CA2342974C - Methods and compositions for inhibition of angiogenesis - Google Patents
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- CA2342974C CA2342974C CA002342974A CA2342974A CA2342974C CA 2342974 C CA2342974 C CA 2342974C CA 002342974 A CA002342974 A CA 002342974A CA 2342974 A CA2342974 A CA 2342974A CA 2342974 C CA2342974 C CA 2342974C
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Abstract
The present invention comprises a group of compounds that effectively inhibit angiogenesis. More specifically, thalidomide and various related compounds such as thalidomide precursors, analogs, metabolites and hydrolysis products have been shown to inhibit angiogenesis. Importantly, these compounds can be administered orally.
Description
METHODS AND COMPOSITIONS
FOR INHIBITION OF ANGIOGENESIS
Th:i~; application is a divisional application of Canadian Patent Fi)_e No. 2,157,288 filed February 24, 1994.
Technical Field ,o The present invention relates to methods and compositions for preventing unwanted angiogenesis in a human or animal. More particularly, the present invention relates to a method for preventing unwanted angiogenesis, particularly in angiogenesis dependent or associated diseases, by administration of compounds such as thalidomide and related compounds.
Background of the Invention As used herein, the terrrl "angiogenesis" means the generation of new blood vessels into a tissue or organ. Under 3o normal physiological conditions, humans or animals only undergo angiogenesis in. very specific restricted situations. For example, ~:~n~io~.;.nesis is normally observed in wound healing, fetal and embryonal development and formation of the col-Fus :meum.
endometrium <irld placenta. The control of angiogenesis is a 35 highly regulated system of angiogenic stimulators and inhibitors.
The control of angiogenesis has been found to be altered in certain disease states and, in many cases, the pathological damage associated with the disease is related to the uncontrolled anglogenesis.
Both controlled and uncontrolled angiogenesis are s thought to proceed in a similar manner. Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the erosion of the basement membr'an.e by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood to vessels, then protrude through the basement membrane.
Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a "sprout" off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts is merge with each other to form capillary loops, creating the new blood vessel. In the disease state, prevention of angiogenesis could avert the damage caused by the invasion of the new microvascular system.
Persistent, unregulated angiogenesis occurs in a ~o multiplicity of disease states, tumor metastasis and abnormal growth by endothelial cells and supports the pathological damage seen in these conditions. The diverse pathological states created due to unregulated angiogenesis have been grouped together as angiogenic dependent or angiogenic associated diseases. Therapies 2s directed at control of the angiogenic processes could lead to the abrogation or mitigation of these diseases.
One example of a disease mediated by angiogenesis is ocular neovascular disease. This disease is characterized by invasion of new blood vessels into the structures of the eye such 3o as the retina or cornea. It is the most common cause of blindness and is involved in approximately twenty eye diseases. In age-related macular degeneration, the associated visual problems are caused by an ingrowth of chorioidal capillaries through defects in Bruch's membrane with proliferation of fibrovascular tissue 3s beneath the retinal pigment epithelium. Angiogenic damage is also associated with diabetic retinopathv, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and retrolental fibroplasia. Other diseases associated with corneal neovascularization include, but are not limited to, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear.
atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis, syphilis.
Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, ftmgal ulcers, Herpes simplex infections, Herpes io =oster infections, protozoan infections, Kaposi sarcoma, Mooren ulcer, Terrien's marginal degeneration, mariginal keratolysis, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, We~eners sarcoidosis, Scleritis, Steven's Johnson disease, periphigoid radial keratotomy, and corneal graph rejection.
is Diseases associated with retinal/choroidal neovascularization include, but are not limited to, diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Pagets disease., vein occlusion, artery occlusion, carotid obstructive disease, chronic o uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales disease, Bechets disease, infections causing a retinitis or choroiditis.
presumed ocular h istoplasmosis, Bests disease, myopia, optic pits.
Stargarts disease, pars planitis, chronic retinal detachment, ~s hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications. (Jther diseases include, but are not limited to, diseases associated with rubeosis (neovasculariation of the angle) and diseases caused by the abnor~rrlal proliferation of fibrovascular or fibrous tissue including all fornls of proliferative 3o vitreoretinopathy.
Another disease in which angiogenesis is believed to be involved is rheumatoid arthritis. Tr.blood vessels in the synovial lining of the joints undergo angiogenesis. In addition to forming new vascular networks, the endothelial cells release 3s factors and reactive oxygen species that lead to pannus growth WO 94120085 PCT/US94l01971 and cartilage destruction. The factors involved in angiogenesls may actively contribute to, and help maintain, the chronically inflamed state of rheumatoid arthritis.
Factors associated with angiogenesis may also have a role in osteoarthritis. The activation of the chondrocvtes by angiogenic-related factors contributes to the destruction of the joint. At a later stage, the angiogenic factors would promote new bone formation. rfherapeutic intervention that prevents the bone destruction could halt the progress of the disease and provide io relief for persons suffering with arthritis.
Chronic inflammation may also involve pathological angiogenesis. Such disease states as ulcerative colitis and C.'rohn's disease show histological changes with the ingrowth of new blood vessels into the inflamed tissues. Bartonellosis, a bacterial a infection found in South America, can result in a chronic stage that is characterized by proliferation of vascular endothelial cells.
Another pathological role associated with angiogenesis is found in atherosclerosis. The plaques formed within the lumen of blood vessels have been shown to have angiogenic stimulatory activity.
o One of the most frequent angiogenic diseases of childhood is the hemangioma. In most cases, the tumors are benign and regress without intervention. In more severe cases.
the tumors progress to large cavernous and infiltrative forms and create clinical complications. Systemic forms of hemangiomas.
~s the hemangiornatoses, have a high mortality rate.
Therapy-resistant hemangiomas exist that cannot be treated with therapeutics currently in use.
Angiogenesis is also responsible for damage found in hereditary diseases such as Osler-Weber-Rendu disease, or 3o hereditary hemorrhagic telangiectasia. This is an inherited disease characterized by multiple small angiomas, tumors of Mood or iyn~ph vessels. The ang~omas are found in the Skin and mucous membranes, often accompanied by epistaxis (nosebleeds) or gastrointestinal bleeding and sometimes with pulmonary or 3s hepatic arteriovenous fistula.
_ j _ Angiogenesis is prominent in solid tumor formation and metastasis. ,A.ngiogenic factors have been found associated with several solid tumors such as rhabdomyosarcomas, retinoblastoma, Ewin~ sarcoma, neuroblastoma, and s osteosarcoma. A tumor cannot expand without a blood supply to provide nutrients wld remove cellular wastes. Tumors in which angiogenesis is important include solid tumors, and benign tumors such as acoustic neuroma, neurofibroma, trachoma and p~yagenic granulomas. Prevention of angiogenesis could halt the growth of to these tumors and the resultant damage to the animal due to the presence of the tumor.
It should be noted that angiogenesis has been associated with blood-born tumors such as leukemias, anv of various acute or chronic neoplastic diseases of the bone marrow is in which unrestrained proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood clotting, and enlargement of the lymph nodes, liver, and spleen. It is believed that angiogenesis plays a role in the abnormalities in the bone marrow that give rise to leukemia-like tumors.
~o Angi.ogenesis is important in two stages of tumor metastasis. T'he first stage where angiogenesis stimulation is important is in t:he 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 ~s 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.
3o Knowledge of the role of angiogenesis in the maintenance and metastasis of tumors has led to a prognostic indicator for breast cancer. The amount of neovascularization found in the primary tumor was determined by counting the microvessel density in the area of the most intense 3s neovascular-ization in yinvasive breast carcinoma. A high level of microvessel density was found to correlate with tumor recurrence. Control of angiogenesis by therapeutic means could possibly lead to cessation of the recurrence of the tumors.
Angiogenesis is also involved in normal physiological s processes such as reproduction and wound healing. Angio~enesis is an important step in ovulation and also in implantation of the blastula after fertilization. Prevention of angiogenesis could be used to induce alr~enorrhea, to block ovulation or to prevent implantation by thc: blastula.
to In wound healing, excessive repair or fibroplasia can be a detrimental aide effect of surgical procedures and may be caused or exacerbated by angiogenesis. Adhesions are a frequent complication of surgery and lead to problems such as small bowel obstruction.
is Several kinds of compounds have been used to prevent angiogenesis. Taylor et al. have used protamine to inhibit angiogenesis, see 'Taylor et al., Nature 297:307 ( 1982). The toxicity of protamine limits its practical use as a therapeutic.
Folkman et al. have disclosed the use of heparin and steroids to 2o control angiogenesis. See Follcman et al., Science 22I :719 ( 1983 ) and U.S. Patent Nos. 5,001,116 and 4,994,443. Steroids, such as tetrahydrocortisol, which lack gluco and mineral corticoid activity, have been found to be angiogenic inhibitors.
Other factors found endogenously in animals, such as ~s a 4 kDa glycoprotein from bovine vitreous humor and a cartilage derived factor, have been used to inhibit angiogenesis. C'.ellular factors such as interferon inhibit angiogenesis. For example, interferon a or human interferon Q has been shown to inhibit tumor-induced a~:lgiogenesis in mouse dermis stimulated by 3o human neoplastic cells. Interferon 13 is also a potent inhibitor of angiogenesis induced by allogeneic spleen cells. See Sidky et al., Cancer Research 47:5155-5161 (1987). Human recombinant a interferon (alphar'A) was reported to be successfully used in the treatment of pulmonary hemangiomatosis, an angiogenesis-- 7 _.
induced disease. See White et al., New England J. ;'bled.
320:1 I 97- I 200 ( 1989).
Other agents which have been used to inhibit angiogenesis include ascorbic acid ethers and related compounds.
s See Japanese Kokai Tokkyo Koho No. 58-131978. Sulfated polysaccharide DS 4152 also shows angiogenic inhibition. See Japanese Kokai Tokkyo Koho No. 63-1 19500. A fungal product, fumagillin, is a patent angiostatic agent in vitro. The compound is toxic In vivo, but a synthetic derivative, AGM 12470, has been to used in vlvo to treat collagen II arthritis. Fumagillin and O-substituted fum<lgillin derivatives are disclosed in EPO
Publication Nos. 032_5199A2 and 0357061 A 1.
PCT .Application No. WO 92/1445 to Kaplan et al.
is directed to a method for controlling abnormal concentration of is TNF-a by administering thalidomide or thalidomide derivatives to a patient with toxic concentrations of TNF-a.
The above compounds are either topical or injectable therapeutics. Therefore, there are drawbacks to their use as a general angiogenic inhibitor and lack adequate potency. For ~o example, in prevention of excessive wound healing, surgery on internal body organs involves incisions in various structures contained within the body cavities. These wounds are not accessible to local applications of angiogenic inhibitors. Local delivery systems also involve frequent dressings which are ~s impracticable for internal wounds, and increase the risk of infection or damage to delicate granulation tissue for surface wounds.
Thus, a method and composition are needed that are capable of inhibiting angiogenesis and which are easily 3o administered. A simple and efficacious method of treatment would be through. the oral route. If an angiogenic inhibitor could be given by an oral route, the many kinds of diseases discussed above, and other angiogenic dependent pathologies, could be treated easily. Tile optimal dosage could be distributed in a form 3s that the patient could self-administer.
Summary of the Invention In accordance with the present invention, compositions and methods are provided that are effective in inhibiting unwanted angiogenesis. These compositions are easily administered by different routes including oral and can be given in dosages that are safe and provide angiogenic inhibition at internal sites. The present invention provides a method of treating mammalian diseases mediated by undesired and uncontrolled angiogenesis by administering a composition comprising an anti-angiogenic compound in a dosage sufficient to inhibit angiogenesis.
The present invention also includes angiogenic inhibiting compounds that contain an epoxide group. These angiogenic inhibiting compounds can be administered to a human or animal alone or with epoxide hydrolase inhibiting compounds.
The present invention is especially useful for treating certain ocular neovascular diseases such as macular degeneration.
The compounds which are contemplated as part of the present invention preferably can be given orally to the patient and thereby halt the progression of the disease. Other disease that can be treated using the present invention are diabetic retinopathy, neovascular glaucoma and retrolental fibroplasia.
