U.S. patent application number 12/576483 was filed with the patent office on 2010-05-13 for anti-angiogenic agents and methods of use.
This patent application is currently assigned to Southern Research Institute. Invention is credited to Subramaniam Ananthan, Zhican Qu, Anshu M. Roy.
Application Number | 20100120745 12/576483 |
Document ID | / |
Family ID | 40351375 |
Filed Date | 2010-05-13 |
United States Patent
Application |
20100120745 |
Kind Code |
A1 |
Qu; Zhican ; et al. |
May 13, 2010 |
ANTI-ANGIOGENIC AGENTS AND METHODS OF USE
Abstract
The present disclosure relates generally to treating or
preventing diseases associated with angiogenesis by administering
to a patient certain compounds found to inhibit or substantially
reduce angiogenesis. Compounds employed according to the present
disclosure exhibit good anti-angiogenic activity as well as
demonstrate a prophylactic effect for preventing and substantially
reducing angiogenesis. Examples of such compounds include
Ritanserin, Amiodarone, Terfenadine, Perphenazine, Bithionol, and
Clomipramine.
Inventors: |
Qu; Zhican; (Birmingham,
AL) ; Roy; Anshu M.; (Birmingham, AL) ;
Ananthan; Subramaniam; (Birmingham, AL) |
Correspondence
Address: |
CONNOLLY BOVE LODGE & HUTZ LLP
1875 EYE STREET, N.W., SUITE 1100
WASHINGTON
DC
20006
US
|
Assignee: |
Southern Research Institute
Birmingham
AL
|
Family ID: |
40351375 |
Appl. No.: |
12/576483 |
Filed: |
October 9, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12595278 |
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PCT/US2008/060186 |
Apr 14, 2008 |
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12576483 |
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60911645 |
Apr 13, 2007 |
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Current U.S.
Class: |
514/217 ;
514/225.8; 514/259.2; 514/317; 514/469; 514/712 |
Current CPC
Class: |
A61K 31/095 20130101;
A61P 35/00 20180101; A61P 17/06 20180101; A61P 27/06 20180101; A61P
3/00 20180101; A61P 15/00 20180101; A61K 31/343 20130101; A61P 3/06
20180101; A61P 19/04 20180101; A61P 1/04 20180101; A61P 15/08
20180101; A61P 35/04 20180101; A61P 1/00 20180101; A61P 29/00
20180101; A61P 43/00 20180101; A61P 3/10 20180101; A61P 9/10
20180101; A61P 27/02 20180101; A61K 31/445 20130101; A61P 9/00
20180101; A61P 3/04 20180101; A61P 17/00 20180101; A61P 19/02
20180101; A61K 31/55 20130101; A61K 31/519 20130101; A61P 9/14
20180101; A61K 31/5415 20130101 |
Class at
Publication: |
514/217 ;
514/259.2; 514/469; 514/317; 514/225.8; 514/712 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61K 31/519 20060101 A61K031/519; A61K 31/343 20060101
A61K031/343; A61K 31/445 20060101 A61K031/445; A61K 31/5415
20060101 A61K031/5415; A61K 31/10 20060101 A61K031/10; A61P 9/10
20060101 A61P009/10 |
Claims
1. A method of inhibiting or reducing angiogenesis in a patient in
need thereof comprising administering to said patient an
anti-angiogenically effective amount of a compound of Formula (I)
##STR00020## wherein: R is hydrogen, hydroxy or lower alkyloxy;
R.sub.1 is a member selected from the group consisting of hydrogen
and lower alkyl; Alk is a lower alkanediyl radical; X is a member
selected from the group consisting of --S--, --CH.sub.2-- and
--C(R.sub.2).dbd.C(R.sub.3)--, said R.sub.2 and R.sub.3 being each
independently hydrogen or lower alkyl; A is a bivalent radical
having the formula --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or ##STR00021## wherein R.sub.4 and
R.sub.5 are each independently selected from the group consisting
of hydrogen, halo, amino and lower alkyl; and Ar.sub.1 and Ar.sub.2
are each independently selected from the group consisting of
pyridinyl, thienyl and phenyl, being optionally substituted with
halo, hydroxy, lower alkyloxy, lower alkyl and trifluoromethyl;
##STR00022## wherein: R.sub.1 is an alkyl group containing 1 to 6
carbon atoms; R.sub.2 is selected from the group consisting of
hydrogen and methyl; NR.sub.3 is a radical selected from the group
consisting of a dimethylamino, diethylamino, dipropylamino,
piperidino, piperazino, pyrrolidino, morpholino, and N-substituted
hetero aryl; and Y and Y.sub.1 are independently selected from the
group consisting of hydrogen, fluorine, bromine, chlorine, and
iodine; ##STR00023## wherein R is selected from the group
consisting of hydrogen or hydroxy; R.sub.1 is hydrogen; or R and
R.sub.1 taken together form a second bond between the carbon atoms
bearing R and R.sub.1; n is an integer from 1 to 3; and Z is
selected from the group consisting of thienyl, phenyl, or
substituted phenyl wherein the substituents on the substituted
phenyl may be attached at the ortho, meta, or para positions of the
substituted phenyl ring and are selected from the group consisting
of a halogen atom, a straight or branched lower alkyl chain of from
1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon
atoms, a di(lower)alkylamino group, or a saturated monocyclic
heterocyclic ring selected from the group consisting of
pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino;
##STR00024## wherein X at each occurrence independently represents
hydrogen, chlorine or bromine; A represents OH, OR,
NR.sub.1R.sub.2, OC(O)R, OC(O)OR, C(O)OH, C(O)OR,
C(O)NR.sub.1R.sub.2, OC(O)N R.sub.1R.sub.2, NHC(O)N R.sub.1R.sub.2
or NHC(NH)N R.sub.1R.sub.2; R represents alkyl, cycloalkyl,
heterocycle, aryl, arylalkyl, or heterocyclalkyl; R.sub.1 and
R.sub.2 each independently represent hydrogen, alkyl, cycloalkyl,
heterocycle, aryl, arylalkyl, heterocyclalkyl, or R.sub.1 and
R.sub.2 can together form a 3 to 8 membered heterocyclic ring which
may be further optionally substituted with one to four
(CH.sub.2).sub.nA substituents; n is a number between 0 and 5
inclusive; or ##STR00025## wherein X represents a member selected
from the group consisting of the ethylene radical --CH2-CH2- and
the vinylene radical --CH.dbd.CH--; R represents a member selected
from the group consisting of the methyl radical, the ethyl radical,
the propyl radical, chlorine and bromine, Y represents an alkylene
radical with 2-3 carbon atoms, and Am represents a member selected
from the group consisting of a lower dialkylamino group, the
pyrrolidinio, piperidino, piperazino, morpholino and
N-methyl-piperidyl(2)-group; and pharmaceutically acceptable salts,
solvates, and prodrugs thereof.
2. The method of claim 1 comprising administering to said patient
an anti-angiogenically effective amount of a compound of Formula
(I): ##STR00026## wherein: R is hydrogen, hydroxy or lower
alkyloxy; R.sub.1 is a member selected from the group consisting of
hydrogen and lower alkyl; Alk is a lower alkanediyl radical; X is a
member selected from the group consisting of --S--, --CH.sub.2--
and --C(R.sub.2).dbd.C(R.sub.3)--, said R.sub.2 and R.sub.3 being
each independently hydrogen or lower alkyl; A is a bivalent radical
having the formula --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or ##STR00027## wherein R.sub.4 and
R.sub.5 are each independently selected from the group consisting
of hydrogen, halo, amino and lower alkyl; and Ar.sub.1 and Ar.sub.2
are each independently selected from the group consisting of
pyridinyl, thienyl and phenyl, being optionally substituted with
halo, hydroxy, lower alkyloxy, lower alkyl and trifluoromethyl; and
pharmaceutically acceptable salts, solvates, and prodrugs
thereof.
3. The method of claim 2 wherein Alk is an 1,2-ethanediyl
radical.
4. The method of claim 2 wherein the compound of Formula (I) is
Ritanserin.
5. The method of claim 1 comprising administering to said patient
an anti-angiogenically effective amount of a compound of Formula
(II): ##STR00028## wherein: R.sub.1 is an alkyl group containing 1
to 6 carbon atoms; R.sub.2 is selected from the group consisting of
hydrogen and methyl; NR.sub.3 is a radical selected from the group
consisting of a dimethylamino, diethylamino, dipropylamino,
piperidino, piperazino, pyrrolidino, morpholino, and N-substituted
heteroaryl; and Y and Y.sub.1 are interpedently selected from the
group consisting of hydrogen, fluorine, bromine, chlorine, and
iodine; and pharmaceutically acceptable salts, solvates, and
prodrugs thereof.
6. The method of claim 5 wherein the compound of Formula (II) is
Amiodarone.
7. The method of claim 1 comprising administering to said patient
an anti-angiogenically effective amount of a compound of Formula
(III): ##STR00029## wherein R is selected from the group consisting
of hydrogen or hydroxy; R.sub.1 is hydrogen; or R and R.sub.1 taken
together form a second bond between the carbon atoms bearing R and
R.sub.1; n is an integer from 1 to 3; and Z is selected from the
group consisting of thienyl, phenyl, or substituted phenyl wherein
the substituents on the substituted phenyl may be attached at the
ortho, meta, or para positions of the substituted phenyl ring and
are selected from the group consisting of a halogen atom, a
straight or branched lower alkyl chain of from 1 to 4 carbon atoms,
a lower alkoxy group of from 1 to 4 carbon atoms, a
di(lower)alkylamino group, or a saturated monocyclic heterocyclic
ring selected from the group consisting of pyrrolidino, piperidino,
morpholino, or N-(lower)alkylpiperazino; and pharmaceutically
acceptable salts, solvates, and prodrugs thereof.
8. The method of claim 7 wherein the compound of Formula (III) is
Terfenadine.
9. The method of claim 1 comprising administering to said patient
an anti-angiogenically effective amount of a compound of Formula
(IV): ##STR00030## wherein X at each occurrence independently
represents hydrogen, chlorine or bromine; A represents OH, OR,
NR.sub.1R.sub.2, OC(O)R, OC(O)OR, C(O)OH, C(O)OR,
C(O)NR.sub.1R.sub.2, OC(O)N R.sub.1R.sub.2, NHC(O)N R.sub.1R.sub.2
or NHC(NH)N R.sub.1R.sub.2; R represents alkyl, cycloalkyl,
heterocycle, aryl, arylalkyl, or heterocyclalkyl; R.sub.1 and
R.sub.2 each independently represent hydrogen, alkyl, cycloalkyl,
heterocycle, aryl, arylalkyl, heterocyclalkyl, or R.sub.1 and
R.sub.2 can together form a 3 to 8 membered heterocyclic ring which
may be further optionally substituted with one to four
(CH.sub.2).sub.nA substituents; n is a number between 0 and 5
inclusive; and pharmaceutically acceptable salts, solvates, and
prodrugs thereof.
