s, 1H), 11.54 (s,
1H), 7.13 (t, 1H, J=9.5 Hz), 7.04 (d, 2H, J=8 Hz), 6.91 (d, 2H, J=7
Hz), 6.72 (d, 2H, J=8 Hz), 4.81 (s, 2H), 2.49 (t, 2H, J=7 Hz), 2.38
(t, 2H, J=7 Hz), 1.82 (m, 2H), 1.46 (s, 6H); .sup.13C NMR
(DMSO-d.sub.6) .delta. 175.8, 163.0 (dd, J=245, 13 Hz), 155.0,
154.1, 147.3, 142.9, 135.0, 129.7, 119.2, 111.1 (m), 103.5 (t, J=26
Hz), 78.9, 47.1, 34.0, 28.3, 26.2, 25.7; IR (CHCl.sub.3) 3096,
3005, 2865, 1708, 1601, 1509, 1465, 1158, 1121 cm.sup.-1; Anal.
Calcd. for C.sub.22H.sub.23F.sub.2N.sub.3O.sub.4: C, 61.25; H,
5.37; N, 9.74. Found: C, 61.21, H, 5.46; N, 9.48.
##STR00323##
Example 124
(3-Methoxyphenyl)methylenehydrazinecarboxylic acid,
1,1-dimethylethyl Ester
[0714] To a solution of t-butyl carbazate (5.59 g, 42.3 mmol) in
ethyl acetate (15 mL) was added with stirring m-anisaldehyde (5.17
mL, 5.76 g, 42.3 mmol). Hexanes (70 mL) was added slowly and
crystallization occurred. The resulting slurry was stirred at rt
for 45 min and then cooled to 0.degree. C. The slurry was stirred
at 0.degree. C. for 60 min, then filtered and rinsed with cold
hexanes (20 mL), and dried in vacuo at 40.degree. C. to afford the
title compound as a solid (9.68 g, 91.4%): mp 135.6-137.4.degree.
C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 10.93 (s, 1H), 7.29 (t, 1H,
J=8 Hz), 7.14 (d, 2H, J=7 Hz), 6.92 (q, 1H, J=7 Hz), 3.75 (s, 3H),
1.45 (s, 9H); .sup.13C NMR (DMSO-d.sub.6) .delta. 160.2, 153.1,
143.7, 136.8, 130.5, 120.0, 116.2, 111.3, 80.1, 55.7, 28.7; IR (KBr
mull) 3360, 3010, 2982, 2838, 1510, 1487 cm.sup.-1. A portion was
recrystallized from ethyl acetate and submitted for elemental
analysis. Anal. Calcd. for C.sub.13H.sub.18N.sub.2O.sub.3: C,
62.38; H, 7.25; N, 11.19. Found: C, 62.34; H, 7.46; N, 11.19.
##STR00324##
(3-Methoxybenzyl)hydrazinecarboxylic acid, 1,1-dimethylethyl
Ester
[0715] (3-Methoxyphenyl)methylenehydrazinecarboxilic acid,
1,1-dimethylethyl ester (7.03 g, 28.1 mmol) and Pt/C (5%, 5.07 g)
were slurried in THF (80 mL) and hydrogenated at rt and 50 psig for
8 hr. The slurry was then filtered through celite and concentrated
in vacuo at 50.degree. C. to afford the title compound as oil (6.68
g, 94.0%): .sup.1H NMR (DMSO-d.sub.6) .delta. 8.22 (s, 1H), 7.19
(t, 1H, J=8 Hz), 6.85 (d, 1H, J=7 Hz), 6.77 (d, 1H, J=7 Hz), 3.84
(s, 2H), 3.72 (s, 3H), 1.37 (s, 9H); .sup.13C NMR (DMSO-d.sub.6)
.delta. 159.9, 157.1, 141.1, 129.7, 121.1, 114.1, 113.1, 78.9,
55.5, 54.9, 28.9; IR (CHCl.sub.3) 3008, 2982, 2935, 1712 cm.sup.-1;
Exact Mass: Calcd. for C.sub.13H.sub.20N.sub.2O.sub.3Na: 275.1372,
Found: 275.1381.
##STR00325##
3-(Aminocarbonyl)-2-(3-methoxyphenylmethyl)hydrazine carboxylic
acid, 1,1-dimethylethyl Ester
[0716] (3-Methoxybenzyl)hydrazinecarboxylic acid, 1,1-dimethylethyl
ester (6.30 g, 25.0 mmol) was dissolved in isopropyl alcohol (65
mL). Trimethylsilyl isocyanate (4.73 g, 34.9 mmol) was added in one
portion via syringe and the solution was allowed to stir at rt for
7 h. The slurry was cooled to 0.degree. C., filtered, and the
solids rinsed with cold isopropanol. The solids were dried in vacuo
at 40.degree. C. to afford the title compound as a white solid
(4.71 g, 63.9%). The filtrate was concentrated and purified by
column chromatography (SiO.sub.2, EtOAc) to afford additional
compound (0.91 g, 12.3%). These two portions were combined to yield
5.82 g (76.2%) of the title compound: mp 136.3-138.5.degree. C.;
.sup.1H NMR (DMSO-d.sub.6, 60.degree. C.) .delta. 8.70 (s, 1H),
7.20 (t, 1H, J=8 Hz), 6.80 (m, 3H), 5.90 (s, 2H), 4.50 (s, 2H),
3.74 (s, 3H), 1.36 (s, 9H); .sup.13C NMR (DMSO-d.sub.6) .delta.
159.9, 159.6, 155.0, 140.2, 129.8, 120.9, 114.0, 113.2, 80.2, 55.6,
51.1, 28.7; IR (CHCl.sub.3) 3003, 2984, 2938, 1745, 1680 cm.sup.-1;
Anal. Calcd. for C.sub.14H.sub.21N.sub.3O.sub.4: C, 56.94; H, 7.17;
N, 14.23. Found: C, 56.54; H, 7.17; N. 13.98.
##STR00326##
1-(3-Methoxyphenylmethyl)hydrazine Carboxamide Methanesulfonate
[0717] 3-(Amino-carbonyl)-2-(3-methoxyphenylmethyl)hydrazine
carboxylic acid, 1,1-dimethyl-ethyl ester (5.30 g, 17.9 mmol) was
dissolved in dichloromethane (60 mL). Methanesulfonic acid (1.93 g,
19.9 mmol) was added in one portion and the solution was allowed to
stir at rt overnight. The resulting slurry was cooled to 0.degree.
C., filtered, and the solids rinsed with cold dichloromethane. The
solids were dried in vacuo at 40.degree. C. to afford the title
compound as a white solid (5.05 g, 96.6%): mp 130.3-132.1.degree.
C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 9.7 (broad s, 3H), 7.30 (t,
1H, J=8 Hz), 7.05 (broad s, 2H), 6.88 (s, 3H), 4.69 (s, 2H), 3.74
(s, 3H), 3.34 (s, 3H); .sup.13C NMR (DMSO-d.sub.6) .delta. 160.1,
158.2, 137.3, 130.5, 120.7, 114.3, 114.0, 55.7, 52.7, 40.4; IR (KBr
mull) 3186, 2939, 1719, 1707, 1168 cm.sup.-1; Anal. Calcd. for
C.sub.9H.sub.13N.sub.3O.sub.2: C, 41.23; H, 5.88; N, 14.42. Found:
C, 40.86; H, 5.92; N, 14.61.
##STR00327##
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(3-methoxyphen-
yl-methyl)semicarbazide
[0718] 4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)-phenyl]butyric acid
(4.86 g, 16.5 mmol) was dissolved in ethyl acetate (40 mL). Oxalyl
chloride (2.43 g, 19.14 mmol) was added to this solution dropwise
in the presence of a catalytic amount of N,N-dimethylformamide (100
mg, 1.37 mmol). Completion of acid chloride formation was verified
by HPLC. This solution was then added dropwise to a suspension of
1-(3-methoxyphenylmethyl)hydrazine carboxamide methanesulfonate
(4.80 g, 16.5 mmol) and pyridine (1.30 g, 16.5 mmol) in ethyl
acetate (55 mL) at 0.degree. C. After stirring at 0.degree. C. for
6 h, an additional charge of pyridine was added (1.30 g, 16.5 mmol)
and the solution was stirred at 0.degree. C. for 1 h. The solution
was warmed to rt and washed with 1N HCl (2.times.80 mL) and 5% aq.
NaHCO.sub.3 (2.times.80 mL). The organic layer was dried
(MgSO.sub.4), filtered and concentrated to a waxy solid. The solids
were recrystallized from a mixture of toluene (17 mL) and heptane
(7 mL) at 60.degree. C., cooled to 0.degree. C. and filtered. The
solids were dried in vacuo at 40.degree. C. to afford the title
compound as a white solid (5.05 g, 65%): mp 91.9-93.4.degree. C.;
.sup.1H NMR (DMSO-d.sub.6, 60.degree. C.) .delta. 9.60 (s, 1H),
7.19 (t, 1H, J=8 Hz), 7.00 (d, 2H), 6.80 (m, 3H), 6.71 (d, 2H, J=8
Hz), 5.92 (s, 2H), 4.52 (s, 2H), 4.15 (q, J=7 Hz), 3.71 (s, 3H),
2.45 (t, 2H, J=7 Hz), 2.07 (t, 2H, J=7 Hz), 1.73 (quint, 2H, J=7
Hz), 1.48 (s, 6H), 1.17 (t, 3H, J=7 Hz); .sup.13C NMR
(DMSO-d.sub.6) .delta. 174.0, 171.9, 159.9, 159.3, 153.7, 140.5,
135.9, 129.9, 129.7, 120.9, 119.4, 114.1, 113.1, 79.2, 61.6, 55.5,
50.9, 34.3, 33.4, 27.2, 25.7, 14.6; IR (KBr mull) 3450, 3320, 3275,
3202, 2997, 2940, 1730, 1646, 1511 cm.sup.-1; Anal. Calcd. for
C.sub.25H.sub.33N.sub.3O.sub.6: C, 63.68; H, 7.05; N, 8.91. Found:
C, 63.49; H, 7.02; N, 8.99.
##STR00328##
2-(4-{3-[1-(3-Methoxybenzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-pr-
opyl}-phenoxy)-2-methyl-propionic Acid Ethyl Ester
[0719]
1-[4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)phenyl]butyryl]-2-(3-meth-
oxyphenylmethyl)semicarbazide (4.08 g, 8.65 mmol) was dissolved in
ethyl acetate (7.5 mL). Camphorsulfonic acid (2.21 g, 9.51 mmol)
was added in one portion and the solution was heated to reflux
overnight. The solution was cooled to rt and washed with sat'd aq.
NaHCO.sub.3 (2.times.40 mL) followed by 1N HCl (2.times.40 mL). The
organic was concentrated to an oil, which was redissolved in ethyl
acetate (40 mL). Amberlyst-15 resin (4.41 g) was added and the
mixture was heated to 50.degree. C. and stirred for 4 h. The
mixture was then cooled to rt, filtered, concentrated, and purified
by column chromatography (SiO.sub.2, 9:1 ethyl acetate:hexanes) to
afford the title compound as an oil (1.93 g, 49.2%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 11.47 (s, 1H), 7.22 (t, 1H, J=8 Hz), 7.04
(d, 2H, J=8 Hz), 6.82 (d, 1H, J=2 Hz), 6.76 (m, 2H), 6.68 (d, 2H,
J=2 Hz), 4.73 (s, 2H), 4.13 (q, 2H, J=7 Hz), 3.69 (s, 3H), 2.48 (t,
2H, J=8 Hz), 2.36 (t, 2H, J=8 Hz), 1.80 (quint, 2H, J=7 Hz), 1.47
(s, 6H), 1.14 (t, 3H, J=7 Hz); .sup.13C NMR (DMSO-d.sub.6) .delta.
174.0, 160.0, 155.0, 153.8, 146.7, 139.8, 135.5, 130.2, 129.8,
120.1, 119.5, 113.8, 113.2, 79.2, 61.6, 55.6, 47.8, 34.0, 28.4,
26.2, 25.7, 14.6; IR (CHCl.sub.3) 2940, 1692, 1508, 1467 cm.sup.-1;
Anal. Calcd. for C.sub.25H.sub.31N.sub.3O.sub.5: C, 66.21; H, 6.89;
N, 9.26. Found: C, 66.29; H, 6.75; N, 9.19.
##STR00329##
2-(4-{3-[1-(3-Methoxy-benzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-p-
ropyl}-phenoxy)-2-methyl-propionic Acid
[0720]
2-(4-{3-[1-(3-Methoxy-benzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-
-yl]-propyl}-phenoxy)-2-methyl-propionic acid ethyl ester (1.55 g,
3.42 mmol) was dissolved in a mixture of ethanol (7.5 mL) and water
(7.5 mL). Solid sodium hydroxide (0.36 g, 8.73 mmol) was added in
one portion and the solution was warmed to 70.degree. C. and
stirred for 1 h. The solution was cooled to rt and the pH adjusted
to 7 with 6N HCl. The solution was concentrated to an oil, which
was partitioned between 1N HCl (10 mL) and ethyl acetate (15 mL).
The aqueous layer was then reextracted with ethyl acetate (15 mL)
and the combined organic layers were dried (MgSO.sub.4), filtered
and concentrated in vacuo at 50.degree. C. to afford the title
compound as an oil (1.41 g, 97.0%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 13.0 (broad s, 1H), 11.47 (s, 1H), 7.23 (t, 1H, J=8 Hz),
7.03 (d, 2H, J=8 Hz), 6.82 (d, 1H, J=2 Hz), 6.75 (m, 5H), 4.73 (s,
2H), 3.70 (s, 3H), 3.35 (broad s, 1H), 2.48 (t, 2H, J=8 Hz), 2.36
(t, 2H, J=8 Hz), 1.80 (quint, 2H, J=7 Hz), 1.46 (s, 6H); .sup.13C
NMR (DMSO-d.sub.6, 20.degree. C.) .delta. 175.8, 160.0, 155.0,
154.1, 146.8, 139.8, 135.0, 130.3, 129.7, 120.1, 119.1, 113.8,
113.2, 78.9, 55.6, 47.8, 40.6, 40.5, 34.0, 28.4, 27.5, 26.2, 25.7;
IR (CHCl.sub.3) 1707, 1603, 1509, 1159 cm.sup.-1; Anal. Calcd. for
C.sub.23H.sub.27N.sub.3O.sub.5: C, 64.93; H, 6.40; N, 9.88. Found:
C, 65.02; H, 6.65; N, 9.57.
Example 125
##STR00330##
[0721] (3,4-Dichlorophenyl)methylenehydrazinecarboxylic Acid,
1,1-dimethylethyl Ester
[0722] To a solution of t-butyl carbazate (4.99 g, 37.76 mmol) in
ethyl acetate (10 mL) was added with vigorous stirring a solution
of 3,4-dichlorobenzaldehyde (6.77 g, 38.6 mmol) in ethyl acetate
(10 ml) followed by hexanes (40 mL). Crystallization occurred and
the resulting slurry was stirred at rt for 15 min, then cooled to
0.degree. C. and held at that temperature for 45 min. The solids
were filtered, rinsed with cold hexanes and dried in vacuo at
60.degree. C. to afford the title compound as a solid (10.10 g,
92.4%): mp 173.8-174.4.degree. C. (dec); .sup.1H NMR (DMSO-d.sub.6)
.delta. 11.16 (br s, 1H), 7.79 (s, 1H), 7.62 (d, 1H, J=1.8 Hz),
7.57 (d, 1H, J=8.5 Hz), 7.55 (m, 1H), 1.44 (s, 9H); .sup.13C NMR
(DMSO-d.sub.6) .delta. 152.9, 141.1, 136.1, 132.3, 132.1, 131.6,
128.6, 127.0, 80.4, 28.7; IR (KBr mull) 3358, 3010, 2983, 1736,
1508, 1475 cm.sup.-1. A portion was recrystallized (ethyl acetate)
for analysis. Anal. Calcd. for
C.sub.12H.sub.14Cl.sub.2N.sub.2O.sub.2: C, 49.84; H, 4.88; Cl,
24.52; N, 9.69. Found: C, 49.59; H, 4.71; Cl, 24.43; N, 9.57.
##STR00331##
2-(3,4-Dichlorophenylmethyl)hydrazinecarboxylic Acid,
1,1-dimethylethyl Ester
[0723] To substrate imine (2.90 g, 10.03 mmol) and 5% Pt/S/C (4.31
g of 55% wet catalyst, 1.94 g) was added tetrahydrofuran (30 mL)
and the resulting slurry hydrogenated at 50 psi hydrogen at rt for
16 h. The slurry was filtered and the filtrate concentrated to an
oil, which was chromatographed on silica gel (gradient of hexanes
to 15% ethyl acetate in hexanes) to afford the title compound as an
oil (2.56 g, 8.79 mmol, 88%): .sup.1H NMR (DMSO-d.sub.6, 60.degree.
C.) .delta. 8.05 (br s, 1H), 7.56 (S, 1H), 7.52 (dd, 1H, J=7.5, 1.5
Hz), 7.27 (d, 1H, J=7.5 Hz), 3.87 (s, 2H), 1.36 (s, 9H); .sup.13C
NMR (DMSO-d.sub.6) .delta. 157.0, 141.0, 131.4, 130.8, 129.8,
129.3, 79.1, 53.6, 28.8; IR (CHCl.sub.3) 3443, 2983, 1713, 1472,
1455, 1369 cm.sup.-1; Anal. Calcd. for
C.sub.12H.sub.16Cl.sub.2N.sub.2O.sub.2: C, 49.50; H, 5.54; N, 9.62.
Found: C, 49.82; H, 5.39; N, 9.50.
##STR00332##
2-(Propylaminocarbonyl)-2-(3,4-dichlorophenylmethyl)hydrazinecarboxylic
Acid, 1,1-dimethylethyl Ester
[0724] To substrate hydrazide (2.30 g, 7.90 mmol) in isopropanol
(25 mL) at rt was added propyl isocyanate (0.89 mL, 0.808 g, 9.50
mmol). After stirring for 30 min, the solution was concentrated to
an oil, and chromatographed on silica gel (40% ethyl acetate in
hexanes) to afford the title compound as an oil (2.63 g, 88%):
.sup.1H NMR (DMSO-d.sub.6, 60.degree. C.) .delta. 8.72 (br s, 1H),
7.52 (dd, 1H, J=8.0, 2.0 Hz), 7.48 (s, 1H), 7.24 (d, 1H, J=8.0 Hz),
6.39 (br s, 1H), 4.50 (br s, 2H), 3.13 (m, 2H), 1.41 (m, 2H), 1.35
(s, 9H), 0.82 (m, 3H); .sup.13C NMR (DMSO-d.sub.6) .delta. 158.4,
155.1, 140.1, 131.3, 130.9, 130.1, 129.3, 80.4, 51.2, 28.6, 23.7,
11.8; IR (CHCl.sub.3) 3454, 3007, 2971, 2936, 2876, 1743, 1671,
1524 cm.sup.-1; Anal. Calcd. for
C.sub.16H.sub.23Cl.sub.2N.sub.3O.sub.3: C, 51.07; H, 6.16; N,
11.17. Found: C, 51.01, H, 6.09; N, 11.15.
##STR00333##
N-Propyl-1-(3,4-dichlorophenylmethyl)hydrazinecarboxamide
Methanesulfonate
[0725] To substrate BOC semicarbazide (2.15 g, 5.71 mmol) in
dichloromethane (20 mL) at rt was added methanesulfonic acid (0.39
mL, 0.578 g, 6.01 mmol) in one portion. The resulting solution was
stirred at rt for 16 h, then heated to reflux for 16 h. The
solution was cooled and concentrated to a foam, which was
triturated with t-butyl methyl ether to afford the title compound
as a solid (2.03 g, 5.53 mmol, 95%). A portion was recrystallized
(ethyl acetate/ethanol) for analysis: mp 134.6-135.5.degree. C.;
.sup.1H NMR, (DMSO-d.sub.6, 60.degree. C.) .delta. 8.35 (br 2, 4H),
7.60 (d, 1H, J=8.5 Hz), 7.51 (d, 1H, J=2.0 Hz), 7.27 (dd, 1H,
J=8.5, 2.0 Hz), 4.66 (s, 2H), 3.06 (t, 2H, J=7.0 Hz), 2.42 (s, 3H),
1.45 (m, 2H), 0.83 (t, 3H, J=7.5 Hz); .sup.13C NMR (DMSO-d.sub.6)
.delta. 157.6, 137.4, 131.8, 131.4, 131.2, 130.8, 129.1, 52.0,
42.7, 40.4, 23.3, 11.9; IR (KBr mull) 3385, 2958, 2933, 2874, 1687,
1525, 1189 cm.sup.-1; Anal. Calcd. for
C.sub.11H.sub.15Cl.sub.2N.sub.3O.CH.sub.4O.sub.3S: C, 38.72; H,
5.14; N, 11.29. Found: C, 38.76; H, 5.14; N, 11.26.
