U.S. patent number 8,716,315 [Application Number 11/880,404] was granted by the patent office on 2014-05-06 for analogs of thalidomide as potential angiogenesis inhibitors.
This patent grant is currently assigned to N/A, The United States of America as represented by the Secretary of the Department of Health and Human Services. The grantee listed for this patent is Kurt Eger, William D. Figg, Michael Guetschow, Sunna Hauschildt, Thomas Hecker, Uwe Teubert, Michael Weiss. Invention is credited to Kurt Eger, William D. Figg, Michael Guetschow, Sunna Hauschildt, Thomas Hecker, Uwe Teubert, Michael Weiss.
United States Patent |
8,716,315 |
Figg , et al. |
May 6, 2014 |
Analogs of thalidomide as potential angiogenesis inhibitors
Abstract
A number of thalidomide metabolites having superior
anti-angiogenic properties have now been isolated and identified.
In addition, thalidomide analogs that mimic the effects of the
isolated and identified active thalidomide metabolites, and
variations of such thalidomide analogs, have been developed. Such
thalidomide analog compounds show enhanced potency in the
inhibition of undesirable angiogenesis without the undesirable
effects of administration of thalidomide.
Inventors: |
Figg; William D. (Fairfax,
VA), Eger; Kurt (Leipzig, DE), Teubert; Uwe
(Hameln, DE), Weiss; Michael (Bethesda, MD),
Guetschow; Michael (Bonn, DE), Hecker; Thomas
(Erfurt, DE), Hauschildt; Sunna (Leipzig,
DE) |
Applicant: |
Name |
City |
State |
Country |
Type |
Figg; William D.
Eger; Kurt
Teubert; Uwe
Weiss; Michael
Guetschow; Michael
Hecker; Thomas
Hauschildt; Sunna |
Fairfax
Leipzig
Hameln
Bethesda
Bonn
Erfurt
Leipzig |
VA
N/A
N/A
MD
N/A
N/A
N/A |
US
DE
DE
US
DE
DE
DE |
|
|
Assignee: |
The United States of America as
represented by the Secretary of the Department of Health and Human
Services (Washington, DC)
N/A (N/A)
|
Family
ID: |
23037728 |
Appl.
No.: |
11/880,404 |
Filed: |
July 19, 2007 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20070293519 A1 |
Dec 20, 2007 |
|
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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10469359 |
|
7320991 |
|
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PCT/US02/05868 |
Feb 26, 2002 |
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60271941 |
Feb 27, 2001 |
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Current U.S.
Class: |
514/323 |
Current CPC
Class: |
C07D
401/04 (20130101); A61K 31/513 (20130101); A61K
31/506 (20130101); C07D 403/04 (20130101); A61K
31/454 (20130101); A61P 43/00 (20180101); C07D
209/48 (20130101); A61K 31/4035 (20130101); A61P
35/02 (20180101); A61P 35/00 (20180101); A61P
9/00 (20180101); A61K 31/4035 (20130101); A61K
2300/00 (20130101); A61K 31/454 (20130101); A61K
2300/00 (20130101); A61K 31/506 (20130101); A61K
2300/00 (20130101) |
Current International
Class: |
A61K
31/445 (20060101) |
Field of
Search: |
;514/323 |
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|
Primary Examiner: Chang; Celia
Attorney, Agent or Firm: Klarquist Sparkman, LLP
Parent Case Text
PRIORITY CLAIM
This is a continuation of U.S. patent application Ser. No.
10/469,359, filed Nov. 14, 2003, which is a .sctn.371 U.S. national
stage of PCT/US02/05868, filed Feb. 26, 2002, which was published
in English under PCT Article 21(2), and claims the benefit of U.S.
Provisional Application No. 60/271,941, filed Feb. 27, 2001, all of
which are incorporated by reference in their entirety.
Claims
We claim:
1. A composition that inhibits angiogenesis in a subject when
administered in an effective amount, wherein the composition
comprises one or more compounds having the following formula or
pharmaceutically acceptable salts thereof; ##STR00012## wherein R4
through R7 are, independently, a halogen, or R5 and R6 are hydrogen
and R4 and R7 are methyl groups.
2. The composition of claim 1, wherein the compound is:
##STR00013## or a pharmaceutically acceptable salt thereof.
3. The composition of claim 1, wherein the compound is:
##STR00014## or a pharmaceutically acceptable salt thereof.
4. The composition of claim 1, further comprising a
pharmaceutically acceptable carrier.
5. The composition of claim 2, further comprising a
pharmaceutically acceptable carrier.
6. The composition of claim 3, further comprising a
pharmaceutically acceptable carrier.
Description
FIELD OF THE INVENTION
The present invention concerns anti-angiogenesis compositions and
methods, and particularly thalidomide analogs that actively inhibit
angiogenesis in humans and animals.
BACKGROUND OF THE INVENTION
Angiogenesis is the formation of new blood vessels from
pre-existing vessels. Angiogenesis is prominent in solid tumor
formation and metastasis. A tumor requires formation of a network
of blood vessels to sustain the nutrient and oxygen supply for
continued growth. Some tumors in which angiogenesis is important
include most solid tumors and benign tumors, such as acoustic
neuroma, neurofibroma, trachoma, and pyogenic granulomas.
Prevention of angiogenesis could halt the growth of these tumors
and the resultant damage due to the presence of the tumor.
It has been shown that there is a direct correlation between tumor
microvessel density and the incidence of metastasis. Tumor cells
themselves can produce factors that stimulate the proliferation of
endothelial cells and new capillary growth. Angiogenesis is
important in two stages of tumor metastasis. The first stage where
angiogenesis stimulation is important is in the vascularization of
the tumor, which allows tumor cells to enter the blood stream and
to circulate throughout the body. After the tumor cells have left
the primary site, and have settled into the secondary, metastasis
site, angiogenesis must occur before the new tumor can grow and
expand. Therefore, prevention of angiogenesis could lead to the
prevention of metastasis of tumors and possibly contain the
neoplastic growth at the primary site. These observations have led
to the investigation of anti-angiogenic agents as possible
therapeutic options for various cancers.