Accordingly, the present invention seeks to provide a compound and method to inhibit unwanted angiogenesis in a human or animal.
Further, the present invention seeks to provide a composition of inhibiting angiogenesis by oral administration of the composition.
I
_g_ Still further, the present invention seeks to provide a treatment for diseases mediated by angiogenesis.
Further still, the present invention seeks to provide a treatment for macular degeneration.
Yet further, the present invention seeks to provide a treatment for all forms of proliferative vitreoretinopathy including those forms not associated with diabetes.
Moreover, the present invention seeks to provide a treatment for solid tumors.
Still further, the present invention seeks to provide a method and composition for the treatment of blood-born tumors such as leukemia.
Further still, the present invention seeks to provide a method and composition for the treatment of hemangioma.
Another aspect of the present invention seeks to provide a method and composition for the treatment of retrolental fibroplasia.
Yet another aspect of the present invention seeks to provide a method and composition for the treatment of psoriasis.
Moreover, the present invention seeks to provide a method and composition for the treatment of Kaposi's sarcoma.
Yet further,, the present invention seeks to provide a method and composition for the treatment of Crohn's diseases.
Still further, the present invention seeks to provide a method and composition for the treatment of diabetic retinopathy.
The invention in a broad aspect comprehends the use of a composition administered for treating undesired angiogenesis in a human or animal. The composition comprises an effective amount of an angiogenesis-inhibiting compound selected from the group consisting of the following compounds:
-9a-A) x RZ Rsw Ra B) i R2 Rs /
Rd t RZ
Rs R Ra-~
wherein R,, R2, R3, and R4 can be selected from: -H; -OH; = O, straight chained and branched alkanes, alkenes, alkynes; cyclic alkanes, alkenes and alkynes; combinations of cyclic and acyclic alkanes, alkenes and alkynes; alcohol, aldehyde, ketone, carboxylic acid, ester, or either moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; -XO~ or -O-XO~, (where X = N and n = 2; X = S and n = 2 or 3; or X = P and n =1-3): and halogens; R5, Rs, R,, and R8 are each independently selected from:
y Y
i -C-RLV: 'N-Wo i - 9b -or -O- where Y is optional and is the same as defined above for R,;
and R,o is the same as defined above for R,, or (where Y is absent) R,o is =O; and R9 is a moiety having formula D), E), F), G) or H):
D) ~lz-~R1\
-Rm- ~ tz -R,1\ ,Rla Rid-R13 Rib-Ri/s E) G) R~z Ria /Riz-Ri° -R
-Rt1 ~ l \ /Ris Ri3'-'-R~s R1~_Rl where each of R" - R" is (independently) the same as defined above for R5;
Ris -C-R,9 I
R2o where R,8, R,9 and R2o are, independently selected from 0 ~ O O
-H, CH3, -C- OH, -C-NH2,- (CHz)o C-OH, or -(CHZ)o - C-NHz.
and n=1 to 4;
provided the compound is not thalidomide.
-9c-The invention in another aspect comprehends the use of a composition administered for treating undesired angiogenesis in a human or animal. The composition comprises an effective amount of an angiogenesis-inhibiting compound selected from the group consisting of the following compounds:
(I) (II) O
~ N
O N' \O I ~1 O
I ~
and X
wherein R is selected from the group consisting of H, (C,-C6)alkyl, phenyl, and benzyl;
R' is selected from the group consisting of phthalimido and succinimido;
X is CH2 or C = O; and R" is H, -CH2CH3, -CsHS, -CH2CsH5, -CHZCH = CH2, or CHZ-N O
and (III) hydrolysis products of (11) wherein R" is H and the piperidino ring or both the piperidino and the imido ring are hydrolyzed provided the compound is not thalidomide.
Further, the invention provides for the use of a composition administered for treating undesired angiogenesis in a human or animal. The composition comprises an effective amount of -9d-an angiogenesis-inhibiting compound selected from the group consisting of a-thalidomide, EM-12, EM-138, phthaloyl glutamic anhydride and phthaloyl glutamic acid and metabolites of thalidomide, EM-12, EM-138, phthaloyl glutamic anhydride and phthaloyl glutamic acid, or mixtures thereof.
Moreover, the invention provides for the use of an angiogenesis inhibiting amount of a compound in administratable form for treating blood-born tumors in a human. The compound comprises the formula:
R' Rio Rio Y
Y
R~ R
,N ~R~a R~ ~/ R~s-N/H
Ra wherein:
R,, R2, R3 and R4 are each independently -H; -OH; straight chained or branched alkane; straight chained or branched alkene; straight chained 2~ or branched alkyne; cyclic alkane; cyclic alkene; cyclic alkyne;
alcohol, aldehyde, ketone, ester or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; -N02; -S02; -S03; -P03; -0-P03 or halogen;
R5 and Rs are each independently, CH2 , CHOH °r C ;
Y is optional and each occurrence of Y is -H; -OH; straight chained or branched alkane; straight chained or branched alkene; straight chained or branched alkyne; cyclic alkane; cyclic alkene; cyclic alkyne;
-9e-alcohol, aldehyde, ketone, ester or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino;
-N02; -SO2; -S03; -P03; -O-P03 or halogen; each occurrence of R,o is -H; -OH; straight chained or branched alkane; straight chained or branched alkene; straight chained or branched alkyne; cyclic alkane;
cyclic alkenecyclic alkyne; alcohol, aldehyde, ketone, carboxylic acid, ester, or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino -N02; -S02; -S03;
P03; -O-P03; halogen, or when Y is absent R,o is = 0; and R,4 and R,s are each independently I
CH2 , CHOH ~r C ;
provided the compound is not thalidomide.
These and other aspects, features and advantages of the present invention will become apparent after a review of the following detailed description of the disclosed embodiments and the appended claims.
Brief Description of the Figures Figures 1 through 3 are a listing of representative compounds in the genus represented by the following General formulas:
s R' Rs ~R
Rb Ra 1=3 ) R, R
Rs-R~
R3 R~
Ra C) t R, Rs R Ra_R9 t0 Figure 4 is a listing of representative compounds in the genus represented by the following general formula:
O
R"
\N-Rza \\
R?.3 is Figure 5 is a listing of representative compounds in the genus represented by the following general formula:
O~ ,OH
~C O
~'.~I-X
H
Figure 6 shows the effect of thalidomide and EMl?
on angiogenesis in a rabbit cornea model of angiogenesis.
Figure 7 shows the effect of thalidomide on the area of corneal vascularization in a rabbit cornea model of angtogenesls.
Detailed Description The present invention includes compositions and to methods for the treatment of diseases that are mediated by angiogenesis. Une embodiment of the present invention is the use of thalidomide or the metabolites of thalidomide as disclosed herein to inhibit unwanted angiogenesis. The present invention also includes compounds which cause dysmelia is the developing is fetus and have anti-angiogenic activity. The present invention comprises a method of treating undesired angiogenesis in a human or animal comprising the steps of administering to the human or animal with the undesired angiogenesis a composition comprising an effective amount of a teratogenic compound that is anti-2o anglogenlc.
Compounds that can be used in accordance with the present invention include compounds included in the following general formulae. Examples of compounds that have anti-angiogenic properties having one of the following three 2s formulae (A), (:B), or (C):
~'O 94120085 PCT/US94l01971 - 1? -A) Rt R, R
5\
R~
R~ /Ra_ R~
Rh Ra B) R, RS
_v Rg-R~
R~ R~
Ra C) R t , RS
R Rs _ R9 Ra In the above formulae A), B), and C). Rl, R2, R3 and R~ can be selected from: ~-H; -OH; =O, straight chained and branched alkanes, alkenes, alkynes; cyclic alkanes, alkenes, and alkynes;
to combinations of cyclic and acyclic alkanes, alkenes, and alkynes:
alcohol, aldehyde, ketone, carboxy 1 is acid, ester, or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; -XOn or -O-XOn, [where X=N and n=2; X=S and n=2 or 3; or X=P and n=l-3]; and is halogens; R5, R6, R7, and Rg are each independently selected from:
Y Y
-L~Rto: -N-Rto:
or -O- where Y is optional and is the same as defined above for R l ; and R 1 p is the same as defined above for R1, or (where Y is w0 94120085 PCTlUS94101971 absent) Rlp is =O; and R9 is a moiety having formula D). E), F).
G) or H):
D) F) / t -RWRm -Rlt/~ Rls R14-Rlz Rt6-Rt;
E) G) Rl,Rt3~
Rts j Rt~-Rta -R
a -Rtt ~ ~ ~Rl~
~Rt;-Rts Rl~'.-Rtb where each of R 1 ~ - R 1'7 is (independently) the same as defined above for R5;
~o ys -C-Rt9 I
R~o where R 1 g, R 19 and R2p are, independently selected from O O O O
-H, CH3, -C- OH, -C-NH,,- (CH2W C-OH, or -(CH,)n- C-NH,.
is and n=1 to 4.
Accordingly, another aspect of the present invention features inhibitin~; angiogenesis in a mammal by administering a therapeutic composition comprising olio of the above-described compounds in a dosage sufficient to inhibit angiogenesis - I.~ -In preferred embodiments, the compound has formula B), where R~ and R6 are selected from the Group consisting of:
CHI , -CHOH, and jC0 and R9 has formula F) or H); and R I4 and R 16 are selected from the group consisting of:
R"
;CH,, ; CHOH, or -C-: and R15 and is -O-, or -~
I I
O
where R~ 1 is -H, -CH,3, or -OH. Specific preferred compounds according to this aspect of the present invention include to thalidomide, its precursors, metabolites and analogs. Particular analogs include EM-12, N-phthaloyl-DL-glutamic acid (P(~A) or N-phthaloyl-DL-g;lutamine anhydride. Examples of compounds that are members of this genus are listed in Figures 1 through 3.
It is to be understood that the compounds included as part of the is present invention are not to be limited to those compounds shown in Figures I through 3 and include all other compounds that are members of the genus described by the general formulas herein.
Compounds of the following formula that have anti-angiogenic properties:
O
R"
\ ~-RZa \\
R~3 O
where R22 and R~3 are (independently), -H, -F, -Cl, -Br, -I.
-CH3, or -CHI -CH3; and R24 is -H, -CH3, or -CH2 -CH3.
The present invention also features inhibiting angiogenesis in a mammal by administering a compound ~s according to the above formulae in a dosage suffi;.:Pnt to inhibit angiogenesis. E:x:amples of specific compounds that are members of this genus are listed in Figure 4.
- IS -Angiogenesis inhibition hydrolysis products of thalidomide having the following general formula can be used in practicing the present invention:
O~ ,OH
C O
' N-X
H
s where X is R6 as defined above, or O I O
X is R,5-C-C-(CH,)~-C-R~6 io and R~5 and R~6 are, independently, -OH, -H, or NH2, and n=1 through 4. Examples of such compounds are shown in Figure 5.
Angiogenesis inhibition compounds having the following general formula can be used in practicing the present tnvennon:
(I) O O R,. (II) i -R' / N
/N O
O i ~O \ X
R
~ (a) CH,-N O
- U
wherein compounds of structure (I), wherein R is selected from the group consisting of hydrogen, alkyl radicals of 1 to 6 carbon atoms, the phenyl radical, and the benzyl radical;
2o and wherein R' is selected from the group consisting of the phthalimido radical and the succinimido radical and of structure (II), wherein X is CH2 or C-n; R" is H, -CH2CH3, -Cf,H~.
-CH2C6H5, -CH~CH=CH2, or (a) and hydrolysis products of the compounds wherein R" is H and the piperidino ring or both the ~s piperidino and flue imido ring are hydrolyzed.