10. The method of claim 9 wherein the compound of Formula (IV) is
Perphenazine.
11. (canceled)
12. (canceled)
13. The method of claim 1 comprising administering to said patient
an anti-angiogenically effective amount of a compound of Formula
(VI): ##STR00031## wherein X represents a member selected from the
group consisting of the ethylene radical --CH2-CH2- and the
vinylene radical --CH.dbd.CH--; R represents a member selected from
the group consisting of the methyl radical, the ethyl radical, the
propyl radical, chlorine and bromine, Y represents an alkylene
radical with 2-3 carbon atoms, and Am represents a member selected
from the group consisting of a lower dialkylamino group, the
pyrrolidinio, piperidino, piperazino, morpholino and
N-methyl-piperidyl(2)-group; and salts, solvates, and prodrugs
thereof.
14. The method of claim 13 wherein the compound of Formula (VI) is
Clomipramine.
15. A method of inhibiting the growth or metastasis of an
angiogenesis-dependent tumor in a patient in need thereof
comprising administering to said patient an effective amount of a
compound of Formula (I) ##STR00032## wherein: R is hydrogen,
hydroxy or lower alkyloxy; R.sub.1 is a member selected from the
group consisting of hydrogen and lower alkyl; Alk is a lower
alkanediyl radical; X is a member selected from the group
consisting of --S--, --CH.sub.2-- and
--C(R.sub.2).dbd.C(R.sub.3)--, said R.sub.2 and R.sub.3 being each
independently hydrogen or lower alkyl; A is a bivalent radical
having the formula --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or ##STR00033## wherein R.sub.4 and
R.sub.5 are each independently selected from the group consisting
of hydrogen, halo, amino and lower alkyl; and Ar.sub.1 and Ar.sub.2
are each independently selected from the group consisting of
pyridinyl, thienyl and phenyl, being optionally substituted with
halo, hydroxy, lower alkyloxy, lower alkyl and trifluoromethyl;
##STR00034## wherein: R.sub.1 is an alkyl group containing 1 to 6
carbon atoms; R.sub.2 is selected from the group consisting of
hydrogen and methyl; NR.sub.3 is a radical selected from the group
consisting of a dimethylamino, diethylamino, dipropylamino,
piperidino, piperazino, pyrrolidino, morpholino, and N-substituted
heteroaryl; and Y and Y.sub.1 are independently selected from the
group consisting of hydrogen, fluorine, bromine, chlorine, and
iodine; ##STR00035## wherein R is selected from the group
consisting of hydrogen or hydroxy; R.sub.1 is hydrogen; or R and
R.sub.1 taken together form a second bond between the carbon atoms
bearing R and R.sub.1; n is an integer from 1 to 3; and Z is
selected from the group consisting of thienyl, phenyl, or
substituted phenyl wherein the substituents on the substituted
phenyl may be attached at the ortho, meta, or para positions of the
substituted phenyl ring and are selected from the group consisting
of a halogen atom, a straight or branched lower alkyl chain of from
1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon
atoms, a di(lower)alkylamino group, or a saturated monocyclic
heterocyclic ring selected from the group consisting of
pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino;
##STR00036## wherein X at each occurrence independently represents
hydrogen, chlorine or bromine; A represents OH, OR,
NR.sub.1R.sub.2, OC(O)R, OC(O)OR, C(O)OH, C(O)OR,
C(O)NR.sub.1R.sub.2, OC(O)N R.sub.1R.sub.2, NHC(O)N R.sub.1R.sub.2
or NHC(NH)N R.sub.1R.sub.2; R represents alkyl, cycloalkyl,
heterocycle, aryl, arylalkyl, or heterocyclalkyl; R.sub.1 and
R.sub.2 each independently represent hydrogen, alkyl, cycloalkyl,
heterocycle, aryl, arylalkyl, heterocyclalkyl, or R.sub.1 and
R.sub.2 can together form a 3 to 8 membered heterocyclic ring which
may be further optionally substituted with one to four
(CH.sub.2).sub.nA substituents; n is a number between 0 and 5
inclusive; ##STR00037## wherein X represents a member selected from
the group consisting of the ethylene radical --CH2-CH2- and the
vinylene radical --CH.dbd.CH--; R represents a member selected from
the group consisting of the methyl radical, the ethyl radical, the
propyl radical, chlorine and bromine, Y represents an alkylene
radical with 2-3 carbon atoms, and Am represents a member selected
from the group consisting of a lower dialkylamino group, the
pyrrolidinio, piperidino, piperazino, morpholino and
N-methyl-piperidyl(2)-group; and pharmaceutically acceptable salts,
solvates, and prodrugs thereof.
16. The method of claim 15 comprising administering to said patient
an effective amount of a compound of Formula (I) ##STR00038##
wherein: R is hydrogen, hydroxy or lower alkyloxy; R.sub.1 is a
member selected from the group consisting of hydrogen and lower
alkyl; Alk is a lower alkanediyl radical; X is a member selected
from the group consisting of --S--, --CH.sub.2-- and
--C(R.sub.2).dbd.C(R.sub.3)--, said R.sub.2 and R.sub.3 being each
independently hydrogen or lower alkyl; A is a bivalent radical
having the formula --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or ##STR00039## wherein R.sub.4 and
R.sub.5 are each independently selected from the group consisting
of hydrogen, halo, amino and lower alkyl; and Ar.sub.1 and Ar.sub.2
are each independently selected from the group consisting of
pyridinyl, thienyl and phenyl, being optionally substituted with
halo, hydroxy, lower alkyloxy, lower alkyl and trifluoromethyl; and
pharmaceutically acceptable salts, solvates, and prodrugs
thereof.
17. The method of claim 16 wherein Alk is an 1,2-ethanediyl
radical.
18. The method of claim 16 wherein the compound of Formula (I) is
Ritanserin.
19. The method of claim 15 comprising administering to said patient
an effective amount of a compound of Formula (II): ##STR00040##
wherein: R.sub.1 is an alkyl group containing 1 to 6 carbon atoms;
R.sub.2 is selected from the group consisting of hydrogen and
methyl; NR.sub.3 is a radical selected from the group consisting of
a dimethylamino, diethylamino, dipropylamino, piperidino,
piperazino, pyrrolidino, morpholino, and N-substituted heteroaryl;
and Y and Y.sub.1 are independently selected from the group
consisting of hydrogen, fluorine, bromine, chlorine, and iodine;
and pharmaceutically acceptable salts, solvates, and prodrugs
thereof.
20. The method of claim 19 wherein the compound of Formula (II) is
Amiodarone.
21. The method of claim 15 comprising administering to said patient
an effective amount of a compound of Formula (III): ##STR00041##
wherein R is selected from the group consisting of hydrogen or
hydroxy; R.sub.1 is hydrogen; or R and R.sub.1 taken together form
a second bond between the carbon atoms bearing R and R.sub.1; n is
an integer from 1 to 3; and Z is selected from the group consisting
of thienyl, phenyl, or substituted phenyl wherein the substituents
on the substituted phenyl may be attached at the ortho, meta, or
para positions of the substituted phenyl ring and are selected from
the group consisting of a halogen atom, a straight or branched
lower alkyl chain of from 1 to 4 carbon atoms, a lower alkoxy group
of from 1 to 4 carbon atoms, a di(lower)alkylamino group, or a
saturated monocyclic heterocyclic ring selected from the group
consisting of pyrrolidino, piperidino, morpholino, or
N-(lower)alkylpiperazino; and pharmaceutically acceptable salts,
solvates, and prodrugs thereof.
22. The method of claim 21 wherein the compound of Formula (III) is
Terfenadine.
23. The method of claim 15 comprising administering to said patient
an effective amount of a compound of Formula (IV): ##STR00042##
wherein X at each occurrence independently represents hydrogen,
chlorine or bromine; A represents OH, OR, NR.sub.1R.sub.2, OC(O)R,
OC(O)OR, C(O)OH, C(O)OR, C(O)NR.sub.1R.sub.2, OC(O)N
R.sub.1R.sub.2, NHC(O)N R.sub.1R.sub.2 or NHC(NH)N R.sub.1R.sub.2;
R represents alkyl, cycloalkyl, heterocycle, aryl, arylalkyl, or
heterocyclalkyl; R.sub.1 and R.sub.2 each independently represent
hydrogen, alkyl, cycloalkyl, heterocycle, aryl, arylalkyl,
heterocyclalkyl, or R.sub.1 and R.sub.2 can together form a 3 to 8
membered heterocyclic ring which may be further optionally
substituted with one to four (CH.sub.2).sub.nA substituents; n is a
number between 0 and 5 inclusive; and pharmaceutically acceptable
salts, solvates, and prodrugs thereof.
24. The method of claim 23 wherein the compound of Formula (IV) is
Perphenazine.
25. (canceled)
26. (canceled)
27. The method of claim 15 comprising administering to said patient
an effective amount of a compound of Formula (VI): ##STR00043##
wherein X represents a member selected from the group consisting of
the ethylene radical --CH.sub.2CH.sub.2-- and the vinylene radical
--CH.dbd.CH--; R represents a member selected from the group
consisting of the methyl radical, the ethyl radical, the propyl
radical, chlorine and bromine, Y represents an alkylene radical
with 2-3 carbon atoms, and Am represents a member selected from the
group consisting of a lower dialkylamino group, the pyrrolidinio,
piperidino, piperazino, morpholino and N-methyl-piperidyl(2)-group;
and salts, solvates, and prodrugs thereof.
28. The method of claim 27 wherein the compound of Formula (VI) is
Clomipramine.
29-44. (canceled)
45. The method of claim 1 where the patient is in need of treatment
for a disease or disorder selected from the group consisting of
neoplastic diseases, restenosis, rheumatoid arthritis, Crohn's
disease, diabetic retinopathy, psoriasis, endometriosis, macular
degeneration, neovascular glaucoma, and adiposity.
Description
TECHNICAL FIELD
[0001] The present disclosure relates generally to treating or
preventing diseases associated with angiogenesis by administering
to the patient certain compounds found to inhibit or substantially
reduce angiogenesis. Compounds employed according to the present
disclosure exhibit good anti-angiogenic activity as well as
demonstrate a prophylactic effect in preventing and substantially
reducing angiogenesis. Examples of such compounds include
Ritanserin, Amiodarone, Terfenadine, Perphenazine, Bithionol, and
Clomipramine.
BACKGROUND
[0002] Angiogenesis is the formation of new blood vessels out of
pre-existing capillaries and is a sequence of events that is of key
importance in many physiologic and pathologic processes. Normal
tissue growth, such as in embryonic development, wound healing, and
the menstrual cycle, is characterized by dependence on new vessel
formation for the supply of oxygen and nutrients as well as removal
of waste products. A large number of different and unrelated
diseases are also associated with formation of new vasculature.
