U.S. patent application number 11/005179 was filed with the patent office on 2005-07-28 for substituted benzofurans and benzothiophenes, methods of making and methods of use as integrin antagonists.
This patent application is currently assigned to 3-Dimensional Pharmaceuticals, Inc.. Invention is credited to Anaclerio, Beth M., Marder, Victor J., Marugan Sanchez, Juan Jose, U'Prichard, David C..
Application Number | 20050165036 11/005179 |
Document ID | / |
Family ID | 26963889 |
Filed Date | 2005-07-28 |
United States Patent
Application |
20050165036 |
Kind Code |
A1 |
Anaclerio, Beth M. ; et
al. |
July 28, 2005 |
Substituted benzofurans and benzothiophenes, methods of making and
methods of use as integrin antagonists
Abstract
The present invention relates to novel substituted benzofurans
and benzothiophenes compounds that are antagonists of alpha V
(.alpha.v) integrins, for example .alpha..sub.v.beta..sub.3 and
.alpha..sub.v.beta..sub.5 integrins, their pharmaceutically
acceptable salts, and pharmaceutical compositions thereof. The
compounds may be used in the treatment of pathological conditions
mediated by .alpha..sub.v.beta..sub.3 and .alpha..sub.v.beta..sub.5
integrins, including such conditions as tumor growth, metastasis,
restenosis, osteoporosis, inflammation, macular degeneration,
diabetic retinopathy, and rheumatoid arthritis. The compounds have
the general formula I: 1 where R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, m, n, i, j and k are defined
herein.
Inventors: |
Anaclerio, Beth M.; (New
Castle, DE) ; Marugan Sanchez, Juan Jose;
(Downingtown, PA) ; Marder, Victor J.; (Los
Angeles, CA) ; U'Prichard, David C.; (Philadelphia,
PA) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Assignee: |
3-Dimensional Pharmaceuticals,
Inc.
|
Family ID: |
26963889 |
Appl. No.: |
11/005179 |
Filed: |
December 6, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11005179 |
Dec 6, 2004 |
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10132706 |
Apr 26, 2002 |
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6872730 |
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60324516 |
Sep 26, 2001 |
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60286532 |
Apr 27, 2001 |
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Current U.S.
Class: |
514/275 ;
514/300; 514/339; 514/419; 544/331; 546/122; 546/277.4;
548/495 |
Current CPC
Class: |
A61P 3/08 20180101; C07D
409/12 20130101; C07D 405/12 20130101; A61P 9/10 20180101; A61P
25/18 20180101; A61P 25/36 20180101; A61P 25/00 20180101; A61P
25/28 20180101; A61P 25/04 20180101; A61P 7/06 20180101; A61P 29/00
20180101; A61P 25/22 20180101; A61P 35/00 20180101; A61P 19/10
20180101; A61P 19/02 20180101 |
Class at
Publication: |
514/275 ;
514/300; 514/339; 514/419; 544/331; 546/122; 546/277.4;
548/495 |
International
Class: |
A61K 031/506; A61K
031/4745; A61K 031/4439; A61K 031/405; C07D 043/02; C07D 471/02;
C07D 209/18 |
Claims
1. A compound having the Formula I: 22or a pharmaceutically
acceptable salt, hydrate, or solvate thereof, wherein R.sup.1
represents hydrogen, alkyl, haloalkyl, aryl or aralkyl; R.sup.2,
R.sup.3 and R.sup.4 independently represent hydrogen, alkyl,
haloalkyl, aryl or aralkyl; Y is oxygen; R.sup.5, R.sup.6, R.sup.7
and R.sup.8 independently represent: hydrogen; hydroxy; alkyl;
haloalkyl; alkoxy; haloalkoxy; cycloalkyl; aryl; or heterocycle
having 5-14 ring members, optionally substituted with one or more
of halogen, hydroxy, cyano, alkyl, haloalkyl, alkoxy, aryl or
arylalkyl, arylalkoxy, aryloxy, alkylsulfonyl, alkyl sulfinyl,
alkylalkoxyaryl, mono- or di-alkylamino, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, alkanoyl, carboxyalkyl;
further wherein: aryl or the aryl group of any aryl-containing
moiety may be optionally substituted by one or more of: halogen,
hydroxy, cyano, alkyl, aryl, alkoxy, haloalkyl, arylalkyl,
arylalkoxy, aryloxy, alkylsulfonyl, alkylsulfinyl, alkylalkoxyaryl,
mono- or di-alkylamino, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, alkanoyl, carboxyalkyl; or R.sup.5 and R.sup.7
are taken together to form --(CH.sub.2)S--, wherein s is 0 or 1 to
4, while R.sup.6 and R.sup.8 are defined as above; or R.sup.6 and
R.sup.8 are taken together to form --(CH.sub.2).sub.t--, wherein t
is 2 to 8, while R.sup.5 and R.sup.7 are defined as above; or
R.sup.7 and R.sup.8 are taken together to form --(CH.sub.2).sub.U--
wherein u is 2 to 8, while R.sup.5 and R.sup.6 are defined as
above; i is from 0 to 4; j is from 0 to 4; and k is 0 or 1; R.sup.9
is hydrogen or a functionality which acts as a prodrug, selected
from the group consisting of: alkyl, haloalkyl, aryl, aralkyl,
dialkylaminoalkyl, 1-morpholinoalkyl, 1-piperidinylalkyl,
pyridinylalkyl, alkoxy(alkoxy)alkoxyalkyl, or
(alkoxycarbonyl)oxyethyl; R.sup.10, R.sup.11, R.sup.12 and R.sup.13
independently represent hydrogen, alkyl, haloalkyl, hydroxyalkyl,
aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl,
aryl or aralkyl; or R.sup.10 and R.sup.u are taken together to form
--(CH.sub.2).sub.p--, where p is 2-8, while R.sup.12 and R.sup.13
are defined as above; or R.sup.12 and R.sup.13 are taken together
to form --(CH.sub.2).sub.q--, where q is 2-8, while R.sup.10 and
R.sup.11 are defined as above; or R.sup.10 and R.sup.12 are taken
together to form --(CH.sub.2).sub.r--, while r is zero, 1 or 2,
while R.sup.11 and R.sup.13 are defined as above; X represents;
oxygen, sulfur, CH.sub.2 or NH; n is from O to 4; m is from 0 to 4;
W is: 23wherein: A, G and M are independently oxygen, sulfur,
CH.sub.2, CH--R.sup.a, C(R.sup.a)(R.sup.b), NH or N--R.sup.a,
wherein R.sup.a and R.sup.b, are independently selected from alkyl,
haloalkyl or aryl; Y' is NH, sulfur or CH; Z is N or CH; R.sup.15
is hydrogen, alkyl, haloalkyl, aryl or aralkyl; and R.sup.14 is
hydrogen, alkyl, haloalkyl or halogen.
2. The compound of claim 1, wherein R.sup.1 represents hydrogen,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl or C.sub.6-10
ar(C.sub.1-6)alkyl.
3. The compound of claim 2, wherein R.sup.1 represents hydrogen,
methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl,
fluoropropyl, fluorobutyl, phenyl, benzyl or phenylethyl.
4. The compound of claim 1, wherein R.sup.2, R.sup.3 and R.sup.4
independently represent hydrogen, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.6-10 aryl, or C.sub.6-10 ar(C.sub.1-6)alkyl.
5. The compound of claim 1, wherein R.sup.2, R.sup.3 and R.sup.4
are hydrogen, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl.
6. The compound of claim 1, wherein R.sup.10, R.sup.11, R.sup.12
and R.sup.13 independently represent hydrogen, C.sub.1-4 alkyl or
C.sub.1-4 haloalkyl.
7. The compound of claim 1, wherein X is oxygen or CH.sub.2.
8. The compound of claim 1, wherein W is 24wherein: A, G and M are
independently oxygen, sulfur, CH.sub.2, CH--R.sup.a,
C(R.sup.a)(R.sup.b),NH or N--R.sup.a, wherein R.sup.a and R.sup.b,
are independently selected from C.sub.1-6 alkyl, C.sub.1-6
haloalkyl or C.sub.6-10 aryl; R.sup.15 is hydrogen, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl or C.sub.6-10 ar(C.sub.1-6)alkyl; and
R.sup.14 is hydrogen, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl.
9. The compound of claim 1, wherein R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 independently represent hydrogen, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl,
C.sub.6-10 ar(C.sub.1-6)alkyl, C.sub.1-6 aminoalkyl,
mono(C.sub.1-4)alkylamino(C.sub.1-6)alkyl,
di(C.sub.1-4)alkylamino(C.sub.1-6)alkyl, carboxy (C.sub.1-6) alkyl,
hydroxy, C.sub.1-6 alkoxy, mono(C.sub.1-4)alkylamino or
di((C.sub.1-4)alkylamino.
10. The compound of claim 1, wherein R.sup.5 and R.sup.6 are taken
together to form --(CH.sub.2).sub.S-- where s is zero or 1 to 4,
and R.sup.6 and R.sup.8 are each hydrogen.
11. The compound of the claim 1, wherein R.sup.5 and R.sup.6 are
taken together to form --(CH.sub.2)--.sub.t, where t is 2 to 5 and
R.sup.7 and R.sup.8 are each hydrogen.
12. The compound of claim 1, wherein i and j are 0.
13. The compound of claim 12, wherein k is 1.
14. The compound of claim 1, wherein R.sup.9 is hydrogen.
15. The compound of claim 1, wherein i and j are each zero; k is
one; R.sup.5, R.sup.6 and R.sup.7 are each hydrogen; and R.sup.8 is
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl or
C.sub.6-10 ar(C.sub.1-4)alkyl.
16. The compound of claim 1, wherein R.sup.1 is hydrogen or
--CH.sub.3; R.sup.2, R.sup.3, R.sup.4, R.sup.10, R.sup.11, R.sup.12
and R.sup.13 are hydrogen; X is oxygen or CH.sub.2; n is 0 or 1; m
is 0 or 1; R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently
represent hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or
C.sub.6-10 aralkyl; or one of the combination R.sup.5 and R.sup.7,
R.sup.6 and R.sup.8, or R.sup.7 and R.sup.8 are taken together to
form --(CH.sub.2).sub.S--, --(CH)t--, or --(CH2)u--, wherein s t,
or u is 1 while the remaining R.sup.5-R.sup.8 are defined above; i
is 0 or 1; j is 0 or 1; k is 0 or 1; R.sup.9 is hydrogen or alkyl;
W is: 25wherein: A, G and M are independently oxygen, sulfur,
CH.sub.2, CH--R.sup.a, C(R.sup.a)(R.sup.b), NH or N--R.sup.a,
wherein R.sup.a and R.sup.b, are independently selected from
C.sub.1-6 alkyl, C.sub.1-6haloalkyl or C.sub.6-10 aryl; R.sup.15 is
C.sub.6-10 ar(C.sub.1-6)alkyl; and R.sup.14 is hydrogen,
C.sub.1-4alkyl or C.sub.1-4 haloalkyl.
17. The compound of claim 1, which is one of:
3-(6-{2-[6-(methylamino)-2-p-
yridyl]ethoxy}benzo[b]furan-3-yl)propanoic acid;
3-quinolin-3-yl-3-{6-[2-(-
5,6,7,8-tetrahydro-[1,8]naphhthyridin-2-yl)-]-benzofuran-3-yl}-propionic
acid;
3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-benzofuran-3-yll}-3-qu-
inolin-3-yl-propionic acid;
3-(2,3-dihydro-benzofuran-6-yl)-3-{6-[2-(5,6,7-
,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-benzofuran-3-yl}-propionic
acid;
3-(2,3-dihyclro-benzofuran-6-yl)-3-{6-[2-(6-methylamino-pyridin-2-y-
l)-ethoxy]-benzofuran-3-yl}-propionic acid;
3-benzo[1,3]dioxol-5-yl-3-{6-[-
2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-ethoxy]-benzofuran-3-yl}--
propionic acid;
3-benzo[1,3]dioxol-5-yl-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]n-
aphthyridin-2-yl)-ethoxy]-benzofuran-3-yl}-propionic acid;
3-benzo[1,3]dioxol-5-yl-3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-benz-
ofuran-3-yl}-propionic acid;
3-pyridin-3-yl-3-{6-[2-(5,6,7,8-tetrahydro-[1-
,8]naphthyridin-2-yl)-ethoxy]-benzofuran-3-yl}-propionic acid;
3-(5-aryl-pyridin-3-yl)-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-y-
l)-ethoxy]-benzofuran-3-yl}-propionic acid; or a pharmaceutically
acceptable salt, hydrate, solvate or prodrug thereof.
18. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier or diluent.
19. A method of treating a pathological condition selected from the
group consisting of tumor growth, metastasis, osteoporosis,
restenosis, inflammation, macular degeneration, diabetic
retinopathy, rheumatoid arthritis, and sickle cell anemia, in a
mammal in need of such treatment, comprising administering to said
mammal an effective amount of a compound of claim 1.
20. The method of claim 19, wherein said condition is tumor
growth.
21. The method of claim 19, wherein said condition is
osteoporosis.
22. The method of claim 19, wherein said condition is
restenosis.
23. The method of claim 19, wherein said condition is
inflammation.
24. The method of claim 19, wherein said condition is macular
degeneration.
25. The method of claim 19, wherein said condition is diabetic
retinopathy.
26. The method of claim 19, wherein said condition is rheumatoid
arthritis.
27. The method of claim 19, wherein said condition is sickle cell
anemia.
28. A process for preparing a compound of claim 1, comprising:
reading a compound of Formula II: 26or a salt, hydrate or solvate
thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, i, j and k are as defined in
claim 1, with a compound of Formula III: 27or a salt, hydrate or
solvate thereof, wherein R.sup.14 is as defined in claim 1, to form
a compound of claim 1.
29. A process for preparing compound of claim 1, comprising:
reacting a compound of Formula II. 28or a salt, hydrate or solvate
thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, i, j and k are as
defined in claim 1, with a compound of Formula IV: 29or a salt,
hydrate or solvate thereof, wherein R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, m and n are as defined in claim 1, to form a
compound of claim 1.
30. A process for preparing a compound of claim 1, comprising:
reacting a compound of Formula V: 30or a salt, hydrate or solvate
thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, i, j, k, m and n are as defined in claim 1, with
R.sup.15NCO, where R.sup.15 is as defined in claim 1, to form a
compound of claim 1.
31. A method for treating a central nervous system (CNS) related
disorder, selected from the group consisting of: neuronal loss
associated with stroke, ischemia, CNS trauma, hypoglycemia,
surgery, a neurodegenerative disease, an adverse consequence of
overstimulation of one or more excitatory amino acids, anxiety,
convulsions, chronic pain, psychosis, anesthesia, and opiate
tolerance, in a mammal in need of such treatment, comprising
administering to said mammal an effective amount of a compound of
claim 1.
32. The method according to claim 31, wherein said CNS related
disorder is neuronal loss associated with stroke.
33. The method according to claim 31, wherein said CNS related
disorder is ischemia.
34. The method according to claim 31, wherein said CNS related
disorder is CNS trauma.
35. The method according to claim 31, wherein said CNS related
disorder is hypoglycemia.
36. The method according to claim 31, wherein said CNS related
disorder is the result of surgery.
37. The method according to claim 31, wherein said CNS related
disorder is a neurodegenerative disease.
38. The method according to claim 37, wherein said
neurodegenerative disease is selected from Alzheimer's disease or
Parkinson's disease.
39. The method according to claim 31, wherein said CNS related
disorder results from the adverse consequence of an overstimulation
of one or more excitatory amino acids.
