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`METHOD OF TREATING ANGIOGENESIS-RELATED DISORDERS
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`FIELD OF THE INVENTION
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`This invention relates to the use of certain 3-benzoylphenylacetic acids
`
`and derivatives to treat or prevent angiogenic diseases.
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`BACKGROUND OF THE INVENTION
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`10
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`3-benzoylphenylacetic acid and certain of its derivatives are known to
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`possess anti-inflammatory activity. U.S. Patent Nos. 4,254, 146, 4,045,576,
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`4, 126,635, and 4,503,073, and U.K. Patent Application Nos. 2,071 ,086A and
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`2,093,027 A disclose various 3-benzoylphenylacetic acids, salts and esters, and
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`15
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`hydrates thereof, having anti-inflammatory activity. U.S. Patent No. 4,568,695
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`discloses 2-amino-3-benzoylphenylethyl alcohols having anti-inflammatory
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`activity.
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`U.S. Patent No. 4,313,949 discloses 2-amino-3-benzoyl(cid:173)
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`phenylacetamides having anti-inflammatory activity.
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`zo
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`Certain derivatives of 2-amino-3-benzoylbenzeneacetic acid (amfenac)
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`and 2-amino-3-(4-chloro-benzoyl)benzeneacetic acid have also been evaluated
`by Walsh et al., J. Med Chern., 33:2296-2304 (1990), in an attempt to discover
`nonsteroidal anti-inflammatory prodrugs with minimal or no gastrointestinal side
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`effects upon oral administration.
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`U.S. patent No. 4,683,242 teaches the transdermal administration of 2-
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`amino-3-benzoylphenylacetic acids, salts, and esters, and hydrates and
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`alcoholates thereof to control inflammation and alleviate pain.
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`U.S. Patent No. 4,910,225 teaches certain benzoylphenylacetic acids for
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`local administration to control ophthalmic, nasal or otic inflammation. Only
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`acetic acids are disclosed in the '225 patent; no esters or amides are
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`mentioned or taught as anti-inflammatory agents for local administration to the
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`eyes, nose and ears.
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`U.S. Patent No. 5,475,034 discloses
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`topically administrable
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`compositions containing certain amide and ester derivatives of 3-
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`benzyolphenylacetic acid, including nepafenac, useful for treating ophthalmic
`inflammatory disorders and ocular pain. According to the '035 patent at Col.
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`15, lines 35-39, "[s]uch disorders include, but are not limited to uveitis scleritis,
`episcleritis, keratitis, surgically-induced inflammation and endophthalmitis."
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`10
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`U.S. Patent No. 6,066,671 discloses the topical use of certain amide and
`ester derivatives of 3-benzoylphenylacetic acid,
`including nepafenac, for
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`treating GLC1 A glaucoma.
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`15 SUMMARY OF THE INVENTION
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`It has now been found that certain 3-benzoylphenlacetic acids and
`derivatives,
`including nepafenac (2-amino,3-benzoyl-phenylacetamide ), are
`useful for the treatment of angiogenesis-related disorders.
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`DETAILED DESCRIPTION OF THE INVENTION
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`The 3-benzoylphenylacetic acids and derivatives useful in the methods
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`of the present invention are those of formula (I) below.
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`2
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`R
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`y
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`(I)
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`R = H, C1-4 (un)branched alkyl, CF3 , SR4;
`Y =OR', NR"R';
`R' = H, C1-1o {un)branched alkyl, {un)substituted {substitution as defined by X
`below), (un)substituted heterocycle (substitution as defined by X below),
`
`-(CH2)nZ(CHz)nA;
`n = 2-6;
`n'= 1-6;
`Z = nothing, 0, C=O, OC(=O), C(=O)O, C(=O)NR3
`CHOR3
`, NR3
`n2 = 0-2;
`R3 = H, C1_6 (un)branched alkyl, (un)substituted aryl (substitution as defined
`by X below), (un)substituted heterocycle (substitution as defined by X below);
`
`, NR3C(=O), S(0);,2,
`
`;
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`A = H, OH, optionally (un)substituted aryl (substitution as defined by X below),
`(un)substituted heterocycle (substitution as defined by X below), -(CH2)nOR3
`R" = H, OH, OR';
`X and X' independently= H, F, Cl, Br, I, OR', CN, OH, S(O)n2R4, CF3 , R4, N02;
`R4 = C1-6 (un)branched alkyl;
`m = 0-3;
`m' = 0-5;
`W=O,H.
`
`;
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`5
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`10
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`15
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`20
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`As used herein, the acid (Y = OH) includes pharmaceutically
`acceptable salts as well.
