U.S. patent application number 09/846821 was filed with the patent office on 2002-01-03 for para-aryl or heterocyclic substituted phenyl glucokinase activators.
Invention is credited to Corbett, Wendy L., Haynes, Nancy-Ellen, Sarabu, Ramakanth.
Application Number | 20020002190 09/846821 |
Document ID | / |
Family ID | 22749667 |
Filed Date | 2002-01-03 |
United States Patent
Application |
20020002190 |
Kind Code |
A1 |
Corbett, Wendy L. ; et
al. |
January 3, 2002 |
Para-aryl or heterocyclic substituted phenyl glucokinase
activators
Abstract
Para-aryl or heteroaryl substituted phenyl amides which are
active as glucokinase activators to increase insulin secretion
which makes them useful for treating type II diabetes.
Inventors: |
Corbett, Wendy L.;
(Randolph, NJ) ; Haynes, Nancy-Ellen; (Cranford,
NJ) ; Sarabu, Ramakanth; (Pine Brook, NJ) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
22749667 |
Appl. No.: |
09/846821 |
Filed: |
May 1, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60202387 |
May 8, 2000 |
|
|
|
Current U.S.
Class: |
514/349 ;
514/370; 546/270.4; 548/192 |
Current CPC
Class: |
C07D 213/80 20130101;
C07D 277/46 20130101; C07D 213/75 20130101; C07D 277/56 20130101;
C07D 295/155 20130101; C07D 213/56 20130101; A61P 43/00 20180101;
C07C 2601/14 20170501; C07C 317/44 20130101; C07D 417/12 20130101;
C07C 2601/08 20170501; C07D 209/18 20130101; A61P 3/10
20180101 |
Class at
Publication: |
514/349 ;
514/370; 548/192; 546/270.4 |
International
Class: |
A61K 031/4439; A61K
031/426; A61K 031/427; C07D 417/02; C07D 277/18 |
Claims
What is claimed is:
1. An amide selected from the group consisting of a compound of the
formula 70wherein R is a heteroaromatic ring, connected by a ring
carbon atom, which contains from 5 to 6 ring members with from 1 to
2 heteroatoms selected from the group consisting of oxygen, sulfur
or nitrogen, aryl containing 6 or 10 ring carbon atoms, aryl
containing from 6 to 10 ring carbon atoms fused with a
heteroaromatic ring containing 5 or 6 ring members with 1 or 2
heteroatoms in the ring being selected from the group consisting of
nitrogen, oxygen or sulfur, or a saturated 5- or 6-membered
cycloheteroalkyl ring, which contains from 1 to 2 heteroatoms
selected from the group consisting of oxygen, sulfur and nitrogen,
or a cycloalkyl ring having 5 or 6 carbon atoms; R.sup.1 is a
cycloalkyl ring having 5 or 6 carbon atoms; R.sup.2 is 71a five- or
six-membered heteroaromatic ring connected by a ring carbon atom to
the amide group shown, which heteroaromatic ring contains from 1 to
3 heteroatoms selected from the group consisting of oxygen, sulfur
and nitrogen with a first heteroatom being nitrogen which is
adjacent to the connecting ring carbon atom, said heteroaromatic
ring being unsubstituted or monosubstituted at a position on a ring
carbon atom other than adjacent to said connecting carbon atom with
a substituent selected from the group consisting of lower alkyl,
--(CH.sub.2).sub.n--OR.sup.6, 72n is 0, 1, 2, 3 or 4; y and z are
independently 0 or 1, * denotes the asymmetric carbon atom center;
R.sup.3 is hydrogen, lower alkyl or 73R.sup.6, R.sup.7 and R.sup.8
are independently hydrogen or lower alkyl; and p is an integer from
0 to 5; or a pharmaceutically acceptable salt thereof.
2. The amide of claim 1 wherein said compound is 74wherein *, y, z,
X, R and R.sup.1 are as above, R.sup.4 is a five- or six-membered
heteroaromatic ring connected by a ring carbon atom to the amide
group shown, which heteroaromatic ring contains from 1 to 3
heteroatoms selected from the group consisting of oxygen, sulfur
and nitrogen with a first heteroatom being nitrogen which is
adjacent to the connecting ring carbon atom, said heteroaromatic
ring being unsubstituted or monosubstituted at a position on a ring
carbon atom other than adjacent to said connecting carbon atom with
a substituent selected from the group consisting of lower alkyl,
75n is 0,1,2,3 or 4; and R.sup.6, R.sup.7 and R.sup.8 are
independently hydrogen or lower alkyl.
3. The amide of claim 2 wherein z is 0.
4. The amide of claim 3 wherein R.sup.1 is cyclopentyl.
5. The amide of claim 4 wherein R is aryl.
6. The amide of claim 5 wherein R.sup.4 is a substituted or
unsubstituted five-membered heteroaromatic ring.
7. The amide of claim 6 wherein said heteroaromatic ring defined by
R.sup.4 is an unsubstituted thiazolyl.
8. The amide of claim 7 wherein said compound is
2-biphenyl-4-yl-3-cyclope- ntyl-N-thiazol-2-yl-propionamide.
9. The amide of claim 8 wherein said compound is
(2R)-2-biphenyl-4-yl-3-cy-
clopentyl-N-thiazol-2-yl-propionamide.
10. The amide of claim 6 wherein said compound is
3-cyclopentyl-2-(4-napht-
halen-1-yl-phenyl)-N-thiazol-2-yl-propionamide.
11. The amide of claim 6 wherein R.sup.4 is thiazolyl which is
substituted with 76and R.sup.7 is as above.
12. The amide of claim 11 wherein said compound is
[2-(2-biphenyl-4-yl-3-c-
yclopentyl-propionylamino)-thiazol-4-yl]-acetic acid methyl
ester.
13. The amide of claim 11 wherein said compound is
[2-(2-biphenyl-4-yl-3-c-
yclopentyl-propionylamino)-thiazol-4-yl]-acetic acid ethyl
ester.
14. The amide of claim 11 wherein said compound is
2-(2-biphenyl-4-yl-3-cy-
clopentyl-propionylamino)-thiazole-4-carboxylic acid ethyl
ester.
15. The amide of claim 11 wherein said compound is
2-(2-biphenyl-4-yl-3-cy-
clopentyl-propionylamino)-thiazole-4-carboxylic acid methyl
ester.
16. The amide of claim 11 wherein said compound is
{2-[3-cyclopentyl-2-(4--
naphthalen-1-yl-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid
methyl ester.
17. The amide of claim 11 wherein said compound is
{2-[3-cyclopentyl-2-(4--
naphthalen-1-yl-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid
ethyl ester.
18. The amide of claim 11 wherein said compound is
2-[3-cyclopentyl-2-(4-n-
aphthalen-1-yl-phenyl)-propionylamino]-thiazole-4-carboxylic acid
methyl ester.
19. The amide of claim 6 wherein R.sup.2 is thiazolyl substituted
with --(CH.sub.2).sub.n--OR.sup.6 or 77and n, R.sup.6 and R.sup.8
are as above.
20. The amide of claim 19 wherein said compound is
[2-(2-biphenyl-4-yl-3-c-
yclopentyl-propionylamino)-thiazol-4-yl]-oxo-acetic acid ethyl
ester.
21. The amide of claim 19 wherein said compound is
2-biphenyl-4-yl-3-cyclo-
pentyl-N-(4-hydroxymethyl-thiazol-2-yl)-propionamide.
22. The amide of claim 19 wherein said compound is
2-biphenyl-4-yl-3-cyclo-
pentyl-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-propionamide.
23. The amide of claim 19 wherein said compound is
3-cyclopentyl-N-[4-(2-h-
ydroxyethyl)-thiazol-2-yl]-2-(4-naphthalen-1-yl-phenyl)-propionamide.
24. The amide of claim 19 wherein said compound is
3-cyclopentyl-N-(4-hydr-
oxymethyl-thiazol-2-yl)-2-(4-naphthalen-1-yl-phenyl)-propionamide.
25. The amide of claim 5 wherein R.sup.4 is unsubstituted
pyridinyl.
26. The amide of claim 25 wherein said compound is
2-biphenyl-4-yl-3-cyclo- pentyl-N-pyridin-2-yl-propionamide.
27. The amide of claim 25 wherein said compound is
3-cyclopentyl-2-(4-naph-
thalen-1-yl-phenyl)-N-pyridin-2-yl-propionamide.
28. The amide of claim 5 wherein said compound is pyridine
monosubstituted with a --(CH.sub.2).sub.n--OR.sup.6 or
78groups.
29. The compound of claim 28 wherein said compound is
6-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-nicotinic acid
methyl ester.
30. The compound of claim 28 wherein said compound is
6-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-nicotinic
acid.
31. The compound of claim 28 wherein said compound is
2-biphenyl-4-yl-3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-propionami-
de.
32. The compound of claim 28 wherein said compound is
6-[3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionylamino]-nicotinic
acid methyl ester.
33. The compound of claim 28 wherein said compound is
6-[3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionylamino]-nicotinic
acid.
34. The compound of claim 28 wherein said compound is
3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-naphthalen-1-yl-pheny-
l)-propionamide.
35. The compound of claim 4 wherein R is a heteroaromatic ring
containing from 5 to 6 ring members with from 1 to 2 heteroatoms
selected form the group consisting of oxygen, sulfur or nitrogen in
the ring.
36. The compound of claim 35 wherein R.sup.4 selected from the
group consisting of unsubstituted or monosubstituted pyridinyl or
thiazolyl.
37. The compound of claim 36 wherein said compound is
3-cyclopentyl-N-thiazol-2-yl-2-(4-thiophen-2-yl-phenyl)-propionamide.
38. The compound of claim 36 wherein said compound is
3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-N-thiazol-2-yl-propionamide.
39. The compound of claim 36 wherein said compound is
3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-N-thiazol-2-yl-propionamide.
40. The amide of claim 36 wherein said compound is
3-cyclopentyl-N-pyridin-
-2-yl-2-(4-pyridin-4-yl-phenyl)-propionamide.
41. The amide of claim 36 wherein said compound is
3-cyclopentyl-N-pyridin-
-2-yl-2-(4-pyridin-3-yl-phenyl)-propionamide.
42. The amide of claim 4 wherein R is aryl fused to a
heteroaromatic ring containing from 5 to 6 ring members with from 1
to 2 heteroatoms in the ring selected from the group consisting of
oxygen, nitrogen or sulfur.
43. The amide of claim 42 wherein said compound R.sup.4 is
thiazolyl.
44. The amide of claim 43 wherein said compound is
3-cyclopentyl-2-[4-(1H--
indol-5-yl)-phenyl]-N-thiazol-2-yl-propionamide.
45. The amide of claim 4 wherein R is a saturated 5- or 6-membered
cycloheteroalkyl.
46. The amide of claim 45 wherein R.sup.4 is thiazole.
47. The amide of claim 46 wherein said amide is
3-cyclopentyl-2-(4-morphol-
in-4-yl-phenyl)-N-thiazol-2-yl-propionamide.
48. The amide of claim 2 wherein said compound is the formula
79wherein R, R.sup.1, R.sup.2 and y are as above.
49. The amide of claim 48 wherein R is aryl.
50. The amide of claim 49 wherein R.sup.4 is unsubstituted
pyridinyl or thiazolyl.
51. The amide of claim 50 wherein said compound is
2-(4-benzyloxy-phenyl)--
3-cyclopentyl-N-thiazol-2-yl-propionamide.
52. The amide of claim 50 wherein said compound is
3-cyclopentyl-2-(4-phen-
oxy-phenyl)-N-thiazol-2-yl-propionamide.
53. The amide of claim 50 wherein said compound is
3-cyclopentyl-2-(4-phen-
oxy-phenyl)-N-pyridin-2-yl-propionamide.
54. The amide of claim 49 wherein R.sup.4 is substituted
thiazolyl.
55. The amide of claim 54 wherein said compound is
{2-[3-cyclopentyl-2-(4--
phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl
ester.
56. The amide of claim 54 wherein said compound is
3-cyclopentyl-N-(4-hydr-
oxymethyl-thiazol-2-yl)-2-(4-phenoxy-phenyl)-propionamide.
57. The amide of claim 54 wherein said compound is
2-[3-cyclopentyl-2-(4-p-
henoxy-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl
ester.
58. The amide of claim 54 wherein said compound is
3-cyclopentyl-N-[4-(2-h-
ydroxy-ethyl)-thiazol-2-yl]-2-(4-phenoxy-phenyl)-propionamide.
59. The amide of claim 54 wherein said compound is
{2-[3-cyclopentyl-2-(4--
phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid.
60. The amide of claim 54 wherein said compound is
{2-[3-cyclopentyl-2-(4--
phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl
ester.
61. The amide of claim 49 wherein R.sup.4 is substituted
pyridinyl.
62. The amide of claim 61 wherein said compound is
3-cyclopentyl-N-(5-meth-
yl-pyridin-2-yl)-2-(4-phenoxy-phenyl)-propionamide.
63. The amide of claim 61 wherein said compound is
6-[3-cyclopentyl-2-(4-p- henoxy-phenyl)-propionylamino]-nicotinic
acid methylester.
64. The amide of claim 61 wherein said compound is
6-[3-cyclopentyl-2-(4-p- henoxy-phenyl)-propionylamino]-nicotinic
acid.
65. The amide of claim 61 wherein said compound is
3-cyclopentyl-N-(5-hydr-
oxymethyl-pyridin-2-yl)-2-(4-phenoxy-phenyl)-propionamide.
66. The amide of claim 2 wherein said compound has the formula
80wherein y, R, R.sup.1 and R.sup.4 are as above.
67. The amide of claim 66 wherein R.sup.1 is cyclopentyl.
68. The amide of claim 67 wherein R.sup.4 is unsubstituted or
monosubstituted thiazolyl.
69. The amide of claim 68 wherein R is aryl.
70. The amide of claim 69 wherein said compound is
2-(4-benzenesulfonyl-ph-
enyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.
71. The amide of claim 68 wherein R is cycloalkyl.
72. The amide of claim 71 wherein said compound is
2-(4-cyclopentanesulfon-
yl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.
73. The amide of claim 71 wherein said compound is
2-(4-cyclohexanesulfony-
l-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.
74. The amide of claim 68 wherein R is a heteroaromatic ring.
75. The amide of claim 74 wherein said compound is
3-cyclopentyl-2-[4-(1H-- imidazole
-2-sulfonyl)-phenyl]-N-thiazol-2-yl-propionamide.
76. The amide of claim 1 being the formula: 81wherein y, z, X, R,
R.sup.1 and R.sup.3 are as above.
77. The amide of claim 76 wherein R.sup.1 is cyclopentyl.
78. The amide of claim 77 wherein z is 0.
79. The amide of claim 78 wherein R is aryl.
80. The amide of claim 79 wherein said compound is
(2-biphenyl-4-yl-3-cycl- opentyl-propionyl)-urea.
81. The amide of claim 79 wherein said compound is
1-(2-biphenyl-4-yl-3-cy- clopentyl-propionyl)-3-methyl-urea.
82. The amide of claim 79 wherein said compound is
1-[3-cyclopentyl-2-(4-n-
aphthalen-1-yl-phenyl)-propionyl]-3-methyl-urea.
83. The amide of claim 78 wherein R is a heteroaromatic ring
containing from 5 to 6 ring members with from 1 to 3 heteroatoms
selected from the group consisting of oxygen, sulfur or
nitrogen.
84. The amide of claim 83 wherein said compound is
1-[3-cyclopentyl-2-(4-p-
yridin-3-yl-phenyl)-propionyl]-3-methyl-urea.
85. The amide of claim 78 wherein R is aryl fused with a
heteroaromatic containing from 5 to 6 ring members.
86. The amide of claim 85 wherein said compound is
1-{3-cyclopentyl-2-[4-(-
1H-indol-5-yl)-phenyl]-propionyl}-3-methyl-urea.
87. The amide of claim 78 wherein R is a saturated 5- or 6-membered
cycloheteroalkyl ring containing from 1 to 2 heteroatoms selected
from the group consisting of oxygen, nitrogen and sulfur.
88. The amide of claim 87 wherein said compound is
1-[3-cyclopentyl-2-(4-m-
orpholin-4-yl-phenyl)-propionyl]-3-methyl-urea.
89. The amide of claim 77 wherein y is 0 and z is 1.
90. The amide of claim 89 wherein R is a saturated cycloalkyl
ring.
91. The amide of claim 90 wherein X is SO.sub.2.
92. The amide of claim 91 wherein said compound is
1-[2-(4-cyclohexanesulf-
onyl-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea.
93. The amide of claim 90 wherein X is oxygen.
94. The amide of claim 93 wherein R is aryl.
95. The amide of claim 94 wherein said compound is
1-[3-cyclopentyl-2-(4-p- henoxy-phenyl)-propionyl]-3-methyl-urea.
Description
PRIORITY TO PROVISIONAL APPLICATION(S) UNDER 35 U.S.C. .sctn.
119(e)
[0001] This application claims priority under 35 U.S.C.
.sctn.119(e) of provisional application Ser. No. 60/202,387, filed
on May 8, 2000.
BACKGROUND OF THE INVENTION
[0002] Glucokinase (GK) is one of four hexokinases found in mammals
[Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic
Press, New York, N.Y., pages 1-48, 1973]. The hexokinases catalyze
the first step in the metabolism of glucose, i.e., the conversion
of glucose to glucose-6-phosphate. Glucokinase has a limited
cellular distribution, being found principally in pancreatic
.beta.-cells and liver parenchymal cells. In addition, GK is a
rate-controlling enzyme for glucose metabolism in these two cell
types that are known to play critical roles in whole-body glucose
homeostasis [Chipkin, S. R., Kelly, K. L., and Ruderman, N. B. in
Joslin's Diabetes (C. R. Khan and G. C. Wier, eds.), Lea and
Febiger, Philadelphia, Pa., pages 97-115, 1994]. The concentration
of glucose at which GK demonstrates half-maximal activity is
approximately 8 mM. The other three hexokinases are saturated with
glucose at much lower concentrations (<1 mM). Therefore, the
flux of glucose through the GK pathway rises as the concentration
of glucose in the blood increases from fasting (5 mM) to
postprandial (>10-15 mM) levels following a
carbohydrate-containing meal [Printz, R. G., Magnuson, M. A., and
Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R. E. Olson, D. M.
Bier, and D. B. McCormick, eds.), Annual Review, Inc., Palo Alto,
Calif., pages 463-496, 1993]. These findings contributed over a
decade ago to the hypothesis that GK functions as a glucose sensor
in .beta.-cells and hepatocytes (Meglasson, M. D. and Matschinsky,
F. M. Amer. J. Physiol. 246, E1-E13, 1984). In recent years,
studies in transgenic animals have confirmed that GK does indeed
play a critical role in whole-body glucose homeostasis. Animals
that do not express GK die within days of birth with severe
diabetes while animals overexpressing GK have improved glucose
tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83,
69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J., 10,
1213-1218, 1996). An increase in glucose exposure is coupled
through GK in .beta.-cells to increased insulin secretion and in
hepatocytes to increased glycogen deposition and perhaps decreased
glucose production.
[0003] The finding that type II maturity-onset diabetes of the
young (MODY-2) is caused by loss of function mutations in the GK
gene suggests that GK also functions as a glucose sensor in humans
(Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. 309, 167-173,
1995). Additional evidence supporting an important role for GK in
the regulation of glucose metabolism in humans was provided by the
identification of patients that express a mutant form of GK with
increased enzymatic activity. These patients exhibit a fasting
hypoglycemia associated with an inappropriately elevated level of
plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New
England J. Med. 338, 226-230, 1998). While mutations of the GK gene
are not found in the majority of patients with type II diabetes,
compounds that activate GK and, thereby, increase the sensitivity
of the GK sensor system will still be useful in the treatment of
the hyperglycemia characteristic of all type II diabetes.
Glucokinase activators will increase the flux of glucose metabolism
in .beta.-cells and hepatocytes, which will be coupled to increased
insulin secretion. Such agents would be useful for treating type II
diabetes.
SUMMARY OF THE INVENTION
[0004] This invention provides a compound, comprising an amide of
the formula: 1
[0005] R is a heteroaromatic ring, connected by a ring carbon atom,
which contains from 5 to 6 ring members with from 1 to 3
heteroatoms selected from the group consisting of oxygen, sulfur or
nitrogen, aryl containing 6 or 10 ring carbon atoms, aryl fused
with a heteroaromatic ring which contains from 5 to 6 ring members
with 1 to 3 heteroatoms in the ring being selected from the group
consisting of nitrogen, oxygen or sulfur, a saturated 5- or
6-membered cycloheteroalkyl ring which contains from 1 to 2
heteroatoms selected from the group consisting of oxygen, sulfur
and nitrogen, or a cycloalkyl ring having 5 or 6 carbon atoms;
R.sup.1 is a cycloalkyl ring having from 5 or 6 carbon atoms; R is
2
[0006] a five- or six-membered heteroaromatic ring connected by a
ring carbon atom to the amide group shown, which contains from 1 to
3 heteroatoms selected from the group consisting of oxygen, sulfur
and nitrogen with a first heteroatom being nitrogen adjacent to the
connecting ring carbon atom, said heteroaromatic ring being
unsubstituted or monosubstituted at a position on a ring carbon
atom other than adjacent to said connecting carbon atom with a
substituent selected from the group consisting of lower alkyl,
--(CH.sub.2).sub.n--OR.sup.6, 3
[0007] n is 0, 1, 2, 3 or 4; y and z are independently 0 or 1;
R.sup.3 is hydrogen, lower alkyl or 4
[0008] R.sup.6, R.sup.7 and R.sup.8 are independently hydrogen or
lower alkyl; p is an integer from 0 to 5; and * denotes the
asymmetric carbon atom center; or a pharmaceutically acceptable
salt thereof.
