(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`11111111111111111111111111111111111111111111111111111111111111111111111111111111
`
`(43) International Publication Date
`21 February 2002 (21.02.2002)
`
`PCT
`
`(10) International Publication Number
`WO 02/13804 A2
`
`(51) International Patent Classification7:
`
`A61K 31/00
`
`(21) International Application Number: PCT/US01/25318
`
`A. [US/US]; 5610 Hunterwood Lane, Arlington, TX 76017
`(US). GRAFF, Gustav [US/US]; 6500 County Road 809,
`Cleburne, TX 76031 (US). YANNI, John, M. [US/US];
`2821 Donnybrook Drive, Burleson, TX 76028 (US).
`
`(22) International Filing Date: 13 August 2001 (13.08.2001)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/225,133
`
`14 August 2000 (14.08.2000) US
`
`(71) Applicant (for all designated States except US): ALCON
`UNIVERSAL LTD. [CHICH]; Bosch 69, P. 0. Box 62,
`CH-6331 Hunenberg (CH).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): KAPIN, Michael,
`A. [US/US]; 3602 Silkwood Trail, Arlington, TX 76016
`(US). BINGAMAN, David, P. [US/US]; 875 Kickapoo
`Falls Road, Lipan, TX 76462 (US). GAMACHE, Daniel,
`
`(74) Agents: RYAN, Patrick, M. et al.; R & D Counsel Q-148,
`6201 South Freeway, Fort Worth, TX 76134-2099 (US).
`
`(81) Designated States (national): AU, BR, CA, CN, JP, KR,
`MX, PL, US, ZA.
`
`(84) Designated States (regional): European patent (AT, BE,
`CH, CY, DE, DK, ES, Fl, FR, GB, GR, IE, IT, LU, MC,
`NL, PT, SE, TR).
`
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`----iiiiiiii
`iiiiiiii -
`
`== -
`
`!!!!!!!! -iiiiiiii
`iiiiiiii ----
`
`~
`0
`QO
`~
`,..-.!
`..........
`~----------------------------------------------------------------------
`0
`(54) Title: METHOD OF TREATING ANGIOGENESIS-RELATED DISORDERS
`
`0 > (57) Abstract: The use of 3-benzolphenylacetic acids and derivatives, including nepafenac, to treat angiogenesis-related disorders,
`
`~ including ophthalmic angiogenesis-related disorders such as diabetic retinopathy and exudative macular degeneration, is disclosed.
`
`Metrics EX1017, Page 1
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`METHOD OF TREATING ANGIOGENESIS-RELATED DISORDERS
`
`FIELD OF THE INVENTION
`
`This invention relates to the use of certain 3-benzoylphenylacetic acids
`
`and derivatives to treat or prevent angiogenic diseases.
`
`BACKGROUND OF THE INVENTION
`
`5
`
`10
`
`3-benzoylphenylacetic acid and certain of its derivatives are known to
`
`possess anti-inflammatory activity. U.S. Patent Nos. 4,254, 146, 4,045,576,
`
`4, 126,635, and 4,503,073, and U.K. Patent Application Nos. 2,071 ,086A and
`
`2,093,027 A disclose various 3-benzoylphenylacetic acids, salts and esters, and
`
`15
`
`hydrates thereof, having anti-inflammatory activity. U.S. Patent No. 4,568,695
`
`discloses 2-amino-3-benzoylphenylethyl alcohols having anti-inflammatory
`
`activity.
`
`U.S. Patent No. 4,313,949 discloses 2-amino-3-benzoyl(cid:173)
`
`phenylacetamides having anti-inflammatory activity.
`
`zo
`
`Certain derivatives of 2-amino-3-benzoylbenzeneacetic acid (amfenac)
`
`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
`
`effects upon oral administration.
`
`25
`
`U.S. patent No. 4,683,242 teaches the transdermal administration of 2-
`
`amino-3-benzoylphenylacetic acids, salts, and esters, and hydrates and
`
`alcoholates thereof to control inflammation and alleviate pain.
`
`3o
`
`U.S. Patent No. 4,910,225 teaches certain benzoylphenylacetic acids for
`
`local administration to control ophthalmic, nasal or otic inflammation. Only
`
`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
`
`eyes, nose and ears.