In the 1950's, thalidomide was marketed as a sedative in Europe but
was withdrawn from the market when it was found to be a potent
teratogen. Recently, thalidomide has been promoted as a possible
inhibitor of angiogenesis. Studies have indicated, however, that
thalidomide itself is not sufficiently active to inhibit
angiogenesis. Instead, the anti-angiogenic activity or effects
previously attributed to thalidomide are the resulting effects of
compounds that are only present following metabolic activation of
thalidomide (i.e., "active" thalidomide metabolites). D'Amato, R.;
Loughman Flynn, E.; Folkman, J., Thalidomide as an Inhibitor of
Angiogenesis. Proc. Nat'l. Acad. Sci., 1994, 91, 4082-4085; M.;
Bauer, K.; Dixon, S.; Figg, W. Inhibition of Angiogenesis by
Thalidomide Requires Metabolic Activation, Which Is
Species-dependent. Biochem. Pharmacology, 1998, 55, 1827-1834.
Accordingly, it has been speculated that certain metabolites of
thalidomide rather than thalidomide itself are responsible for its
anti-angiogenic properties. However, the specific thalidomide
metabolites responsible for the anti-angiogenic properties have not
yet been isolated and identified.
There are hundreds, if not thousands of compounds formed as a
result of metabolism of thalidomide and the actively metabolized
products of hydrolysis compounds of the thalidomide. Many of the
thalidomide metabolites are inactive and/or unstable. There is no
way to predict which metabolite(s) will have superior
anti-angiogenic properties. As such, "active" thalidomide
metabolites (or "active" thalidomide analogs) having superior
anti-angiogenic properties are not yet available.
If the anti-angiogenic activity can be attributed to one or a small
number of thalidomide metabolites and those metabolites could be
isolated and identified, then active thalidomide analogs may be
synthesized to provide exceptionally effective compounds inhibiting
angiogenic effects. This is especially true when comparing
thalidomide to "active" thalidomide analogs. To obtain such active
compounds from thalidomide, thalidomide must first be activated via
metabolism; only a very small amount of thalidomide would actually
be metabolized to one or more "active" metabolites. Further, it may
be possible to administer such "active" thalidomide analogs in
lower amounts and still achieve the desired anti-angiogenic
effects. Moreover, such "active" thalidomide analogs could be safer
than thalidomide in avoiding undesirable side effects, e.g.,
teratogenicity or neurotoxicity, and may be more specific to tumor
angiogenesis than thalidomide-thalidomide has a host of undesirable
biological activities.
Accordingly, there is a need for isolation and identification of
the thalidomide metabolites having superior anti-angiogenic
properties. Further, there is a need for the synthesis of purified
thalidomide analogs that can mimic the effects of the isolated and
identified thalidomide metabolites that display such
anti-angiogenic activity. In addition, there is a need for a method
for treating undesired angiogenesis using such active thalidomide
analogs.
SUMMARY OF THE INVENTION
The present invention provides compounds having superior
anti-angiogenic properties. More specifically, a number of
thalidomide metabolites having superior anti-angiogenic properties
have now been isolated and identified. Accordingly, the present
invention provides active thalidomide analogs that mimic the
effects of the isolated and identified active thalidomide
metabolites, and variations of such thalidomide analogs. Such
thalidomide analog compounds of the present invention show enhanced
potency in the inhibition of undesirable angiogenesis.
The present method further provides for inhibiting unwanted
angiogenesis in a human or animal by administering to the human or
animal with the undesired angiogenesis a composition comprising an
effective amount of active thalidomide analog of the present
invention. Specifically, the invention includes a method of
inhibiting angiogenesis by exposing the mass having the undesirable
angiogenesis to an angiogenesis inhibiting amount of one or more of
the present invention thalidomide analogs (and variations of the
same) or pharmaceutically acceptable salts of such compounds,
wherein such thalidomide analogs (and variations of the same) have
the following general formula (Formula A):
##STR00001## wherein R1 is a hydrogen when R2 is methyl alcohol, a
branched or unbranched alkyl alcohol, alkyl acid or amino acid,
alkylamine, substituted cycloalkyl, substituted alkylphenyl, or
phenylalkyl or R1 is a hydroxyl group, a substituted or
unsubstituted cycloalkyl aryl or heteroaryl when R2 is a hydrogen,
methyl alcohol, a branched alkylalcohol, alkyl acid, amino acid,
alkylamino, substituted cycloalkyl, substituted phenylalkyl or
alkylphenyl. Additionally, the phthalimid moiety may be replaced by
bicyclo [2,2,1]hepten-icarboxylicimid.
In another embodiment the thalidomide analogs (and variations of
the same) have the following general formula (Formula B):
##STR00002## wherein R4 through R7 are fluoride or are another
halogen, R4 through R7 may comprise the same or different halogens
or R5 and R6 are hydrogen and R4 and R7 are methyl groups.
Alternatively, there may be substitutions on the isoindole ring,
e.g., R4 through R7 may comprise different groups on the isoindole
ring to obtain 4-chloro; 4-nitro; 5,6-dichloro; 4-methyl; 5-methyl;
5,6-dimethyl; and 4,5,6,7-tetrachloro. Further, the isoindole ring
may be replaced with succinimides or maleimides. Additionally,
other halogens may be substituents at the phenyl ring. For example,
rather than 2,4-fluoro, the following groups may be substituents on
the phenyl ring: 2,3-difluoro; 2,5-difluoro; 2,6-difluoro;
3,4-difluoro; 3,5-difluoro; 2,3-dichloro; 2,4-dichloro;
2,4-dichloro; 2,6-dichloro; 2,4-dibromo; 2,5-dibromo; 2,6-dibromo;
2-fluoro; 3-fluoro; 4-fluoro; 2-chloro; 3-chloro; 4-chloro;
2-bromo; 3-bromo; 4-bromo; 2,3,4-trifluoro. Additionally, the
phthalimid moiety may be replaced by bicyclo
[2,2,1]hepten-icarboxylicimid.
In another aspect of the invention, the thalidomide analogs (and
variations of the same) have the following general formula (Formula
C):
##STR00003## wherein R8 through R11 are hydrogen, R12 is an alkyl
residue, R13 is a double-bonded oxygen, sulfur or nitrogen, and R14
is an alkyl, cycloalkyl, substituted phenyl, or a cyclic alkyl,
such as cyclo-hexane or wherein R8 through R11 are fluoride or are
one or more other halogens, R12 is an alkyl residue, R13 is a
double-bonded oxygen, sulfur or nitrogen and R14 is benzene or
wherein R8 through R11 are fluoride or are one or more other
halogens, and R12 through R14 are hydrogen. In addition, the N--H
may be substituted by R15, wherein R15 is an alkylamine,
substituted cycloalkyl, substituted alkylphenyl or phenylalkyl,
methyl alcohol, branched or unbranched alkyl alcohol, alkyl acid or
amino acid.