Among certain pathologies are conditions in which angiogenesis is
low, and should be enhanced to improve disease conditions.
Pathologies which involve inadequate blood vessel formation include
peripheral and coronary ischemia and infarction, chronic wound
healing failure, and ulcers. More frequently, however, excessive
angiogenesis is an important characteristic of various pathologies
including pathologies characterized or associated with an abnormal
or uncontrolled proliferation of cells. Pathologies which involve
excessive angiogenesis include, for example, cancer (both solid and
hematologic tumors), cardiovascular diseases (such as
atherosclerosis and restenosis), chronic inflammation (rheumatoid
arthritis, Crohn's disease), diabetes (diabetic retinopathy),
psoriasis, endometriosis, neovascular glaucoma and adiposity. See
Griffioen & Molema, Angiogenesis: Potentials for Pharmacologic
Intervention in the Treatment of Cancer, Cardiovascular Diseases,
and Chronic Inflammation, PHARMACOL. REV. 52, 237-268 (2000).
[0003] Generally speaking, the angiogenic process entails the
proliferation and migration of a normally quiescent endothelium,
the controlled proteolysis of the pericellular matrix, and the
synthesis of new extracellular matrix components by developing
capillaries. The establishment of new intra- and intercellular
contacts and the morphological differentiation of endothelial cells
to capillary-like tubular networks provide support for their
subsequent maturation, branching, remodeling and selective
regression to form a highly organized, functional microvascular
network. The autocrine, paracrine and amphicrine interactions of
the vascular endothelium with its surrounding stromal components,
as well as with the pro-angiogenic and angiostatic cytokines and
growth factors orchestrating physiologic angiogenesis, are normally
tightly regulated both spatially and temporally. See Gasparini, The
Rationale and Future Potential of Angiogenesis Inhibitors in
Neoplasia, DRUGS, 58(1):17-38 (1999)
[0004] The best known anti-angiogenic agents targeting endothelial
cell proliferation are Vascular Endothelial Growth Factor ("VEGF")
inhibitors. VEGF, a potent angiogenic growth factor, is over
expressed in most human solid tumors and in the retina associated
eye disorders. The VEGF receptors are mainly enriched in
endothelial cells transducing VEGF signaling in many pathological
angiogenesis conditions. Growth-stimulated endothelial cells are
also sensitive to tyrosine kinase inhibitors targeting VEGF
receptors, such as the recent FDA approved anti-cancer drugs
Sunitinib (SU11248) and Srafenib (BAY 43-9006). Anti-VEGF and VEGF
receptor agents are able to arrest endothelial cell proliferation
and prevent new blood vessel growth. In addition to VEGF, many
other growth factors such as fibroblast growth factors (FGFs) and
platelet derived growth factors (PDGF) also play important roles in
endothelial activation. Recently, resistance to anti-angiogenic
agents targeting only VEGF signaling is emerging presumably due to
other growth factor mediated alternative signaling pathways.
[0005] Angiogenesis is crucial to the growth of neoplastic tissues.
For more than 100 years, tumors have been observed to be more
vascular than normal tissues. Several experimental studies have
suggested that both primary tumor growth and metastasis require
neovascularization. In contrast to the well orchestrated process
described above for normal tissue growth, the pathologic
angiogenesis necessary for active tumor growth is generally
sustained and persistent, with the initial acquisition of the
angiogenic phenotype being a common mechanism for the development
of a variety of solid and hematopoietic tumor types. See Folkman,
J., CANCER MEDICINE, 132-152 (5th Ed., B.C. Decker Inc.) (2000).
Tumors that are unable to recruit and sustain a vascular network
typically remain dormant as asymptomatic lesions in situ.
Metastasis is also angiogenesis-dependent--for a tumor cell to
metastasize successfully, it generally must gain access to the
vasculature in the primary tumor, survive the circulation, arrest
in the microvasculature of the target organ, exit from this
vasculature, grow in the target organ, and induce angiogenesis at
the target site. Thus, angiogenesis appears to be necessary at the
beginning as well as the completion of the metastatic cascade.
[0006] The criticality of angiogenesis to the growth and metastasis
of neoplasms thus provides an optimal potential target for
chemotherapeutic efforts. Appropriate anti-angiogenic agents may
act directly or indirectly to influence tumor-associated
angiogenesis either by delaying its onset (i.e., blocking an
"angiogenic switch") or by blocking the sustained and focal
neovascularization that is characteristic of many tumor types.
Anti-angiogenesis therapies directed against the tumor-associated
endothelium and the multiple molecular and cellular processes and
targets implicated in sustained pathologic angiogenesis are being
actively evaluated for their safety and efficacy in multiple
clinical trials. See Deplanque & Harris, Anti-angiogenic
Agents: Clinical Trial Design and Therapies in Development, EUR. J.
CANCER, 36: 1713-1724 (2000). However, there has been limited
success to date with the discovery and/or identification of safe
and/or effective anti-angiogenic agents.
SUMMARY
[0007] The present disclosure relates generally to treating or
preventing diseases associated with angiogenesis.
[0008] In one embodiment, there are provided methods for inhibiting
angiogenesis with a compound of Formula (I)
##STR00001##
[0009] wherein:
[0010] R is hydrogen, hydroxy or lower alkyloxy;
[0011] R.sub.1 is a member selected from the group consisting of
hydrogen and lower alkyl;
[0012] Alk is a lower alkanediyl radical;
[0013] X is a member selected from the group consisting of --S--,
--CH.sub.2-- and --C(R.sub.2).dbd.C(R.sub.3)--, said R.sub.2 and
R.sub.3 being each independently hydrogen or lower alkyl;
[0014] A is a bivalent radical having the formula
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2-- or
##STR00002##
[0015] wherein R.sub.4 and R.sub.5 are each independently selected
from the group consisting of hydrogen, halo, amino and lower alkyl;
and
[0016] Ar.sub.1 and Ar.sub.2 are each independently selected from
the group consisting of pyridinyl, thienyl and phenyl, being
optionally substituted with halo, hydroxy, lower alkyloxy, lower
alkyl and trifluoromethyl; and pharmaceutically acceptable salts,
solvates, and prodrugs thereof. Alternatively, Alk is an
1,2-ethanediyl radical.
[0017] In one embodiment, the compound of Formula (I) is
Ritanserin.
[0018] In another embodiment, there are provided methods for
inhibiting angiogenesis with a compound of Formula (II):
##STR00003##
[0019] wherein:
[0020] R.sub.1 is an alkyl group containing 1 to 6 carbon
atoms;
[0021] R.sub.2 is selected from the group consisting of hydrogen
and methyl;
[0022] NR.sub.3 is a radical selected from the group consisting of
a dimethylamino, diethylamino, dipropylamino, piperidino,
piperazino, pyrrolidino, morpholino, and N-substituted heteroaryl;
and
[0023] Y and Y.sub.1 are independently selected from the group
consisting of hydrogen, fluorine, bromine, chlorine, and iodine;
and pharmaceutically acceptable salts, solvates, and prodrugs
thereof. Alternatively, Y and Y.sub.1 are identical and are
selected from hydrogen, fluorine, bromine, chlorine, and
iodine.
[0024] In one embodiment, the compound of Formula (II) is
Amiodarone.
[0025] In another embodiment, there are provided methods for
inhibiting angiogenesis with a compound of Formula (III):
##STR00004##
[0026] wherein
[0027] R is selected from the group consisting of hydrogen or
hydroxy;
[0028] R.sub.1 is hydrogen; or
[0029] R and R.sub.1 taken together form a second bond between the
carbon atoms bearing R and R.sub.1;
[0030] n is a positive whole integer of from 1 to 3; and
[0031] Z is selected from the group consisting of thienyl, phenyl,
or substituted phenyl wherein the substituents on the substituted
phenyl may be attached at the ortho, meta, or para positions of the
substituted phenyl ring and are selected from the group consisting
of a halogen atom, a straight or branched lower alkyl chain of from
1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon
atoms, a di(lower)alkylamino group, or a saturated monocyclic
heterocyclic ring selected from the group consisting of
pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino;
and pharmaceutically acceptable salts, solvates, and prodrugs
thereof.
[0032] In one embodiment, the compound of Formula (III) is
Terfenadine.
[0033] In another embodiment, there are provided methods for
inhibiting angiogenesis with a compound of Formula (IV):
##STR00005##
[0034] wherein
[0035] X at each occurrence independently represents hydrogen,
chlorine or bromine;
[0036] A represents OH, OR, NR.sub.1R.sub.2, OC(O)R, OC(O)OR,
C(O)OH, C(O)OR, C(O)NR.sub.1R.sub.2, OC(O)N R.sub.1R.sub.2, NHC(O)N
R.sub.1R.sub.2 or NHC(NH)N R.sub.1R.sub.2;
[0037] R represents alkyl, cycloalkyl, heterocycle, aryl,
arylalkyl, or heterocyclalkyl;
[0038] R.sub.1 and R.sub.2 each independently represent hydrogen,
alkyl, cycloalkyl, heterocycle, aryl, arylalkyl, heterocyclalkyl,
or R.sub.1 and R.sub.2 can together form a 3 to 8 membered
heterocyclic ring which may be further optionally substituted with
one to four (CH.sub.2).sub.nA substituents;
[0039] n is a number between 0 and 5 inclusive; and
pharmaceutically acceptable salts, solvates, and prodrugs
thereof.
[0040] In another embodiment, there are provided methods for
inhibiting angiogenesis with a compound of Formula (IV-a):
##STR00006##
[0041] wherein
[0042] X represents hydrogen, chlorine or bromine;
[0043] A represents OH, OR, NR.sub.1R.sub.2, OC(O)R, OC(O)OR,
C(O)OH, C(O)OR, C(O)NR.sub.1R.sub.2, OC(O)N R.sub.1R.sub.2, NHC(O)N
R.sub.1R.sub.2 or NHC(NH)N R.sub.1R.sub.2;
[0044] R represents alkyl, cycloalkyl, heterocycle, aryl,
arylalkyl, or heterocyclalkyl;
[0045] R.sub.1 and R.sub.2 each independently represent hydrogen,
alkyl, cycloalkyl, heterocycle, aryl, arylalkyl, heterocyclalkyl,
or R.sub.1 and R.sub.2 can together form a 3 to 8 membered
heterocyclic ring;
[0046] n is a number between 0 and 5 inclusive; and
pharmaceutically acceptable salts, solvates, and prodrugs
thereof.
[0047] In one embodiment, the compound of Formula (IV) or Formula
(IV-a) is Perphenazine.