##STR00334##
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(3,4-dichlorop-
henyl-methyl)-4-(propyl)semicarbazide
[0726] To 4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]-butyric
acid (1.005 g, 3.41 mmol) in ethyl acetate (10 mL) at rt was added
DMF (1 pipette drop), followed by oxalyl chloride (0.4 mL, 0.582 g,
4.58 mmol) dropwise over 3 min. The resulting solution was stirred
for 30 min at rt, then concentrated to an oil. The oil was twice
reconstituted into toluene (20 mL) and concentrated to an oil, then
dissolved in ethyl acetate (3 mL).
N-Propyl-1-(3,4-dichlorophenylmethyl)hydrazine methane-sulfonate
(1.1458 g, 3.08 mmol) was suspended in ethyl acetate (10 mL) at
0.degree. C., and pyridine (0.65 mL, 636 mg, 8.04 mmol) was added.
The solution of acid chloride in ethyl acetate was then added
dropwise over 2 min, and the resulting mixture stirred for 15 min
at 0.degree. C. The mixture was then diluted with ethyl acetate and
washed with 1 N HCl (2.times.) followed by sat'd aq. NaCl. It was
then dried (MgSO.sub.4), filtered and concentrated to an oil, which
was chromatographed on silica gel (3:2 ethyl acetate:hexanes) to
afford the title compound as an oil (1.4397 g, 85%): .sup.1H NMR
(DMSO-d.sub.6, 60.degree. C.) .delta. 9.61 (s, 1H), 7.50 (d, 1H,
J=8 Hz), 7.47 (d, 1H, J=2 Hz), 7.23 (dd, 1H, J=8, 2 Hz), 7.01 (d,
2H, J=8.5 Hz), 6.71 (d, 2H, J=8.5 Hz), 6.41 (br m, 1H), 4.53 (br s,
2H), 4.15 (q, 2H, J=7 Hz), 3.00 (m, 2H), 2.43 (m, 2H), 2.09 (t, 2H,
J=7 Hz), 1.74 (m, 2H), 1.48 (s, 6H), 1.40 (m, 2H), 0.81 (t, 3H,
J=7.5 Hz); .sup.13C NMR (DMSO-d.sub.6) .delta. 174.0, 172.1, 158.1,
153.8, 140.4, 135.8, 131.4, 130.9, 130.6, 130.1, 129.7, 129.1,
119.5, 79.2, 61.6, 50.9, 42.3, 34.4, 33.5, 27.1, 25.7, 23.7, 14.6,
11.9; IR (CHCl.sub.3) 3457, 3008, 2876, 1727, 1673, 1509 cm.sup.-1;
Anal. Calcd. for C.sub.27H.sub.35Cl.sub.2N.sub.3O.sub.5: C, 58.70;
H, 6.39; N, 7.61. Found: C, 58.60; H, 6.49; N, 7.67.
##STR00335##
1-[4-[4-(1-Carboxy-1-methylethoxy)phenyl]butyryl]-2-(3,4-dichlorophenylme-
thyl)-4-(propyl)semicarbazide
[0727] To substrate
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)-phenyl]butyryl]-2-(3,4-dichloro-
phenylmethyl)-4-(propyl)semicarbazide (0.609 g, 1.10 mmol) in
methanol (5 mL) at rt was added 1 N NaOH (2.0 mL, 2.0 mmol) and the
resulting solution stirred for 16 h. The solution was then
concentrated to an oil, and partitioned between ethyl acetate and 1
N HCl. The organic phase was then washed with sat'd aq. NaCl, dried
(MgSO.sub.4), filtered and concentrated to afford the title
compound as an amorphous solid (0.5563 g, 1.06 mmol, 96%): .sup.1H
NMR (DMSO-d.sub.6, 60.degree. C.) .delta. 9.61 (s, 1H), 7.50 (d,
1H, J=8 Hz), 7.47 (d, 1H, J=1.5 Hz), 7.23 (dd, 1H, J=8, 1.5 Hz),
7.01 (d, 2H, J=8.5 Hz), 6.75 d, 2H, J=8.5 Hz), 6.40 (br m, 1H),
4.53 (br s, 2H), 2.99 (q, 2H, J=6.5 Hz), 2.46 (t, 2H, J=7.5 Hz),
2.09 (t, 2H, J=7.5 Hz), 1.74 (m, 2H), 1.47 (s, 6H), 1.40 (q, 2H,
J=7.5 Hz), 0.81 (t, 3H, J=7.5 Hz); .sup.13C NMR (DMSO-d.sub.6)
.delta. 175.8, 172.1, 158.1, 154.1, 140.4, 135.3, 131.5, 130.9,
130.6, 130.1, 129.6, 129.1, 119.1, 78.9, 50.9, 42.3, 40.7, 34.4,
33.5, 27.1, 25.7, 23.7, 11.9; IR (CHCl.sub.3) 3379, 3291, 2960,
2915, 1719, 1671, 1618, 1542, 1508 cm.sup.-1; Anal. Calcd. for
C.sub.25H.sub.31Cl.sub.2N.sub.3O.sub.5: C, 57.26; H, 5.96; N, 8.01.
Found: C, 57.15; H, 5.89; N, 7.94.
##STR00336##
2-(4-{3-[1-(3,4-Dichlorobenzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-
-propyl}-phenoxy)-2-methylpropionic acid
[0728] To substrate
1-[4-[4-(1-Carboxy-1-methylethoxy)--phenyl]butyryl]-2-(3,4-dichlorophenyl-
methyl)-4-(propyl)semicarbazide (0.3658 g, 0.697 mmol) and
camphorsulfonic acid (0.1658 g, 0.714 mmol) was added toluene (10
mL) and the resulting solution heated to 90.degree. C. for 1 h. The
solution was concentrated to an oil, and chromatographed on silica
gel (7:3 ethyl acetate:hexanes) to afford title compound as an oil
(0.2397 g, 0.473 mmol, 68%): .sup.1H NMR (DMSO-d.sub.6) .delta.
12.95 (br s, 1H), 7.58 (d, 2H, J=8 Hz), 7.46 (d, 1H, J=1.5 Hz),
7.19 (dd, 1H, J=8, 1.5 Hz), 7.03 (d, 2H, J=8.5 Hz), 6.72 (d, 2H,
J=8.5 Hz), 4.85 (s, 2H), 3.47 (t, 2H, J=7 Hz), 2.54 (t, 2H, J=7.5
Hz), 1.83 (m, 2H), 1.52 (q, 2H, J=7 Hz), 1.45 (s, 6H), 0.79 (t, 3H,
J=7 Hz); .sup.13C NMR (DMSO-d.sub.6) .delta. 175.8, 154.1, 147.3,
139.2, 135.2, 131.7, 131.5, 130.8, 130.1, 129.7, 128.4, 119.3,
79.0, 47.3, 42.9, 34.0, 27.8, 25.7, 24.8, 22.5, 11.5; IR
(CHCl.sub.3) 3028, 3005, 2939, 2878, 1696, 1574, 1509, 1472
cm.sup.-1; Anal. Calcd. for C.sub.25H.sub.29Cl.sub.2N.sub.3O.sub.4:
C, 59.29; H, 5.77; N, 8.30. Found: C, 59.33; H, 5.63; N, 8.10.
##STR00337##
2-(4-{3-[1-(3,4-Dichlorobenzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-
-propyl}-phenoxy)-2-methylpropionic Acid, Ethyl Ester
[0729] To substrate
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(3,4-dichlorop-
henylmethyl)-4-(propyl)semicarbazide (0.4976 g, 0.901 mmol) and
camphorsulfonic acid (0.2078 g, 0.895 mmol) was added ethyl acetate
(10 mL) and the resulting solution heated to reflux for 12 h. The
solution was diluted with ethyl acetate, then washed with sat'd aq.
NaHCO.sub.3 followed by sat'd aq. NaCl. It was then dried
(MgSO.sub.4), filtered and concentrated to afford the title
compound as an oil (0.4532 g (0.848 mmol, 94%): .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.59 (d, 1H, J=8.5 Hz), 7.47 (d, 1H, J=2
Hz), 7.19 (dd, 1H, J=8.5, 2 Hz), 7.03 (d, 2H, J=8.5 Hz), 6.69 (d,
2H, J=8.5 Hz), 4.85 (s, 2H), 4.13 (q, 2H, J=7 Hz), 3.48 (t, 2H, J=8
Hz), 2.55 (t, 2H, J=7 Hz), 1.83 (m, 2H), 1.52 (q, 2H, J=7 Hz), 1.47
(s, 6H), 1.14 (t, 3H, J=7 Hz), 0.79 (t, 3H, J=7 Hz); .sup.13C NMR
(DMSO-d.sub.6) .delta. 174.0, 154.1, 153.8, 147.3, 139.2, 135.6,
131.7, 131.5, 130.8, 130.1, 129.8, 128.4, 119.6, 79.3, 61.6, 47.3,
42.9, 34.0, 27.7, 25.7, 24.7, 22.4, 14.6, 11.5; IR (CHCl.sub.3)
3003, 2939, 1728, 1696, 1509 cm.sup.-1; HRMS calcd. for
C.sub.27H.sub.34Cl.sub.2N.sub.3O.sub.4 (M+H).sup.+: 524.1926.
Found: 534.1935
##STR00338##
2-(4-{3-[1-(3,4-Dichlorobenzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-
-propyl}-phenoxy)-2-methylpropionic Acid
[0730] To substrate triazolone ethyl ester (0.3879 g, 0.726 mmol)
in methanol (5 mL) at rt was added sodium hydroxide (2.0 mL of 2.0
M solution, 2.0 mmol) and the resulting mixture stirred at rt for
16 h. The mixture was then concentrated to an oil and partitioned
between ethyl acetate and 1 N HCl. The organic phase was washed
with sat'd aq. NaCl, dried (MgSO.sub.4), filtered and concentrated
to afford the title compound (0.336 g, 0.646 mmol, 89%) as an
oil.
Example 126
##STR00339##
[0731] Phenylmethylenehydrazinecarboxylic acid, 1,1-dimethylethyl
Ester
[0732] To a solution of t-butyl carbazate (5.62 g, 42.5 mmol) in
ethyl acetate (15 mL) was added with stirring benzaldehyde (4.51 g,
42.5 mmol). Crystallization occurred and the resulting slurry was
stirred at rt for 45 min. Hexanes (70 mL) was added and the slurry
was cooled to 0.degree. C. The slurry was stirred at 0.degree. C.
for 60 min, then filtered and rinsed with cold hexanes (20 mL) and
dried in vacuo at 40.degree. C. to afford the title compound as a
solid (8.34 g, 89.0%): mp 184.1-184.9.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta. 10.91 (s, 1H), 7.99 (s, 1H), 7.58 (d, 2H,
J=3 Hz), 7.39 (m, 3H), 1.45 (s, 9H); .sup.13C NMR (DMSO-d.sub.6)
.delta. 153.0, 143.8, 135.3, 130.0, 129.4, 127.2, 80.1, 28.8; IR
(KBr mull) 2983, 1735, 1511, 1157 cm.sup.-1; A portion was
recrystallized (ethyl acetate) for analysis. Anal. Calcd. For
C.sub.12H.sub.16N.sub.2O.sub.2: C, 65.43; H, 7.32; N, 12.72. Found:
C, 65.16; H, 7.43; N. 12.62.
##STR00340##
Phenylmethylhydrazinecarboxylic acid, 1,1-dimethylethyl Ester
[0733] Phenylmethylene-hydrazinecarboxylic acid, 1,1-dimethylethyl
ester (7.00 g, 31.8 mmol) and 5% Pt/C (5.32 g) were slurried in THF
(70 mL) and stirred and hydrogenated (50 psig) at rt for 3 hr. The
slurry was then filtered through celite to remove the catalyst and
concentrated in vacuo at 50.degree. C. to afford the title compound
as a clear oil (6.36 g, 90.0%): .sup.1H NMR (DMSO-d.sub.6) .delta.
8.23 (s, 1H), 7.29 (m, 4H), 7.20 (m, 1H), 4.62 (br s, 1H), 3.85 (s,
2H), 1.37 (s, 9H); .sup.13C NMR (DMSO-d.sub.6) .delta. 157.1,
139.4, 129.1, 128.7, 127.4, 79.0, 55.1, 28.9; IR (CHCl.sub.3) 2982,
1712, 1454, 1273, 1159 cm.sup.-1; Exact Mass Calcd for
C.sub.12H.sub.21N.sub.2O.sub.2: 245.1266. Found: 245.1273.
##STR00341##
2-(Propylaminocarbonyl)-2-(phenylmethyl)hydrazine carboxylic Acid,
1,1-dimethylethyl Ester
[0734] To a solution of phenylmethylhydrazinecarboxylic acid,
1,1-dimethylethyl ester (2.54 g, 11.4 mmol) in isopropanol (25 mL)
was added propyl isocyanate (1.51 g, 17.6 mmol) and the solution
was stirred at rt for 1 h. The solution was concentrated to a white
solid. This solid was dissolved in ethyl acetate (25 mL) and washed
with water (25 mL) and 10% aq. NaCl (25 mL), dried (MgSO.sub.4),
filtered and concentrated to an off-white solid. It was then
recrystallized (2:3 ethyl acetate:hexanes) and dried in vacuo to
afford the title compound as a white solid (2.53 g, 72.1%): mp
122.8-124.5.degree. C.; .sup.1H NMR (DMSO-d.sub.6, 60.degree. C.)
.delta. 8.58 (s, 1H), 7.28 (m, 2H), 7.23 (m, 3H), 6.26 (s, 1H),
4.53 (s, 2H), 3.02 (q, 2H, J=7 Hz), 1.41 (quint, 2H, J=7 Hz), 1.35
(s, 9H), 0.83 (t, J=7 Hz); .sup.13C NMR (DMSO-d.sub.6) .delta.
158.6, 155.0, 138.7, 128.9, 128.8, 127.6, 80.2, 51.5, 42.3, 28.6,
23.7, 11.8; IR (CHCl.sub.3) 3007, 1745, 1665, 1523 cm.sup.-1. Anal.
Calcd. For C.sub.16H.sub.25N.sub.3O.sub.3: C, 62.52; H, 8.20; N,
13.67. Found: C, 62.28; H, 8.14; N, 13.51.
##STR00342##
N-Propyl-1-phenylmethylhydrazine Carboxamide Methanesulfonate
[0735] 2-(Propylaminocarbonyl)-2-(phenylmethyl)hydrazine carboxylic
acid, 1,1-dimethylethyl ester (2.33 g, 7.58 mmol) was dissolved in
dichloromethane (25 mL). Methanesulfonic acid (615 .mu.L, 9.48
mmol) was added in one portion and the solution was allowed to stir
at rt overnight. The solution was heated to reflux for 8 h, then
concentrated to afford the title compound as a crude white solid
(2.47 g, 107%): mp 78.1-82.9.degree. C.; .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.7 (br s, 3H), 7.61 (br s, 1H), 7.38 (t, 1H, J=8 Hz), 7.32
(m, 4H), 4.74 (s, 2H), 3.07 (t, 2H, J=8 Hz), 2.38 (s, 3H), 1.43,
(quint, 2H, J=8 Hz), 0.81 (t, 3H, J=8 Hz); .sup.13C NMR
(DMSO-d.sub.6) .delta. 157.5, 135.6, 129.3, 128.7, 128.6, 52.8,
42.7, 40.3, 23.3, 11.9; IR (CHCl.sub.3) 3009, 1691, 1543, 1196
cm.sup.-1; Exact Mass Calcd. For C.sub.11H.sub.17N.sub.3O:
208.1450. Found: 208.1462.
##STR00343##
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-phenylmethyl-4-
-(propyl)semicarbazide
[0736] 4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)-phenyl]butyric acid
(1.50 g, 5.04 mmol) was dissolved in ethyl acetate (10 mL). Oxalyl
chloride (524 .mu.L, 6.01 mmol) was added to this solution dropwise
in the presence of a catalytic amount of N,N-dimethylformamide
(30.1 .mu.L, 0.41 mmol). Completion of acid chloride formation was
verified by HPLC. This solution was then concentrated to remove
residual oxalyl chloride and the resulting oil was redissolved in
ethyl acetate (10 mL). This solution was then added dropwise to a
suspension of N-propyl-1-phenylmethylhydrazine carboxamide
methanesulfonate (1.52 g, 5.01 mmol) and pyridine (970 .mu.L, 12.6
mmol) in ethyl acetate (15 mL) at 0.degree. C. After stirring at
0.degree. C. for 1 h, the solution was warmed to rt and washed with
1N HCl (2.times.20 mL) and 5% aq. NaHCO.sub.3 (2.times.20 mL)
followed by sat'd aq. NaCl (20 mL). The organic layer was dried
(MgSO.sub.4), filtered and concentrated to a yellow oil. The oil
was purified by column chromatography (SiO.sub.2, 1:1 ethyl
acetate:hexanes) to afford the title compound as a clear oil (1.42
g, 59%): .sup.1H NMR (DMSO-d.sub.6, 60.degree. C.) .delta. 9.51 (s,
1H), 7.20 (m, 5H), 7.01 (d, 2H, J=8 Hz), 6.71 (t, 1H, J=7 Hz), 4.55
(s, 2H), 4.17 (q, J=7 Hz), 3.00 (q, 2H, J=7 Hz), 2.45 (t, 2H, J=2
Hz), 2.07 (t, 2H, J=2 Hz), 1.73 (quint, 2H, J=7 Hz), 1.48 (s, 6H),
1.40 (q, 2H, J=7 Hz), 1.17 (t, 3H, J=7 Hz), 0.81 (t, 3H, J=7 Hz);
.sup.13C NMR (DMSO-d.sub.6) .delta. 174.0, 172.0, 158.2, 153.8,
139.0, 135.8, 129.7, 128.84, 128.79, 127.6, 119.4, 79.2, 61.6,
51.3, 42.3, 34.3, 33.4, 27.1, 25.7, 23.7, 14.6, 11.9; IR
(CHCl.sub.3) 3009, 1726, 1672, 1143 cm.sup.-1; Anal. Calcd. For
C.sub.27H.sub.37N.sub.3O.sub.5: C, 67.05; H, 7.71; N, 8.69. Found:
C, 66.65; H, 7.63; N, 8.57.
##STR00344##
[0737]
2-{4-[3-(1-Phenylmethyl-5-oxo-4-propyl-4,5-dihydro-1H-[1,2,4]triazo-
l-3-yl)-propyl]-phenoxy}-2-methylpropionic acid ethyl ester
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-phenylmethyl-4-
-(propyl)semicarbazide (1.26 g, 2.61 mmol) was dissolved in ethyl
acetate (15 mL). Camphorsulfonic acid (670 mg, 2.88 mmol) was added
in one portion and the solution was heated to reflux for 1 h. The
solution was cooled to rt and washed with sat'd aq. NaHCO3
(2.times.10 mL) followed by 1N HCl (2.times.10 mL). The organic
phase was dried (MgSO4) and concentrated to a clear, colorless oil.