40. The method according to claim 31, wherein said CNS related
disorder is schizophrenia.
41. The method according to claim 31, wherein said CNS related
disorder is anxiety.
42. The method according to claim 31, wherein said CNS related
disorder is convulsions.
43. The method according to claim 31, wherein said CNS related
disorder is chronic pain.
44. The method according to claim 31, wherein said CNS related
disorder is psychosis.
45. The method according to claim 31, wherein said CNS related
disorder is anesthesia.
46. The method according to claim 31, wherein said CNS related
disorder is opiate tolerance.
Description
[0001] This application claims priority to Provisional application
60/324,516, filed Oct. 26, 2001, and also claims priority to
Provisional application 60/286,532, filed on Apr. 27, 2001.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to novel substituted
benzofurans and benzothiophenes that are antagonists of alpha V
(.alpha.v) integrins, for example .alpha..sub.v.beta..sub.3 and
.alpha..sub.v.beta..sub.5 integrins, their pharmaceutically
acceptable salts, and pharmaceutical compositions thereof.
[0004] 2. Background Art
[0005] Integrins are cell surface glycoprotein receptors which bind
extracellular matrix proteins and mediate cell-cell and
cell-extracellular matrix interactions (generally referred to as
cell adhesion events) (Hynes, R. O., Cell 69: 11-25 (1992)). These
receptors are composed of noncovalently associated alpha (.alpha.)
and beta (.beta.) chains which combine to give a variety of
heterodimeric proteins with distinct cellular and adhesive
specificities (Albeda, S. M., Lab. Invest. 68: 4-14 (1993)). Recent
studies have implicated integrins in the regulation of cellular
adhesion, migration, invasion, proliferation, apoptosis and gene
expression (Albeda, S. M., Lab. Invest. 68: 4-14 (1993); Juliano,
R., Cancer Met. Rev. 13: 25-30 (1994); Ruoslahti, E. and Reed, J.
C., Cell 77: 477-478 (1994); and Ruoslahti, E. and Giancotti, F.
G., Cancer Cells 1: 119-126 (1989)).
[0006] One member of the integrin family which has been shown to
play a significant role in a number of pathological conditions is
the integrin .alpha..sub.v.beta..sub.31 or vitronectin receptor
(Brooks, P. C., DN&P 10(8): 456-461 (1997)). This integrin
binds a variety of extracellular matrix components and other
ligands, including fibrin, fibrinogen, fibronectin, vitronectin,
laminin, thrombospondin, and proteolyzed or denatured collagen
(Cheresh, D. A., Cancer Met. Rev. 10: 3-10 (1991) and Shattil, S.
J., Thromb. Haemost. 74: 149-155 (1995)). The two related .alpha.v
integrins, .alpha..sub.v.beta..sub.5 and .alpha..sub.v.beta..sub-
.1 (also vitronectin receptors), are more specific and bind
vitronectin (.alpha..sub.v.beta..sub.5) or fibronectin and
vitronectin (.alpha..sub.v.beta..sub.1) (Horton, M., Int. J. Exp.
Pathol. 71: 741-759 (1990)). .alpha..sub.v.beta..sub.3 and the
other integrins recognize and bind to their ligands through the
tripeptide sequence Arg-Gly-Asp ("RGD") (Cheresh, D. A., Cancer
Met. Rev. 10: 3-10 (1991) and Shattil, S. J., Thromb. Haemost. 74:
149-155 (1995)) found within all the ligands mentioned above.
[0007] The .alpha..sub.v.beta..sub.3 integrin has been implicated
in a number of pathological processes and conditions, including
metastasis and tumor growth, pathological angiogenesis, and
restenosis. For example, several studies have clearly implicated
.alpha..sub.v.beta..sub.3 in the metastatic cascade (Cheresh, D.
A., Cancer Met. Rev. 10: 3-10 (1991); Nip, J. et al., J. Clin.
Invest. 95: 2096-2103 (1995); and Yun, Z., et al., Cancer Res. 56:
3101-3111 (1996)). Vertically invasive lesions in melanomas are
also commonly associated with high levels of
.alpha..sub.v.beta..sub.3, whereas horizontally growing noninvasive
lesions have little if any .alpha..sub.v.beta..sub.3 (Albeda, S.
M., et al., Cancer Res. 50: 6757-6764 (1990)). Moreover, Brooks et
al. (in Cell 79: 1157-1164 (1994)) have demonstrated that systemic
administration of .alpha..sub.v.beta..sub.3 antagonists disrupts
ongoing angiogenesis on chick chorioallantoic membrane ("CAM"),
leading to the rapid regression of histologically distinct human
tumors transplanted onto the CAM. These results indicate that
antagonists of .alpha..sub.v.beta..sub.3 may provide a therapeutic
approach for the treatment of neoplasia (solid tumor growth).
[0008] .alpha..sub.v.beta..sub.3 has also been implicated in
angiogenesis, which is the development of new vessels from
preexisting vessels, a process that plays a significant role in a
variety of normal and pathological biological events. It has been
demonstrated that .alpha..sub.v.beta..sub.3 is up-regulated in
actively proliferating blood vessels undergoing angiogenesis during
wound healing as well as in solid tumor growth. Also, antagonists
of .alpha..sub.v.beta..sub.3 have been shown to significantly
inhibit angiogenesis induced by cytokines and solid tumor fragments
(Brooks, P. C., et al., Science 264: 569-571 (1994); Enenstein, J.
and Kramer, R. H., J. Invest. Dermatol. 103: 381-386 (1994);
Gladson, C. L., J. Neuropathol. Exp. Neurol 55: 1143-1149 (1996);
Okada, Y., et al., Amer. J. Pathol. 149: 37-44 (1996); and Brooks,
P. C., et al., J. Clin. Invest. 96: 1815-1822 (1995)). Such
.alpha..sub.v.beta..sub.3 antagonists would be useful for treating
conditions that are associated with pathological angiogenesis, such
as rheumatoid arthritis, diabetic retinopathy, macular
degeneration, and psoriasis (Nicosia, R. F. and Madri, J. A., Amer.
J. Pathol. 128: 78-90 (1987); Boudreau, N. and Rabinovitch, M.,
Lab. Invest. 64: 187-99 (1991); and Brooks, P. C., Cancer Met Rev.
15: 187-194 (1996)).
[0009] There is also evidence that .alpha..sub.v.beta..sub.3 plays
a role in neointimal hyperplasia after angioplasty and restenosis.
For example, peptide antagonists and monoclonal antibodies directed
to both .alpha..sub.v.beta..sub.3 and the platelet receptor
.alpha.II.sub.b.beta..sub.3 have been shown to inhibit neointimal
hyperplasia in vivo (Choi, E. T., et al., J. Vasc. Surg. 19:
125-134 (1994); and Topol, E. J., et al., Lancet 343: 881-886
(1994)), and recent clinical trials with a monoclonal antibody
directed to both .alpha.II.sub.b.beta..sub.3 and
.alpha..sub.v.beta..sub.3 have resulted in significant reduction in
restenosis, providing clinical evidence of the therapeutic utility
of .beta.3 antagonists (Topol, E. J., et al., Lancet 343: 881-886
(1994)).
[0010] It has also been reported that .alpha..sub.v.beta..sub.3 is
the major integrin on osteoclasts responsible for attachment to
bone. Osteoclasts cause bone resorption. When bone resorbing
activity exceeds bone forming activity, the result is osteoporosis,
a condition which leads to an increased number of bone fractures,
incapacitation and increased mortality. Antagonists of
.alpha..sub.v.beta..sub.3 have been shown to be potent antagonists
of osteoclastic activity both in vitro (Sato, M., et al., J. Cell
Biol. 111: 1713-1723 (1990)) and in vivo (Fisher, J. E., et al.,
Endocrinology 132: 1411-1413 (1993)).
[0011] Lastly, White (in Current Biology 3(9): 596-599 (1993)) has
reported that adenovirus uses .alpha..sub.v.beta..sub.3 for
entering host cells. The .alpha..sub.v.beta..sub.3 integrin appears
to be required for endocytosis of the virus particle and may be
required for penetration of the viral genome into the host cell
cytoplasm. Thus, compounds which inhibit .alpha..sub.v.beta..sub.3
could be useful as antiviral agents.
[0012] The .alpha..sub.v.beta..sub.5 integrin has been implicated
in pathological processes as well. Friedlander et al. have
demonstrated that a monoclonal antibody for
.alpha..sub.v.beta..sub.5 can inhibit VEGF-induced angiogenesis in
rabbit cornea and chick chorioalloantoic membrane, indicating that
the .alpha..sub.v.beta..sub.5 integrin plays a role in mediating
growth factor-induced angiogenesis (Friedlander, M. C., et al.,
Science 270: 1500-1502 (1995)). Compounds that act as
.alpha..sub.v.beta..sub.5 antagonists could be used to inhibit
pathological angiogenesis in tissues of the body, including ocular
tissue undergoing neovascularization, inflamed tissue, solid
tumors, metastases, or tissues undergoing restenosis.
[0013] Discovery of the involvement of .alpha..sub.v.beta..sub.3
and .alpha..sub.v.beta..sub.5 in such processes and pathological
conditions has led to an interest in these integrins as potential
therapeutic targets, as suggested above. A number of specific
antagonists of .alpha..sub.v.beta..sub.3 and
.alpha..sub.v.beta..sub.5 that can block the activity of these
integrins have been developed. One major group of such antagonists
includes nonpeptide mimetics and organic-type compounds. For
example, a number of organic non-peptidic mimetics have been
developed that appear to inhibit tumor cell adhesion to a number of
.alpha..sub.v.beta..sub.3 ligands, including vitronectin,
fibronectin, and fibrinogen (Greenspoon, N., et al., Biochemistry
32: 1001-1008 (1993); Ku, T. W., et al., J. Amer. Chem. Soc. 115:
8861-8862 (1993); Hershkoviz, R., et al., Clin. Exp. Immunol. 95:
270-276 (1994); and Hardan, L., et al., Int. J. Cancer 55:
1023-1028 (1993)).
[0014] Additional organic compounds developed specifically as
.alpha..sub.v.beta..sub.3 or .alpha..sub.v.beta..sub.5 integrin
antagonists or as compounds useful in the treatment of
.alpha.v-mediated conditions have been described in several recent
publications.
[0015] For example, U.S. Pat. No. 5,741,796, issued Apr. 21, 1998,
discloses pyridyl and naphthyridyl compounds for inhibiting
osteoclast-mediated bone resorption.
[0016] PCT Published Application WO 97/45137, published Oct. 9,
1997, discloses non-peptide sulfotyrosine derivatives, as well as
cyclopeptides, fusion proteins, and monoclonal antibodies, that are
useful as antagonists of .alpha..sub.v.beta..sub.3
integrin-mediated angiogenesis.
[0017] PCT Published Application WO 97/36859, published Oct. 9,
1997, discloses para-substituted phenylpropanoic acid derivatives.
The publication also discloses the use of the compounds as
.alpha..sub.v.beta..sub.3 integrin antagonists.
[0018] PCT Published Application WO 97/06791, published February
1997, discloses methods for inhibition of angiogenesis in tissue
using vitronectin .alpha..sub.v.beta..sub.5 antagonists.
[0019] More recently, PCT Published Application WO 97/23451,
published Jul. 3, 1997, discloses tyrosine derivatives that are
.alpha.v-integrin antagonists (especially .alpha..sub.v.beta..sub.3
antagonists) useful in the treatment of tumors, osteoporoses, and
osteolytic disorders and for suppressing angiogenesis.
[0020] PCT Published Application WO 98/00395, published Jan. 8,
1998, discloses novel tyrosine and phenylalanine derivatives as
.alpha.v integrin and GPIIb/IIIa antagonists.
[0021] The publication discloses the use of the compounds in
pharmaceutical preparations for the treatment of thrombosis,
infarction, coronary heart disease, tumors, arteriosclerosis,
infection and inflammation.
[0022] PCT Published Application WO 99/30713, published Jun. 24,
1999, discloses carboxylic acid derivatives having a cyclic core
structure. The derivatives are described as integrin antagonists
useful for inhibiting bone resorption, treating and preventing
osteoporosis, and inhibiting vascular restenosis, diabetic
retinopathy, macular degeneration, angiogenesis, atherosclerosis,
inflammation, wound healing, viral disease, tumor growth, and
metastasis.
[0023] U.S. Pat. No. 6,066,648, issued May 23, 2000, discloses
carboxylic acid derivatives of compounds having a 5-membered
aromatic or nonaromatic mono- or bicyclic ring system having one
heteroatom. The compounds are described as antagonists of the
vitronectin receptors and are useful for inhibiting bone
resorption, treating and preventing osteoporosis, and inhibiting
vascular restenosis, diabetic retinopathy, macular degeneration,
angiogenesis, atherosclerosis, inflammation, viral disease, and
tumor growth.
[0024] PCT Published Application WO 2000/02874, published Jan. 20,
2000, discloses benzofuran derivatives that are integrin
antagonists useful in the treatment of a variety of
integrin-mediated disease states.
[0025] A need continues to exist for non-peptide compounds that are
potent and selective integrin antagonists, and which possess
greater bioavailability or fewer side-effects than currently
available integrin antagonists.
BRIEF SUMMARY OF THE INVENTION
[0026] The present invention is directed to substituted benzofurans
and benzothiophenes having Formula I (below).
[0027] Also provided is a process for preparing compounds of
Formula I.
[0028] The novel compounds of the present invention exhibit
inhibition of .alpha..sub.v.beta..sub.3 and
.alpha..sub.v.beta..sub.5 integrin receptor binding. Also provided
is a method of treating .alpha..sub.v.beta..sub.3 integrin- and
.alpha..sub.v.beta..sub.5 integrin-mediated pathological conditions
such as tumor growth, metastasis, osteoporosis, restenosis,
inflammation, macular degeneration, diabetic retinopathy, and
rheumatoid arthritis in a mammal in need of such treatment
comprising administering to said mammal an effective amount of a
compound of Formula I.