The invention also includes pharmaceutical compositions that
include one or more of the compounds of the present invention, or
pharmaceutically acceptable salts thereof, and pharmaceutically
acceptable carriers. Further, it is to be understood that the
compounds included as part of the present invention shown generally
in Formulas A-C above, but include all other compounds that are
members of the genus described by such general formulas.
Examples of a couple specific thalidomide analog compounds (having
superior anti-angiogenic activity) that are members of the genus of
Formula A of the present invention are
##STR00004## i.e.,
2-(5-hydroxy-2,6-dioxo-piperidin-3-yl)-1H-isoindole-1,3[2H]-dione,
and
##STR00005## i.e.,
2-(1-hydroxymethyl-2,6-dioxo-piperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-
-dione.
Examples of some specific thalidomide analog compounds (having
superior anti-angiogenic activity) that are members of the genus of
Formula B of the present invention are
##STR00006## i.e.,
2-(2,4-difluorophenyl)-4,7-dimethyl-1H-isoindole-1,3(2H)-dione,
and
##STR00007## i.e.,
2-(2,4-difluorophenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione.
Examples of specific thalidomide analog compounds (having superior
anti-angiogenic activity) that are members of the genus of Formula
C of the present invention are
##STR00008## i.e., 1-cyclohexyl-5-ethyl-phthalimidobarbituric acid,
and
##STR00009## i.e.,
5-ethyl-1-phenyl-5-(tetrafluorophthalimido)barbituric acid, and
##STR00010## i.e.,
5-(tetrafluorophthalimido)pyrimidine-2,4(1H,3H)-dione.
The invention also includes pharmaceutical compositions that
include one or more of the above-described compounds.
The foregoing and other objects, features, and advantages of the
invention will become more apparent from the following detailed
description of particular examples that proceed with reference to
the accompanying figures.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a photomicrograph of a control comprising a rat aorta
ring treated with DMSO.
FIG. 2 is a photomicrograph of a rat aorta ring treated with
CPS3.
FIG. 3 is a photomicrograph of a rat aorta ring treated with about
100 .mu.M of CPS11.
FIG. 4 is a photomicrograph of another rat aorta ring treated with
about 100 .mu.M of CPS11.
FIG. 5 is a photomicrograph of another rat aorta ring treated with
about 100 .mu.M of CPS11.
FIG. 6 is a photomicrograph of a rat aorta ring treated with about
100 .mu.M of CPS44.
FIG. 7 is a photomicrograph of a rat aorta ring treated with about
100 .mu.M of CPS45.
FIG. 8 is a photomicrograph of another rat aorta ring treated with
about 100 .mu.M of CPS48.
FIG. 9 is a photomicrograph of another rat aorta ring treated with
about 100 .mu.M of CPS49.
DETAILED DESCRIPTION OF PARTICULAR EXAMPLES
Definitions
The term "halogen" refers to fluoro, bromo, chloro and iodo
substituents.
A "pharmaceutical agent" or "drug" refers to a chemical compound or
composition capable of inducing a desired therapeutic or
prophylactic effect when properly administered to a subject.
The pharmaceutically acceptable salts of the compounds of this
invention include those formed from cations such as sodium,
potassium, aluminum, calcium, lithium, magnesium, zinc, and from
bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine,
arginine, ornithine, choline, N,N'-dibenzylethylenediamine,
chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,
diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and
tetramethylammonium hydroxide. These salts may be prepared by
standard procedures, for example by reacting the free acid with a
suitable organic or inorganic base. Any chemical compound recited
in this specification may alternatively be administered as a
pharmaceutically acceptable salt thereof.
All chemical compounds include both the (+) and (-) stereoisomers,
as well as either the (+) or (-) stereoisomer.
A thalidomide "analog" as used herein is a synthetic chemical
compound using the thalidomide structure as a backbone (i.e., side
groups have been added or such groups have been deleted from the
parent structure). The analog differs in structure from thalidomide
and its metabolite compounds such as by a difference in the length
of an alkyl chain, a molecular fragment, by one or more functional
groups, or a change in ionization. Thalidomide analogs generally
are not naturally occurring compounds. That is, thalidomide analogs
generally cannot be enzymatically or nonenzymatically formed in the
body by administration of thalidomide.
A thalidomide "metabolite" is a thalidomide derivative that is
formed by enzymatic action, i.e., metabolism of thalidomide in the
body. The metabolite is formed by phase-one reactions (e.g.,
oxidation, reduction, and hydrolysis) or by phase-two reactions
(e.g., conjugations). Thalidomide metabolites require an enzyme
reaction to be produced.
"Angiogenesis" refers to the development of blood vessels.
Accordingly, "anti-angiogenic activity" refers to the inhibition
and/or complete cessation of angiogenesis.
"Tumor" refers to a mass of cells resulting from excessive cellular
multiplication.
The term "halogen" refers to fluoro, bromo, chloro and iodo
substituents.
The term "alcohol" refers to any member of a class of organic
compounds in which a hydrogen atom of a hydrocarbon has been
replaced by a hydroxy (--OH) group. Unless otherwise mentioned,
such an alcohol contains one to twelve carbon atoms.
The term "acid" refers to a compound capable of transferring a
hydrogen atom in solution.
The term "alkyl" refers to a cyclic, branched, or straight chain
alkyl group containing only carbon and hydrogen, and unless
otherwise mentioned contains one to twelve carbon atoms. This term
is further exemplified by groups such as methyl, ethyl, n-propyl,
isobutyl, t-butyl, pentyl, pivalyl, heptyl, adamantyl, and
cyclopentyl. Alkyl groups can either be unsubstituted or
substituted with one or more substituents, e.g., halogen, alkyl,
alkoxy, alkylthio, trifluoromethyl, acyloxy, hydroxy, mercapto,
carboxy, aryloxy, aryloxy, aryl, arylalkyl, heteroaryl, amino,
alkylamino, dialkylamino, morpholino, piperidino, pyrrolidin-1-yl,
piperazin-1-yl, or other functionality.