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`Preferred compounds for use in the methods of the present invention
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`are those of Formula I wherein:
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`5
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`;
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`R = H, C1-2 alkyl;
`Y = NR'R";
`R' = H, C1-6 (un)branched alkyl, -(CHz)nZ(CHz )n·A;
`Z =nothing, 0, CHOR3
`, NR3
`R3 = H;
`10 A= H, OH, (un)substituted aryl (substitution as defined by X below);
`X and X' independently= H, F, Cl, Br, CN, CF3, OR', SR4, R4;
`R"=H;
`R4 = C1-4 (un)branched alkyl;
`m = 0-2;
`15 m' = 0-2;
`W=H;
`n = 2-4;
`n' = 0-3.
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`20
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`The most preferred compounds for use in the compositions or method
`of the present invention are 2-Amino-3-(4-fluorobenzoyl)-phenylacetamide; 2-
`Amino-3-benzoyl-phenylacetamide
`(nepafenac);
`and
`2-Amino-3-(4-
`chlorobenzoyl)-phenylacetamide.
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`According to the present invention, a therapeutically effective amount of
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`a compound of formula (I) is administered topically, locally or systemically to
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`treat or prevent angiogenesis-related disorders. Such disorders include those
`that involve the proliferation of tumor cells, such as prostate cancer, lung
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`cancer, breast cancer, bladder cancer, renal cancer, colon cancer, gastric
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`cancer, pancreatic cancer, ovarian cancer, melanoma, hepatoma, sarcoma and
`lymphoma. Ophthalmic angiogenesis-related disorders include, but are not
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`limited to exudative macular degeneration; proliferative diabetic retinopathy;
`ischemic retinopathy (e.g., retinal vein or artery occlusion); retinopathy of
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`prematurity; neovascular glaucoma; iritis rubeosis; corneal neovascularization;
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`cyclitis; sickle cell retinopathy; and pterygium. Certain disorders, such as sickle
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`cell retinopathy and retinal vein or artery occlusion, can be characterized by
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`both angiogenesis and neurodegenerative components. According to the
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`5
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`present invention, a compound of formula (I) is administered to treat or prevent
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`disorders characterized, at least in part, by angiogenesis.
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`The compounds of formula (I) can be administered in a variety of ways,
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`including all forms of local delivery to the eye, such as subconjunctival
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`injections or implants, intravitreal injections or implants, sub-Tenon's injections
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`or implants, incorporation in surgical irrigating solutions, etc. Additionally, the
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`compounds of formula (I) can be administered systemically, such as orally or
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`intravenously. Suitable pharmaceutical vehicles or dosage forms for injectable
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`compositions,
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`implants, and systemic administration are known.
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`The
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`compounds of formula (I) and especially those wherein Y = NR'R", however,
`are preferably administered topically to the eye and can be formulated into a
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`variety of topically administrable ophthalmic compositions, such as solutions,
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`suspensions, gels or ointment.
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`Pharmaceutical compositions comprising a compound of formula (I) in
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`aqueous solution or suspension, optionally containing a preservative for
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`multidose use and other conventionally employed ophthalmic adjuvants, can be
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`topically administered to the eye. The most preferred form of delivery is by
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`aqueous eye drops, but gels or ointments can also be used. Aqueous eye
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`drops, gels and ointments can be formulated according to conventional
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`technology and would include one or more excipients. For example, topically
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`administrable compositions may contain tonicity-adjusting agents, such as
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`mannitol or sodium chloride; preservatives such as chlorobutanol,
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`benzalkonium chloride, polyquaternium-1, or chlorhexidine; buffering agents,
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`such as phosphates, borates, carbonates and citrates; and thickening agents,
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`such as high molecular weight carboxy vinyl polymers, including those known
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`as carbomers, hydroxyethylcellulose, or polyvinyl alcohol.
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`The doses of the compounds of formula (I) used in the treatment or
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`prevention of ophthalmic angiogenesis-related disorders will depend on the
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`type of disorder to be prevented or treated, the age and body weight of the
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`patient, and the form of preparation/route of administration. Compositions
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`s
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`intended for topical ophthalmic administration will typically contain a compound
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`of formula (I) in an amount of from about 0.001 to about 4.0% (w/v), preferably
`from about 0.01 to about 0.5% (w/v), with 1-2 drops once to several times a
`day.
`Likewise, representative doses for other forms of preparations are
`approximately 1 - 100 mg/day/adult for injections and approximately 10 - 1000
`10 mg/adult for oral preparations, each administered once to several times a day.
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`Additional
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`therapeutic agents may be added to supplement the
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`compounds of formula (I).
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`1s
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`The following examples are presented to illustrate various aspects of the
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`present invention, but are not intended to limit the scope of the invention in any
`respect. The percentages are expressed on a weight/volume basis.