[0029] Further provided is a pharmaceutical composition comprising
a compound of Formula I and one or more pharmaceutically acceptable
carriers or diluents.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The present invention is directed to compounds of Formula I:
2
[0031] and pharmaceutically acceptable salts thereof; wherein
[0032] R.sup.1 represents hydrogen, alkyl, haloalkyl, aryl or
aralkyl;
[0033] R.sup.2, R.sup.3 and R.sup.4 independently represent
hydrogen, alkyl, haloalkyl, aryl or aralkyl;
[0034] Y is oxygen or sulfur;
[0035] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently
represent: hydrogen; hydroxy; alkyl; haloalkyl; alkoxy; haloalkoxy;
cycloalkyl; aryl; or heterocycle having 5-14 ring members,
optionally substituted with one or more of halogen, hydroxy, cyano,
alkyl, haloalkyl, alkoxy, aryl or arylalkyl, arylalkoxy, aryloxy,
alkylsulfonyl, alkylsulfinyl, alkylalkoxyaryl, mono- or
di-alkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,
alkanoyl, carboxyalkyl; further wherein: aryl or the aryl group of
any aryl-containing moiety may be optionally substituted by one or
more of: halogen, hydroxy, cyano, alkyl, aryl, alkoxy, haloalkyl,
arylalkyl, arylalkoxy, aryloxy, alkylsulfonyl, alkylsulfinyl,
alkylalkoxyaryl, mono- or di-alkylamino, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, alkanoyl, carboxyalkyl;
[0036] or R.sup.5 and R.sup.7 are taken together to form
--(CH.sub.2).sub.s--, wherein s is 0 (a bond) or 1 to 4, while
R.sup.6 and R.sup.8 are defined as above; or R.sup.10 and R.sup.11
are taken together to form --(CH.sub.2).sub.t--, wherein t is 2 to
8, while R.sup.5 and R.sup.7 are defined as above; or R.sup.7 and
R.sup.8 are taken together to form --(CH.sub.2).sub.u-- wherein u
is 2 to 8, while R.sup.5 and R.sup.6 are defined as above;
[0037] i is from 0 to 4;
[0038] j is from o to 4; and
[0039] k is 0 or 1;
[0040] R.sup.9 is hydrogen or a functionality which acts as a
prodrug (i.e., converts to the active species by an endogenous
biological process such as an esterase, lipase, or other
hydrolase), such as alkyl, haloalkyl, aryl, aralkyl,
dialkylaminoalkyl, 1-morpholinoalkyl, 1-piperidinylalkyl,
pyridinylalkyl, alkoxy(alkoxy)alkoxyalkyl, or
(alkoxycarbonyl)oxyethyl;
[0041] R.sup.10, R.sup.11, R.sup.12 and R.sup.13 independently
represent hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, aryl or
aralkyl;
[0042] or R.sup.10 and R.sup.11 are taken together to form
--(CH.sub.2).sub.p--, where p is 2-8, while R.sup.12 and R.sup.13
are defined as above; or R.sup.12 and R.sup.13 are taken together
to form --(CH.sub.2).sub.q--, where q is 2-8, while R.sup.10 and
R.sup.11 are defined as above; or R.sup.10 and R.sup.12 are taken
together to form --(CH.sub.2).sub.r--, while r is zero (a bond), 1
or 2, while R.sup.11 and R.sup.13 are defined as above;
[0043] X represents oxygen, sulfur, CH.sub.2 or NH;
[0044] n is from 0 to 4;
[0045] m is from 0 to 4;
[0046] W is: 3
[0047] wherein:
[0048] A, G and M are independently oxygen, sulfur, CH.sub.2,
CH--R.sup.a, C(R.sup.a)(R.sup.b), NH or N--R.sup.a, wherein R.sup.a
and R.sup.b, are independently selected from alkyl, haloalkyl or
aryl;
[0049] Y' is NH, sulfur or CH;
[0050] Z is N or CH;
[0051] R.sup.15 is hydrogen, alkyl, haloalkyl, aryl or arylalkyl;
and
[0052] R.sup.14 is hydrogen, alkyl, haloalkyl or halogen.
[0053] When any variable occurs more than one time in any
constituent or in Formula I, its definition on each occurrence is
independent of its definition at every other occurrence. Also,
combinations of substituents and/or variables are permissible only
if such combinations result in stable compounds.
[0054] The term "alkyl" as employed herein by itself or as part of
another group refers to both straight and branched chain radicals
of up to 12 carbons, preferably 1 to 8 carbons, such as methyl,
ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl,
isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl,
nonyl, decyl, undecyl, dodecyl. Alkyl having from 1-6 carbon atoms
is more preferred; and alkyl having from 1-4 carbons is most
preferred.
[0055] The term "alkenyl" is used herein to mean a straight or
branched chain radical of 2-20 carbon atoms, unless the chain
length is limited thereto, including, but not limited to, ethenyl,
1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl,
and the like. Preferably, the alkenyl chain is 2 to 10 carbon atoms
in length, more preferably, 2 to 8 carbon atoms in length most
preferably from 2 to 4 carbon atoms in length.
[0056] The term "alkoxy" is used herein to mean a straight or
branched chain radical of 1 to 20 carbon atoms, unless the chain
length is limited thereto, bonded to an oxygen atom, including, but
not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the
like. Preferably the alkoxy chain is 1 to 10 carbon atoms in
length, more preferably 1 to 8 carbon atoms in length. Alkoxy from
1-4 carbon atoms is most preferred.
[0057] The term "aryl" as employed herein by itself or as part of
another group refers to monocyclic or bicyclic aromatic groups
containing from 6 to 14 carbons in the ring portion, preferably
6-10 carbons in the ring portion, such as phenyl, naphthyl or
tetrahydronaphthyl.
[0058] The term "aryloxy" as employed herein by itself or as part
of another group refers to monocyclic or bicyclic aromatic groups
containing from 6 to 14 carbons in the ring portion, preferably
6-10 carbons in the ring portion, bonded to an oxygen atom.
Examples include, but are not limited to, phenoxy, naphthoxy, and
the like.
[0059] The term "heteroaryl" as employed herein refers to groups
having 5 to 14 ring atoms; 6, 10 or 14 .pi. electrons shared in a
cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen,
nitrogen or sulfur heteroatoms (where examples of heteroaryl groups
are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl,
furyl, pyranyl, benzofuranyl, isobenzofuranyl, benzoxazolyl,
chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl,
imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl,
indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,
phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl,
4aH-carbazolyl, carbazolyl, .beta.-carbolinyl, phenanthridinyl,
acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl,
phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups).
[0060] The term "aralkyl" or "arylalkyl" as employed herein by
itself or as part of another group refers to C.sub.1-6alkyl groups
as discussed above having an aryl substituent, such as benzyl,
phenylethyl or 2-naphthylmethyl.
[0061] The term "cycloalkyl" as employed herein by itself or as
part of another group refers to cycloalkyl groups containing 3 to 9
carbon atoms. Typical examples are cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and
cyclononyl.
[0062] The term "heterocycle" or "heterocyclyl" as used herein,
except where noted, represents a stable 5- to 7-membered mono- or
bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring
system any ring of which may be saturated or unsaturated, and which
consists of carbon atoms and from one to three heteroatoms selected
from the group consisting of N, O and S, and wherein the nitrogen
and sulfur heteroatoms may optionally be oxidized, and the nitrogen
heteroatom may optionally be quaternized, and including any
bicyclic group in which any of the above-defined heterocyclic rings
is fused to a benzene ring. Especially useful are rings containing
one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or
sulfur combined with one or two nitrogen atoms. The heterocyclic
ring may be attached at any heteroatom or carbon atom which results
in the creation of a stable structure. Examples of such
heterocyclic groups include piperidinyl, piperazinyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,
2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,
pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl,
pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,
oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
indolyl, quinolinyl, isoquinolinyl, chromanyl, benzimidazolyl,
thiadiazoyl, benzopyranyl, benzothiazolyl, benzo[b]thiophenyl,
benzo[2,3-c]1,2,5-oxadiazolyl, benzoxazolyl, benzodioxolyl,
furanyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as
morpholinyl.
[0063] The term "halogen" or "halo" as employed herein by itself or
as part of another group (e.g., haloalkyl) refers to chlorine,
bromine, fluorine or iodine with chlorine or fluorine being
preferred.
[0064] The term "monoalkylamino" as employed herein by itself or as
part of another group refers to an amino group which is substituted
with one alkyl group, preferably having from 1 to 6 carbon
atoms.
[0065] The term "dialkylamino" as employed herein by itself or as
part of another group refers to an amino group which is substituted
with two alkyl groups, each perferably having from 1 to 6 carbon
atoms.
[0066] The term "hydroxyalkyl" as employed herein refers to any of
the above alkyl groups substituted by one or more hydroxyl
moieties.
[0067] The term "carboxyalkyl" as employed herein refers to any of
the above alkyl groups substituted by one or more carboxylic acid
moieties.
[0068] The term "haloalkyl" as employed herein refers to any of the
above alkyl groups substituted by one or more chlorine, bromine,
fluorine or iodine with fluorine and chlorine being preferred, such
as chloromethyl, iodomethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
and 2-chloroethyl.
[0069] The term "haloalkoxy" as used herein refers to any of the
above haloalkyl groups bonded to an oxygen atom, such as
trifluromethoxy, trichloromethoxy, and the like.
[0070] Preferred compounds of the present invention are those of
Formula I, wherein R.sup.1 represents hydrogen, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.6-10 aryl or C.sub.6-10
ar(C.sub.1-6)alkyl, preferably hydrogen, methyl, ethyl, propyl,
butyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl phenyl,
benzyl or phenylethyl.
[0071] Also preferred are compounds of Formula I, wherein R.sup.2,
R.sup.3 and R.sup.4 independently represent hydrogen, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.6-10 aryl, or C.sub.6-10 ar
(C.sub.1-6) alkyl, preferably, R.sup.2, R.sup.3 and R.sup.4 are
hydrogen, C.sub.1-4 alkyl or C.sub.1-4 fluoroalkyl.
[0072] Preferred compounds are those of Formula I, wherein
R.sup.10, R.sup.11, R.sup.12 and R.sup.13 independently represent
hydrogen, C.sub.1-4 alkyl or C.sub.1-4 fluoroalkyl.
[0073] Preferred compounds are those of Formula I, wherein X is
oxygen or CH.sub.2.
[0074] Also preferred are compounds of Formula I, wherein W is
4
[0075] wherein
[0076] R.sup.15 is hydrogen, C.sub.1-6 alkyl or C.sub.6-10
ar(C.sub.1-6)alkyl;
[0077] R.sup.14 is hydrogen or C.sub.1-4 alkyl;
[0078] A and G are independently selected from CH.sub.2,
CH--R.sup.a or C(R.sup.a)(R.sup.b), wherein R.sup.a and R.sup.b,
are independently selected from alkyl, haloalkyl or aryl; and
[0079] M is selected from CH.sub.2, CH--R.sup.a or
C(R.sup.a)(R.sup.b), wherein R.sup.a and R.sup.b, are as defined
above, or oxygen.
[0080] Further preferred compounds are those of Formula I, wherein
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently represent:
hydrogen; hydroxy; C.sub.1-6 alkyl; C.sub.1-6haloalkyl; C.sub.1-6
alkoxy; C.sub.1-6 haloalkoxy; C.sub.3-7 cycloalkyl; C.sub.6-14
aryl; or quinolyl, benzofuranyl, benzodioxolyl, or pyridyl, each of
which are optionally substituted with one or more of halogen,
hydroxy, cyano, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6
alkoxy, C.sub.6-14 aryl or C.sub.6-14 aryl(C.sub.1-6)alkyl,
C.sub.6-14 aryl(C.sub.1-6)alkoxy, C.sub.6-14 aryloxy, C.sub.1-6
alkylsulfonyl, C.sub.1-6 alkylsulfinyl, C.sub.1-6
alkyl(C.sub.1-6)alkoxy(C.sub.6-14)aryl, mono- or
di-(C.sub.1-6)alkylamino- , amino(C.sub.1-6)alkyl,
mono(C.sub.1-6)alkylamino(C.sub.1-6)alkyl,
di(C.sub.1-6)alkylamino(C.sub.1-6)alkyl, C.sub.1-6 alkanoyl,
carboxy(C.sub.1-6)alkyl; further wherein: aryl or the aryl group of
any aryl-containing moiety may be optionally substituted by one or
more of: halogen, hydroxy, cyano, C.sub.1-6 alkyl, C.sub.6-14 aryl,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl,
C.sub.6-14aryl(C.sub.1-6)alkyl, C.sub.6-14 aryl(C.sub.1-6)alkoxy,
C.sub.6-14aryloxy, C.sub.1-6 alkylsulfonyl, C.sub.1-6
alkylsulfinyl, (C.sub.1-6)alkylalkoxy(C.sub.6-14)aryl, mono- or
di-(C.sub.1-6)alkylamino, amino(C.sub.1-6)alkyl,
mono(C.sub.1-6)alkylamin- o(C.sub.1-6)alkyl,
di(C.sub.1-6)alkylamino(C.sub.1-6)alkyl, alkanoyl, or
carboxy(C.sub.1-6)alkyl.
[0081] Preferred compounds of the present invention are also those
wherein one of R.sup.5 and R.sup.6 is hydrogen, and the other is
selected from: quinol-3-yl; benzofuran-6-yl; benzodioxol-5-yl; or
pyrid-3-yl, each of which may be optionally substituted with one or
more of halogen, hydroxy, cyano, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkoxy, C.sub.6-14 aryl or C.sub.6-14
aryl(C.sub.1-6)alkyl, C.sub.6-14 aryl(C.sub.1-6)alkoxy, C.sub.6-14
aryloxy, C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylsulfinyl,
C.sub.1-6 alkyl(C.sub.1-6)alkoxy(C.sub.6-14)aryl- , mono- or
di-(C.sub.1-6)alkylamino, amino(C.sub.1-6)alkyl,
mono(C.sub.1-6)alkylamino(C.sub.1-6)alkyl,
di(C.sub.1-6)alkylamino(C.sub.- 1-6)alkyl, C.sub.1-6 alkanoyl,
carboxy(C.sub.1-6)alkyl; further wherein: aryl or the aryl group of
any aryl-containing moiety may be optionally substituted by one or
more of: halogen, hydroxy, cyano, C.sub.1-6 alkyl, C.sub.6-14 aryl,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl,
C.sub.6-14aryl(C.sub.1-6)alkyl, C.sub.6-14 aryl(C.sub.1-6)alkoxy,
C.sub.6-14 aryloxy, C.sub.1-6 alkylsulfonyl, C.sub.1-6
alkylsulfinyl, (C.sub.1-6)alkylalkoxy(C.sub.6-14)aryl, mono- or
di-(C.sub.1-6)alkylamino- , amino(C.sub.1-6)alkyl,
mono(C.sub.1-6)alkylamino(C.sub.1-6)alkyl,
di(C.sub.1-6)alkylamino(C.sub.1-6)alkyl, alkanoyl, or
carboxy(C.sub.1-6)alkyl.
[0082] Additionally preferred compounds according to this aspect of
the invention are those wherein one of R.sup.5 and R.sup.6 is
hydrogen, and the other is pyrid-3-yl, which is optionally
substituted with aryl, wherein the aryl is phenyl, and the phenyl
is optionally substituted by one or more of: halogen, hydroxy,
cyano, C.sub.1-6 alkyl, C.sub.6-14 aryl, C.sub.1-6 alkoxy,
C.sub.1-6 haloalkyl, C.sub.6-14aryl(C.sub.1-6)alk- yl, C.sub.6-14
aryl(C.sub.1-6)alkoxy, C.sub.6-14aryloxy, C.sub.1-6 alkylsulfonyl,
C.sub.1-6 alkylsulfinyl, (C.sub.1-6)alkylalkoxy(C.sub.6-14- )aryl,
mono- or di-(C.sub.1-6)alkylamino, amino(C.sub.1-6)alkyl,
mono(C.sub.1-6)alkylamino(C.sub.1-6)alkyl,
di(C.sub.1-6)alkylamino(C.sub.- 1-6)alkyl, alkanoyl, or
carboxy(C.sub.1-6)alkyl.
[0083] Also preferred are those compounds of Formula I, wherein
R.sup.5 and R.sup.7 are taken together to form --(CH.sub.2).sub.s--
where s is zero or 1 to 4, and R.sup.6 and R.sup.8 are each
hydrogen.
[0084] Preferred compounds are those of Formula I, wherein R.sup.5
and R.sup.6 are taken together to form --(CH.sub.2).sub.t, where t
is 2 to 5 and R.sup.7 and R.sup.8 are each hydrogen.
[0085] Further preferred compounds are those of Formulal, wherein i
and j are 0.
[0086] Preferred compounds are those of Formula I, wherein k is
1.
[0087] Also preferred compounds are those of Formula I, wherein
R.sup.9 is hydrogen.