[0009] The compounds of formula I are glucokinase activators are
useful for increasing insulin secretion in the treatment of type II
diabetes.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The compounds of formula I have the following embodiments
5
[0011] wherein *, R, R.sup.1, R.sup.3, X, y, n and z are as
above;
[0012] R.sup.4 is a five- or six-membered heteroaromatic ring
connected by a ring carbon atom to the amide group shown, which
heteroaromatic ring contains from 1 to 3 heteroatoms selected from
the group consisting of oxygen, sulfur and nitrogen with a first
heteroatom being nitrogen adjacent to the connecting ring carbon
atom, said heteroaromatic ring being unsubstituted or
monosubstituted at a position on a ring carbon atom other than
adjacent to said connecting carbon atom with a substituent selected
from the group consisting of lower alkyl,
--(CH.sub.2).sub.n--OR.sup.6, 6
[0013] n is 0, 1, 2, 3 or 4;
[0014] R.sup.6, R.sup.7 and R.sup.8 are independently hydrogen or
lower alkyl;
[0015] or a pharmaceutically acceptable salt thereof.
[0016] In the compound of formulae I, IA and IB, the "*" designates
the asymmetric carbon atom in this compound with the R optical
configuration being preferred. The compounds of formula I may be
present in the pure R form or as a racemic or other mixtures of
compounds having the R and S optical configuration at the
asymmetric carbon shown. The pure R enantiomers are preferred.
[0017] As used throughout this application, the term "lower alkyl"
includes both straight chain and branched chain alkyl groups having
from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl,
preferably methyl and ethyl. As used herein, the term "halogen or
halo" unless otherwise stated, designates all four halogens, i.e.
fluorine, chlorine, bromine and iodine.
[0018] R can be any five- or six-membered saturated cyclic
heteroalkyl ring containing from 1 to 2 heteroatoms selected from
the group consisting of sulfur, oxygen or nitrogen. Any such five-
or six-membered saturated heterocyclic ring can be used in
accordance with this invention. Among the preferred rings are
morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, etc.
[0019] As used herein, the term "aryl" signifies "polynuclear" and
mononuclear unsubstituted aromatic hydrocarbon groups such as
phenyl or naphthyl containing either 6 or 10 carbon atoms.
[0020] The heteroaromatic ring defined by R, R.sup.2 and R.sup.4
can be five- or six-membered heteroaromatic ring having from 1 to 3
heteroatoms selected from the group consisting of oxygen, nitrogen,
and sulfur which is connected by a ring carbon to the remainder of
the molecule as shown. The heteroaromatic ring defined by R.sup.2
and R.sup.4 contains a first nitrogen heteroatom adjacent to the
connecting ring carbon atom and if present, the other heteroatoms
can be oxygen, sulfur, or nitrogen. Among the preferred
heteroaromatic rings include pyridinyl, pyrimidinyl and thiazolyl.
On the other hand, the heteroaromatic ring defined by R need not
contain a nitrogen heteroatom. These heteroaromatic rings which
constitute R.sup.2 or R.sup.4 are connected via a ring carbon atom
to the amide group to form the amides of formula I. The ring carbon
atom of the heteroaromatic ring which is connected via the amide
linkage to form the compound of formula I does not contain any
substituent. When R.sup.2 or R.sup.4 is an unsubstituted or
mono-substituted five- or six-membered heteroaromatic ring, the
rings contain a nitrogen heteroatom adjacent to the connecting ring
carbon.
[0021] When R is aryl fused with a heteroaromatic ring, the term
"aryl" is as defined above and the term "heteroaromatic" is as
defined above. In the compounds of formulae I, IA and IB, the
preferred aryl is phenyl. The heteroaromatic substituent is
connected to the remainder of the molecule through the aryl
substituent. The preferred heteroaromatic ring formed by fusing to
aryl substituents which define R, are indolyl, quinolyl,
isoquinolyl, 2H-chromanyl and benzo[b]thienyl. When R is a
cycloalkyl group, R can be any cycloalkyl group containing 5 or 6
carbon atoms such as cyclohexyl or cyclopentyl.
[0022] The term "amino protecting group" designates any
conventional amino protecting group which can be cleaved to yield
the free amino group. The preferred protecting groups are the
conventional amino protecting groups utilized in peptide synthesis.
Especially preferred are those amino protecting groups which are
cleavable under mildly acidic conditions from about pH 2.0 to 3.
Particularly preferred amino protecting groups such as
t-butoxycarbonyl carbamate, benzyloxycarbonyl carbamate,
9-flurorenylmethyl carbamate.
[0023] The term "pharmaceutically acceptable salts" as used herein
include any salt with both inorganic or organic pharmaceutically
acceptable acids such as hydrochloric acid, hydrobromic acid,
nitric acid, sulfuric acid, phosphoric acid, citric acid, formic
acid, maleic acid, acetic acid, succinic acid, tartaric acid,
methanesulfonic acid, para-toluene sulfonic acid and the like. The
term "pharmaceutically acceptable salts" also includes any
pharmaceutically acceptable base salt such as amine salts, trialkyl
amine salts and the like. Such salts can be formed quite readily by
those skilled in the art using standard techniques.
[0024] During the course of the reaction the various functional
groups such as the free carboxylic acid or hydroxy groups will be
protected via conventional hydrolyzable ester or ether protecting
groups. As used herein the term "hydrolyzable ester or ether
protecting groups" designates any ester or ether conventionally
used for protecting carboxylic acids or alcohols which can be
hydrolyzed to yield the respective hydroxyl or carboxyl group.
Exemplary ester groups useful for those purposes are those in which
the acyl moieties are derived from a lower alkanoic, aryl lower
alkanoic, or lower alkane dicarboxylic acid. Among the activated
acids which can be utilized to form such groups are acid
anhydrides, acid halides, preferably acid chlorides or acid
bromides derived from aryl or lower alkanoic acids. Example of
anhydrides are anhydrides derived from monocarboxylic acid such as
acetic anhydride, benzoic acid anhydride, and lower alkane
dicarboxylic acid anhydrides, e.g. succinic anhydride as well as
chloro formates e.g. trichloro, ethylchloro formate being
preferred. A suitable ether protecting group for alcohols are, for
example, the tetrahydropyranyl ethers such as
4-methoxy-5,6-dihydroxy-2H-pyranyl ethers. Others are
aroylmethylethers such as benzyl, benzhydryl or trityl ethers or
.alpha.-lower alkoxy lower alkyl ethers, for example, methoxymethyl
or allylic ethers or alkyl silylethers such as
trimethylsilylether.
[0025] The compounds of formula I-B have the following embodiments:
7
[0026] wherein X, R, R.sup.1, R.sup.4, * and y are as above.
[0027] Among the compounds of formulae IB-1 and IB-2 are those
compounds where R.sup.1 is cyclopentyl, i.e., the compounds of
formulae I-B1(a) and I-B2(a). Among the embodiments of compounds of
formula I-B1(a) are those compounds where R is aryl [the compound
of formula I-B1(a)(1)]. Among those compounds of formula I-B1(a)(1)
are those compounds where R.sup.4 is
[0028] an unsubstituted thiazolyl;
[0029] thiazolyl substituted with 8
[0030] wherein n and R.sup.7 are as above;
[0031] thiazolyl substituted with
--(CH.sub.2).sub.n--OR.sup.6 or 9
[0032] where n, R, R.sup.6 and R.sup.8 are as above;
[0033] an unsubstituted pyridinyl;
[0034] pyridinyl monosubstituted with 10
[0035] where n and R are as above; or
[0036] pyridinyl monosubstituted with
--(CH.sub.2).sub.n--OR.sup.6
[0037] where R.sup.6 and n are as above.
[0038] Among the embodiments of compounds of formula I-B1(a) are
those compounds where R is a heteroaromatic ring containing from 5
to 6 ring members with from 1 to 2 heteroatoms selected from the
group consisting of oxygen, nitrogen and sulfur. In this case, the
preferred embodiments are those compounds where R.sup.4 is an
unsubstituted pyridinyl or thiazolyl. In accordance with this
preferred embodiment, where R.sup.4 is pyridinyl or thiazolyl, the
heteroaromatic substituent defined by R is, most preferably, also
pyridinyl or thiophenyl.
[0039] Other embodiments of the compounds of formula I-B1(a) are
those compounds where R is aryl fused to a 5- or 6-membered
heteroaromatic ring containing from 1 to 2 heteroatoms in the ring
selected from the group consisting of oxygen, sulfur and nitrogen.
In this case, the preferred embodiment are those compounds where
R.sup.4 is thiazolyl. Among the embodiments of compounds of formula
I-B2(a) are those compounds where X is --O-- [the compound of
formula I-B2(a)(1)]. Among the embodiments of the formula of
I-B2(a)(1) are compounds where R is aryl. In this case, the
preferred compounds are those where R.sup.4 is unsubstituted or
substituted pyridinyl or thiazolyl.
[0040] Among the embodiments of the compounds of formula I-B2(a)
are those compounds where X is 11
[0041] the compounds of formula I-B2(a)(2). Among the embodiments
of the compounds of formula I-B2(a)(2) are those compounds where R
is aryl, with compounds where R.sup.4 is thiazolyl being especially
preferred. Among the embodiments of the compounds of formula
I-B(2)a(2) are those compounds where R is cycloalkyl and R.sup.4 is
thiazolyl.
[0042] Among the embodiments of the compounds of formula I-B2(a)(2)
are those compounds where R is a heteroaromatic ring and
preferably, in this case those compounds where R.sup.4 is
thiazolyl.
[0043] The compounds of formula I-A have the following embodiments:
12
[0044] where X, R, R.sup.1, R.sup.3 and y are as above.
[0045] Among the embodiments of compounds of the formulae I-A1 and
I-A2 are those compounds where R.sup.1 is cyclopentyl, i.e., the
compounds of formulae I-A1(a) and I-A2(a). Among the embodiments of
the compounds of formulae I-A1(a) and I-A2(a) are those compounds
where
[0046] R is aryl;
[0047] R is a 5- or 6-memberred heteroaromatic ring containing from
1 to 3 heteroatoms selected from the group consisting of oxygen,
nitrogen and sulfur;
[0048] R is a saturated 5- or 6-membered cycloheteroalkyl ring
containing from 1 to 2 heteroatoms selected from the group
consisting of oxygen, nitrogen and sulfur; and
[0049] R is cycloalkyl.
[0050] The compounds of formulae I-B1 and I-A1 can be prepared from
compounds of the formula 13
[0051] The compounds of formulae IB-1 and IA-1 are produced from
the compound of formula V via the following reaction scheme: 14
[0052] wherein R, R.sup.1, R.sup.3 and R.sup.4 are as above and
R.sup.5, taken together with its attached oxygen atom forms a
hydrolyzable ester.
[0053] In the first step of this reaction, the carboxylic acid
group of the compound of formula V is protected by converting it to
a hydrolyzable ester protecting group. In this conversion, the
compound of formula V is converted to the compound of formula V-A
treating the compound of formula V with an organic alcohol such as
a lower alkanol in the presence of a strong inorganic acid such as
sulfuric acid. In carrying out this reaction, any conventional
method of esterification can be utilized. In accordance with the
preferred embodiment, the ester of formula V-A is a methyl ester
produced by reacting the compound of formula V with methanol
utilizing sulfuric acid as an esterification catalyst. In the next
step, the compound of formula V-A is alkylated with the compound of
formula III to produce the compound of formula VI. Any conventional
method of alkylating the alpha carbon atom of an organic acid ester
with an alkyl bromide or iodide can be utilized to effect this
conversion and produce the compound of formula VI. In the next step
of this reaction, the compound of formula VI is coupled with the
compound of formula XIII to produce the compound of formula VII via
a Suzuki coupling reaction. These coupling reactions are carried
out in an inert organic polar solvent, preferably dimethylformamide
and dimethoxyethane utilizing a tertiary amine such as tri-lower
alkyl amine, preferably tri-ethylamine and a ligand forming
reagent. Among the preferred ligand forming reagents are tri-lower
alkyl or tri-aryl phosphines. This reaction is carried out in the
presence of a noble metal catalyst such as a palladium II
catalysts, preferably palladium diacetate. In carrying out this
reaction, temperatures of from 80.degree. C. to the reflux
temperature of a solvent medium are utilized. In the next step, the
compound of formula VII is converted to the compound of formula
VIII by hydrolyzing the R.sup.5 protecting group to form the
corresponding organic acid of formula VIII. Any conventional method
of hydrolyzing an ester can be utilized to effect this conversion.
In the next step of this process, the organic acid of formula VIII
is reacted with the amine of formula IV to produce the compound of
formula I-B1. This reaction is carried out by condensing the
compound of formula IV with the compound of formula VIII to form
the amide of formula I-B1. This condensation reaction can be
carried out utilizing any of the conventional means for amide
formation.
[0054] On the other hand, the compound of formula VIII can be
converted to the compound of formula IA-1. The coupling of the
compound of formula VIII with either compounds of the formulae 15
R.sup.3N.dbd.C.dbd.O XII-B
[0055] wherein R.sup.3 is as above
[0056] produces the compound of formula IA-1.
[0057] The carboxylic acid of formula VIII can be converted to the
corresponding amide. This amide formation is carried out in two
steps first by converting the carboxylic acid of formula VIII to
the corresponding acid chloride and then by reacting this acid
chloride with ammonia. Any of the conditions conventional for
converting a carboxylic acid to a corresponding carboxylic acid
chloride can be utilized in this procedure. Furthermore the
reactions of carboxylic acid chloride with ammonia to produce the
corresponding amide is also a well known reaction and the
conditions conventional in this well known reaction can be utilized
in the formation of the amide corresponding to the compound of
formula VIII. The amide is then reacted with the isocyanate of
formula XII-B to form the urea adduct of the compound of formula
I-A1. Any conventional method of reacting an isocyanate with an
amide to form a urea linkage can be utilized to produce the
compound of formula I-A1. On the other hand, the acid chloride can
directly reacted with the compound of urea reagent formula X11-A to
produce a urea adduct. Any of the conditions conventional in a
method of reacting a chloride with a urea reagent can be utilized
in carrying out this procedure.
[0058] The compound of formula V-A wherein R is cycloalkyl or aryl
are known compounds. On the other hand, compounds of formula V-A
wherein R is a heteroaromatic ring or a saturated 5 to 6-membered
heteroalkyl ring or aryl fused with a heteroaromatic ring can be
prepared from known compounds of formula: 16
[0059] wherein R.sup.10 is a heteroaromatic ring containing from 5
to 6 ring members with from 1 to 2 heteroatoms selected from the
group consisting of oxygen, sulfur and nitrogen; a saturated 5- or
6-membered cycloheteroalkyl ring containing from 1 to 2 heteroatoms
selected from the group consisting of oxygen, sulfur and nitrogen;
or aryl fused with a heteroaromatic ring which contain 5 or 6 ring
members with 1 to 3 heteroatoms in the ring being selected from the
group consisting of nitrogen, oxygen and sulfur.
[0060] The compound of formula XI is converted to the compound of
formula VIII, where R is R.sup.10 (the compound of formula VIII-A),
by the following reaction scheme: 17
[0061] wherein R.sup.1, R.sup.5 and R.sup.10 are as above.
[0062] The compound of formula XI is converted to the compound of
formula XI-A by utilizing any conventional means of converting an
acetophenone to acetic acid. In general, this reaction is carried
out by treating the compound of formula XI with morpholine in a
inert organic solvent while heating to a temperature of above
80.degree. C. to reflux. While this is done, acetic acid and
sulfuric acid are added to the reaction mixture to cause the methyl
ketone to convert to acetic acid derivative of formula XI-A. The
compound of formula XI-A is esterified with a conventional
esterifying agent so that the free acid forms a hydrolyzable ester
of formula XII. This reaction is carried out utilizing the same
procedure described in connection with the conversion of the
compound of formula V to the compound of formula V-A. The compound
of formula XII is then alkylated with the compound of formula III
to produce the compound of formula VII-A. This reaction is carried
out in the same manner as disclosed in connection with the
conversion of the compound of formula V-A to the compound of
formula VI. The compound of formula VII-A is then hydrolyzed as
described hereinbefore in connection with the conversion of the
compound of formula VII to the compound formula VIII to produce to
the compound of formula VIII-A. The compound of formula VIII-A can
be converted to the compounds of formulae I-A1 and I-B1, where R is
R.sup.10, in the manner described herein before in connection with
the conversion of the compound of formula VIII to the compounds of
formulae I-A1 and I-B1.
[0063] When in the compound of formula I, when X is --O--, y is 0
and z is 1, i.e., compounds of the formula 18
[0064] wherein R, R.sup.1 and R.sup.2 are as above,
[0065] these compounds are prepared from compounds of the formula
19
[0066] via the following reaction scheme: 20
[0067] wherein R, R.sup.1, R.sup.3 and R.sup.4 are as above.
[0068] The compound of the formula V-C is converted to the compound
of formula VIII-C by alkylation with the compound of formula III in
the same manner described in connection with the conversion of the
compound of formula V-A to the compound of formula VI. The compound
of formula VIII-C can be converted to the compound of formula I-C1
in the same manner as described for the conversion of the compound
of formula VIII to the compound of formula I-B1. On the other hand,
the compound of formula VIII-C can be converted to the compound of
formula I-C2 in the same manner as described in connection with the
conversion of compound of formula VIII into the compound of formula
I-A1.
[0069] On the other hand, when X is O and y is 1, the compound of
formula: 21
[0070] wherein R, R.sup.1 and R.sup.2 are as above.
[0071] These compounds can be prepared from compounds of the
formula 22
[0072] wherein R.sup.5 is as above,
[0073] via the following reaction scheme: 23
[0074] The compound of formula XX is condensed with the compound of
formula XVII to produce the compound of formula V-D utilizing any
of the known procedures for condensing an alcohol with an alkyl
bromide to form an ether. Any of the conditions conventionally
utilized in forming an ether by utilizing a bromide and an alcohol
can be utilized to affect this conversion. In accordance with the
preferred embodiment of this invention, this reaction is carried
out in the presence of an alkaline earth metal carbonate in the
presence of an organic solvent such as acetone. In carrying out
this reaction, elevated temperatures are utilized, i.e.,
temperatures of from about 80.degree. C. to reflux. The compound of
formula V-D is converted to the compound of formula VI-D utilizing
the same procedure described in connection with the reaction of the
compound of formula III with the compound of formula V-A to produce
the compound of formula VI. The compound of formula VI-D is
converted to the compound of formula VIII-D by conventional
hydrolysis as described hereinbefore. The compound of formula
VIII-D can be converted to the compound of formula I-D2 in the same
manner as described herein in connection with the conversion of
formula VIII to the compound of formula I-B1. On the other hand,
the compound of formula VIII-D can be converted to the compound of
formula I-D1 utilizing the same procedure as described hereinbefore
in converting the compound of formula VIII to the compound of
formula I-A1.
[0075] In accordance with another embodiment of this invention, the
compound of formula I wherein y is 0 or 1 and X is 24
[0076] i.e., a compound of the formula 25
[0077] wherein y, R, R.sup.1 and R.sup.2 are as above,
[0078] can be prepared from a compound of the formula 26
[0079] wherein R.sup.5 is as above,
[0080] via the following reaction scheme: 27
[0081] In this procedure, the compound of formula XXIX is reacted
with the compound of formula III via an alkylation reaction to
produce the compound of formula XXX. This alkylation reaction is
carried out in the same manner described in connection with the
alkylation compound of formula V-A to the compound of formula VI by
the reaction of the compound of formula VI-A with the compound of
formula III. The compound of formula XXX is converted to the
compound of formula XXXI by conventional reduction of a nitro group
to an amine group. Any of the conditions conventional in reducing a
nitro group to an amine group can be utilized. Among the preferred
methods are hydrogenation over palladium carbon catalyst. The step
of converting the compound of formula XXX to the compound of
formula XXXI is carried out through the use of such conventional
reduction techniques. In the next step of this reaction of compound
of formula XXXI is converted the compound of formula XXXII by
reacting the compound of formula XXXI with the compound of formula
XVII. This is carried out by conventional means such as converting
a phenylamino group to a phenylthio group by elimination of the
amino substituent and the addition of the thio substituent to the
phenyl ring. In the next step of the process, the compound of
formula XXXII is converted to the compound of formula VII-E by
oxidizing the thio group to a sulfone group. Any conventional
method of oxidizing a thio to a sulfone group can be utilized in
carrying out this procedure. The compound of formula VII-E is
converted to the compound of formula VIII-E by conventional ester
hydrolysis. The compound of formula VIII-E is converted to the
compound of formula I-E1 in accordance with the procedure already
described in connection with the conversion of a compound of
formula VIII to a compound of formula I-A1. On the other hand, the
compound of formula VIII-E can be converted to the compound of
formula I-E2 by the same procedure hereinbefore described in
connection with the conversion of the compound of formula VIII to a
compound of formula I-B1.
[0082] Those phenyl compounds of the formula
[0083] or 28
[0084] are known compounds. When one wants to prepare the
corresponding para iodo substituted phenyl compounds, these para
iodo substituted phenyl compounds are formed from these known para
nitro phenyl compounds listed above. The para nitro group can then
be reduced to an amino group. Any conventional method of reducing a
nitro group to an amine can be utilized to effect this conversion.