The term "amino acid" refers to any of the organic compounds that
contain one or more basic amino groups (--NH.sub.2) and one or more
acidic carboxyl groups (--COOH) and that are polymerized to form
peptides and proteins.
The term "aryl" refers to a monovalent unsaturated aromatic
carbocyclic group having a single ring (e.g., phenyl) or multiple
condensed rings (e.g., naphthyl or anthryl), which can optionally
be unsubstituted or substituted with, e.g., halogen, alkyl, alkoxy,
mercapto (--SH), alkylthio, trifluoromethyl, acyloxy, hydroxy,
mercapto, carboxy, aryloxy, aryl, arylalkyl, heteroaryl, amino,
alkylamino, dialkylamino, morpholino, piperidino, pyrrolidin-1-yl,
piperazin-1-yl, or other functionality.
The term "alkyl residue" refers to a branched or straight chain
alkyl group containing only carbon and hydrogen, and unless
otherwise mentioned contains one to twelve carbon atoms. The term
is further exemplified by groups such as methyl, ethyl, n-propyl,
isobutyl, pentyl, pivalyl and heptyl. Alkyl groups can either be
substituted or unsubstituted.
Other chemistry terms herein are used according to conventional
usage in the art, as exemplified by The McGraw-Hill Dictionary of
Chemical Terms (1985), The Condensed Chemical Dictionary (1981),
and Dorland's Illustrated Medical Dictionary (1974).
A "mammal" includes both human and non-human mammals. Similarly,
the term "subject" includes both human and veterinary subjects.
An "animal" is a living multicellular vertebrate organism, a
category that includes, for example, mammals and birds.
"Thalidomide" or N-(2,6-dioxopiperidin-3-yl)phthalimide has the
following chemical structure:
##STR00011## Materials and Methods
Where necessary, solvents were dried and purified according to the
recommended procedures. Organic solutions were dried over
NaSO.sub.4. Evaporation refers to removal of solvent on a
Vacuubrand rotary evaporator under reduced pressure of from about
200 to about 15 mbar. Melting points were determined using a
Boetius apparatus and are uncorrected. .sup.1H NMR spectra (300
Mhz), .sup.13C NMR spectra (75 MHz), and .sup.19F spectra (188 MHz)
were recorded on a Varian Gemini 300 spectrometer with
tetramethylsilane as internal standard; the values of chemical
shifts (.delta.) are given in ppm and coupling constants (J) in Hz.
Mass spectral data were determined by direct insertion at 70 eV
with a Varian MAT CH6 spectrometer as well as a HP-MS Engine 5989A.
Yields refer to purified products and are not optimized.
Compound Reference Numbers
Compounds are identified throughout this detailed description using
alpha-numeric references in bold, which correspond to the
identification of the compounds as set forth in the Summary of the
Invention, and in the following examples.
EXAMPLE 1
Synthesis of and Analytical Results for
2-(5-hydroxy-2,6-dioxo-piperidin-3-yl)-1H-isoindole-1,3[2H]-dione
(CPS3)
This example illustrates the preparation of
2-(5-hydroxy-2,dioxo-piperidin-3(2H)-dione) having a molecular
weight of about 274.2. A mixture of about 1.0 g (about 3.2 mmol) of
acetic acid
5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,6-dioxo-piperidin-3-yl-ester
(single diastereomer) prepared according to Teubert, U. et al.,
Arch. Pharm. Pharm. Med. Chem., 1998, 331, 7 (incorporated herein
by reference) and about 0.3 g (about 1.6 mmol) of p-toluenesulfonic
acid was refluxed in about 30 ml of methanol for about 5 hours. The
solution was allowed to cool to about room temperature. After
cooling, the precipitated product was filtered and recrystallized
from acetone/petroleum ether (having a boiling point of about
60.degree. to about 80.degree. C.). Alternatively, the
precipitated, filtered product was recrystallized from
acetonitrile. A yield of about 0.52 g (about a 60% yield) of
2-(5-hydroxy-2,6-dioxo-piperidin-3-yl)-1H-isoindole-1,3[2H]-dione
having a melting point of about 195.degree. to about 230.degree. C.
resulted.
The .sup.1H NMR spectral analysis results were as follows:
(DMSO-d6) 2.27-2.53 (m, 2H, 4'-H), 4.53-4.57 (m, 1H, 5'-H), 5.29
(dd, J=13.1, 5.2 Hz, 1H, 3'-H), 5.82 (d, J=6.0 Hz, 1H, OH),
7.90-7.94 (m, 4H, aromatic H), 11.22 (s, 1H, NH). The .sup.13C NMR
spectral analysis results were as follows: (DMSO-d6) 31.3 (C-4'),
48.22 (C-3'), 66.33 (C-5'), 123.29, 131.19, 138.88 (C-aromatic),
166.86, 176.17, 169.70, 174.71 (C.dbd.O). Mass spectrometry
analysis (EI) results yielded, m/z (relative intensity), 274
(13)[M+].
EXAMPLE 2
Synthesis of and Analytical Results for
2-(1-hydroxymethyl-2,6-dioxo-piperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-
-dione (CPS11)
This example illustrates the preparation and analysis of
2-(1-hydroxymethyl-2,6-dioxo-piperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-
-dione having a molecular weight of about 288.25.
A suspension of about 12.9 g (about 50 mmol) of rac-thalidomide in
about 100 mL of an about 35% aqueous formaldehyde solution was
refluxed until dissolved. The solution was then allowed to cool to
room temperature. After about 24 hours, the precipitate was
collected by filtration and washed with about 3% aqueous
formaldehyde solution and was then dried with Na.sub.2SO.sub.4. A
yield of about 10.1 g (about a 70% yield) of
2-(1-hydroxymethyl-2,6-dioxo-piperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-
-dione having a melting point of about 165.degree. C. resulted.
The .sup.1H NMR spectral analysis results were as follows:
(DMSO-d6) 2.16-2.67 (m, 2H, 4'-H), 2.87-3.11 (m, 2H, 5'-H), 5.08
(d, J=7.2 Hz, 2H, NCH.sub.2OH), 5.52 (m, 1H, CHCH.sub.2), 6.17 (t,
Jab=7.2 Hz, Jbc=7.2 Hz, 1H, OH), 7.92 (s, 4H, Harom.). Analytical
values for the compound C.sub.14H.sub.12N.sub.2O.sub.5 were carbon
about 58.27%, hydrogen about 4.09%, and nitrogen about 9.52%.