[0088] Preferred compounds are those of Formula I, wherein i and j
are each zero; k is one; R.sup.5, R.sup.6 and R.sup.7 are each
hydrogen; and R.sup.8 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.6-10 aryl or C.sub.6-10ar(C.sub.1-4)alkyl.
[0089] Preferred compounds of the present invention are those of
Formula I wherein:
[0090] R.sup.1 is hydrogen, C.sub.1-4 alkyl or C.sub.1-6 haloalkyl,
more preferably, hydrogen, methyl or fluoromethyl;
[0091] R.sup.2, R.sup.3, and R.sup.4 are hydrogen, C.sub.1-4 alkyl
or C.sub.1-6 haloalkyl, more preferably hydrogen, methyl or
fluoromethyl;
[0092] R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are preferably
hydrogen, C.sub.1-4 alkyl or C.sub.1-6 haloalkyl, more preferably,
hydrogen, methyl or fluoromethyl;
[0093] X is oxygen or CH.sub.2;
[0094] n is 0 or 1;
[0095] m is 0 or 1;
[0096] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently
represent hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl or
C.sub.6-10ar(C.sub.1-6)- alkyl;
[0097] or one of the combination R.sup.5 or R.sup.6, R.sup.7 or
R.sup.8, R.sup.5 and R.sup.7 are taken together to form
--(CH.sub.2).sub.s--, wherein s is 1 or 2 while the remaining
R.sup.5-R.sup.8 are defined above;
[0098] i is 0 or 1;
[0099] j is 0 or 1;
[0100] k is 0 or 1;
[0101] R.sup.9 is hydrogen, C.sub.1-6 alkyl or benzyl;
[0102] W is: 5
[0103] wherein
[0104] R.sup.15 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl
or C.sub.6-10ar(C.sub.1-6)alkyl such as benzyl;
[0105] R.sup.14 is hydrogen, C.sub.1-4 alkyl or C.sub.1-4
haloalkyl; and
[0106] A and G are independently selected from CH.sub.2,
CH--R.sup.a or C(R.sup.a)(R.sup.b), wherein R.sup.a and R.sup.b,
are independently selected from C.sub.1-6 alkyl, C.sub.1-6
haloalkyl or C.sub.6-10 aryl; and
[0107] M is selected from CH.sub.2, CH--R.sup.a or
C(R.sup.a)(R.sup.b) or oxygen, wherein R.sup.a and R.sup.b are as
defined above.
[0108] Preferred compounds of the present invention include:
[0109]
3-(6-{2-[6-methylamino)-2-pyridyl]ethoxy}benzo[b]thiophen-3-yl)prop-
anoic acid;
[0110]
3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]furan-3-yl)propan-
oic acid;
[0111]
3-quinolin-3-yl-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-
-ethoxy]-benzo[b]thiophen-3-yl}-propionic acid;
[0112]
3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-benzo[b]thiophen-3-yl}-
-3-quinolin-3-yl-propionic acid;
[0113]
3-(2,3-dihydro-benzofuran-6-yl)-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]na-
phthyridin-2-yl)-ethoxy]-benzo[b]thiophen-3-yl}-propionic acid;
[0114]
3-(2,3-dihydro-benzofuran-6-yl)-3-{6-[2-(6-methylamino-pyridin-2-yl-
)-ethoxy]-benzo[b]thiophen-3-yl}-propionic acid;
[0115]
3-benzo[1,3]dioxol-5-yl-3-{6-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]o-
xazin-6-yl)-ethoxy]-benzo[b]thiophen-3-yl}-propionic acid;
[0116]
3-benzo[1,3]dioxol-5-yl-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]naphthyrid-
in-2-yl)-ethoxy]-benzo[b]thiophen-3-yl}-propionic acid;
[0117]
3-benzo[1,3]dioxol-5-yl-3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy-
]-benzo[b]thiophen-3-yl}-propionic acid;
[0118]
3-pyridin-3-yl-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)--
ethoxy]-benzo[b]thiophen-3-yl}-propionic acid;
[0119]
3-(5-phenyl-pyridin-3-yl)-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]naphthyr-
idin-2-yl)-ethoxy]-benzo[b]thiophen-3-yl}-propionic acid;
[0120]
3-quinolin-3-yl-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-
-ethoxy]-benzofuran-3-yl}-propionic acid;
[0121]
3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-benzofuran-3-yl}-3-qui-
nolin-3-yl-propionic acid;
[0122]
3-(2,3-dihydro-benzofuran-6-yl)-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]na-
phthyridin-2-yl)-ethoxy]-benzofuran-3-yl}-propionic acid;
[0123]
3-(2,3-dihydro-benzofuran-6-yl)-3-{6-[2-(6-methylamino-pyridin-2-yl-
)-ethoxy]-benzofuran-3-yl}-propionic acid;
[0124]
3-benzo[1,3]dioxol-5-yl-3-{6-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]o-
xazin-6-yl)-ethoxy]-benzofuran-3-yl}-propionic acid;
[0125]
3-benzo[1,3]dioxol-5-yl-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]naphthyrid-
in-2-yl)-ethoxy]-benzofuran-3-yl}-propionic acid;
[0126]
3-benzo[1,3]dioxol-5-yl-3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy-
]-benzofuran-3-yl}-propionic acid;
[0127]
3-pyridin-3-yl-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)--
ethoxy]-benzofuran-3-yl}-propionic acid; and
[0128]
3-(5-phenyl-pyridin-3-yl)-3-{6-[2-(5,6,7,8-tetrahydro-[1,8]naphthyr-
idin-2-yl)-ethoxy]-benzofuran-3-yl}-propionic acid;
[0129] or a pharmaceutically acceptable salt, hydrate, solvate or
prodrug thereof.
[0130] It is also to be understood that the present invention is
considered to include stereoisomers as well as optical isomers,
e.g. mixtures of enantiomers as well as individual enantiomers and
diastereomers, which arise as a consequence of structural asymmetry
in selected compounds of the present series.
[0131] The present invention is also directed to method for
preparing compounds of Formula I, comprising:
[0132] reacting a compound of Formula II: 6
[0133] or a salt, hydrate or solvate thereof, wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, i, j and k are as defined as above,
[0134] with a compound of Formula III: 7
[0135] or a salt, hydrate or solvate thereof, wherein R.sup.14 is
as defined above, to form the compound Formula I.
[0136] The present invention is also directed to a method for
preparing compounds of Formula I, comprising reacting a compound of
Formula II: 8
[0137] or a salt, hydrate or solvate thereof, wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, i, j and k are as defined above,
[0138] with a compound of Formula IV: 9
[0139] or a salt, hydrate or solvate thereof, wherein R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, m and n are as defined
above, to form the compound of Formula I.
[0140] The present invention is also directed to a method for
preparing compounds of Formula I, comprising reacting a compound of
Formula V: 10
[0141] or a salt, hydrate or solvate thereof, wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, i, j, k, m and n
are as defined in claim 1, with R.sup.15NCO, where R.sup.15 is as
defined in claim 1, to form a substituted benzofuran or
benzothiophene compound of claim 1.
[0142] The compounds of the present invention may be prepared by
the general procedures outlined in Schemes I, II and III (below),
where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, n, m, i, j, X and W are as defined above.
[0143] Additionally, for each of the schemes below, R.sub.16,
R.sub.17, R.sub.18, R.sub.19, R.sub.20 and R.sub.27 are
independently selected from: hydrogen, C.sub.1-6 alkyl,
C.sub.1-6haloalkyl or C.sub.6-10 aryl.
[0144] Schemes Ia, Ib, Ic, Id and Ie outline the synthetic steps to
produce the compounds of the present invention.
[0145] For each of the schemes depicted below, the R-groups having
reference numbers as subscripts are not intended to represent a
plurality of said R-group, but rather, distinguish between
different R-groups throughout the application. Thus, the
subscripted reference numbers on each of the R-groups should be
interpreted as though they were superscripts. 11
[0146] In Scheme Ia, the protected compound 1 (P is a protecting
group), such as
3-[1,1-bis(Methylethyl)-2-methyl-1-silapropylthio]phenyl acetate,
is deprotected by conditions well known in the art (Greene, T. W.
and Wuts, P. G. M., supra). For example, deprotection of acetyl
esters may be effected through basic hydrolysis, using aqueous
sodium hydroxyde as a base in a suitable solvent, such as methanol
or tetrahydrofuran. Phenol 2 is coupled to compound 3 using a
Mitsunobu coupling procedure (Mitsunobu, O., Synthesis, 1 (1981))
to give compound 4. Preferred coupling conditions include using a
trialkylphosphine or triarylphosphine, such as triphenylphosphine
or tri-n-butylphosphine, in a suitable solvent, such as
tetrahydrofuran or methylene chloride, and an azodicarbonyl
reagent, such as diethyl azodicarboxylate, diisopropyl
azodicarboxylate or 1,1'-(azodicarbonyl)dipiperidine. Compound 4,
[6-(2-{3-[1,1-bis(Methyleth-
yl)-2-methyl-1-silapropylthio]phenoxy}ethyl)(2-pyridyl)]methylamine,
is reacted with a .beta.-halogen ketone 5, such as Ethyl
5-bromo-4-oxopentanoate, in a suitable solvent, such a
tetrahydrofuran, in the presence of tetrabutylamonium fluoride, to
yield compound 6. Formation of the five member pseudoaromatic ring
can be accomplished dissolving the compound 6 in a strong acid,
such as Sulfuric acid or Polyphophoric acid. The reaction can be
performed at a wide range of temperatures, from -5.degree. C. to
120.degree. C., with or without a co-solvent, such a toluene or
chlorobenzene. Alternatively, compound 6 can be obtaining using
BF.sub.3OEt.sub.2 (Kim S. et al., Tethahedron Letters, 40, 1999,
2909-2912). Compound 8 could be obtained via basic hydrolysis of
ester 7, using aqueous sodium hydroxide as a base in a suitable
solvent, such methanol or tetrahydrofuran. 12
[0147] In Scheme Ib, compound 1, for example
3-[1,1-bis(Methylethyl)-2-met- hyl-1-silapropylthio]phenyl acetate,
is reacted with a .beta.-halogen ketone 5, such as Ethyl
5-bromo-4-oxopentanoate, in a suitable solvent, such a
tetrahydrofuran, in the presence of tetrabutylamonium fluoride, to
yield compound 8. Formation of the five member pseudoaromatic ring
can be accomplished dissolving the compound 8 in a strong acid,
such as sulfuric acid or polyphophoric acid to yield compound 9.
The reaction can be performed in a wide range of temperatures, from
-5.degree. C. to 120.degree. C., with or without a co-solvent, such
a toluene or chlorobenzene. Alternatively, compound 9 can be
obtaining using BF.sub.3OEt.sub.2 (Kim S. et al., Tethahedron
Letters, 40, 1999, 2909-2912). Phenol 9 is coupled to the compound
3 using a Mitsunobu coupling procedure (Mitsunobu, O., Synthesis, 1
(1981)) to give compound 7. Preferred coupling conditions include
using a trialkylphosphine or triarylphosphine, such as
triphenylphosphine or tri-n-butylphosphine, in a suitable solvent,
such as tetrahydrofuran or methylene chloride, and an azodicarbonyl
reagent, such as diethyl azodicarboxylate, diisopropyl
azodicarboxylate or 1,1'-(azodicarbonyl)dipiperidine.
[0148] It is also possible to alkylate compound 9 using the
alkylating agent 10 in the present of an adequate base, such as
sodium hydride, in a suitable solvent, such as
N,N-dimethylformamide.
[0149] The alkylating agent 10 could be synthesized from compound
3, transforming the alcohol to a living group, such as a halogen or
methylsulfonate. 13
[0150] In Scheme Ic, a suitable protected phenol is brominated with
N-bromosuccinimide regiospecific fashion (Garcia Ruano, J. L. et
al., J. Org. Chem., 1995, 60, 5328-5331) to arrive to compound 11.
Then, cross coupling reaction with the proper thiol or alcohol can
be accomplished using an adequate palladium catalyst, a suitable
ligand and a base to obtain compound 12. In the case of the thiol,
preferred coupling conditions are
tris(dibenzylideneacetone)dipalladium (0) as calatyst,
1,1'-Bis(diphenylphosphino)ferrocene as ligand, triethylamine as
base and N-N-dimethylformamide as solvent (Ortar, G. et al,
Tetrahedron Letters, 1995, 36(23), 4133-4136). In the case of the
alcohol, preferred coupling conditions are Palladium (II) acetate
as calatyst, [1,1']Binaphthalenyl-2-yl-di-tert-butyl-phosphane as
ligand, and cesium carbonate as base (Stephen Buchwald, personal
communication). Compound 12 can be reacted in an other
cross-coupling type reaction, this time with a terminal acetylene
13. Preferred coupling conditions are
dichlorobis(triphenylphosphine)palladium (II) as calatyst, copper
(I) idodide as co-catalyst, and triethylamine as base (Larock, R.
C. et al, J. Org. Chem., 2002, 67, 1905-1909). A range of
electrophiles can accomplish cyclization of compound 14. Preferred
conditions are iodine, bromine or N-bromosuccinimide (Larock, R. C.
et al, Tetrahedron Letters, 2001,42,6011-6013; Larock, R. C. et al,
J. Org. Chem., 2002,67,1905-1909; Flynn B. L. et al., Organic
Letters, 2001, 3(5), 651-654). Introduction of the boronic ester
can be done reacting the compound 15 with
4,4,5,5,4',4',5',5'-Octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] 16.
Preferred coupling conditions are
dichloro[1,1'-bis(diphenylphosphino)fer- rocene]palladium (II) as
calatyst, potassium acetate as base and dimetylsulfoxide as solvent
(Miyaura N. et al., J. Org. Chem., 1995,60,7508-7510). Compound 17
can be coupling with a suitable vinyl halide 18 to yield compound
19. Preferred coupling conditions are
tris(dibenzylideneacetone)dipalladium (0) as calatyst,
tri-t-butylphosphine as ligand, potassium fluoride as base and
tetrahydrofuran as solvent (Fu G. C. et al., J. Am. Chem. Soc.,
2000, 122,4020-4028). Compound 19 can be transformed to compound 20
via reduction or conjugate addition to the double bond. Preferred
reduction conditions are palladium (0) on activated carbon as
catalyst under hydrogen atmosphere and methanol as solvent. In the
case of the conjugate addition, preferred conditions are
acetylacetonatebis(1,5-cylooctadiene)r- hodium (I) as catalyst, in
the presence of a suitable alkyl or aryl boronic acid or ester and
2,2'-Bis(diphenylphosphino)-1,1'-binaphtyl (Miyaura N. et al., J.
Org. Chem., 2000, 65, 5951-5955) or in the presence of an organotin
reagent (Li, C-J. et al, Tetrahedron Letters, 2001, 42, 4459-4462).
Compound 19 can be deprotected to yield compound 20. When the
protecting group is a methyl, preferred deprotection conditions are
borotribromide in methylene choride. Compound 9 can be transformed
to final compound following schemes Ia and Ib. 14
[0151] In Scheme Id, Compound 15 can be reacted with an alkene 21
to yield compound 19 using a Heck reaction. Preferred coupling
conditions are tris(dibenzylideneacetone)dipalladium (0) as
calatyst, tri-t-butylphosphine as ligand, cesium carbonate as base
and dioxane as solvent (Fu G. C. et al., J. Org. Chem., 1999, 64,
10-11; Hartwig. et al., J. Am. Chem. Soc., 2001, 123, 2677-2678).