This amine group can be used to prepare the corresponding para iodo
compound via a diazotization reaction. Any conventional method of
converting amino group to an iodo group (see, for example, Lucas,
H. J.; Kennedy, E. R. Org. Synth. Coll. Vol., II 1943, 351) can be
utilized to effect this conversion.
[0085] The compound of formula I, "*" designates an asymmetric
carbon atom through which the group --CH.sub.2R.sup.2 and the acid
amide substituents are connected. In accordance with this
invention, the preferred stereoconfiguration of this group is
R.
[0086] If it is desired to produce the "R" or the S isomer of the
compound of formula I, this compound can be separated into these
isomers by any conventional chemical means. Among the preferred
chemical means is to react the free acid compounds of formulae
VIII, VIII-A, VIII-C, VIII-D or VIII-E with an optically active
base. Any conventional optically active base can be utilized to
carry out this resolution. Among the preferred optically active
bases are the optically active amine bases such as
alpha-methylbenzylamine, quinine, dehydroabietylamine and
alpha-methylnaphthylamine. Any of the conventional techniques
utilized in resolving organic acids with optically active organic
amine bases can be utilized in carrying out this reaction.
[0087] In the resolution step, the compound of formula VIII is
reacted with the optically active base in an inert organic solvent
medium to produce salts of the optically active amine with both the
R and S isomers of this compound of formula VIII. In the formation
of these salts, temperatures and pressure are not critical and the
salt formation can take place at room temperature and atmospheric
pressure. The R and S salts can be separated by any conventional
method such as fractional crystallization. After crystallization,
each of the salts can be converted to the respective compounds of
formula VIII in the R and S configuration by hydrolysis with an
acid. Among the preferred acids are dilute aqueous acids, i.e.,
from about 0.001N to 2N aqueous acids, such as aqueous sulfuric or
aqueous hydrochloric acid. The configuration of formula VIII which
are produced by this method of resolution is carried out throughout
the entire reaction scheme to produce the desired R or S isomer of
formula I. The separation of R and S isomers can also be achieved
using an enzymatic ester hydrolysis of any lower alkyl esters
corresponding to the compound of the formula VIII (see for example,
Ahmar, M.; Girard, C.; Bloch, R, Tetrahedron Lett, 1989, 7053),
which results in the formation of corresponding chiral acid and
chiral ester. The ester and the acid can be separated by any
conventional method of separating an acid from an ester. The
preferred method of resolution of racemates of the compounds of the
formula VIII is via the formation of corresponding diastereomeric
esters or amides. These diastereomeric esters or amides can be
prepared by coupling the carboxylic acids of the formula VIII with
a chiral alcohol, or a chiral amine. This reaction can be carried
out using any conventional method of coupling a carboxylic acid
with an alcohol or an amine. The corresponding diastereomers of
compounds of the formula VIII can then be separated using any
conventional separation methods. The resulting pure diastereomeric
esters or amides can then be hydrolyzed to yield the corresponding
pure R or S isomers. The hydrolysis reaction can be carried out
using conventional known methods to hydrolyze an ester or an amide
without racemization.
[0088] All of the compounds of formula I which include the
compounds set forth in the Examples, activated glucokinase in vitro
by the procedure of Example A. In this manner, they increase the
flux of glucose metabolism which causes increased insulin
secretion. Therefore, the compounds of formula I are glucokinase
activators useful for increasing insulin secretion.
EXAMPLE 1
2-Biphenyl-4-yl-3-cyclopentyl-N-thiazol-2-yl-propionamide
[0089] 29
[0090] A solution of diisopropylamine (6.93 mL, 49.5 mmol) in dry
tetrahydrofuran (64 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (16 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (19.8 mL, 49.5 mmol).
The yellow reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of 4-biphenylacetic
acid (5.00 g, 23.6 mmol) in a small amount of dry tetrahydrofuran.
The reaction mixture turned dark in color and was allowed to stir
at -78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (4.96 g, 23.6 mmol) in a small amount of dry
tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. over a period of 15 h. The
reaction mixture was quenched with water (100 mL), and the reaction
mixture was concentrated in vacuo to remove tetrahydrofuran. The
remaining aqueous layer was acidified to pH=2 with concentrated
hydrochloric acid and then extracted with ethyl acetate
(2.times.150 mL). The combined organic extracts were dried over
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 2/1
hexanes/ethyl acetate) afforded
2-biphenyl-4-yl-3-cyclopentylpropionic acid (5.13 g, 74%) as a
white solid: mp 131-133.degree. C.; FAB-HRMS m/e calcd for
C.sub.20H.sub.22O.sub.2 (M+H).sup.+ 294.1620, found 294.1626.
[0091] A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid
(121.0 mg, 0.41 mmol),
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (218.1 mg, 0.49 mmol), triethylamine (172
.mu.L, 1.23 mmol), and 2-aminothiazole (45.3 mg, 0.45 mmol) in dry
N,N-dimethylformamide (1 mL) was stirred at 25.degree. C. under
nitrogen for 24 h. The reaction mixture was concentrated in vacuo
to remove N,N-dimethylformamide. The resulting residue was diluted
with ethyl acetate (100 mL). The organic layer was washed with a
10% aqueous hydrochloric acid solution (1.times.100 mL), water
(1.times.100 mL), and a saturated aqueous sodium chloride solution
(1.times.100 mL). The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 9/1 to 3/1 hexanes/ethyl acetate
gradient elution) afforded
2-biphenyl-4-yl-3-cyclopentyl-N-thiazol-2-yl-propionamide (102.2
mg, 66%) as a white solid: mp 194-195.degree. C.; EI-HRMS m/e calcd
for C.sub.23H.sub.24N.sub.2OS (M.sup.+) 376.1609, found
376.1612.
[0092] In an analogous manner, there were obtained:
[0093] From 2-biphenyl-4-yl-3-cyclopentylpropionic acid and methyl
2-amino-4-thiazoleacetate:
[2-(2-Biphenyl-4-yl-3-cyclopentyl-propionylami-
no)-thiazol-4-yl]-acetic acid methyl ester as a white foam: mp
57-58.degree. C.; FAB-HRMS m/e calcd for
C.sub.26H.sub.28N.sub.2O.sub.3S (M+H).sup.+ 449.1899, found
449.1897.
[0094] From 2-biphenyl-4-yl-3-cyclopentylpropionic acid and ethyl
2-amino-4-thiazoleglyoxylate:
[2-(2-Biphenyl-4-yl-3-cyclopentyl-propionyl-
amino)-thiazol-4-yl]-oxo-acetic acid ethyl ester as a yellow glass:
mp 87-88.degree. C.; FAB-HRMS m/e calcd for
C.sub.27H.sub.28N.sub.2O.sub.4S (M+H).sup.+ 477.1848, found
477.1842.
[0095] From 2-biphenyl-4-yl-3-cyclopentylpropionic acid and ethyl
2-amino-4-thiazoleacetate:
[2-(2-Biphenyl-4-yl-3-cyclopentyl-propionylami-
no)-thiazol-4-yl]-acetic acid ethyl ester as a white foam: mp
78-80.degree. C.; FAB-HRMS m/e calcd for
C.sub.27H.sub.30N.sub.2O.sub.3S (M+H).sup.+ 463.2055, found
463.2052.
[0096] From 2-biphenyl-4-yl-3-cyclopentylpropionic acid and
2-amino-thiazole-4-carboxylic acid ethyl ester:
2-(2-Biphenyl-4-yl-3-cycl-
opentyl-propionylamino)-thiazole-4-carboxylic acid ethyl ester as a
white solid: mp 81-84.degree. C.; FAB-HRMS m/e calcd for
C.sub.26H.sub.28N.sub.2O.sub.3S (M+H).sup.+ 449.1899, found
449.1885.
EXAMPLE 2
2-(2-Biphenyl-4-yl-3-cyclopentyl-propionylamino)-thiazole-4-carboxylic
acid methyl ester
[0097] 30
[0098] A solution of
2-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-thia-
zole-4-carboxylic acid ethyl ester (prepared in Example 1B-d, 200
mg, 0.45 mmol) in methanol (4 mL) was treated with concentrated
sulfuric acid (2 drops). The reaction mixture was heated under
reflux for 15 h. The reaction mixture was allowed to cool to
25.degree. C. and then concentrated in vacuo to remove methanol.
The resulting residue was partitioned between water and ethyl
acetate. The organic layer was dried over magnesium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded
2-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-thiazo-
le-4-carboxylic acid methyl ester (80 mg, 41%) as a white solid: mp
98-101.degree. C.; FAB-HRMS m/e calcd for
C.sub.25H.sub.26N.sub.2O.sub.3S (M+H).sup.+ 435.1743, found
435.1752.
EXAMPLE 3
2-Biphenyl-4-yl-3-cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-propionamid-
e
[0099] 31
[0100] A solution of
2-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-thia-
zole-4-carboxylic acid ethyl ester (prepared in Example 1B-d, 150
mg, 0.33 mmol) in diethyl ether (3 mL) at 0.degree. C. under
nitrogen was slowly treated with lithium aluminum hydride powder
(16 mg, 0.44 mmol). The resulting reaction mixture continued to
stir at 0.degree. C. and was then allowed to gradually warm to
25.degree. C. The reaction mixture was then stirred at 25.degree.
C. over a period of 64 h. The reaction mixture was slowly quenched
by the dropwise addition of water (5 mL). The resulting reaction
mixture was partitioned between water and ethyl acetate, and the
layers were separated. The aqueous layer was further extracted with
ethyl acetate (1.times.25 mL). The combined organic extracts were
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/2
hexanes/ethyl acetate) afforded
2-biphenyl-4-yl-3-cyclopentyl-N-(4-hydroxymethyl-thiazo-
l-2-yl)-propionamide (65 mg, 48%) as a white solid: mp
102-104.degree. C.; EI-HRMS m/e calcd for
C.sub.24H.sub.26N.sub.2O.sub.2S (M.sup.+) 406.1715, found
406.1711.
[0101] In an analogous manner, there was obtained:
[0102] From
[2-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-thiazol-4-yl-
]-acetic acid ethyl ester:
2-Biphenyl-4-yl-3-cyclopentyl-N-[4-(2-hydroxyet-
hyl)-thiazol-2-yl]-propionamide as a clear glass: mp 58-59.degree.
C.; EI-HRMS m/e calcd for C.sub.25H.sub.28N.sub.2O.sub.2S (M.sup.+)
420.1872, found 420.1862.
EXAMPLE 4
(2R)-2-Biphenyl-4-yl-3-cyclopentyl-N-thiazol-2-yl-propionamide
[0103] 32
[0104] A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid
(prepared in Example 1A, 1.12 g, 3.80 mmol) in dry tetrahydrofuran
(36 mL) under nitrogen was cooled to -78.degree. C. and then
treated with triethylamine (606 mL, 4.35 mmol). The reaction
mixture was stirred at -78.degree. C. for 15 min and then treated
dropwise with trimethylacetyl chloride (491 mL, 3.98 mmol). The
resulting reaction mixture was stirred at -78.degree. C. for 15
min, at which time, the cooling bath was removed, and the reaction
mixture was allowed to warm to 25.degree. C. where it was stirred
for 45 min. At this time, the reaction mixture was cooled back to
-78.degree. C. for the addition of the chiral auxiliary. Into a
separate reaction flask, a solution of
(4S)-(-)-4-isopropyl-2-oxazolidinone (467.9 mg, 3.62 mmol) in dry
tetrahydrofuran (18 mL) under nitrogen was cooled to -78.degree. C.
and then treated with a 2.5M solution of n-butyllithium in hexanes
(1.6 mL, 3.80 mmol). After complete addition of the n-butyllithium,
the reaction mixture was allowed to warm to 25.degree. C. where it
was stirred for 1 h. This cloudy white solution was then added
dropwise by syringe to the previously cooled (-78.degree. C.)
pivalate solution. The resulting reaction mixture was stirred at
-78.degree. C. for 1 h and then allowed to gradually warm to
25.degree. C. The reaction mixture was stirred at 25.degree. C. for
15 h. The resulting reaction mixture was quenched with a saturated
aqueous sodium bisulfite solution and concentrated in vacuo to
remove tetrahydrofuran. The resulting aqueous residue was diluted
with ethyl acetate (150 mL). The organic layer was washed with a
saturated aqueous sodium chloride solution (1.times.100 mL), dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 19/1 to 17/3
hexanes/ethyl acetate gradient elution) afforded the higher R.sub.f
product 3-{2(S)-biphenyl-4-yl-3-cyclopentyl-propionyl}-4(S)-isopr-
opyl-oxazolidin-2-one (679.2 mg, 92%) as a yellow oil: EI-HRMS m/e
calcd for C.sub.26H.sub.31NO.sub.3 (M.sup.+) 405.2304, found
405.2310; and the lower R.sub.f product
3-{2(R)-biphenyl-4-yl-3-cyclopentyl-propionyl}-4(S)-
-isopropyl-oxazolidin-2-one (127.4 mg, 17%) as a yellow oil:
EI-HRMS m/e calcd for C.sub.26H.sub.31NO.sub.3 (M.sup.+) 405.2304,
found 405.2313.
[0105] A solution of
3-{2(R)-biphenyl-4-yl-3-cyclopentyl-propionyl}-4(S)-i-
sopropyl-oxazolidin -2-one (127.4 mg, 0.31 mmol) in tetrahydrofuran
(1.3 mL) and water (300 .mu.L) was cooled to 0.degree. C. and then
sequentially treated with a 30% aqueous hydrogen peroxide solution
(39 .mu.L, 1.25 mmol) and an 0.8M aqueous lithium hydroxide
solution (628 .mu.L, 0.50 mmol). The reaction mixture was allowed
to warm to 25.degree. C. where it was stirred for 7 h. At this
time, the reaction mixture was treated with solution of sodium
sulfite (158.4 mg, 1.26 mmol) in water (952 .mu.L). The reaction
mixture was stirred at 0.degree. C. for 30 min and then
concentrated in vacuo to remove tetrahydrofuran. The resulting
aqueous layer was extracted with diethyl ether (1.times.100 mL).
The aqueous layer was then acidified to pH=1 with a 10% aqueous
hydrochloric acid solution and extracted with ethyl acetate
(1.times.100 mL). The organic extract was washed with water, dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 1/1
hexanes/ethyl acetate) afforded
2(R)-biphenyl-4-yl-3-cyclopentylpropionic acid (43 mg, 46%) as a
white solid: mp 136-137.degree. C.; EI-HRMS m/e calcd for
C.sub.20H.sub.22O.sub.2 (M.sup.+) 294.1620, found 294.1618.
[0106] A solution of 2(R)-biphenyl-4-yl-3-cyclopentylpropionic acid
(36.9 mg, 0.13 mmol),
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (52.3 mg, 0.14 mmol), N,N-diisopropylethylamine
(66 .mu.L, 0.38 mmol), and 2-aminothiazole (25.1 mg, 0.25 mmol) in
dry N,N-dimethylformamide (627 .mu.L) was stirred at 25.degree. C.
under nitrogen for 13 h. The reaction mixture was concentrated in
vacuo to remove the N,N-dimethylformamide. The resulting residue
was diluted with ethyl acetate (100 mL). The organic layer was
washed with a 10% aqueous hydrochloric acid solution (1.times.100
mL), a saturated aqueous sodium bicarbonate solution (1.times.100
mL), and a saturated aqueous sodium chloride solution (1.times.100
mL). The organic layer was dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
(2R)-2-biphenyl-4-yl-3-cyclopentyl-N-thiazol-2-yl-propionamide
(29.4 mg, 62%) as a white foam: mp 132-134.degree. C.; FAB-HRMS m/e
calcd for C.sub.23H.sub.24N.sub.2OS (M+H).sup.+ 377.1687, found
377.1696.
EXAMPLE 5
3-Cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-N-thiazol-2-yl-propionamide
[0107] 33
[0108] A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry
tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (18 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a 10M
solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The
yellow reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of 4-iodophenylacetic
acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-te- trahydro-2(1H)-pyrimidinone (18 mL). The
reaction mixture turned dark in color and was allowed to stir at
-78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of
dry tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 42 h. The
reaction mixture was concentrated in vacuo to remove
tetrahydrofuran and then quenched with a 10% aqueous hydrochloric
acid solution (100 mL). The resulting aqueous layer was extracted
with ethyl acetate (3.times.200 mL). The combined organic extracts
were washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a
cream solid: mp 121-122.degree. C.; EL-HRMS m/e calcd for
C.sub.14H.sub.17IO.sub.2 (M.sup.+) 344.0273, found 344.0275.
[0109] A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
(13.00 g, 37.77 mmol) in methanol (94 mL) was treated slowly with
concentrated sulfuric acid (5 drops). The resulting reaction
mixture was heated under reflux for 67 h. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
remove methanol. The residue was diluted with ethyl acetate (300
mL). The organic phase was washed with a saturated aqueous sodium
chloride solution (1.times.100 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 100% hexanes then 19/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
methyl ester (13.18 g, 97%) as a yellow semi-solid: EI-HRMS m/e
calcd for C.sub.15H.sub.19IO.sub.2 (M.sup.+) 358.0430, found
358.0434.
[0110] A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
methyl ester (3.87 g, 10.81 mmol), 1-naphthaleneboronic acid (2.79
g, 16.22 mmol), triethylamine (4.5 mL, 32.44 mmol), palladium (11)
acetate (72.8 mg, 0.324 mmol), and tri-o-tolylphosphine (204.1 mg,
0.670 mmol) in dry N,N-dimethylformamide (43 mL) was heated at
100.degree. C. under nitrogen for 1 h. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
remove N,N-dimethylformamide. The residue was diluted with ethyl
acetate (200 mL). The organic phase was washed with a saturated
aqueous sodium bicarbonate solution (1.times.100 mL) and water
(1.times.100 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 19/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-naphthalen-- 1-yl-phenyl)-propionic acid methyl
ester (3.51 g, 90%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.25H.sub.26O.sub.2 (M.sup.+) 358.1933, found 358.1930.
[0111] A solution of
3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic acid methyl
ester (3.32 g, 9.26 mmol) in tetrahydrofuran (12 mL) was treated
with a 0.8M aqueous lithium hydroxide solution (12 mL). The
resulting reaction mixture was stirred at 25.degree. C. for 24 h,
at which time, thin layer chromatography indicated the presence of
starting material. The reaction mixture was then heated at
80.degree. C. for 18 h. The reaction mixture was then allowed to
cool to 25.degree. C. and concentrated in vacuo to remove
tetrahydrofuran. The residue was acidified to pH=2 with a 10%
aqueous hydrochloric acid solution and then extracted with ethyl
acetate (2.times.150 mL). The combined organic extracts were dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl-
)-propionic acid (1.74 g, 55%) as a white foam: mp 63-64.degree.
C.; EI-HRMS m/e calcd for C.sub.24H.sub.24O.sub.2 (M.sup.+)
344.1776, found 344.1770.
[0112] A solution of
3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic acid (100 mg,
0.29 mmol) in dry N,N-dimethylformamide (2 mL) was treated with
0-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (110 mg, 0.29 mmol), N,N-diisopropylethylamine
(61 .mu.L, 0.35 mmol), and 2-aminothiazole (45 mg, 0.44 mmol). The
reaction mixture was stirred at 25.degree. C. under nitrogen for 15
h. The reaction mixture was poured into a mixture of water and
ethyl acetate (1:1), and the layers were separated. The organic
layer was washed with a 1N aqueous hydrochloric acid solution and a
saturated aqueous sodium chloride solution. The organic layer was
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 70-230 mesh, 2/1
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-naphthalen-1-
-yl-phenyl)-N-thiazol-2-yl-propionamide (92 mg, 74%) as a white
foam: mp 202-204.degree. C.; FAB-HRMS m/e calcd for
C.sub.27H.sub.26N.sub.2OS (M+H).sup.+ 427.1844, found 427.1837.
[0113] In an analogous manner, there were obtained:
[0114] From 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic
acid and methyl 2-amino-4-thiazoleacetate:
{2-[3-Cyclopentyl-2-(4-naphthalen-1-yl--
phenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester as a
white foam: mp 65-69.degree. C.; EI-HRMS m/e calcd for
C.sub.30H.sub.30N.sub.2O- .sub.3S (M.sup.+) 498.1977, found
498.1982.
[0115] From 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic
acid and ethyl 2-amino-4-thiazoleacetate:
{2-[3-Cyclopentyl-2-(4-naphthalen-1-yl-p-
henyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester as a
white foam: mp 63-68.degree. C.; EI-HRMS m/e calcd for
C.sub.31H.sub.32N.sub.2O- .sub.3S (M.sup.+) 512.2134, found
512.2136.
[0116] From 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic
acid and 2-amino-thiazole-4-carboxylic acid methyl ester:
2-[3-Cyclopentyl-2-(4-na-
phthalen-1-yl-phenyl)-propionylamino]-thiazole-4-carboxylic acid
methyl ester as a white foam: mp 103-107.degree. C.; EI-HRMS m/e
calcd for C.sub.29H.sub.28N.sub.2O.sub.3S (M.sup.+) 484.1821, found
484.1825.
[0117] From 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic
acid and 2-amino-4-(hydroxymethyl)thiazole hydrochloride:
3-Cyclopentyl-N-(4-hydro-
xymethyl-thiazol-2-yl)-2-(4-naphthalen-1-yl-phenyl)-propionamide as
a white foam: mp 90-93.degree. C.; EI-HRMS m/e calcd for
C.sub.28H.sub.28N.sub.2O.sub.2S (M.sup.+) 456.1872, found
456.1867.