~?VO 94120085 PCT/US94J01971 S
Another set of compounds that are considered part of the present invention are the epoxides of thalidomide, EM-1? and EM-138. Repres~°ntative epoxide compounds are shown as follows:
O
O ~ C
C' _ ( 'N ~=0 ~~O Ci N
\ C ~-- N ~ I I ~ ' II i ' O O O H
O O H
Epoxides of thalidomide O O O
C \ C' 'N~~~O ~ N ~O
\ ~-- N
'' N' O O H
O H
to Epoxides of EM 12 O O
II II
O C'~OH
O O C~OH
C~ \ v N~ I N
\ I=O O C-O
OH OH
Epoxides of EM 138 is It should be understood that the epoxide can be attached at the 6,1 site on the benzene ring, the 1,2 site, the ? .
site 3,4 or the 4.5 site. All of these compounds are contemplated as part of the present invention.
o The epoxides of the thalidomide, EM-12, and EM 138 can be hydrolized to the following compounds:
O O
HO / C~ HO / Cv _ ~O HO I C N N~O
i C N I I
I I
O O H O O H
O
II
HO / C HO / C
_ p ~ N ~O
\ ~ HO \ ~.
O' H O H
O O
O OH O OH
II II
HO / Cv. HO / I CAN
N HO \ OH
OH
O O
to It is to be understood that the hydroxyl group can be on carbons l, :?, ~, 4, 5 and 6 of the benzene ring. Also contemplated as part of the present invention are dihydroxyl compounds wherein the two hydroxyl groups are located bis to each other on carbons l, 2, 3, 5 and 5 of the above compounds.
is The epoxides, the hydrolysis products of the epoxides, and the hydrolysis products of the thalidomide are all contemplated to be part of the present invention.
Lt is known that epoxides are hydrolized by a group of enzymes known as epoxide hydrolases. There i~ a class of 2o compounds which are epoxide hydrolase inhibitors. Examples of these compounds are valpromide (2-propylpentanamide) and valproic acid ( ~-propylpentanoic acid). Because epoxides are important angiogenesis inhibitors, it is contemplated as part of the present invention. compositions comprising anv of the angiogenesis inhibitors compounds recited herein in combination with epoxide hydrolase inhibitors. The epoxide hvdrolase inhibitors can be administered to a human or animal together or sequentially. The expoxide group appears to be an important substituent common to several angiogenesis inhibitors. The use of epoxide hydrolase inhibitors to potentiate the activity of any angiogenesis inhibitor containing an epoxide is contemplated as io pan of the present invention. For example, the epoxide hvdrolase inhibitors can be administered with the following epoxide-containing anti-angiogenesis compounds: AGNI 1470.
Eponimycin, microbial metabolites of Scolecobasidium arenarium designated f/20:~1:~, fr/111142 and fr/18487. See Oikawa.
is Biochem Biophys. Res. Comm, Vol. 81:1070 (1971) and Otsuka, J. Microbial. Bi orech., Vol 1:1 b3 ( 1991 ).
It is contemplated as an embodiment of the present invention the use of the epoxide containing angiogenesis inhibitors with or without epoxide hydrolase inhibitors as a treatment for 'o diseases mediated by elevated or toxic levels of TNF-a. TNF-a has been recognized as manifesting a dose dependent toxicity. If present at low levels for a long period of time, TNF-a can result in cachexia. Cachexia is a general weight loss and wasting occurring in the course of some chronic diseases such as cancer.
opportunistic infections of AIDS, inflammatory diseases, parasitic diseases, tuberculosis, and high dose IL-2 therapy. The epoxide containing angiogenesis inhibitors, with or without epoxide hydrolase inhibitors, are also effective in treating diseases such as septic shock, leprosy and graph vs. host disease.
3o Other embodiments are within the present invention.
For example, other dysmelia-causing compounds can be used according to the present invention, e.g. 4-methylphthalic acid.
pyridoxine, vasopressin, acetazolamide, or a compound having the following formula (where R= H, -OH, or -CH3):
WO 94!20085 PCT/US94101971 _ lg _ O NCO
I
R
Other compounds which are teratogens, such as valproic acid (2-propylpentar~oic acid), the retinoids, such as cis-retinoic acid.
and rifampin may also be used in accordance with the invention.
In summary, the preferred compounds are thalidomide, as urell as analogs, hydrolysis products. metabolites and precursors of thalidomide that are teratogenic, and. more specifically, that cause dismelia. However, it is to be understood that it is not necessary for a compound to have both teratogenic to activity and angiogenesis inhibiting activity to be considered part of the present invention. Dysmelia-causing compounds can be identified by the general procedures of Helm, Ar=nelmittle-forschung, 31 (i/6):941-949 ( 1981 ), in which rabbit pups are examined after exposure to the compound in utero. The is compounds can generally be purchased, e.g., from Andrulis Pharmaceuticals., Beltsville, MD, or synthesized according to known procedures. It is to be understood that the compounds of the present invf:ntion can exist as enantiomers and that the racemic mixture of enantiomers or the isolated enantiomers are ~o all considered as within the scope of the present invention.
Many of the compounds that are contemplated as part of the present invention can be enriched in optically active enantiomers of the compounds specified above. Specifically.
Blaschke has reported that the S enanantiomers may be ~s disproportionately responsible for the dismelia-producing effect of these compounds. See, generally Blaschke, Ar~neimittclf~~; s~hung 29:1640-1642 (1979). The above described articles generally describe procedures to obtain optically active preparations of the compounds of interest. See.
3o e.g. Shealy et al.., Chem. Indus. 1030 ( 1965); and Casini et al..
Farmaco Ed. Sci. 19:563 ( 1964).
The compounds described above can be provided as pharmaceutically acceptable formulations using formulation methods known to those of ordinary skill in the art. These formulations can 'be administered by standard routes. In general.
the combination:, may be administered by the topical.
transdermal, oral, rectal or parenteral (e.g., intravenous, subcutaneous or intramuscular) route. In addition. the combinations ma:y be incorporated into biodegradable polymers o allowing for sustained release of the compound, the polymers being implanted in the vicinity of where drug delivery is desired.
for example, at the site of a tumor. The biodegradable polymers and their use are described, for example, irl detail in Brem et al..
J. Neurosurg. 74:441-446 ( 1991 ).
n The dosage of the compound will depend on the condition being treated, the particular compound, and other clinical factors such as weight and condition of the human or animal and the route of administration of the compound. It is to be understood that the present invention has application for both ~o human alld veterinary use. For oral administration to humans, a dosage of between approximately 0.1 to 300 mg~kg/day.
preferably between approximately 0.~ and 50 mg/kg/day. and most preferably between approximately I to 10 mg/kg/day, is generally sufficient.
The formulations include those suitable for oral.
rectal, ophthalmic, (including intravitreal or intracameral) nasal.
topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal.
intratracheal, and epidural) administration. The formulations 3o may conveniently be presented in unit dosage form and may be prepared by conventional pharrrlaceutical techniques. Such techniques include the step of bringing into association the active ingredient and tlhe pharmaceutical carriers) or excipient(s). In general, the formulations are prepared by uniformly and 3s intimately bringing into associate the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Fc:>rmulations of the present invention suitable for oral administration may be presented as discrete units such as s capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion and as a bolus, etc.
to A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine.
the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, Is preservative, surface active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally coated or scored and may be formulated so as to provide a slow or controlled release of the active ~o ingredient therein.
Formulations suitable for topical administration in the mouth include lozenges comprising the ingredients in a flavored basis, 'usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin ~s and glycerin, or sucrose and acacia; and mouthwashes comprising the ingredient to be administered in a suitable liquid carrier.
Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the ingredient to be administered in a pharmaceutical 3o acceptable carrier. A preferred topical delivery system is a transdermal patch containing the ingredient to be administered.
Formulations for rectal administration may be presented as a suppository with a suitabie base comprising, for example, cocoa butter or a salicylate.
'~'VO 94120085 PCT/US9410I971 _ 7~ _ Formulations suitable for nasal administration.
wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered in the manner in which snuff is s administered, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops.
include aqueous or oily solutions of the active ingredient.
io Formulations suitable for vagina( administration may be presented as pessaries, tamports, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration t5 include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The ~u formulations may be presented in unit-dose or mufti-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) conditions requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection ~s solutions and suspensions may be prepared from sterile powders.
granules and tablets. of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the administered 3o ingredient.
It should be understood that in addition to the ingredients, particularly mentioned above, the formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.
Diseases associated with corneal neovascularization that can be treated according to the present invention include but s are not limited to, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and retrolental fibroplasia, epidemic keratoconjunctivitis, Vitamin ~1 deficiency, contact: lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea.
to phylectenulosis, syphilis, Mycobacteria infections. lipid degeneration. chemical burns, bacterial ulcers, fungal ulcers.
Herpes simplex infections, Herpes poster infections, protozoan infections, Kaposi sarcoma, Mooren ulcer, Terrien's m<~rainal degeneration, mariginal keratolysis, trauma, rheumatoid arthritis.
is systemic lupus, polyarteritis, Wegeners sarcoidosis, Scleritis, Steven's Johnson disease, periphigoid radial keratotomy, and corneal graph rejection.
Diseases associated with retinal/choroidal neovascularization that can be treated according to the present ~o invention include, but are not limited to, diabetic retinopathv, macular degeneration, sickle cell anemia, sarcoid. syphilis.
pseudoxanthoma f:lasticum, Pagets disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis.
mycobacterial infections, Lyme's disease, systemic lupus ~s erythematosis, retinopathy of prematurity, Eales disease. Bechets disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Bests disease, myopia, optic pits, Stargarts disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications.
~o Other diseases include, but are not limited to, diseases associated with rubeosis (neovasculariation of the angle) and diseases caused by rhC «bnormal proliferation of fibrovascular o: fibrous tissue including all forms of proliferative vitreoretinopathy, whether or not associated with diabetes.
Another disease which can be treated according to the present inventicm is rheumatoid arthritis. It is believed that the blood vessels in the synovial lining of the joints undergo angiogenesis. In addition to forming new vascular networks. the ;_ endothelial cells release factors and reactive oxygen species that lead to pannus growth and cartilage destruction. The factors involved in angiogenesis may actively contribute to, and help maintain, the chronically inflamed state of rheumatoid arthritis.
Another disease that can be treated according to the to present invention are hemangiomas. Osier-Weber-Rendu disease.
or hereditary hemorrhagic telangiectasia, solid or blood borne tumors and acquired imrrlune deficiency syndrome.
This invention is further illustrated by the following examples, which are not to be construed in any way as imposing is limitations upon the scope thereof. On the contrary, it is to be clearly understood, that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to those skilled in the art without departing from the spirit of the present ~o invention and/or thf: scope of the appended claims.
Example I
The chick embryo chorioallantoic membrane assay described by Crum et al., Science 230:1375 et seq. ( 1985), is used ~s to identify compounds that do not require further metabolic conversion. See also, U.S. Patent 5,001,116, hereby incorporated by reference, which describes the CAM assay at col. 7 of the patent. Briefly, fertilized chick embryos are removed from their shell on day 3 or 4, and a methylcellulose disc containing the ~o compound is implanted on the chorioallantoic membrane. The embryos are examined 48 hours later and, if a clear avascular zone appears around the methylcellulosP disc, tl:e diarrleter of that zone is measured.
Example II
Rabbit cornea an,~iogenesis assay Pellets for implantation into rabbit corneas were made by mixing 1 1.0 pl of saline containing 12 ~tg of recombinant bFGF (Takeda Pharmaceuticals-Japan) with 40 mg of sucralfate (Bukh Meditec-Denmark); this suspension was added to ~0 ul of 12% hydron (Interferon Sciences) in ethanol. 10 ~tl aliquots of this mixture was then pipetted onto teflon pegs and allowed to dry producing approximately 17 pellets. A pellet was implanted into u~ corneal micropockets of each eye of an anesthetized female New Zealand white raldbit. 2mm from the limbus followed by topical application of eythromycin ointment onto the surface of the cornea. The animals were fed daily from 2 days post-implantation by gastric lavage with either drug suspended in 0.5%
t, carboxymethyl cellulose or 0.5% carboxymethyl cellulose alone.