The material was purified by plug silica gel filtration (gradient
dichloromethane to ethyl acetate) to afford the title compound as a
clear, colorless oil (0.86 g, 71%). .sup.1H NMR (DMSO-d.sub.6)
.quadrature. 7.30 (t, 3H, J=7 Hz), 7.24 (d, 1H, J=7 Hz), 7.20 (d,
2H, J=7 Hz), 7.04 (d, 2H, J=8 Hz), 6.69 (d, 2H, J=8 Hz), 4.13 (q,
2H, J=7 Hz), 3.47 (t, 2H, J=7 Hz), 2.55 (t, 2H, J=7 Hz), 2.48 (t,
2H, J=7 Hz), 1.83 (quint, 2H, J=7 Hz), 1.52, (m, 2H), 1.47 (s, 6H),
1.14 (t, 3H, J=7 Hz), 0.79 (t, 3H, J=7 Hz); .sup.13C NMR
(DMSO-d.sub.6) .quadrature. 174.0, 154.1, 153.8, 146.9, 138.1,
135.6, 129.8, 129.1, 128.0, 119.6, 79.3, 61.6, 48.5, 42.8, 34.0,
27.8, 25.7, 24.8, 22.5, 14.5, 11.5; IR (CHCl3) 2878, 1692, 1509,
1143 cm.sup.-1; Anal. Calcd. For C.sub.27H.sub.35N.sub.3O.sub.4: C,
69.65; H, 7.58; N, 9.03. Found: C, 69.28; H, 7.96; N, 8.84.
##STR00345##
2-(4-{3-[1-(Phenylmethyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-propy-
l}-phenoxy)-2-methylpropionic Acid
[0738]
2-(4-{3-[1-(Phenylmethyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-
-propyl}-phenoxy)-2-methylpropionic acid ethyl ester (557 mg, 1.20
mmol) was dissolved in ethanol (5 mL) and 1N aq. NaOH (3.6 mL, 3.6
mmol) was added in one portion and the solution was stirred at room
temperature for 16 h. The solution was then concentrated to a hazy
colorless oil. This oil was diluted with water (5 mL) and washed
with t-butyl methyl ether (5 mL). The pH of the aqueous layer was
adjusted to <1 with conc. HCl and the aqueous was extracted with
ethyl acetate (10 mL, then 5 mL). This solution was washed with 1 N
aqueous HCl (5 mL) and sat'd aq. NaCl (5 mL), dried (MgSO.sub.4),
and concentrated in vacuo to afford the title compound as a clear
colorless oil (442 mg, 84.5%). .sup.1H NMR (DMSO-d.sub.6) .delta.
12.9 (br s, 1H), 7.30 (t, 2H, J=7 Hz), 7.25 (d, 1H, J=7 Hz), 7.20
(d, 2H, J=7 Hz), 7.04 (d, 2H J=8 Hz), 6.72 (d, 2H, J=8 Hz), 4.83
(s, 2H), 3.47 (t, 2H, J=7 Hz), 2.54 (t, 2H, J=8 Hz), 2.49 (t, 2H,
J=8 Hz), 1.83 (quint, 2H, J=7 Hz), 1.53, (m, 2H), 1.46 (s, 6H),
0-80 (t, 3H, J=7 Hz); .sup.13C NMR (DMSO-d.sub.6) .delta. 175.8,
154.1, 146.0, 138.1, 135.2, 129.7, 129.2, 128.0, 119.3, 79.0, 48.5,
42.8, 34.0, 27.9, 25.7, 24.8, 22.5, 11.5; IR (CHCl.sub.3) 2938,
1509, 1468, 1233, 1155 cm.sup.-1; Anal. Calcd. For
C.sub.25H.sub.31N.sub.3O.sub.4: C, 68.63; H, 7.14; N, 9.60. Found:
C, 68.24; H, 6.95; N, 9.40.
Example 127
Step A;
##STR00346##
[0740] The N-4 ethyl triazolinone (1 g, 0.003 mol) was combined
with benzyl bromoacetate (0.089 ml, 0.0056 mol) and powdered
K.sub.2CO.sub.3 (1.99 g, 0.014 mol) in DMF (28 ml) and stirred at
67.degree. C. overnight. Ether was added to the reaction mixture
and the solution was extracted with water. Purification by flash
chromatography (2:1 hexanes:ethyl acetate) gave the desired
amide.
[0741] C.sub.27H.sub.33N.sub.3O.sub.6 (MW 495.65); mass
spectroscopy (MH.sup.+)=496.2
Step B
##STR00347##
[0743] The amide from Step A (1.28 g, 0.0026 mol) was dissolved in
ethyl acetate (20 ml) and purged with nitrogen. Palladium catalyst
(0.128 g, 10%) was added to the solution. The reaction mixture was
purged again. Hydrogen gas was released across the system and the
reaction was stirred overnight. The reaction mixture was filtered
and the filtrate was concentrated. The resulting residue was
carried forth without further purification.
[0744] C.sub.20H.sub.27N.sub.3O.sub.6 (MW=405.45); mass
spectroscopy (MH.sup.+)=406.3
Step C
##STR00348##
[0746] The ester from Step B (0.200 g, 0.00049 mol) was dissolved
in ethanol (6 ml) and treated with 2N NaOH (3 ml). The solution was
refluxed for one hour. Water was added to the mixture and the layer
was extracted with ether. The aqueous layer was acidified with 1N
HCl and extracted with ethyl acetate. The organic layer was washed
with brine, dried over Na.sub.2SO.sub.4 then concentrated to yield
the desired product as a white foam.
[0747] C.sub.19H.sub.25N.sub.3O.sub.6 (MW=391.43); mass
spectroscopy (MH.sup.+)=392.3
Example 128
Step A
##STR00349##
[0749] A THF solution of the acid described in Example 127, Step B
(0.190 g, 0.00047 mol) was treated with EDC (0.134 g, 0.0007 mol)
and HOAt (0.064 g, 0.0047 mol). An equivalent of 4-methyl benzyl
amine (0.060 ml, 0.00047 mol) was added and the reaction was
stirred overnight. The solvent was concentrated and the residue was
redissolved in methylene chloride and extracted with water.
Purification by flash chromatography (100% ethyl acetate) gave the
desired amide.
[0750] C.sub.28H.sub.36N.sub.4O.sub.5 (MW 508.62); mass
spectroscopy (MH.sup.+)=509.4
Step B
##STR00350##
[0752] The amide from Step A (0.150 g, 0.00029 mol) was dissolved
in dioxane (3 ml) and water (3 ml) then treated with LiOH (0.007 g,
0.00029 mol). The reaction was stirred for two hours. Water was
added to the mixture and the layer was extracted with ether. The
aqueous layer was acidified with 1N HCl and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4 then concentrated to yield the desired product as
a white foam. C.sub.27H.sub.34N.sub.4O.sub.5 (MW=494.60); mass
spectroscopy (MH.sup.+)=495.4
Example 129
##STR00351##
[0753] (Naphthalen-2-yl)methylenehydrazinecarboxylic Acid,
1,1-dimethylethyl Ester
[0754] To a solution of t-butyl carbazate (7.59 g, 57.4 mmol) in
ethyl acetate (22 mL) was added with stirring 2-napthaldehyde (8.98
g, 57.5 mmol). This clear yellow solution was stirred at rt for 15
min. Hexanes (105 mL) was added dropwise and solids precipitated
from solution. The slurry was cooled to 0.degree. C., the solids
were then filtered and rinsed with cold hexanes (20 mL). A second
crop of solids was obtained from the filtrate, filtered and
combined with the first crop. The combined solids were
recrystallized (EtOAc) and filtered. A second crop was collected by
concentrating the filtrate to half its original volume and
filtering the resulting solids at 0.degree. C. The two crops of
solids were combined and dried in vacuo at 40.degree. C. to afford
the title compound as a solid (13.17 g, 85.0%): mp
182.1-190.degree. C. (dec.); .sup.1H NMR (DMSO-d.sub.6) .delta.
11.04 (s, 1H), 8.17 (s, 1H), 7.99 (s, 1H), 7.93-7.86 (m, 4H),
7.52-7.49 (m, 2H), 1.47 (s, 9H); .sup.13C NMR (DMSO-d.sub.6)
.delta. 153.1, 143.9, 134.1, 133.6, 133.1, 129.1, 128.9, 128.5,
128.4, 127.5, 127.3, 123.1, 80.1, 28.8; IR (CHCl.sub.3) 3061, 3010,
2982, 1733, 1505, 1369 cm.sup.-1; Anal. Calcd. for
C.sub.16H.sub.18N.sub.2O.sub.2: C, 71.09; H, 6.71; N, 10.36. Found:
C, 70.95; H, 6.89; N, 10.31.
##STR00352##
(Naphthalen-2-yl)methylhydrazinecarboxylic Acid, 1,1-dimethylethyl
Ester
[0755] (Naphthalen-2-yl)methylenehydrazinecarboxylic acid,
1,1-dimethylethyl ester (7.08 g, 26.2 mmol) and 5% Pt/C (7.11 g)
were slurried in THF (70 mL) and hydrogenated at 50 pisg at rt for
4 hr. A second charge of 5% Pt/C (1.78 g) was added and
hydrogenation continued for 16 h. The slurry was then filtered
through celite to remove the catalyst and concentrated in vacuo at
50.degree. C. to afford the title compound as a clear oil (7.01 g,
98.3%): .sup.1H NMR (DMSO-d.sub.6) .delta. 8.27 (s, 1H), 7.83 (m,
4H), 7.48 (m, 3H), 6.97 (m, 1H), 4.88 (s, 1H), 4.04 (s, 2H), 1.37
(s, 9H); .sup.13C NMR (DMSO-d.sub.6) .delta. 137.1, 133.6, 132.9,
128.2, 128.1, 127.7, 127.3, 126.6, 126.4, 126.2, 79.0, 55.1, 28.9,
23.5; IR (CHCl.sub.3) 3445, 1711, 1454, 1393, 1331 cm.sup.-1; Exact
Mass Calcd for C.sub.16H.sub.20N.sub.2O.sub.2: 295.1422. Found:
295.1414.
##STR00353##
2-(Ethylaminocarbonyl)-2-(Naphthalen-2-yl)methylhydrazine
Carboxylic Acid, 1,1-dimethylethyl Ester
[0756] (Naphthalen-2-yl)methyl-hydrazinecarboxylic acid,
1,1-dimethylethyl ester (2.84 g, 10.4 mmol) was dissolved in
isopropanol (30 mL). Ethyl isocyanate (1.23 mL, 15.6 mmol) was
added in one portion and the solution was stirred at rt for 1 h,
then concentrated to a yellow oil. Column chomatography (SiO.sub.2,
2:3 EtOAc:hexanes) afforded the title compound as a clear,
colorless oil (2.66 g, 55%): .sup.1H NMR (DMSO-d.sub.6, 60.degree.
C.) .delta. 8.60 (s, 1H), 7.8 (m, 3H), 7.72, (s, 1H), 7.4 (m, 3H),
6.37 (s, 1H), 4.71 (s, 2H), 3.11 (quint, 2H, J=6 Hz), 1.32 (s, 9H),
1.04 (t, 3H, J=7 Hz); .sup.13C NMR (DMSO-d.sub.6) .delta. 158.6,
155.0, 136.2, 133.5, 133.0, 129.3, 128.2, 128.1, 127.5, 126.7,
126.3, 60.4, 35.4, 28.6, 16.3, 14.7; IR (CHCl.sub.3) 3453, 2983,
1664, 1370, 1156 cm.sup.-1; Exact Mass Calcd for
C.sub.19H.sub.25N.sub.3O.sub.3: 366.1794. Found: 366.1797.
##STR00354##
N-Ethyl-2-(naphthalen-2-yl)methylhydrazine Carboxamide
Methanesulfonate
[0757] 2-(Ethylaminocarbonyl)-2-(naphthalen-2-yl)methylhydrazine
carboxylic acid, 1,1-dimethylethyl ester (2.52 g, 7.34 mmol) was
dissolved in dichloromethane (25 mL). Methanesulfonic acid (524
.mu.L, 8.07 mmol) was added in one portion and the solution was
stirred at rt overnight. The solution was then heated to reflux for
8 h, then concentrated to afford the title compound as a white
amorphous solid (2.49 g, 96%): m.p. 46.2-48.1.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta. 9.7 (br s, 3H), 7.9 (m, 3H), 7.82, s,
1H, 7.61 (br s, 1H), 7.52 (m, 2H,), 7.44 (d, 1H, J=7 Hz), 3.18
(quint, 2H, J=8 Hz), 2.38 (s, 3H), 1.07 (t, 3H, J=7 Hz); .sup.13C
NMR (DMSO-d.sub.6) .delta. 157.5, 133.4, 133.3, 133.1, 129.0,
128.5, 128.3, 127.7, 127.1, 126.9, 126.7, 53.2, 40.4, 35.9, 15.8;
IR (CHCl.sub.3) 3415, 2939, 1543, 1191, 1043 cm.sup.-1; Exact Mass
Calcd. for C.sub.14H.sub.17N.sub.3O: 244.1450. Found: 244.1460.
##STR00355##
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(naphthalen-2--
yl)methyl-4-(propyl)semicarbazide
[0758] 4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)-phenyl]butyric acid
(1.35 g, 4.59 mmol) was dissolved in ethyl acetate (10 mL). Oxalyl
chloride (425 .mu.L, 4.86 mmol) was added to this solution dropwise
in the presence of a catalytic amount of N,N-dimethylformamide (25
.mu.L, 0.34 mmol). Completion of acid chloride formation was
verified by HPLC. This solution was then concentrated to remove
residual oxalyl chloride and the resulting oil dissolved in ethyl
acetate (10 mL). This solution was then added dropwise to a
suspension of K-ethyl-2-(naphthalen-2-yl)methylhydrazine
carboxamide methanesulfonate (1.50 g, 4.42 mmol) and pyridine (895
.mu.L, 11.1 mmol) in ethyl acetate (15 mL) at 0.degree. C. After
stirring at 0.degree. C. for 4 h, the solution was warmed to rt and
washed with 1N HCl (2.times.25 mL) and 5% aq. NaHCO.sub.3
(2.times.25 mL) followed by sat'd aq. NaCl (25 mL). The organic
layer was dried (MgSO.sub.4), filtered and concentrated to a yellow
oil, which was purified by column chromatography (SiO.sub.2, 7:3
ethyl acetate:hexanes) to afford the title compound as an oil (1.59
g, 69%): .sup.1H NMR (DMSO-d.sub.6, 60.degree. C.) .quadrature.
9.51 (s, 1H), 7.85 (m, 3H), 7.70 (s, 1H), 7.42 (m, 3H), 6.94 (d,
2H, J=7 Hz), 6.67 (d, 2H, J=7 Hz), 6.38 (s, 1H), 4.72 (s, 2H), 4.16
(q, J=7 Hz), 3.08 (t, 2H, J=7 Hz), 2.41 (t, 2H, J=8 Hz), 2.07 (t,
2H, J=8 Hz), 1.72 (quint, 2H, J=7 Hz), 1.47 (s, 6H), 1.17 (t, 3H,
J=7 Hz), 1.01 (t, 3H, J=7 Hz); .sup.13C NMR (DMSO-d.sub.6)
.quadrature. 174.0, 172.1, 158.2, 153.7, 136.4, 135.8, 133.5,
133.0, 129.7, 128.4, 128.2, 128.1, 127.4, 126.7, 126.3, 119.4,
79.2, 61.6, 51.3, 35.4, 34.3, 33.5, 27.2, 25.7, 16.3, 14.6; IR
(CHCl.sub.3) 3454, 2938, 1727, 1670, 1509, 1233, 1142 cm.sup.-1;
Anal. Calcd. for C.sub.30H.sub.37N.sub.3O.sub.5: C, 69.34H, 7.18;
N, 8.09. Found: C, 69.19; H, 7.49; N, 7.93.
##STR00356##
[0759]
2-{4-[3-(4-Ethyl-1-(naphthalen-2-yl)methyl-5-oxo-4,5-dihydro-1H-[1,-
2,4]triazol-3-yl)-propyl]-phenoxy}-2-methylpropionic acid ethyl
ester
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(naphthalen-2--
yl)methyl-4-(propyl)semicarbazide (1.30 g, 2.51 mmol) was dissolved
in ethyl acetate (15 mL). Camphorsulfonic acid (0.645 g, 2.78 mmol)
was added in one portion and the solution was heated to reflux for
4 h. The solution was cooled to rt and washed with sat'd aq.
NaHCO.sub.3 (2.times.20 mL) followed by 1N HCl (2.times.20 mL). The
organic was dried (MgSO.sub.4) and concentrated to afford the title
compound as a clear, colorless oil (1.23 g, 98%). .sup.1H NMR
(DMSO-d.sub.6) .quadrature. 7.85 (t, 3H, J=8 Hz), 7.73 (s, 1H),
7.48 (quint, 2H, J=4 Hz), 7.38 (d, 1H, J=8 Hz), 7.02 (d, 2H, J=8
Hz), 6.66 (d, 2H, J=8 Hz), 4.99 (s, 2H), 4.13 (q, 2H, J=7 Hz), 3.57
(q, 2H, J=8 Hz), 2.53 (m, 4H), 1.82 (quint, 2H, J=7 Hz), 1.46 (s,
6H), 1.13 (m, 6H); .sup.13C NMR (DMSO-d.sub.6) .quadrature. 174.0,
154.0, 146.7, 135.6, 135.5, 133.5, 132.9, 129.7, 128.9, 128.3,
128.2, 127.0, 126.8, 126.4, 119.5, 79.2, 61.6, 48.7, 36.4, 34.0,
27.9, 25.7, 24.8, 14.9, 14.5; IR (CHCl.sub.3) 2940, 1729, 1693,
1509, 1233, 1179, 1142 cm.sup.-1; Anal. Calcd. for
C.sub.30H.sub.35N.sub.3O.sub.4: C, 71.83; H, 7.03; N, 8.38. Found:
C, 71.64; H, 7.12; N, 8.19.
2-{4-[3-(4-Ethyl-1-(naphthalen-2-yl)methyl-5-oxo-4,5-dihydro-1H-[1,2,4]tri-
azol-3-yl)-propyl]-phenoxy}-2-methylpropionic Acid
[0760]
2-{4-[3-(4-Ethyl-1-(naphthalen-2-yl)-methyl-5-oxo-4,5-dihydro-1H-[1-
,2,4]triazol-3-yl)-propyl]-phenoxy}-2-methylpropionic acid ethyl
ester (725 mg, 1.45 mmol) was dissolved in ethanol (10 mL) and 1N
NaOH (4.3 mL, 4.3 mmol) was added in one portion and the solution
was stirred at room temperature for 1 h. The solution was then
concentrated to an oil, which was washed with t-butyl methyl ether
(5 mL). The pH of the aqueous phase was adjusted to <1 with
conc. HCl, and extracted with ethyl acetate (2.times.10 mL). The
combined extracts dried (MgSO.sub.4), filtered and concentrated to
afford the title compound as a clear yellow oil (0.570 g, 83%).
.sup.1H NMR (DMSO-d.sub.6) .delta. 12.9 (br s, 1H), 7.86 (t, 2H,
J=8 Hz), 7.73 (s, 1H), 7.48 (quint, 2H, J=4 Hz), 7.38 (d, 1H), 7.01
(d, 2H, J=7 Hz), 6.69 (d, 2H, J=7 Hz), 4.99 (s, 2H), 3.57 (quint,
2H, J=7 Hz), 2.52 (t, 2H, J=8 Hz), 1.82 (quint, 2H, J=7 Hz), 1.45
(s, 6H), 1.12 (t, 3H, J=7 Hz); .sup.13C NMR (DMSO-d.sub.6) .delta.
175.8, 154.1, 154.0, 146.8, 135.6, 135.2, 133.5, 132.9, 129.7,
128.9, 128.3, 128.2, 127.0, 126.8, 126.7, 126.4, 119.2, 79.0, 48.7,
36.4, 34.0, 27.9, 25.7, 24.8, 14.9; IR (CHCl.sub.3) 2940, 1693,
1509, 1469, 1156 cm.sup.-1; Exact Mass Calcd. for
C.sub.28H.sub.31N.sub.3O.sub.4: 474.2393. Found: 474.2393.