EXAMPLE 6
3-Cyclopentyl-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-2-(4-naphthalen-1-yl-phe-
nyl)-propionamide
[0118] 34
[0119] A solution of
{2-[3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propio-
nylamino]-thiazol-4-yl}-acetic acid ethyl ester (prepared in
Example 5B-b, 60 mg, 0.117 mmol) in diethyl ether (1 mL) was cooled
to 0.degree. C. and then slowly treated with lithium aluminum
hydride powder (6.7 mg, 0.176 mmol). The reaction mixture was
stirred at 0.degree. C. for 30 min, at which time, thin layer
chromatography showed the absence of starting material. The
reaction mixture was slowly quenched by the dropwise addition of a
saturated aqueous sodium bicarbonate solution (2 mL). The resulting
reaction mixture was treated with ethyl acetate (2 mL) and allowed
to stir at 25.degree. C. for 15 h. The two-phase reaction mixture
was then partitioned between water (20 mL) and ethyl acetate (20
mL), and the layers were separated. The aqueous layer was further
extracted with ethyl acetate (1.times.20 mL). The combined organic
extracts were dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 1/2 hexanes/ethyl acetate) afforded
3-cyclopentyl-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-2-(4--
naphthalen-1-yl-phenyl)-propionamide (19 mg, 34%) as a yellow foam:
mp 84-87.degree. C.; EI-HRMS m/e calcd for
C.sub.29H.sub.30N.sub.2O.sub.2S (M.sup.+) 470.2028, found
470.2020.
EXAMPLE 7
3-Cyclopentyl-N-thiazol-2-yl-2-(4-thiophen-2-yl-phenyl)-propionamide
[0120] 35
[0121] A solution of diisopropylamine (7.7 mL, 54.88 mmol) in dry
tetrahydrofuran (23 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrirni- dinone (10 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (22.0 mL, 54.88 mmol).
The reaction mixture was stirred at -78.degree. C. for 30 min and
then treated dropwise with a solution of 4-bromophenylacetic acid
(5.62 g, 26.13 mmol) in dry tetrahydrofuran (23 mL) and
1,3-dimethyl-3,4,5,6-te- trahydro-2(1H)-pyrimidinone (10 mL). The
reaction mixture turned dark in color and was allowed to stir at
-78.degree. C. for 1 h, at which time, a solution of
iodomethylcyclopentane (5.76 g, 27.44 mmol) in a small amount of
dry tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 24 h. The
reaction mixture was quenched with water and then concentrated in
vacuo to remove tetrahydrofuran. The aqueous residue was acidified
using a 10% aqueous hydrochloric acid solution. The resulting
aqueous layer was extracted with ethyl acetate (2.times.100 mL).
The combined organic extracts were dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded
2-(4-bromo-phenyl)-3-cyclopentyl-propioni- c acid (3.88 g, 50%) as
a light yellow solid: mp 91-93.degree. C.; EI-HRMS m/e calcd for
C.sub.14H.sub.17BrO.sub.2 (M.sup.+) 296.0412, found 296.0417.
[0122] A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic
acid (1.01 g, 3.39 mmol) in methylene chloride (8.5 mL) was treated
with dry N,N-dimethylformamide (2 drops). The reaction mixture was
cooled to 0.degree. C. and then treated with oxalyl chloride (3 mL,
33.98 mmol). The reaction mixture was stirred at 0.degree. C. for
10 min and then stirred at 25.degree. C. for 15 h. The reaction
mixture was concentrated in vacuo. The resulting yellow oil was
dissolved in a small amount of methylene chloride and slowly added
to a cooled solution (0.degree. C.) of 2-aminothiazole (680.6 mg,
6.79 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.79 mmol) in
methylene chloride (17 mL). The resulting reaction mixture was
stirred at 0.degree. C. for 10 min and then at 25.degree. C. for 15
h. The reaction mixture was concentrated in vacuo to remove
methylene chloride. The resulting residue was diluted with ethyl
acetate (200 mL). The organic phase was washed with a 10% aqueous
hydrochloric acid solution (2.times.100 mL), a saturated aqueous
sodium bicarbonate solution (2.times.100 mL), and a saturated
aqueous sodium chloride solution (1.times.100 mL). The organic
layer was then dried over sodium sulfate, filtered, and
concentrated in vacuo to afford
2-(4-bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (1.23
g, 95%) as an orange solid which was used in subsequent reactions
without further purification. An analytical sample was
recrystallized from ethyl acetate to provide a cream solid: mp
201-202.degree. C.; EI-HRMS m/e calcd for
C.sub.17H.sub.19BrN.sub.2OS (M.sup.+) 378.0401, found 378.0405.
[0123] A mixture of
2-(4-bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propio- namide
(102.5 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium(0)
(15.6 mg, 0.014 mmol), 2-thiopheneboronic acid (69.2 mg, 0.54
mmol), and a 2M aqueous sodium carbonate solution (405 .mu.L, 0.81
mmol) in 1,2-dimethoxyethane (9 mL) was heated under reflux for 24
h. The reaction mixture was allowed to cool to 25.degree. C. and
then filtered to remove the catalyst. The filtrate was concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-N-thiazol-2-yl-2-(4-thiophen-2-yl-phenyl)-
-propionamide (4.5 mg, 4%) as a yellow solid: mp 194.degree. C.
(dec); EI-HRMS m/e calcd for C.sub.21H.sub.22N.sub.2OS.sub.2
(M.sup.+) 382.1174, found 382.1175.
EXAMPLE 8
3-Cyclopentyl-2-(4-pyridin-3-yl-phenyl)-N-thiazol-2-yl-propionamide
[0124] 36
[0125] A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry
tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (18 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a 10M
solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The
yellow reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of 4-iodophenylacetic
acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-te- trahydro-2(1H)-pyrimidinone (18 mL). The
reaction mixture turned dark in color and was allowed to stir at
-78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of
dry tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 42 h. The
reaction mixture was concentrated in vacuo to remove
tetrahydrofuran and then quenched with a 10% aqueous hydrochloric
acid solution (100 mL). The resulting aqueous layer was extracted
with ethyl acetate (3.times.200 mL). The combined organic extracts
were washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a
cream solid: mp 121-122.degree. C.; EL-HRMS m/e calcd for
C.sub.14H.sub.17IO.sub.2 (M.sup.+) 344.0273, found 344.0275.
[0126] A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
(13.00 g, 37.77 mmol) in methanol (94 mL) was treated slowly with
concentrated sulfuric acid (5 drops). The resulting reaction
mixture was heated under reflux for 67 h. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
remove methanol. The residue was diluted with ethyl acetate (300
mL). The organic phase was washed with a saturated aqueous sodium
chloride solution (1.times.100 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 100% hexanes then 19/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
methyl ester (13.18 g, 97%) as a yellow semi-solid: EI-HRMS m/e
calcd for C.sub.15H.sub.19IO.sub.2 (M.sup.+) 358.0430, found
358.0434.
[0127] A slurry of dichlorobis(triphenylphosphine)palladium(II)
(119 mg, 0.17 mmol) in 1,2-dimethoxyethane (10 mL) was treated with
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.00
g, 2.79 mmol). The reaction slurry was stirred at 25.degree. C. for
10 min and then treated with a solution of pyridine-3-boronic acid
(515 mg, 4.19 mmol) and a 2M aqueous sodium carbonate solution (2.8
mL, 5.58 mmol) in water (5 mL). The resulting reaction mixture was
heated under reflux for 90 min. The reaction mixture was allowed to
cool to 25.degree. C. and then filtered to remove the catalyst. The
filtrate was partitioned between water and methylene chloride, and
the layers were separated. The aqueous layer was further extracted
with methylene chloride (75 mL). The combined organic extracts were
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyri-
din-3-yl-phenyl)-propionic acid methyl ester (800 mg, 92%) as a
brown oil: EI-HRMS m/e calcd for C.sub.20H.sub.23NO.sub.2 (M.sup.+)
309.1729, found 309.1728.
[0128] A solution of
3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionic acid methyl ester
(450 mg, 1.45 mmol) in tetrahydrofuran (5 mL) was treated with a
0.8M aqueous lithium hydroxide solution (2.18 mL, 1.74 mmol). The
resulting reaction mixture was stirred at 25.degree. C. for 3 d.
The reaction mixture was then partitioned between water (50 mL) and
ethyl acetate (50 mL), and the layers were separated. The aqueous
layer was further extracted with ethyl acetate (2.times.50 mL). The
combined organic extracts were dried over magnesium sulfate,
filtered, and concentrated in vacuo. The resulting solid was
purified by precipitation from methylene chloride/ethyl acetate to
afford 3-cyclopentyl-2-(4-pyridi- n-3-yl-phenyl)-propionic acid
(271 mg, 63%) as a white solid: mp 136-138.degree. C.; EI-HRMS m/e
calcd for C.sub.19H.sub.21NO.sub.2 (M.sup.+) 295.1572, found
295.1572.
[0129] A solution of triphenylphosphine (160 mg, 0.61 mmol) in
methylene chloride (4 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (109 mg, 0.61 mmol). The
reaction mixture was stirred at 0.degree. C. for 30 min and then
treated with 3-cyclopentyl-2-(4-pyrid- in-3-yl-phenyl)-propionic
acid (150 mg, 0.51 mmol). The resulting reaction mixture was
stirred at 0.degree. C. for 5 min and then allowed to warm to
25.degree. C. where it was stirred for 30 min. The reaction mixture
was then treated with 2-aminothiazole (112 mg, 1.12 mmol). The
resulting reaction mixture was stirred at 25.degree. C. for 15 h.
The crude reaction mixture was then directly purified by flash
chromatography (Merck Silica gel 60, 230-400 mesh, 100% diethyl
ether then 1/1 diethyl ether/ethyl acetate then 1/3 diethyl
ether/ethyl acetate) to afford
3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-N-thiazol-2-yl-propionamide
(15 mg, 8%) as a pale yellow foam: mp 48-52.degree. C.; EI-HRMS m/e
calcd for C.sub.22H.sub.23N.sub.3OS (M.sup.+) 377.1562, found
377.1564.
EXAMPLE 9
3-Cyclopentyl-2-(4-pyridin-4-yl-phenyl)-N-thiazol-2-yl-propionamide
[0130] 37
[0131] A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry
tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (18 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a 10M
solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The
yellow reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of 4-iodophenylacetic
acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-te- trahydro-2(1H)-pyrimidinone (18 mL). The
reaction mixture turned dark in color and was allowed to stir at
-78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of
dry tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 42 h. The
reaction mixture was concentrated in vacuo to remove
tetrahydrofuran and then quenched with a 10% aqueous hydrochloric
acid solution (100 mL). The resulting aqueous layer was extracted
with ethyl acetate (3.times.200 mL). The combined organic extracts
were washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a
cream solid: mp 121-122.degree. C.; EI-HRMS m/e calcd for
C.sub.14H.sub.17IO.sub.2 (M.sup.+) 344.0273, found 344.0275.
[0132] A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
(13.00 g, 37.77 mmol) in methanol (94 mL) was treated slowly with
concentrated sulfuric acid (5 drops). The resulting reaction
mixture was heated under reflux for 67 h. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
remove methanol. The residue was diluted with ethyl acetate (300
mL). The organic phase was washed with a saturated aqueous sodium
chloride solution (1.times.100 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 100% hexanes then 19/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
methyl ester (13.18 g, 97%) as a yellow semi-solid: EI-HRMS m/e
calcd for C.sub.15H.sub.19IO.sub.2 (M.sup.+) 358.0430, found
358.0434.
[0133] A slurry of dichlorobis(triphenylphosphine)palladium(II)
(119 mg, 0.17 mmol) in 1,2-dimethoxyethane (10 mL) was treated with
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.00
g, 2.79 mmol). The reaction slurry was stirred at 25.degree. C. for
10 min and then treated with a solution of pyridine-4-boronic acid
(515 mg, 4.19 mmol) and a 2M aqueous sodium carbonate solution (2.8
mL, 5.58 mmol) in water (5 mL). The resulting reaction mixture was
heated under reflux for 8 h. The reaction mixture was allowed to
cool to 25.degree. C. where it was stirred for 3 d. The reaction
mixture was partitioned between water (75 mL) and methylene
chloride (75 mL), and the layers were separated. The aqueous layer
was further extracted with methylene chloride (75 mL). The combined
organic extracts were dried over magnesium sulfate, filtered, and
concentrated in vacuo to afford 3-cyclopentyl-2-(4-pyridin--
4-yl-phenyl)-propionic acid methyl ester (240 mg, 28%) as a brown
oil that was used without further purification and
characterization.
[0134] A solution of
3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester
(240 mg, 0.78 mmol) in tetrahydrofuran (3 mL) was treated with a
0.8M aqueous lithium hydroxide solution (1.45 mL, 1.16 mmol). The
resulting reaction mixture was stirred at 25.degree. C. for 30 min
and then heated under reflux for 15 h. The reaction mixture was
allowed to cool to 25.degree. C. and then partitioned between water
(100 mL) and ethyl acetate (70 mL). The layers were separated, and
the aqueous layer was further extracted with ethyl acetate
(1.times.30 mL). The combined organic extracts were dried over
magnesium sulfate, filtered, and concentrated in vacuo to afford a
yellow oil that solidified upon sitting. The solid was collected to
afford 3-cyclopentyl-2-(4-pyridin-4-y- l-phenyl)-propionic acid
(127 mg, 55%) as a yellow solid: mp 118-121.degree. C.; FAB-HRMS
m/e calcd for C.sub.19H.sub.21NO.sub.2 (M+H).sup.+ 296.1650, found
296.1658.
[0135] A solution of triphenylphosphine (59 mg, 0.22 mmol) in
methylene chloride (1 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (39 mg, 0.22 mmol). The
reaction mixture was stirred at 0.degree. C. for 20 min and then
treated with 3-cyclopentyl-2-(4-pyrid- in-4-yl-phenyl)-propionic
acid (55 mg, 0.19 mmol). The resulting reaction mixture was stirred
at 0.degree. C. for 10 min and then allowed to warm to 25.degree.
C. where it was stirred for 20 min. The reaction mixture was then
treated with 2-aminothiazole (41 mg, 0.41 mmol). The resulting
reaction mixture was stirred at 25.degree. C. for 15 h. The crude
reaction mixture was then directly purified by flash chromatography
(Merck Silica gel 60, 230-400 mesh, 20/1 methylene
chloride/methanol) to afford impure
3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-N-thiazol-2-yl-prop-
ionamide as an orange foam. The impure foam was treated with a
solution of hexanes/ethyl acetate (5 mL, 1:3), and a precipitate
formed. The reaction mixture was placed in the freezer for 15 h,
and the solid was collected by filtration to afford
3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-N-thiazol-
-2-yl-propionamide (26 mg, 37%) as a pale orange solid: mp
213-215.degree. C.; EI-HRMS m/e calcd for C.sub.22H.sub.23N.sub.3OS
(M.sup.+) 377.1562, found 377.1564.
EXAMPLE 10
3-Cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-N-thiazol-2-yl-propionamide
[0136] 38
[0137] A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry
tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (18 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a 10M
solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The
yellow reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of 4-iodophenylacetic
acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-te- trahydro-2(1H)-pyrimidinone (18 mL). The
reaction mixture turned dark in color and was allowed to stir at
-78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of
dry tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 42 h. The
reaction mixture was concentrated in vacuo to remove
tetrahydrofuran and then quenched with a 10% aqueous hydrochloric
acid solution (100 mL). The resulting aqueous layer was extracted
with ethyl acetate (3.times.200 mL). The combined organic extracts
were washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a
cream solid: mp 121-122.degree. C.; EI-HRMS m/e calcd for
C.sub.14H.sub.17IO.sub.2 (M.sup.+) 344.0273, found 344.0275.
[0138] A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
(13.00 g, 37.77 mmol) in methanol (94 mL) was treated slowly with
concentrated sulfuric acid (5 drops). The resulting reaction
mixture was heated under reflux for 67 h. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
remove methanol. The residue was diluted with ethyl acetate (300
mL). The organic phase was washed with a saturated aqueous sodium
chloride solution (1.times.100 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 100% hexanes then 19/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
methyl ester (13.18 g, 97%) as a yellow semi-solid: EI-HRMS m/e
calcd for C.sub.151H.sub.9IO.sub.2 (M.sup.+) 358.0430, found
358.0434.
[0139] A slurry of dichlorobis(triphenylphosphine)palladium(II)
(119 mg, 0.17 mmol) in 1,2-dimethoxyethane (10 mL) was treated with
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.00
g, 2.79 mmol). The reaction slurry was stirred at 25.degree. C. for
10 min and then treated with a mixture of 5-indolylboronic acid
(670 mg, 4.19 mmol) in water (5 mL) and a 2M aqueous sodium
carbonate solution (2.8 mL, 5.58 mmol). The resulting reaction
mixture was heated under reflux for 2 h. The reaction mixture was
allowed to cool to 25.degree. C. and then filtered to remove the
catalyst. The filtrate was partitioned between water (50 mL) and
methylene chloride (50 mL), and the layers were separated. The
aqueous layer was further extracted with methylene chloride (50
mL). The combined organic extracts were dried over magnesium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 1/2 hexanes/ethyl acetate)
afforded 3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionic acid
methyl ester (347 mg, 36%) as a light brown oil: EI-HRMS m/e calcd
for C.sub.23H.sub.25NO.sub.2 (M.sup.+) 347.1885, found
347.1887.
[0140] A solution of
3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionic acid methyl
ester (310 mg, 0.89 mmol) in tetrahydrofuran (2 mL) was treated
with a 0.8M aqueous lithium hydroxide solution (1.45 mL, 1.16
mmol). The resulting reaction mixture was stirred at 25.degree. C.
for 39 h and then heated at 80.degree. C. for 4 h. The reaction
mixture was then allowed to cool to 25.degree. C. where it was
stirred for 3 d. The reaction mixture was then concentrated in
vacuo to remove tetrahydrofuran. The resulting aqueous layer was
extracted with methylene chloride (2.times.40 mL). The combined
organic extracts were dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 1/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionic acid (170 mg,
58%) as a pale yellow foam: mp 62-65.degree. C.; FAB-HRMS m/e calcd
for C.sub.22H.sub.23NO.sub.2 (M+H).sup.+ 333.1729, found
333.1731.
[0141] A solution of triphenylphosphine (71 mg, 0.27 mmol) in
methylene chloride (1.5 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (48 mg, 0.27 mmol). The
reaction mixture was stirred at 0.degree. C. for 25 min and then
treated with 3-cyclopentyl-2-[4-(1H-i- ndol-5-yl)-phenyl]-propionic
acid (75 mg, 0.23 mmol). The resulting reaction mixture was stirred
at 0.degree. C. for 5 min and then allowed to warm to 25.degree. C.
where it was stirred for 30 min. The reaction mixture was then
treated with 2-aminothiazole (50 mg, 0.50 mmol). The resulting
reaction mixture was stirred at 25.degree. C. for 5 d. The crude
reaction mixture was then directly purified by flash chromatography
(Merck Silica gel 60, 230-400 mesh, 9/1 chloroform/methanol) to
afford impure
3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-N-thiazol-2-yl-propiona-
mide. Repurification by flash chromatography (Merck Silica gel 60,
230-400 mesh, 1/3 hexanes/ethyl acetate) afforded pure
3-cyclopentyl-2-[4-(1H-ind-
ol-5-yl)-phenyl]-N-thiazol-2-yl-propionamide (8 mg, 9%) as a white
solid: mp 112-115.degree. C.; EI-HRMS m/e calcd for
C.sub.25H.sub.25N.sub.3OS (M.sup.+) 415.1718, found 415.1714.
EXAMPLE 11
2-(4-Benzyloxy-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
[0142] 39
[0143] A mixture of (4-hydroxy-phenyl)-acetic acid methyl ester
(5.0 g, 30.0 mmol) and potassium carbonate (5.0 g, 36.1 mmol) in
acetone (10 mL) was treated with benzyl bromide (4.29 mL, 36.1
mmol). The reaction mixture was then heated at 90.degree. C. for 6
h. At this time, the potassium carbonate was removed by filtration.
The filtrate was concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) afforded
(4-benzyloxy-phenyl)-acetic acid methyl ester (7.1 g, 92.1%) as a
clear oil: EI-HRMS m/e calcd for C.sub.16H.sub.16O.sub.3 (M.sup.+)
256.1099 found 256.1103.
[0144] A solution of freshly prepared lithium diisopropylamide (23
mL of a 0.31M stock solution, 7.13 mmol) was cooled to -78.degree.
C. and then treated with a solution of (4-benzyloxy-phenyl)-acetic
acid methyl ester (1.66 g, 6.48 mmol) in
tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(-
1H)-pyrimidinone (16.1 mL, 3:1). The resulting solution was stirred
at -78.degree. C. for 45 min. At this time, the reaction was
treated with a solution of iodomethylcyclopentane (1.50 g, 7.13
mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL).
The reaction mixture was stirred at -78.degree. C. for 4 h. The
reaction was then warmed to 25.degree. C. and was stirred at
25.degree. C. for 48 h. At this time, the reaction mixture was
quenched by the dropwise addition of a saturated aqueous ammonium
chloride solution (10 mL). This mixture was poured into water (100
mL) and extracted with ethyl acetate (3.times.50 mL). The combined
organic extracts were washed with a saturated aqueous lithium
chloride solution (1.times.100 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 98/2 hexanes/ethyl acetate) afforded
2-(4-benzyloxy-phenyl)-3-cyclopentyl-propionic acid methyl ester
(1.90 g, 86.6%) as a white wax: mp 55-57.degree. C.; EI-HRMS m/e
calcd for C.sub.22H.sub.26O.sub.3 (M.sup.+) 338.1881 found
228.1878.