Alternately, compound 15 can be react with 3,3,3-Triethoxy-propyne
22 to produce compound 23. Preferred coupling conditions are
dichlorobis(triphenylphosphine)palladiu- m (II) as calatyst, copper
(I) idodide as co-catalyst, and triethylamine as base. Compound 23
can be transformed to compound 19 via reduction or conjugate
addition to the triple bond. Preferred reduction conditions are
chlorotris(triphenylphosphine)rhodium (I) as catalyst under
hydrogen atmosphere. In the case of the conjugate addition,
preferred conditions are
acetylacetonatebis(1,5-cylooctadiene)rhodium (I) as catalyst, in
the presence of a suitable alkyl or aryl boronic acid or ester and
2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (Hayashy T. et al., J.
Am. Chem. Soc., 2001, 123, 9918-9919). Compound 19 can be
transformed to final compound following Scheme Ic. 15
[0152] In Scheme Ie, compound 24 can be acylated by a
Friedel-Crafts reaction. Preferred conditions are the use of an
anhydride in the presence of a Lewis acid such as aluminum
trichloride to obtain compound 25. Then, cross coupling reaction
with the proper thiol or alcohol 26 can be accomplished using an
adequate palladium catalyst, a suitable ligand and a base to obtain
compound 27. In the case of the thiol, preferred coupling
conditions are tris(dibenzylideneacetone)dipalladium (0) as
catalyst, 1,1'-Bis(diphenylphosphino)ferrocene as ligand,
triethylamine as base and N-N-dimethylformamide as solvent (Ortar,
G. et al, Tetrahedron Letters, 1995, 36(23), 4133-4136). In the
case of the alcohol, preferred coupling conditions are Palladium
(II) acetate as calatyst,
[1,1']Binaphthalenyl-2-yl-di-tert-butyl-phosphane as ligand, and
cesium carbonate as base (Stephen Buchwald, personal
communication). Compound 27 is reacted with an alkyl halides or an
aryl halides, 28 and 29, in the presence of a base to yield
compound 30. In the case of the aryl halides the reactions proceed
via a cross coupling reacition. Preferred coupling conditions are
palladium (II) acetate as calatyst,
Biphenyl-2-yl-di-tert-butyl-phosphane as ligand, and sodium
tert-butoxide as base (Buchwald. et al., J. Am. Chem. Soc., 2000,
122, 1360-1370). Compound 30 is alkylated with the alkyl halide 31
to yield compound 32 under standard conditions. Wittig reaction of
compound 32 with phosphane 33 produces compound 34. Deprotection
and cross coupling reaction of compound 34 yield compound 20.
[0153] Scheme IIa, IIb, IIc, IId and IIe outline the synthetic
steps to produce compound 3 of the present invention where W is one
of: 16
[0154] where A, G and M are as defined above, and where R.sup.10
through R.sub.16 and R.sub.27 are as defined above. 17
[0155] In Scheme IIa, 2-chloropyridine N-oxide derivative 35 is
refluxed with aminoalkyl alcohol 36 in the presence of a base, such
as sodium bicarbonate, and a suitable solvent, such as tert-amyl
alcohol, to give compound 37. Compound 37 is then converted to
pyridinyl aminoalkyl alcohol 38 using standard reduction
conditions. Preferred conditions include treating compound 37 with
cyclohexene in the presence of a catalyst, such as palladium on
carbon, and a solvent, such as ethanol. 18
[0156] In Scheme IIb, a 2-amino-5-methylpyridine analogue 39 is
first protected with a tert-butyloxycarbonyl (Boc) group using
conditions well known in art (Greene, T. W. and Wuts, P. G. M.,
Protective Groups in Organic Synthesis, 2.sup.nd edition, John
Wiley and Sons, Inc., New York (1991)), followed by treatment with
an alkyl halide, such as iodomethane, in the presence of a base,
such as sodium hydride, and a solvent, such as tetrahydrofuran
(THF) or dimethylformamide (DMF), to give compound 40. Converting
compound 40 to 41 is accomplished by reacting compound 40 with a
base, such as lithium diisopropylamide (LDA), and diethyl carbonate
in a solvent, such as tetrahydrofuran (THF). The Boc protecting
group of compound 41 is removed by standard procedures well known
in the art (Greene, T. W. and Wuts, P. G. M., supra), such as
trifluoroacetic acid in methylene chloride. The ester is then
reduced by standard conditions, such as lithium aluminum hydride
(LAH) in tetrahydrofuran (THF), to give compound 42. Alternatively,
compound 41 can be treated with a reducing agent, such as lithium
borohydride in a solvent such as tetrahydrofuran to give compound
43. 19
[0157] In Scheme IIc, Compound 44 (Miller, H.; Manley, P. J., PCT
Int. Appl.) No. WO 00/33838) is treated with a reducing agent such
as lithium borohydride, in a solvent such as tetrahydrofuran, to
give compound 45. 20
[0158] In Scheme IId, 3-hydroxy-6-methyl-2-nitropyridine derivative
46 is reduced under suitable conditions, such as hydrogenation in
the presence of palladium catalyst, with a solvent, such as
ethanol, to give compound 47. Reaction of compound 47 (L. Savelon,
et. al., Biorganic and Medicinal Chemistry, 6, 133, (1998)) with
2-haloacid chloride 48, such as chloroacetyl chloride, in the
presence of base, such as sodium bicarbonate, in suitable solvents,
such as water and 2-butanone, gives compound 79. Reduction of
compound 49 with suitable reagent, such as lithium aluminum
hydride, in a suitable solvent, such as THF, gives compound 50.
Compound 50 is protected using suitable conditions, to introduce a
protecting group, such as Boc, to give compound 51 (Greene, T. W.
and Wuts, P. G. M., Protective Groups in Organic Synthesis,
2.sup.nd edition, John Wiley and Sons, Inc., New York (1991)).
Compound 51 is alkylated under suitable conditions, such as
deprotonation with base, such as LDA, followed by reaction with
alkylating reagent, such as dialkylcarbonate, to produce compound
52. Reduction of compound 53 is achieved with suitable reducing
reagent, such as lithium borohydride in a solvent such as
tetrahydrofuran, to give compound 53. 21
[0159] Phenol 54 is coupled to benzyloxycarbonyl (Cbz) protected
amino alcohol 55 using a Mitsunobu coupling procedure (Mitsunobu,
O., Synthesis, 1 (1981)) to give compound 56. Preferred coupling
conditions include using a trialkylphosphine or triarylphosphine,
such as triphenylphosphine or tri-n-butylphosphine, in a suitable
solvent, such as tetrahydrofuran or methylene chloride, and an
azodicarbonyl reagent, such as diethyl azodicarboxylate,
diisopropyl azodicarboxylate or
1,1'-(azodicarbonyl)dipiperidine.
[0160] Deprotection of the Cbz protecting group is accomplished
through catalytic hydrogenation using palladium on carbon as a
catalyst in solvents such as ethanol or tetrahydrofuran. The amine
57 is treated with isocyanate 58 in a solvent such as acetonitrile
to give compound 59. The urea ester 59 may be optionally converted
to acid 60 by a standard procedure such as sodium hydroxide in a
solvent, such as methanol and water.
[0161] Compounds of the present invention can be tested for the
ability to inhibit or antagonize .alpha..sub.v.beta..sub.3 or
.alpha..sub.v.beta..sub.5 cell surface receptors by assays known to
those of ordinary skill in the art. Such assays are described in
Example 4 herein.
[0162] The present invention also provides a method of treating
.alpha..sub.v.beta..sub.3 integrin- or .alpha..sub.v.beta..sub.5
integrin-mediated conditions by selectively inhibiting or
antagonizing .alpha..sub.v.beta..sub.3 and
.alpha..sub.v.beta..sub.5 cell surface receptors, which method
comprises administering a therapeutically effective amount of a
compound selected from the class of compounds depicted by Formula
I, wherein one or more compounds of Formula I is administered in
association with one or more non-toxic, pharmaceutically acceptable
carriers and/or diluents and/or adjuvants and if desired other
active ingredients.
[0163] More specifically, the present invention provides a method
for inhibition of the .alpha..sub.v.beta..sub.3 cell surface
receptor. Most preferably, the present invention provides a method
for inhibiting bone resorption, treating osteoporosis, inhibiting
humoral hypercalcemia of malignancy, treating Paget's disease,
inhibiting tumor metastasis, inhibiting neoplasia (solid tumor
growth), inhibiting angiogenesis including tumor angiogenesis,
treating diabetic retinopathy, age-related macular degeneration,
retinopathy of prematurity and other neo-vascular eye diseases,
inhibiting arthritis, psoriasis and periodontal disease, and
inhibiting smooth muscle cell migration including neointimal
hyperplasia and restenosis.
[0164] The present invention also provides a method for inhibition
of the .alpha..sub.v.beta..sub.5 cell surface receptor. Most
preferably, the present invention provides a method for inhibiting
angiogenesis associated with pathological conditions such as
inflammatory disorders such as immune and non-immune inflammation,
chronic articular rheumatism and psoriasis, disorders associated
with inappropriate or inopportune invasion of vessels such as
restenosis, capillary proliferation in atherosclerotic plaques and
osteoporosis, and cancer associated disorders, such as solid
tumors, solid tumor metastases, angiofibromas, retrolental
fibroplasia, hemangiomas, Kaposi sarcoma and similar cancers which
require neovascularization to support tumor growth. The present
invention also provides a method for treating eye diseases
characterized by angiogenesis, such as diabetic retinopathy,
age-related macular degeneration, presumed ocular histoplasmosis,
retinopathy of prematurity, and neovascular glaucoma.
[0165] The compounds of the present invention are useful in
treating cancer, including tumor growth, metastasis and
angiogenesis. For example, compounds of the present invention can
be employed to treat breast cancer and prostate cancer.
[0166] The compounds of the present invention are also useful in
the treatment of sickle cell anemia.
.alpha..sub.v.beta..sub.3-integrin has recently been implicated in
the mechanism of adhesion of sickled red blood cells (RBCs) to
vascular structures within the circulatory system of those
suffering from sickle cell anemia. Adhesion of RBCs is responsible
for the reoccurring episodes of painful vasocclusive crisis and
multiple organ damage. Kaul et al., Blood 95(2): 368-373 (2000).
Monoclonal antibodies which bind to .alpha..sub.v.beta..sub.3 have
been shown to inhibit the adhesion of sickled RBCs in the ex vivo
mesocecum vasculature of the rat. Id. By blocking
.alpha..sub.v.beta..sub.3--integr- in which assist in adhesion of
sickled cells to vascular components, a reduction in the harmful
affects of sickle cell anemia is realized.
[0167] The compounds of the present invention are also useful in
the treatment of central nervous system (CNS) related disorders.
Treatment of such CNS related disorders includes, but is not
limited to: treating or preventing neuronal loss associated with
stroke, ischemia, CNS trauma, hypoglycemia, and surgery, as well as
treating neurodegenerative diseases including Alzheimer's disease,
and Parkinson's disease, treating or preventing the adverse
consequences of the overstimulation of the excitatory amino acids,
as well as treating schizophrenia, anxiety, convulsions, chronic
pain, psychosis, including anesthesia, and preventing opiate
tolerance.
[0168] Studies have shown that there is a correlation between the
activity of .alpha..sub.4 integrin and the establishment of
inflammatory lesions in the CNS. Brocke, S. et al., Proc. Natl.
Acad. Sci. USA 96: 6896-6901 (1999). Specifically, antibodies
directed against CD44 and .alpha..sub.4 integrin could interfere in
several ways with the establishment of inflammatory lesions in the
CNS and thus prevent experimental autoimmune encephalomyelitis
(EAE), an inflammatory disease of the CNS similar to multiple
sclerosis. Brocke at 6899.
[0169] Relton and co-workers have also shown that inhibition of
.alpha..sub.4 integrin activity protects the brain against ischemic
brain injury, thereby implicating .alpha..sub.4 integrin as a
factor in acute brain injury. Relton, et al., Stroke 32(1): 199-205
(2001).
[0170] The compounds of the present invention may be administered
in an effective amount within the dosage range of about 0.01 mg/kg
to about 300 mg/kg, preferably between 1.0 mg/kg to 100 mg/kg body
weight. Compounds of the present invention may be administered in a
single daily dose, or the total daily dosage may be administered in
divided doses of two, three or four times daily.
[0171] The pharmaceutical compositions of the present invention can
be administered to any animal that can experience the beneficial
effects of the compounds of the invention. Foremost among such
animals are humans, although the invention is not intended to be so
limited.
[0172] The pharmaceutical compositions of the present invention can
be administered by any means that achieve their intended purpose.
For example, administration can be by parenteral, subcutaneous,
intravenous, intramuscular, intraperitoneal, transdermal, buccal,
or ocular routes. Alternatively, or concurrently, administration
can be by the oral route. The dosage administered will be dependent
upon the age, health, and weight of the recipient, kind of
concurrent treatment, if any, frequency of treatment, and the
nature of the effect desired.
[0173] In addition to the pharmacologically active compounds, the
pharmaceutical preparations of the compounds can contain suitable
pharmaceutically acceptable carriers comprising excipients and
auxiliaries that facilitate processing of the active compounds into
preparations that can be used pharmaceutically. The pharmaceutical
preparations of the present invention are manufactured in a manner
that is, itself, known, for example, by means of conventional
mixing, granulating, dragee-making, dissolving, or lyophilizing
processes. Thus, pharmaceutical preparations for oral use can be
obtained by combining the active compounds with solid excipients,
optionally grinding the resulting mixture and processing the
mixture of granules, after adding suitable auxiliaries, if desired
or necessary, to obtain tablets or dragee cores.
[0174] Suitable excipients are, in particular, fillers such as
saccharides, for example, lactose or sucrose, mannitol or sorbitol,
cellulose preparations and/or calcium phosphates, for example,
tricalcium phosphate or calcium hydrogen phosphate, as well as
binders, such as starch paste, using, for example, maize starch,
wheat starch, rice starch, potato starch, gelatin, tragacanth,
methyl cellulose, hydroxypropylmethylcellulose, sodium
carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,
disintegrating agents can be added, such as the above-mentioned
starches and also carboxymethyl-starch, cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof, such as
sodium alginate. Auxiliaries are, above all, flow-regulating agents
and lubricants, for example silica, talc, stearic acid or salts
thereof, such as magnesium stearate or calcium stearate, and/or
polyethylene glycol. Dragee cores are provided with suitable
coatings, that, if desired, are resistant to gastric juices. For
this purpose, concentrated saccharide solutions can be used, which
may optionally contain gum arabic, talc, polyvinyl pyrrolidone,
polyethylene glycol, and/or titanium dioxide, lacquer solutions and
suitable organic solvents or solvent mixtures. In order to produce
coatings resistant to gastric juices, solutions of suitable
cellulose preparations, such as acetylcellulose phthalate or
hydroxypropylmethylcellulose phthalate, are used. Dye stuffs or
pigments can be added to the tablets or dragee coatings, for
example, for identification or in order to characterize
combinations of active compound doses.
[0175] Other pharmaceutical preparations that can be used orally
include push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer such as glycerol or
sorbitol. The push-fit capsules can contain the active compounds in
the form of granules that may be mixed with fillers such as
lactose, binders such as starches, and/or lubricants such as talc
or magnesium stearate and, optionally, stabilizers. In soft
capsules, the active compounds are preferably dissolved or
suspended in suitable liquids such as fatty oils or liquid
paraffin. In addition, stabilizers may be added.
[0176] Suitable formulations for parenteral administration include
aqueous solutions of the active compounds in water-soluble form,
for example water-soluble salts and alkaline solutions. Alkaline
salts can include ammonium salts prepared, for example, with Tris,
choline hydroxide, bis-Tris propane, N-methylglucamine, or
arginine. In addition, suspensions of the active compounds as
appropriate oily injection suspensions can be administered.