Example 130
##STR00357##
[0761]
5-[3-(4-hydroxy-phenyl)-propyl]-2-(4-methyl-benzyl)-4-propyl-2,4-di-
hydro-[1,2,4]-triazol-3-one
[0762]
1-[(4-Methoxyphenyl)butyryl]-2-(4-methylphenylmethyl)-4-propyl)semi-
-carbazide (0.312 g, 0.785 mmol) and excess pyridine hydrochloride
were melted together with stirring at 180.degree. C. for 1 h. After
cooling to room temperature, the contents were diluted with ethyl
acetate (25 mL) and 5 N HCl (25 mL). The organic layer was washed
with additional 5 N HCl (25 mL) followed by sat'd aq. NaHCO.sub.3
(2.times.25 mL). The organic layer was then washed with sat'd aq.
NaCl (25 mL), dried (MgSO.sub.4), filtered, and concentrated to
afford the title compound as a yellow oil (0.201 g, 0.55 mmol,
70%). Spectral data in accord with previous example. Exact Mass
Calc'd. for C.sub.22H.sub.28N.sub.3O.sub.3 (M+H).sup.+: 366.2182.
Found: 366.2192.
Example 131
##STR00358##
[0763] (3,4-dimethylphenyl)methylenehydrazinecarboxylic acid,
1,1-dimethylethyl Ester
[0764] To a solution of t-butyl carbazate (5.06 g, 38.3 mmol) in
ethyl acetate (15 mL) was added with stirring
3,4-dimethylbenzaldehyde (5.20 mL, 5.26 g, 39.2 mmol).
Crystallization occurred and the resulting slurry was stirred at rt
for 45 min. Hexanes (70 mL) was added and the slurry was cooled to
0.degree. C. The slurry was stirred at 0.degree. C. for 60 min,
then filtered and rinsed with cold hexanes (20 mL), and dried in
vacuo at 40.degree. C. to afford the title compound as a solid
(8.76 g, 92.1%): mp 167.7-168.6.degree. C. .sup.1H NMR
(DMSO-d.sub.6) .delta. 10.82 (s, 1H), 7.92 (s, 1H), 7.36 (s, 1H),
7.28 (d, 2H, J=3 Hz), 7.14 (d, 2H, J=3 Hz), 2.206 (s, 3H), 2.20 (s,
3H) 1.44 (s, 9H); .sup.13C NMR (DMSO-d.sub.6) .delta. 153.0, 144.1,
138.5, 137.3, 132.9, 130.5, 128.1, 124.8, 79.9, 28.8, 19.99, 19.97;
IR (KBr mull) 3361, 3009, 2981, 2981, 1513, 1495 cm.sup.-1. A
portion was further purified by recrystallization from ethyl
acetate for analysis. Anal. Calcd. for
C.sub.14H.sub.20N.sub.2O.sub.2: C, 67.71; H, 8.12; N, 11.28. Found:
C, 67.51; H, 8.07; N, 11.22.
##STR00359##
(3,4-dimethylbenzyl)hydrazinecarboxylic Acid, 1,1-dimethylethyl
Ester
[0765] (3,4-dimethylphenyl)methylenehydrazinecarboxilic acid,
1,1-dimethylethyl ester (7.02 g, 28.3 mmol) and 5% Pt/C (5.04 g)
were slurried in THF (70 mL) and hydrogenated at 50 psi at rt for 4
hr. The slurry was then filtered through celite and concentrated in
vacuo at 50.degree. C. to afford the title compound as a clear oil
(6.74 g, 95.2%): .sup.1H NMR (DMSO-d.sub.6, 20.degree. C.) .delta.
8.20 (s, 1H), 7.06 (s, 1H), 7.01 (dd, 2H, J=8, 2 Hz), 4.56 (s, 1H),
3.77 (s, 2H), 2.18 (s, 6H), 1.38 (s, 9H); .sup.13C NMR
(DMSO-d.sub.6) .delta. 157.1, 136.5, 136.3, 135.2, 130.4, 129.8,
126.5, 78.9, 54.9, 28.9, 20.0, 19.7; IR (CHCl.sub.3) 2982, 1712,
1453, 1369 cm.sup.-1; Exact Mass Calcd. for
C.sub.14H.sub.22N.sub.2O.sub.2: 251.1759. Found: 251.1757.
##STR00360##
2-(Methylaminocarbonyl)-2-(3,4-dimethylphenylmethyl)hydrazine
Carboxylic Acid, 1,1-dimethylethyl Ester
[0766] (3,4-Dimethylphenylmethyl)hydrazine carboxylic acid,
1,1-dimethylethyl ester (2.51 g, 10.0 mmol) was dissolved in
isopropanol (25 mL). Methyl isocyanate (1.0 mL, 16.7 mmol) was
added in one portion via syringe and the solution was allowed to
stir at ambient temperature for 1 h. The solution was concentrated
to afford the title compound as a white solid (3.30 g of 87%
potency material by
[0767] .sup.1H-NMR, 2.86 g, 93%): mp 99.7-104.9.degree. C.; .sup.1H
NMR (DMSO-d.sub.6, 60.degree. C.) .delta. 8.45 (s, 1H), 7.03 (d,
1H, J=8 Hz), 6.99 (s, 1H), 6.93 (d, 1H), 6.26 (S, 1H), 4.45 (s,
2H), 2.60 (d, 3H, J=7 Hz), 2.18 (s, 6H), 1.35 (s, 9H); .sup.13C NMR
(DMSO-d.sub.6, 20.degree. C.) .delta. 159.0, 155.0, 136.3, 135.7,
135.3, 130.3, 129.9, 126.6, 80.1, 50.8, 28.7, 27.7, 20.1, 19.7; IR
(CHCl.sub.3) 3466, 1681, 1528, 1247, 1155 cm.sup.-1. A portion was
recrystallized for elemental analysis: Anal. Calcd. for
C.sub.16H.sub.25N.sub.3O.sub.3: C, 62.52; H, 8.20; N, 13.67. Found:
C, 62.87; H, 8.15; N, 13.59.
##STR00361##
N-Methyl-1-(3,4-dimethylphenylmethyl)hydrazine Carboxamide
Methanesulfonate
[0768]
2-(Methylaminocarbonyl)-2-(3,4-dimethylphenylmethyl)hydrazine
carboxylic acid, 1,1-dimethylethyl ester (2.52 g, 8.20 mmol) was
dissolved in dichloromethane (25 mL). Methanesulfonic acid (717
.mu.L, 11.04 mmol) was added in one portion and the solution was
allowed to stir at rt for 4 h. An additional charge of
methanesulfonic acid (132 .mu.L, 2.0 mmol) was added and the
solution stirred at rt for 12 h. The resulting slurry was cooled to
0.degree. C., filtered, and the solids rinsed with cold
dichloromethane. The solids were dried in vacuo at 40.degree. C.
overnight to afford a white solid (1.44 g). The filtrate was
concentrated and purified by recrystallization (ethyl acetate) to
afford an additional amount of white solid (0.73 g). The two crops
were combined and homogenized to afford the title compound as a
white solid (2.17 g, 87%): m.p. 124.3-125.6.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta. 9.4 (broad s, 3H), 7.45 (broad s, 1H), 7.10
(d, 1H, J=8 Hz), 7.05 (s, 1H), 7.00 (d, 1H, J=8 Hz), 4.61 (s, 2H),
2.67 (s, 3H), 2.36 (s, 3H), 2.19 (s, 6H); .sup.13C NMR
(DMSO-d.sub.6) .delta. 158.2, 137.0, 136.7, 132.8, 130.4, 129.9,
126.2, 52.7, 40.4, 27.7, 20.2, 19.7; IR (CHCl.sub.3) 3004, 2946,
1693, 1505, 1171 cm.sup.-1; Anal. Calcd. for
C.sub.12H.sub.21N.sub.3O.sub.5: C, 47.51; H, 6.98; N, 13.85. Found:
C, 47.30; H, 7.01; N, 13.51.
##STR00362##
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(3,4-dimethylp-
henyl-methyl)-4-methylsemicarbazide
[0769] 4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)-phenyl]butyric acid
(1.46 g, 4.96 mmol) was dissolved in ethyl acetate (10 mL). Oxalyl
chloride (474 .mu.L, 5.46 mmol) was added to this solution dropwise
in the presence of a catalytic amount of N,N-dimethylformamide
(30.6 .mu.L, 0.39 mmol). Completion of acid chloride formation was
verified by HPLC. This solution was then added dropwise to a
suspension of N-Methyl-1-(3,4-dimethylphenylmethyl)hydrazine
carboxamide methanesulfonate (1.50 g, 4.95 mmol) and pyridine (1.00
mL, 12.9 mmol) in ethyl acetate (15 mL) at 0.degree. C. After
stirring at 0.degree. C. for 6 h, the solution was warmed to rt and
washed with 1N HCl (2.times.20 mL), 5% aq. NaHCO.sub.3 (2.times.20
mL) and sat'd aq. NaCl. The organic layer was dried (MgSO.sub.4),
filtered and concentrated to a yellow oil. The oil was purified by
column chromatography (SiO.sub.2, 9:1 ethyl acetate:hexanes), to
afford the title compound as a clear oil (1.48 g, 62%): .sup.1H NMR
(DMSO-d.sub.6, 60.degree. C.) .delta. 9.42 (s, 1H), 6.97 (m, 5H),
6.71 (d, 2H, J=8 Hz), 6.23 (s, 1H), 4.46 (s, 2H), 4.15 (q, J=7 Hz),
2.59 (s, 3H), 2.43 (t, 2H, J=8 Hz), 2.15 (s, 6H), 2.06 (t, 2H, J=8
Hz), 1.70 (quint, 2H, J=7 Hz), 1.48 (s, 6H), 1.17 (t, 3H, J=7 Hz);
.sup.13C NMR (DMSO-d.sub.6) .delta. 174.0, 172.0, 158.7, 153.8,
136.4, 136.0, 135.9, 135.4, 130.2, 129.9, 129.7, 126.5, 119.5,
79.2, 61.6, 50.6, 34.4, 33.5, 27.6, 27.2, 25.7, 20.0, 19.7, 14.6;
IR (CHCl.sub.3) 3009, 1669, 1509, 1142 cm.sup.-1; Exact Mass Calcd.
for C.sub.27H.sub.38N.sub.3O.sub.5: 484.2811.
[0770] Found: 484.2822.
##STR00363##
2-(4-{3-[1-(3,4-Dimethylphenylmethyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-
-3-yl]-propyl}-phenoxy)-2-methyl-propionic Acid Ethyl Ester
[0771]
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(3,4-dim-
ethylphenylmethyl)-4-methylsemicarbazide (1.20 g, 2.47 mmol) was
dissolved in ethyl acetate (10 mL). Camphorsulfonic acid (0.64 g,
2.72 mmol) was added in one portion and the solution was heated to
reflux for 1 h. The solution was cooled to rt and washed with sat'd
aq. NaHCO.sub.3 (2.times.8 mL) followed by 1N HCl (2.times.8 mL).
The organic phase was dried (MgSO.sub.4) and concentrated to afford
the title compound as a clear, colorless oil (1.08 g, 94%). .sup.1H
NMR (DMSO-d.sub.6) .delta. 7.04 (m, 3H), 7.03 (S, 1H), 6.93 (d, 1H,
J=2 Hz), 6.68 (d, 2H, J=7 Hz), 4.72 (s, 2H), 4.13 (q, 2H, J=7 Hz),
3.08 (s, 3H), 2.53 (t, 2H, J=8 Hz), 2.47 (t, 2H, J=8 Hz), 1.80
(quint, 2H, J=7 Hz), 1.47 (s, 6H), 1.14 (t, 3H, J=7 Hz); .sup.13C
NMR (DMSO-d.sub.6) .delta. 174.0, 154.1, 147.1, 136.8, 135.9,
135.6, 135.3, 130.1, 129.8, 129.4, 125.7, 119.5, 79.2, 61.6, 48.4,
34.1, 27.7, 27.6, 25.7, 25.0, 20.0, 19.7, 14.6; IR (CHCl.sub.3)
2941, 1729, 1509, 1238, 1143 cm.sup.-1; Anal. Calcd. for
C.sub.27H.sub.35N.sub.3O.sub.4: C, 69.65; H, 7.58; N, 9.03. Found:
C, 69.25; H, 7.47; N, 8.88.
##STR00364##
2-(4-{3-[1-(3,4-Dimethylphenylmethyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-
-3-yl]-propyl}-phenoxy)-2-methylpropionic Acid
[0772]
2-(4-{3-[1-(3,4-Dimethylphenylmethyl)-5-oxo-4,5-dihydro-1H-[1,2,4]t-
riazol-3-yl]-propyl}-phenoxy)-2-methylpropionic acid ethyl ester
(916 mg, 1.97 mmol) was dissolved in ethanol (10 mL) and 2N NaOH
(3.0 mL, 6.0 mmol) was added in one portion. The solution was
stirred at room temperature for one hour, then concentrated to a
hazy colorless oil. This oil was partitioned between 1N HCl (10 mL)
and ethyl acetate (10 mL). The aqueous layer was then reextracted
with ethyl acetate (10 mL). Solids precipitated from this solution
on stirring. The slurry was cooled to 0.degree. C., filtered and
dried in vacuo at 50.degree. C. overnight to afford the title
compound as a white solid (695 mg, 80%): mp 145.8-149.6.degree. C.;
.sup.1H-NMR (DMSO-d.sub.6) .delta. 12.98 (s, 1H), 7.05 (dd, 3H,
J=8.5, 3.0 Hz), 7.00 (s, 1H), 6.93 (d, 1H, J=7.5 Hz), 6.73 (d, 2H,
J=8.5 Hz), 4.73 (s, 2H), 2.52 (t, 2H, J=7.5 Hz), 2.47 (t, 2H, J=7.5
Hz), 2.14 (s, 6H), 1.80 (quint, 2H, J=7.5 Hz), 1.46 (s, 6H);
.sup.13C NMR (DMSO-d.sub.6, 20.degree. C.) .delta. 175.8, 154.1,
154.0, 147.1, 136.8, 135.9, 135.3, 135.2, 130.1, 129.7, 129.4,
125.7, 119.2, 78.9, 48.4, 34.1, 27.7, 27.6, 25.7, 25.1, 20.0, 19.7;
IR (CHCl.sub.3) 2936, 2490, 1730, 1658, 1510, 1148 cm.sup.-1; Anal.
Calcd. for C.sub.25H.sub.31N.sub.3O.sub.4: C, 68.63; H, 7.14; N,
9.60. Found: C, 68.23; H, 7.01; N, 9.44.
Example 132
##STR00365##
[0773] (4-t-Butyl)methylenehydrazinecarboxylic acid,
1,1-dimethylethyl Ester
[0774] To a solution of t-butyl carbazate (5.02 g, 37.9 mmol) in
ethyl acetate (15 mL) was added with stirring 4-t-butylbenzaldehyde
(6.40 mL, 6.21 g, 37.9 mmol). Crystallization occurred and the
resulting slurry was stirred at rt for 15 min. Hexanes (30 mL) was
added and the slurry was cooled to 0.degree. C. The slurry was
stirred at 0.degree. C. for 30 min, filtered and rinsed with cold
hexanes (20 mL), then dried in vacuo at 40.degree. C. to afford the
title compound as a solid (9.27 g, 88.3%): mp 173.7-175.7.degree.
C. (dec.); .sup.1H NMR (DMSO-d.sub.6) .delta. 10.85 (s, 1H), 7.96
(s, 1H), 7.63 (s, 1H), 7.50 (d, 2H, J=3 Hz), 7.40 (d, 2H, J=3 Hz),
1.45 (s, 9H), 1.25 (s, 9H); .sup.13C NMR (DMSO-d.sub.6) .delta.
152.7, 143.8, 132.6, 127.0, 126.2, 80.0, 39.7, 35.2, 31.7, 28.8; IR
(KBr mull) 3361, 3010, 2968, 1514, 1500 cm.sup.-1; A portion was
recrystallized (ethyl acetate) for analysis. Anal. Calcd. for
C.sub.16H.sub.24N.sub.2O.sub.2: C, 69.53; H, 8.75; N, 10.13. Found:
C, 69.20; H, 8.85; N, 10.09.
##STR00366##
(4-t-Butylbenzyl)hydrazinecarboxylic acid, 1,1-dimethylethyl
Ester
[0775] (4-t-Butylphenyl)methylenehydrazinecarboxilic acid,
1,1-dimethylethyl ester (7.05 g, 25.5 mmol) and 5% Pt/C (5.01 g)
were slurried in THF (70 mL) and hydrogenated at 50 psig at rt for
3 hr. The slurry was then filtered through celite to remove the
catalyst and concentrated in vacuo at 50.degree. C. to afford the
title compound as a clear oil (6.79 g, 95.6%): .sup.1H NMR
(DMSO-d.sub.6, 60.degree. C.) .delta. 7.30 (m, 2H), 7.23 (m, 2H),
4.44 (s, 1H), 3.82 (s, 1H), 1.38 (s, 9H), 1.27 (s, 9H); .sup.13C
NMR (DMSO-d.sub.6) .delta. 157.1, 149.8, 136.3, 128.9, 125.5, 78.9,
54.7, 34.8, 31.9, 28.9; IR (CHCl.sub.3) 3008, 2967, 2869, 1712
cm.sup.-1; Anal. Calcd. for C.sub.16H.sub.26N.sub.2O.sub.2: C,
69.03; H, 9.41; N, 10.06. Found: C, 68.83; H, 9.21; N, 9.98.
##STR00367##
2-(Methylaminocarbonyl)-2-(4-t-butylphenylmethyl)hydrazine
carboxylic acid, 1,1-dimethylethyl Ester
[0776] (4-t-Butylbenzyl) hydrazinecarboxilic acid,
1,1-dimethylethyl ester (2.54 g, 9.12 mmol) was dissolved in
isopropanol (25 mL). Methyl isocyanate (0.83 g, 14.11 mmol) was
added in one portion via syringe and the solution was allowed to
stir at rt for 1 h. The solution was concentrated to afford the
title compound as a waxy white solid (3.22 g of 89% potency
material by .sup.1H-NMR, 2.87 g, 93.7%): mp 124.1-128.6.degree. C.;
.sup.1H NMR (DMSO-d.sub.6, 60.degree. C.) .delta. 8.54 (br s, 1H),
7.30 (d, 2H, J=2 Hz), 7.16 (d, 2H, J=2 Hz), 6.28 (s, 1H), 4.48 (s,
2H), 2.59 (d, 3H,
##STR00368##
J=2 Hz), 1.31 (S, 9H), 1.26 (S, 9H); .sup.13C NMR (DMSO-d.sub.6,
60.degree. C.) .delta. 159.1, 155.0, 149.9, 135.5, 128.9, 125.5,
80.1, 50.9, 34.8, 31.9, 28.7, 27.7; IR (CHCl.sub.3) 3005, 2968,
2938, 1666 cm.sup.-1. A portion of this material was recrystallized
(toluene) for analysis. Anal. Calcd. for
C.sub.18H.sub.29N.sub.3O.sub.3: C, 64.45; H, 8.71; N, 12.53. Found:
C, 63.91; H, 8.51; N, 12.44.