[0048] In another embodiment, there are provided methods for
inhibiting angiogenesis with a compound of Formula (V):
##STR00007##
[0049] wherein,
[0050] Y represents O, S, or S.dbd.O;
[0051] X at each occurrence independently represents halogen or OH;
and
[0052] n at each occurrence is independently an integer between 0
and 5 inclusive; and pharmaceutically acceptable salts, solvates,
and prodrugs thereof.
[0053] Also provided are methods for inhibiting angiogenesis with a
compound of Formula (V-a)
##STR00008##
[0054] wherein
[0055] Y represents O, S, or S.dbd.O;
[0056] X at each occurrence independently represents halogen or OH;
and
[0057] n at each occurrence is independently an integer between 0
and 5 inclusive; and pharmaceutically acceptable salts, solvates,
and prodrugs thereof.
[0058] In one embodiment, the compound of Formula (V) or Formula
(V-a) is Bithionol.
[0059] In another embodiment, there are provided methods for
inhibiting angiogenesis with a compound of Formula (VI):
##STR00009##
[0060] wherein
[0061] X represents a member selected from the group consisting of
the ethylene radical --CH.sub.2CH.sub.2-- and the vinylene radical
--CH.dbd.CH--;
[0062] R represents a member selected from the group consisting of
the methyl radical, the ethyl radical, the propyl radical, chlorine
and bromine,
[0063] Y represents an alkylene radical with 2-3 carbon atoms,
and
[0064] Am represents a member selected from the group consisting of
a lower dialkylamino group, the pyrrolidinio, piperidino,
piperazino, morpholino and N-methyl-piperidyl(2)-group; and
pharmaceutically acceptable salts, solvates, and prodrugs
thereof.
[0065] In one embodiment, the compound of Formula (VI) is
Clomipramine.
[0066] Also provided are methods of inhibiting the growth or
metastasis of an angiogenesis-dependent tumor with compounds of the
present disclosure. Another embodiment is drawn to methods for
treating a disease or disorder associated with angiogenesis such as
neoplastic diseases, restenosis, rheumatoid arthritis, Crohn's
disease, diabetic retinopathy, psoriasis, endometriosis, macular
degeneration, neovascular glaucoma, and adiposity with compounds of
the present disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0067] FIG. 1 shows the dose response curve plotted against
concentration for cell proliferation assays using Ritanserin.
[0068] FIG. 2 shows the results of an endothelial cell migration
assay using Ritanserin and plots the percent of migrated cells
relative to a control.
[0069] FIG. 3. shows the results of an endothelial tube-formation
assay using Ritanserin and plots the percentage of tubule formation
relative to a control.
[0070] FIG. 4 shows the results of an ex vivo angiogenesis CAM
assay using Ritanserin and plots the vascular density index.
[0071] FIG. 5. plots the results in microvessel density of an in
vivo mouse matrigel plug assay using Ritanserin.
[0072] FIG. 6 shows the results of a xenograft mouse model assay
using Ritanserin and plots the change in tumor volume over
time.
[0073] FIG. 7 shows the dose response curve plotted against
concentration for cell proliferation assays using Amiodarone
Hydrochloride.
[0074] FIG. 8 shows the results of an endothelial cell migration
assay using Amiodarone Hydrochloride and plots the percent of
migrated cells relative to a control.
[0075] FIG. 9 shows the results of an endothelial tube-formation
assay using Amiodarone Hydrochloride and plots the percentage of
tubule formation relative to a control.
[0076] FIG. 10 shows the results of an ex vivo angiogenesis CAM
assay using Amiodarone and plots the vascular density index.
[0077] FIG. 11 shows the dose response curve plotted against
concentration for cell proliferation assays using Terfenadine.
[0078] FIG. 12 shows the results of an endothelial cell migration
assay using Terfenadine and plots the percent of migrated cells
relative to a control.
[0079] FIG. 13 shows the results of an endothelial tube-formation
assay using Terfenadine and plots the percentage of tubule
formation relative to a control.
[0080] FIG. 14. shows the results of an ex vivo angiogenesis CAM
assay using Terfenadine and plots the vascular density index.
[0081] FIG. 15 shows the dose response curve plotted against
concentration for cell proliferation assays using Perphenazine.
[0082] FIG. 16 shows the results of an endothelial cell migration
assay using Perphenazine and plots the percent of migrated cells
relative to a control.
[0083] FIG. 17 shows the results of an endothelial tube-formation
assay using Perphenazine and plots the percentage of tubule
formation relative to a control.
[0084] FIG. 18 shows the dose response curve plotted against
concentration for cell proliferation assays using Bithionol.
[0085] FIG. 19 shows the results of an endothelial cell migration
assay using Bithionol and plots the percent of migrated cells
relative to a control.
[0086] FIG. 20 shows the results of an endothelial tube-formation
assay using Bithionol and plots the percentage of tubule formation
relative to a control.
[0087] FIG. 21. shows the results of an ex vivo angiogenesis CAM
assay using Bithionol and plots the vascular density index.
[0088] FIG. 22 shows the dose response curve plotted against
concentration for cell proliferation assays using Clomipramine.
[0089] FIG. 23 shows the results of an endothelial cell migration
assay using Clomipramine and plots the percent of migrated cells
relative to a control.
[0090] FIG. 24 shows the results of an endothelial tube-formation
assay using Clomipramine and plots the percentage of tubule
formation relative to a control.
[0091] FIG. 25. shows the results of an ex vivo angiogenesis CAM
assay using Clomipramine and plots the vascular density index.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0092] The present disclosure relates generally to treating or
preventing diseases associated with angiogenesis in a patient in
need thereof by administering to the patient certain compounds
found to inhibit or substantially reduce angiogenesis.
[0093] As employed above and throughout the disclosure, the
following terms, unless otherwise indicated, shall be understood to
have the following meanings.
[0094] "Alkyl" refers to an aliphatic hydrocarbon group which may
be straight, branched or cyclic having from 1 to about 10 carbon
atoms in the chain, and all combinations and subcombinations of
ranges therein. "Branched" refers to an alkyl group in which a
lower alkyl group, such as methyl, ethyl or propyl, is attached to
a linear alkyl chain. In certain embodiments, the alkyl group is a
C.sub.1-C.sub.4 alkyl group, i.e., a branched or linear alkyl group
having from 1 to about 4 carbons. In other embodiments, the alkyl
group is a C.sub.1-C.sub.3 alkyl group, i.e., a branched or linear
alkyl group having from 1 to about 3 carbons. Exemplary alkyl
groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and
decyl.
[0095] "Aryl" refers to an aromatic carbocyclic radical containing
from about 6 to about 10 carbons, and all combinations and
subcombinations of ranges therein. The aryl group may be optionally
substituted with one or two or more substituents. Exemplary aryl
groups include monocyclic groups, such as phenyl, and bicyclic
groups, such as naphthyl.
[0096] "Heteroaryl" refers to an aromatic carbocyclic radical
containing from about 4 to about 10 members, and all combinations
and subcombinations of ranges therein, wherein one or more of the
members is an element other than carbon, for example, nitrogen,
oxygen or sulfur. Exemplary heteroaryl groups include monocylic
groups, such as pyridyl, and bicyclic groups, such as indolyl.
[0097] "Arylalkyl" refers to an alkyl substituted with an aryl
group. A "C.sub.1-C.sub.4 arylalkyl group", for example, has a
C.sub.1-C.sub.4 alkyl group substituted with an aryl group.
[0098] "Heteroarylalkyl" refers to an alkyl substituted with a
heteroaryl group. A "C.sub.1-C.sub.4 heteroarylalkyl group", for
example, has a C.sub.1-C.sub.4 alkyl group substituted with an
heteroaryl group.
[0099] The term "cycloalkyl" used alone or as part of a larger
moiety shall include cyclic C.sub.3-C.sub.10 hydrocarbons which are
completely saturated or which contain one or more units of
unsaturation, but which are not aromatic. Cycloaliphatic groups are
typically C.sub.3-C.sub.10, more typically C.sub.3-C.sub.7.
[0100] The term "non-aromatic heterocycle", used alone or as part
of a larger moiety as in "heterocyclalkyl", refers to non-aromatic
ring systems typically having five to fourteen members, preferably
five to ten, in which one or more ring carbons, preferably one to
four, are each replaced by a heteroatom such as N, O, or S.
[0101] "Effective amount" refers to an amount of a compound as
described herein that may be therapeutically effective to treat a
disease or disorder associated with angiogenesis. The precise
amount of these compounds required will vary with the particular
compounds or employed, the age and condition of the subject to be
treated, and the nature and severity of the condition. However, the
effective amount may be determined by one of ordinary skill in the
art with only routine experimentation.
[0102] "Pharmaceutically acceptable" refers to those compounds,
materials, compositions, and/or dosage forms which are, within the
scope of sound medical judgment, suitable for contact with the
tissues of human beings and animals without excessive toxicity,
irritation, allergic response, or other problem complications
commensurate with a reasonable benefit/risk ratio.
[0103] "Pharmaceutically acceptable salts" refer to derivatives of
the disclosed compounds wherein the parent compound is modified by
making acid or base salts thereof. The compounds of this disclosure
form acid and base addition salts with a wide variety of organic
and inorganic acids and bases and includes the physiologically
acceptable salts which are often used in pharmaceutical chemistry.
Such salts are also part of this disclosure. Typical inorganic
acids used to form such salts include hydrochloric, hydrobromic,
hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the
like. Salts derived from organic acids, such as aliphatic mono and
dicarboxylic acids, phenyl substituted alkonic acids,
hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids,
aliphatic and aromatic sulfonic acids, may also be used. Such
pharmaceutically acceptable salts thus include acetate,
phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate,
chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,
methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide,
isobutyrate, phenylbutyrate, .beta.-hydroxybutyrate,
butyne-1,4-dioate, hexyne-1,4-dioate, cabrate, caprylate, chloride,
cinnamate, citrate, formate, fumarate, glycollate, heptanoate,
hippurate, lactate, malate, maleate, hydroxymaleate, malonate,
mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate,
phthalate, teraphthalate, phosphate, monohydrogenphosphate,
dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate,
propionate, phenylpropionate, salicylate, sebacate, succinate,
suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite,
sulfonate, benzene-sulfonate, p-bromobenzenesulfonate,
chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate,
methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,
p-toleunesulfonate, xylenesulfonate, tartarate, and the like.
[0104] Bases commonly used for formation of salts include ammonium
hydroxide and alkali and alkaline earth metal hydroxides,
carbonates, as well as aliphatic and primary, secondary and
tertiary amines, aliphatic diamines. Bases especially useful in the
preparation of addition salts include sodium hydroxide, potassium
hydroxide, ammonium hydroxide, potassium carbonate, methylamine,
diethylamine, and ethylene diamine.