Suitable lipophilic solvents or vehicles include fatty oils, for
example, sesame oil, or synthetic fatty acid esters, for example,
ethyl oleate or triglycerides or polyethylene glycol-400 (the
compounds are soluble in PEG-400). Aqueous injection suspensions
can contain substances that increase the viscosity of the
suspension, for example sodium carboxymethyl cellulose, sorbitol,
and/or dextran. Optionally, the suspension may also contain
stabilizers.
[0177] The compounds of the present invention may be administered
to the eye in animals and humans as a drop, or within ointments,
gels, liposomes, or biocompatible polymer discs, pellets or carried
within contact lenses. The intraocular composition may also contain
a physiologically compatible ophthalmic vehicle as those skilled in
the art can select using conventional criteria. The vehicles may be
selected from the known ophthalmic vehicles which include but are
not limited to water, polyethers such s polyethylene glycol 400,
polyvinyls such as polyvinyl alcohol, povidone, cellulose
derivatives such as carboxymethylcellulose, methylcellulose and
hydroxypropyl methylcellulose, petroleumn derivatives such as
mineral oil and white petrolatum, animal fats such as lanolin,
vegetable fats such as peanut oil, polymers of acrylic acid such as
carboxylpolymethylene gel, polysaccharides such as dextrans and
glycosaminoglycans such as sodium chloride and potassium, chloride,
zinc chloride and buffer such as sodium bicarbonate or sodium
lactate. High molecular weight molecules can also be used.
Physiologically compatible preservatives which do not inactivate
the compounds of the present invention in the composition include
alcohols such as chlorobutanol, benzalknonium chloride and EDTA, or
any other appropriate preservative known to those skilled in the
art.
[0178] The following examples are illustrative, but not limiting,
of the method and compositions of the present invention. Other
suitable modifications and adaptations of the variety of conditions
and parameters normally encountered and obvious to those skilled in
the art are within the spirit and scope of the invention.
EXAMPLES
Example 1
Synthesis of
3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]thiophen-3--
yl)propanoic Acid
a) Synthesis of 3-Iodophenyl Acetate
[0179] A solution of 3-iodophenol (3 g, 13.6 mmol), acetyl chloride
(2.9 ml, 40.9 mmol) and potassium carbonate (9.42 g, 68.2 mmol) in
N,N-dimethylformamide (75 ml) was stirred for 16 h at room
temperature. The mixture was partitioned between water and ethyl
acetate. The organic layer was washed with 1N NaOH, dried over
magnesium sulfate, and evaporated under vacuum. The crude product
was chromatographed over silica gel, eluting with 20% ethyl
acetate/hexanes to yield 2.3 g (65%) of 3-iodophenyl acetate. NMR
.sup.1H Cl.sub.3CD .delta.: 7.57 (1H, m), 7.46 (1H, m), 7.08 92H,
m) 2.29 (3H, s).
b) Synthesis of
3-[1,1-bis(Methylethyl)-2-methyl-1-silapropylthio]phenyl
Acetate
[0180] Triisopropylsilanethiol (2.91 ml, 13.5 mmol) was added
dropwise to a suspension of sodium hydride (325 mg, 13.5 mmol) in
THF (10 ml). After the evolution of hydrogen ceased, a solution of
3-iodophenyl acetate (2.37 g, 9.0 mmol) and
tetrakis(triphenylphosphine)palladium (0) (1.04 g, 0.9 mmol) in
toluene (90 ml) was added. After refluxing for 16 h under argon,
the reaction was cooled to room temperature and the solvent was
evaporated under vacuum. The resulting residue was dissolved in
ethyl acetate, washed with 1N NaOH and brine, dried with sodium
sulfate, filtered, and evaporated under vacuum. The crude product
was chomatrographed over silica gel to yield 1.53 g (52%) of
3-[1,1-bis(Methylethyl)-2-methyl-1-silapropylthio]phenyl acetate.
NMR .sup.1H Cl.sub.3CD .delta.: 7.34 (m, 2H), 7.23 (t, 1H, J=2.4
Hz), 6.94 (dd, 1H, J=1.2, 8.4 Hz), 2.28 (s, 3H), 1.25 (m, 3H), 1.08
(d, 18H, J=7.2 Hz).
c) Synthesis of Ethyl 5-bromo-4-oxopentanoate
[0181] (Trimethylsilyl)diazomethane (34 ml, 67 mmol, 2.0M solution
in hexanes) was added dropwise to a solution of ethyl succinyl
chloride (5 g, 30.3 mmol) in acetonitrile (60 ml) over a period of
30 minutes. After stirring for 2 h, hydrogen bromide (14 ml, 30%
solution in acetic acid) was slowly added over 15 minutes. After
the reaction stirred for an additional 1 h, the solvent was
evaporated under vacuum. The residue was dissolved in ethyl acetate
and washed with 1N NaOH and brine. The organic layer was dried with
sodium sulfate, filtered, and evaporated under vacuum to yield 4.3
g (64%) of Ethyl 5-bromo-4-oxopentanoate. NMR .sup.1H Cl.sub.3CD
.delta.: 4.13 (c, 2H, J=7.2 Hz), 3.96 (s, 2H), 2.95 (t, 2H, J=6.4
Hz), 2.65 (t, 2H, J=6.4 Hz), 1.24 (t, 1H, J=7.2 Hz).
d) Synthesis of Ethyl 5-(3-acetyloxyphenylthio)-4-oxopentanoate
[0182] Tetrabutylammonium fluoride (7 ml, 7.0 mmol 1M in THF) was
added to a solution of
3-[1,1-bis(Methylethyl)-2-methyl-1-silapropylthio]phenyl acetate
(1.53 g, 4.7 mmol) in THF (10 ml) under argon at room temperature.
The reaction was stirred for 15 minutes followed by addition of a
solution of ethyl 5-bromo-4-oxopentanoate (1.15 g, 5.17 mmol) in
THF (5 ml). After stirring for 3 hours, the solvent was removed
under vacuum and the crude product was chromatographed over silica
gel to yield 920 mg (73%) of ethyl
5-(3-acetyloxyphenylthio)-4-oxopentanoate. NMR .sup.1H Cl.sub.3CD
.delta.: 7.29 (t, 1H, J=8.0 Hz), 7.18 (dd, 1H, J=0.8, 7.6 Hz), 7.07
(t, 1H, J=1.6 Hz), 6.94 (dd, 1H, J=1.2, 8.0 Hz), 4.12 (c, 2H, J=7.2
Hz), 3.75 (s, 2H), 2.89 (t, 2H, J=6.8 Hz), 2.60 (t, 2H, J=6.8 Hz),
2.29 (s, 3H), 1.24 (t, 1H, J=7.2 Hz).
e) Synthesis of Ethyl
3-(6-hydroxybenzo[b]thiophen-3-yl)propanoate
[0183] Concentrated sulfuric acid (20 ml) was cooled in an
ice-water bath to 0.degree. C. and added to a flask containing
ethyl 5-(3-acetyloxyphenylthio)-4-oxopentanoate (920 mg, 3.4 mmol)
at 0.degree. C. The reaction was stirred at 0.degree. C. for 15
minutes, and then poured over ice. The mixture was extracted with
ethyl acetate, dried, filtered, and evaporated under vacuum to
yield 700 mg (82%) of Ethyl
3-(6-hydroxybenzo[b]thiophen-3-yl)propanoate. NMR .sup.1H
DMSO-d.sub.6 .delta.: 9.59 (s, 1H), 7.59 (d, 1H, J=8.4 Hz), 7.25
(d, 1H, J=2.4 Hz), 7.08 (s, 1H), 6.89 (dd, 1H, J=2.4, 8.4 Hz), 4.06
(c, 2H, J=7.2 Hz), 2.99 (t, 2H, J=6.8 Hz), 2.70 (t, 2H, J=6.8 Hz),
1.16 (t, 1H, J=7.2 Hz).
f) Synthesis of
(tert-Butoxy)-N-(6-methyl(2-pyridyl))carboxamide
[0184] 2-Amino-6-picoline (10 g, 92.2 mmol) and di-tert-butyl
dicarbonate (22 g, 100.8 mmol) were heated at 50.degree. C. under
argon for 16 h. The mixture was cooled to room temperature and
poured into ice-water. The reaction was extracted with ethyl
acetate, dried with sodium sulfate, filtered, and evaporated under
vacuum. The resulting oil was flushed through a plug of silica gel,
eluting with 20% ethyl acetate/hexanes to yield 20.2 g (100%) of
(tert-Butoxy)-N-(6-methyl(2-pyridyl))carboxamide. NMR .sup.1H
Cl.sub.3CD 8: 7.70 (d, 1H, J=7.6 Hz), 7.54 (t, 1H, J=7.6 Hz), 6.80
(d, 1H, J=7.6 Hz), 2.42 (s, 3H), 1.53 (s, 9H).
g) Synthesis of
(tert-Butoxy)-N-methyl-N-(6-methyl(2-pyridyl))carboxamide
[0185] (tert-Butoxy)-N-(6-methyl(2-pyridyl))carboxamide (20.2 g,
102 mmol) dissolved in N,N-dimethylformamide (75 ml) was slowly
added to a suspension of sodium hydride (3.67 g, 153 mmol) in DMF
(150 ml) at 0.degree. C. The reaction mixture was warmed to room
temperature and stirred for 1 h. Methyl iodide (9.5 ml, 153 mmol)
was added dropwise at 0.degree. C. After stirring at room
temperature for 16 h, the reaction mixture was poured over
ice-water and extracted with ethyl acetate. The organic layer was
washed with brine, dried with sodium sulfate, filtered, and
evaporated under vacuum. The crude product was chromatographed over
silica gel to yield 15.3 g (66%) of
(tert-Butoxy)-N-methyl-N-(6-methyl(2-- pyridyl))carboxamide. NMR
.sup.1H Cl.sub.3CD .delta.: 7.50 (t, 1H, J=7.6 Hz), 7.37 (d, 1H,
J=7.6 Hz), 6.85 (d, 1H, J=7.6 Hz), 3.38 (s, 3H), 2.48 (s, 3H), 1.50
(s, 9H).
h) Synthesis of Ethyl
2-{6-[(tert-butoxy)-N-methylcarbonylamino]-2-pyridyl- }acetate
[0186] To a solution of diisopropylamine (6.16 ml, 44 mmol) and THF
(50 ml), at -78.degree. C. under argon, was added butyllithium (27
ml, 44 mmol, 1.6 M in hexane) dropwise. The mixture was warmed to
room temperature and stirred for 10 minutes. The reaction was
cooled to -78.degree. C. and a solution of
(tert-Butoxy)-N-methyl-N-(6-methyl(2-pyr- idyl))carboxamide (5.0 g,
22 mmol) in THF (100 ml) was added dropwise. The reaction mixture
was stirred for 15 minutes at -78.degree. C., followed by addition
of diethylcarbonate (4.25 ml, 35 mmol). The mixture was warmed to
room temperature and stirred for 2 h. The reaction was quenched
with saturated aqueous ammonium chloride and extracted with ethyl
acetate. The organic layer was dried with sodium sulfate, filtered,
and evaporated under vacuum. The resulting yellow oil was
chromatographed over silica gel to yield 2.45 g (38%) of Ethyl
2-{6-[(tert-butoxy)-N-meth- ylcarbonylamino]-2-pyridyl}acetate. NMR
.sup.1H Cl.sub.3CD .delta.: 7.57 (m, 2H), 6.97 (m, 1H), 4.18 (c,
2H, J=7.2 Hz) 3.76 (s, 2H), 3.42 (s, 3H), 1.51 (s, 9H), 1.27 (t,
3H, J=7.2 Hz).
i) Synthesis of Ethyl 2-[6-(methylamino)-2-pyridyl]acetate
[0187] To a solution of ethyl
2-{6-[(tert-butoxy)-N-methylcarbonylamino]-2- -pyridyl}acetate
(3.56 g, 12.1 mmol) in dichloromethane (15 ml) was added
trifluoroacetic acid (8 ml). The reaction was stirred for 16 h. The
solvent was removed under vacuum and the crude product was
chromatographed over silica gel to yield 2.2 g (100%) of Ethyl
2-[6-(methylamino)-2-pyridyl]acetate. NMR .sup.1H Cl.sub.3CD
.delta.: 7.41 (t, 1H, J=8.0 Hz), 6.55 (d, 1H, J=8.0 Hz), 6.27 (d,
1H, J=8.0 Hz), 4.15 (c, 2H, J=7.2 Hz) 3.64 (s, 2H), 2.88 (d, 3H,
J=5.2 Hz), 1.26 (t, 3H, J=7.2 Hz).
j) Synthesis of 2-[6-(Methylamino)-2-pyridyl]ethan-1-ol
[0188] A solution of ethyl 2-[6-(methylamino)-2-pyridyl]acetate
(2.2 g, 12.5 mmol) in THF (30 ml) was added dropwise to a
suspension of lithium aluminum hydride (1.24 g, 31.2 mmol) in THF
(25 ml) under argon at 0.degree. C. The reaction was stirred for 30
minutes and quenched carefully with water (4 ml) and 1 N NaOH (4
ml). The mixture was filtered through a pad of Celite and washed
several times with ethyl acetate. The filtrate was dried with
sodium sulfate, filtered, and evaporated under vacuum. The crude
product was chromatographed over silica gel to yield 1.50 g (79%)
of 2-[6-(Methylamino)-2-pyridyl]ethan-1-ol. NMR .sup.1H Cl.sub.3CD
.delta.: 7.35 (dd, 1H, J=7.6, 8.4 Hz), 6.41 (d, 1H, J=7.6 Hz), 6.26
(d, 1H, J=8.4 Hz), 3.96 (t, 2H, J=5.2 Hz), 2.90 (d, 3H, J=5.2 Hz),
2.83 (t, 2H, J=5.2 Hz).
k) Synthesis of 2-[6-(Methylamino)-2-pyridyl]ethyl
Methylsulfonate
[0189] A mixture of 2-[6-(Methylamino)-2-pyridyl]ethan-1-ol (300
mg, 1.9 mmol), triethylamine (0.3 ml, 2.2 mmol), methanesulfonyl
chloride (0.17 ml, 2.2 mmol), and dichloromethane (15 ml) was
stirred at 0.degree. C. for 30 minutes. The reaction mixture was
diluted with dichloromethane and washed with water. The organic
layer was dried with sodium sulfate, filtered, and evaporated under
vacuum to give a yellow oil. The crude product was chromatographed
over silica gel to yield 300 mg (69%) of
2-[6-(Methylamino)-2-pyridyl]ethyl methylsulfonate. NMR .sup.1H
Cl.sub.3CD .delta.: 7.45 (dd, 1H, J=7.2, 8.4 Hz), 6.51 (d, 1H,
J=7.2 Hz), 6.33 (d, 1H, J=8.4 Hz), 4.65 (t, 2H, J=6.4 Hz), 3.06 (t,
2H, J=6.4 Hz), 2.92 (m, 6H).