N-Methyl-1-(4-t-butylphenylmethyl)hydrazine carboxamide
Methanesulfonate
[0777] 3-(Methylaminocarbonyl)-2-(4-t-butylphenylmethyl)hydrazine
carboxylic acid, 1,1-dimethylethyl ester (2.56 g, 7.90 mmol) was
dissolved in dichloromethane (25 mL). Methanesulfonic acid (641
.mu.L, 9.88 mmol) was added in one portion and the solution was
stirred at rt overnight. The resulting slurry was cooled to
0.degree. C., filtered, and the solids rinsed with cold
dichloromethane. The solids were dried in vacuo at 40.degree. C. to
afford the title compound as a white solid (2.10 g, 80.1%): mp
96.8-97.4.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 9.7 (br s,
3H), 7.5 (br s, 1H), 7.39 (d, 2H, J=3 Hz), 7.20 (d, 2H, T=3 Hz),
4.65 (S, 2H), 2.67 (s, 3H), 2.35 (s, 3H), 1.26 (s, 9H); .sup.13C
NMR (DMSO-d.sub.6) .delta. 158.2, 151.1, 132.7, 128.4, 126.1, 52.6,
40.4, 34.9, 31.8, 27.7; IR (KBr mull) 2967, 1690, 1550, 1188, 1076
cm.sup.-1; Exact Mass Calcd. for C.sub.13H.sub.22N.sub.3O:
236.1763. Found: 236.1758.
##STR00369##
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(4-t-butylphen-
yl-methyl)-4-methylsemicarbazide
[0778] 4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)-phenyl]butyric acid
(0.89 g, 3.02 mmol) was dissolved in ethyl acetate (10 mL). Oxalyl
chloride (316 .mu.L, 3.62 mmol) was added to this solution dropwise
in the presence of a catalytic amount of N,N-dimethylformamide (17
.mu.L, 0.24 mmol). Completion of acid chloride formation was
verified by HPLC. The solution was then concentrated to remove
excess oxalyl chloride and then redissolved in ethyl acetate (7
mL). This solution was then added dropwise to a suspension of
N-Methyl-1-(4-t-butylphenylmethyl)hydrazine carboxamide
methanesulfonate (1.02 g, 3.07 mmol) and pyridine (256 .mu.L, 6.14
mmol) in ethyl acetate (10 mL) at 0.degree. C. After stirring at
0.degree. C. for 3 h, an additional charge of pyridine (256 .mu.L,
6.14 mmol) was added and the solution was stirred at 0.degree. C.
for 1 h. The solution was warmed to rt and washed with 1N HCl
(2.times.10 mL) and then with 5% aq. NaHCO.sub.3 (2.times.10 mL).
The organic layer was dried (MgSO.sub.4), filtered and concentrated
to an orange oil. Column chromatography (SiO.sub.2, ethyl acetate)
afforded the title compound as a clear oil (1.06 g, 68%): .sup.1H
NMR (DMSO-d.sub.6, 60.degree. C.) .delta. 9.50 (s, 1H), 7.29 (d,
2H, J=8 Hz), 7.16 (d, 2H, J=8 Hz), 7.01 (d, 2H, J=8 Hz), 6.71 (d, 2
H, J=8 Hz), 6.27 (br s, 1H), 4.52 (br s, 2H), 4.15 (q, J=7 Hz),
2.58 (d, 3H, J=4 Hz), 2.44 (t, 2H, J=7 Hz), 2.07 (t, 2H, J=7 Hz),
1.72 (quint, 2H, J=7 Hz), 1.48 (s, 6H), 1.25 (s, 9H), (1.17 (t, 3H,
J=7 Hz); .sup.13C NMR (DMSO-d.sub.6) .delta. 174.0, 172.0, 158.7,
153.8, 149.9, 135.9, 129.7, 128.7, 125.6, 119.5, 79.2, 61.6, 50.8,
34.8, 34.4, 33.4, 31.8, 27.7, 27.1, 25.7, 14.6; IR (CHCl.sub.3)
3009, 2966, 1671, 1509, 1211 cm.sup.-1; Anal. Calcd. for
C.sub.29H.sub.41N.sub.3O.sub.5: C, 68.08; H, 8.08; N, 8.21. Found:
C, 67.70; H, 7.86; N, 8.11.
##STR00370##
2-(4-{3-[1-(4-t-Butylphenylmethyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]t-
riazol-3-yl]-propyl}-phenoxy)-2-methyl-propionic Acid Ethyl
Ester
[0779]
1-[4-[4-(1-Ethoxycarbonyl-1-methylethoxy)phenyl]butyryl]-2-(4-t-but-
yl phenylmethyl)-4-methylsemicarbazide (0.93 g, 1.82 mmol) was
dissolved in ethyl acetate (10 mL). Camphorsulfonic acid (0.46 g,
1.98 mmol) was added in one portion and the solution was heated to
reflux and stirred for 1 h. The solution was cooled to rt and
washed with sat'd aq. NaHCO.sub.3 (2.times.8 mL), 1N HCl (2.times.8
mL) and sat'd aq. NaCl (8 mL). The organic phase was dried
(MgSO.sub.4), filtered and concentrated to afford the title
compound as clear, colorless oil (0.84 g, 93.6%): .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.30 (d, 2H, J=8 Hz), 7.15 (d, 2H, J=8 Hz),
7.05 (d, 2H, J=8 Hz), 6.68 (d, 2H, J=8 Hz), 4.77 (s, 2H), 4.13 (q,
2H, J=7 Hz), 3.69 (s, 3H), 2.53 (t, 2H, J=8 Hz), 2.47 (t, 2H, J=8
Hz), 1.81 (quint, 2H, J=7 Hz), 1.47 (s, 6H), 1.22 (s, 9H), 1.14 (t,
3H, J=7 Hz); .sup.13C NMR (DMSO-d.sub.6) .delta. 174.0, 154.1,
153.8, 150.4, 147.1, 135.6, 135.0, 129.8, 128.0, 125.9, 119.5,
79.2, 61.6, 48.3, 34.9, 34.1, 31.8, 27.7, 27.6, 25.7, 25.1, 14.6;
IR (CHCl.sub.3) 2967, 1695, 1509, 1475, 1232 cm.sup.-1; Anal.
Calcd. for C.sub.29H.sub.39N.sub.3O.sub.4: C, 70.56; H, 7.96; N,
8.51. Found: C, 70.28; H, 7.85; N, 8.43.
##STR00371##
2-(4-{3-[1-(4-t-Butylbenzyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-
-3-yl]-propyl}-phenoxy)-2-methyl-propionic Acid
[0780]
2-(4-{3-[1-(4-t-Butylbenzyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]t-
riazol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid ethyl ester
(0.69 g, 1.39 mmol) was dissolved in ethanol (4 mL), 1 N NaOH (4.75
mL) was added in one portion and the solution was stirred at
ambient temperature overnight. The solution was concentrated to a
hazy, colorless oil. This oil was partitioned between 1N HCl (5 mL)
and ethyl acetate (5 mL). The aqueous layer was then reextracted
with ethyl acetate (5 mL) and the organic layers combined, dried
(MgSO.sub.4), filtered and concentrated in vacuo at 50.degree. C.
to afford the title compound as a clear oil (0.56 g, 86%): .sup.1H
NMR (DMSO-d.sub.6) .delta. 12.9 (br s, 1H), 7.31 (d, 2H, J=6 Hz),
7.14 (d, 2H, J=8 Hz), 7.05 (d, 2H, J=7 Hz), 6.73 (d, 2H, J=2 Hz),
4.77 (s, 2H), 3.09 (s, 3H), 2.53 (t, 2H, J=8 Hz), 2.49 (t, 2H, J=8
Hz), 1.81 (quint, 2H, J=7 Hz), 1.46 (s, 6H), 1.22 (s, 9H); .sup.13C
NMR (DMSO-d.sub.6) .delta. 175.8, 154.14, 154.10, 150.5, 147.2,
135.2, 135.0, 129.7, 128.0, 125.9, 119.2, 79.0, 48.3, 34.9, 34.1,
31.8, 27.7, 27.6, 25.7, 25.1; IR (CHCl.sub.3) 2966, 1695, 1509,
1235 cm.sup.-1; Anal. Calcd. for C.sub.27H.sub.35N.sub.3O.sub.4: C,
69.65; H, 7.58; N, 9.02.
[0781] Found: C, 69.30; H, 7.30; N, 8.96.
Example 133
2-Methyl-2-(4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro--
1H-[1,2,4]triazol-3-yl]-ethyl}-phenoxy)-propionic acid
##STR00372##
[0782] Step A: Preparation of
3-(4-Methoxy-phenyl)-N-propyl-propionamide
##STR00373##
[0784] To a solution of 3-(4-methoxyphenyl)propionic acid (8.0 g,
44.4 mmol), propylamine hydrochloride (4.24 g, 44.4 mmol),
4-dimethylaminopyridine (0.65 g, 5.33 mmol) and triethylamine (6.9
mL, 48.96 mmol) in methylene chloride (70 mL) was added
1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
(10.21 g, 53.28 mmol). The reaction mixture was stirred overnight
at ambient temperature followed by dilution with methylene
chloride. The mixture was washed with 1N hydrochloric acid, 2N
sodium hydroxide, water, brine and dried. Evaporation of the
solvent yielded the pure product (10.36 g; 95.4%): .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 7.76 (brs, 1H), 7.10 (d, 2H, J=8.8 Hz),
6.79 (d, 2H, J=8.0 Hz), 3.68 (s, 3H), 2.95 (q, 2H, J=5.6 Hz). 2.71
(t, 2H, J=7.6 Hz), 2.28 (t, 2H, J=7.2 Hz), 1.34 (m, 2H), 0.77 (t,
3H, J=7.2 Hz); ESMS m/z (relative intensity) 222.2 (M+H.sup.+,
100).
Step B: Preparation of 3-(4-Methoxyphenyl)-N-propyl-propionimidic
acid methyl ester
##STR00374##
[0785] To a solution of 3-(4-Methoxy-phenyl)-N-propyl-propionamide
(3.0 g, 13.57 mmol in methylene chloride (15 mL) was added
trimethyloxonium tetrafluoroborate (2.0 g, 13.57 mmol) and the
reaction mixture stirred overnight at ambient temperature. HPLC and
TLC analysis indicated the presence of starting material. More
trimethyloxonium tetrafluoroborate (0.25 g) was added and the
reaction mixture was allowed to stir for 2.5 h and quenched with
cold saturated aqueous potassium carbonate solution. The mixture
was extracted ethyl acetate. The combined organic extracts were
washed with water, brine, dried and evaporated to dryness to afford
the pure product (3.0 g, 93.8%): .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 7.10 (d, 2H), 6.80 (d, 2H, J=8.4 Hz), 3.78 (s, 3H), 3.61
(s, 3H), 3.08 (t, 2H, J=7.6 Hz), 2.70 (m, 2H), 2.48 (m, 2H), 1.45
(m, 2H), 0.86 (t, 3H, J=7.6 Hz); ESMS M/z (relative intensity)
236.1 (M+H.sup.+, 100).
Step C: Preparation of
##STR00375##
[0787] To a solution of 3-(4-Methoxyphenyl)-N-propyl-propionimidic
acid methyl ester (3.0 g, 12.77 mmol) in methylene chloride (10 mL)
was added 4-trifluoromethylphenylhydrazine (2.25 g, 12.77 mmol) in
methylene chloride (10 mL) and the reaction mixture is stirred
overnight at 45.degree. C. HPLC and TLC analysis revealed the
presence of considerable starting material. The reaction mixture
was refluxed overnight with no appreciable change. The reaction
solvent was evaporated and replaced with 1,2-dichloroethane (20
mL). The reaction mixture was stirred at 84.degree. C. over 72 hr.
The reaction mixture was quenched with water, extracted with ethyl
acetate. The combined organic extracts were washed with water,
brine, dried and evaporated to dryness to afford the crude product
(5.3 g) which was carried on to the next step without further
purification: ESMS m/z (relative intensity) 378.0 (M-H.sup.+,
50).
Step D: Preparation of
5-[2-(4-Methoxyphenyl)ethyl]-4-propyl-2-(4-trifluoromethylphenyl)-2,4-dih-
ydro-[1,2,4]triazol-3-one
##STR00376##
[0788] To a solution of the crude hydrazine intermediate from step
C (5.3 g) in anhydrous THF (25 mL) was added carbonyldiimidazole
(2.5 g, 15.38 mmol) and the reaction mixture is stirred overnight
at ambient temperature. The solvent was evaporated and the residue
was purified by flash chromatography on silica gel (gradient of
ethyl acetate in hexanes) yielding the title compound (1.52 g,).
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.18 (d, 2H, J=8.0 Hz),
7.65 (d, 2H, J=8.0 Hz), 7.18 (d, 2H, J=7.8 Hz), 7.83 (d, 2H, 8.0
Hz), 3.80 (s, 3H), 3.55 (t, 2H, J=8.0 Hz), 3.08 (t, 2H, J=8.0 Hz),
2.82 (m, 2H), 1.65 (m, 2H), 0.96 (s, 3H); ESMS m/z (relative
intensity) 406.2 (M+H.sup.+, 100).
Step E: Preparation of
5-[2-(4-Hydroxyphenyl)ethyl]-4-propyl-2-(4-trifluoromethylphenyl)-2,4-dih-
ydro-[1,2,4]triazol-3-one
##STR00377##
[0789] To a solution of
5-[2-(4-Methoxyphenyl)ethyl]-4-propyl-2-(4-trifluoromethylphenyl)-2,4-dih-
ydro-[1,2,4]triazol-3-one (1.52 g, 3.75 mmol) in methylene chloride
(36 mL) at -78.degree. C. was added boron tribromide (0.75 mL) and
allowed to warm to ambient temperature. After 2 h, the reaction was
quenched with water and extracted with ethyl acetate. The combined
organic layers were washed with water, brine, dried and evaporated
to dryness to yield the product (1.35 g, 92.5%). .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 8.13 (d, 2H, J=8.8 Hz), 7.81 (d, 2H, J=8.8
Hz), 7.09 (d, 2H, J=8.4 Hz), 6.66 (m, 2H), 3.56 (t, 2H), 2.89 (m,
4H), 1.58 (m, 2H), 0.84 (m, 3H); ESMS m/z (relative intensity)
392.2 (M+H.sup.+, 100), 390.1 (M-H.sup.+, 100).
Step F: Preparation of
2-Methyl-2-(4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-
-1H-[1,2,4]triazol-3-yl]-ethyl}-phenoxy)-propionic acid ethyl
ester
##STR00378##
[0790] To a mixture of
5-[2-(4-Hydroxyphenyl)ethyl]-4-propyl-2-(4-trifluoromethylphenyl)-2,4-dih-
ydro-[1,2,4]triazol-3-one (0.10 g, 0.26 mmol) and cesium carbonate
(0.16 g, 0.49 mmol) in anhydrous DMF (2.5 mL) was added ethyl
2-bromoisobutyrate (81.1 mg, 60.6 .quadrature.L, 0.42 mmol). The
reaction mixture was heated to 75.degree. C. overnight. More ethyl
2-bromoisobutyrate (30.3 .quadrature.L) was added and the mixture
was stirred at 110.degree. C. overnight and ambient temperature
over the weekend. The reaction mixture was quenched with water and
extracted with ethyl acetate. The combined organic extracts were
washed with 5% aqueous lithium chloride solution, water, brine,
dried and evaporated. Chromatotron chromatography (gradient of
ethyl acetate in hexanes) gave the pure compound (94 mg, 70.7%):
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.14 (m, 2H), 7.65 (m,
2H,), 7.10 (m, 2H), 6.80 (m, 2H), 4.23 (m, 2H), 3.53 (m, 2H), 3.05
(m, 2H), 2.83 (m, 2H), 1.70 (m, 2H), 1.57 (s, 6H), 1.26 (m, 6H);
ESMS m/z (relative intensity) 506.1 (M+H.sup.+, 100).
Step G:
2-Methyl-2-(4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-
-dihydro-1H-[1,2,4]triazol-3-yl]-ethyl}-phenoxy)-propionic acid
##STR00379##
[0791]
2-Methyl-2-(4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-d-
ihydro-1H-[1,2,4]triazol-3-yl]-ethyl}-phenoxy)-propionic acid ethyl
ester (94 mg, 0.19 mmol) and a 2N solution of sodium hydroxide (2.3
mL) in ethanol (5 mL) was heated to 80.degree. C. for 35 min. The
solvent was evaporated, water added and the solution made acidic
with concentrated hydrochloric acid (pH 0-1), extracted with ether.
The combined organic extracts were washed with water, brine, dried
and evaporated to dryness to afford the pure compound (82 mg,
92.3%): .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.06 (d, 2H, J=8.3
Hz), 7.59 (d, 2H, J=8.3 Hz), 7.09 (d, 2H, 6.4 Hz), 6.83 (d, 2H,
J=8.3 Hz), 3.45 (t, 2H, J=7.4 Hz), 3.02 (d, 2H, J=7.3 Hz), 2.79 (m,
2H), 1.60 (m, 2H), 1.52 (s, 6H), 0.87 (t, 3H, J=7.8 Hz); ESMS m/z
(relative intensity) 476.1 (M-H.sup.+, 50).
[0792] The following compounds were made in substantially similar
method:
Example 134
(4-{2-[5-Oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-[1,2,4]t-
riazol-3-yl]-ethyl}-phenoxy)-acetic acid
##STR00380##
[0794] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.08 (d, 2H, J=8.3
Hz), 7.60 (d, 2H, J=8.3 Hz), 7.12 (d, 2H, J=8.8 Hz), 6.82 (d, 2H,
8.8 Hz), 4.60 (s, 2H) 3.48 (t, 2H, J=7.4 Hz), 3.03 (d, 2 H, J=7.4
Hz), 2.80 (t, 2H, J=7.4 Hz), 1.60 (m, 2H), 0.88 (t, 3H, J=7.3 Hz);
ESMS m/z (relative intensity) 450.2 (M+H.sup.+, 80).
Example 135
2-Methyl-2-(4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro--
1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-propionic acid
##STR00381##
[0796] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.12 (d, 2H, J=8.8
Hz), 7.80 (d, 2H, J=8.81 Hz), 7.12 (d, 2H, J=8.31 Hz), 6.74 (d, 2H,
8.8 Hz), 3.56 (m, 2H), 2.64 (m, 4H), 1.96 (m, 2H), 1.60 (m, 2H),
1.45 (s, 6H), 0.85 (t, 3H, J=7.33 Hz); ESMS m/z 492.15
(M+H.sup.+).
Example 136
(4-{2-[5-Oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-[1,2,4]t-
riazol-3-yl]-propyl}-phenoxy)-acetic acid
##STR00382##
[0798] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.12 (d, 2H, J=8.8
Hz), 7.80 (d, 2H, J=8.8 Hz), 7.14 (d, 2H, J=8.31 Hz), 6.82 (d, 2H,
8.32 Hz), 4.60 (s, 2H), 3.56 (t, 2H, J=7.33 Hz), 2.64 (m, 4H), 1.96
(m, 2H), 1.60 (m, 2H), 0.85 (t, 3H, J=7.34 Hz); ESMS m/z 464.14
(M+H.sup.+).
Example 137
(4-{2-[4-[2-(2-Fluoro-phenyl)-ethyl]-5-oxo-1-(4-trifluoromethyl-phenyl)-4,-
5-dihydro-1H-[1,2,4]triazol-3-yl]-ethyl}-phenoxy)-acetic acid
##STR00383##
[0800] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 2.48-2.52 (m,
2H), 2.75-2.79 (m, 2H), 2.96 (m, 2H), 3.85 (m, 2H), 4.44 (s, 2H),
6.78 (d, J=7.82 Hz, 2H), 7.06-7.14 (m, 4H), 7.24-7.28 (m, 2H), 7.80
(d, J=8.32 Hz, 2H), 8.10 (d, J=8.32 Hz, 2H); MS (ES, m/z):
C.sub.27H.sub.23F.sub.4N.sub.3O.sub.4: 529.99 (M.sup.++1), 528.01
(M.sup.+-1)
Example 138
2-(4-{2-[4-[2-(2-Fluoro-phenyl)-ethyl]-5-oxo-1-(4-trifluoromethyl-phenyl)--
4,5-dihydro-1H-[1,2,4]triazol-3-yl]-ethyl}-phenoxy)-2-methyl-propionic
acid
##STR00384##
[0802] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 1.54 (s, 6H),
2.62 (t, J=7.33 Hz, 2H), 2.87 (t, J=7.34 Hz, 2H), 3.05 (m, 2H),
3.93 (m, 2H), 6.82 (d, J=8.32 Hz, 2H), 7.15-7.23 (m, 4H), 7.33-7.37
(m, 2H), 7.89 (d, J=8.32 Hz, 2H), 8.18 (d, J=8.31 Hz, 2H); MS (ES,
m/z): C.sub.29H.sub.27F.sub.4N.sub.3O.sub.4: 558.05 (M.sup.++1),
556.07 (M.sup.+-1).