EXAMPLE 3
Synthesis of and Analytical Results for
2-(2,4-difluorophenyl)-4,7-dimethyl-1H-isoindole-1,3(2H)-dione
(CPS42)
This example illustrates the preparation and analysis of
2-(2,4-difluorophenyl)-4,7-dimethyl-1H-isoindole-1,3(2H)-dione
having an exact mass of 287.08, a molecular weight of about 287.6
(carbon about 66.90%, hydrogen about 3.86%, fluoride about 13.23%,
nitrogen about 4.88%, and oxygen about 11.14%).
A mixture of about 2 g (about 15.5 mmol) of 2,4-difluoroaniline,
about 2.46 g (about 14 mmol) of 3,6-dimethylphthalic anhydride, and
about 100 mL of glacial acetic acid was refluxed for about 3.5
hours. The 3,6-dimethylphthalic anhydride was prepared according to
Newman, M. S.; Lord, B. T., J. Am. Chem. Soc., 1944, 66, 733, which
is incorporated herein by reference.
The solvent was evaporated to dryness under reduced pressure of
from about 200 to about 15 mbar. The residue was dissolved in about
150 mL of CH.sub.2C.sub.12. The solution was washed three times
with about 50 mL of about 0.1 M HCl and twice with about 50 mL of
H.sub.2O and was then dried with Na.sub.2SO.sub.4. After removal of
the solvent, the residue was recrystallized from ethyl alcohol to
yield about 1.27 g (32%)
2-(2,4-difluorophenyl)-4,7-dimethyl-1H-isoindole-1,3(2H)-dione
having a melting point of about 212.degree. to about 212.5.degree.
C.
The .sup.1H NMR spectral analysis results were as follows:
(DMSO-d6) 2.59 (s, 6H), 7.24-7.32 (m, 1H), 7.46-7.56 (m, 1H), 7.54
(s, 2H) 7.56-7.66 (m, 1H). The .sup.13C NMR spectral analysis
results were as follows: (DMSO-d6) 16.87 (CH.sub.3), 104.93 (dd,
2J=27.1, 24.2 Hz, C-3'), 112.08 (dd, 2J=22.6, 4J=3.6 Hz, C-5'),
115.93 (dd, 2J=13.2, 4J=3.9 Hz, C-1'), 128.15 (C-4, C-7), 132.07
(dd, 3J=10.1, 2.1 Hz, C-6') 135.37 (C-3a, C-7a), 136.62 (C-5, C-6),
157.81 and 162.08 (d, J=264.1 Hz and d, J=235.6 Hz, C-2' and C-4'),
166.64 (C-1, C-3). Mass spectrometry analysis (EI) results yielded,
m/z (relative intensity), 287 (M+, 100), 259 (81c). Analytically
calculated values for the compound C.sub.16H.sub.11NO.sub.2F.sub.2
were carbon 66.90%, hydrogen 3.86%, and nitrogen 4.88%. As
determined from the NMR and mass spectrometry analysis result
values for the compound C.sub.16H.sub.11NO.sub.2F.sub.2 were carbon
about 67.20%, hydrogen about 3.77%, and nitrogen about 4.59%.
EXAMPLE 4
Synthesis of and Analytical Results for
1-cyclohexyl-5-ethyl-5-phthalimidobarbituric acid (CPS44)
This example illustrates the preparation and analysis of
1-cyclohexyl-5-ethyl-5-phthalimidobarbituric acid
(C.sub.20H.sub.21N.sub.3O.sub.5) having an exact mass of 283.15 and
a molecular weight of about 383.4 (carbon about 62.65%, hydrogen
about 5.52%, nitrogen about 10.96%, and oxygen about 20.87%). The
same compound might alternatively be named, e.g.,
1-cyclohexyl-5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5-ethyl-pyrimidine-2-
,4,6(1H,3H,5H)-trione or
1-cyclohexyl-5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5-ethyl-pyrimidine-2-
,4,6-trione.
A mixture of about 500 mg (about 2 mmol) of
5-amino-1-cyclohexyl-5-ethylbarbituric acid available from
5-azido-1-cyclohexyl-5-ethylbarbituric acid as described in
Guetschow, M. et al., Synthesis, 1999, 410-414 (incorporated herein
by reference) and about 300 mg (about 2 mmol) of phthalic anhydride
and about 20 mL of glacial acetic acid was refluxed for about 5
hours. The mixture was cooled to room temperature and the
precipitate was filtered off. The precipitate was next washed with
H.sub.2O and dried to give about 470 mg of
1-cyclohexyl-5-ethyl-5-phthalimidobarbituric acid (a yield of about
61%). The 1-cyclohexyl-5-ethyl-5-phthalimidobarbituric acid had a
melting point of about 248 to about 253.degree. C.
The .sup.1H NMR spectral analysis results were as follows:
(DMSO-d.sub.6)* 0.99 (t, 3H, J=7.4 Hz), 1.01-2.21 (m, 10H), 2.68
(q, 2H, J=7.4 Hz), 4.13-4.29 (m, 1H), 7.90 (s, 4H), 12.09 (s, 1H).
The .sup.13C NMR spectral analysis results were as follows:
(DMSO-d.sub.6)* 9.10, 24.83, 25.62, 25.71, 27.23, 27.92, 29.05,
54.66, 67.83, 123.74, 130.32, 135.56, 149.24, 167.20, 167.79,
168.28. The mass spectral (EI) analysis results were as follows:
m/z (relative intensity) 383 (M.sup.+, 5), 302 (M.sup.+, 100), 105
(52). Analytically calculated values for the compound
C.sub.20H.sub.21N.sub.3O.sub.5 were carbon 62.65%, hydrogen 5.52%,
and nitrogen 10.96%. As determined from the NMR and mass
spectrometry analysis results values for the compound
C.sub.20H.sub.21N.sub.3O.sub.5 were carbon about 62.30%, hydrogen
about 5.85%, nitrogen about 10.89%, and oxygen about 20.87%.