[0105] "Patient" refers to animals, including mammals, preferably
humans.
[0106] "Metabolite" refers to any substance resulting from chemical
changes involved in the processes of growth and repair in a living
organism, including the anabolic and catabolic processes.
[0107] A "Prodrug" is a compound that is converted within the body
into its active form that has a medical effect. Prodrugs may be
useful when the active drug may be too toxic to administer
systemically, the active drug is absorbed poorly by the digestive
tract, or the body breaks down the active drug before it reaches
its target. Methods of making prodrugs are disclosed in Hans
Bundgaard, DESIGN OF PRODRUGS (Elsevier Science Publishers B.V.
1985), which is incorporated herein by reference in its
entirety.
[0108] "Solvates" refers to the compound formed by the interaction
of a solvent and a solute and includes hydrates. Solvates are
usually crystalline solid adducts containing solvent molecules
within the crystal structure, in either stoichiometric or
nonstoichiometric proportions.
[0109] The term "comprising" (and its grammatical variations) as
used herein is used in the inclusive sense of "having" or
"including" and not in the exclusive sense of "consisting only of."
The term "consisting essentially of" as used herein is intended to
refer to including that which is explicitly recited along with what
does not materially affect the basic and novel characteristics of
that recited or specified.
[0110] The terms "a", "an", and "the" as used herein are understood
to encompass the plural as well as the singular unless the context
clearly dictates otherwise.
[0111] Certain acidic or basic compounds of the present disclosure
may exist as zwitterions. All forms of the compounds, including
free acid, free base and zwitterions, are contemplated to be within
the scope of the present disclosure.
[0112] In the formulas described and claimed herein, it is intended
that when any symbol appears more than once in a particular formula
or substituent, its meaning in each instance is independent of the
other.
[0113] In one embodiment, there are provided methods for inhibiting
angiogenesis with a compound of Formula (I)
##STR00010##
[0114] wherein:
[0115] R is hydrogen, hydroxy or lower alkyloxy;
[0116] R.sub.1 is a member selected from the group consisting of
hydrogen and lower alkyl; Alk is a lower alkanediyl radical;
[0117] X is a member selected from the group consisting of --S--,
--CH.sub.2-- and --C(R.sub.2).dbd.C(R.sub.3)--, said R.sub.2 and
R.sub.3 being each independently hydrogen or lower alkyl;
[0118] A is a bivalent radical having the formula
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2-- or
##STR00011##
[0119] wherein R.sub.4 and R.sub.5 are each independently selected
from the group consisting of hydrogen, halo, amino and lower alkyl;
and
[0120] Ar.sub.1 and Ar.sub.2 are each independently selected from
the group consisting of pyridinyl, thienyl and phenyl, being
optionally substituted with halo, hydroxy, lower alkyloxy, lower
alkyl and trifluoromethyl; and pharmaceutically acceptable salts,
solvates, and prodrugs thereof. Alternatively, Alk is an
1,2-ethanediyl radical.
[0121] In one embodiment, the compound of Formula (I) is
Ritanserin.
[0122] Methods of synthesizing compounds of Formula (I) are well
known in the art and disclosed in U.S. Pat. No. 4,533,665 to Kennis
et al. and U.S. Pat. No. 4,485,107 to Kennis et al., both of which
are incorporated herein by reference in their entireties.
[0123] In another embodiment, there are provided methods for
inhibiting angiogenesis with a compound of Formula (II):
##STR00012##
[0124] wherein:
[0125] R.sub.1 is an alkyl group containing 1 to 6 carbon
atoms;
[0126] R.sub.2 is selected from the group consisting of hydrogen
and methyl;
[0127] NR.sub.3 is a radical selected from the group consisting of
a dimethylamino, diethylamino, dipropylamino, piperidino,
piperazino, pyrrolidino, morpholino, and N-substituted hetero aryl;
and
[0128] Y and Y.sub.1 are independently selected from the group
consisting of hydrogen, fluorine, bromine, chlorine, and iodine;
and pharmaceutically acceptable salts, solvates, and prodrugs
thereof. Alternatively, Y and Y.sub.1 are identical and are
selected from hydrogen, fluorine, bromine, chlorine, and
iodine.
[0129] In certain embodiments, NR.sub.3 is selected from the group
consisting of dimethylamino, diethylamino, dipropylamino,
piperidino, pyrrolidino, and morpholino; Y and Y.sub.1 are the same
or different and are selected from the group consisting of
hydrogen, iodine, and bromine.
[0130] In one embodiment, the compound of Formula (II) is
Amiodarone.
[0131] Methods of synthesizing compounds of Formula (II) are well
known in the art and are disclosed in U.S. Pat. No. 3,248,401 to
Tondeur et al. and is incorporated herein by reference in its
entirety.
[0132] In another embodiment, there are provided methods for
inhibiting angiogenesis with a compound of Formula (III):
##STR00013##
[0133] wherein
[0134] R is selected from the group consisting of hydrogen or
hydroxy;
[0135] R.sub.1 is hydrogen; or
[0136] R and R.sub.1 taken together form a second bond between the
carbon atoms bearing R and R.sub.1;
[0137] n is an integer from 1 to 3; and
[0138] Z is selected from the group consisting of thienyl, phenyl,
or substituted phenyl wherein the substituents on the substituted
phenyl may be attached at the ortho, meta, or para positions of the
substituted phenyl ring and are selected from the group consisting
of a halogen atom, a straight or branched lower alkyl chain of from
1 to 4 carbon atoms, a lower alkoxy group of from 1 to 4 carbon
atoms, a di(lower)alkylamino group, or a saturated monocyclic
heterocyclic ring selected from the group consisting of
pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino;
and pharmaceutically acceptable salts, solvates, and prodrugs
thereof.
[0139] In one embodiment, the compound of Formula (III) is
Terfenadine.
[0140] Methods of synthesizing compounds of Formula (III) are well
known in the art and disclosed in U.S. Pat. No. 3,878,217 to Carr
et al. and U.S. Pat. No. 4,254,129 to Carr et al., both of which
are incorporated herein by reference in their entireties.
[0141] In another embodiment, there are provided methods for
inhibiting angiogenesis with a compound of Formula (IV):
##STR00014##
[0142] wherein
[0143] X at each occurrence independently represents hydrogen,
chlorine or bromine;
[0144] A represents OH, OR, NR.sub.1R.sub.2, OC(O)R, OC(O)OR,
C(O)OH, C(O)OR, C(O)NR.sub.1R.sub.2, OC(O)N R.sub.1R.sub.2, NHC(O)N
R.sub.1R.sub.2 or NHC(NH)N R.sub.1R.sub.2;
[0145] R represents alkyl, cycloalkyl, heterocycle, aryl,
arylalkyl, or heterocyclalkyl;
[0146] R.sub.1 and R.sub.2 each independently represent hydrogen,
alkyl, cycloalkyl, heterocycle, aryl, arylalkyl, heterocyclalkyl,
or R.sub.1 and R.sub.2 can together form a 3 to 8 membered
heterocyclic ring which may be further optionally substituted with
one to four (CH.sub.2).sub.nA substituents;
[0147] n is a number between 0 and 5 inclusive; and
pharmaceutically acceptable salts, solvates, and prodrugs
thereof.
[0148] Methods of synthesizing compounds of Formula (IV) are well
known in the art and are disclosed in U.S. Pat. No. 2,645,640 to
Choisy-le-Roi and is incorporated herein by reference in its
entirety.
[0149] In another embodiment, there are provided methods for
inhibiting angiogenesis with a compound of Formula (IV-a):
##STR00015##
[0150] wherein
[0151] X represents hydrogen, chlorine or bromine;
[0152] A represents OH, OR, NR.sub.1R.sub.2, OC(O)R, OC(O)OR,
C(O)OH, C(O)OR, C(O)NR.sub.1R.sub.2, OC(O)N R.sub.1R.sub.2, NHC(O)N
R.sub.1R.sub.2 or NHC(NH)N R.sub.1R.sub.2;
[0153] R represents alkyl, cycloalkyl, heterocycle, aryl,
arylalkyl, or heterocyclalkyl;
[0154] R.sub.1 and R.sub.2 each independently represent hydrogen,
alkyl, cycloalkyl, heterocycle, aryl, arylalkyl, heterocyclalkyl,
or R.sub.1 and R.sub.2 can together form a 3 to 8 membered
heterocyclic ring;
[0155] n is a number between 0 and 5 inclusive; and
pharmaceutically acceptable salts, solvates, and prodrugs
thereof.
[0156] In one embodiment, the compound of Formula (IV) or Formula
(IV-a) is Perphenazine.
[0157] Methods of synthesizing compounds of Formula (IV-a) are well
known in the art and are disclosed in U.S. Pat. No. 2,860,138 to
Sherlock et al. and is incorporated herein by reference in its
entirety.
[0158] In another embodiment, there are provided methods for
inhibiting angiogenesis with a compound of Formula (V):
##STR00016##
[0159] wherein,
[0160] Y represents O, S, or S.dbd.O;
[0161] X at each occurrence independently represents halogen or OH;
and
[0162] n is an integer between 0 and 5 inclusive; and
pharmaceutically acceptable salts, solvates, and prodrugs
thereof.
[0163] In one embodiment, the compound of Formula (V) or Formula
(V-a) is Bithionol.
[0164] Also provided are methods for inhibiting angiogenesis with a
compound of Formula (V-a)
##STR00017##
[0165] wherein
[0166] Y represents O, S, or S.dbd.O;
[0167] X at each occurrence independently represents halogen or OH;
and
[0168] n at each occurrence is independently an integer between 0
and 5 inclusive; and pharmaceutically acceptable salts, solvates,
and prodrugs thereof.
[0169] Methods of synthesizing compounds of Formula (V) and Formula
(V-a) are well known in the art and disclosed in U.S. Pat. No.
3,506,720 to Basel et al. and U.S. Pat. No. 2,849,494 to Cooper et
al., and are both incorporated herein by reference in their
entireties.
[0170] In another embodiment, there are provided methods for
inhibiting angiogenesis with a compound of Formula (VI):
##STR00018##
[0171] wherein
[0172] X represents a member selected from the group consisting of
the ethylene radical --CH.sub.2CH.sub.2-- and the vinylene radical
--CH.dbd.CH--;
[0173] R represents a member selected from the group consisting of
the methyl radical, the ethyl radical, the propyl radical, chlorine
and bromine,
[0174] Y represents an alkylene radical with 2-3 carbon atoms,
and
[0175] Am represents a member selected from the group consisting of
a lower dialkylamino group, the pyrrolidinio, piperidino,
piperazino, morpholino and N-methyl-piperidyl(2)-group; and
pharmaceutically acceptable salts, solvates, and prodrugs
thereof.
[0176] In one embodiment, the compound of Formula (VI) is
Clomipramine.