l) Synthesis of
{6-[2-(3-Iodophenoxy)ethyl](2-pyridyl)}methylamine
[0190] To a stirring solution of 3-iodophenol (1.11 g, 5.1 mmol),
2-[6-(Methylamino)-2-pyridyl]ethan-1-ol (700 mg, 4.6 mmol),
triphenylphosphine (1.3 g, 5.1 mmol), and THF (20 ml), was added
diethyl azodicarboxylate (0.80 ml, 5.1 mmol) at 0.degree. C. After
stirring overnight under argon at room temperature, the solvent was
evaporated under vacuum. The crude product was chromatographed over
silica gel to yield 1.2 g (74%) of
{6-[2-(3-Iodophenoxy)ethyl](2-pyridyl)}methylamine. NMR .sup.1H
Cl.sub.3CD .delta.: 7.40 (t, 1H, J=8.0 Hz), 7.26 (m, 2H), 6.96 (t,
1H, J=8.0 Hz), 6.87 (m, 1H), 6.52 (d, 1H, J=8.0 Hz), 6.25 (d, 1H,
J=4.0 Hz), 4.51 (br s, 1H), 4.29 (t, 2H, J=6.8 Hz), 3.07 (t, 2H,
J=6.8 Hz), 2.90 (d, 3H, J=8 Hz).
m) Synthesis of
[6-(2-{3-[1,1-bis(Methylethyl)-2-methyl-1-silapropylthio]p-
henoxy}ethyl)(2-pyridyl)]methylamine
[0191] To a suspension of sodium hydride (128 mg, 5.1 mmol) in THF
(30 ml) was added triisopropylsilanethiol (1.1 ml, 5.1 mmol)
dropwise. After the evolution of hydrogen ceased, a solution of
{6-[2-(3-Iodophenoxy)ethyl](2- -pyridyl)}methylamine (1.2 g, 3.4
mmol) and tetrakis(triphenylphosphine)pa- lladium(0) (390 mg, 0.3
mmol) in toluene (30 ml) was added. After refluxing for 16 h under
argon, the reaction mixture was cooled to room temperature and
evaporated under vacuum. The residue was dissolved in ethyl acetate
and washed with 1N NaOH and brine. The organic layer was dried with
sodium sulfate, filtered, and evaporated. The crude product was
chomatrographed over silica gel to yield 1.34 g (95%) of
[6-(2-{3-[1,1-bis(Methylethyl)-2-methyl-1-silapropylthio]phenoxy}ethyl)(2-
-pyridyl)]methylamine. NMR .sup.1H Cl.sub.3CD .delta.: 7.38 (dd,
1H, J=7.2, 8.0 Hz), 7.04 (m, 3H), 6.77 (m, 1H), 6.52 (d, 1H, J=8.0
Hz), 6.25 (d, 1H, J=4.0 Hz), 4.29 (t, 2H, J=6.8 Hz), 3.06 (t, 2H,
J=6.8 Hz), 2.90 (d, 3H, J=8 Hz), 1.85 (m, 3H), 1.09 (m, 2H).
n) Synthesis of Ethyl
5-(3-{2-[6-(Methylamino)(2-pyridyl)]ethoxy}phenylthi-
o)-4-oxopentanoate
[0192] To a solution of
[6-(2-{3-[1,1-bis(Methylethyl)-2-methyl-1-silaprop-
ylthio]phenoxy}ethyl)(2-pyridyl)]methylamine (1.34 g, 3.2 mmol) and
THF (25 ml) under Argon, was added tetrabutylamonium floride (3.5
ml, 3.5 mmol, 1M in THF) at room temperature. After stirring for 15
minutes, a solution of ethyl 5-bromo-4-oxopentanoate (0.79 g, 3.5
mmol) in THF (5 ml) was added. The mixture was stirred for 3 h. The
solvent was removed under vacuum and the remaining residue was
chromatographed over silica gel to yield 830 mg (64%) of Ethyl
5-(3-{2-[6-(Methylamino)(2-pyridyl)]et-
hoxy}phenylthio).sub.4-oxopentanoate. NMR .sup.1H Cl.sub.3CD
.delta.: 7.38 (dd, 1H, J=7.2, 8.0 Hz), 7.17 (t, 1H, J=8.0 Hz), 6.89
(m, 2H), 6.71 (m, 1H), 6.54 (d, 1H, J=8.0 Hz), 6.25 (d, 1H, J=4.0
Hz), 4.30 (t, 2H, J=6.8 Hz), 4.13 (c, 2H, J=7.2 Hz), 3.72 (s, 2H),
3.07 (t, 2H, J=6.8 Hz), 2.91 (m, 5H), 2.59 (t, 2H, J=6.8 Hz), 1.24
(t, 3H, J=7.2 Hz).
o) Synthesis of Ethyl
3-(6-{2-[6-(Methylamino)-2-pyridyl]ethoxy}benzo[b]th-
iophen-3-yl)propanoate
[0193] Method o-1:
[0194] Ethyl 3-(6-hydroxybenzo[b]thiophen-3-yl)propanoate (100 mg,
0.4 mmol) was dissolved in a minimal amount of DMF and added
carefully to a suspension of sodium hydride (10 mg, 0.4 mmol) in
DMF (5 ml) at 0.degree. C. under argon. After stirring for 15
minutes, a solution of 2-[6-(Methylamino)-2-pyridyl]ethyl
methylsulfonate (84 mg, 0.36 mmol) in DMF (1 ml) was added. The
reaction was stirred at room temperature for 16 h and then poured
over ice-water. The product was extracted with ethyl acetate, and
washed with 1N NaOH and brine. The organic layer was dried with
sodium sulfate, filtered and evaporated under vacuum. The crude
product was chromatographed over silica gel to yield 5.8 mg (4%) of
Ethyl
3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]thiophen-3-yl)propanoat-
e.
[0195] Method o-2:
[0196] Ethyl 3-(6-hydroxybenzo[b]thiophen-3-yl)propanoate (100 mg,
0.4 mmol) and 4-methylmorpholine (0.05 ml, 0.44 mmol) were
dissolved in THF (5 ml) and stirred for 5 minutes.
2-[6-(Methylamino)-2-pyridyl]ethan-1-ol (91 mg, 0.6 mmol),
triphenylphosphine (210 mg, 0.8 mmol) and diisopropyl
azodicarboxylate (0.16 ml, 0.8 mmol) were added to the mixture
sequentially. After stirring overnight under argon, the reaction
mixture was partitioned between ethyl acetate and water. The
organic layer was dried with sodium sulfate, filtered and
evaporated under vacuum. The crude product was chromatographed over
silica gel to yield 30 mg (19%) of Ethyl
3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]thiophen-3-yl)pro-
panoate.
[0197] Method o-3:
[0198] Concentrated sulfuric acid (20 ml) was cooled in an
ice-water bath to 0.degree. C. and added to a flask containing
5-(3-{2-[6-(Methylamino)(-
2-pyridyl)]ethoxy}phenylthio)-4-oxopentanoate (830 mg, 2.1 mmol) at
0.degree. C. The reaction was stirred at 0.degree. C. for 15
minutes, and then poured over ice. The solution was neutralized
with solid sodium hydrogencarbonate (pH=7) and extracted with ethyl
acetate. The organic layer was dried with sodium sulfate, filtered,
and evaporated under vacuum to yield 250 mg (30%) of Ethyl
3-(6-{2-[6-(methylamino)-2-pyridyl]-
ethoxy}benzo[b]thiophen-3-yl)propanoate. N .sup.1H Cl.sub.3CD
.delta.: 7.60 (d, 1H, J=8.8 Hz), 7.38 (dd, 1H, J=7.2, 8.0 Hz), 7.35
(d, 1H, J=2.0 Hz), 7.01 (dd, 1H, J=2.4, 8.8 Hz), 6.93 (m, 1H), 6.56
(d, 1H, J=7.2 Hz), 6.25 (d, 1H, J=8.0 Hz), 4.40 (t, 2H, J=6.8 Hz),
4.15 (c, 2H, J=7.2 Hz), 3.10 (t, 2H, J=6.4 Hz), 2.90 (m, 5H), 2.74
(t, 2H, 3=6.4 Hz), 1.25 (t, 1H, J=7.2 Hz).
p) Synthesis of
3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]thiophen-
-3-yl)propanoic Acid
[0199] 1N NaOH (10 ml) was added to a solution of
3-(6-{2-[6-(Methylamino)-
-2-pyridyl]ethoxy}benzo[b]thiophen-3-yl)propanoate and THF (10 ml).
The reaction was stirred at room temperature for 16 h. The mixture
was diluted with water and ethyl acetate. The separated aqueous
layer was neutralized with 1 N HCl to pH=6.5. The resulting
precipitate was filtered, washed with distilled water, and dried to
yield 74 mg (55%) of
3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]thiophen-3-yl)propanoic
acid as a white solid. NMR .sup.1H DMSO-d.sub.6 .delta.: 7.67 (d,
1H, J=8.0 Hz), 7.58 (d, 1H, J=2.4 Hz), 7.31 (dd, 1H, J=7.2, 8.0
Hz), 7.18 (s, 1H), 7.00 (dd, 1H, 3=2.4, 8.0 Hz), 6.45 (d, 1H, J=7.2
Hz), 6.37 (m, 1H), 6.27 (d, 1H, J=8.0 Hz), 4.36 (t, 2H, J=6.4 Hz),
2.99 (t, 2H, J=6.4 Hz), 2.90 (d, 3H, J=8.0 Hz), 2.64 (t, 2H, J=6.4
Hz). Mass Spectrum (LCMS, ESI) calculate for
C.sub.19H.sub.21N.sub.2O.sub.3S 357.1 (M+H) found: 357.3.
Example 2
Synthesis of
3-{6-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-b-
enzo[b]thiophen-3-yl}-propionic Acid
a)
7-(2-Hydroxy-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic
Acid tert-butyl Ester
[0200]
7-Ethoxycarbonylmethyl-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxyl-
ic acid tert-butyl ester (synthetic methodology described in WO
00/33838) (6.11 g, 19.0 mmol) was dissolved in tetrahydrofuran (40
ml) at room temperature. The solution was place under argon.
Lithium borohydride [2M in tetrahydrofuran](22.8 mmol, 11.43 mL)
was carefully added and the reaction was refluxed overnight (16 h).
The mixture was poured into a solution of saturated ammonium
chloride and extracted with ethyl acetate. The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and evaporated under vacuum
to give a crude mixture, which was purified via column
chromatography to give 7-(2-hydroxy-ethyl)-3,4-dihydro-2H-[1,8]nap-
hthyridine-1-carboxylic acid tert-butyl ester (49% yield). .sup.1H
NMR (Cl.sub.3CD), .delta.: 7.30 (d, 1H, J=7.6 Hz), 7.76(d, 1H,
J=7.6 Hz), 3.98 (m, 2H), 3.78 (m, 2H), 2.92 (m, 2H), 2.71 (m, 2H),
1.92(m, 2H), 1.54 (s, 9H).
b)
7-{2-[3-(2-Ethoxycarbonyl-ethyl)-benzo[b]thiophen-6-yloxy]-ethyl}-3,4-d-
ihydro-2H-[1,8]naphthyridine-1-carboxylic Acid tert-butyl Ester
[0201] Ethyl 3-(6-hydroxybenzo[b]thiophen-3-yl)propanoate (207 mg,
82.6 mmol),
7-(2-hydroxy-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic
acid tert-butyl ester (276 mg, 99.2 mmol) and triphenylphosphine
(435 mg, 165 mmol) were dissolved in THF (15 ml) and stirred for 15
minutes under argon atmosphere at 0.degree. C. Then, diisopropyl
azodicarboxylate (0.325 ml, 165 mmol) was added to the mixture.
After stirring overnight under argon, the reaction mixture was
partitioned between ethyl acetate and water. The organic layer was
dried with sodium sulfate, filtered and evaporated under vacuum.
The crude product was chromatographied over silica gel to yield 338
mg (80%) of 7-{2-[3-(2-Ethoxycarbonyl-ethyl)-benz-
o[b]thiophen-6-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxyli-
c acid tert-butyl ester. NMR .sup.1H Cl.sub.3CD .delta.: 7.59 (d,
1H, J=8.8 Hz), 7.33 (m, 2H), 7.00 (dd, 1H, J=2.3, 8.8 Hz), 6.93 (m,
2H), 4.42 (t, 2H, J=6.7 Hz), 4.14 (m, 2H), 3.76 (m, 2H), 3.22 (m,
2H), 3.12 (m, 2H), 2.73 (m, 4H), 1.92 (m, 2H) 1.51 (s, 9H), 1.26
(m, 3H).
c)
7-{2-[3-(2-Carboxy-ethyl)-benzo[b]thiophen-6-yloxy]-ethyl}-3,4-dihydro--
2H-[1,8]naphthyridine-1-carboxylic Acid tert-butyl Ester
[0202]
7-{2-[3-(2-Ethoxycarbonyl-ethyl)-benzo[b]thiophen-6-yloxy]-ethyl}-3-
,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester
(338 mg, 0.66 mmol) was dissolved THF (5 ml). Then a solution of
sodium hydroxide (132 mg, 3.30 mmol) in water (1 ml) was added. The
reaction was stirred at room temperature for 16 hours. After that
period, the solvent was evaporated under vacuum and the crude was
extracted with ethyl acetate and hydrochloric acid (1M). The
organic layer was collected, dried with anhydrous sodium sulfated,
filtrated and evaporated under vacuum to yield 268 mg (84%) of
7-{2-[3-(2-Carboxy-ethyl)-benzo[b]thiophe-
n-6-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic
acid tert-butyl ester. NMR .sup.1HCl.sub.3CD .delta.: 7.59 (d, 1H,
J=8.8 Hz), 7.47 (d, 1H, J=7.7 Hz), 7.35 (d, 1H, J=2.3 Hz), 7.05 (d,
1H, J=7.6 Hz); 7.01 (s, 1H), 6.96 (dd, 1H, J=2.3, 8.8 Hz), 4.35 (t,
2H, J=6.5 Hz), 3.73 (m, 2H), 3.18 (m, 2H), 3.05 (m, 2H), 2.72 (m,
2H), 2.66 (m, 2H), 1.88 (m, 2H) 1.49 (s, 9H).
d)
3-{6-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-benzo[b]thi-
ophen-3-yl}-propionic Acid
[0203]
7-{2-[3-(2-Carboxy-ethyl)-benzo[b]thiophen-6-yloxy]-ethyl}-3,4-dihy-
dro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (168
mg, 0.35 mmol) was dissolved in THF (10 ml). Hydrogen chloride gas
was bubbled through the solution until the starting material
disappears by TLC. Then the solvent was evaporated under vacuum and
the crude was chromatographied over silica gel using 5%
methanol/methylene chloride as solvent to yield 32 mg (24%) of
3-{6-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyr-
idin-2-yl)-ethoxy]-benzo[b]thiophen-3-yl}-propionic acid. NMR
.sup.1H Cl.sub.3CD .delta.: 7.55 (d, 1H, J=8.7 Hz), 7.25 (m, 2H),
6.93 (s, 1H), 6.88 (dd, 1H, J=2.1, 8.7 Hz), 6.43 (d, 1H, J=7.2 Hz),
4.24 (t, 2H, J=6.1 Hz), 3.45 (m, 2H), 3.10 (m, 4H), 2.71 (m, 4H),
1.88 (m, 2H). Mass Spectrum (LCMS, ESI) calculate for
C.sub.21H.sub.23N.sub.2O.sub.3S 383.14 (M+H) found: 383.3.
Example 3
Synthesis of 3-(6-{2-[6-(Methylamino)-2-pyridyl]ethoxy)
benzo[b]furan-3-yl)propanoic Acid
a) Synthesis of
3-[1,1-bis(Methylethyl)-2-methyl-1-silapropoxy]phenyl Acetate.