EXAMPLE 5
Synthesis of and Analytical Results for
5-ethyl-1-phenyl-5-(tetrafluorophthalimido)barbituric acid
(CPS45)
This example illustrates the preparation and analysis of
5-ethyl-1-phenyl-5-(tetrafluorophthalimido)barbituric acid
(C.sub.20H.sub.11N.sub.3O.sub.5F.sub.4) having an exact mass of
377.10 and a molecular weight of about 377.4 (carbon about 63.66%,
hydrogen about 4.01%, nitrogen about 11.14%, and oxygen about
21.20%). The same compound might alternatively be named, e.g.,
5-(1,3-dioxo-1,3-dihydro-4,5,6,7-tetrafluoro-isoindol-2-yl)-5-ethyl-1-phe-
nyl-pyrimidine-2,4,6-(1H,3H,5H)-trione.
A mixture of about 250 mg (about 1 mmol) of
5-amino-5-ethyl-1-phenylbarbituric acid, about 260 mg (about 1.2
mmol) of tetrafluorophthalic anhydride, and about 7 mL of acetic
acid was refluxed for about 3 hours. The solvent was evaporated to
dryness under reduced pressure of from about 200 to about 15 mbar.
The residue was recrystallized from ethyl alcohol to yield about
270 mg 5-ethyl-1-phenyl-5-(tetrafluorophthalimido)barbituric acid
(a 60% yield) having a melting point of about 218.degree. to about
220.degree. C.
The .sup.1H NMR spectral analysis results were as follows:
(DMSO-d6), 1.09 (t, 3H, J=7.2 Hz), 2.86 (q, 2H, J=7.3 Hz),
7.20-7.32 (m, 2H), 7.45-7.59 (m, 3H). The .sup.13C NMR spectral
analysis results were as follows: (DMSO-d6), 9.36, 26.90, 68.10,
112.20, 112.65, 128.05, 128.56, 129.27, 133.91, 141.10, 147.05,
148.88, 162.51, 166.85, 167.18. The mass spectral (EI) analysis
results were as follows: m/z (relative intensity), 449 (M.sup.+,
62), 421 (M.sup.+, 20), 230 (39), 176 (70), 119 (100). Analytically
calculated values for the compound
C.sub.20H.sub.11N.sub.3O.sub.5F.sub.4 were carbon 53.46%, hydrogen
2.47%, and nitrogen 9.35%. As determined from the NMR and mass
spectrometry analysis results values for the compound
C.sub.20H.sub.11N.sub.3O.sub.5F.sub.4 were carbon about 53.26%,
hydrogen about 2.78%, oxygen about 21.20%, and nitrogen about
9.04%.
EXAMPLE 6
Synthesis of and Analytical Results for
5-(tetrafluorophthalimido)pyrimidine-2,4(1H,3H)-dione (CPS48)
This example illustrates the preparation and analysis of
5-(tetrafluorophthalimido)pyrimidine-2,4(1H,3H)-dione
(C.sub.12H.sub.3F.sub.4N.sub.3O.sub.4) having an exact mass of
329.01 and a molecular weight of about 329.2 (carbon about 43.79%,
hydrogen about 0.92%, fluoride about 23.09%, nitrogen about 12.7%,
and oxygen about 19.44%). The same compound might alternatively be
named, e.g.,
2-(2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4,5,6,7-tetrafluoro-1H-is-
oindole-1,3(2H)-dione.
A mixture of about 440 mg anhydride (about 2 mmol) of
tetrafluorophthalic, about 254 mg (about 2 mmol) of 5-aminouracil,
and about 50 mL of glacial acetic acid was refluxed for about 6
hours. The solution was allowed to cool to about room temperature.
After cooling, the precipitated product was filtered, washed with
water, and dried with Na.sub.2SO.sub.4 to yield about 260 mg (about
40%) of 5-(tetrafluorophthalimido)pyrimidine-2,4(1H,3H)-dione with
a melting point of about 3500 to about 355.degree. C.
The .sup.1H NMR spectral analysis results were as follows:
(DMSO-d6) 7.89 (d, 1H, J=6.2 Hz), 11.47 (d, 1H, J=6.2 Hz), 11.72
(s, 1H). The .sup.19F NMR spectral analysis results were as
follows: (DMSO-d6/CFCl3) -142.0 (m, 2F), -136.5 (m, 2F). The mass
spectral (EI) analysis results were as follows: m/z (relative
intensity), 329 (M.sup.+, 50), 176 (100). Analytically calculated
values for the compound C.sub.12H.sub.3F.sub.4N.sub.3O.sub.4 were
carbon about 43.79%, hydrogen about 0.92%, and nitrogen about
12.77%. As determined from the NMR and mass spectrometry analysis
result values for the compound C.sub.12H.sub.3F.sub.4N.sub.3O.sub.4
were carbon about 43.60%, hydrogen about 1.16%, nitrogen about
12.50%.
EXAMPLE 7
Synthesis of and Analytical Results for (CPS49)
2-(2,4-difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione
This example illustrates the preparation and analysis of
2-(2,4-difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione
(C.sub.14H.sub.3F.sub.6NO.sub.2) having an exact mass of 331.01 and
a molecular weight of about 331.2 (carbon about 50.77%, hydrogen
about 0.91%, fluoride about 34.42%, nitrogen about 4.23%, and
oxygen about 9.66%).
A mixture of about 1 g (about 7.75 mmol) of 2,4-difluoroaniline,
about 1.54 g (about 7 mmol) of tetrafluorophthalic anhydride and
about 50 mL of glacial acetic acid was refluxed for about 3.5
hours. The solvent was evaporated to dryness under reduced pressure
of from about 200 to about 15 mbar. The residue was dissolved in
about 75 mL of CH.sub.2C.sub.12. The solution was washed three
times with about 25 mL of about 0.1 M HCl and twice with about 25
mL of water. The residue was then dried with Na.sub.2SO.sub.4.
After removal of the solvent, the residue was recrystallized from
ethyl alcohol to yield about 980 mg (about 42%) of
2-(2,4-difluorophenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione
with a melting point of about 145.degree. to about 146.degree.
C.
The .sup.1H NMR spectral analysis results were as follows:
(DMSO-d6) 7.22-7.38 (m, 1H), 7.50-7.66 (m, 2H). The .sup.19F NMR
spectral analysis results were as follows: (DMSO-d6/CFCl3) -142.3
(m, 2F), -136.9 (m, 2F), -113.8 (m, 1F), -105.6 (m, 1F). The mass
spectral (EI) analysis results were as follows: m/z (relative
intensity), 331 (M.sup.+, 65), 287 (68), 148 (100). Analytically
calculated values for the compound C.sub.14H.sub.3NO.sub.2F.sub.6
were carbon about 50.78%, hydrogen about 0.91%, and nitrogen about
4.23%. As determined from the NMR and mass spectrometry analysis
results values for the compound C.sub.14H.sub.3NO.sub.2F.sub.6 were
carbon about 50.60%, hydrogen about 0.83%, and nitrogen about
3.95%.