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`Example 1 : The following formulations are representative of the topical
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`compositions useful in the present invention.
`
`Formulation 1
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`Compound of formula (I)
`Polysorbate 80
`Benzalkonium Chloride
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`Disodium EDTA
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`Monobasic Sodium Phosphate
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`Dibasic Sodium Phosphate
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`30
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`Sodium Chloride
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`pH adjustment with NaOH and/or HCI
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`Water
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`0.01-0.5%
`0.01%
`0.01% + 10% excess
`0.1%
`0.03%
`0.1%
`q.s. 290-300 mOsm/Kg
`pH 4.2-7.4
`q.s. 100%
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`Formulation 2
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`Compound of formula (I)
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`Hydroxypropyl Methylcellulose
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`Polysorbate 80
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`Benzalkonium Chloride
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`Disodium EDTA
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`Dibasic Sodium Phosphate
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`Sodium Chloride
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`pH adjustment with NaOH and/or HCI
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`Water
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`0.01-0.5%
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`0.5%
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`0.01%
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`0.01% + 5% excess
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`0.01%
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`0.2%
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`q.s. 290-300 mOsm/Kg
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`pH 4.2-7.4
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`q.s. 100%
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`Formulation 3
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`Nepafenac
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`0.1 + 6% excess
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`Carbo pol 97 4P
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`Tyloxapol
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`Glycerin
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`Disodium EDTA
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`Benzalkonium Chloride
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`pH adjustment with NaOH and/or HCI
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`Water
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`0.08%
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`0.01%
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`2.4%
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`0.01%
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`0.01%
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`pH 7.5 ± 0.2
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`q.s. 100%
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`This invention has been described by reference to certain preferred
`
`embodiments; however, it should be understood that it may be embodied in
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`other specific forms or variations thereof without departing from its special or
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`essential characteristics. The embodiments described above are therefore
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`considered to be illustrative in all respects and not restrictive, the scope of the
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`invention being indicated by the appended claims rather than by the foregoing
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`description.
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`R4 = C1-6 (un)branched alkyl;
`m = 0-3;
`m' = 0-5; and
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`W=O,H.
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`5
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`2.
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`The method of Claim 1 wherein
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`R = H, C1-2 alkyl;
`Y = NR'R";
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`10
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`;
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`R' = H, C1-6 (un)branched alkyl, -(CHz)nZ(CHz )n·A;
`Z =nothing, 0, CHOR3
`, NR3
`R3 = H;
`A= H, OH, (un)substituted aryl (substitution as defined by X below);
`, R4
`X and X' independently= H, F, Cl, Br, CN, CF3, OR', SR4
`R" = H;
`15 R4 = C1-4 (un)branched alkyl;
`m = 0-2;
`m' = 0-2;
`W=H;
`n = 2-4; and
`n' = 0-3.
`
`;
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`20
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`The method of Claim 2 wherein the 3-benzoylphenylacetic acid or
`3.
`derivative
`is . selected
`from
`the group consisting of 2-Amino-3-(4-
`fluorobenzoyl)-phenylacetamide; 2-Amino-3-benzoyl-phenylacetamide; and
`2-Amino-3-( 4-chlorobenzoyl)-phenylacetamide.
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`25
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`4.
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`The method of Claim 1 wherein the angiogenesis-related disorder is an
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`ophthalmic angiogenesis-related disorder.
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`5.
`The method of Claim 4 wherein the 3-benzoylphenylacetic acid or
`derivative is topically administered to the eye.
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`The method of Claim 5 wherein the therapeutically effective amount of
`6.
`3-benzoylphenylacetic acid or derivative is from about 0.001 to about 4.0%
`(w/v).
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`5
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`7.
`
`The method of Claim 4 wherein the angiogenesis-related disorder is
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`the group consisting of exudative macular degeneration;
`selected from
`proliferative diabetic
`retinopathy;
`ischemic
`retinopathy;
`retinopathy of
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`prematurity; neovascular glaucoma; iritis rubeosis; corneal neovascularization;
`cyclitis; sickle cell retinopathy; and pterygium.
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`10
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`15
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`8.
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`The method of Claim 1 wherein the 3-benzoylphenylacetic acid or
`
`derivative is administered orally, intravenously, in a subconjunctival injection
`or implant, in a sub-Tenon's injection or implant, in an intravitreal injection or
`implant, or in a surgical irrigating solution.
`
`The method of Claim 1 wherein the angiogenesis-related disorder is
`9.
`selected from the group consisting of prostate cancer; lung cancer; breast
`cancer; bladder cancer; renal cancer; colon cancer; gastric cancer; pancreatic
`cancer; ovarian cancer; melanoma; hepatoma; sarcoma; and lymphoma.
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`Innopharma EX1016, Page 11
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