Example 139
(4-{3-[4-[2-(2-Fluoro-phenyl)-ethyl]-5-oxo-1-(4-trifluoromethyl-phenyl)-4,-
5-dihydro-1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-acetic acid
##STR00385##
[0804] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 1.76-1.80 (m,
2H), 2.23 (t, J=7.82 Hz, 2H), 2.51 (t, J=7.34 Hz, 2H), 2.97 (t,
J=6.85 Hz, 2H), 3.83 (t, J=6.85 Hz, 2H), 4.61 (s, 2H), 6.81 (d,
J=8.80 Hz, 2H), 7.07-7.13 (m, 4H), 7.22-7.26 (m, 2H), 7.80 (d,
J=8.80 Hz, 2H), 8.10 (d, J=8.82 Hz, 2H); MS (ES, m/z):
C.sub.28H.sub.25F.sub.4N.sub.3O.sub.4: 544.24 (M.sup.++1), 542.21
(M.sup.+-1).
Example 140
2-(4-{3-[4-[2-(2-Fluoro-phenyl)-ethyl]-5-oxo-1-(4-trifluoromethyl-phenyl)--
4,5-dihydro-1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-2-methyl-propionic
acid
##STR00386##
[0806] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 1.46 (s, 6H),
1.78 (m, 2H), 2.24 (t, J=7.83 Hz, 2H), 2.51 (t, J=7.82 Hz, 2H),
2.97 (t, J=6.36 Hz, 2H), 3.83 (t, J=6.80 Hz, 2H), 6.74 (d, J=8.32
Hz, 2H), 7.05-7.11 (m, 4H), 7.24 (m, 2H), 7.79 (d, J=8.80 Hz, 2H),
8.10 (d, J=8.32 Hz, 2H); MS (ES, m/z):
C.sub.30H.sub.29F.sub.4N.sub.3O.sub.4: 572.20 (M.sup.++1), 570.30
(M.sup.+-1)
Example 141
2-methyl-4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H--
[1,2,4]triazol-3-yl]-ethyl}-phenoxy)acetic acid
##STR00387##
[0807] Step A: Preparation of
(2-Iodo-4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H--
[1,2,4]triazol-3-yl]-ethyl}-phenoxy)-acetic acid ethyl ester
##STR00388##
[0808] A mixture of
(4-{2-[5-Oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-[1,2,4]-
triazol-3-yl]-ethyl}-phenoxy)acetic acid ethyl ester (180 mg, 0.38
mmol), iodine (105 mg, 0.42 mmol), silver sulfate (131 mg, 0.42
mmol) and ethanol were stirred at room temperature. After 3.5 h,
more iodine (86 mg) and silver sulfate (106 mg) were added and
stirred for another 0.5 h. The reaction mixture was quenched with
water and extracted with ethyl acetate. The combined organic
extracts were washed with water, brine, dried and evaporated to
dryness to afford the product (217 mg, 95%). .sup.1HMR (400 MHz,
CDCl.sub.3) .delta. 8.15 (d, 2H, J=8.4 Hz), 7.73 (s, 1H), 7.67 (d,
2H, J=8.4 Hz), 7.18 (m, 1H), 6.67 (d, 1H, J=8.0 Hz), 4.66 (s, 2H),
4.26 (q, 2H, J=7.6 Hz), 3.68 (t, 2H, J=7.3 Hz), 3.05 (t, 2H, J=7.4
Hz), 2.82 (t, 2H, J=7.3 Hz), 1.7 (m, 2H), 1.29 (t, 3H, J=7.6 Hz),
0.96 (t, 3H, J=7.6 Hz); ESMS m/z (relative intensity) 604.2
(M+H.sup.+, 100).
Step B: Preparation of
2-methyl-4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-
-[1,2,4]triazol-3-yl]-ethyl}-phenoxy)acetic acid ethyl ester
##STR00389##
[0809] A mixture of
2-iodo-4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-[-
1,2,4]triazol-3-yl]-ethyl}-phenoxy)acetic acid (182 mg, 0.3 mmol),
methylboronic acid (53.9 mg, 0.9 mmol) and cesium fluoride (136.7
mg, 0.9 mmol) in dioxane (3 mL) was degassed and filled with
nitrogen for three times, then
[1,1'bis(diephenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (1:1) (36 mg, 0.04 mmol) was added and
the reaction mixture was heated to 80.degree. C. After 4 h,
reaction mixture was filtered through celite and evaporated. Flash
chromatography on silica gel (gradient of ethyl acetate in hexanes)
yielded the pure compound (73 mg, 49.3%): .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 8.16 (d, 2H, J=8.4 Hz), 7.66 (d, 2H, J=8.8 Hz),
7.05 (s, 1H), 7.00 (m, 1H), 6.64 (d, 1H, J=8.0 Hz), 4.62 (s, 2H),
4.25 (m, 2H), 3.56 (t, 2H, J=8.0 Hz), 3.02 (t, 2H, J=8.4 Hz), 2.83
(t, 2H, J=8.4 Hz), 2.29 (s, 3H), 1.7 (m, 2H), 1.29 (t, 3H, J=6.8
Hz), 0.95 (t, 3H, J=7.2 Hz); ESMS m/z (relative intensity) 492.2
(M+H.sup.+, 75).
Step C: Preparation of
2-methyl-4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-
-[1,2,4]triazol-3-yl]-ethyl}-phenoxy)acetic acid
##STR00390##
[0810] A mixture of
2-methyl-4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-
-[1,2,4]triazol-3-yl]-ethyl}-phenoxy)acetic acid ethyl ester (70
mg, 0.14 mmol) and a 2N solution of sodium hydroxide (1.6 mL) in
ethanol (3.3 mL) was heated to 75.degree. C. for 45 min. The
solvent was evaporated, water added and the solution made acidic
with concentrated hydrochloric acid (pH 0-1), extracted with ether.
The combined organic extracts were washed with water, brine, dried
and evaporated to dryness to afford the pure compound (60 mg,
96.4%): .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.09 (d, 2H, J=8.8
Hz), 7.60 (d, 2H, J=8.8 Hz), 6.99 (S, 1H), 6.94 (m, 1H), 6.60 (d,
1H, 8.4 Hz), 4.61 (s, 2H), 3.48 (t, 2H, J=8.0 Hz), 2.98 (t, 2H,
J=8.4 Hz), 2.76 (t, 2H, J=7.2 Hz), 2.21 (s. 3H), 1.62 (m, 2H), 0.88
(t, 3H, J=7.6 Hz); ESMS m/z (relative intensity) 464.2 (M+H.sup.+,
40), 462.1 (M-H.sup.+, 100).
[0811] The following compounds were made in a substantially similar
method:
Example 142
2-Methyl-2-(2-methyl-4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-
-dihydro-1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-propionic
acid
##STR00391##
[0813] HNMR (400 MHz, CDCl.sub.3) F 8.15 (m, 2H), 7.80 (m, 2H),
6.99 (s, 1H), 6.94 (m, 1H), 6.62 (m, 1H), 3.56 (m, 2H), 2.62 (m,
4H), 2.10 (s, 3H), 1.98 (m, 2H), 1.60 (m, 2H), 1.45 (s, 6H), 0.85
(m, 3H); ESMS m/z 506.3 (M+H.sup.+)
Example 143
2-Methyl-2-(2-methyl-4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-
-dihydro-1H-[1,2,4]triazol-3-yl]-ethyl}-phenoxy)-propionic acid
##STR00392##
[0815] HNMR (400 MHz, CDCl.sub.3) D 8.13 (d, 2H, J=8.8 Hz), 7.82
(d, 2H, J=9.3 Hz), 7.1 (m, 1H), 7.0 (m, 1H), 6.62 (m, 1H), 3.58 (m,
2H), 2.91 (s, 4H), 2.12 (s, 3H), 1.59 (m, 2H), 1.46 (s, 6H), 0.85
(m, 3H); ESMS m/z 492.3 (M+H.sup.+)
Example 144
2-Methyl-2-(2-vinyl-4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5--
dihydro-1H-[1,2,4]triazol-3-yl]-ethyl}-phenoxy)-propionic acid
##STR00393##
[0817] HNMR (400 MHz, CDCl.sub.3) .quadrature. 8.13 (d, 2H, J=8.32
Hz), 7.81 (d, 2H, J=8.8 Hz), 7.51 (d, 1H, J=2.44 Hz), 7.13 (m, 1H),
6.96 (m, 1H), 6.69 (m, 1H), 5.78 (m, 1H), 5.23 (m, 1H), 3.58 (t,
2H, J=7.34 Hz), 2.96 (m, 4H), 1.60 (m, 2H), 1.46 (s, 6H), 0.84 (t,
3H, J=7.3 Hz); ESMS m/z 504.03 (M+H.sup.+)
Example 145
(2-Iodo-4-{2-[5-oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-[-
1,2,4]triazol-3-yl]-ethyl}-phenoxy)acetic acid
##STR00394##
[0819] .sup.1HNMR (400 MHz, CDCl.sub.3) .quadrature. 8.08 (d, 2H,
J=8.4 Hz), 7.69 (s, 1H), 7.61 (d, 2H, J=8.8 Hz), 7.11 (d, 1H, J=8.4
Hz), 6.65 (d, 1H, 8.0 Hz), 4.63 (s, 2H), 3.51 (t, 2H, J=7.6 Hz),
3.01 (t, 2H, J=7.6 Hz), 2.77 (t, 2H, J=7.2 Hz), 1.63 (m, 2H), 0.89
(t, 3H, J=7.2 Hz); ESMS M/z (relative intensity) 576.0 (M+H.sup.+,
100), 574.0 (M-H.sup.+, 100).
Example 146
(4-{2-[4-[2-(2-Fluoro-phenyl)-ethyl]-5-oxo-1-(4-trifluoromethyl-phenyl)-4,-
5-dihydro-1H-[1,2,4]triazol-3-yl]-ethyl}-2-methyl-phenoxy)-acetic
acid
##STR00395##
[0821] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 2.15 (s, 3H),
2.47-2.51 (m, 2H), 2.75 (t, J=7.34 Hz, 2H), 2.97 (t, J=6.36 Hz,
2H), 3.85 (t, J=6.36 Hz, 2H), 4.63 (s, 2H), 6.70 (d, J=8.32 Hz,
1H), 6.91-6.96 (m, 2H), 7.08-7.14 (m, 2H), 7.24-7.29 (m, 2H), 7.81
(d, J=8.31 Hz, 2H), 8.10 (d, J=8.31 Hz, 2H); MS (ES, m/z):
C.sub.28H.sub.25F.sub.4N.sub.3O.sub.4: 544.01 (M.sup.++1), 542.05
(M.sup.+-1)
Example 147
2-(4-{2-[4-[2-(2-Fluoro-phenyl)-ethyl]-5-oxo-1-(4-trifluoromethyl-phenyl)--
4,5-dihydro-1H-[1,2,4]triazol-3-yl]-ethyl}-2-methyl-phenoxy)-2-methyl-prop-
ionic acid
##STR00396##
[0823] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 1.46 (s, 6H),
2.12 (s, 3H), 2.50-2.52 (m, 2H), 2.74 (t, J=7.83 Hz, 2H), 2.96 (t,
J=6.85 Hz, 2H), 3.84 (t, J=6.85 Hz, 2H), 6.59 (d, J=7.83 Hz, 1H),
6.88 (d, J=8.31 Hz, 1H), 6.97 (s, 1H), 7.10-7.12 (m, 2H), 7.25-7.29
(m, 2H), 7.81 (d, J=8.30 Hz, 2H), 8.10 (d, J=8.30 Hz, 2H); MS (ES,
M/z): C.sub.30H.sub.29F.sub.4N.sub.3O.sub.4: 571.97 (M.sup.++1),
570.00 (M.sup.+-1)
Example 148
(4-{3-[4-[2-(2-Fluoro-phenyl)-ethyl]-5-oxo-1-(4-trifluoromethyl-phenyl)-4,-
5-dihydro-1H-[1,2,4]triazol-3-yl]-propyl}-2-methyl-phenoxy)-acetic
acid
##STR00397##
[0825] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 1.76-1.80 (m,
2H), 2.15 (s, 3H), 2.23 (t, J=7.82 Hz, 2H), 2.45-2.48 (m, 2H), 2.96
(t, J=6.36 Hz, 2H), 3.83 (t, J=6.85 Hz, 2H), 4.63 (s, 2H), 6.70 (d,
J=8.32 Hz, 1H), 6.90 (d, J=7.83 Hz, 1H), 6.95 (s, 1H), 7.07-7.12
(m, 2H), 7.22 (m, 2H), 7.80 (d, J=8.80 Hz, 2H), 8.10 (d, J=8.32 Hz,
2H); MS (ES, m/z): C.sub.29H.sub.27F.sub.4N.sub.3O.sub.4: 558.23
(M.sup.++1), 556.23 (M.sup.+-1)
Example 149
2-(4-{3-[4-[2-(2-Fluoro-phenyl)-ethyl]-5-oxo-1-(4-trifluoromethyl-phenyl)--
4,5-dihydro-1H-[1,2,4]triazol-3-yl]-propyl}-2-methyl-phenoxy)-2-methyl-pro-
pionic acid
##STR00398##
[0827] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 1.46 (S, 6H),
1.76-1.80 (m, 2H), 2.11 (s, 3H), 2.23 (t, J=7.82 Hz, 2H), 2.45 (t,
J=7.82 Hz, 2H), 2.96 (t, J=6.36 Hz, 2H), 3.83 (t, J=6.85 Hz, 2H),
6.60 (d, J=8.31 Hz, 1H), 6.86 (dd, J.sub.1=8.31 Hz, J.sub.2=1.96
Hz, 1H), 6.96 (d, J=1.96 Hz, 1H), 7.07-7.11 (m, 2H), 7.21-7.26 (m,
2H), 7.79 (d, J=8.80 Hz, 2H), 8.10 (d, J=8.80 Hz, 2H); MS (ES,
m/z): C.sub.31H.sub.31F.sub.4N.sub.3O.sub.4: 586.2 (M.sup.++1),
584.2 (M.sup.+-1)
Example 150
##STR00399##
[0828] Preparation of Form Iv Polymorph
[0829] Title compound (5.75 g) is combined with ethyl acetate (30
mL) and heated to reflux as a slurry. Additional ethyl acetate (19
mL) is added and solution at reflux is obtained. The solution is
cooled and crystallization occurs. The slurry is cooled to
0.degree. C. and held at that temperature for 1 hr. then filtered
and the filter cake rinsed with cold ethyl acetate. The crystals
obtained are dried in vacuo at 60.degree. C. overnight to afford
the title compound as the desired form IV polymorph: 5.45 g, 94.5%.
mp: 129.4-130.3.degree. C.
TABLE-US-00041 Form IV Angle d value 2-Theta .degree. Angstrom %
Intensity % 6.863 12.87 4.7 7.933 11.135 25.7 13.225 6.689 49.9
13.746 6.437 12.5 15.023 5.893 1.2 15.97 5.545 33.9 16.669 5.314
4.3 17.005 5.21 3.1 17.327 5.114 23.1 17.925 4.944 12 19.598 4.526
30.5 20.132 4.407 2 20.453 4.339 3.2 20.764 4.274 100 21.714 4.089
2 21.954 4.045 2.2 22.736 3.908 2.4 24.055 3.697 32.5 24.538 3.625
3.2 24.803 3.587 5.5 25.498 3.491 5 26.667 3.34 7.4 27.83 3.203 3.4
28.333 3.147 1.6 28.739 3.104 6.5 29.503 3.025 0.8 30.193 2.9575
4.2 30.552 2.9236 1.4 30.894 2.8921 0.8 32.905 2.7197 1.1 33.296
2.6887 1 34.198 2.6198 2.7
Example 151
Preparation of
##STR00400##
[0830] Step A: Preparation of
##STR00401##
[0832] To a solution of 5-bromo salicylaldehyde (3.15 g, 15.6 mmol)
in DMF (10 mL) at room temperature was added K.sub.2CO.sub.3 (5.0
g, 36.2 mmol) and ethyl bromoacetate (2.6 mL, 23.4 mmol). The
mixture was stirred at room temperature for one hour. The mixture
was diluted with diethyl ether (20 mL) and 1N HCl was added until
pH 3-4. The organic layer was separated and washed with water and
brine. The organic layer was dried over MgSO.sub.4 and the solvent
removed under reduced pressure to give the titled compound.
[0833] C.sub.11H.sub.11BrO.sub.4. (MW: 287.11); MS: m/z (M.sup.++1)
288.1.
Step B: Preparation of
##STR00402##
[0835] To a solution of MeONa (prepared from 88 mg of Na (3.8 mmol)
in 10 mL of MeOH) was added a solution of the Step A product in
methanol (1 mL) at room temperature. The mixture was refluxed for
10 minutes in a preheated bath at 80.degree. C. Then, the reaction
mixture was allowed to cool to room temperature and the titled
compound precipitate from the solution as a white solid. The solid
was filtered off and dry under vacuum.
[0836] C.sub.10H.sub.7BrO.sub.3 (MW: 255.07); MS: m/z (M.sup.++1)
256.
Step C: Preparation of
##STR00403##
[0838] To a solution of the product prepared as in Example 38, Step
D (11.3 g, 0.0436 mol) in methyl ethyl ketone (300 mL), was added
3,4-dimethylbenzyl chloride (16.0 mL, 0.1089 mol) followed by
potassium carbonate powder (30.1 g, 0.1382 mol) The resulting
mixture was stirred at 80-85.degree. C. under a drying tube for 48
hours. The reaction mixture was cooled to room temperature and then
partitioned between ethyl acetate (300 mL) and NH.sub.4Cl saturated
aqueous solution (300 mL). The aqueous layer was extracted with
ethyl acetate (200 mL) and the combined organic phase dried over
Na.sub.2SO.sub.4 and filtered. Evaporation of solvent gave a crude
product, which was purified on a silica gel column eluting with 50%
ethyl acetate in hexane to give the titled compound as colorless
oil.
[0839] C.sub.23H.sub.29N.sub.3O.sub.2 (MW=379.51); MS: m/z
(M.sup.++1)=380.2
Step D: Preparation of
##STR00404##
[0841] To a solution of the Step C product (16.0 g, 0.0421 mol) in
ethanol (400 mL) at room temperature, palladium, 10% on activated
carbon (4.2 g) was added. Mixture was stirred under hydrogen
atmosphere (balloon) for 3 hours and then filtered through a plug
of celite. Evaporation of the solvent gave the titled compound that
was used in Step E without further purification.
[0842] C.sub.16H.sub.23N.sub.3O.sub.2 (MW=289.38); MS: m/z
(M.sup.++1)=290.2
Step E: Preparation of
##STR00405##
[0844] To a solution of triphenylphosphine (8.1 g, 31.0 mmol) and
imidazole (2.1 g, 31.0 mmol) in a 3:1 mixture of
Et.sub.2O--CH.sub.3CN (160 mL) at 0.degree. C. under nitrogen
atmosphere, iodine (7.8 g, 31.0 mmol) was added in small portions
with vigorous stirring. The resulting mixture was warmed at room
temperature and stirred for 30 minutes. Then, mixture was cooled to
0.degree. C. and a solution of the Step D product (6.0 g, 20.7
mmol) in a 1:1 mixture of Et.sub.2O--CH.sub.3CN (40 mL) was added.
Reaction was stirred at 0.degree. C. for 15 min and at room
temperature for 30 minutes and then poured onto 0.5N HCl (200 mL).
The aqueous layer was extracted twice with a 1:1 mixture of
Et.sub.2O-hexanes (300 mL) and the combined organic phase dried
over Na.sub.2SO.sub.4 and filtered. Evaporation of solvent gave a
crude product, which was purified on a silica gel column eluting
with 50% ethyl acetate in hexane to give the titled compound as
yellow oil.