EXAMPLE 8
HUVEC MTT Assay for Selected Present Invention Thalidomide
Analogs
HUVEC MTT assays were performed for the selected thalidomide
analogs of the present invention to determine a rough estimate of
the efficacy of such compounds in the inhibition of angiogenesis.
For the MTT assay, 1.0 to 2.5.times.10.sup.3 cells per well were
plated in 96-well plates in 0.1 ml medium, in triplicate. After 24
hours, the cells were exposed to treatment for 5 days. One plate
was analyzed every 24 hours by the addition of 20 .mu.L of 5 mg/ml
MTT solution (available from Sigma of St. Louis, Mo.) in PBS, to
each well for 4 hours. The MTT solution was aspirated and 170 .mu.L
DMSO was added to each well to dissolve the formazan crystals. The
absorbance at 540 nm was measured using a Biokinetics plate reader
(available from Bio-Tek Instruments of Winooski, Vt.). Triplicate
wells were assayed for each condition. The assay protocol described
herein stems from Kruger et al., a protein kinase C inhibitor,
inhibits endothelial cell proliferation and angiogenic hypoxic
response, Invasion and Metastasis, 18(4): 209-218 (incorporated
herein by reference).
The following results for the selected compounds were determined
measured utilizing growth curves comparing control wells to treated
wells using the MTT assays.
2-(5-hydroxy-2,6-dioxo-piperidin-3-yl)-1H-isoindole-1,3[2H]-dione
(CPS 3)--No cytostatic activity was noted at either 100 .mu.M or at
10 .mu.M.
2-(1-hydroxymethyl-2,6-dioxo-piperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-
-dione (CPS11)--Potent inhibition (>90%) at 100 .mu.M was found
at about 72 hours. An inhibition of about 60% was found at 10 .mu.M
was noted at about 72 hours.
2-(2,4-difluorophenyl)-4,7-dimethyl-1H-isoindole-1,3(2H)-dione
(CPS42)--An inhibition of about 44% was found at 100 .mu.M but no
such activity was found at a level of about 10 .mu.M.
1-cyclohexyl-5-ethyl-5-phthalimidobarbituric acid (CPS44)--An
inhibition of about 50% was found at 100 .mu.M but no such activity
was found at a level of about 10 .mu.M.
5-ethyl-1-phenyl-5-(tetrafluorophthalimido)barbituric acid
(CPS45)--Potent inhibition (>90%) at 100 .mu.M and at 10 .mu.M
was noted.
5-(tetrafluorophthalimido)pyrimidine-2,4(1H,3H)-dione (CPS48)
Potent inhibition (about 85%) at 100 .mu.M and at 10 .mu.M was
noted.
2-(2,4-difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione
(CPS49)--A potent inhibition of about 90% was found at 100 .mu.M
but no such activity was found at a level of about 10 .mu.M.
EXAMPLE 9
Anti-angiogenic Activity Analysis Results for Selected Present
Invention Thalidomide Analogs Measured Utilizing Rat Aortic
Rings
The efficacy of selected thalidomide analogs of the present
invention was studied by five-day treatment of rat aortic rings
(utilizing Sprague-Dawley rats available from Charles River Labs)
with varied doses of the analogs. A DMSO control was utilized (FIG.
1). The results, determined using image analysis comparing control
rings versus the treated rings (using NIM Image software), of the
studies are as follows:
2-(5-hydroxy-2,6-dioxo-piperidin-3-yl)-1H-isoindole-1,3[2H]-dione
(CPS3)--A daily dosage of 100 .mu.M showed about a 50% angiogenesis
inhibition activity (FIG. 2).
2-(1-hydroxymethyl-2,6-dioxo-piperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-
-dione (CPS11)--A daily dosage of 100 .mu.M showed a potent 90%
angiogenesis inhibition activity (FIGS. 3-5).
1-cyclohexyl-5-ethyl-5-phthalimidobarbituric acid (CPS44)--No
inhibition of angiogenesis was found at 100 .mu.M (FIG. 6).
5-ethyl-1-phenyl-5-(tetrafluorophthalimido)barbituric acid (CPS45)
--A daily dosage of 100 .mu.M showed a potent 90% angiogenesis
inhibition activity (FIG. 7).
5-(tetrafluorophthalimido)pyrimidine-2,4(1H,3H)-dione (CPS48)--A
daily dosage of 100 .mu.M showed a potent 90% angiogenesis
inhibition activity (FIG. 8).
2-(2,4-difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione
(CPS49)--A daily dosage of 100 .mu.M showed extensive angiogenesis
inhibition activity (FIG. 9).
EXAMPLE 10
Anti-angiogenic Activity Analysis Results for
2-(1-hydroxymethyl-2,6-dioxo-piperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-
-dione (CPS11) Measured Utilizing Human Saphenous Vein
The efficacy of
2-(1-hydroxymethyl-2,6-dioxo-piperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-
-dione (CPS11) was studied by 14 day treatment of human saphenous
veins (obtained through an IRB-approved protocol, Surgery Brand
NCI) with 100 .mu.M doses of the analog. A CAI,
carboxyamido-triazole, 12 .mu.g/ml control was utilized. The
results of such studies using image analysis as discussed above,
indicate that daily dosages of 100 .mu.M of
2-(1-hydroxymethyl-2,6-dioxo-piperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-
-dione (CPS11) showed a potent 90% angiogenesis inhibition activity
level.
EXAMPLE 11
Toxicology Screen Analysis Results for Selected Present Invention
Thalidomide Analogs
Toxicology screen studies have been performed for the thalidomide
analogs of the present invention. The results of such toxicology
screening studies for selected thalidomide analogs are as
follows:
2-(1-hydroxymethyl-2,6-dioxo-piperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-
-dione (CPS11)--Treatment was safe at dosage levels of 10 and 100
mg/kg, i.p., single dose. Some amount of sedation was noted.