[0145] A solution of 2-(4-benzyloxy-phenyl)-3-cyclopentyl-propionic
acid methyl ester (1.38 g, 4.08 mmol) in
tetrahydrofuran/water/methanol (10.2 mL, 3:1:1) was treated with a
2N aqueous sodium hydroxide solution (3.06 mL, 6.12 mmol). The
reaction was stirred at 25.degree. C. for 16 h. At this time, an
additional amount of the 2N aqueous sodium hydroxide solution (3.06
mL, 6.12 mmol) was added. The reaction was stirred at 25.degree. C.
for an additional 24 h. At this time, the reaction mixture was
poured into water and extracted into methylene chloride. The layers
were separated. The aqueous layer was acidified to pH=1 with a 1N
aqueous hydrochloric acid solution and was then extracted with a
solution of methylene chloride/methano (90/10). The combined
organic extracts were dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 50150 hexanes/ethyl acetate) afforded
2-(4-benzyloxy-phenyl)-3-cyclopentyl-propionic acid (0.79 g, 60.2%)
as a white solid: mp 112-114.degree. C.
[0146] A solution of 2-(4-benzyloxy-phenyl)-3-cyclopentyl-propionic
acid (0.15 g, 0.46 mmol) in methylene chloride (4.6 mL) was cooled
to 0.degree. C. and then treated with a 2.0M solution of oxalyl
chloride in methylene chloride (0.25 mL, 0.50 mmol) and a few drops
of N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 10 min and at 25.degree. C. for 30 min. The
reaction mixture was then treated with a solution of
2-aminothiazole (0.10 g, 1.01 mmol) and N,N-diisopropylethylamine
(0.19 mL, 1.10 mmol) in tetrahydrofuran (2.3 mL). The reaction
mixture was stirred at 25.degree. C. for 18 h. At this time, the
reaction was concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh 80/20 hexanes/ethyl acetate) afforded
2-(4-benzyloxy-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
(119.4 mg, 63.5%) as a white solid: mp 48-50.degree. C.; EI-HRMS
m/e calcd for C.sub.24H.sub.26N.sub.2O.sub.2S (M.sup.+) 406.1715,
found 406.1716.
EXAMPLE 12
3-Cyclopentyl-2-(4-phenoxy-phenyl)-N-thiazol-2-yl-propionamide
[0147] 40
[0148] A solution of diisopropylamine (2.52 mL, 19.3 mmol) in
tetrahydrofuran (50 mL) was cooled to -78.degree. C. under a
nitrogen atmosphere and then treated with a 2.5M solution of
n-butyllithium in hexanes (7.7 mL, 19.3 mmol). The reaction mixture
was stirred at -78.degree. C. for 15 min and then slowly treated
with a solution of 4-phenoxyphenylacetic acid (2.00 g, 8.8 mmol) in
tetrahydrofuran (12 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4 mL) via
cannulation. The resulting bright yellow solution was allowed to
stir for 1 h at -78.degree. C. After this time, the reaction
mixture was treated with a solution of iodomethylcyclopentane (2.02
g, 9.6 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(1 mL) via cannulation. The resulting reaction mixture was stirred
for 1 h at -78.degree. C. and then allowed to warm to 25.degree. C.
where it was stirred for 14 h. The reaction was then acidified to
pH=2 by the dropwise addition of a 1N aqueous hydrochloric acid
solution and then extracted with ethyl acetate (3.times.25 mL). The
combined organic extracts were dried over sodium sulfate, filtered,
and concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, 50/50 hexanes/ethyl acetate plus 1% acetic acid)
afforded 3-cyclopentyl-2-(4-phenoxy-phenyl)p- ropionic acid (2.49
g, 91%) as a white foam: EI-HRMS m/e calcd for
C.sub.20H.sub.22O.sub.3 (M.sup.+) 310.1568, found 310.1568.
[0149] A solution of 3-cyclopentyl-2-(4-phenoxy-phenyl)-propionic
acid (50 mg, 0.16 mmol),
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (106 mg, 0.24 mmol), and 2-aminothiazole (21
mg, 0.24 mmol) in methylene chloride (10 mL) at 25.degree. C. was
treated with triethylamine (0.067 mL, 0.48 mmol). The reaction
mixture was then stirred at 25.degree. C. for 14 h.
[0150] After this time, the reaction mixture was diluted with water
(10 mL) and then extracted with methylene chloride (3.times.10 mL).
The combined organic extracts were then washed with water
(1.times.10 mL), a 1N aqueous sodium hydroxide solution (1.times.10
mL), and a 1N aqueous hydrochloric acid solution (1.times.10
mL).
[0151] The organic layer was then dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-phenoxy-ph- enyl)-N-thiazol-2-yl-propionamide
(48 mg, 76%) as an off-white solid: mp 154.9-155.1.degree. C.;
EI-HRMS m/e calcd for C.sub.23H.sub.24O.sub.2N.su- b.2S (M.sup.+)
392.1558, found 392.1546.
[0152] In an analogous manner, there was obtained:
[0153] From 3-cyclopentyl-2-(4-phenoxy-phenyl)propionic acid and
2-aminothiazol-4-yl-acetic acid ethyl ester:
{2-[3-Cyclopentyl-2-(4-pheno-
xy-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester as
a white foam: FAB-HRMS m/e calcd for
C.sub.27H.sub.30N.sub.2O.sub.4S (M+H).sup.+ 479.2004, found
479.2001.
EXAMPLE 13
3-Cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-2-(4-phenoxy-phenyl)-propio-
namide
[0154] 41
[0155] A solution of 3-cyclopentyl-2-(4-phenoxy-phenyl)-propionic
acid (prepared in Example 12A, 767 mg, 2.47 mmol) in methylene
chloride (20 mL) at 25.degree. C. was treated with
2-amino-thiazole-4-carboxylic acid ethyl ester (553 mg, 3.21 mmol),
benzotriazol-1-yloxytris(dimethylamino)p- hosphonium
hexafluorophosphate (1.64 g, 3.71 mmol), and triethylamine (1 mL,
7.41 mmol). The resulting reaction mixture was stirred at
25.degree. C. for 16 h. The reaction mixture was then diluted with
water (10 mL) and then extracted with methylene chloride
(3.times.15 mL). The combined organic extracts were washed with a
1N aqueous sodium hydroxide solution (1.times.10 mL), a 1N aqueous
hydrochloric acid solution (1.times.10 mL), and a saturated aqueous
sodium chloride solution (1.times.10 mL). The organic layer was
then dried over sodium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
90/10 hexanes/ethyl acetate) afforded
2-[3-cyclopentyl-2-(4-phenoxy-
-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester
(564 mg, 49%) as a white foam: FAB-HRMS m/e calcd for
C.sub.26H.sub.28N.sub.2O.sub- .4 S (M+H).sup.+ 465.1848, found
465.1831.
[0156] A solution of
2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-
-thiazole-4-carboxylic acid ethyl ester (100 mg, 0.22 mmol) in
diethyl ether (10 mL) was cooled to 0.degree. C. and then treated
with lithium aluminum hydride (13 mg, 0.32 mmol). The reaction
mixture was slowly warmed to 25.degree. C. where it was stirred for
16 h. After this time, the reaction mixture was slowly diluted with
water (5 mL) and then extracted with ethyl acetate (3.times.10 mL).
The combined organic extracts were dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded
3-cyclopentyl-N-(4-hydroxymethyl-thiazol--
2-yl)-2-(4-phenoxy-phenyl)-propionamide (50 mg, 55%) as a white
solid: mp 83.7-87.degree. C.; EI-HRMS m/e calcd for
C.sub.24H.sub.26N.sub.2O.sub.3S (M.sup.+) 422.1664, found
422.1674.
EXAMPLE 14
2-[3-Cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazole-4-carboxyli-
c acid methyl ester
[0157] 42
[0158] A solution of
2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-
-thiazole-4-carboxylic acid ethyl ester (prepared in Example 13,
300 mg, 0.65 mmol) in ethanol (20 mL) at 25.degree. C. was treated
with a solution of potassium hydroxide (109 mg, 1.94 mmol) in water
(6 mL). This light yellow solution was stirred at 25.degree. C. for
2 h and then concentrated in vacuo to remove ethanol. The resulting
aqueous solution was acidified to pH=2 with a 1N aqueous
hydrochloric acid solution and then extracted with methylene
chloride (3.times.10 mL). The combined organic extracts were dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 20/80
hexanes/ethyl acetate plus 1% acetic acid) afforded
2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazole-4-carboxyl-
ic acid (226 mg, 80%) as a white solid: mp >200.degree. C.;
FAB-HRMS m/e calcd for C.sub.24H.sub.24N.sub.2O.sub.4S (M+H).sup.+
437.1535, found 437.1534.
[0159] A solution of
2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-
-thiazole-4-carboxylic acid (100 mg, 0.23 mmol) in methanol (10 mL)
was treated with concentrated hydrochloric acid (1 mL) and then
heated under reflux for 16 h. At this time, the reaction mixture
was concentrated in vacuo. The residue was dissolved in ethyl
acetate (10 mL) and then washed with water (5 mL). The aqueous
layer was further extracted with ethyl acetate (3.times.5 mL). The
combined organic extracts were dried over sodium sulfate, filtered,
and concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded
2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazole-4-carboxyl-
ic acid methyl ester (40 mg, 39%) as a white foam: EI-HRMS m/e
calcd for C.sub.25H.sub.26N.sub.2O.sub.4S (M.sup.+) 450.1613, found
450.1615.
EXAMPLE 15
3-Cyclopentyl-N-[4-(2-hydroxy-ethyl)-thiazol-2-yl]-2-(4-phenoxy-phenyl)-pr-
opionamide
[0160] 43
[0161] A solution of
{2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino-
]-thiazol-4-yl}-acetic acid ethyl ester (prepared in Example 12B-a,
86 mg, 0.18 mmol) in diethyl ether (5 mL) was cooled to 0.degree.
C. and then treated with lithium aluminum hydride (10 mg, 0.27
mmol). The reaction mixture was slowly warmed to 25.degree. C.
where it was stirred for 16 h. At this time, the reaction mixture
was slowly diluted with water (5 mL) and then extracted with ethyl
acetate (3.times.10 mL). The combined organic extracts were dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 70/30
hexanes/ethyl acetate) afforded 3-cyclopentyl-N-[4-(2-hydroxy-
-ethyl)-thiazol-2-yl]-2-(4-phenoxy-phenyl)-propionamide (21 mg,
27%) as an off-white solid: FAB-HRMS m/e calcd for
C.sub.25H.sub.28N.sub.2O.sub.3S (M+H).sup.+ 437.1899, found
437.1900.
EXAMPLE 16
{2-[3-Cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-aceti-
c acid
[0162] 44
[0163] A solution of
{2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino-
]-thiazol-4-yl}-acetic acid ethyl ester (prepared in Example 12B-a,
276 mg, 0.58 mmol) in ethanol (20 mL) at 25.degree. C. was treated
with a solution of potassium hydroxide (100 mg, 1.78 mmol) in water
(6 mL). This light yellow solution was stirred at 25.degree. C. for
2 h and then concentrated in vacuo to remove ethanol. The resulting
aqueous solution was acidified to pH=2 with a 1N aqueous
hydrochloric acid solution and then extracted with methylene
chloride (3.times.10 mL). The combined organic extracts were dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 10/90
hexanes/ethyl acetate plus 1% acetic acid) afforded
{2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-acet-
ic acid (222 mg, 80%) as a white foam: FAB-HRMS m/e calcd for
C.sub.25H.sub.26N.sub.2O.sub.4S (M+H).sup.+ 451.1691, found
451.1686.
EXAMPLE 17
{2-[3-Cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-aceti-
c acid methyl ester
[0164] 45
[0165] A solution of
{2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino-
]-thiazol-4-yl}-acetic acid (prepared in Example 16, 80 mg, 0.18
mmol) in methanol (10 mL) was treated with concentrated
hydrochloric acid (1 mL) and then heated under reflux for 16 h. At
this time, the reaction mixture was concentrated in vacuo. The
residue was dissolved in ethyl acetate (10 mL) and then washed with
water (5 mL). The aqueous layer was further extracted with ethyl
acetate (3.times.5 mL). The combined organic extracts were dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 90/10
hexanes/ethyl acetate) afforded
{2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-pr-
opionylamino]-thiazol-4-yl}-acetic acid methyl ester (50 mg, 61%)
as a yellow oil: EI-HRMS m/e calcd for
C.sub.26H.sub.28N.sub.2O.sub.4S (M.sup.+) 464.1770, found
464.1769.
EXAMPLE 18
3-Cyclopentyl-2-(4-morpholin-4-yl-phenyl)-N-thiazol-2-yl-propionamide
[0166] 46
[0167] A mixture of 4-morpholinoacetophenone (4.61 g, 22 mmol),
sulfur (2.16 g, 67 mmol), and morpholine (6 mL, 67 mmol) was heated
at 80.degree. C. for 1 h then heated under reflux for 18 h. The hot
reaction mixture was poured into warm ethanol. Upon cooling to
25.degree. C., a precipitate formed. The precipitate was filtered
to provide a tan solid (4.16 g). This crude tan solid was then
treated with concentrated acetic acid (16 mL), concentrated
sulfuric acid (2.4 mL), and water (3.6 mL). The resulting reaction
mixture was heated under reflux for 4 h and then poured into water.
The water was removed in vacuo to provide crude
(4-morpholin-4-yl-phenyl)-acetic acid as a brown oil (8.20 g). This
crude (4-morpholin-4-yl-phenyl)-acetic acid was dissolved in
methanol (100 mL) and then slowly treated with concentrated
sulfuric acid (1 mL). The reaction mixture was heated under reflux
for 66 h. The reaction mixture was allowed to cool to 25.degree. C.
and then concentrated in vacuo to remove methanol. The residue was
diluted with water (200 mL) and then treated with a 10% aqueous
sodium hydroxide solution until pH=9. The aqueous phase was
extracted with ethyl acetate (3.times.100 mL). The combined organic
extracts were washed with a saturated aqueous sodium chloride
solution (1.times.100 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 to 1/1 hexanes/ethyl acetate gradient elution)
afforded (4-morpholin-4-yl-phenyl)-acetic acid methyl ester (2.22
g, 42% for 3 steps) as a yellow oil: EI-HRMS m/e calcd for
C.sub.13H.sub.17NO.sub.3 (M.sup.+) 235.1208, found 235.1214.
[0168] A solution of diisopropylamine (344 .mu.L, 2.45 mmol) in dry
tetrahydrofuran (2.9 mL) was cooled to -78.degree. C. under
nitrogen and then treated with a 2.5M solution of n-butyllithium in
hexanes (981 .mu.L, 2.45 mmol). The reaction mixture was stirred at
-78.degree. C. for 15 min and then treated dropwise with a solution
of (4-morpholin-4-yl-phenyl)-acetic acid methyl ester (549.9 mg,
2.34 mmol) in dry tetrahydrofuran (2 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-p- yrimidinone (1 mL). The
resulting reaction mixture was allowed to stir at -78.degree. C.
for 30 min, at which time, a solution of iodomethylcyclopentane
(540.0 mg, 2.57 mmol) in a small amount of dry tetrahydrofuran was
added dropwise. The reaction mixture was then allowed to warm to
25.degree. C. where it was stirred for 67 h. The reaction mixture
was quenched with water and then concentrated in vacuo to remove
tetrahydrofuran. The aqueous residue was diluted with ethyl acetate
(200 mL). The organic phase was washed with a saturated aqueous
sodium chloride solution (1.times.100 mL), dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate)
afforded 3-cyclopentyl-2-(4-morp- holin-4-yl-phenyl)-propionic acid
methyl ester (381.4 mg, 51%) as a white solid: mp 68-70.degree. C.;
EI-HRMS m/e calcd for C.sub.19H.sub.27NO.sub.- 3 (M.sup.+)
317.1991, found 317.2001.
[0169] A solution of
3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid methyl
ester (210.8 mg, 0.66 mmol) in tetrahydrofuran (830 .mu.L) was
treated with a 0.8M aqueous lithium hydroxide solution (1.2 mL).
The reaction mixture was stirred at 25.degree. C. for 23 h and then
concentrated in vacuo to remove tetrahydrofuran. The white residue
was acidified to pH=2 with a 10% aqueous hydrochloric solution. The
resulting aqueous phase was extracted with ethyl acetate
(2.times.75 mL). The combined organic extracts were washed with a
saturated aqueous sodium chloride solution (1.times.100 mL), dried
over sodium sulfate, filtered, and concentrated in vacuo.
Trituration from hexanes/diethyl ether afforded
3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid (173.7 mg,
86%) as a white solid: mp 145-147.degree. C.; EI-HRMS m/e calcd for
C.sub.18H.sub.25NO.sub.3 (M.sup.+) 303.1834, found 303.1843.
[0170] A solution of
3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid (202.5 mg,
0.67 mmol) in dry N,N-dimethylformamide (3.3 mL) was treated with
N,N-diisopropylethylamine (350 .mu.L, 2.00 mmol),
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (303.8 mg, 0.80 mmol), and 2-aminothiazole
(133.7 mg, 1.34 mmol). The reaction mixture was stirred at
25.degree. C. under nitrogen for 15 h. The reaction mixture was
then concentrated in vacuo to remove N,N-dimethylformamide. The
residue was diluted with ethyl acetate (150 mL), and the organic
phase was washed with a 10% aqueous hydrochloric acid solution
(1.times.75 mL) and a saturated aqueous sodium chloride solution
(1.times.75 mL). The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-N-thiazol-2-yl-propionamide
(87.5 mg, 34%) as a white solid: mp 244-246.degree. C.; EI-HRMS m/e
calcd for C.sub.21H.sub.27N.sub.3O.sub.2S (M.sup.+) 385.1824, found
385.1832.
EXAMPLE 19
2-(4-Cyclopentanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamid-
e
[0171] 47
[0172] A solution of freshly prepared lithium diisopropylamide
(430.55 mL of a 0.3M stock solution, 129.16 mmol) was cooled to
-78.degree. C. and then treated with a solution of
(4-nitro-phenyl)-acetic acid ethyl ester (26.32 g, 125.83 mmol) in
tetrahydrofuran/hexamethylphosphoramide (312.5 mL, 3:1). The
resulting solution was stirred at -78.degree. C. for 45 min. At
this time, the reaction was treated with a solution of
iodomethylcyclopentane (27.75 g, 132.1 mmol) in
hexarnethylphosphoramide (27.75 mL). The mixture was stirred at
-78.degree. C. for 4 h. The reaction was then warmed to 25.degree.
C. and was stirred at 25.degree. C. for 16 h. At this time, the
reaction mixture was quenched by the dropwise addition of a
saturated aqueous ammonium chloride solution (250 mL). This mixture
was concentrated in vacuo, diluted with water (250 mL), and
extracted with ethyl acetate (3.times.300 mL). The combined organic
extracts were washed with a saturated aqueous lithium chloride
solution (2.times.250 mL), dried over magnesium sulfate, filtered,
and concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, 98/2 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-nitro-pheny- l)-propionic acid ethyl ester
(28.30 g, 77.2%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.16H.sub.21NO.sub.4 (M.sup.+) 291.1470, found 291.1470.
[0173] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic
acid ethyl ester (7.37 g, 25.3 mmol) in ethyl acetate (316 mL) was
treated with 10% palladium on activated carbon (500 g). The
reaction mixture was shaken under 60 psi of hydrogen gas at
25.degree. C. for 18 h. The catalyst was then removed by filtration
through a pad of celite and washed with ethyl acetate. The filtrate
was concentrated in vacuo to give
2-(4-amino-phenyl)-3-cyclopentyl-propionic acid ethyl ester (3.52
g, 53.3%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.16H.sub.23NO.sub.2 (M.sup.+) 261.1727, found 261.1727.
[0174] A mixture of concentrated hydrochloric acid (0.47 mL) and
ice (475 mg) was cooled to 0.degree. C. and then treated with
2-(4-amino-phenyl)-3-cyclopentyl-propionic acid ethyl ester (620
mg, 2.37 mmol). After 5 min, a solution of sodium nitrite (174 mg,
2.51 mmol) in water (0.37 mL) was added to the reaction mixture.
The resulting solution was stirred at 0.degree. C. for 5 min. At
this time, the solution was added to a solution of
cyclopentanethiol (0.29 mL, 2.75 mmol) in water (0.45 mL) warmed to
45.degree. C. The reaction was stirred at 45.degree. C. for 18 h.
At this time, the reaction was diluted with water (100 mL) and
extracted with chloroform (3.times.50 mL). The combined organic
extracts were dried over sodium sulfate, filtered, and concentrated
in vacuo. The crude brown oil (679 mg) was dissolved in methylene
chloride (9.80 mL), cooled to 0.degree. C., and then treated with
3-chloroperoxybenzoic acid (80-85% grade, 1.69 g, 9.79 mmol). The
reaction mixture was stirred at 25.degree. C. for 18 h. At this
time, the reaction was diluted with methylene chloride (100 mL).
This solution was washed with a saturated aqueous sodium bisulfite
solution (1.times.100 mL), a saturated aqueous sodium chloride
solution (1.times.100 mL), a saturated aqueous sodium bicarbonate
solution (1.times.100 mL), and a saturated aqueous sodium chloride
solution (1.times.100 mL). The organic layer was dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate)
afforded 2-(4-cyclopentanesulfonyl-phenyl)-3-cyclo-
pentyl-propionic acid ethyl ester (164 mg, 18.3%) as a red oil:
FAB-HRMS m/e calcd for C.sub.21H.sub.30O.sub.4S (M+H).sup.+
379.1925 found 379.1943.