[0845] C.sub.16H.sub.221N.sub.3O (MW=399.28); MS: m/z
(M.sup.++1)=400.2
Step F: Preparation of
##STR00406##
[0847] To a stirred slurry of zinc dust (0.968 g, 14.7 mmol) in
anhydrous THF (5 mL) under nitrogen atmosphere at 60.degree. C. was
added 1,2-dibromoethane (63 .mu.L, 0.7 mmol). After 15 minutes of
vigorous stirring, the slurry was allowed to cool to room
temperature and chlorotrimethylsilane (78 .mu.L, 0.6 mmol) was
added. Mixture was stirred for 30 minutes and then a solution of
the Step E product (0.98 g, 2.46 mmol) in anhydrous THF (5 mL) was
added dropwise. Mixture was reheated to 60.degree. C. and then
stirred for 10 minutes. A solution of the Step B (0.210 g, 0.82
mmol), Pd(dba).sub.2 (0.0237 g, 0.04 mmol) and tri-o-tolylphosphine
(0.025 g, 0.082 mmol) in anhydrous THF (2.5 mL) was added and the
resulting solution maintained at 60.degree. C. for 2 h. Reaction
was then cooled at room temperature and poured onto a 1:1 mixture
of AcOEt and 0.5N HCl (40 mL). The layers were separated and the
aqueous phase was extracted with ethyl acetate (20 mL). The
combined organic layers were washed with 0.5N HCl (20 mL), dried
over Na.sub.2SO.sub.4 and filtered. Evaporation of solvent gave a
crude product, which was purified on a silica gel column eluting
with 50% ethyl acetate in hexane to give the titled compound as
colorless oil.
[0848] C.sub.26H.sub.29N.sub.3O.sub.4 (MW=447.54); MS: m/z
(M.sup.++1)=448.2.
Step G: Preparation of
##STR00407##
[0850] To a solution of Step F product (0.235 g, 0.52 mmol) in THF
(10.5 mL) at room temperature a 1N solution of LiOH (4.2 mL, 4.2
mmol) was added. The mixture was stirred overnight, and then layers
were separated. The aqueous layer was washed with diethyl ether
(3.times.10 mL), and cooled to 0.degree. C. After the pH was
adjusted to 1-2 by addition of 1N HCl, the aqueous layer was
extracted with AcOEt (2.times.20 mL). The combined organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated to
dryness to give the titled compound.
[0851] C.sub.25H.sub.27N.sub.3O.sub.4 (MW=433.51); MS: m/z
(M.sup.++1)=434.2.
Example 152
Preparation of
##STR00408##
[0852] Step A: Preparation of
##STR00409##
[0854] To a solution Step A Example 151 product (2.5 g, 8.7 mmol)
in EtOH (10 mL) at 0.degree. C. was added in one portion NaBH.sub.4
(0.394 g, 10.4 mmol). The mixture was stirred for 90 min allowing
the temperature to rise. Then acetone (1 mL) was added and the
solvent was removed under vacuum. The oil obtained was dissolved in
CH.sub.2Cl.sub.2 (20 mL) and washed with Brine (20 mL). The layers
were separated and the organic one was dried over Na.sub.2SO.sub.4
and filtered. Evaporation of solvent yielded the titled compound in
pure form.
[0855] C.sub.11H.sub.11BrO.sub.4. (MN: 289.11); MS: m/z (M.sup.++1)
290.1.
Step B: Preparation of
##STR00410##
[0857] To a solution SOCl.sub.2 (0.7 mL, 10.3 mmol) and Pyridine (3
drops) in CH.sub.2Cl.sub.2 (10 mL) at room temperature was added
dropwise a solution of Step A product (2.5 g, 8.6 mmol) in
CH.sub.2Cl.sub.2 (5 mL). The reaction mixture was heated at
50.degree. C. for 2 h, then allowed to cool and washed with a
saturated aqueous solution of NaHCO.sub.3 (10 mL). The layers were
separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2
(2.times.10 mL). The organics were joined, dried over
Na.sub.2SO.sub.4 and filtered. Evaporation of solvent yielded the
titled compound in pure form.
[0858] C.sub.11H.sub.12BrClO.sub.3. (MW: 307.57); MS: m/z
(M.sup.++1) 307.0.
Step C: Preparation of
##STR00411##
[0860] To a solution of Step B product (1.83 g, 5.9 mmol) in
N-methyl-2-pyrrolidinone (6 mL) at 0.degree. C. under N.sub.2
atmosphere was added in one portion NaH (60% mineral oil, 0.283 g,
7 mmol). The reaction mixture was stirred at room temperature for a
day, then some drops of MeOH were added. The mixture was diluted in
AcOEt (20 mL) and HCl 10% (20 mL). The layers were separated and
the organic layer was wasted with HCl 10% (2.times.20 mL), and
finally with Brine (20 mL). The organic layer was dried over
Na.sub.2SO.sub.4 and filtered. Evaporation of solvent yield the
titled compound.
[0861] C.sub.10HgBrO.sub.3 (MW: 257.09); MS: m/z (M.sup.++1)
257.0.
Step D: Preparation of
##STR00412##
[0863] To a solution of the Example 38, Step B product (82.2 g,
0.423 mol) in THF (400 mL), was added a solution of propyl
isocyanate (Aldrich, 47.6 mL, 0.508 mol) in THF (400 mL) dropwise
and the mixture was stirred at room temperature for an hour.
Evaporation of solvent gave the titled compound as an off-white
powder that was used in step E without further purification.
[0864] C.sub.15H.sub.23N.sub.3O.sub.3 (MW=293.37); MS: m/z
(M.sup.++1)=294.2
Step E: Preparation of
##STR00413##
[0866] A suspension of the Step D product (124.0 g, 0.423 mol) in a
solution of KOH (28.5 g, 0.508 mol) in water (570 mL) (1.2 eq of 5%
KOH aqueous solution) was heated at 11.degree. C. for 1 hour (as
soon as the temperature is increased, suspension disappear). At
that time, TLC showed no starting material remained and reaction
was cooled to room temperature. Then, pH was adjusted to pH=6-7 by
addition of 1N HCl, and extracted with AcOEt (3.times.500 mL). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and evaporated to give the titled compound as white solid.
[0867] C.sub.15H.sub.21N.sub.3O.sub.2 (MW 275.35); MS: m/z
(M.sup.++1)=276.2
Step F: Preparation of
##STR00414##
[0869] To a solution of the Step E product (11.5 g, 0.0418 mol) in
methyl ethyl ketone (300 mL), was added 4-methylbenzyl bromide
(11.6 g, 0.0616 mol) followed by potassium carbonate powder (28.9
g, 0.209 mol). The resulting mixture was stirred at 80-85.degree.
C. under a drying tube for 24 hours. The reaction mixture was
cooled to room temperature and then partitioned between ethyl
acetate (300 mL) and NH.sub.4Cl saturated aqueous solution (300
mL). The aqueous layer was extracted with ethyl acetate (200 mL)
and the combined organic phase dried over Na.sub.2SO.sub.4 and
filtered. Evaporation of solvent gave a crude product, which was
purified on a silica gel column eluting with 50% ethyl acetate in
hexane to give the titled compound as colorless oil.
[0870] C.sub.23H.sub.29N.sub.3O.sub.2 (NW=379.51); MS: m/z
(M.sup.++1)=380.2
Step G: Preparation of
##STR00415##
[0872] To a solution of the Step F product (10.0 g, 0.0263 mol) in
ethanol (500 mL) at room temperature, palladium, 10% on activated
carbon (2.6 g) was added. Mixture was stirred under hydrogen
atmosphere (balloon) for 3 hours and then filtered through a plug
of celite. Evaporation of the solvent gave the titled compound as
white solid that was used in Step H without further
purification.
[0873] C.sub.16H.sub.23N.sub.3O.sub.2 (MW=289.38); MS: m/z
(M.sup.++1)=290.2
Step H: Preparation of
##STR00416##
[0875] To a solution of triphenylphosphine (10.3 g, 39.4 mmol) and
imidazole (2.7 g, 39.4 mmol) in a 3:1 mixture of
Et.sub.2O--CH.sub.3CN (200 mL) at 0.degree. C. under nitrogen
atmosphere, iodine (10.0 g, 39.4 mmol) was added in small portions
with vigorous stirring. The resulting mixture was warmed at room
temperature and stirred for 1 hour. Then, mixture was cooled to
0.degree. C. and a solution of the Step G product (7.6 g, 26.3
mmol) in a 1:1 mixture of Et.sub.2O--CH.sub.3CN (50 mL) was added.
Reaction was stirred at 0.degree. C. for 15 min and at room
temperature for 1 hour and then poured onto 0.5N HCl (100 mL). The
aqueous layer was extracted twice with a 1:1 mixture of
Et.sub.2O-hexanes (200 mL) and the combined organic phase dried
over Na.sub.2SO.sub.4 and filtered. Evaporation of solvent gave a
crude product, which was purified on a silica gel column eluting
with 50% ethyl acetate in hexane to give the titled compound as
yellow oil.
[0876] C.sub.16H.sub.22IN.sub.3O (MW=399.28); MS: m/z
(M.sup.++1)=400.2
Step I: Preparation of
##STR00417##
[0878] To a stirred slurry of zinc dust (0.411 g, 6.3 mmol) in
anhydrous THF (1.5 mL) under nitrogen atmosphere at 60.degree. C.
was added 1,2-dibromoethane (27 .mu.L, 0.31 mmol). After 15 minutes
of vigorous stirring, the slurry was allowed to cool to room
temperature and chlorotrimethylsilane (33 .mu.L, 0.26 mmol) was
added. Mixture was stirred for 30 minutes and then a solution of
the Step H product (0.42 g, 1.05 mmol) in anhydrous THF (1.5 mL)
was added dropwise. Mixture was reheated to 60.degree. C. and then
stirred for 10 minutes. A solution of Step C product (0.285 g, 1.05
mmol), Pd(dba).sub.2 (0.030 g, 0.052 mmol) and tri-o-tolylphosphine
(0.032 g, 0.105 mmol) in anhydrous THF (2.5 mL) was added and the
resulting solution maintained at 60.degree. C. for 2 h. Reaction
was then cooled at room temperature and poured onto a 1:1 mixture
of AcOEt and 0.5N HCl (50 mL). The layers were separated and the
aqueous phase was extracted with ethyl acetate (2.times.20 mL). The
combined organic layers were washed with 0.5N HCl (25 mL), dried
over Na.sub.2SO.sub.4 and filtered. Evaporation of solvent gave a
crude product, which was purified on a silica gel column eluting
with 50% ethyl acetate in hexane to give the titled compound as
colorless oil.
[0879] C.sub.26H.sub.31N.sub.3O.sub.4 (MW=449.55); MS: m/z
(M.sup.++1)=450.2.
Step J: Preparation of
##STR00418##
[0881] To a solution of Step I product (0.05 g, 0.11 mmol) in THF
(2.5 mL) at room temperature a 1N solution of NaOH (2.5 mL, 2.5
mmol) was added. The mixture was stirred for two days and then
layers were separated. The aqueous layer was washed with diethyl
ether (4.times.5 mL), and cooled to 0.degree. C. After the pH was
adjusted to 1-2 by addition of 1N HCl, the aqueous layer was
extracted with AcOEt (2.times.10 mL). The combined organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated to
dryness to give the titled compound.
[0882] C.sub.25H.sub.29N.sub.3O.sub.4 (MW=435.53); MS: m/z
(M.sup.++1)=435.2.
Example 153
Preparation of
##STR00419##
[0883] Step A: Preparation of
##STR00420##
[0885] To a solution of 5-bromo salicylaldehyde (2.6 g, 13 mmol) in
DMF (10 mL) at room temperature was added K.sub.2CO.sub.3 (5.5 g,
39 mmol) and ethyl 2-bromopropionate (2.6 mL, 19.5 mmol). The
mixture was stirred at room temperature for two hours. The solid
was filtered off and the filtrate was washed with 1N HCl (10 mL)
and H.sub.2O (10 mL). The organic layer was dried over
Na.sub.2SO.sub.4 and filtered. Evaporation of solvent gave a solid
which was suspended in hexane (30 mL) and filtered yielding the
titled compound in pure form. C.sub.12H.sub.13BrO.sub.4. (MW:
301.14); MS: m/z (M.sup.++1) 302.2.
Step B: Preparation of
##STR00421##
[0887] To a solution Step A product (1.5 g, 4.98 mmol) in EtOH (25
mL) at 0.degree. C. was added in one portion NaBH.sub.4 (0.206 g,
5.47 mmol). The mixture was stirred for 30 min allowing the
temperature to rise. Then acetone (1 mL) was added and the solvent
was removed under vacuum. The oil obtained was dissolved in
CH.sub.2Cl.sub.2 (20 mL) and washed with Brine (20 mL). The layers
were separated and the organic one was dried over Na.sub.2SO.sub.4
and filtered. Evaporation of solvent yielded the titled compound in
pure form.
[0888] C.sub.12H.sub.15BrO.sub.4. (MW: 303.14); MS: m/z (M.sup.++1)
304.2.
Step C: Preparation of
##STR00422##
[0890] To a solution SOCl.sub.2 (0.43 mL, 5.97 mmol) and Pyridine
(2 drops) in CH.sub.2Cl.sub.2 (5 mL) at room temperature was added
dropwise a solution of Step B product (1.3 g, 4.38 mmol) in
CH.sub.2Cl.sub.2 (3 mL). The reaction mixture was heated at
50.degree. C. for 90 min, then allowed to cool and washed with a
saturated aqueous solution of NaHCO.sub.3 (10 mL). The layers were
separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2
(2.times.10 mL). The organics were joined, dried over
Na.sub.2SO.sub.4 and filtered. Evaporation of solvent yielded the
titled compound in pure form.
[0891] C.sub.12H.sub.14BrClO.sub.3. (MW: 321.60); MS: m/z
(M.sup.++1) 321.0.
Step D: Preparation of
##STR00423##
[0893] To a solution of Step C product (1.3 g, 4 mmol) in
N-methyl-2-pyrrolidinone (4 mL) at 0.degree. C. under N.sub.2
atmosphere was added in one portion NaH (60% mineral oil, 0.194 g,
4.85 mmol). The reaction mixture was stirred at room temperature
for a day, then some drops of MeOH were added. The mixture was
diluted in AcOEt (20 mL) and HCl 10% (20 mL). The layers were
separated and the organic layer was wasted with HCl 10% (2.times.20
mL), and finally with Brine (20 mL). The organic layer was dried
over Na.sub.2SO.sub.4 and filtered. Evaporation of solvent yield
the titled compound.
[0894] C.sub.11H.sub.11BrO.sub.3 (MW: 271.11); MS: m/z (M.sup.++1)
271.0.
Step E: Preparation of
##STR00424##
[0896] To a stirred slurry of zinc dust (0.411 g, 6.3 mmol) in
anhydrous THF (1.5 mL) under nitrogen atmosphere at 60.degree. C.
was added 1,2-dibromoethane (27 .quadrature.L, 0.31 mmol). After 15
minutes of vigorous stirring, the slurry was allowed to cool to
room temperature and chlorotrimethylsilane (33 .mu.L, 0.26 mmol)
was added. Mixture was stirred for 30 minutes and then a solution
of the Example 152, Step H product (0.42 g, 1.05 mmol) in anhydrous
THF (1.5 mL) was added dropwise. Mixture was reheated to 60.degree.
C. and then stirred for 10 minutes. A solution of Step D product
(0.271 g, 1.0 mmol), Pd(dba).sub.2 (0.030 g, 0.052 mmol) and
tri-o-tolylphosphine (0.032 g, 0.105 mmol) in anhydrous THF (2.5
mL) was added and the resulting solution maintained at 60.degree.
C. for 2 h. Reaction was then cooled at room temperature and poured
onto a 1:1 mixture of AcOEt and 0.5N HCl (50 mL). The layers were
separated and the aqueous phase was extracted with ethyl acetate
(2.times.20 mL). The combined organic layers were washed with 0.5N
HCl (25 mL), dried over Na.sub.2SO.sub.4 and filtered. Evaporation
of solvent gave a crude product, which was purified on a silica gel
column eluting with 50% ethyl acetate in hexane to give the titled
compound as colorless oil.
[0897] C.sub.27H.sub.33N.sub.3O.sub.4 (MW=463.58); MS: m/z
(M.sup.++1)=464.2.
Step F: Preparation of
##STR00425##
[0899] To a solution of Step D product (0.05 g, 0.10 mmol) in THF
(2 mL) at room temperature a 1N solution of NaOH (2 mL, 2 mmol) was
added. The mixture was stirred for three days, and then layers were
separated. The aqueous layer was washed with diethyl ether
(3.times.10 mL), and cooled to 0.degree. C. After the pH was
adjusted to 1-2 by addition of 1N HCl, the aqueous layer was
extracted with AcOEt (2.times.10 mL). The combined organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated to
dryness to give the titled compound.
[0900] C.sub.26H.sub.31N.sub.3O.sub.4 (MW=449.55); MS: m/z
(M.sup.++1)=450.2.
Example 154
Step A
##STR00426##
[0902] A THF solution of the acid described in Example 127, Step B
(0.300 g, 0.0007 mol) was treated with EDC (0.212 g, 0.0011 mol)
and HOAt (0.095 g, 0.0007 mol). An equivalent 3, 4 dimethyl benzyl
amine (0.10 ml, 0.0007 mol) was added and the reaction was stirred
overnight. The solvent was concentrated and the residue was
redissolved in methylene chloride and extracted with water.
Purification by flash chromatography (100% ethyl acetate) gave the
desired amide.
[0903] C.sub.29H.sub.38N.sub.4O.sub.5 (MW=522.65); mass
spectroscopy (MH.sup.+) 523.3
Step B
##STR00427##
[0905] The amide from Step A (0.260 g, 0.0005 mol) was dissolved in
dioxane (3 ml) and water (3 ml) then treated with LiOH (0.012 g,
0.0005 mol). The reaction was stirred for two hours. Water was
added to the mixture and the layer was extracted with ether. The
aqueous layer was acidified with 1N HCl and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4 then concentrated to yield the desired product as
a white foam.
[0906] C.sub.28H.sub.36N.sub.4O.sub.5 (MW=508.62); mass
spectroscopy (MH.sup.+)=509.4
Example 155
Step A
##STR00428##
[0908] A THF solution of the acid described in Example 127, Step B
(0.300 g, 0.0007 mol) was treated with EDC (0.212 g, 0.0011 mol)
and HOAt (0.095 g, 0.0007 mol). An equivalent of benzyl amine
(0.076 ml, 0.0007 mol) was added and the reaction was stirred
overnight. The solvent was concentrated and the residue was
redissolved in methylene chloride and extracted with water.
Purification by flash chromatography (100% ethyl acetate) gave the
desired amide. C.sub.27H.sub.34N.sub.4O.sub.5 (MW=494.60); mass
spectroscopy (MH.sup.+)=495.2
Step B
##STR00429##
[0910] The amide from Step A (0.176 g, 0.00035 mol) was dissolved
in dioxane (3 ml) and water (3 ml) then treated with LiOH (0.0085
g, 0.00035 mol). The reaction was stirred for two hours. Water was
added to the mixture and the layer was extracted with ether. The
aqueous layer was acidified with 1N HCl and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4 then concentrated to yield the desired product as
a white foam.
[0911] C.sub.26H.sub.32N.sub.4O.sub.5 (MW=480.57); mass
spectroscopy (MH.sup.+)=481.4
Example 156
Step A
##STR00430##
[0913] A THF solution of the acid described in Example 127, Step B
(0.300 g, 0.0007 mol) was treated with EDC (0.212 g, 0.0011 mol)
and HOAt (0.095 g, 0.0007 mol). An equivalent of 3-methoxy benzyl
amine (0.090 ml, 0.0007 mol) was added and the reaction was stirred
overnight. The solvent was concentrated and the residue was
redissolved in methylene chloride and extracted with water.