2-(2,4-difluorophenyl)-4,7-dimethyl-1H-isoindole-1,3(2H)-dione
(CPS42)--Treatment was safe at a dosage level 200 mg/kg, i.p.,
single dose. Slight sedation was noted within 15 minutes of
injection.
5-ethyl-1-phenyl-5-(tetrafluorophthalimido)barbituric acid (CPS45)
--A dose of 200 mg/kg, i.p., single dose, was a lethal dose.
Animals treated with such dosage died within 2.5 hours of
treatment.
2-(2,4-difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione
(CPS49)--A dose of 200 mg/kg, i.p., single dose, was a lethal dose.
Animals treated with such dosage died within 18 hours of
treatment.
EXAMPLE 12
Methods of Treatment
The present invention includes a treatment for undesirable
angiogenesis and angiogenesis dependent or associated diseases, in
a subject such as an animal, for example a rat or human. The method
includes administering one or more of the compounds of the present
invention, or a combination of one or more of the compounds and one
or more other pharmaceutical agents, to the subject in a
pharmaceutically compatible carrier. The administration is made in
an amount effective to inhibit the development or progression of
angiogenesis and diseases associated with the same. Although the
treatment can be used prophylactically in any patient in a
demographic group at significant risk for such diseases, subjects
can also be selected using more specific criteria, such as a
definitive diagnosis of the condition.
The vehicle in which the drug is delivered can include
pharmaceutically acceptable compositions of the drugs, using
methods well known to those with skill in the art. Any of the
common carriers, such as sterile saline or glucose solution, can be
utilized with the drugs provided by the invention. Routes of
administration include but are not limited to oral and parenteral
routes, such as intravenous (iv), intraperitoneal (ip), rectal,
topical, ophthalmic, nasal, and transdermal.
The drugs may be administered in a suitable manner now known or
later developed, e.g., orally or intravenously, in any conventional
medium. For example, intravenous injection may be by an aqueous
saline medium. The medium may also contain conventional
pharmaceutical adjunct materials such as, for example,
pharmaceutically acceptable salts to adjust the osmotic pressure,
lipid carriers such as cyclodextrins, proteins such as serum
albumin, hydrophilic agents such as methyl cellulose, detergents,
buffers, preservatives and the like. A more complete explanation of
parenteral pharmaceutical carriers can be found in Remington: The
Science and Practice of Pharmacy (19.sup.th Edition, 1995) in
chapter 95.
Embodiments of other pharmaceutical compositions can be prepared
with conventional pharmaceutically acceptable carriers, adjuvants
and counterions as would be known to those of skill in the art. The
compositions are preferably in the form of a unit dose in solid,
semi-solid and liquid dosage forms such as tablets, pills, powders,
liquid solutions or suspensions.
The compounds of the present invention are ideally administered as
soon as possible after detected unwanted angiogenesis. For example,
once unwanted angiogenesis has been confirmed or the presence of a
tumor has been identified, a therapeutically effective amount of
the drug is administered. The dose can be given orally or by
frequent bolus administration.
Therapeutically effective doses of the compounds of the present
invention can be determined by one of skill in the art, with a goal
of achieving a desired level of anti-angiogenesis as illustrated in
the foregoing examples. The relative toxicities of the compounds
make it possible to administer in various dosage ranges. An example
of such a dosage range is from about 0.5 to about 50 mg/kg body
weight orally in single or divided doses. Another example of a
dosage range is from about 0.5 to about 50 mg/kg body weight orally
in single or divided doses. For oral administration, the
compositions are, for example, provided in the form of a tablet
containing from about 25 to about 500 mg of the active ingredient,
particularly 100 mg of the active ingredient for the symptomatic
adjustment of the dosage to the subject being treated.
The specific dose level and frequency of dosage for any particular
subject may be varied and will depend upon a variety of factors,
including the activity of the specific compound, the extent of
existing angiogenic activity, the age, body weight, general health,
sex, diet, mode and time of administration, rate of excretion, drug
combination, and severity of the condition of the host undergoing
therapy.
The pharmaceutical compositions can be used in the treatment of a
variety of diseases mediated by angiogenesis. Examples of such
diseases include all types of cancer, ocular neovascular disease,
solid tumor formation and metastasis in solid tumors such as
rhabdomyosarcomas, retinoblastoma, Ewing sarcoma, neuroblastoma,
osteosarcoma, colon, prostate, head and neck, breast, bladder,
liver, pancreatic, lung, CNS, and blood-born tumors such as
leukemia, also diseases such as hemangioma, ulcerative colitis,
Crohn's disease, diabetic retinopathy, macular degeneration, sickle
cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's
disease, vein occlusion, artery occlusion, carotid obstructive
disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's
disease, systemic lupus erythematosis, retinopathy of prematurity,
Eale's disease, Bechet's disease, infections causing a retinitis or
choroiditis, presumed ocular histoplasmosis, Best's disease,
myopia, optic pits, Stargart's disease, pars planitis, chronic
retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma
and post-laser complications. Other diseases include, but are not
limited to, diseases associated with rubeosis (neovasculariation of
the angle) and diseases caused by the abnormal proliferation of
fibrovascular or fibrous tissue including all forms of
proliferative vitreoretinopathy.
EXAMPLE 13
Combination Therapy
The present invention also includes combinations of the thalidomide
analogs of the present invention and/or combination of the same
with various other angiogenesis inhibitor compounds. For example,
the compounds of this invention may be administered in combination
with effective doses of other anti-angiogenic agents. The term
"administration" refers to both concurrent and sequential
administration of the active agents. Examples of anti-angiogenic
agents that can be used in combination with the thalidomide analogs
of the present invention are TNP-470, carbonic anhydrase
inhibitors, endostatin, angiostatin, 2-methoxyestradiol, IMiD
(Immune-modulating inhibitor drug) CC5013, matrix metalloproteinase
inhibitors, and COL-3. In addition, the thalidomide analogs of this
invention may be used in combination with other forms of cancer
therapy, e.g., chemotherapy, radiation therapy, hormonal
therapy).
In view of the many possible embodiments to which the principles of
our invention may be applied, it should be recognized that the
illustrated embodiment is only a preferred example of the invention
and should not be taken as a limitation on the scope of the
invention. Rather, the scope of the invention is defined by the
following claims. We therefore claim as our invention all that
comes within the scope and spirit of these claims.
* * * * *