[0175] A solution of
2-(4-cyclopentanesulfonyl-phenyl)-3-cyclopentyl-propi- onic acid
ethyl ester (160 mg, 0.42 mmol) in tetrahydrofuran/water/methano- l
(1.05 mL, 3:1:1) was treated with a 1N aqueous lithium hydroxide
solution (0.85 mL, 0.85 mmol). The reaction was stirred at
25.degree. C. for 18 h. At this time, the reaction was diluted with
chloroform (30 mL) and water (50 mL), acidified to pH=1 with a 1N
aqueous hydrochloric acid solution, and extracted with a solution
of chloroform/methanol (90/10, 3.times.50 mL). The combined organic
extracts were dried over sodium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
90/10 chloroform/methanol) afforded
2-(4-cyclopentanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
(101.9 mg, 68.7%) as an off white solid: mp 165-167.degree. C.;
FAB-HRMS m/e caled for C.sub.19H.sub.26O.sub.4S (M+H).sup.+
351.1630 found 351.1646.
[0176] A solution of triphenylphosphine (106 mg, 0.40 mmol) and
N-bromosuccinimide (82 mg, 0.45 mmol) in methylene chloride (1.35
mL) was cooled to 0.degree. C. and then treated with a solution of
2-(4-cyclopentanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
(94.8 mg, 0.27 mmol) in methylene chloride. The reaction mixture
was stirred at 25.degree. C. for 45 min. At this time, the reaction
was treated with 2-aminothiazole (35 mg, 0.35 mmol) and pyridine
(0.03 mL, 0.40 mmol). The reaction was stirred at 25.degree. C. for
18 h. The reaction was then diluted with water (100 mL) and
extracted with chloroform (3.times.50 mL). The combined organic
extracts were dried over sodium sulfate, filtered, and concentrated
in vacuo.
[0177] Flash chromatography (Merck Silica gel 60, 230-400 mesh,
50/50 hexanes/ethyl acetate) afforded
2-(4-cyclopentanesulfonyl-phenyl)-3-cyclo-
pentyl-N-thiazol-2-yl-propionamide (84 mg, 71.8%) as a light-orange
solid: mp 180-182.degree. C.; EI-HRMS m/e calcd for
C.sub.22H.sub.28N.sub.2O.sub- .3S.sub.2 (M.sup.+) 432.1541 found
432.1543.
[0178] In an analogous manner, there were obtained:
[0179] From
2-(4-cyclohexanesulfonyl-phenyl)-3-cyclopentyl-propionic acid and
2-aminothiazole:
2-(4-Cyclohexanesulfonyl-phenyl)-3-cyclopentyl-N-thi-
azol-2-yl-propionamide as an off-white solid: mp 220-222.degree.
C.; EI-HRMS m/e calcd for C.sub.23H.sub.30N.sub.2O.sub.3S.sub.2
(M.sup.+) 446.1698 found 446.1700.
[0180] From 2-(4-benzenesulfonyl-phenyl)-3-cyclopentyl-propionic
acid and 2-aminothiazole:
2-(4-Benzenesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-y-
l-propionamide as a yellow foam: mp 128-131.degree. C.; EI-HRMS m/e
calcd for C.sub.23H.sub.24N.sub.2O.sub.3S.sub.2 (M.sup.+) 440.122,
found 440.1222.
EXAMPLE 20
3-Cyclopentyl-2-[4-(1H-imidazole-2-sulfonyl)-phenyl]-N-thiazol-2-yl-propio-
namide
[0181] 48
[0182] A mixture of concentrated hydrochloric acid (0.49 mL) and
ice (493 mg) was cooled to 0.degree. C. and then treated with
2-(4-amino-phenyl)-3-cyclopentyl-propionic acid ethyl ester
(prepared in Example 19A, 716 mg, 2.74 mmol). After 5 min, a
solution of sodium nitrite (200 mg, 2.90 mmol) in water (0.45 mL)
was added to the reaction mixture. The resulting solution was
stirred at 0.degree. C. for 5 min. At this time, the solution was
added to a solution of 1H-imidazole-2-thiol (318 mg, 1.16 mmol) in
water (0.60 mL) warmed to 45.degree. C. The reaction was stirred at
45.degree. C. for 4 h. At this time, the reaction was diluted with
water (50 mL) and extracted with chloroform (3.times.50 mL). The
combined organic extracts were dried over sodium sulfate, filtered,
and concentrated in vacuo. The crude brown oil (683 mg) was
dissolved in formic acid (5.72 mL, 99.71 mmol), cooled to 0.degree.
C., and then treated with a 30% aqueous hydrogen peroxide solution
(3.82 mL, 9.11 mmol). This solution was stirred at 0.degree. C. for
1 h and at 25.degree. C. for 5 h. At this time, the reaction was
quenched by the dropwise addition of a saturated aqueous sodium
bisulfite solution. This solution was extracted with chloroform
(3.times.50 mL). The combined organic extracts were washed with a
saturated aqueous sodium chloride solution (1.times.100 mL), dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 70/30
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(1H-imidaz-
ole-2-sulfonyl)-phenyl]-propionic acid ethyl ester (222.4 mg,
21.5%) as a yellow oil: EL-HRMS m/e calcd for
C.sub.19H.sub.24N.sub.2O.sub.4S (M.sup.+) 376.1456 found
376.1454.
[0183] A mixture of
3-cyclopentyl-2-[4-(1H-imidazole-2-sulfonyl)-phenyl]-p- ropionic
acid ethyl ester (113.5 mg, 0.30 mmol) and 2-aminothiazole (45.3
mg, 0.45 mmol) in a solution of magnesium methoxide in methanol
(7.4 wt. %, 0.86 mL, 0.60 mmol) was heated at 110.degree. C. for 8
h. At this time, the reaction was cooled to 25.degree. C., filtered
through a plug of celite, and washed with ethyl acetate. The
filtrate was concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded
the 3-cyclopentyl-2-[4-(1H-imidazole-2-su-
lfonyl)-phenyl]-N-thiazol-2-yl-propionamide (24.7 mg, 19%) as a tan
solid: mp 249-251.degree. C.; EI-HRMS m/e calcd for
C.sub.20H.sub.22N.sub.4O.sub- .2S.sub.2 (M.sup.+) 430.1133 found
430.1133.
EXAMPLE 21
2-Biphenyl-4-yl-3-cyclopentyl-N-pyridin-2-yl-propionamide
[0184] 49
[0185] A solution of diisopropylamine (6.93 mL, 49.5 mmol) in dry
tetrahydrofuran (64 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (16 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (19.8 mL, 49.5 mmol).
The yellow reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of 4-biphenylacetic
acid (5.00 g, 23.6 mmol) in a small amount of dry tetrahydrofuran.
The reaction mixture turned dark in color and was allowed to stir
at -78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (4.96 g, 23.6 mmol) in a small amount of dry
tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. over a period of 15 h. The
reaction mixture was quenched with water (100 mL), and the reaction
mixture was concentrated in vacuo to remove tetrahydrofuran. The
remaining aqueous layer was acidified to pH=2 with concentrated
hydrochloric acid and then extracted with ethyl acetate
(2.times.150 mL). The combined organic extracts were dried over
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 2/1
hexanes/ethyl acetate) afforded
2-biphenyl-4-yl-3-cyclopentylpropionic acid (5.13 g, 74%) as a
white solid: mp 131-133.degree. C.; FAB-HRMS m/e calcd for
C.sub.20H.sub.22O.sub.2 (M+H).sup.+ 294.1620, found 294.1626.
[0186] A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid
(300 mg, 1.02 mmol),
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (386 mg, 1.02 mmol), N,N-diisopropylethylamine
(220 .mu.L, 1.22 mmol), and 2-aminopyridine (144 mg, 1.53 mmol) in
dry N,N-dimethylformamide (5 mL) was stirred at 25.degree. C. under
nitrogen for 15 h. The reaction mixture was partitioned between
water and ethyl acetate, and the layers were separated. The organic
layer was washed with a 1N aqueous hydrochloric acid solution,
water, and a saturated aqueous sodium chloride solution. The
organic layer was dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 2/1 hexanes/ethyl acetate) afforded
2-biphenyl-4-yl-3-cyclopentyl-N-pyridin-2-yl-propionamide (79 mg,
21%) as a white solid: mp 57-59.degree. C.; EI-HRMS m/e calcd for
C.sub.25H.sub.26NO (M.sup.+) 370.2045, found 370.2049.
EXAMPLE 22
6-(2-Biphenyl-4-yl-3-cyclopentyl-propionylamino)-nicotinic Acid
Methyl Ester
[0187] 50
[0188] A slurry of 2-biphenyl-4-yl-3-cyclopentylpropionic acid
(prepared in Example 21, 1.25 g, 4.25 mmol) in methylene chloride
(10 mL) was treated with dry N,N-dimethylformamide (5 drops). The
reaction mixture was cooled to 0.degree. C. and then treated
dropwise with oxalyl chloride (1.85 mL, 21.23 mmol). The reaction
mixture was allowed to stir at 0.degree. C. for 30 min and then
allowed to warm to 25.degree. C. where it was stirred for 2 h. The
reaction mixture was concentrated in vacuo to provide an orange
semi-solid residue. This residue was treated with a small amount of
methylene chloride and was slowly added to a cooled (0.degree. C.)
solution of 6-aminonicotinic acid methyl ester (776 mg, 5.10 mmol)
and triethylamine (1.19 mL, 8.50 mmol) in methylene chloride (10
mL). The resulting reaction mixture was stirred at 0.degree. C. and
allowed to warm to 25.degree. C. The reaction mixture was stirred
at 25.degree. C. for 15 h. The reaction mixture was then
concentrated in vacuo to remove methylene chloride. The resulting
residue was partitioned between water and ethyl acetate, and the
layers were separated. The aqueous layer was further extracted with
ethyl acetate (1.times.100 mL). The combined organic extracts were
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1
hexanes/ethyl acetate) afforded
6-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-nicotinic acid
methyl ester (325 mg, 18%) as a white solid: mp 63-65.degree. C.;
EI-HRMS m/e calcd for C.sub.27H.sub.28N.sub.2O.sub.3 (M.sup.+)
428.2099, found 428.2100.
EXAMPLE 23
6-(2-Biphenyl-4-yl-3-cyclopentyl-propionylamino)-nicotinic Acid
[0189] 51
[0190] A solution of
6-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-nico- tinic acid
methyl ester (prepared in Example 22, 100 mg, 0.23 mmol) in
methanol (2 mL) was treated with a 1N aqueous sodium hydroxide
solution (350 mL, 0.35 mmol). The reaction mixture was heated under
reflux for 30 min and then allowed to cool to 25.degree. C. The
reaction mixture was then concentrated in vacuo. The resulting
residue was partitioned between water and ethyl acetate, and the
layers were separated. The aqueous layer was further extracted with
ethyl acetate (1.times.25 mL). The combined organic extracts were
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1
hexanes/ethyl acetate then 100% methanol) afforded
6-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-nicotinic acid (27
mg, 28%) as a white solid: mp 271-272.degree. C. (dec); FAB-HRMS
m/e calcd for C.sub.26H.sub.26N.sub.2O.sub.3 (M+H).sup.+ 415.2021,
found 415.2010.
EXAMPLE 24
2-Biphenyl-4-yl-3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-propionamid-
e
[0191] 52
[0192] A solution of
6-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-nico- tinic acid
methyl ester (prepared in Example 22, 100 mg, 0.23 mmol) in diethyl
ether (3 mL) at 0.degree. C. under nitrogen was slowly treated with
lithium aluminum hydride powder (12 mg, 0.30 mmol). The resulting
reaction mixture continued to stir at 0.degree. C. and was allowed
to gradually warm to 25.degree. C. The reaction mixture was then
stirred at 25.degree. C. over a period of 64 h. The reaction
mixture was slowly quenched by the dropwise addition of water (5
mL). The resulting reaction mixture was partitioned between water
and ethyl acetate, and the layers were separated. The aqueous layer
was further extracted with ethyl acetate (1.times.25 mL). The
combined organic extracts were dried over magnesium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 1/2 hexanes/ethyl acetate) afforded
2-biphenyl-4-yl-3-cyclopentyl-N-(5-hydroxymethyl-pyridi-
n-2-yl)-propionamide (33 mg, 36%) as a white solid: mp
67-70.degree. C.; EI-HRMS m/e calcd for
C.sub.26H.sub.28N.sub.2O.sub.2 (M.sup.+) 400.2151, found
400.2147.
EXAMPLE 25
3-Cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-N-pyridin-2-yl-propionamide
[0193] 53
[0194] A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry
tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (18 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a 10M
solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The
yellow reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of 4-iodophenylacetic
acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-te- trahydro-2(1H)-pyrimidinone (18 mL). The
reaction mixture turned dark in color and was allowed to stir at
-78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of
dry tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 42 h. The
reaction mixture was concentrated in vacuo to remove
tetrahydrofuran and then quenched with a 10% aqueous hydrochloric
acid solution (100 mL). The resulting aqueous layer was extracted
with ethyl acetate (3.times.200 mL). The combined organic extracts
were washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a
cream solid: mp 121-122.degree. C.; EI-HRMS m/e calcd for
C.sub.14H.sub.17IO.sub.2 (M.sup.+) 344.0273, found 344.0275.
[0195] A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
(13.00 g, 37.77 mmol) in methanol (94 mL) was treated slowly with
concentrated sulfuric acid (5 drops). The resulting reaction
mixture was heated under reflux for 67 h. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
remove methanol. The residue was diluted with ethyl acetate (300
mL). The organic phase was washed with a saturated aqueous sodium
chloride solution (1.times.100 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 100% hexanes then 19/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
methyl ester (13.18 g, 97%) as a yellow semi-solid: EI-HRMS m/e
calcd for C.sub.15H.sub.19IO.sub.2 (M.sup.+) 358.0430, found
358.0434.
[0196] A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
methyl ester (3.87 g, 10.81 mmol), 1-naphthaleneboronic acid (2.79
g, 16.22 mmol), triethylamine (4.5 mL, 32.44 mmol), palladium (II)
acetate (72.8 mg, 0.324 mmol), and tri-o-tolylphosphine (204.1 mg,
0.670 mmol) in dry N,N-dimethylformamide (43 mL) was heated at
100.degree. C. under nitrogen for 1 h. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
remove N,N-dimethylformamide. The residue was diluted with ethyl
acetate (200 mL). The organic phase was washed with a saturated
aqueous sodium bicarbonate solution (1.times.100 mL) and water
(1.times.100 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 19/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-naphthalen-- 1-yl-phenyl)-propionic acid methyl
ester (3.51 g, 90%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.25H.sub.26O.sub.2 (M.sup.+) 358.1933, found 358.1930.
[0197] A solution of
3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic acid methyl
ester (3.32 g, 9.26 mmol) in tetrahydrofuran (12 mL) was treated
with a 0.8M aqueous lithium hydroxide solution (12 mL). The
resulting reaction mixture was stirred at 25.degree. C. for 24 h,
at which time, thin layer chromatography indicated the presence of
starting material. The reaction mixture was then heated at
80.degree. C. for 18 h. The reaction mixture was then allowed to
cool to 25.degree. C. and concentrated in vacuo to remove
tetrahydrofuran. The residue was acidified to pH=2 with a 10%
aqueous hydrochloric acid solution and then extracted with ethyl
acetate (2.times.150 mL). The combined organic extracts were dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl-
)-propionic acid (1.74 g, 55%) as a white foam: mp 63-64.degree.
C.; EI-HRMS m/e calcd for C.sub.24H.sub.24O.sub.2 (M.sup.+)
344.1776, found 344.1770.
[0198] A solution of 2-aminopyridine (25 mg, 0.26 mmol) in
acetonitrile (500 .mu.L) was treated with
3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-p- ropionic acid (75 mg,
0.22 mmol), triphenylphosphine (63 mg, 0.24 mmol), triethylamine
(91 .mu.L, 0.66 mmol), and carbon tetrachloride (300 .mu.L). The
resulting reaction mixture was stirred at 25.degree. C. for 15 h.
The cloudy reaction mixture was diluted with water and then
extracted with methylene chloride. The organic layer was dried over
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate) afforded impure
3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-N-pyr-
idin-2-yl-propionamide. Repurification by flash chromatography
(Merck Silica gel 60, 230-400 mesh, 100% methylene chloride)
afforded pure 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-N-pyridin
-2-yl-propionamide. (40 mg, 43%) as a white foam: mp 73-77.degree.
C.; EI-HRMS m/e calcd for C.sub.29H.sub.28N.sub.2O (M.sup.+)
420.2202, found 420.2003.
[0199] In an analogous manner, there was obtained:
[0200] From 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic
acid and 6-aminonicotinic acid methyl ester:
6-[3-Cyclopentyl-2-(4-naphthalen-1-yl-
-phenyl)-propionylamino]-nicotinic acid methyl ester as a pale
yellow foam: mp 78-82.degree. C.;
[0201] EL-HRMS m/e calcd for C.sub.31H.sub.30N.sub.2O.sub.3
(M.sup.+) 478.2256, found 478.2254.
EXAMPLE 26
6-[3-Cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionylamino]-nicotinic
Acid
[0202] 54
[0203] A solution of
6-[3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propion-
ylamino]-nicotinic acid methyl ester (prepared in Example 25B-a, 45
mg, 0.094 mmol) in methanol (500 .mu.L) was treated with a 1N
aqueous sodium hydroxide solution (188 .mu.L, 0.188 mmol). The
reaction mixture was heated under reflux for 1 h and then allowed
to cool to 25.degree. C. The reaction mixture was then concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
15/1 methylene chloride/methanol) afforded
6-[3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionylamino]-ni-
cotinic acid (15 mg, 34%) as a pale yellow solid: mp
155-158.degree. C.; FAB-HRMS m/e calcd for
C.sub.30H.sub.28N.sub.2O.sub.3 (M+H).sup.+ 465.2178, found
465.2169.
EXAMPLE 27
3-Cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-naphthalen-1-yl-phenyl-
)-propionamide
[0204] 55
[0205] A solution
6-[3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionyla-
mino]-nicotinic acid methyl ester (prepared in Example 25B-a, 140
mg, 0.29 mmol) in diethyl ether (2 mL) was cooled to 0.degree. C.
and then slowly treated with lithium aluminum hydride powder (17
mg, 0.44 mmol). The reaction mixture was stirred at 0.degree. C.
for 30 min and then allowed to warm to 25.degree. C. where it was
stirred for 3.5 h. The reaction mixture was then slowly quenched by
the dropwise addition of water (5 mL). The resulting mixture was
partitioned between water (25 mL) and ethyl acetate (25 mL), and
the layers were separated. The organic layer was dried over
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 1/1
hexanes/ethyl acetate) afforded
3-cyclopentyl-N-(5-hydroxymethyl-pyridin--
2-yl)-2-(4-naphthalen-1-yl-phenyl)-propionamide (47 mg, 37%) as a
light yellow foam: mp 72-75.degree. C.; EI-HRMS m/e calcd for
C.sub.30H.sub.30N.sub.2O.sub.2 (M.sup.+) 450.2307, found
450.2312.
EXAMPLE 28
3-Cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-3-yl-phenyl)-propionamide
[0206] 56
[0207] A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry
tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (18 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a 10M
solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The
yellow reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of 4-iodophenylacetic
acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-te- trahydro-2(1H)-pyrimidinone (18 mL). The
reaction mixture turned dark in color and was allowed to stir at
-78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of
dry tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 42 h. The
reaction mixture was concentrated in vacuo to remove
tetrahydrofuran and then quenched with a 10% aqueous hydrochloric
acid solution (100 mL). The resulting aqueous layer was extracted
with ethyl acetate (3.times.200 mL). The combined organic extracts
were washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a
cream solid: mp 121-122.degree. C.; EI-HRMS m/e calcd for
C.sub.14H17IO.sub.2 (M.sup.+) 344.0273, found 344.0275.
[0208] A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
(13.00 g, 37.77 mmol) in methanol (94 mL) was treated slowly with
concentrated sulfuric acid (5 drops). The resulting reaction
mixture was heated under reflux for 67 h. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
remove methanol. The residue was diluted with ethyl acetate (300
mL). The organic phase was washed with a saturated aqueous sodium
chloride solution (1.times.100 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 100% hexanes then 19/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
methyl ester (13.18 g, 97%) as a yellow semi-solid: EI-HRMS m/e
calcd for C.sub.15H.sub.19IO.sub.2 (M.sup.+) 358.0430, found
358.0434.
[0209] A slurry of dichlorobis(triphenylphosphine)palladium(II)
(119 mg, 0.17 mmol) in 1,2-dimethoxyethane (10 mL) was treated with
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.00
g, 2.79 mmol). The reaction slurry was stirred at 25.degree. C. for
10 min and then treated with a solution of pyridine-3-boronic acid
(515 mg, 4.19 mmol) and a 2M aqueous sodium carbonate solution (2.8
mL, 5.58 mmol) in water (5 mL). The resulting reaction mixture was
heated under reflux for 90 min. The reaction mixture was allowed to
cool to 25.degree. C. and then filtered to remove the catalyst. The
filtrate was partitioned between water and methylene chloride, and
the layers were separated. The aqueous layer was further extracted
with methylene chloride (75 mL). The combined organic extracts were
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyri-
din-3-yl-phenyl)-propionic acid methyl ester (800 mg, 92%) as a
brown oil: EI-HRMS m/e calcd for C.sub.20H.sub.23NO.sub.2 (M.sup.+)
309.1729, found 309.1728.