Thalidomide was purchased from Andrulus Pharmaceutical (Maryland) and the EM-12 and Supidimide were kindly provided by Grunenthal GMBH (Germany). The animals were examined with a slit lamp every other day in a masked manner by the same ~o corneal specialist. The area of corneal neovascularization was determined by measuring with a reticule the vessel length (L) from the limbus and the number of clock hours (C) of limbus involved. A fornnula was used to determine the area of a circular band segment: C/12 * 3.1416 (r'-(r-L)2] where r=6 mm the measured radius of the rabbit cornea. Various mathematical models were utilized to determine the amount of vascularized cornea and this formula was found to provide the most accurate approximation o:F the area of the band of neovascularization that grows towards flue pellet.
3o It is important to note that the rabbit cornea assay is preferable because it will generally recognize compounds that are inactive per se hut are nmtz'oo!ized to yield active compounds.
Thalidomide related compounds, as shown below in Example III.
are known to be teratogens and are candidates for use in the 3s presenmnvention.
iV0 94/20085 PCT/US94101971 -?6-Example III
Inhibition o~~ bFGF induced corneal neovasculari=ation by thalidomide and related analog expressed as percent of median s control on day 8 Pellets containing bFGF and sucralfate were implanted into micropockets of both corneas of rabbits according to Example II. Vessel ingrowth into clear cornea from the limbus was first noted on day 2 and treatments (200 mg/kg orally) were to begun on this day. 'The area of corneal neovascularization was measured from day 4 through day 12. Day 8 measurements were used for comparison between groups. No regression of vessels and near maximal neovascularization was seen at this time point.
Statistical analysis was performed with ANOVA with ranked data is to account for interexperimental variation and to guard against a non-normal distribution of data (i.e. outliers) by utilizing a nonparametric method.
The compounds tested were as follows:
O
il C
CO
'C N
ii O O H
thalidomide O
I I
C
~ O ,N Oo N
O H
~s O
I I
C
\N ~ O
O
I I
O O
phthaloyl glutamic anhydride (PGA) O
OH
O
\N
OH
O O
s phthaloyl glutamic acid (PCJ Acid) O
il C
N ~O
~SO~ N
v O H
supidimide.
Treatment with a dose of (200 mg/kg) of thalidomide resulted in an inhibition of the area of vascularized cornea that io ranged from 30-51 % in three experiments with a median inhibition of 3fi~lo (Figure 6) (n=30 eyes, p=0.0001. '? way ANOVA with ranked data). The inhibition of angiogenesis by thalidomide was seen after only two doses (Figure 7). The rabbits did not demonstrate obvious sedation and there were no signs of is toxicity or weight loss. The teratogenic analog EM-1'?. which shares the other' properties of thalidomide was also inhibitory.
with a median inhibition of 42% (n=10 eyes, p=0.00?. l-way ANOVA with rmked data). Supidimide, a nonteratogenic analog of thalidomide that retains the sedative properties of thalidomide.
2o exhibited no acaivity (area 107% of control, n=10 eyes, not statistically different from control). Other analogs, PGA and PG
acid displayed weaker inhibitory effects than thalidomide (data ' WO 94/20085 PCT/US94101971 not shown). The density of vessel ingrowth in thalidomide-treated animals was also markedly reduced.
Example IV
s EM-12 in rabbit cornea assay EM-1:? was tested in the rabbit cornea assay described in Example II at 100 mg/kg/day and showed 21 inhibition, and at 2Wmg/kg/day the assay showed 43% inhibition.
to Example V
Phthaloyl glutamic acid in CAM
Phthaloyl glutamic acid was tested in the above described CAM assay and exhibit an avascular zone with a mild scar.
is Example VI
Phthalovl ~lutamic acid in rabbit cornea assay Phthaloyl glutamic acid described above at 200 mg/kg and exhibited 29% inhibition of angiogenesis.
Example VII
Phthaloyl glutamic anhydride in CAM assay Phthaloyl glutamic anhydride was test in the CAM
assay described above and exhibited an avascular zone.
It should be understood, of course, that the foregoing ~s relates only to preferred embodiments of the present invention and that numerous modifications or alterations may be made therein without departing from the spirit and the scope of the invention as set forth in the appended claims.
FOR INHIBITION OF ANGIOGENESIS
Th:i~; application is a divisional application of Canadian Patent Fi)_e No. 2,157,288 filed February 24, 1994.
Technical Field ,o The present invention relates to methods and compositions for preventing unwanted angiogenesis in a human or animal. More particularly, the present invention relates to a method for preventing unwanted angiogenesis, particularly in angiogenesis dependent or associated diseases, by administration of compounds such as thalidomide and related compounds.
Background of the Invention As used herein, the terrrl "angiogenesis" means the generation of new blood vessels into a tissue or organ. Under 3o normal physiological conditions, humans or animals only undergo angiogenesis in. very specific restricted situations. For example, ~:~n~io~.;.nesis is normally observed in wound healing, fetal and embryonal development and formation of the col-Fus :meum.
endometrium <irld placenta. The control of angiogenesis is a 35 highly regulated system of angiogenic stimulators and inhibitors.
The control of angiogenesis has been found to be altered in certain disease states and, in many cases, the pathological damage associated with the disease is related to the uncontrolled anglogenesis.
Both controlled and uncontrolled angiogenesis are s thought to proceed in a similar manner. Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the erosion of the basement membr'an.e by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood to vessels, then protrude through the basement membrane.
Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a "sprout" off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts is merge with each other to form capillary loops, creating the new blood vessel. In the disease state, prevention of angiogenesis could avert the damage caused by the invasion of the new microvascular system.
Persistent, unregulated angiogenesis occurs in a ~o multiplicity of disease states, tumor metastasis and abnormal growth by endothelial cells and supports the pathological damage seen in these conditions. The diverse pathological states created due to unregulated angiogenesis have been grouped together as angiogenic dependent or angiogenic associated diseases. Therapies 2s directed at control of the angiogenic processes could lead to the abrogation or mitigation of these diseases.
One example of a disease mediated by angiogenesis is ocular neovascular disease. This disease is characterized by invasion of new blood vessels into the structures of the eye such 3o as the retina or cornea. It is the most common cause of blindness and is involved in approximately twenty eye diseases. In age-related macular degeneration, the associated visual problems are caused by an ingrowth of chorioidal capillaries through defects in Bruch's membrane with proliferation of fibrovascular tissue 3s beneath the retinal pigment epithelium. Angiogenic damage is also associated with diabetic retinopathv, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and retrolental fibroplasia. Other diseases associated with corneal neovascularization include, but are not limited to, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear.
atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis, syphilis.
Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, ftmgal ulcers, Herpes simplex infections, Herpes io =oster infections, protozoan infections, Kaposi sarcoma, Mooren ulcer, Terrien's marginal degeneration, mariginal keratolysis, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, We~eners sarcoidosis, Scleritis, Steven's Johnson disease, periphigoid radial keratotomy, and corneal graph rejection.
is Diseases associated with retinal/choroidal neovascularization include, but are not limited to, diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Pagets disease., vein occlusion, artery occlusion, carotid obstructive disease, chronic o uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales disease, Bechets disease, infections causing a retinitis or choroiditis.
presumed ocular h istoplasmosis, Bests disease, myopia, optic pits.
Stargarts disease, pars planitis, chronic retinal detachment, ~s hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications. (Jther diseases include, but are not limited to, diseases associated with rubeosis (neovasculariation of the angle) and diseases caused by the abnor~rrlal proliferation of fibrovascular or fibrous tissue including all fornls of proliferative 3o vitreoretinopathy.
Another disease in which angiogenesis is believed to be involved is rheumatoid arthritis. Tr.blood vessels in the synovial lining of the joints undergo angiogenesis. In addition to forming new vascular networks, the endothelial cells release 3s factors and reactive oxygen species that lead to pannus growth WO 94120085 PCT/US94l01971 and cartilage destruction. The factors involved in angiogenesls may actively contribute to, and help maintain, the chronically inflamed state of rheumatoid arthritis.
Factors associated with angiogenesis may also have a role in osteoarthritis. The activation of the chondrocvtes by angiogenic-related factors contributes to the destruction of the joint. At a later stage, the angiogenic factors would promote new bone formation. rfherapeutic intervention that prevents the bone destruction could halt the progress of the disease and provide io relief for persons suffering with arthritis.
Chronic inflammation may also involve pathological angiogenesis. Such disease states as ulcerative colitis and C.'rohn's disease show histological changes with the ingrowth of new blood vessels into the inflamed tissues. Bartonellosis, a bacterial a infection found in South America, can result in a chronic stage that is characterized by proliferation of vascular endothelial cells.
Another pathological role associated with angiogenesis is found in atherosclerosis. The plaques formed within the lumen of blood vessels have been shown to have angiogenic stimulatory activity.
o One of the most frequent angiogenic diseases of childhood is the hemangioma. In most cases, the tumors are benign and regress without intervention. In more severe cases.
the tumors progress to large cavernous and infiltrative forms and create clinical complications. Systemic forms of hemangiomas.
~s the hemangiornatoses, have a high mortality rate.
Therapy-resistant hemangiomas exist that cannot be treated with therapeutics currently in use.
Angiogenesis is also responsible for damage found in hereditary diseases such as Osler-Weber-Rendu disease, or 3o hereditary hemorrhagic telangiectasia. This is an inherited disease characterized by multiple small angiomas, tumors of Mood or iyn~ph vessels. The ang~omas are found in the Skin and mucous membranes, often accompanied by epistaxis (nosebleeds) or gastrointestinal bleeding and sometimes with pulmonary or 3s hepatic arteriovenous fistula.
_ j _ Angiogenesis is prominent in solid tumor formation and metastasis. ,A.ngiogenic factors have been found associated with several solid tumors such as rhabdomyosarcomas, retinoblastoma, Ewin~ sarcoma, neuroblastoma, and s osteosarcoma. A tumor cannot expand without a blood supply to provide nutrients wld remove cellular wastes. Tumors in which angiogenesis is important include solid tumors, and benign tumors such as acoustic neuroma, neurofibroma, trachoma and p~yagenic granulomas. Prevention of angiogenesis could halt the growth of to these tumors and the resultant damage to the animal due to the presence of the tumor.
It should be noted that angiogenesis has been associated with blood-born tumors such as leukemias, anv of various acute or chronic neoplastic diseases of the bone marrow is in which unrestrained proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood clotting, and enlargement of the lymph nodes, liver, and spleen. It is believed that angiogenesis plays a role in the abnormalities in the bone marrow that give rise to leukemia-like tumors.
~o Angi.ogenesis is important in two stages of tumor metastasis. T'he first stage where angiogenesis stimulation is important is in t:he 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 ~s 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.
3o Knowledge of the role of angiogenesis in the maintenance and metastasis of tumors has led to a prognostic indicator for breast cancer. The amount of neovascularization found in the primary tumor was determined by counting the microvessel density in the area of the most intense 3s neovascular-ization in yinvasive breast carcinoma. A high level of microvessel density was found to correlate with tumor recurrence. Control of angiogenesis by therapeutic means could possibly lead to cessation of the recurrence of the tumors.
Angiogenesis is also involved in normal physiological s processes such as reproduction and wound healing. Angio~enesis is an important step in ovulation and also in implantation of the blastula after fertilization. Prevention of angiogenesis could be used to induce alr~enorrhea, to block ovulation or to prevent implantation by thc: blastula.
to In wound healing, excessive repair or fibroplasia can be a detrimental aide effect of surgical procedures and may be caused or exacerbated by angiogenesis. Adhesions are a frequent complication of surgery and lead to problems such as small bowel obstruction.
is Several kinds of compounds have been used to prevent angiogenesis. Taylor et al. have used protamine to inhibit angiogenesis, see 'Taylor et al., Nature 297:307 ( 1982). The toxicity of protamine limits its practical use as a therapeutic.
Folkman et al. have disclosed the use of heparin and steroids to 2o control angiogenesis. See Follcman et al., Science 22I :719 ( 1983 ) and U.S. Patent Nos. 5,001,116 and 4,994,443. Steroids, such as tetrahydrocortisol, which lack gluco and mineral corticoid activity, have been found to be angiogenic inhibitors.