`
`U.S. Patent No. 5,475,034 discloses
`
`topically administrable
`
`5
`
`compositions containing certain amide and ester derivatives of 3-
`
`benzyolphenylacetic acid, including nepafenac, useful for treating ophthalmic
`inflammatory disorders and ocular pain. According to the '035 patent at Col.
`
`15, lines 35-39, "[s]uch disorders include, but are not limited to uveitis scleritis,
`episcleritis, keratitis, surgically-induced inflammation and endophthalmitis."
`
`10
`
`U.S. Patent No. 6,066,671 discloses the topical use of certain amide and
`ester derivatives of 3-benzoylphenylacetic acid,
`including nepafenac, for
`
`treating GLC1 A glaucoma.
`
`15 SUMMARY OF THE INVENTION
`
`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.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The 3-benzoylphenylacetic acids and derivatives useful in the methods
`
`of the present invention are those of formula (I) below.
`
`20
`
`25
`
`2
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`Metrics EX1017, Page 3
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`R
`
`y
`
`(I)
`
`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,
`
`;
`
`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.
`
`;
`
`5
`
`10
`
`15
`
`20
`
`25
`
`As used herein, the acid (Y = OH) includes pharmaceutically
`acceptable salts as well.
`
`3
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`Metrics EX1017, Page 4
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`Preferred compounds for use in the methods of the present invention
`
`are those of Formula I wherein:
`
`5
`
`;
`
`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.
`
`20
`
`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.
`
`25
`
`According to the present invention, a therapeutically effective amount of
`
`a compound of formula (I) is administered topically, locally or systemically to
`
`treat or prevent angiogenesis-related disorders. Such disorders include those
`that involve the proliferation of tumor cells, such as prostate cancer, lung
`
`cancer, breast cancer, bladder cancer, renal cancer, colon cancer, gastric
`
`3o
`
`cancer, pancreatic cancer, ovarian cancer, melanoma, hepatoma, sarcoma and
`lymphoma. Ophthalmic angiogenesis-related disorders include, but are not
`
`limited to exudative macular degeneration; proliferative diabetic retinopathy;
`ischemic retinopathy (e.g., retinal vein or artery occlusion); retinopathy of
`
`4
`
`Metrics EX1017, Page 5
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`prematurity; neovascular glaucoma; iritis rubeosis; corneal neovascularization;
`
`cyclitis; sickle cell retinopathy; and pterygium. Certain disorders, such as sickle
`
`cell retinopathy and retinal vein or artery occlusion, can be characterized by
`
`both angiogenesis and neurodegenerative components. According to the
`
`5
`
`present invention, a compound of formula (I) is administered to treat or prevent
`
`disorders characterized, at least in part, by angiogenesis.
`
`The compounds of formula (I) can be administered in a variety of ways,
`
`including all forms of local delivery to the eye, such as subconjunctival
`
`10
`
`injections or implants, intravitreal injections or implants, sub-Tenon's injections
`
`or implants, incorporation in surgical irrigating solutions, etc. Additionally, the
`
`compounds of formula (I) can be administered systemically, such as orally or
`
`intravenously. Suitable pharmaceutical vehicles or dosage forms for injectable
`
`compositions,
`
`implants, and systemic administration are known.
`
`The
`
`15
`
`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
`
`variety of topically administrable ophthalmic compositions, such as solutions,
`
`suspensions, gels or ointment.
`
`20
`
`Pharmaceutical compositions comprising a compound of formula (I) in
`
`aqueous solution or suspension, optionally containing a preservative for
`
`multidose use and other conventionally employed ophthalmic adjuvants, can be
`
`topically administered to the eye. The most preferred form of delivery is by
`
`aqueous eye drops, but gels or ointments can also be used. Aqueous eye
`
`25
`
`drops, gels and ointments can be formulated according to conventional
`
`technology and would include one or more excipients. For example, topically
`
`administrable compositions may contain tonicity-adjusting agents, such as
`
`mannitol or sodium chloride; preservatives such as chlorobutanol,
`
`benzalkonium chloride, polyquaternium-1, or chlorhexidine; buffering agents,
`
`3o
`
`such as phosphates, borates, carbonates and citrates; and thickening agents,
`
`such as high molecular weight carboxy vinyl polymers, including those known
`
`as carbomers, hydroxyethylcellulose, or polyvinyl alcohol.