[0210] A solution of
3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionic acid methyl ester
(450 mg, 1.45 mmol) in tetrahydrofuran (5 mL) was treated with a
0.8M aqueous lithium hydroxide solution (2.18 mL, 1.74 mmol). The
resulting reaction mixture was stirred at 25.degree. C. for 3 d.
The reaction mixture was then partitioned between water (50 mL) and
ethyl acetate (50 mL), and the layers were separated. The aqueous
layer was further extracted with ethyl acetate (2.times.50 mL). The
combined organic extracts were dried over magnesium sulfate,
filtered, and concentrated in vacuo. The resulting solid was
purified by precipitation from methylene chloride/ethyl acetate to
afford 3-cyclopentyl-2-(4-pyridi- n-3-yl-phenyl)-propionic acid
(271 mg, 63%) as a white solid: mp 136-138.degree. C.; EI-HRMS m/e
calcd for C.sub.19H.sub.21NO.sub.2 (M.sup.+) 295.1572, found
295.1572.
[0211] A solution of triphenylphosphine (133 mg, 0.51 mmol) in
methylene chloride (5 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (90 mg, 0.51 mmol). The
reaction mixture was stirred at 0.degree. C. for 20 min and then
treated with 3-cyclopentyl-2-(4-pyrid- in-3-yl-phenyl)-propionic
acid (125 mg, 0.42 mmol). The resulting reaction mixture was
stirred at 0.degree. C. for 5 min and then allowed to warm to
25.degree. C. where it was stirred for 20 min. The reaction mixture
was then treated with 2-aminopyridine (88 mg, 0.93 mmol). The
resulting reaction mixture was stirred at 25.degree. C. for 15 h.
The crude reaction mixture was then directly purified by flash
chromatography (Merck Silica gel 60, 230-400 mesh, 1/2
hexanes/ethyl acetate) to afford impure
3-cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-3-yl-phenyl)-propionamid-
e as a pink foam. The impure foam was dissolved in methylene
chloride (40 mL) and washed with a saturated aqueous sodium
bicarbonate solution (1.times.40 mL). The organic layer was dried
over magnesium sulfate, filtered and concentrated in vacuo to
afford pure 3-cyclopentyl-N-pyridin-
-2-yl-2-(4-pyridin-3-yl-phenyl)-propionamide (75 mg, 48%) as a pink
foam: mp 139-140.degree. C.; EI-HRMS m/e calcd for
C.sub.24H.sub.25N.sub.3O (M.sup.+) 371.1998, found 371.2006.
EXAMPLE 29
3-Cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-4-yl-phenyl)-propionamide
[0212] 57
[0213] A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry
tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (18 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a 10M
solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The
yellow reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of 4-iodophenylacetic
acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-te- trahydro-2(1H)-pyrimidinone (18 mL). The
reaction mixture turned dark in color and was allowed to stir at
-78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of
dry tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 42 h. The
reaction mixture was concentrated in vacuo to remove
tetrahydrofuran and then quenched with a 10% aqueous hydrochloric
acid solution (100 mL). The resulting aqueous layer was extracted
with ethyl acetate (3.times.200 mL). The combined organic extracts
were washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a
cream solid: mp 121-122.degree. C.; EI-HRMS m/e calcd for
C.sub.14H.sub.17IO.sub.2 (M.sup.+) 344.0273, found 344.0275.
[0214] A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
(13.00 g, 37.77 mmol) in methanol (94 mL) was treated slowly with
concentrated sulfuric acid (5 drops). The resulting reaction
mixture was heated under reflux for 67 h. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
remove methanol. The residue was diluted with ethyl acetate (300
mL). The organic phase was washed with a saturated aqueous sodium
chloride solution (1.times.100 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 100% hexanes then 19/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
methyl ester (13.18 g, 97%) as a yellow semi-solid: EI-HRMS ni/e
calcd for C.sub.15H.sub.19IO.sub.2 (M.sup.+) 358.0430, found
358.0434.
[0215] A slurry of dichlorobis(triphenylphosphine)palladium(II)
(119 mg, 0.17 mmol) in 1,2-dimethoxyethane (10 mL) was treated with
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.00
g, 2.79 mmol). The reaction slurry was stirred at 25.degree. C. for
10 min and then treated with a solution of pyridine-4-boronic acid
(515 mg, 4.19 mmol) and a 2M aqueous sodium carbonate solution (2.8
mL, 5.58 mmol) in water (5 mL). The resulting reaction mixture was
heated under reflux for 8 h. The reaction mixture was allowed to
cool to 25.degree. C. where it was stirred for 3 d. The reaction
mixture was partitioned between water (75 mL) and methylene
chloride (75 mL), and the layers were separated. The aqueous layer
was further extracted with methylene chloride (75 mL). The combined
organic extracts were dried over magnesium sulfate, filtered, and
concentrated in vacuo to afford 3-cyclopentyl-2-(4-pyridin--
4-yl-phenyl)-propionic acid methyl ester (240 mg, 28%) as a brown
oil that was used without further purification and
characterization.
[0216] A solution of
3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester
(240 mg, 0.78 mmol) in tetrahydrofuran (3 mL) was treated with a
0.8M aqueous lithium hydroxide solution (1.45 mL, 1.16 mmol). The
resulting reaction mixture was stirred at 25.degree. C. for 30 min
and then heated under reflux for 15 h. The reaction mixture was
allowed to cool to 25.degree. C. and then partitioned between water
(100 mL) and ethyl acetate (70 mL). The layers were separated, and
the aqueous layer was further extracted with ethyl acetate
(1.times.30 mL). The combined organic extracts were dried over
magnesium sulfate, filtered, and concentrated in vacuo to afford a
yellow oil that solidified upon sitting. The solid was collected to
afford 3-cyclopentyl-2-(4-pyridin-4-y- l-phenyl)-propionic acid
(127 mg, 55%) as a yellow solid: mp 118-121.degree. C.; FAB-HRMS
m/e calcd for C.sub.19H.sub.21NO.sub.2 (M+H).sup.+ 296.1650, found
296.1658.
[0217] A solution of triphenylphosphine (59 mg, 0.22 mmol) in
methylene chloride (1 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (39 mg, 0.22 mmol). The
reaction mixture was stirred at 0.degree. C. for 20 min and then
treated with 3-cyclopentyl-2-(4-pyrid- in-4-yl-phenyl)-propionic
acid (55 mg, 0.19 mmol). The resulting reaction mixture was stirred
at 0.degree. C. for 10 min and then allowed to warm to 25.degree.
C., where it was stirred for 20 min. The reaction mixture was then
treated with 2-aminopyridine (39 mg, 0.41 mmol). The resulting
reaction mixture was stirred at 25.degree. C. for 15 h. The crude
reaction mixture was then directly purified by flash chromatography
(Merck Silica gel 60, 230-400 mesh, 20/1 methylene
chloride/methanol) to afford impure
3-cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-4-yl-phenyl)-prop-
ionamide as a yellow solid. Repurification by flash chromatography
(Merck Silica gel 60, 230-400 mesh, 100% ethyl acetate) afforded
pure
3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-N-thiazol-2-yl-propionamide
(10 mg, 14%) as a yellow solid: mp 165-167.degree. C.; EI-HRMS m/e
calcd for C.sub.24H.sub.25N.sub.3O (M.sup.+) 371.1998, found
371.1998.
EXAMPLE 30
3-Cyclopentyl-2-(4-phenoxy-phenyl)-N-pyridin-2-yl-propionamide
[0218] 58
[0219] A solution of 3-cyclopentyl-2-(4-phenoxy-phenyl-propionic
acid (prepared in Example 12A, 51 mg, 0.16 mmol) in methylene
chloride (10 mL) and one drop of N,N-dimethylformamide was cooled
to 0.degree. C. and then treated with a 2.0M solution of oxalyl
chloride in methylene chloride (0.10 mL, 0.18 mmol). The reaction
mixture was stirred at 0.degree. C. for 30 min and then treated
with a solution of 2-aminopyridine (32 mg, 0.34 mmol) in
tetrahydrofuran (2 mL) and N,N-diisopropylethylamine (0.07 mL, 0.39
mmol). The reaction mixture was stirred at 25.degree. C. for 14 h.
At this time, the reaction mixture was diluted with water (10 mL)
and then extracted with methylene chloride (3.times.10 mL). The
combined organic extracts were washed with water (1.times.10 mL), a
1N aqueous sodium hydroxide solution (1.times.10 mL), and a 1N
aqueous hydrochloric acid solution (1.times.10 mL).
[0220] The organic layer was dried over sodium sulfate, filtered,
and concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-phenoxy-ph- enyl)-N-pyridin-2-yl-propionamide
(22 mg, 35%) as glassy solid: EI-HRMS m/e calcd for
C.sub.25H.sub.26N.sub.2O.sub.2 (M) 386.1994, found 386.2001.
[0221] In an analogous manner, there were obtained:
[0222] From 3-cyclopentyl-2-(4-phenoxy-phenyl)propionic acid and
2-amino-5-methyl-pyridine:
3-Cyclopentyl-N-(5-methyl-pyridin-2-yl)-2-(4-p-
henoxy-phenyl)-propionamide as a glassy solid: FAB-HRMS m/e calcd
for C.sub.26H.sub.28N.sub.2O.sub.2 (M+H).sup.+ 401.2229, found
401.2229.
[0223] From 3-cyclopentyl-2-(4-phenoxy-phenyl)propionic acid and
2-amino-nicotinic acid methyl ester:
6-[3-Cyclopentyl-2-(4-phenoxy-phenyl- )-propionylamino]-nicotinic
acid methyl ester as a white foam: FAB-HRMS m/e calcd for
C.sub.27H.sub.28N.sub.2O.sub.4 (M+H).sup.+ 445.2127, found
445.2127.
EXAMPLE 31
6-[3-Cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-nicotinic
Acid
[0224] 59
[0225] A solution of
6-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]- -nicotinic
acid methyl ester (prepared in Example 30B-b, 102 mg, 0.23 mmol) in
ethanol (10 mL) at 25.degree. C. was treated with a solution of
potassium hydroxide (40 mg, 0.69 mmol) in water (2.5 mL). This
light yellow solution was stirred at 25.degree. C. for 2 h and then
concentrated in vacuo to remove ethanol. The resulting aqueous
solution was acidified to pH=2 with a 1N aqueous hydrochloric acid
solution and then extracted with methylene chloride (3.times.10
mL). The combined organic extracts were dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 10/90 hexanes/ethyl acetate plus 1%
acetic acid) afforded
6-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-nicotinic
acid (74 mg, 76%) as a white solid: FAB-HRMS m/e calcd for
C.sub.26H.sub.26N.sub.2- O.sub.4 (M+H).sup.+ 431.1971, found
431.1987.
EXAMPLE 32
-Cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-phenoxy-phenyl)-propion-
amide
[0226] 60
[0227] A solution of
6-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]- -nicotinic
acid methyl ester (prepared in Example 30B -b, 5 9 mg, 0.13 mmol)
in diethyl ether (5 mL) was cooled to 0.degree. C. and then treated
with lithium aluminum hydride (8 mg, 0.20 mmol). The reaction was
slowly warmed to 25.degree. C. where it was stirred for 16 h. At
this time, the reaction mixture was slowly diluted with water (5
mL) and then extracted with ethyl acetate (3.times.10 mL). The
combined organic extracts were dried over sodium sulfate, filtered,
and concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded
3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-phe-
noxy-phenyl)-propionamide (28 mg, 51%) as a yellow foam: FAB-HRMS
m/e calcd for C.sub.26H.sub.28N.sub.2O.sub.3 (M+H).sup.+ 417.2178,
found 417.2163.
EXAMPLE 33
(2-Biphenyl-4-yl-3-cyclopentyl-propionyl) Urea
[0228] 61
[0229] A solution of diisopropylamine (6.93 mL, 49.5 mmol) in dry
tetrahydrofuran (64 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (16 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (19.8 mL, 49.5 mmol).
The yellow reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of 4-biphenylacetic
acid (5.00 g, 23.6 mmol) in a small amount of dry tetrahydrofuran.
The reaction mixture turned dark in color and was allowed to stir
at -78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (4.96 g, 23.6 mmol) in a small amount of dry
tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. over a period of 15 h. The
reaction mixture was quenched with water (100 mL), and the reaction
mixture was concentrated in vacuo to remove tetrahydrofuran. The
remaining aqueous layer was acidified to pH=2 with concentrated
hydrochloric acid and then extracted with ethyl acetate
(2.times.150 mL). The combined organic extracts were dried over
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 2/1
hexanes/ethyl acetate) afforded
2-biphenyl-4-yl-3-cyclopentylpropionic acid (5.13 g, 74%) as a
white solid: mp 131-133.degree. C.; FAB-HRMS m/e calcd for
C.sub.20H.sub.22O.sub.2 (M+H).sup.+ 294.1620, found 294.1626.
[0230] A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid
(192.3 mg, 0.653 mmol) in methanol (3.3 mL) was treated slowly with
concentrated sulfuric acid (1 drop). The resulting reaction mixture
was heated under reflux for 24 h. The reaction mixture was allowed
to cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. The residue was diluted with ethyl acetate (50 mL). The
organic phase was washed with a saturated aqueous sodium
bicarbonate solution (1.times.100 mL), water (1.times.100 mL), and
a saturated aqueous sodium chloride solution (1.times.100 mL). The
organic layer was dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 9/1 hexanes/ethyl acetate) afforded
2-biphenyl-4-yl-3-cyclopentylpropionic acid methyl ester (191.5 mg,
95%) as a yellow oil: EL-HRMS m/e calcd for C.sub.21H.sub.24O.sub.2
(M.sup.+) 308.1776, found 308.1774.
[0231] A mixture of 2-biphenyl-4-yl-3-cyclopentylpropionic acid
methyl ester (415.5 mg, 1.35 mmol) and urea (202.3 mg, 3.37 mmol,
2.5 equiv) was treated with a solution of magnesium methoxide in
methanol (7.4 wt. %, 7.7 mL, 5.39 mmol). The resulting reaction
mixture was then heated under reflux for 23 h. The reaction mixture
was allowed to cool to 25.degree. C. and then filtered through
celite. The filtrate was concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate then 1/1 hexanes/ethyl acetate) afforded
(2-biphenyl-4-yl-3-cyclopentyl-propionyl) urea (67.8 mg, 15%) as a
white solid: mp 184-185.degree. C.; FAB-HRMS m/e calcd for
C.sub.21H.sub.24N.sub.2O.sub.2 (M+H).sup.+ 337.1917, found
337.1924.
EXAMPLE 34
1-(2-Biphenyl-4-yl-3-cyclopentyl-propionyl)-3-methyl Urea
[0232] 62
[0233] A solution of diisopropylamine (6.93 mL, 49.5 mmol) in dry
tetrahydrofuran (64 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (16 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (19.8 mL, 49.5 mmol).
The yellow reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of 4-biphenylacetic
acid (5.00 g, 23.6 mmol) in a small amount of dry tetrahydrofuran.
The reaction mixture turned dark in color and was allowed to stir
at -78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (4.96 g, 23.6 mmol) in a small amount of dry
tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. over a period of 15 h. The
reaction mixture was quenched with water (100 mL), and the reaction
mixture was concentrated in vacuo to remove tetrahydrofuran. The
remaining aqueous layer was acidified to pH=2 with concentrated
hydrochloric acid and then extracted with ethyl acetate
(2.times.150 mL). The combined organic extracts were dried over
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 2/1
hexanes/ethyl acetate) afforded
2-biphenyl-4-yl-3-cyclopentylpropionic acid (5.13 g, 74%) as a
white solid: mp 131-133.degree. C.; FAB-HRMS m/e calcd for
C.sub.20H.sub.22O.sub.2 (M+H).sup.+ 294.1620, found 294.1626.
[0234] A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid
(192.3 mg, 0.653 mmol) in methanol (3.3 mL) was treated slowly with
concentrated sulfuric acid (1 drop). The resulting reaction mixture
was heated under reflux for 24 h. The reaction mixture was allowed
to cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. The residue was diluted with ethyl acetate (50 mL). The
organic phase was washed with a saturated aqueous sodium
bicarbonate solution (1.times.100 mL), water (1.times.100 mL), and
a saturated aqueous sodium chloride solution (1.times.100 mL). The
organic layer was dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 9/1 hexanes/ethyl acetate) afforded
2-biphenyl-4-yl-3-cyclopentylpropionic acid methyl ester (191.5 mg,
95%) as a yellow oil: EI-HRMS m/e calcd for C.sub.21H.sub.24O.sub.2
(M.sup.+) 308.1776, found 308.1774.
[0235] A mixture of 2-biphenyl-4-yl-3-cyclopentylpropionic acid
methyl ester (987.4 mg, 3.20 mmol) and methyl urea (948.7 mg, 12.80
mmol) was treated with a solution of magnesium methoxide in
methanol (7.4 wt. %, 18 mL, 12.80 mmol). The resulting reaction
mixture was then heated under reflux for 19 h. The reaction mixture
was allowed to cool to 25.degree. C. and then filtered through
celite. The filtrate was concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexaneslethyl acetate) afforded
1-(2-biphenyl-4-yl-3-cyclopentyl-propiony- l)-3-methyl urea (152.5
mg, 14%) as a white solid: mp 195-197.degree. C.; EI-HRMS m/e calcd
for C.sub.22H.sub.26N.sub.2O.sub.2 (M.sup.+) 350.1994, found
350.2004.
EXAMPLE 35
1-[3-Cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionyl]-3-methyl
Urea
[0236] 63
[0237] A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry
tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (18 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a 10M
solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The
yellow reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of 4-iodophenylacetic
acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-te- trahydro-2(1H)-pyrimidinone (18 mL). The
reaction mixture turned dark in color and was allowed to stir at
-78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of
dry tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 42 h. The
reaction mixture was concentrated in vacuo to remove
tetrahydrofuran and then quenched with a 10% aqueous hydrochloric
acid solution (100 mL). The resulting aqueous layer was extracted
with ethyl acetate (3.times.200 mL). The combined organic extracts
were washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a
cream solid: mp 121-122.degree. C.; EI-HRMS m/e calcd for
C.sub.14H.sub.17IO.sub.2 (M.sup.+) 344.0273, found 344.0275.
[0238] A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
(13.00 g, 37.77 mmol) in methanol (94 mL) was treated slowly with
concentrated sulfuric acid (5 drops). The resulting reaction
mixture was heated under reflux for 67 h. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
remove methanol. The residue was diluted with ethyl acetate (300
mL). The organic phase was washed with a saturated aqueous sodium
chloride solution (1.times.100 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 100% hexanes then 19/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
methyl ester (13.18 g, 97%) as a yellow semi-solid: EI-HRMS m/e
calcd for C.sub.15H.sub.19IO.sub.2 (M.sup.+) 358.0430, found
358.0434.
[0239] A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
methyl ester (3.87 g, 10.81 mmol), 1-naphthaleneboronic acid (2.79
g, 16.22 mmol), triethylamine (4.5 mL, 32.44 mmol), palladium (II)
acetate (72.8 mg, 0.324 mmol), and tri-o-tolylphosphine (204.1 mg,
0.670 mmol) in dry N,N-dimethylformamide (43 mL) was heated at 1
00.degree. C. under nitrogen for 1 h. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
remove N,N-dimethylformamide. The residue was diluted with ethyl
acetate (200 mL). The organic phase was washed with a saturated
aqueous sodium bicarbonate solutio (1.times.100 mL) and water
(1.times.100 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 19/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-naphthalen-- 1-yl-phenyl)-propionic acid methyl
ester (3.51 g, 90%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.25H.sub.26O.sub.2 (M.sup.+) 358.1933, found 358.1930.
[0240] A mixture of
3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic acid methyl
ester (196.5 mg, 0.548 mmol) and methyl urea (121.8 mg, 1.64 mmol)
was treated with a solution of magnesium methoxide in methanol (7.4
wt. %, 3.1 mL, 2.19 mmol). The resulting reaction mixture was then
heated under reflux for 24 h. The reaction mixture was allowed to
cool to 25.degree. C. and then filtered through celite. The
filtrate was concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate then 3/1 to
1/1 hexanes/ethyl acetate gradient elution) afforded
1-[3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-- propionyl]-3-methyl
urea (76.9 mg, 35%) as a white foam: mp 85-88.degree. C.; EI-HRMS
m/e calcd for C.sub.26H.sub.28N.sub.2O.sub.2 (M.sup.+) 400.2151,
found 400.2150.
EXAMPLE 36
1-[3-Cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionyl]-3-methyl-urea
[0241] 64
[0242] A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry
tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (18 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a 10M
solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The
yellow reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of 4-iodophenylacetic
acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-te- trahydro-2(1H)-pyrimidinone (18 mL). The
reaction mixture turned dark in color and was allowed to stir at
-78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of
dry tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 42 h. The
reaction mixture was concentrated in vacuo to remove
tetrahydrofuran and then quenched with a 10% aqueous hydrochloric
acid solution (100 mL). The resulting aqueous layer was extracted
with ethyl acetate (3.times.200 mL). The combined organic extracts
were washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a
cream solid: mp 121-122.degree. C.; EI-HRMS m/e calcd for
C.sub.14H.sub.17IO.sub.2 (M.sup.+) 344.0273, found 344.0275.