Other factors found endogenously in animals, such as ~s a 4 kDa glycoprotein from bovine vitreous humor and a cartilage derived factor, have been used to inhibit angiogenesis. C'.ellular factors such as interferon inhibit angiogenesis. For example, interferon a or human interferon Q has been shown to inhibit tumor-induced a~:lgiogenesis in mouse dermis stimulated by 3o human neoplastic cells. Interferon 13 is also a potent inhibitor of angiogenesis induced by allogeneic spleen cells. See Sidky et al., Cancer Research 47:5155-5161 (1987). Human recombinant a interferon (alphar'A) was reported to be successfully used in the treatment of pulmonary hemangiomatosis, an angiogenesis-- 7 _.
induced disease. See White et al., New England J. ;'bled.
320:1 I 97- I 200 ( 1989).
Other agents which have been used to inhibit angiogenesis include ascorbic acid ethers and related compounds.
s See Japanese Kokai Tokkyo Koho No. 58-131978. Sulfated polysaccharide DS 4152 also shows angiogenic inhibition. See Japanese Kokai Tokkyo Koho No. 63-1 19500. A fungal product, fumagillin, is a patent angiostatic agent in vitro. The compound is toxic In vivo, but a synthetic derivative, AGM 12470, has been to used in vlvo to treat collagen II arthritis. Fumagillin and O-substituted fum<lgillin derivatives are disclosed in EPO
Publication Nos. 032_5199A2 and 0357061 A 1.
PCT .Application No. WO 92/1445 to Kaplan et al.
is directed to a method for controlling abnormal concentration of is TNF-a by administering thalidomide or thalidomide derivatives to a patient with toxic concentrations of TNF-a.
The above compounds are either topical or injectable therapeutics. Therefore, there are drawbacks to their use as a general angiogenic inhibitor and lack adequate potency. For ~o example, in prevention of excessive wound healing, surgery on internal body organs involves incisions in various structures contained within the body cavities. These wounds are not accessible to local applications of angiogenic inhibitors. Local delivery systems also involve frequent dressings which are ~s impracticable for internal wounds, and increase the risk of infection or damage to delicate granulation tissue for surface wounds.
Thus, a method and composition are needed that are capable of inhibiting angiogenesis and which are easily 3o administered. A simple and efficacious method of treatment would be through. the oral route. If an angiogenic inhibitor could be given by an oral route, the many kinds of diseases discussed above, and other angiogenic dependent pathologies, could be treated easily. Tile optimal dosage could be distributed in a form 3s that the patient could self-administer.
Summary of the Invention In accordance with the present invention, compositions and methods are provided that are effective in inhibiting unwanted angiogenesis. These compositions are easily administered by different routes including oral and can be given in dosages that are safe and provide angiogenic inhibition at internal sites. The present invention provides a method of treating mammalian diseases mediated by undesired and uncontrolled angiogenesis by administering a composition comprising an anti-angiogenic compound in a dosage sufficient to inhibit angiogenesis.
The present invention also includes angiogenic inhibiting compounds that contain an epoxide group. These angiogenic inhibiting compounds can be administered to a human or animal alone or with epoxide hydrolase inhibiting compounds.
The present invention is especially useful for treating certain ocular neovascular diseases such as macular degeneration.
The compounds which are contemplated as part of the present invention preferably can be given orally to the patient and thereby halt the progression of the disease. Other disease that can be treated using the present invention are diabetic retinopathy, neovascular glaucoma and retrolental fibroplasia.
Accordingly, the present invention seeks to provide a compound and method to inhibit unwanted angiogenesis in a human or animal.
Further, the present invention seeks to provide a composition of inhibiting angiogenesis by oral administration of the composition.
I
_g_ Still further, the present invention seeks to provide a treatment for diseases mediated by angiogenesis.
Further still, the present invention seeks to provide a treatment for macular degeneration.
Yet further, the present invention seeks to provide a treatment for all forms of proliferative vitreoretinopathy including those forms not associated with diabetes.
Moreover, the present invention seeks to provide a treatment for solid tumors.
Still further, the present invention seeks to provide a method and composition for the treatment of blood-born tumors such as leukemia.
Further still, the present invention seeks to provide a method and composition for the treatment of hemangioma.
Another aspect of the present invention seeks to provide a method and composition for the treatment of retrolental fibroplasia.
Yet another aspect of the present invention seeks to provide a method and composition for the treatment of psoriasis.
Moreover, the present invention seeks to provide a method and composition for the treatment of Kaposi's sarcoma.
Yet further,, the present invention seeks to provide a method and composition for the treatment of Crohn's diseases.
Still further, the present invention seeks to provide a method and composition for the treatment of diabetic retinopathy.
The invention in a broad aspect comprehends the use of a composition administered for treating undesired angiogenesis in a human or animal. The composition comprises an effective amount of an angiogenesis-inhibiting compound selected from the group consisting of the following compounds:
-9a-A) x RZ Rsw Ra B) i R2 Rs /
Rd t RZ
Rs R Ra-~
wherein R,, R2, R3, and R4 can be selected from: -H; -OH; = O, straight chained and branched alkanes, alkenes, alkynes; cyclic alkanes, alkenes and alkynes; combinations of cyclic and acyclic alkanes, alkenes and alkynes; alcohol, aldehyde, ketone, carboxylic acid, ester, or either moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; -XO~ or -O-XO~, (where X = N and n = 2; X = S and n = 2 or 3; or X = P and n =1-3): and halogens; R5, Rs, R,, and R8 are each independently selected from:
y Y
i -C-RLV: 'N-Wo i - 9b -or -O- where Y is optional and is the same as defined above for R,;
and R,o is the same as defined above for R,, or (where Y is absent) R,o is =O; and R9 is a moiety having formula D), E), F), G) or H):
D) ~lz-~R1\
-Rm- ~ tz -R,1\ ,Rla Rid-R13 Rib-Ri/s E) G) R~z Ria /Riz-Ri° -R
-Rt1 ~ l \ /Ris Ri3'-'-R~s R1~_Rl where each of R" - R" is (independently) the same as defined above for R5;
Ris -C-R,9 I
R2o where R,8, R,9 and R2o are, independently selected from 0 ~ O O
-H, CH3, -C- OH, -C-NH2,- (CHz)o C-OH, or -(CHZ)o - C-NHz.
and n=1 to 4;
provided the compound is not thalidomide.
-9c-The invention in another aspect comprehends the use of a composition administered for treating undesired angiogenesis in a human or animal. The composition comprises an effective amount of an angiogenesis-inhibiting compound selected from the group consisting of the following compounds:
(I) (II) O
~ N
O N' \O I ~1 O
I ~
and X
wherein R is selected from the group consisting of H, (C,-C6)alkyl, phenyl, and benzyl;
R' is selected from the group consisting of phthalimido and succinimido;
X is CH2 or C = O; and R" is H, -CH2CH3, -CsHS, -CH2CsH5, -CHZCH = CH2, or CHZ-N O
and (III) hydrolysis products of (11) wherein R" is H and the piperidino ring or both the piperidino and the imido ring are hydrolyzed provided the compound is not thalidomide.
Further, the invention provides for the use of a composition administered for treating undesired angiogenesis in a human or animal. The composition comprises an effective amount of -9d-an angiogenesis-inhibiting compound selected from the group consisting of a-thalidomide, EM-12, EM-138, phthaloyl glutamic anhydride and phthaloyl glutamic acid and metabolites of thalidomide, EM-12, EM-138, phthaloyl glutamic anhydride and phthaloyl glutamic acid, or mixtures thereof.
Moreover, the invention provides for the use of an angiogenesis inhibiting amount of a compound in administratable form for treating blood-born tumors in a human. The compound comprises the formula:
R' Rio Rio Y
Y
R~ R
,N ~R~a R~ ~/ R~s-N/H
Ra wherein:
R,, R2, R3 and R4 are each independently -H; -OH; straight chained or branched alkane; straight chained or branched alkene; straight chained 2~ or branched alkyne; cyclic alkane; cyclic alkene; cyclic alkyne;
alcohol, aldehyde, ketone, ester or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; -N02; -S02; -S03; -P03; -0-P03 or halogen;
R5 and Rs are each independently, CH2 , CHOH °r C ;
Y is optional and each occurrence of Y is -H; -OH; straight chained or branched alkane; straight chained or branched alkene; straight chained or branched alkyne; cyclic alkane; cyclic alkene; cyclic alkyne;
-9e-alcohol, aldehyde, ketone, ester or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino;
-N02; -SO2; -S03; -P03; -O-P03 or halogen; each occurrence of R,o is -H; -OH; straight chained or branched alkane; straight chained or branched alkene; straight chained or branched alkyne; cyclic alkane;
cyclic alkenecyclic alkyne; alcohol, aldehyde, ketone, carboxylic acid, ester, or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino -N02; -S02; -S03;
P03; -O-P03; halogen, or when Y is absent R,o is = 0; and R,4 and R,s are each independently I
CH2 , CHOH ~r C ;
provided the compound is not thalidomide.
These and other aspects, features and advantages of the present invention will become apparent after a review of the following detailed description of the disclosed embodiments and the appended claims.
Brief Description of the Figures Figures 1 through 3 are a listing of representative compounds in the genus represented by the following General formulas:
s R' Rs ~R
Rb Ra 1=3 ) R, R
Rs-R~
R3 R~
Ra C) t R, Rs R Ra_R9 t0 Figure 4 is a listing of representative compounds in the genus represented by the following general formula:
O
R"
\N-Rza \\
R?.3 is Figure 5 is a listing of representative compounds in the genus represented by the following general formula:
O~ ,OH
~C O
~'.~I-X
H
Figure 6 shows the effect of thalidomide and EMl?
on angiogenesis in a rabbit cornea model of angiogenesis.
Figure 7 shows the effect of thalidomide on the area of corneal vascularization in a rabbit cornea model of angtogenesls.
Detailed Description The present invention includes compositions and to methods for the treatment of diseases that are mediated by angiogenesis. Une embodiment of the present invention is the use of thalidomide or the metabolites of thalidomide as disclosed herein to inhibit unwanted angiogenesis. The present invention also includes compounds which cause dysmelia is the developing is fetus and have anti-angiogenic activity. The present invention comprises a method of treating undesired angiogenesis in a human or animal comprising the steps of administering to the human or animal with the undesired angiogenesis a composition comprising an effective amount of a teratogenic compound that is anti-2o anglogenlc.
Compounds that can be used in accordance with the present invention include compounds included in the following general formulae. Examples of compounds that have anti-angiogenic properties having one of the following three 2s formulae (A), (:B), or (C):
~'O 94120085 PCT/US94l01971 - 1? -A) Rt R, R
5\
R~
R~ /Ra_ R~
Rh Ra B) R, RS
_v Rg-R~
R~ R~
Ra C) R t , RS
R Rs _ R9 Ra In the above formulae A), B), and C). Rl, R2, R3 and R~ can be selected from: ~-H; -OH; =O, straight chained and branched alkanes, alkenes, alkynes; cyclic alkanes, alkenes, and alkynes;
to combinations of cyclic and acyclic alkanes, alkenes, and alkynes:
alcohol, aldehyde, ketone, carboxy 1 is acid, ester, or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; -XOn or -O-XOn, [where X=N and n=2; X=S and n=2 or 3; or X=P and n=l-3]; and is halogens; R5, R6, R7, and Rg are each independently selected from:
Y Y
-L~Rto: -N-Rto:
or -O- where Y is optional and is the same as defined above for R l ; and R 1 p is the same as defined above for R1, or (where Y is w0 94120085 PCTlUS94101971 absent) Rlp is =O; and R9 is a moiety having formula D). E), F).
G) or H):
D) F) / t -RWRm -Rlt/~ Rls R14-Rlz Rt6-Rt;
E) G) Rl,Rt3~
Rts j Rt~-Rta -R
a -Rtt ~ ~ ~Rl~
~Rt;-Rts Rl~'.-Rtb where each of R 1 ~ - R 1'7 is (independently) the same as defined above for R5;
~o ys -C-Rt9 I
R~o where R 1 g, R 19 and R2p are, independently selected from O O O O
-H, CH3, -C- OH, -C-NH,,- (CH2W C-OH, or -(CH,)n- C-NH,.
is and n=1 to 4.