`
`5
`
`Metrics EX1017, Page 6
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`The doses of the compounds of formula (I) used in the treatment or
`
`prevention of ophthalmic angiogenesis-related disorders will depend on the
`
`type of disorder to be prevented or treated, the age and body weight of the
`
`patient, and the form of preparation/route of administration. Compositions
`
`s
`
`intended for topical ophthalmic administration will typically contain a compound
`
`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.
`
`Additional
`
`therapeutic agents may be added to supplement the
`
`compounds of formula (I).
`
`1s
`
`The following examples are presented to illustrate various aspects of the
`
`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.
`
`Example 1 : The following formulations are representative of the topical
`
`20
`
`compositions useful in the present invention.
`
`Formulation 1
`
`25
`
`Compound of formula (I)
`Polysorbate 80
`Benzalkonium Chloride
`
`Disodium EDTA
`
`Monobasic Sodium Phosphate
`
`Dibasic Sodium Phosphate
`
`30
`
`Sodium Chloride
`
`pH adjustment with NaOH and/or HCI
`
`Water
`
`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%
`
`6
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`Formulation 2
`
`Compound of formula (I)
`
`Hydroxypropyl Methylcellulose
`
`5
`
`Polysorbate 80
`
`Benzalkonium Chloride
`
`Disodium EDTA
`
`Dibasic Sodium Phosphate
`
`Sodium Chloride
`
`10
`
`pH adjustment with NaOH and/or HCI
`
`Water
`
`0.01-0.5%
`
`0.5%
`
`0.01%
`
`0.01% + 5% excess
`
`0.01%
`
`0.2%
`
`q.s. 290-300 mOsm/Kg
`
`pH 4.2-7.4
`
`q.s. 100%
`
`Formulation 3
`
`15
`
`Nepafenac
`
`0.1 + 6% excess
`
`Carbo pol 97 4P
`
`Tyloxapol
`
`Glycerin
`
`Disodium EDTA
`
`20
`
`Benzalkonium Chloride
`
`pH adjustment with NaOH and/or HCI
`
`Water
`
`0.08%
`
`0.01%
`
`2.4%
`
`0.01%
`
`0.01%
`
`pH 7.5 ± 0.2
`
`q.s. 100%
`
`25
`
`This invention has been described by reference to certain preferred
`
`embodiments; however, it should be understood that it may be embodied in
`
`other specific forms or variations thereof without departing from its special or
`
`essential characteristics. The embodiments described above are therefore
`
`considered to be illustrative in all respects and not restrictive, the scope of the
`
`3o
`
`invention being indicated by the appended claims rather than by the foregoing
`
`description.
`
`7
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`We Claim:
`
`PCT/USOl/25318
`
`1.
`
`A method of treating or preventing an angiogenesis-related disorder in a
`
`patient suffering from or predisposed to such a disorder which comprises
`
`5
`
`administering
`
`to
`
`the patient a
`
`therapeutically effective amount of 3-
`
`benzoylphenylacetic acid or derivative of the formula:
`
`R
`
`y
`
`(X')m•
`
`0
`
`wherein
`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),
`
`10
`
`15
`
`20
`
`25
`
`.
`'
`
`, NR3C(=O), S(O)n2,
`
`-(CH2)nZ(CH2)n·A;
`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);
`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;
`
`;
`
`8
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`Metrics EX1017, Page 9
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`R4 = C1-6 (un)branched alkyl;
`m = 0-3;
`m' = 0-5; and
`
`W=O,H.
`
`5
`
`2.
`
`The method of Claim 1 wherein
`
`R = H, C1-2 alkyl;
`Y = NR'R";
`
`10
`
`;
`
`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.
`
`;
`
`20
`
`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.
`
`25
`
`4.
`
`The method of Claim 1 wherein the angiogenesis-related disorder is an
`
`ophthalmic angiogenesis-related disorder.
`
`30
`
`5.
`The method of Claim 4 wherein the 3-benzoylphenylacetic acid or
`derivative is topically administered to the eye.
`
`9
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`Metrics EX1017, Page 10
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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).
`
`5
`
`7.
`
`The method of Claim 4 wherein the angiogenesis-related disorder is
`
`the group consisting of exudative macular degeneration;
`selected from
`proliferative diabetic
`retinopathy;
`ischemic
`retinopathy;
`retinopathy of
`
`prematurity; neovascular glaucoma; iritis rubeosis; corneal neovascularization;
`cyclitis; sickle cell retinopathy; and pterygium.
`
`10
`
`15
`
`8.
`
`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.
`
`10
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`Metrics EX1017, Page 11