[0204] Lithium bis(trimethylsilyl)amide (73 ml, 73 ml, 1M solution
in THF) was added dropwise to a solution of resorcinol monoacetate
(10 g, 65.7 mmol) in THF (100 ml) at 78.degree. C. under argon. The
solution was stirred for 10 minutes and then triisopropylsilyl
chloride (15.5 ml, 73 mmol) was added via syringe. After stirring
at room temperature overnight, the mixture was partitioned between
water and ethyl acetate. The organic layer was dried, filtered and
evaporated under vacuum to yield 13 g of crude
3-[1,1-bis(Methylethyl)-2-methyl-1-silapropoxy]phenyl acetate which
was used in the next step without further purification. NMR .sup.1H
Cl.sub.3CD .delta.: 7.19 (t, 1H, J=8 Hz), 6.75 (m, 1H), 6.68 (m,
1H), 6.63 (t, 1H, J=4 Hz), 2.29 (s, 3H), 1.25 (m, 3H), 1.11 (d,
18H, J=7.0 Hz).
b) Synthesis of
3-[1,1-bis(Methylethyl)-2-methyl-1-silapropoxy]phenol
[0205] An aqueous (50 ml) solution of NaOH (3.25 g, 81 mmol) was
added to a solution of
3-[1,1-bis(Methylethyl)-2-methyl-1-silapropoxy]phenyl acetate (5 g,
16.2 mmol) in THF (50 ml). After stirring overnight at room
temperature, the reaction mixture was partitioned between ethyl
acetate and water. The organic layer was washed with brine, dried,
filtered, and evaporated under vacuum. The crude product was
chromatographed over silica gel to yield 3.89 g (90%) of
3-[1,1-bis(Methylethyl)-2-methyl-1-si- lapropoxy]phenol. NMR
.sup.1H Cl.sub.3CD .delta.: 7.06 (t, 1H, J=8.0 Hz), 6.42 (m, 3H),
1.28 (m, 3H), 1.10 (d, 18H, J=7.0 Hz).
c) Synthesis of
[6-(2-(3-[1,1-bis(Methylethyl)-2-methyl-1-silapropoxy]phen-
oxy}ethyl)(2-pyridyl)]methylamine
[0206] To a stirring solution of
3-[1,1-bis(methylethyl)-2-methyl-1-silapr- opoxy]phenol (200 mg,
0.75 mmol), 2-[6-(methylamino)-2-pyridyl]ethan-1-ol (104 mg, 0.68
mmol), triphenylphosphine (199 mg, 0.75 mmol) and THF (25 ml), was
added diethyl azodicarboxylate (0.12 ml, 0.75 mmol) at 0.degree. C.
The reaction was stirred overnight under argon. The solvent was
removed under vaccum and the crude product was chromatographed over
silica gel to yield 76 mg (28%) of
[6-(2-{3-[1,1-bis(Methylethyl)-2-methy-
l-1-silapropoxy]phenoxy}ethyl)(2-pyridyl)]methylamine. NMR .sup.1H
Cl.sub.3CD .delta.: 7.39 (m, 1H), 7.07 (t, 1H, J=8.0 Hz), 6.5 (m,
3H), 6.25 (d, 1H, J=8 Hz), 4.27 (t, 2H, J=6.8 Hz), 3.06(t, 2H,
J=6.8 Hz), 2.90 (d, 3H, J=8 Hz), 1.28 (m, 3H), 1.10 (d, 18H, J=7.0
Hz).
d) Synthesis of Ethyl
5-(3-{2-[6-(methylamino)(2-pyridyl)]ethoxy}phenoxy)--
4-oxopentanoate
[0207] To a solution of
[6-(2-{3-[1,1-bis(Methylethyl)-2-methyl-1-silaprop-
oxy]phenoxy}ethyl)(2-pyridyl)]methylamine (1.60 g, 4.0 mmol) in THF
(30 ml) under argon at room temperature, was added
tetrabutylammonium fluoride (4.4 ml, 4.4 mmol, 1M in THF). After
stirring for 15 minutes, a solution of ethyl
5-bromo-4-oxopentanoate (0.98 g, 4.4 mmol) in THF (5 ml) was added.
The mixture was stirred for an additional 3 hours. The solvent was
removed under vacuum and the remaining residue was chromatographed
over silica gel to yield 860 mg (56%) of Ethyl
5-(3-{2-[6-(methylamino)(2-pyridyl)]ethoxy}phenoxy)-4-oxopentanoate.
NMR .sup.1H Cl.sub.3CD .delta.: 7.38 (m, 1H), 7.16 (t, 1H, J=8.2
Hz), 7.08 (t, 1H, J=7.9 Hz), 6.64 (m, 1H), 6.45 (m, 3H), 6.26 (dd,
1H, J=8.2, 2.3 Hz), 4.57 (s, 2H), 4.30 (t, 2H, J=6.8 Hz), 4.13 (c,
2H, J=7.2 Hz), 3.07 (m, 2H), 2.91 (m, 5H), 2.63 (t, 2H, J=6.6 Hz),
1.24 (t, 3H, J=7.2 Hz).
e) Synthesis of Ethyl
3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]fu-
ran-3-yl)propanoate
[0208] Concentrated sulfuric acid (3 ml) was cooled in an ice-water
bath to 0.degree. C. and added to a flask containing ethyl
5-(3-{2-[6-(methylamino)(2-pyridyl)]ethoxy}phenoxy)-4-oxopentanoate
(190 mg, 0.5 mmol) at 0.degree. C. The reaction was stirred 15
minutes and then poured over ice. The solution was neutralized with
solid sodium hydrogencarbonate (pH=7) and the product was extracted
with ethyl acetate. The organic layer was dried, filtered and
evaporated under vacuum to yield 104 mg (57%) of Ethyl
3-(6-{2-[6-(methylamino)-2-pyridyl]-
ethoxy}benzo[b]furan-3-yl)propanoate. NMR .sup.1H Cl.sub.3CD 6:
7.36 (m, 3H), 7.01 (d, 1H, J=2.1 Hz), 6.87 (dd, 1H, J=8.5, 2.1 Hz),
6.54 (d, 1H, 3=7.2 Hz), 6.23 (d, 1H, J=8.2 Hz), 4.68 (br s, 1H),
4.15 (c, 2H, J=7.4 Hz), 3.09 (t, 2H, J=6.9 Hz), 2.97 (t, 2H, J=6.9
Hz), 2.87 (d, 3H, J=5.1 Hz), 2.68 (t, 2H, J=6.9 Hz), 1.26 (t, 1H,
J=7.4 Hz).
f) Synthesis of
3-(6-{2-[6-(Methylamino)-2-pyridyl]ethoxy}benzo[b]furan-3--
yl)propanoic Acid
[0209] 1N NaOH (4 ml) was added to a solution ethyl
3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]furan-3-yl)propanoate
in THF (4 ml) and stirred for 16 h. The reaction mixture was
partitioned between ethyl acetate and water. The aqueous layer was
neutralized with 1N HCl (pH=6.5). The resulting precipitate was
filtered, rinsed with distilled water, and dried to yield 70 mg
(74%) of
3-(6-{2-[6-(Methylamino)-2-pyridyl]ethoxy}benzo[b]furan-3-yl)propanoic
acid as a white solid. NMR .sup.1H DMSO-d.sub.6 .delta.: 7.54 (dd,
1H, J=7.3, 8.6 Hz), 7.34 (m, 2H), 6.99 (d, 1H, J=2.0 Hz), 6.77 (dd,
1H, J=2.0, 8.6 Hz), 6.53 (d, 1H, J=7.1 Hz), 6.37 (d, 1H, J=7.1 Hz),
6.27 (d, 1H, J=8.5 Hz), 4.19 (t, 2H, J=6.5 Hz), 3.09 (t, 2H, J=6.5
Hz), 2.94 m, 2H), 2.87 (s, 3H), 2.69 (t, 2H, J=6.5 Hz). Mass
Spectrum (LCMS, ESI) calculate for C.sub.19H.sub.21N.sub.2O.sub.4
341.1 (M+H) found: 341.4.
Example 4
In Vitro Inhibition of Purified Enzymes.
[0210] Fibrinogen-IIb-IIIa Assay
[0211] The assay is based on the method of Dennis (Dennis, M. S.,
et al., Proteins 15: 312-321 (1993)). Costar 9018 flat-bottom
96-well ELISA plates were coated overnight at 4.degree. C. with 100
.mu.L/well of 10 .mu.g/mL human fibrinogen (Calbiochem 341578) in
20 mM Tris-HCl pH 7.5, 150 mM NaCl, 2 mM CaCl.sub.2, 0.02%
NaN.sub.3 (TAC buffer), and blocked for 1 hr at 37.degree. C. with
150 .mu.L/well of TAC buffer containing 0.05% Tween 20 and 1%
bovine serum albumin (TACTB buffer). After washing 3 times with 200
.mu.L/well of 10 mM Na.sub.2HPO.sub.4 pH 7.5, 150 mM NaCl, 0.01%
Tween 20 (PBST buffer), controls or test compound (0.027-20.0
.mu.M) were mixed with 40 .mu.g/mL human GPIIbIIIa (Enzyme Research
Laboratories) in TACTB buffer, and 100 .mu.L/well of these
solutions were incubated for 1 hr at 37.degree. C. The plate was
then washed 5 times with PBST buffer, and 100 .mu.L/well of a
monoclonal anti-GPIIbIIIa antibody in TACTB buffer (1 .mu.g/mL,
Enzyme Research Laboratories MabGP2b3a) was incubated at 37.degree.
C. for 1 hr. After washing (5 times with PBST buffer), 100
.mu.L/well of goat anti-mouse IgG conjugated to horseradish
peroxidase (Kirkegaard & Perry 14-23-06) was incubated at
37.degree. C. for 1 hr (25 ng/mL in PBST buffer), followed by a
6-fold PBST buffer wash. The plate was developed by adding 100
.mu.L/well of 0.67 mg o-phenylenediamine dihydrochloride per mL of
0.012% H.sub.2O.sub.2, 22 mM sodium citrate, 50 mM sodium
phosphate, pH 5.0 at room temperature. The reaction was stopped
with 50 .mu.L/well of 2M H.sub.2SO.sub.4, and the absorbence at 492
nm was recorded. Percent (%) inhibition was calculated from the
average of three separate determinations relative to buffer
controls (no test compound added), and a four parameter fit
(Marquardt, D. W., J. Soc. Indust. Appl. Math. 11: 431-441 (1963))
was used to estimate the half maximal inhibition concentration
(IC.sub.50).
[0212] .alpha..sub.v.beta..sub.3-vitronectin Assay
[0213] The assay was based on the method of Niiya (Niiya, K., et
al., Blood 70: 475-483 (1987)). Costar 9018 flat-bottom 96-well
ELISA plates were coated overnight at room temperature with 100
.mu.L/well of 0.4 .mu.g/mL human .alpha..sub.v.beta..sub.3
(Chemicon CC1019) in TS buffer (20 mM Tris-HCl pH 7.5, 150 mM NaCl,
1 mM CaCl.sub.2, 1 mM MgCl.sub.2, 1 mM MnCl.sub.2). All subsequent
steps were performed at room temperature. Plates were blocked for 2
hr with 150 .mu.L/well of TS buffer containing 1% BSA (TSB buffer),
and washed 3 times with 200 .mu.L/well of PBST buffer. Controls or
test compound (0.0001-20.0 .mu.M) were mixed with 1 .mu.g/mL of
human vitronectin (Chemicon CC080) that had been biotinylated
in-house with sulfo-NHS-LC-LC-biotin (Pierce 21338, 20:1 molar
ratio), and 100 .mu.L/well of these solutions (in TSB buffer) were
incubated for 2 hr. The plate was then washed 5 times with PBST
buffer, and 100 .mu.L/well of 0.25 .mu.g/mL NeutrAvidin-horseradish
peroxidase conjugate (Pierce 31001) in TSB buffer was incubated for
1 hr. Following a 5-fold PBST buffer wash, the plate was developed
and results were calculated as described for the fibrinogen-IIbIIIa
assay. IC.sub.50 values for inhibition of the
.alpha..sub.v.beta..sub.3-vitronectin interaction by other
compounds of the invention are presented in Table I.
1TABLE 1 In Vitro Activity of New .alpha..sub..nu..beta..sub.3
Antagonists Example # IC.sub.50 (nM) 1 30 2 8 3 33
.alpha..sub..nu..beta..sub.5-vitronectin assay
[0214] The assay is similar to the
.alpha..sub.v.beta..sub.3-vitronectin assay. Costar 9018 flat-botom
96-well ELISA plates are coated overnight at room temperature with
100 .mu.L/well of 1 .mu.g/mL human .alpha..sub.v.beta..sub.5
(Chemicon CC1023) in TS buffer. Plates are blocked for 2 hr at
30.degree. C. with 150 .mu.L/well of TSB buffer, and washed 3 times
with 200 .mu.L/well of PBST buffer. Controls or test compound
(0.027-20 .mu.M) are mixed with 1 .mu.g/mL of human vitronectin
(Chemicon CC080) that is been biotinylated in-house with
sulfa-NHS-LC-LC-biotin (Pierce 21338,20:1 molar ratio), and 100
.mu.L/well of these solutions (in TSB buffer) are incubated at
30.degree. C. for 2 hr. The plate is then washed 5 times with PBST
buffer, and 100 .mu.L/well of 0.25 .mu.g/mL. NeurAvidin-horseradish
peroxidase conjugate (Pierce 31001) in TSB buffer is incubated at
30.degree. C. for 1 hr. Following a 6-fold PBST buffer wash, the
plate is developed and results are calculated as described for the
fibrinogen-IIbIIIa assay.
Example 5
Tablet Preparation
[0215] Tablets containing 25.0, 50.0, and 100.0 mg, respectively,
of the compound of Example 1 ("active compound") are prepared as
illustrated below:
2 TABLET FOR DOSES CONTAINING FROM 25-100 MG OF THE ACTIVE COMPOUND
Amount-mg Active compound 25.0 50.0 100.00 Microcrystalline
cellulose 37.25 100.0 200.0 Modified food corn starch 37.25 4.25
8.5 Magnesium stearate 0.50 0.75 1.5
[0216] All of the active compound, cellulose, and a portion of the
corn starch are mixed and granulated to 10% corn starch paste. The
resulting granulation is sieved, dried and blended with the
remainder of the corn starch and the magnesium stearate. The
resulting granulation is then compressed into tablets containing
25.0, 50.0, and 100.0 mg, respectively, of active ingredient per
tablet.
Example 6
Intravenous Solution Preparation
[0217] An intravenous dosage form of the compound of Example 1
("active compound") is prepared as follows:
3 INTRAVENOUS SOLUTION CONTAINING FROM 0.5-10.0 MG OF THE ACTIVE
COMPOUND Active compound 0.5-10.0 mg Sodium citrate 5-50 mg Citric
acid 1-15 mg Sodium chloride 1-8 mg Water for injection (USP) q.s.
to 1 ml
[0218] Utilizing the above quantities, the active compound is
dissolved at room temperature in a previously prepared solution of
sodium chloride, citric acid, and sodium citrate in Water for
Injection (USP, see page 1636 of United States
Pharmacopeia/National Formulary for 1995, published by United
States Pharmacopeial Convention, Inc., Rockville, Md. (1994).
[0219] Having now fully described this invention, it will be
understood to those of ordinary skill in the art that the same can
be performed within a wide and equivalent range of conditions,
formulations, and other parameters without affecting the scope of
the invention or any embodiment thereof. All patents and
publications cited herein are fully incorporated by reference
herein in their entirety.
* * * * *