Accordingly, another aspect of the present invention features inhibitin~; angiogenesis in a mammal by administering a therapeutic composition comprising olio of the above-described compounds in a dosage sufficient to inhibit angiogenesis - I.~ -In preferred embodiments, the compound has formula B), where R~ and R6 are selected from the Group consisting of:
CHI , -CHOH, and jC0 and R9 has formula F) or H); and R I4 and R 16 are selected from the group consisting of:
R"
;CH,, ; CHOH, or -C-: and R15 and is -O-, or -~
I I
O
where R~ 1 is -H, -CH,3, or -OH. Specific preferred compounds according to this aspect of the present invention include to thalidomide, its precursors, metabolites and analogs. Particular analogs include EM-12, N-phthaloyl-DL-glutamic acid (P(~A) or N-phthaloyl-DL-g;lutamine anhydride. Examples of compounds that are members of this genus are listed in Figures 1 through 3.
It is to be understood that the compounds included as part of the is present invention are not to be limited to those compounds shown in Figures I through 3 and include all other compounds that are members of the genus described by the general formulas herein.
Compounds of the following formula that have anti-angiogenic properties:
O
R"
\ ~-RZa \\
R~3 O
where R22 and R~3 are (independently), -H, -F, -Cl, -Br, -I.
-CH3, or -CHI -CH3; and R24 is -H, -CH3, or -CH2 -CH3.
The present invention also features inhibiting angiogenesis in a mammal by administering a compound ~s according to the above formulae in a dosage suffi;.:Pnt to inhibit angiogenesis. E:x:amples of specific compounds that are members of this genus are listed in Figure 4.
- IS -Angiogenesis inhibition hydrolysis products of thalidomide having the following general formula can be used in practicing the present invention:
O~ ,OH
C O
' N-X
H
s where X is R6 as defined above, or O I O
X is R,5-C-C-(CH,)~-C-R~6 io and R~5 and R~6 are, independently, -OH, -H, or NH2, and n=1 through 4. Examples of such compounds are shown in Figure 5.
Angiogenesis inhibition compounds having the following general formula can be used in practicing the present tnvennon:
(I) O O R,. (II) i -R' / N
/N O
O i ~O \ X
R
~ (a) CH,-N O
- U
wherein compounds of structure (I), wherein R is selected from the group consisting of hydrogen, alkyl radicals of 1 to 6 carbon atoms, the phenyl radical, and the benzyl radical;
2o and wherein R' is selected from the group consisting of the phthalimido radical and the succinimido radical and of structure (II), wherein X is CH2 or C-n; R" is H, -CH2CH3, -Cf,H~.
-CH2C6H5, -CH~CH=CH2, or (a) and hydrolysis products of the compounds wherein R" is H and the piperidino ring or both the ~s piperidino and flue imido ring are hydrolyzed.
~?VO 94120085 PCT/US94J01971 S
Another set of compounds that are considered part of the present invention are the epoxides of thalidomide, EM-1? and EM-138. Repres~°ntative epoxide compounds are shown as follows:
O
O ~ C
C' _ ( 'N ~=0 ~~O Ci N
\ C ~-- N ~ I I ~ ' II i ' O O O H
O O H
Epoxides of thalidomide O O O
C \ C' 'N~~~O ~ N ~O
\ ~-- N
'' N' O O H
O H
to Epoxides of EM 12 O O
II II
O C'~OH
O O C~OH
C~ \ v N~ I N
\ I=O O C-O
OH OH
Epoxides of EM 138 is It should be understood that the epoxide can be attached at the 6,1 site on the benzene ring, the 1,2 site, the ? .
site 3,4 or the 4.5 site. All of these compounds are contemplated as part of the present invention.
o The epoxides of the thalidomide, EM-12, and EM 138 can be hydrolized to the following compounds:
O O
HO / C~ HO / Cv _ ~O HO I C N N~O
i C N I I
I I
O O H O O H
O
II
HO / C HO / C
_ p ~ N ~O
\ ~ HO \ ~.
O' H O H
O O
O OH O OH
II II
HO / Cv. HO / I CAN
N HO \ OH
OH
O O
to It is to be understood that the hydroxyl group can be on carbons l, :?, ~, 4, 5 and 6 of the benzene ring. Also contemplated as part of the present invention are dihydroxyl compounds wherein the two hydroxyl groups are located bis to each other on carbons l, 2, 3, 5 and 5 of the above compounds.
is The epoxides, the hydrolysis products of the epoxides, and the hydrolysis products of the thalidomide are all contemplated to be part of the present invention.
Lt is known that epoxides are hydrolized by a group of enzymes known as epoxide hydrolases. There i~ a class of 2o compounds which are epoxide hydrolase inhibitors. Examples of these compounds are valpromide (2-propylpentanamide) and valproic acid ( ~-propylpentanoic acid). Because epoxides are important angiogenesis inhibitors, it is contemplated as part of the present invention. compositions comprising anv of the angiogenesis inhibitors compounds recited herein in combination with epoxide hydrolase inhibitors. The epoxide hvdrolase inhibitors can be administered to a human or animal together or sequentially. The expoxide group appears to be an important substituent common to several angiogenesis inhibitors. The use of epoxide hydrolase inhibitors to potentiate the activity of any angiogenesis inhibitor containing an epoxide is contemplated as io pan of the present invention. For example, the epoxide hvdrolase inhibitors can be administered with the following epoxide-containing anti-angiogenesis compounds: AGNI 1470.
Eponimycin, microbial metabolites of Scolecobasidium arenarium designated f/20:~1:~, fr/111142 and fr/18487. See Oikawa.
is Biochem Biophys. Res. Comm, Vol. 81:1070 (1971) and Otsuka, J. Microbial. Bi orech., Vol 1:1 b3 ( 1991 ).
It is contemplated as an embodiment of the present invention the use of the epoxide containing angiogenesis inhibitors with or without epoxide hydrolase inhibitors as a treatment for 'o diseases mediated by elevated or toxic levels of TNF-a. TNF-a has been recognized as manifesting a dose dependent toxicity. If present at low levels for a long period of time, TNF-a can result in cachexia. Cachexia is a general weight loss and wasting occurring in the course of some chronic diseases such as cancer.
opportunistic infections of AIDS, inflammatory diseases, parasitic diseases, tuberculosis, and high dose IL-2 therapy. The epoxide containing angiogenesis inhibitors, with or without epoxide hydrolase inhibitors, are also effective in treating diseases such as septic shock, leprosy and graph vs. host disease.
3o Other embodiments are within the present invention.
For example, other dysmelia-causing compounds can be used according to the present invention, e.g. 4-methylphthalic acid.
pyridoxine, vasopressin, acetazolamide, or a compound having the following formula (where R= H, -OH, or -CH3):
WO 94!20085 PCT/US94101971 _ lg _ O NCO
I
R
Other compounds which are teratogens, such as valproic acid (2-propylpentar~oic acid), the retinoids, such as cis-retinoic acid.
and rifampin may also be used in accordance with the invention.
In summary, the preferred compounds are thalidomide, as urell as analogs, hydrolysis products. metabolites and precursors of thalidomide that are teratogenic, and. more specifically, that cause dismelia. However, it is to be understood that it is not necessary for a compound to have both teratogenic to activity and angiogenesis inhibiting activity to be considered part of the present invention. Dysmelia-causing compounds can be identified by the general procedures of Helm, Ar=nelmittle-forschung, 31 (i/6):941-949 ( 1981 ), in which rabbit pups are examined after exposure to the compound in utero. The is compounds can generally be purchased, e.g., from Andrulis Pharmaceuticals., Beltsville, MD, or synthesized according to known procedures. It is to be understood that the compounds of the present invf:ntion can exist as enantiomers and that the racemic mixture of enantiomers or the isolated enantiomers are ~o all considered as within the scope of the present invention.
Many of the compounds that are contemplated as part of the present invention can be enriched in optically active enantiomers of the compounds specified above. Specifically.
Blaschke has reported that the S enanantiomers may be ~s disproportionately responsible for the dismelia-producing effect of these compounds. See, generally Blaschke, Ar~neimittclf~~; s~hung 29:1640-1642 (1979). The above described articles generally describe procedures to obtain optically active preparations of the compounds of interest. See.
3o e.g. Shealy et al.., Chem. Indus. 1030 ( 1965); and Casini et al..
Farmaco Ed. Sci. 19:563 ( 1964).
The compounds described above can be provided as pharmaceutically acceptable formulations using formulation methods known to those of ordinary skill in the art. These formulations can 'be administered by standard routes. In general.
the combination:, may be administered by the topical.
transdermal, oral, rectal or parenteral (e.g., intravenous, subcutaneous or intramuscular) route. In addition. the combinations ma:y be incorporated into biodegradable polymers o allowing for sustained release of the compound, the polymers being implanted in the vicinity of where drug delivery is desired.
for example, at the site of a tumor. The biodegradable polymers and their use are described, for example, irl detail in Brem et al..
J. Neurosurg. 74:441-446 ( 1991 ).
n The dosage of the compound will depend on the condition being treated, the particular compound, and other clinical factors such as weight and condition of the human or animal and the route of administration of the compound. It is to be understood that the present invention has application for both ~o human alld veterinary use. For oral administration to humans, a dosage of between approximately 0.1 to 300 mg~kg/day.
preferably between approximately 0.~ and 50 mg/kg/day. and most preferably between approximately I to 10 mg/kg/day, is generally sufficient.
The formulations include those suitable for oral.
rectal, ophthalmic, (including intravitreal or intracameral) nasal.
topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal.
intratracheal, and epidural) administration. The formulations 3o may conveniently be presented in unit dosage form and may be prepared by conventional pharrrlaceutical techniques. Such techniques include the step of bringing into association the active ingredient and tlhe pharmaceutical carriers) or excipient(s). In general, the formulations are prepared by uniformly and 3s intimately bringing into associate the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Fc:>rmulations of the present invention suitable for oral administration may be presented as discrete units such as s capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion and as a bolus, etc.
to A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine.
the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, Is preservative, surface active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally coated or scored and may be formulated so as to provide a slow or controlled release of the active ~o ingredient therein.
Formulations suitable for topical administration in the mouth include lozenges comprising the ingredients in a flavored basis, 'usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin ~s and glycerin, or sucrose and acacia; and mouthwashes comprising the ingredient to be administered in a suitable liquid carrier.
Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the ingredient to be administered in a pharmaceutical 3o acceptable carrier. A preferred topical delivery system is a transdermal patch containing the ingredient to be administered.
Formulations for rectal administration may be presented as a suppository with a suitabie base comprising, for example, cocoa butter or a salicylate.
'~'VO 94120085 PCT/US9410I971 _ 7~ _ Formulations suitable for nasal administration.
wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered in the manner in which snuff is s administered, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops.
include aqueous or oily solutions of the active ingredient.
io Formulations suitable for vagina( administration may be presented as pessaries, tamports, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration t5 include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The ~u formulations may be presented in unit-dose or mufti-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) conditions requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection ~s solutions and suspensions may be prepared from sterile powders.
granules and tablets. of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the administered 3o ingredient.
It should be understood that in addition to the ingredients, particularly mentioned above, the formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.
Diseases associated with corneal neovascularization that can be treated according to the present invention include but s are not limited to, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and retrolental fibroplasia, epidemic keratoconjunctivitis, Vitamin ~1 deficiency, contact: lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea.
to phylectenulosis, syphilis, Mycobacteria infections. lipid degeneration. chemical burns, bacterial ulcers, fungal ulcers.
Herpes simplex infections, Herpes poster infections, protozoan infections, Kaposi sarcoma, Mooren ulcer, Terrien's m<~rainal degeneration, mariginal keratolysis, trauma, rheumatoid arthritis.
is systemic lupus, polyarteritis, Wegeners sarcoidosis, Scleritis, Steven's Johnson disease, periphigoid radial keratotomy, and corneal graph rejection.