[0177] Methods of synthesizing compounds of Formula (VI) are well
known in the art and disclosed in U.S. Pat. No. 3,467,650 to Riehen
et al. and is incorporated herein by reference in its entirety.
[0178] In another embodiment, there are provided methods for
inhibiting angiogenesis with a compound selected from Ritanserin,
Amiodarone hydrochloride, Terfenadine, Perphenazine, Bithionol,
Bithionol sulfoxide, Clomipramine hydrochloride, Fexofenadine, and
combinations thereof.
[0179] Also provided are methods of inhibiting the growth or
metastasis of an angiogenesis-dependent tumor with compounds of the
present disclosure. Another embodiment is drawn to methods for
treating a disease or disorder associated with angiogenesis such as
neoplastic diseases, restenosis, rheumatoid arthritis, Crohn's
disease, diabetic retinopathy, psoriasis, endometriosis, macular
degeneration, neovascular glaucoma, and adiposity with compounds of
the present disclosure.
[0180] In certain embodiments, the present disclosure is directed
to methods for inhibiting angiogenesis and/or inhibiting the growth
or metastasis of a tumor. As used herein, the term "inhibit" means
that the amount of tumor growth or metastasis and/or the occurrence
of angiogenesis in patients that have received a compound, as
described herein, may be desirably reduced as compared to patients
that have not received that compound. Thus, in one form, the
inhibitory methods of the present disclosure comprise administering
to a patient an effective amount of an anti-angiogenic agent. The
term "anti-angiogenic agent", as used herein, refers to compounds
which may inhibit angiogenesis.
[0181] In other embodiments, the disclosure is directed to methods
for treating a disease or disorder associated with angiogenesis.
These methods may include the step of identifying a patient having
such a disease, including patients who would benefit from the
treatment methods described herein. Diseases or disorders
associated with angiogenesis include, for example, conditions in
which angiogenesis plays a role in the pathology or progression of
the condition, such that inhibition of angiogenesis in a patient
having such a condition may delay or prevent the further
progression of the condition, or lead to remission or regression of
the disease state. Such conditions are frequently characterized by
or associated with abnormal cellular proliferation and include, for
example, neoplastic diseases. As used herein, the term "treating a
disease or disorder" refers to the administration of agents
intended to limit the extent, progression and/or severity of a
condition in a patient, as compared to patients that have not been
so treated. As used herein, the term "neoplastic disease" refers to
any condition characterized by the presence of an aberrant growth
of abnormal cells or tissue, including, but not limited to all
cancers and tumors, whether benign or malignant. "Treating
neoplastic disease" refers to the administration of a
chemotherapeutic agent that will inhibit the further growth or
metastasis of any neoplastic tissue that may exist in a patient
and/or stimulate regression of such neoplasms, including reducing
the size and/or number of such neoplasms and/or inducing the death
of neoplastic cells.
[0182] Prodrug forms of the compounds bearing various nitrogen
functions (amino, hydroxyamino, amide, etc.) may include the
following types of derivatives where each R group individually may
be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl,
alkynyl, heterocycle, alkylaryl, aralkyl, aralkenyl, aralkynl,
cycloalkyl or cycloalkenyl groups as defined earlier.
[0183] (a) Carboxamides, --NHC(O)R
[0184] (b) Carbamates, --NHC(O)OR
[0185] (c) (Acyloxy)alkyl Carbamates, NHC(O)OROC(O)R
[0186] (d) Enamines, --NHCR(.dbd.CHCO.sub.2R) or
--NHCR(.dbd.CHCONR.sub.2)
[0187] (e) Schiff Bases, --N.dbd.CR.sub.2
[0188] (f) Mannich Bases (from carboximide compounds),
RCONHCH.sub.2NR.sub.2
[0189] Preparations of such prodrug derivatives are discussed in
various literature sources (examples are: Alexander et al., J. Med.
Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO pp/41531, p. 30).
The nitrogen function converted in preparing these derivatives is
one (or more) of the nitrogen atoms of a compound of the
invention.
[0190] Prodrug forms of carboxyl-bearing compounds of the invention
include esters (--CO.sub.2R) where the R group corresponds to any
alcohol whose release in the body through enzymatic or hydrolytic
processes would be at pharmaceutically acceptable levels. Another
prodrug derived from a carboxylic acid form of the invention may be
a quaternary salt type
##STR00019##
of structure described by Bodor et al., J. Med. Chem. 1980, 23,
469.
[0191] It is of course understood that the compounds of the present
invention relate to all optical isomers and stereo-isomers at the
various possible atoms of the molecule.
[0192] Pharmaceutically acceptable salts of the compounds of the
present invention include those derived from pharmaceutically
acceptable inorganic or organic acids. Examples of suitable acids
include hydrochloric, hydrobromic, sulfuric, nitric, perchloric,
fumaric, maleic, phosphoric, glycollic, lactic, salicyclic,
succinic, toluene-p-sulfonic, tartaric, acetic, citric,
methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,
trifluoroacetic and benzenesulfonic acids. Salts derived from
appropriate bases include alkali such as sodium and ammonia.
[0193] The compounds of the present invention can be synthesized by
persons skilled in the art once aware of the present disclosure
without undue experimentation. Procedures are available in the
chemical literature suitable for preparing the requisite sugars or
nucleosides. Along these lines, see Choi, Jong-Ryoo; Kim,
Jeong-Min; Roh, Kee-Yoon; Cho, Dong-Gyu; Kim, Jae-Hong; Hwang,
Jae-Taeg; Cho, Woo-Young; Jong, Hyun-Sook; Lee, Chang-Ho; Choi,
Tae-Saeng; Kim, Chung-Mi; Kim, Yong-Zu; Kim, Tae-Kyun; Cho,
Seung-Joo; Kim, Gyoung-Won PCT Int. Appl. (2002), 100 pp. WO
0257288 A1 20020725. Holy, Antonin; Votruba, Ivan; Tloustova, Eva;
Masojidkova, Milena. Collection of Czechoslovak Chemical
Communications (2001), 66(10), 1545-1592. Rejman, Dominik;
Masojidkova, Milena; De Clercq, Eric; Rosenberg, Ivan Nucleosides,
Nucleotides & Nucleic Acids (2001), 20(8), 1497-1522; Ubasawa,
Masaru; Sekiya, Kouichi PCT Int. Appl. (2001), 39 pp WO 0164693 A1
20010907. Otmar, Miroslav; Masojfdkova, Milena; Votruba, Ivan;
Holy, Antonin. Collection of Czechoslovak Chemical Communications
(2001), 66(3), 500-506. Michal; Hocek, Michal; Holy, Antonin.
Collection of Czechoslovak Chemical Communications (2000), 65(8),
1357-1373. Jeffery, A. L.; Kim, J.-H.; Wiemer, D. F. Tetrahedron
(2000), 56(29), 5077-5083. Holy, Antonin; Guenter, Jaroslav;
Dvorakova, Hana; Masojidkova, Milena; Andrei, Graciela; Snoeck,
Robert; Balzarini, Jan; De Clercq, Erik. Journal of Medicinal
Chemistry (1999), 42(12), 2064-2086. Janeba, Zlatko; Holy, Antonin;
Masojidkova, Milena. Collection of Czechoslovak Chemical
Communications (2001), 66(9), 1393-1406. Holy, Antonin; Guenter,
Jaroslav; Dvorakova, Hana; Masojidkova, Milena; Andrei, Graciela;
Snoeck, Robert; Balzarini, Jan; De Clercq, Erik. Journal of
Medicinal Chemistry (1999), 42(12), 2064-2086. Dang, Qun; Erion,
Mark D.; Reddy, M. Rami; Robinsion, Edward D.; Kasibhatla, Srinivas
Rao; Reddy, K. Raja. PCT Int. Appl. (1998), 126 pp WO 9839344 A1
19980911. Arimilli, Murty N.; Cundy, Kenneth C.; Dougherty, Joseph
P.; Kim, Choung U.; Oliyai, Reza; Stella, Valentino J. PCT Int.
Appl. (1998), 74 pp WO 9804569. Sekiya, Kouichi; Takashima,
Hideaki; Ueda, Naoko; Kamiya, Naohiro; Yuasa, Satoshi; Fujimura,
Yoshiyuki; Ubasawa, MasaruJournal of Medicinal Chemistry (2002),
45(14), 3138-3142. Ubasawa, Masaru; Sekiya, Kouichi; Takashima,
Hideaki; Ueda, Naoko; Yuasa, Satoshi; Kamiya, Naohiro. Eur. Pat.
Appl. (1997), 56 pp EP 785208 A1 19970723. Hocek, Michal;
Masojidkova, Milena; Holy, Antonin, Collection of Czechoslovak
Chemical Communications (1997), 62(1), 136-146. Holy, Antonin;
Votruba, Ivan; Tloustova, Eva; Masojidkova, Milena. Collection of
Czechoslovak Chemical Communications (2001), 66(10), 1545-1592.
Holy, Antonin; De Clercq, Erik Desire Alice. PCT Int. Appl. (1996),
57 pp. WO 9633200 A1 19961024. Rejman, Dominik; Rosenberg, Ivan.
Collection of Czechoslovak Chemical Communications (1996), 61
(Spec. Issue), 5122-S123. Holy, Antonin; Dvorakova, Hana; Jindrich,
Jindrich; Masojidkova, Milena; Budesinsky, Milos; Balzarini, Jan;
Andrei, Graciella; De Clercq, Erik. Journal of Medicinal Chemistry
(1996), 39(20), 4073-4088. Guanti, Giuseppe; Merlo, Valeria;
Narisano, Enrica. Tetrahedron (1995), 51(35), 9737-46. Takashima,
Hideaki; Inoue, Naoko; Ubasawa, Masaru; Sekiya, Kouichi; Yabuuchi,
Shingo Eur. Pat. Appl. (1995), 88 pp. EP 632048 A1 19950104.
Alexander, Petr; Holy, Antonin; Masojidkova, Milena, Collection of
Czechoslovak Chemical Communications (1994), 59(8), 1853-69.
Alexander, Petr; Holy, Antonin; Masojidkova, Milena; Collection of
Czechoslovak Chemical Communications (1994), 59(8), 1853-69.
Jindrich, Jindrich; Holy, Antonin; Dvorakova, Hana. Collection of
Czechoslovak Chemical Communications (1993), 58(7), 1645-67. Holy,
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[0194] The following non-limiting examples illustrate and describe
aspects of the present disclosure. The examples show and describe
only limited embodiments but it is to be understood that the
disclosure is capable of use in various other combinations,
modifications, and environments and is capable of changes or
modifications within the scope of the concept as expressed herein,
commensurate with the teachings and/or the skill or knowledge of
the relevant art.