[0243] A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
(13.00 g, 37.77 mmol) in methanol (94 mL) was treated slowly with
concentrated sulfuric acid (5 drops). The resulting reaction
mixture was heated under reflux for 67 h. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
remove methanol. The residue was diluted with ethyl acetate (300
mL). The organic phase was washed with a saturated aqueous sodium
chloride solution (1.times.100 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 100% hexanes then 19/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
methyl ester (13.18 g, 97%) as a yellow semi-solid: EI-HRMS m/e
calcd for C.sub.15H.sub.19IO.sub.2 (M.sup.+) 358.0430, found
358.0434.
[0244] A slurry of dichlorobis(triphenylphosphine)palladium(II)
(119 mg, 0.17 mmol) in 1,2-dimethoxyethane (10 mL) was treated with
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.00
g, 2.79 mmol). The reaction slurry was stirred at 25.degree. C. for
10 min and then treated with a solution of pyridine-3-boronic acid
(515 mg, 4.19 mmol) and a 2M aqueous sodium carbonate solution (2.8
mL, 5.58 mmol) in water (5 mL). The resulting reaction mixture was
heated under reflux for 90 min. The reaction mixture was allowed to
cool to 25.degree. C. and then filtered to remove the catalyst. The
filtrate was partitioned between water and methylene chloride, and
the layers were separated. The aqueous layer was further extracted
with methylene chloride (75 mL). The combined organic extracts were
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyri-
din-3-yl-phenyl)-propionic acid methyl ester (800 mg, 92%) as a
brown oil: EI-HRMS m/e calcd for C.sub.20H.sub.23NO.sub.2 (M.sup.+)
309.1729, found 309.1728.
[0245] A mixture of
3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionic acid methyl ester
(275 mg, 0.89 mmol) and methyl urea (165 mg, 2.22 mmol) was treated
with a solution of magnesium methoxide in methanol (7.4 wt. %, 5.5
mL, 2.67 mmol). The reaction mixture was then concentrated in vacuo
to approximately one-half the volume of methanol. The resulting
reaction mixture was then heated under reflux for 3 d. The reaction
mixture was allowed to cool to 25.degree. C. and then partitioned
between water and ethyl acetate. The layers were separated, and the
aqueous layer was further extracted with ethyl acetate (2.times.40
mL). The combined organic extracts were dried over magnesium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate)
afforded 1-[3-cyclopentyl-2-(4-pyridin-3-
-yl-phenyl)-propionyl]-3-methyl-urea (17 mg, 6%) as a white solid:
mp 158-160.degree. C.; FAB-HRMS m/e calcd for
C.sub.21H.sub.25N.sub.3O.sub.2 (M+H).sup.+ 352.2025, found
352.2028.
EXAMPLE 37
1-{3-Cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionyl}-3-methyl-urea
[0246] 65
[0247] A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry
tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (18 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a 10M
solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The
yellow reaction mixture was stiffed at -78.degree. C. for 30 min
and then treated dropwise with a solution of 4-iodophenylacetic
acid (15.25 g, 5 8.19 mmol) in dry tetrahydrofuran (55 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The
reaction mixture turned dark in color and was allowed to stir at
-78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of
dry tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 42 h. The
reaction mixture was concentrated in vacuo to remove
tetrahydrofuran and then quenched with a 10% aqueous hydrochloric
acid solution (100 mL). The resulting aqueous layer was extracted
with ethyl acetate (3.times.200 mL). The combined organic extracts
were washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a
cream solid: mp 121-122.degree. C.; EI-HRMS m/e calcd for
C.sub.14H.sub.17IO.sub.2 (M.sup.+) 344.0273, found 344.0275.
[0248] A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
(13.00 g, 37.77 mmol) in methanol (94 mL) was treated slowly with
concentrated sulfuric acid (5 drops). The resulting reaction
mixture was heated under reflux for 67 h. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
remove methanol. The residue was diluted with ethyl acetate (300
mL). The organic phase was washed with a saturated aqueous sodium
chloride solution (1.times.100 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 100% hexanes then 19/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid
methyl ester (13.18 g, 97%) as a yellow semi-solid: EI-HRMS m/e
calcd for C.sub.15H.sub.19IO.sub.2 (M.sup.+) 358.0430, found
358.0434.
[0249] A slurry of dichlorobis(triphenylphosphine)palladium(II)
(119 mg, 0.17 mmol) in 1,2-dimethoxyethane (10 mL) was treated with
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.00
g, 2.79 mmol). The reaction slurry was stirred at 25.degree. C. for
10 min and then treated with a mixture of 5-indolylboronic acid
(670 mg, 4.19 mmol) in water (5 mL) and a 2M aqueous sodium
carbonate solution (2.8 mL, 5.58 mmol). The resulting reaction
mixture was heated under reflux for 2 h. The reaction mixture was
allowed to cool to 25.degree. C. and then filtered to remove the
catalyst. The filtrate was partitioned between water (50 mL) and
methylene chloride (50 mL), and the layers were separated. The
aqueous layer was further extracted with methylene chloride (50
mL). The combined organic extracts were dried over magnesium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 1/2 hexanes/ethyl acetate)
afforded 3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionic acid
methyl ester (347 mg, 36%) as a light brown oil: EI-HRMS m/e calcd
for C.sub.23H.sub.25NO.sub.2 (M.sup.+) 347.1885, found
347.1887.
[0250] A mixture of
3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionic acid methyl
ester (245 mg, 0.71 mmol) and methyl urea (131 mg, 1.76 mmol) was
treated with a solution of magnesium methoxide in methanol (7.4 wt.
%, 5.5 mL, 2.12 mmol). The reaction mixture was then concentrated
in vacuo to approximately one-half the volume of methanol. The
resulting reaction mixture was then heated under reflux for 15 h.
The reaction mixture was allowed to cool to 25.degree. C. and then
partitioned between water (20 mL) and ethyl acetate (50 mL). The
layers were separated, and the aqueous layer was further extracted
with ethyl acetate (1.times.25 mL). The combined organic extracts
were dried over magnesium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1
hexanes/ethyl acetate) afforded
1-{3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionyl}-3-methyl-urea
(79 mg, 29%) as a white foam: mp 91-95.degree. C. (foam to gel);
FAB-HRMS m/e calcd for C.sub.24H.sub.27N.sub.3O.sub.2 (M+H).sup.+
390.2181, found 390.2192.
EXAMPLE 38
1-[3-Cyclopentyl-2-(4-phenoxy-phenyl)-propionyl]-3-methyl-urea
[0251] 66
[0252] A solution of diisopropylamine (2.52 mL, 19.3 mmol) in
tetrahydrofuran (50 mL) was cooled to -78.degree. C. under a
nitrogen atmosphere and then treated with a 2.5M solution of
n-butyllithium in hexanes (7.7 mL, 19.3 mmol). The reaction mixture
was stirred at -78.degree. C. for 15 min and then slowly treated
with a solution of 4-phenoxyphenylacetic acid (2.00 g, 8.8 mmol) in
tetrahydrofuran (12 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4 mL) via
cannulation. The resulting bright yellow solution was allowed to
stir for 1 h at -78.degree. C. After this time, the reaction
mixture was treated with a solution of iodomethylcyclopentane (2.02
g, 9.6 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(1 mL) via cannulation. The resulting reaction mixture was stirred
for 1 h at -78.degree. C. and then allowed to warm to 25.degree. C.
where it was stirred for 14 h. The reaction was then acidified to
pH=2 by the dropwise addition of a 1N aqueous hydrochloric acid
solution and then extracted with ethyl acetate (3.times.25 mL). The
combined organic extracts were dried over sodium sulfate, filtered
and concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, 50/50 hexanes/ethyl acetate plus 1% acetic acid)
afforded 3-cyclopentyl-2-(4-phenoxy-phenyl)p- ropionic acid (2.49
g, 91%) as a white foam: EI-HRMS m/e calcd for
C.sub.20H.sub.22O.sub.3 (M.sup.+) 310.1568, found 310.1568.
[0253] A solution of 3-cylopentyl-2-(4-phenoxy-phenyl)-propionic
acid (200 mg, 0.64 mmol) in methylene chloride (10 mL) with one
drop of N,N-dimethylformamide was cooled to 0.degree. C. under a
nitrogen atmosphere. The reaction mixture was then treated with a
2.0M solution of oxalyl chloride in methylene chloride (0.48 mL,
0.97 mmol), and the resulting reaction mixture was stirred at
0.degree. C. for 30 min. The reaction mixture was then treated with
1,1,1,3,3,3-hexamethyldisilazane (0.47 mL, 2.24 mmol) and then
allowed to warm to 25.degree. C. where it was stirred for 16 h.
After such time, the reaction mixture was treated with methanol (10
mL) and then allowed to stir at 25.degree. C. for 10 min. The
resulting reaction mixture was washed with a 5% aqueous sulfuric
acid solution (2.times.10 mL). The combined aqueous extracts were
further extracted with methylene chloride (2.times.10 mL). The
combined organic extracts were then washed with a saturated aqueous
sodium chloride solution (1.times.10 mL), dried over magnesium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate)
afforded 3-cyclopentyl-2-(4-phenoxy-ph- enyl)-propionamide (120 mg,
61%,) as a white solid: mp 91.6-94.4.degree. C.; EI-HRMS m/e calcd
for C.sub.20H.sub.23NO.sub.2 (M.sup.+) 309.1729, found
309.1733.
[0254] A solution of
3-cyclopentyl-2-(4-phenoxy-phenyl)-propionamide (143 mg, 0.46 mmol)
in toluene (10 mL) was treated with methyl isocyanate (0.04 mL,
0.69 mmol). The reaction mixture was heated under reflux for 24 h.
The reaction was then concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate)
afforded
1-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionyl]-3-methyl-urea (116
mg, 69%) as a white solid: EI-HRMS m/e calcd for
C.sub.22H.sub.26N.sub.2O.sub- .3 (M.sup.+) 366.1943, found
366.1946.
EXAMPLE 39
1-[3-Cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionyl]-3-methyl-urea
[0255] 67
[0256] A mixture of 4-morpholinoacetophenone (4.61 g, 22 mmol),
sulfur (2.16 g, 67 mmol), and morpholine (6 mL, 67 mmol) was heated
at 80.degree. C. for 1 h then heated under reflux for 18 h. The hot
reaction mixture was poured into warm ethanol. Upon cooling to
25.degree. C., a precipitate formed. The precipitate was filtered
to provide a tan solid (4.16 g). This crude tan solid was then
treated with concentrated acetic acid (16 mL), concentrated
sulfuric acid (2.4 mL), and water (3.6 mL). The resulting reaction
mixture was heated under reflux for 4 h and then poured into water.
The water was removed in vacuo to provide crude
(4-morpholin-4-yl-phenyl)-acetic acid as a brown oil (8.20 g). This
crude (4-morpholin-4-yl-phenyl)-acetic acid was dissolved in
methanol (100 mL) and then slowly treated with concentrated
sulfuric acid (1 mL). The reaction mixture was heated under reflux
for 66 h. The reaction mixture was allowed to cool to 25.degree. C.
and then concentrated in vacuo to remove methanol. The residue was
diluted with water (200 mL) and then treated with a 10% aqueous
sodium hydroxide solution until pH=9. The aqueous phase was
extracted with ethyl acetate (3.times.100 mL). The combined organic
extracts were washed with a saturated aqueous sodium chloride
solution (1.times.100 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 to 1/1 hexanes/ethyl acetate gradient elution)
afforded (4-morpholin-4-yl-phenyl)-acetic acid methyl ester (2.22
g, 42% for 3 steps) as a yellow oil: EI-HRMS m/e calcd for
C.sub.13H.sub.17NO.sub.3 (M.sup.+) 235.1208, found 235.1214.
[0257] A solution of diisopropylamine (344 .mu.L, 2.45 mmol) in dry
tetrahydrofuran (2.9 mL) was cooled to -78.degree. C. under
nitrogen and then treated with a 2.5M solution of n-butyllithium in
hexanes (981 .mu.L, 2.45 mmol). The reaction mixture was stirred at
-78.degree. C. for 15 min and then treated dropwise with a solution
of (4-morpholin-4-yl-phenyl)-acetic acid methyl ester (549.9 mg,
2.34 mmol) in dry tetrahydrofuran (2 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-p- yrimidinone (1 mL). The
resulting reaction mixture was allowed to stir at -78.degree. C.
for 30 min, at which time, a solution of iodomethylcyclopentane
(540.0 mg, 2.57 mmol) in a small amount of dry tetrahydrofuran was
added dropwise. The reaction mixture was then allowed to warn to
25.degree. C. where it was stirred for 67 h. The reaction mixture
was quenched with water and then concentrated in vacuo to remove
tetrahydrofuran. The aqueous residue was diluted with ethyl acetate
(200 mL). The organic phase was washed with a saturated aqueous
sodium chloride solution (1.times.100 mL), dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate)
afforded 3-cyclopentyl-2-(4-morp- holin-4-yl-phenyl)-propionic acid
methyl ester (381.4 mg, 51%) as a white solid: mp 68-70.degree. C.;
EI-HRMS m/e calcd for C.sub.19H.sub.27NO.sub.- 3 (M.sup.+)
317.1991, found 317.2001.
[0258] A mixture of
3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid methyl
ester (364.0 mg, 1.15 mmol) and methyl urea (254.8 mg, 3.44 mmol)
was treated with a solution of magnesium methoxide in methanol (7.4
wt. %, 6.6 mL, 4.59 mmol). The resulting reaction mixture was
heated under reflux for 3 d. The reaction mixture was allowed to
cool to 25.degree. C. and then filtered through a pad of celite.
The pad of celite was washed well with ethyl acetate until the
washings showed the absence of product by thin layer
chromatography. The filtrate was then concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate then 1/1 hexanes/ethyl acetate) afforded
1-[3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionyl]-3-methyl-urea
(43.5 mg, 11%) as a white solid: mp 206-207.degree. C.; FAB-HRMS
m/e calcd for C.sub.20H.sub.29N.sub.3O.sub.3 (M.sup.+) 359.2209,
found 359.2206.
EXAMPLE 40
1-[2-(4-Cyclohexanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea
[0259] 68
[0260] A solution of freshly prepared lithium diisopropylamide
(430.55 mL of a 0.3M stock solution, 129.16 mmol) was cooled to
-78.degree. C. and then treated with a solution of
(4-nitro-phenyl)-acetic acid ethyl ester (26.32 g, 125.83 mmol) in
tetrahydrofuran/hexamethylphosphoramide (312.5 mL, 3:1). The
resulting solution was stirred at -78.degree. C. for 45 min. At
this time, the reaction was treated with a solution of
iodomethylcyclopentane (27.75 g, 132.1 mmol) in
hexamethylphosphoramide (27.75 mL). The mixture was stirred at
-78.degree. C. for 4 h. The reaction was then warmed to 25.degree.
C. and was stirred at 25.degree. C. for 16 h. The reaction mixture
was then quenched by the dropwise addition of a saturated aqueous
ammonium chloride solution (250 mL). This mixture was concentrated
in vacuo, diluted with water (250 mL), and extracted with ethyl
acetate (3.times.300 mL). The combined organic extracts were washed
with a saturated aqueous lithium chloride solution (2.times.250
mL), dried over magnesium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
98/2 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-nitro-pheny- l)-propionic acid ethyl ester
(28.30 g, 77.2%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.16H.sub.21NO.sub.4 (M.sup.+) 291.1470, found 291.1470.
[0261] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic
acid ethyl ester (7.37 g, 25.3 mmol) in ethyl acetate (316 mL) was
treated with 10% palladium on activated carbon (500 g). The
reaction mixture was shaken under 60 psi of hydrogen gas at
25.degree. C. for 18 h. The catalyst was then filtered off through
a pad of celite and was washed with ethyl acetate. The filtrate was
concentrated in vacuo to give
2-(4-amino-phenyl)-3-cyclopentyl-propionic acid ethyl ester (3.52
g, 53.3%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.16H.sub.23NO.sub.2 (M.sup.+) 261.1727, found 261.1727.
[0262] A mixture of concentrated hydrochloric acid (0.32 mL) and
ice (320 mg) was cooled to 0.degree. C. and then treated with
2-(4-amino-phenyl)-3-cyclopentyl-propionic acid ethyl ester (419.4
mg, 1.60 mmol). After 5 min, a solution of sodium nitrite (117 mg,
1.70 mmol) in water (0.26 mL) was added to the reaction mixture.
The resulting solution was stirred at 0.degree. C. for 5 min. At
this time, the solution was added to a solution of cyclohexanethiol
(0.23 mL, 1.86 mmol) in water (0.35 mL) warmed to 45.degree. C. The
reaction was stirred at 45.degree. C. for 12 h. At this time, the
reaction was diluted with water (100 mL) and extracted with ethyl
acetate (3.times.50 mL). The combined organic extracts were dried
over sodium sulfate, filtered, and concentrated in vacuo. The
residue was passed through a plug of silica (90/10 hexanes/ethyl
acetate) to afford a crude brown oil (128.2 mg). This oil was
dissolved in methylene chloride (8.8 mL), cooled to 0.degree. C.,
and then treated with 3-chloroperoxybenzoic acid (80-85% grade, 307
mg, 1.77 mmol). The reaction mixture was stirred at 25.degree. C.
for 1.5 h. At this time, the reaction was diluted with ethyl
acetate (50 mL). This solution was washed with a saturated aqueous
sodium bisulfite solution (1.times.50 mL) and a saturated aqueous
sodium chloride solution (1.times.50 mL). The organic layer was
dried over sodium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20
hexanes/ethyl acetate) afforded
2-(4-cyclohexanesulfonyl-phenyl)-3-cyclopentyl-propionic acid ethyl
ester (37.7 mg, 23.7%) as a brown oil: EI-HRMS m/e calcd for
C.sub.22H.sub.32O.sub.4S (M.sup.+) 392.2021 found 392.2022.
[0263] A mixture of
2-(4-cyclohexanesulfonyl-phenyl)-3-cyclopentyl-propion- ic acid
ethyl ester (71.5 mg, 0.16 mmol) and methyl urea (18 mg, 0.24 mmol)
was treated with a solution of magnesium methoxide in methanol (7.4
wt. %, 0.46 mL, 0.32 mmol). The resulting reaction mixture was
heated at 100.degree. C. for 8 h. At this time, the reaction was
cooled to 25.degree. C. and passed through a plug of celite. The
celite was washed with ethyl acetate. The filtrate was concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
50/50 hexanes/ethyl acetate) afforded
1-[3-cyclopentyl-2-(3,4-difluoro-phenyl)-propionyl]-3-m- ethyl-urea
(12.6 mg, 18.7%) as a white solid: mp 244-246.degree. C.; FAB-HRMS
m/e calcd for C.sub.16H.sub.20F.sub.2N.sub.2O.sub.2 (M+H).sup.+
421.2153, found 421.2161.
BIOLOGICAL ACTIVITY EXAMPLES
EXAMPLE A
In Vitro Glucokinase Activity
[0264] Glucokinase Assay:
[0265] Glucokinase (GK) was assayed by coupling the production of
glucose-6-phosphate to the generation of NADH with
glucose-6-phosphate dehydrogenase (G6PDH, 0.75-1 kunits/mg;
Boehringer Mannheim, Indianapolis, 1N) from Leuconostoc
mesenteroides as the coupling enzyme (Scheme 2). Recombinant 69
[0266] Human liver GK1 was expressed in E. coli as a glutathione
S-transferase fusion protein (GST-GK) [Liang et al, 1995] and was
purified by chromatography over a glutathione-Sepharose 4B affinity
column using the procedure provided by the manufacturer (Amersham
Pharmacia Biotech, Piscataway, N.J.). Previous studies have
demonstrated that the enzymatic properties of native GK and GST-GK
are essentially identical (Liang et al, 1995; Neet et al.,
1990).
[0267] The assay was conducted at 25.degree. C. in a flat bottom
96-well tissue culture plate from Costar (Cambridge, Mass.) with a
final incubation volume of 120 .mu.l. The incubation mixture
contained: 25 mM Hepes buffer (pH, 7.1), 25 mM KCl, 5 mM D-glucose,
1 mM ATP, 1.8 mM NAD, 2 mM MgCl.sub.2, 1 .mu.M
sorbitol-6-phosphate, 1 mM dithiothreitol, test drug or 10% DMSO,
1.8 unit/ml G6PDH, and GK (see below). All organic reagents were
>98% pure and were from Boehringer Mannheim with the exceptions
of D-glucose and Hepes that were from Sigma Chemical Co, St Louis,
Mo. Test compounds were dissolved in DMSO and were added to the
incubation mixture minus GST-GK in a volume of 12 .mu.l to yield a
final DMSO concentration of 10%. This mix was preincubated in the
temperature controlled chamber of a SPECTRAmax 250 microplate
spectrophotometer (Molecular Devices Corporation, Sunnyvale,
Calif.) for 10 minutes to allow temperature equilibrium and then
the reaction was started by the addition of 20 .mu.l GST-GK.
[0268] After addition of enzyme, the increase in optical density
(OD) at 340 nm was monitored over a 10 minute incubation period as
a measure of GK activity. Sufficient GST-GK was added to produce an
increase in OD.sub.340 of 0.08 to 0.1 units over the 10 minute
incubation period in wells containing 10% DMSO, but no test
compound. Preliminary experiments established that the GK reaction
was linear over this period of time even in the presence of
activators that produced a 5-fold increase in GK activity. The GK
activity in control wells was compared with the activity in wells
containing test GK activators, and the concentration of activator
that produced a 50% increase in the activity of GK, i.e., the
SC.sub.1.5, was calculated. All of the compounds of formula I
described in the Synthesis Examples had an SC.sub.1.5 less than or
equal to 30 .mu.M.
* * * * *