Diseases associated with retinal/choroidal neovascularization that can be treated according to the present ~o invention include, but are not limited to, diabetic retinopathv, macular degeneration, sickle cell anemia, sarcoid. syphilis.
pseudoxanthoma f:lasticum, Pagets disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis.
mycobacterial infections, Lyme's disease, systemic lupus ~s erythematosis, retinopathy of prematurity, Eales disease. Bechets disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Bests disease, myopia, optic pits, Stargarts disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications.
~o Other diseases include, but are not limited to, diseases associated with rubeosis (neovasculariation of the angle) and diseases caused by rhC «bnormal proliferation of fibrovascular o: fibrous tissue including all forms of proliferative vitreoretinopathy, whether or not associated with diabetes.
Another disease which can be treated according to the present inventicm is rheumatoid arthritis. It is believed that the blood vessels in the synovial lining of the joints undergo angiogenesis. In addition to forming new vascular networks. the ;_ endothelial cells release factors and reactive oxygen species that lead to pannus growth and cartilage destruction. The factors involved in angiogenesis may actively contribute to, and help maintain, the chronically inflamed state of rheumatoid arthritis.
Another disease that can be treated according to the to present invention are hemangiomas. Osier-Weber-Rendu disease.
or hereditary hemorrhagic telangiectasia, solid or blood borne tumors and acquired imrrlune deficiency syndrome.
This invention is further illustrated by the following examples, which are not to be construed in any way as imposing is limitations upon the scope thereof. On the contrary, it is to be clearly understood, that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to those skilled in the art without departing from the spirit of the present ~o invention and/or thf: scope of the appended claims.
Example I
The chick embryo chorioallantoic membrane assay described by Crum et al., Science 230:1375 et seq. ( 1985), is used ~s to identify compounds that do not require further metabolic conversion. See also, U.S. Patent 5,001,116, hereby incorporated by reference, which describes the CAM assay at col. 7 of the patent. Briefly, fertilized chick embryos are removed from their shell on day 3 or 4, and a methylcellulose disc containing the ~o compound is implanted on the chorioallantoic membrane. The embryos are examined 48 hours later and, if a clear avascular zone appears around the methylcellulosP disc, tl:e diarrleter of that zone is measured.
Example II
Rabbit cornea an,~iogenesis assay Pellets for implantation into rabbit corneas were made by mixing 1 1.0 pl of saline containing 12 ~tg of recombinant bFGF (Takeda Pharmaceuticals-Japan) with 40 mg of sucralfate (Bukh Meditec-Denmark); this suspension was added to ~0 ul of 12% hydron (Interferon Sciences) in ethanol. 10 ~tl aliquots of this mixture was then pipetted onto teflon pegs and allowed to dry producing approximately 17 pellets. A pellet was implanted into u~ corneal micropockets of each eye of an anesthetized female New Zealand white raldbit. 2mm from the limbus followed by topical application of eythromycin ointment onto the surface of the cornea. The animals were fed daily from 2 days post-implantation by gastric lavage with either drug suspended in 0.5%
t, carboxymethyl cellulose or 0.5% carboxymethyl cellulose alone.
Thalidomide was purchased from Andrulus Pharmaceutical (Maryland) and the EM-12 and Supidimide were kindly provided by Grunenthal GMBH (Germany). The animals were examined with a slit lamp every other day in a masked manner by the same ~o corneal specialist. The area of corneal neovascularization was determined by measuring with a reticule the vessel length (L) from the limbus and the number of clock hours (C) of limbus involved. A fornnula was used to determine the area of a circular band segment: C/12 * 3.1416 (r'-(r-L)2] where r=6 mm the measured radius of the rabbit cornea. Various mathematical models were utilized to determine the amount of vascularized cornea and this formula was found to provide the most accurate approximation o:F the area of the band of neovascularization that grows towards flue pellet.
3o It is important to note that the rabbit cornea assay is preferable because it will generally recognize compounds that are inactive per se hut are nmtz'oo!ized to yield active compounds.
Thalidomide related compounds, as shown below in Example III.
are known to be teratogens and are candidates for use in the 3s presenmnvention.
iV0 94/20085 PCT/US94101971 -?6-Example III
Inhibition o~~ bFGF induced corneal neovasculari=ation by thalidomide and related analog expressed as percent of median s control on day 8 Pellets containing bFGF and sucralfate were implanted into micropockets of both corneas of rabbits according to Example II. Vessel ingrowth into clear cornea from the limbus was first noted on day 2 and treatments (200 mg/kg orally) were to begun on this day. 'The area of corneal neovascularization was measured from day 4 through day 12. Day 8 measurements were used for comparison between groups. No regression of vessels and near maximal neovascularization was seen at this time point.
Statistical analysis was performed with ANOVA with ranked data is to account for interexperimental variation and to guard against a non-normal distribution of data (i.e. outliers) by utilizing a nonparametric method.
The compounds tested were as follows:
O
il C
CO
'C N
ii O O H
thalidomide O
I I
C
~ O ,N Oo N
O H
~s O
I I
C
\N ~ O
O
I I
O O
phthaloyl glutamic anhydride (PGA) O
OH
O
\N
OH
O O
s phthaloyl glutamic acid (PCJ Acid) O
il C
N ~O
~SO~ N
v O H
supidimide.
Treatment with a dose of (200 mg/kg) of thalidomide resulted in an inhibition of the area of vascularized cornea that io ranged from 30-51 % in three experiments with a median inhibition of 3fi~lo (Figure 6) (n=30 eyes, p=0.0001. '? way ANOVA with ranked data). The inhibition of angiogenesis by thalidomide was seen after only two doses (Figure 7). The rabbits did not demonstrate obvious sedation and there were no signs of is toxicity or weight loss. The teratogenic analog EM-1'?. which shares the other' properties of thalidomide was also inhibitory.
with a median inhibition of 42% (n=10 eyes, p=0.00?. l-way ANOVA with rmked data). Supidimide, a nonteratogenic analog of thalidomide that retains the sedative properties of thalidomide.
2o exhibited no acaivity (area 107% of control, n=10 eyes, not statistically different from control). Other analogs, PGA and PG
acid displayed weaker inhibitory effects than thalidomide (data ' WO 94/20085 PCT/US94101971 not shown). The density of vessel ingrowth in thalidomide-treated animals was also markedly reduced.
Example IV
s EM-12 in rabbit cornea assay EM-1:? was tested in the rabbit cornea assay described in Example II at 100 mg/kg/day and showed 21 inhibition, and at 2Wmg/kg/day the assay showed 43% inhibition.
to Example V
Phthaloyl glutamic acid in CAM
Phthaloyl glutamic acid was tested in the above described CAM assay and exhibit an avascular zone with a mild scar.
is Example VI
Phthalovl ~lutamic acid in rabbit cornea assay Phthaloyl glutamic acid described above at 200 mg/kg and exhibited 29% inhibition of angiogenesis.
Example VII
Phthaloyl glutamic anhydride in CAM assay Phthaloyl glutamic anhydride was test in the CAM
assay described above and exhibited an avascular zone.
It should be understood, of course, that the foregoing ~s relates only to preferred embodiments of the present invention and that numerous modifications or alterations may be made therein without departing from the spirit and the scope of the invention as set forth in the appended claims.
Claims (32)
1. The use of a composition administered for treating undesired angiogenesis in a human or animal wherein the composition comprises an effective amount of an angiogenesis-inhibiting compound selected from the group consisting of the following compounds:
wherein R1, R2, R3 and R4 can be selected from: --H; -OH; =O, straight chained and branched alkanes, alkenes, alkynes; cyclic alkanes, alkenes and alkynes;
combinations of cyclic and acyclic alkanes, alkenes and alkynes; alcohol, aldehyde, ketone, carboxylic acid, ester, or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; -XO n or -O-XO n, (where X=N and n=z; X=S and n=2 or 3;
of X=P and n=1-3); and halogens; R5, R6, R7, and R8 are each independently selected from:
or -O- where Y is optional and is the same as defined above for R1;
and R10 is the same as defined above for R1, or (where Y is absent) R10 is =O; and R9 is a moiety having formula D), E), F), G) or H):
where each of R11 - R17 is (independently) the same as defined above for R5;
where R18, R19 and R20 are, independently selected from -H, CH3, and n=1 to 4;
provided the compound is not thalidomide.
wherein R1, R2, R3 and R4 can be selected from: --H; -OH; =O, straight chained and branched alkanes, alkenes, alkynes; cyclic alkanes, alkenes and alkynes;
combinations of cyclic and acyclic alkanes, alkenes and alkynes; alcohol, aldehyde, ketone, carboxylic acid, ester, or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; -XO n or -O-XO n, (where X=N and n=z; X=S and n=2 or 3;
of X=P and n=1-3); and halogens; R5, R6, R7, and R8 are each independently selected from:
or -O- where Y is optional and is the same as defined above for R1;
and R10 is the same as defined above for R1, or (where Y is absent) R10 is =O; and R9 is a moiety having formula D), E), F), G) or H):
where each of R11 - R17 is (independently) the same as defined above for R5;
where R18, R19 and R20 are, independently selected from -H, CH3, and n=1 to 4;
provided the compound is not thalidomide.
2. The use according to claim 1, wherein the compound has the following formula:
and R5 and R6 are selected from the group consisting of and in which R9 has formula F) or H) and R14 and R16 are selected from the group consisting of, ; and R15 and is -O-, or where R21 is -H, -CH3, or -OH.
and R5 and R6 are selected from the group consisting of and in which R9 has formula F) or H) and R14 and R16 are selected from the group consisting of, ; and R15 and is -O-, or where R21 is -H, -CH3, or -OH.
3. The use according to claim 1, wherein the compound is a thalidomide metabolite or hydrolysis product.
4. The use according to claim 1, wherein the compound is selected from the group consisting of the following compounds;
5. The use according to claim 1, wherein the compound is selected from the group consisting of N-phthaloyl-DL-glutamic acid (PGA) and N-phthaloyl-DL-glutamine anhydride.
6. The use according to claim 1, wherein the compound is EM-12.
7. The use according to claim 1, wherein the compound is selected from the group of compounds shown below:
Where R = -H, -OH, or -CH3
Where R = -H, -OH, or -CH3
8. The use according to claim 1, wherein the composition further comprises an epoxide hydrolase inhibitor.
9. The use of a composition administered for treating undesired angiogenesis in a human or animal wherein a composition comprises an effective amount of an angiogenesis-inhibiting compound selected from the group consisting of the following compounds:
where R22 and R23 are (independently), -H, -F, -Cl, -Br, -I, -CH3, or -CH2 -CH3 and R24 is -H, -OH, -CH3, of -CH2 -CH3.
where R22 and R23 are (independently), -H, -F, -Cl, -Br, -I, -CH3, or -CH2 -CH3 and R24 is -H, -OH, -CH3, of -CH2 -CH3.
10. The use according to claim 9 , wherein the composition further comprises an epoxide hydrolase inhibitor.
11. The use according to claim 9 , wherein the compound is selected from the group of compounds shown below:
12. The use of a compound administered for treating undesired angiogenesis in a human or animal wherein the compound is selected from the group consisting of the following compounds:
where X is R6 as defined above, or X is and R25 and R26 are independently, -OH, -H, or -NH2.
where X is R6 as defined above, or X is and R25 and R26 are independently, -OH, -H, or -NH2.
13. The use according to claim 12 , wherein the compound is selected from the group consisting of the compounds shown below:
14. The use according to claim 12 , wherein the composition further comprises an epoxide hydrolase inhibitor.
15. The use of a composition administered for treating undesired angiogenesis in a human or animal wherein the composition comprises an effective amount of an angiogenesis-inhibiting compound selected from the group consisting of the following compounds:
wherein R is selected from the group consisting of H, (C1-C6)alkyl, phenyl, and benzyl;
R' is selected from the group consisting of phthalimido and succinimido;
X is CH2 or C=O; and R" is H. -CH2CH3, -C6H5, -CH2C6H5, -CH2CH=CH2, or and (III) hydrolysis products of (II) wherein R" is H and the piperidino ring or both the piperidino and the imido ring are hydrolyzed;
provided the compound is not thalidomide.
wherein R is selected from the group consisting of H, (C1-C6)alkyl, phenyl, and benzyl;
R' is selected from the group consisting of phthalimido and succinimido;
X is CH2 or C=O; and R" is H. -CH2CH3, -C6H5, -CH2C6H5, -CH2CH=CH2, or and (III) hydrolysis products of (II) wherein R" is H and the piperidino ring or both the piperidino and the imido ring are hydrolyzed;
provided the compound is not thalidomide.