Purification by flash chromatography (100% ethyl acetate) gave the
desired amide.
[0914] C.sub.28H.sub.36N.sub.4O.sub.6 (MW=524.62); mass
spectroscopy (MH.sup.+)=525.3
Step B
##STR00431##
[0916] The amide from Step A (0.260 g, 0.00049 mol) was dissolved
in dioxane (3 ml) and water (3 ml) then treated with LiOH (0.012 g,
0.00049 mol). The reaction was stirred for two hours. Water was
added to the mixture and the layer was extracted with ether. The
aqueous layer was acidified with 1N HCl and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4 then concentrated to yield the desired product as
a white foam.
[0917] C.sub.27H.sub.34N.sub.4O.sub.6 (MW=510.59); mass
spectroscopy (MH.sup.+)=511.3
Example 157
Step A
##STR00432##
[0919] A THF solution of the acid described in Example 127, Step B
(0.300 g, 0.0007 mol) was treated with EDC (0.212 g, 0.0011 mol)
and HOAt (0.095 g, 0.0007 mol). An equivalent of 3-methoxy benzyl
amine (0.091 ml, 0.0007 mol) was added and the reaction was stirred
overnight. The solvent was concentrated and the residue was
redissolved in methylene chloride and extracted with water.
Purification by flash chromatography (100% ethyl acetate) gave the
desired amide.
[0920] C.sub.27H.sub.40N.sub.4O.sub.5 (MW=500.6); mass spectroscopy
(MH.sup.+)=501.4
Step B
##STR00433##
[0922] The amide from Step A (0.290 g, 0.00058 mol) was dissolved
in dioxane (3 ml) and water (3 ml) then treated with LiOH (0.013 g,
0.00058 mol). The reaction was stirred for two hours. Water was
added to the mixture and the layer was extracted with ether. The
aqueous layer was acidified with 1N HCl and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4 then concentrated to yield the desired product as
a white solid.
[0923] C.sub.26H.sub.35N.sub.4O.sub.5 (MW=486.62); mass
spectroscopy (MH.sup.+)=487.4
Biological Assays
Binding and Cotransfection Studies
[0924] The in vitro potency of compounds in modulating PPAR.alpha.
receptors were determined by the procedures detailed below.
DNA-dependent binding (ABCD binding) was carried out using SPA
technology with PPAR receptors. Tritium-labeled PPAR.alpha.
agonists were used as radioligands for generating displacement
curves and IC.sub.50 values with compounds of the invention.
Cotransfection assays were carried out in CV-1 cells. The reporter
plasmid contained an acylCoA oxidase (AOX) PPRE and TK promoter
upstream of the luciferase reporter cDNA. Appropriate PPARs were
constitutively expressed using plasmids containing the CMV
promoter. For PPAR.alpha., interference by endogenous PPAR.gamma.
in CV-1 cells was an issue. In order to eliminate such
interference, a GAL4 chimeric system was used in which the DNA
binding domain of the transfected PPAR was replaced by that of
GAL4, and the GAL4 response element was utilized in place of the
AOX PPRE. Cotransfection efficacy was determined relative to
PPAR.alpha. agonist reference molecules. Efficacies were determined
by computer fit to a concentration-response curve, or in some cases
at a single high concentration of agonist (10 .mu.M).
[0925] These studies were carried out to evaluate the ability of
compounds of the invention to bind to and/or activate various
nuclear transcription factors, particularly huPPAR.alpha. ("hu"
indicates "human"). These studies provide in vitro data concerning
efficacy and selectivity of compounds of the invention.
Furthermore, binding and cotransfection data for compounds of the
invention were compared with corresponding data for marketed
compounds that act on huPPAR.alpha..
[0926] The binding and cotransfection efficacy values found, for
compounds of the invention and compounds of this invention which
are useful for modulating a PPAR alpha receptor, were .ltoreq.100
nM and .gtoreq.50%, respectively.
Evaluation of Triglyceride Reduction and HDL Cholesterol Elevation
in HuapoAI Transgenic Mice
[0927] Seventeen different series of studies were performed to
evaluate the effect of compounds of the present invention upon HDL
and triglyceride levels in human apoAI mice. For each compound
tested, seven to eight week old male mice, transgenic for human
apoAI (C57BL/6-tgn(apoa1)1rub, Jackson Laboratory, Bar Harbor, Me.)
were acclimated in individual cages for two weeks with standard
chow diet (Purina 5001) and water provided ad libitum. After the
acclimation, mice and chow were weighed and assigned to test groups
(n=5) with randomization by body weight. Mice were dosed daily by
oral gavage for 8 days using a 29 gauge, 11/2 inch curved feeding
needle (Popper & Sons). The vehicle for the controls, test
compounds and the positive control (fenofibrate 100 mg/kg) was 1%
carboxymethylcellulose (w/v) with 0.25% tween 80 (w/v). All mice
were dosed daily between 6 and 8 a.m. with a dosing volume of 0.2
ml. Prior to termination, animals and diets were weighed and body
weight change and food consumption were calculated. Three hours
after last dose, mice were euthanized with CO.sub.2 and blood was
removed (0.5-1.0 ml) by cardiac puncture. After sacrifice, the
liver, heart, and epididymal fat pad were excised and weighed.
Blood was permitted to clot and serum was separated from the blood
by centrifugation.
[0928] Cholesterol and triglycerides were measured calorimetrically
using commercially prepared reagents (for example, as available
from Sigma #339-1000 and Roche #450061 for triglycerides and
cholesterol, respectively). The procedures were modified from
published work (McGowan M. W. et al., Clin Chem 29:538-542, 1983;
Allain C. C. et al., Clin Chem 20:470-475, 1974. Commercially
available standards for triglycerides and total cholesterol,
respectively, commercial quality control plasma, and samples were
measured in duplicate using 200 .mu.l of reagent. An additional
aliquot of sample, added to a well containing 200 .mu.l water,
provided a blank for each specimen. Plates were incubated at room
temperature on a plate shaker and absorbance was read at 500 nm and
540 nm for total cholesterol and triglycerides, respectively.
Values for the positive control were always within the expected
range and the coefficient of variation for samples was below 10%.
All samples from an experiment were assayed at the same time to
minimize inter-assay variability.
[0929] Serum lipoproteins were separated and cholesterol
quantitated by fast protein liquid chromatography (FPLC) coupled to
an in line detection system. Samples were applied to a Superose 6
HR size exclusion column (Amersham Pharmacia Biotech) and eluted
with phosphate buffered saline-EDTA at 0.5 ml/min. Cholesterol
reagent (Roche Diagnostics Chol/HP 704036) at 0.16 ml/min mixed
with the column effluent through a T-connection and the mixture
passed through a 15 m.times.0.5 mm id knitted tubing reactor
immersed in a 37 C water bath. The colored product produced in the
presence of cholesterol was monitored in the flow stream at 505 nm
and the analog voltage from the monitor was converted to a digital
signal for collection and analysis. The change in voltage
corresponding to change in cholesterol concentration was plotted vs
time and the area under the curve corresponding to the elution of
very low density lipoprotein (VLDL), low density lipoprotein (LDL)
and high density lipoprotein (HDL) was calculated using Perkin
Elmer Turbochrome software. The results of these studies are
provided in the following tables for triglyceride and HDL
cholesterol levels. Note that the superscripted numbers in the
following tables refer to the study numbers. Further, the values,
determined in each study, for triglyceride levels in the control
mice and for HDL cholesterol levels in fenofibrate-treated mice are
also provided in the following tables.
[0930] Triglyceride Serum Levels in Mice Dosed with a Compound of
the Invention was Compared to Mice Receiving the Vehicle to
identify compounds which could be particularly useful for lowering
triglycerides. Generally, triglyceride decreases of greater than or
equal to 30% (thirty percent) compared to control following a 30
mg/kg dose suggests a compound that can be especially useful for
lowering triglyceride levels.
[0931] The percent increase of HDLc serum levels in mice receiving
a compound of the invention was compared to mice receiving vehicle
to identify compounds of the invention that could be particularly
useful for elevating HDL levels. Generally, and increase of greater
than or equal to 25% (twenty five percent) increase in HDLc level
following a 30 mg/kg dose suggests a compound that can be
especially useful for elevating HDLc levels.
[0932] It may be particularly desirable to select compounds of this
invention that both lower triglyceride levels and increase HDLc
levels. However, compounds that either lower triglyceride levels or
increase HDLc levels may be desirable as well.
Evaluation of Glucose Levels in db/db Mice
[0933] The effects, upon plasma glucose of administering various
dose levels of five different compounds of the present invention
and the PPAR gamma agonist rosiglitazone (BRL49653) or the PPAR
alpha agonist fenofibrate, and the control, to male db/db mice,
were studied.
[0934] Five week old male diabetic (db/db) mice [for example,
C57BlKs/j-m+/+Lepr(db), Jackson Laboratory, Bar Harbor, Me.] or
lean littermates were housed 6 per cage with food and water
available at all times. After an acclimation period of 2 weeks,
animals were individually identified by ear notches, weighed, and
bled via the tail vein for determination of initial glucose levels.
Blood was collected (100 .mu.l) from unfasted animals by wrapping
each mouse in a towel, cutting the tip of the tail with a scalpel,
and milking blood from the tail into a heparinized capillary tube.
Sample was discharged into a heparinized microtainer with gel
separator and retained on ice. Plasma was obtained after
centrifugation at 4.degree. C. and glucose measured immediately.
Remaining plasma was frozen until the completion of the experiment,
when glucose and triglycerides were assayed in all samples. Animals
were grouped based on initial glucose levels and body weights.
Beginning the following morning, mice were dosed daily by oral
gavage for 7 days. Treatments were test compounds (30 mg/kg), a
positive control agent (30 mg/kg) or vehicle [1%
carboxymethylcellulose (w/v)/0.25% Tween80 (w/v); 0.3 ml/mouse]. On
day 7, mice were weighed and bled (tail vein) 3 hours after dosing.
Twenty-four hours after the 7.sup.th dose (i.e., day 8), animals
were bled again (tail vein). Samples obtained from conscious
animals on days 0, 7 and 8 were assayed for glucose. After the 24
hour bleed, animals were weighed and dosed for the final time.
Three hours after dosing on day 8, animals were anesthetized by
inhalation of isoflurane and blood obtained via cardiac puncture
(0.5-0.7 ml). Whole blood was transferred to serum separator tubes,
chilled on ice and permitted to clot. Serum was obtained after
centrifugation at 4.degree. C. and frozen until analysis for
compound levels. After sacrifice by cervical dislocation, the
liver, heart and epididymal fat pads were excised and weighed.
[0935] Glucose was measured calorimetrically using commercially
purchased reagents. According to the manufacturers, the procedures
were modified from published work (McGowan, M. W., Artiss, J. D.,
Strandbergh, D. R. & Zak, B. Clin Chem, 20:470-5 (1974) and
Keston, A. Specific calorimetric enzymatic analytical reagents for
glucose. Abstract of papers 129th Meeting ACS, 31C (1956).); and
depend on the release of a mole of hydrogen peroxide for each mole
of analyte, coupled with a color reaction first described by
Trinder (Trinder, P. Determination of glucose in blood using
glucose oxidase with an alternative oxygen acceptor. Ann Clin
Biochem, 6:24 (1969)). The absorbance of the dye produced is
linearly related to the analyte in the sample. The assays were
further modified in our laboratory for use in a 96 well format. The
commercially available standard for glucose, commercially available
quality control plasma, and samples (2 or 5 .mu.l/well) were
measured in duplicate using 200 .mu.l of reagent. An additional
aliquot of sample, pipetted to a third well and diluted in 200
.mu.l water, provided a blank for each specimen. Plates were
incubated at room temperature for 18 minutes for glucose on a plate
shaker (DPC Micormix 5) and absorbance read at 500 nm on a plate
reader. Sample absorbances were compared to a standard curve
(100-800 for glucose). Values for the quality control sample were
always within the expected range and the coefficient of variation
for samples was below 10%. All samples from an experiment were
assayed at the same time to minimize inter-assay variability.
[0936] The results of the study, suggest compounds of the present
invention that significantly reduced db/db mouse plasma glucose
levels while resulting in body weight gains that were less than
those observed for rosiglitazone.
Evaluation of the Effects of Compounds of the Present Invention
Upon A.sup.y Mice Body Weight, Fat Mass, Glucose and Insulin
Levels
Female A.sup.y Mice
[0937] Female A.sup.y mice were singly housed, maintained under
standardized conditions (22.degree. C., 12 h light: dark cycle),
and provided free access to food and water throughout the duration
of the study. At twenty weeks of age the mice were randomly
assigned to vehicle control and treated groups based on body weight
and body fat content as assessed by DEXA scanning (N=6). Mice were
then dosed via oral gavage with either vehicle or a Compound of
this invention (50 mg/kg) one hour after the initiation of the
light cycle (for example, about 7 A.M.) for 18 days. Body weights
were measured daily throughout the study. On day 14 mice were
maintained in individual metabolic chambers for indirect
calorimetry assessment of energy expenditure and fuel utilization.
On day 18 mice were again subjected to DEXA scanning for post
treatment measurement of body composition.
[0938] The results of p.o. dosing of compound for 18 days on body
weight, fat mass, and lean mass were evaluated and suggest which
compounds of this invention can be especially useful for
maintaining desirable weight and/or promoting desired lean to fat
mass.
[0939] Indirect calorimetry measurements revealed a significant
reduction in respiratory quotient (RQ) in treated animals during
the dark cycle [0.864.+-.0.013 (Control) vs. 0.803.+-.0.007
(Treated); p<0.001]. This reduction in RQ is indicative of an
increased utilization of fat during the animals' active (dark)
cycle. Additionally, treated animals displayed significantly higher
rates of energy expenditure than control animals (17.40.+-.0.49 vs.
13.62.+-.0.26 kcal/kg/hr, respectively).
Male KK/A.sup.y Mice
[0940] Male KK/A.sup.y mice were singly housed, maintained under
standardized conditions (22.degree. C., 12 h light:dark cycle), and
provided free access to food and water throughout the duration of
the study. At twenty-two weeks of age the mice were randomly
assigned to vehicle control and treated groups based on plasma
glucose levels. Mice were then dosed via oral gavage with either
vehicle or a Compound of this invention (30 mg/kg) one hour after
the initiation of the light cycle (7 A.M.) for 14 days. Plasma
glucose, triglyceride, and insulin levels were assessed on day
14.
[0941] The results of p.o. dosing of compound for 14 days on plasma
glucose, triglycerides, and insulin are evaluated to identify
compounds of this invention which may be especially desired.
Method to Elucidate the LDL-Cholesterol Total-Cholesterol and
Triglyceride Lowering Effect of Compound 5(8)
[0942] Male Syrian hamsters (Harlan Sprague Dawley) weighing 80-120
g were placed on a high-fat cholesterol-rich diet for two to three
weeks prior to use. Feed and water were provided ad libitum
throughout the course of the experiment. Under these conditions,
hamsters became hypercholesterolemic showing plasma cholesterol
levels between 180-280 mg/dl. (Hamsters fed with normal chow had a
total plasma cholesterol level between 100-150 mg/dl.) Hamsters
with high plasma cholesterol (180 mg/dl and above) were randomized
into treatment groups based on their total cholesterol level using
the GroupOptimizeV211.xls program.
[0943] A Compound of this invention was dissolved in an aqueous
vehicle (containing CMC with Tween 80) such that each hamster
received once a day approx. 1 ml of the solution by garvage at
doses 3 and 30 mg/kg body weight. Fenofibrate (Sigma Chemical,
prepared as a suspension in the same vehicle) was given as a known
alpha-agonist control at a dose of 200 mg/kg, and the blank control
was vehicle alone. Dosing was performed daily in the early morning
for 14 days.
[0944] Quantification of Plasma Lipids
On the last day of the test, hamsters were bled (400 ul) from the
suborbital sinus while under isoflurane anesthesia 2 h after
dosing. Blood samples were collected into heparinized microfuge
tubes chilled in ice bath. Plasma samples were separated from the
blood cells by brief centrifugation. Total cholesterol and
triglycerides were determined by means of enzymatic assays carried
out automatically in the Monarch equipment (Instrumentation
Laboratory) following the manufacturer's precedure. Plasma
lipoproteins (VLDL, LDL and HDL) were resolved by injecting 25 ul
of the pooled plasma samples into an FPLC system eluted with
phosphate buffered saline at 0.5 ml/min through a Superose 6 HR
10/30 column (Pharmacia) maintained room temp. Detection and
characterization of the isolated plasma lipids were accomplished by
postcolumn incubation of the effluent with a Cholesterol/HP reagent
(for example, Roche Lab System; infused at 0.12 ml/min) in a
knitted reaction coil maintained at 37.degree. C. The intensity of
the color formed was proportional to the cholesterol concentration
and was measured photometrically at 505 nm.
[0945] The effect of administration of a Compound of this invention
for 14 days is studied for the percent reduction in LDL level with
reference to the vehicle group. The LDL-lowering efficacy for
certain compounds of this invention is markedly more potent than
that of fenofibrate. Compounds of this invention that decrease LDL
greater than or equal to 30% (thirty percent) compared to vehicle
can be especially desired.
[0946] The total-cholesterol and triglyceride lowering effects of a
Compound of this invention was also studied. The data for reduction
in total cholesterol and triglyceride levels after treatment with a
compound of this invention for 14 days was compared to the vehicle
to suggest compounds that can be particularly desired. The known
control fenofibrate did not show significant efficacy under the
same experimental conditions.
Method to Elucidate the Fibrinogen-Lowering Effect of
PPARModulators
Zucker Fatty Rat Model:
[0947] The life phase of the study on fibrinogen-lowering effect of
compounds of this invention was part of the life phase procedures
for the antidiabetic studies of the same compounds. On the last
(14.sup.th) day of the treatment period, with the animals placed
under surgical anesthesia, .about.3 ml of blood is collected, by
cardiac puncture, into a syringe containing citrate buffer. The
blood sample is chilled and centrifuged at 4.degree. C. to isolate
the plasma that was stored at -70.degree. C. prior to fibrinogen
assay.
Quantification of Rat Plasma Fibrinogen:
[0948] Rat plasma fibrinogen levels were quantified by using a
commercial assay system consists of a coagulation instrument
following the manufacturer's protocol. In essence, 100 ul of plasma
was sampled from each specimen and a 1/20 dilution is prepared with
buffer. The diluted plasma is incubated at 37.degree. C. for 240
seconds. Fifty microliters of clotting reagent thrombin solution
(provided by the instrument's manufacturer in a standard
concentration) is then added. The instrument monitored the clotting
time, a function of fibrinogen concentration quantified with
reference to standard samples.
Results
[0949] Compounds of this invention are capable of lowering
fibrinogen level in vivo. Compounds that lower fibrinogen level
greater than vehicle can be especially desired.
[0950] Cholesterol and triglyceride lowering effects of compounds
of this intention were also produced in Zucker rats.
Method to Elucidate the Anti-Body Weight Gain and Anti-Appetite
Effects of Compounds of this Invention
Fourteen-Day Study in Zucker Fatty Rat.sup.1 or ZDF Rat.sup.2
Models
[0951] Male Zucker Fatty rats, non-diabetic (Charles River
Laboratories, Wilmington, Mass.) or male ZDF rats (Genetic Models,
Inc, Indianapolis, Ind.) of comparable age and weight were
acclimated for 1 week prior to treatment. Rats were on normal chow
and water was provided ad libitum throughout the course of the
experiment. .alpha.-agonists were dissolved in an aqueous vehicle
such that each rat received once a day approximately 1 ml of the
solution by garvage at doses 0.1, 0.3, 1 and 3 mg/kg body weight.
Fenofibrate (Sigma Chemical, prepared as a suspension in the same
vehicle) a known alpha-agonist given at doses of 300 mg/kg, as well
as the vehicle were controls. Dosing was performed daily in the
early morning for 14 days. Over the course of the experiment, body
weight and food consumption were monitored.
[0952] Using this assay, compounds of this invention were found to
result in significant weight reduction.
EQUIVALENTS
[0953] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
* * * * *