Example 1
Cell Proliferation Assay
[0195] Human primary cell lines, arterial endothelia, such as HAEC
and HPAEC, venous endothelia HUVEC (from Cambrex BioScience
Rockland Inc.), and lung fibroblasts LL47 (from the American Type
Culture Collection) are cultured by following the instruction and
used to evaluate the target compounds for their differential
activity against human endothelia verses fibroblasts by
CellTiter-Glo Luminescent Cell viability Assay. This assay,
generating luminescent signals, is based on quantification of ATP
levels in cell cultures. Amount of ATP produced in cell culture
reflects the number of viable cells. Hence, this assay is often
used to estimate cell proliferation and cytotoxic effects of test
compounds. Cells are seeded in 96-well plates with their growth
medium, about 5.times.10.sup.3 cell per well. After 24 hours,
various doses of the target compounds are added to the cultures,
having four replicates for each dose. After 72 hours of treatment,
CellTiter-Glo reagent is added to the cultures following the
manufacturer's instruction and luminescence is measured. The
control groups are given DMSO vehicle only. IC.sub.50s of target
compounds for endothelia and fibroblasts proliferation in their
growth medium are determined based on the dose response curve and
plotted against the range of concentrations.
Example 2
Endothelial Cell Migration Assay
[0196] Endothelial cell migration is a key step of the angiogenesis
process, which is crucial for on-site recruitment of blood vessel
formation. The trans-well filter/inserts chamber of Biocoat
Endothelial Cell Migration Angiogenesis System (BD Biosciences) is
used for endothelial cell migration assay, which is a 24-Transwell
chamber plate containing 3-um pore size inserts coated with human
fibronectin. The inserts are incubated at 37.degree. C. with 0.1%
bovine serum albumin containing endothelial cell basal medium for 1
hour. Endothelial cells (HUVEC) are starved with 0.1% bovine serum
albumin in endothelial cell basal medium for 4 to 5 hours before
the cell harvest and then seeded (1.times.10.sup.5 per well) in
upper chambers of the Transwell plate with various treatments in
100 ul of 0.1% bovine serum albumin in endothelial cell basal
medium. The full growth medium that contains various
chemoattractants is added in the lower chambers. The cells are
allowed to migrate for 22.+-.1 hours at 37.degree. C. Unmigrated
cells at the inside of the inserts are carefully removed with a
Q-tip. Migrated cells at the lower part of the Transwell inserts
are then fixed with 4% paraformaldehyde, stained with Hoechst
33342, and photographed under a fluorescent microscope. Three
microscopic view fields of each filter/insert are analyzed for the
number of migrated cells. Triplicate filter/insert chamber cultures
are carried for each test concentration and control. Data are
expressed as average number of migrated cells per microscopic view
field of 10.times. magnification and IC.sub.50 are calculated based
on the dose curve.
Example 3
Endothelial Tube Formation Assay
[0197] Human endothelial cells are cultured in vitro on
extracellular matrix, which stimulates the attachment and
differentiation of endothelial cells into tubules. The endothelial
tube formation assay is based on this phenomenon. Endothelial cells
(HUVEC) are seeded (1.5.times.10.sup.4 per well) in a 96-well
plates coated with extracellular matrix and treated with the target
compounds at different concentrations with the full growth medium
in triplicate. The cells are allowed to form endothelial tubes at
37.degree. C. for about 18 hours and photographed under an inverted
light microscope. The tubule lengths are quantified using image
analysis software, Image-Pro Plus (Media Cybernetics, Inc., Siler
Spring, Md.). Data are expressed as average tube lengths of three
view fields for each well and triplicate wells for each treatment
condition. IC.sub.50 values are calculated based on the dose
curve.
Example 4
Chick Chorioallantoic Membrane (CAM) Assay
[0198] Chicken embryo chorioallantoic membrane provides an ideal in
vivo model for the physiologic process of angiogenesis. Angiogenic
modulators applied on methylcellulose discs placed on top of
chicken embryo chorioallantoic membrane are able to alter the
development of new blood vasculature. See Staton et al, Current
Methods for Assaying Angiogenesis in vitro and in vivo, INT. J.
EXP. PATROL., 85:233-48 (2004), which is incorporated herein by
reference in its entirety. The angiogenesis chorioallantoic
membrane assay is used for ex vivo evaluation of the
anti-angiogenic potential of synthetic compounds. Fertilized
chicken eggs are incubated at 37.5.degree. C. in a humidified egg
incubator with forced air circulation. On embryo Day 3, eggs are
cracked open and embryos are transferred into 100-mm.sup.3 Petri
plates to continue their development in a cell culture incubator at
37.5.degree. C. Pre-made methylcellulose discs in about 2 mm in
diameter are gently implanted on top of embryo chorioallantoic
membrane on embryonic Day 5 and then testing compound in solution
or control vehicle is applied on top of methylcellulose disc. The
embryos are incubated for two more days in the cell culture
incubator. The chorioallantoic membranes are examined and
quantitatively analyzed for new blood vessel formation at embryonic
Day 7. The treatment effects on angiogenesis are evaluated by
determining vascular density index (VDI) of each CAM with viable
chicken embryos. The VDI represents the number of intersections
made by blood vessels with three equidistant concentric circles on
the area covered by methylcellulose discs by using Image Pro Plus
software. The data are expressed as average VDI based on the
quantitative analysis for each treatment group (N.gtoreq.5) with
stander deviation.
Example 5
Matrigel Plug Assay in Mouse
[0199] The Matrigel Plug Assay is an in vivo new blood vessel
formation assay, which is widely used for evaluation of
anti-angiogenic activities of synthetic compounds and recombinant
proteins. Female C57BL/6 mice around 8-10 weeks old and High
Concentration Matrigel Matrix is used for the Matrigel Plug
experiments. There are four or five mice in each treatment group
and two Matrigel plugs in each mouse. Matrigel is mixed with 50
ng/ml VEGF, 50 ng/ml FGFb, and 3 ng/ml heparin as angiogenic
stimuli. Target compounds in different dosages are either mixed
with Matrigel or given by i.p. or i.v. or by oral. Matrigel at
4.degree. C. is subcutaneously injected, 500 ul Matrigel for each
plug, into each sides of mouse where the hair has been shaved. The
injected Matrigel will rapidly form a single solid gel plug. Plugs
from each group are collected about two weeks after the Matrigel
inoculation. Mice are euthanized by inhalation of CO.sub.2 and
mouse skin is pulled back to expose the plug. The intact plugs are
removed and fixed in 10% formalin for histological analysis.
Sections (5 um thickness) of paraffin-embedded plugs are
immunostained with specific antibody against CD31 and
counterstained with H&E. CD31-positive microvessels in an
entire cross sectional area of each Matrigel plug are counted. For
each group of mice, about six Matrigel plugs are quantitatively
analyzed to assess any statistical significant difference of
microvessel density between control and compound treated
groups.
Example 6
Anti-Tumor Efficacy of Compounds Evaluated by Xenograft Nude Mouse
Model
[0200] Tumor growth depends on angiogenesis. Inhibition of tumor
angiogenesis has become an effective treatment for cancers.
Standard Xenograft nude mouse models are used to evaluate potential
anti-angiogenic agents for their anti-tumor activity. Human tumor
cells or fragments are implanted into 5 to 7-weeks old nude mice.
Target compounds are given to each group of mice by i.p., or i.v.,
or oral. Tumor size and mouse body weight are monitored twice a
week. Average tumor volumes at each time points are expressed with
standard deviation against tumor growth time, which is days after
xenograft inoculation.
[0201] Procedures such as those described in the above examples
were employed to give the data presented in the Figures and in
Table I below.
TABLE-US-00001 TABLE I IC.sub.50 (.mu.M) IC.sub.50 (.mu.M)
Inhibition in Inhibition in Arterial Venous IC.sub.50 (.mu.M)
Endothlial Endothlia Inhibition in Endothelia endothelia
Fibroblasts migration Tube-Formation CAM Assay Compound
Proliferation Proliferation Proliferation 2 .mu.M 8 .mu.M 2 .mu.M 8
.mu.M (10 .mu.g) Ritanserin 11.0 10.5 >50 55% 65% 11% 33% 21%
Amiodarone 7.5 8.8 20.0 36% 38% 33% 33% 27% hydrochloride
Terfenadine 3.0 5.5 7.0 34% 100% 20% 43% 28% Clomipramine 10.8 4.5
28.0 58% 63% 12% 26% 19% hydrochloride Perphenazine 4.2 11.1 10.8
43% 46% 7% 22% -- Bithionol 2.0 6.0 10.5 5% 100% 19% 38% 30%
Formulations
[0202] The compounds of the present disclosure can be administered
by any conventional means available for use in conjunction with
pharmaceuticals, either as individual therapeutic agents or in a
combination of therapeutic agents. They can be administered alone,
but generally administered with a pharmaceutical carrier selected
on the basis of the chosen route of administration and standard
pharmaceutical practice. The compounds can also be administered in
conjunction with other therapeutic agents such as interferon (IFN),
interferon .alpha.-2a, interferon .alpha.-2b, consensus interferon
(CIFN), ribavirin, amantadine, remantadine, interleukine-12,
ursodeoxycholic acid (UDCA), and glycyrrhizin.
[0203] The pharmaceutically acceptable carriers described herein,
for example, vehicles, adjuvants, excipients, or diluents, are
well-known to those who are skilled in the art. Typically, the
pharmaceutically acceptable carrier is chemically inert to the
active compounds and has no detrimental side effects or toxicity
under the conditions of use. The pharmaceutically acceptable
carriers can include polymers and polymer matrices.
[0204] The compounds of this disclosure can be administered by any
conventional method available for use in conjunction with
pharmaceuticals, either as individual therapeutic agents or in a
combination of therapeutic agents.
[0205] The dosage administered will, of course, vary depending upon
known factors, such as the pharmacodynamic characteristics of the
particular agent and its mode and route of administration; the age,
health and weight of the recipient; the nature and extent of the
symptoms; the kind of concurrent treatment; the frequency of
treatment; and the effect desired. A daily dosage of active
ingredient can be expected to be about 0.001 to 1000 milligrams
(mg) per kilogram (kg) of body weight, with the preferred dose
being 0.1 to about 60 mg/kg.
[0206] Dosage forms (compositions suitable for administration)
contain from about 1 mg to about 500 mg of active ingredient per
unit. In these pharmaceutical compositions, the active ingredient
will ordinarily be present in an amount of about 0.5-95% weight
based on the total weight of the composition.
[0207] The active ingredient can be administered orally in solid
dosage forms, such as capsules, tablets, and powders, or in liquid
dosage forms, such as elixirs, syrups and suspensions. It can also
be administered parenterally, in sterile liquid dosage forms. The
active ingredient can also be administered intranasally (nose
drops) or by inhalation of a drug powder mist. Other dosage forms
are potentially possible such as administration transdermally, via
patch mechanism or ointment.