16. The use of a composition administered for treating undesired angiogenesis in a human or animal wherein the composition comprises an effective amount of an angiogenesis-inhibiting compound selected from the group consisting of .alpha.-thalidomide, EM-12, EM-138, phthaloyl glutamic anhydride and phthaloyl glutamic acid and metabolites of thalidomide, EM-12, EM-138, phthaloyl glutamic anhydride and phthaloyl glutamic acid, or mixtures thereof.
17. The use according to claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16, wherein the undesired angiogenesis occurs in a disease selected from the group consisting of diabetic retinopathy, retinopathy of prematurity, corneal.
graph rejection, neovascular glaucoma, retrolental fibroplasia, epidemic keratoconjunctivitis, Vitamin A
deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogren's syndrome, acne rosacea, phylectenulosis, syphilis, Micobacteria infections other than leprosy, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi's sarcoma, Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis, trauma, rheumatoid arthritis, systemic lupus erythematosis, polyarteritis, Wegener's sarcoidosis, scleritis, Stevens-Johnson disease, radial keratotomy, macular degeneration, sickle cell anemia, sarcoid, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis, chronic vitritis, Lyme's disease, Eales' disease, Behcet's disease, infections causing retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, post-laser complications, rubeosis, abnormal proliferation of fibrovascular or fibrous tissue, proliferative vitreoretinopathy, Bartonellosis, hemangiomas, Osler-Weber-Rendu disease, solid tumors, blood-borne tumors, acquired immune deficiency syndrome, ocular neovascular disease, age-related macular degeneration, osteoarthritis, diseases caused by chronic inflammation, Crohn's disease, ulcerative colitis, tumors of rhabdomyosarcoma, tumors of retinblastoma, tumors of Ewing's sarcoma, tumors of neuroblastoma, tumors of osteosarcoma, leukemia, psoriasis, atherosclerosis, acoustic neuroma, neurofibroma, trachoma, pyogenic granulomas and pemphigoid.
graph rejection, neovascular glaucoma, retrolental fibroplasia, epidemic keratoconjunctivitis, Vitamin A
deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogren's syndrome, acne rosacea, phylectenulosis, syphilis, Micobacteria infections other than leprosy, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi's sarcoma, Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis, trauma, rheumatoid arthritis, systemic lupus erythematosis, polyarteritis, Wegener's sarcoidosis, scleritis, Stevens-Johnson disease, radial keratotomy, macular degeneration, sickle cell anemia, sarcoid, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis, chronic vitritis, Lyme's disease, Eales' disease, Behcet's disease, infections causing retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, post-laser complications, rubeosis, abnormal proliferation of fibrovascular or fibrous tissue, proliferative vitreoretinopathy, Bartonellosis, hemangiomas, Osler-Weber-Rendu disease, solid tumors, blood-borne tumors, acquired immune deficiency syndrome, ocular neovascular disease, age-related macular degeneration, osteoarthritis, diseases caused by chronic inflammation, Crohn's disease, ulcerative colitis, tumors of rhabdomyosarcoma, tumors of retinblastoma, tumors of Ewing's sarcoma, tumors of neuroblastoma, tumors of osteosarcoma, leukemia, psoriasis, atherosclerosis, acoustic neuroma, neurofibroma, trachoma, pyogenic granulomas and pemphigoid.
18. The use of an angiogenesis inhibiting amount of a compound in administratable form for treating solid tumors in a human comprising administering to a human in need wherein the compound comprises the formula:
wherein:
R1, R2, R3 and R4 are each independently -H; -OH; straight chained or branched alkane;
straight chained or branched alkene; straight chained or branched alkyne;
cyclic alkane; cyclic alkene; cyclic alkyne; alcohol, aldehyde, ketone, ester or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; -NO2; -SO2; -SO3; -PO3;
-0-PO3 or halogen;
R5 and R6 are each independently, Y is optional and each occurrence of Y is -H; -OH; straight chained or branched alkane;
straight chained or branched alkene; straight chained or branched alkyne;
cyclic alkane; cyclic alkene; cyclic alkyne; alcohol, aldehyde, ketone, ester or ether moieties in combination with acyclic, cyclic, or combination acycliclcyclic moieties; aza; amino; -NO2; -SO2; -SO3; -PO3;
-0-PO3 or halogen;
each occurrence of R10 is -H; -OH; straight chained or branched alkane;
straight chained or branched alkene; straight chained or branched alkyne; cyclic alkane; cyclic alkenecyclic alkyne;
alcohol, aldehyde, ketone, carboxylic acid, ester, or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino -NO2; -SO2; -SO3; -PO3; -0-PO3;
halogen, or when Y is absent R10 is =O; and R14 and R16 are each independently provided the compound is not thalidomide.
wherein:
R1, R2, R3 and R4 are each independently -H; -OH; straight chained or branched alkane;
straight chained or branched alkene; straight chained or branched alkyne;
cyclic alkane; cyclic alkene; cyclic alkyne; alcohol, aldehyde, ketone, ester or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; -NO2; -SO2; -SO3; -PO3;
-0-PO3 or halogen;
R5 and R6 are each independently, Y is optional and each occurrence of Y is -H; -OH; straight chained or branched alkane;
straight chained or branched alkene; straight chained or branched alkyne;
cyclic alkane; cyclic alkene; cyclic alkyne; alcohol, aldehyde, ketone, ester or ether moieties in combination with acyclic, cyclic, or combination acycliclcyclic moieties; aza; amino; -NO2; -SO2; -SO3; -PO3;
-0-PO3 or halogen;
each occurrence of R10 is -H; -OH; straight chained or branched alkane;
straight chained or branched alkene; straight chained or branched alkyne; cyclic alkane; cyclic alkenecyclic alkyne;
alcohol, aldehyde, ketone, carboxylic acid, ester, or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino -NO2; -SO2; -SO3; -PO3; -0-PO3;
halogen, or when Y is absent R10 is =O; and R14 and R16 are each independently provided the compound is not thalidomide.
19. The use according to claim 18 wherein the solid tumour is of the group consisting of breast carcinoma, rhabdomyosarcoma, retinoblastoma, Ewing sarcoma, neuroblastoma, osteosarcoma, acoustic neuroma, neurofibroma, trachoma and pyogenic granuloma.
20. The use according to claim 19 wherein the solid tumour is breast carcinoma.
21. The use of an angiogenesis inhibiting amount of a compound in administratable form for treating blood-born tumors in a human wherein the compound comprises the formula:
wherein:
R1, R2, R3 and R4 are each independently -H; -OH; straight chained or branched alkane;
straight chained or branched alkene; straight chained or branched alkyne;
cyclic alkane; cyclic alkene; cyclic alkyne; alcohol, aldehyde, ketone, ester or ether moieties in combination with acyclic, cyclic, or combination acycliclcyclic moieties; aza; amino; -NO2; -SO2; -SO3; -PO3;
-O-PO3 or halogen;
R5 and R6 are each independently, Y is optional and each occurrence of Y is -H; -OH; straight chained or branched alkane;
straight chained or branched alkene; straight chained or branched alkyne;
cyclic alkane; cyclic alkene; cyclic alkyne; alcohol, aldehyde, ketone, ester or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; -NO,; -SO2; -SO3; -PO3;
-O-PO3 or halogen; each occurrence of R10 is -H; -OH; straight chained or branched alkane;
straight chained or branched alkene; straight chained or branched alkyne;
cyclic alkane; cyclic alkenecyclic alkyne; alcohol, aldehyde, ketone, carboxylic acid, ester, or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza;
amino -NO,;
-SO,; -SO3; -PO3; -O-PO3; halogen, or when Y is absent R10 is =O; and R14 and R16 are each independently provided the compound is not thalidomide.
wherein:
R1, R2, R3 and R4 are each independently -H; -OH; straight chained or branched alkane;
straight chained or branched alkene; straight chained or branched alkyne;
cyclic alkane; cyclic alkene; cyclic alkyne; alcohol, aldehyde, ketone, ester or ether moieties in combination with acyclic, cyclic, or combination acycliclcyclic moieties; aza; amino; -NO2; -SO2; -SO3; -PO3;
-O-PO3 or halogen;
R5 and R6 are each independently, Y is optional and each occurrence of Y is -H; -OH; straight chained or branched alkane;
straight chained or branched alkene; straight chained or branched alkyne;
cyclic alkane; cyclic alkene; cyclic alkyne; alcohol, aldehyde, ketone, ester or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza; amino; -NO,; -SO2; -SO3; -PO3;
-O-PO3 or halogen; each occurrence of R10 is -H; -OH; straight chained or branched alkane;
straight chained or branched alkene; straight chained or branched alkyne;
cyclic alkane; cyclic alkenecyclic alkyne; alcohol, aldehyde, ketone, carboxylic acid, ester, or ether moieties in combination with acyclic, cyclic, or combination acyclic/cyclic moieties; aza;
amino -NO,;
-SO,; -SO3; -PO3; -O-PO3; halogen, or when Y is absent R10 is =O; and R14 and R16 are each independently provided the compound is not thalidomide.
22. The use according to claim 21 wherein the blood-born tumour is leukemia.
23. The use according to claim 18 or 21, wherein R14 and R16 are both
24. The use according to claim 18 or 21, wherein R5 is
25. The use according to claim 18 or 21, wherein R6 is
26. The use according to claim 18 or 21, wherein R5 and R6 are both
27. The use according to claim 26 wherein R1, R2, R3 or R4 is -OH.
28. The use according to claim 18 or 21, wherein the amount administrable form is such as to provide between approximately 0.1 and approximately 300 mg/kg/day.
29. The use according to claim 28 wherein the amount administrable form is such as to provide between approximately 0.5 and approximately 50 mg/kg/day.
30. The use according to claim 29 wherein the amount administrable form is such as to provide between approximately 1 and approximately 10 mg/kg/day.
31. The use according to claim 18 or 21, wherein the administrable form of the compound includes a pharmaceutical acceptable carrier.
32. The use according to claim 18 or 21, wherein the administrable form of the compound provides oral, parenteral, transdermal or topical usage.
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US168,817 | 1993-12-15 | ||
US08/168,817 US5629327A (en) | 1993-03-01 | 1993-12-15 | Methods and compositions for inhibition of angiogenesis |
CA002157288A CA2157288C (en) | 1993-03-01 | 1994-02-24 | Methods and compositions for inhibition of angiogenesis |
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CA2512926A Expired - Lifetime CA2512926C (en) | 1993-03-01 | 1994-02-24 | Methods and compositions for inhibition of angiogenesis |
CA002157288A Expired - Lifetime CA2157288C (en) | 1993-03-01 | 1994-02-24 | Methods and compositions for inhibition of angiogenesis |
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1993
- 1993-12-15 US US08/168,817 patent/US5629327A/en not_active Expired - Lifetime
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1994
- 1994-02-24 EP EP02012280A patent/EP1245229A3/en not_active Withdrawn
- 1994-02-24 AT AT94909773T patent/ATE218865T1/en active
- 1994-02-24 WO PCT/US1994/001971 patent/WO1994020085A1/en active IP Right Grant
- 1994-02-24 AU AU62486/94A patent/AU676722B2/en not_active Expired
- 1994-02-24 EP EP05002523A patent/EP1537870A3/en not_active Withdrawn
- 1994-02-24 PT PT94909773T patent/PT688211E/en unknown
- 1994-02-24 DK DK02011928T patent/DK1264597T3/en active
- 1994-02-24 DE DE69430796T patent/DE69430796T2/en not_active Expired - Lifetime
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- 1994-02-24 DK DK94909773T patent/DK0688211T3/en active
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1995
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- 1995-06-06 US US08/468,792 patent/US5712291A/en not_active Ceased
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1997
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2001
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- 2001-07-05 US US09/899,318 patent/US20010056113A1/en not_active Abandoned
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2002
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