[0208] Formulations suitable for oral administration can consist of
(a) liquid solutions, such as an effective amount of the compound
dissolved in diluents, such as water, saline, or orange juice; (b)
capsules, sachets, tablets, lozenges, and troches, each containing
a predetermined amount of the active ingredient, as solids or
granules; (c) powders; (d) suspensions in an appropriate liquid;
and (e) suitable emulsions. Liquid formulations may include
diluents, such as water and alcohols, for example, ethanol, benzyl
alcohol, propylene glycol, glycerin, and the polyethylene alcohols,
either with or without the addition of a pharmaceutically
acceptable surfactant, suspending agent, or emulsifying agent.
Capsule forms can be of the ordinary hard- or soft-shelled gelatin
type containing, for example, surfactants, lubricants, and inert
fillers, such as lactose, sucrose, calcium phosphate, and corn
starch. Tablet forms can include one or more of the following:
lactose, sucrose, mannitol, corn starch, potato starch, alginic
acid, microcrystalline cellulose, acacia, gelatin, guar gum,
colloidal silicon dioxide, croscarmellose sodium, talc, magnesium
stearate, calcium stearate, zinc stearate, stearic acid, and other
excipients, colorants, diluents, buffering agents, disintegrating
agents, moistening agents, preservatives, flavoring agents, and
pharmacologically compatible carriers. Lozenge forms can comprise
the active ingredient in a flavor, usually sucrose and acacia or
tragacanth, as well as pastilles comprising the active ingredient
in an inert base, such as gelatin and glycerin, or sucrose and
acadia, emulsions, and gels containing, in addition to the active
ingredient, such carriers as are known in the art.
[0209] The compounds of the present disclosure, alone or in
combination with other suitable components, can be made into
aerosol formulations to be administered via inhalation. These
aerosol formulations can be placed into pressurized acceptable
propellants, such as dichlorodifluoromethane, propane, and
nitrogen. They also may be formulated as pharmaceuticals for
non-pressured preparations, such as in a nebulizer or an
atomizer.
[0210] Formulations suitable for parenteral administration include
aqueous and non-aqueous, isotonic sterile injection solutions,
which can contain anti-oxidants, buffers, bacteriostats, and
solutes that render the formulation isotonic with the blood of the
intended recipient, and aqueous and non-aqueous sterile suspensions
that can include suspending agents, solubilizers, thickening
agents, stabilizers, and preservatives. The compound can be
administered in a physiologically acceptable diluent in a
pharmaceutical carrier, such as a sterile liquid or mixture of
liquids, including water, saline, aqueous dextrose and related
sugar solutions, an alcohol, such as ethanol, isopropanol, or
hexadecyl alcohol, glycols, such as propylene glycol or
polyethylene glycol such as poly(ethyleneglycol) 400, glycerol
ketals, such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, an
oil, a fatty acid, a fatty acid ester or glyceride, or an
acetylated fatty acid glyceride with or without the addition of a
pharmaceutically acceptable surfactant, such as a soap or a
detergent, suspending agent, such as pectin, carbomers,
methylcellulose, hydroxypropylmethylcellulose, or
carboxymethylcellulose, or emulsifying agents and other
pharmaceutical adjuvants.
[0211] Oils, which can be used in parenteral formulations include
petroleum, animal, vegetable, or synthetic oils. Specific examples
of oils include peanut, soybean, sesame, cottonseed, corn, olive,
petrolatum, and mineral. Suitable fatty acids for use in parenteral
formulations include oleic acid, stearic acid, and isostearic acid.
Ethyl oleate and isopropyl myristate are examples of suitable fatty
acid esters. Suitable soaps for use in parenteral formulations
include fatty alkali metal, ammonium, and triethanolamine salts,
and suitable detergents include (a) cationic detergents such as,
for example, dimethyldialkylammonium halides, and alkylpyridinium
halides, (b) anionic detergents such as, for example, alkyl, aryl,
and olefin sulfonates, alkyl, olefin, ether, and monoglyceride
sulfates, and sulfosuccinates, (c) nonionic detergents such as, for
example, fatty amine oxides, fatty acid alkanolamides, and
polyoxyethylene polypropylene copolymers, (d) amphoteric detergents
such as, for example, alkyl .beta.-aminopropionates, and
2-alkylimidazoline quaternary ammonium salts, and (e) mixtures
thereof.
[0212] The parenteral formulations typically contain from about
0.5% to about 25% by weight of the active ingredient in solution.
Suitable preservatives and buffers can be used in such
formulations. In order to minimize or eliminate irritation at the
site of injection, such compositions may contain one or more
nonionic surfactants having a hydrophile-lipophile balance (HLB) of
from about 12 to about 17. The quantity of surfactant in such
formulations ranges from about 5% to about 15% by weight. Suitable
surfactants include polyethylene sorbitan fatty acid esters, such
as sorbitan monooleate and the high molecular weight adducts of
ethylene oxide with a hydrophobic base, formed by the condensation
of propylene oxide with propylene glycol.
[0213] Pharmaceutically acceptable excipients are also well-known
to those who are skilled in the art. The choice of excipient will
be determined in part by the particular compound, as well as by the
particular method used to administer the composition. Accordingly,
there is a wide variety of suitable formulations of the
pharmaceutical composition of the present disclosure. The following
methods and excipients are merely exemplary and are in no way
limiting. The pharmaceutically acceptable excipients preferably do
not interfere with the action of the active ingredients and do not
cause adverse side-effects. Suitable carriers and excipients
include solvents such as water, alcohol, and propylene glycol,
solid absorbants and diluents, surface active agents, suspending
agent, tableting binders, lubricants, flavors, and coloring
agents.
[0214] The formulations can be presented in unit-dose or multi-dose
sealed containers, such as ampules and vials, and can be stored in
a freeze-dried (lyophilized) condition requiring only the addition
of the sterile liquid excipient, for example, water, for
injections, immediately prior to use. Extemporaneous injection
solutions and suspensions can be prepared from sterile powders,
granules, and tablets. The requirements for effective
pharmaceutical carriers for injectable compositions are well known
to those of ordinary skill in the art (5, 6). See Banker and
Chalmers PHARMACEUTICS AND PHARMACY PRACTICE, 238-250 (J.B.
Lippincott Co., Philadelphia, Pa. Eds. 1982) and Toissel, ASHP
HANDBOOK ON INJECTABLE DRUGS, 622-630 (4th ed. 1986), which are
incorporated herein by reference in its entirety.
[0215] Formulations suitable for topical administration include
lozenges comprising the active ingredient in a flavor, usually
sucrose and acacia or tragacanth; pastilles comprising the active
ingredient in an inert base, such as gelatin and glycerin, or
sucrose and acacia; and mouthwashes comprising the active
ingredient in a suitable liquid carrier; as well as creams,
emulsions, and gels containing, in addition to the active
ingredient, such carriers as are known in the art.
[0216] Additionally, formulations suitable for rectal
administration may be presented as suppositories by mixing with a
variety of bases such as emulsifying bases or water-soluble bases.
Formulations suitable for vaginal administration may be presented
as pessaries, tampons, creams, gels, pastes, foams, or spray
formulas containing, in addition to the active ingredient, such
carriers as are known in the art to be appropriate.
[0217] Suitable pharmaceutical carriers are described in
Remington's Pharmaceutical Sciences, Mack Publishing Company, a
standard reference text in this field.
[0218] The dose administered to an animal, particularly a human, in
the context of the present disclosure should be sufficient to
affect a therapeutic response in the animal over a reasonable time
frame. One skilled in the art will recognize that dosage will
depend upon a variety of factors including a condition of the
animal, the body weight of the animal, as well as the severity and
stage of the condition being treated.
[0219] A suitable dose is that which will result in a concentration
of the active agent in a patient which is known to affect the
desired response. The preferred dosage is the amount which results
in maximum inhibition of the condition being treated, without
unmanageable side effects.
[0220] The size of the dose also will be determined by the route,
timing and frequency of administration as well as the existence,
nature, and extend of any adverse side effects that might accompany
the administration of the compound and the desired physiological
effect.
[0221] Useful pharmaceutical dosage forms for administration of the
compounds according to the present disclosure can be illustrated as
follows:
Hard Shell Capsules
[0222] A large number of unit capsules are prepared by filling
standard two-piece hard gelatine capsules each with 100 mg of
powdered active ingredient, 150 mg of lactose, 50 mg of cellulose
and 6 mg of magnesium stearate.
Soft Gelatin Capsules
[0223] A mixture of active ingredient in a digestible oil such as
soybean oil, cottonseed oil or olive oil is prepared and injected
by means of a positive displacement pump into molten gelatin to
form soft gelatin capsules containing 100 mg of the active
ingredient. The capsules are washed and dried. The active
ingredient can be dissolved in a mixture of polyethylene glycol,
glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets
[0224] A large number of tablets are prepared by conventional
procedures so that the dosage unit was 100 mg of active ingredient,
0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate,
275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg
of lactose. Appropriate aqueous and non-aqueous coatings may be
applied to increase palatability, improve elegance and stability or
delay absorption.
Immediate Release Tablets/Capsules
[0225] These are solid oral dosage forms made by conventional and
novel processes. These units are taken orally without water for
immediate dissolution and delivery of the medication. The active
ingredient is mixed in a liquid containing ingredient such as
sugar, gelatin, pectin and sweeteners. These liquids are solidified
into solid tablets or caplets by freeze drying and solid state
extraction techniques. The drug compounds may be compressed with
viscoelastic and thermoelastic sugars and polymers or effervescent
components to produce porous matrices intended for immediate
release, without the need of water.
[0226] Moreover, the compounds of the present disclosure can be
administered in the form of nose drops, or metered dose and a nasal
or buccal inhaler. The drug is delivered from a nasal solution as a
fine mist or from a powder as an aerosol.
[0227] The foregoing description of the disclosure illustrates and
describes the present disclosure. Additionally, the disclosure
shows and describes only the preferred embodiments but, as
mentioned above, it is to be understood that the disclosure is
capable of use in various other combinations, modifications, and
environments and is capable of changes or modifications within the
scope of the concept as expressed herein, commensurate with the
above teachings and/or the skill or knowledge of the relevant
art.
[0228] The embodiments described hereinabove are further intended
to explain best modes known of practicing it and to enable others
skilled in the art to utilize the disclosure in such, or other,
embodiments and with the various modifications required by the
particular applications or uses. Accordingly, the description is
not intended to limit it to the form disclosed herein. Also, it is
intended that the appended claims be construed to include
alternative embodiments.
[0229] All publications, patents and patent applications cited in
this specification are herein incorporated by reference, and for
any and all purposes, as if each individual publication, patent or
patent application were specifically and individually indicates to
be incorporated by reference.
* * * * *