(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`21 February 2002 (21.02.2002)
`
` (10) International Publication Number
`
`W0 02/ 13805 A2
`
`(51) International Patent Classification7:
`
`A61K 31/00
`
`(21) International Application Number:
`
`PCT/USOI/25319
`
`Road 809, Cleburne, TX 76031 (US). YANNI, John, M.
`[US/US]; 2821 Donnybrook Drive, Burleson, TX 76028
`(US). KAPIN, Michael, A.
`[US/US]; 3602 Silkwood
`Trail, Arlington, TX 76016 (US).
`
`(22) International Filing Date: 13 August 2001 (13.08.2001)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(74) Agents: RYAN, Patrick, M. et a1.; 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.
`
`(30) Priority Data:
`60/225,132
`
`14 August 2000 (14.08.2000)
`
`US
`
`(71) Applicant (for all designated States except US): ALCON
`UNIVERSAL LTD. [CH/CH]; Bosch 69, PO. Box 62,
`CH—6331 Hunenberg (CH).
`
`(84) Designated States (regional): European patent (AT, BE,
`CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC,
`NL, PT, SE, TR).
`
`Published:
`
`7 without international search report and to be republished
`upon receipt of that report
`
`(72) Inventors; and
`GAMACHE,
`(for US only):
`(7S) Inventors/Applicants
`Daniel, A. [US/US]; 5610 Hunterwood Lane, Arlington,
`TX 76017 (US). GRAFF, Gustav [US/US]; 6500 County
`
`For two-letter codes and other abbreviations, refer to the ”Guid-
`ance Notes on Codes andAbbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`
`
`002/13805A2
`
`(54) Title: METHOD OF TREATING NEURODEGENERATIVE DISORDERS OF THE RETINA AND OPTIC NERVE HEAD
`
`(57) Abstract: The use of 3—benzolpheny1acetic acids and derivatives, including nepafenac, to treat neurodegenerative retinal disor—
`ders is disclosed.
`
`Page 1 of 13
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`LUPIN EX 1033
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`LUPIN EX 1033
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`Page 1 of 13
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`WO 02/13805
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`PCT/US01/25319
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`METHOD OF TREATING NEURODEGENERATIVE DISORDERS OF THE
`
`RETINA AND OPTIC NERVE HEAD
`
`FIELD OF THE INVENTION
`
`This invention relates to the treatment of retinopathy.
`
`In particular, this
`
`invention relates to the use of certain 3-benzoylphenylacetic acids and
`
`derivatives to treat or prevent neurodegenerative disorders of the retina and
`
`optic nerve head.
`
`BACKGROUND OF THE INVENTION
`
`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 UK. “Patent Application Nos. 2,071,086A and
`
`2,093,027A disclose various 3-benzoylphenylacetic acids, salts and esters, and
`
`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-
`
`phenylacetamides having anti-inflammatory activity.
`
`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 Chem., 332296-2304 (1990), in an attempt to discover
`
`nonsteroidal anti-inflammatory prodrugs with minimal or no gastrointestinal side
`
`effects upon oral administration.
`
`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.
`
`10
`
`15
`
`20
`
`25
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`30
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`PCT/US01/25319
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`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
`
`mentioned or taught as anti-inflammatory agents for local administration to the
`
`5
`
`eyes, nose and ears.
`
`U.S.
`
`Patent No.
`
`5,475,034
`
`discloses
`
`topically
`
`administrable
`
`compositions
`
`containing
`
`certain
`
`amide
`
`and
`
`ester
`
`derivatives
`
`of
`
`3-
`
`benzyolphenylacetic acid,
`
`including nepafenac, useful for treating ophthalmic
`
`10
`
`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.”
`
`U.S. Patent No. 6,066,671 discloses the topical use of certain amide and
`
`15
`
`ester derivatives of 3-benzoylphenylacetic acid,
`
`including nepafenac,
`
`for
`
`treating GLC1A glaucoma.
`
`SUMMARY OF THE lNVENTlON
`
`' 20
`
`It has now been found that certain 3-benzoylphenylacetic acids and
`
`derivatives,
`
`including nepafenac (2-amino,3-benzoyl-phenylacetamide), are
`
`useful in treating neurodegenerative disorders of the retina and optic nerve
`
`head.
`
`Page 3 of 13
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`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.
`
`
`
`(l)
`
`R = H, (31.4 (un)branched alkyl, CF3, SR4
`
`Y = OR', NR"R';
`
`R‘ = H, 01-10 (un)branched alkyl, (un)substituted (substitution as defined by X
`
`‘IO
`
`below), (un)substituted heterocycle (substitution as defined by X below),
`
`-(CH2)nZ(CH2)n:A;
`
`n = 2-6;
`
`n'= —6;
`
`z = nothing, 0, 0:0, OC(=O), C(=O)O, C(=O)NR3, NR3C(=O), 5(0),,2,
`
`15
`
`CHOR3, NR3:
`
`n2 = 0-2;
`
`R3 = H, 01-5 (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;
`
`R4 = 01-6 (un)branched alkyl;
`
`m = 0-3;
`
`m' = 0—5;
`
`W = O, H.
`
`20
`
`25
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`As used herein, the acid (Y = OH) includes pharmaceutically
`
`acceptable salts as well.
`
`Preferred compounds for use in the methods of the present invention
`
`are those of Formula I wherein:
`
`R = H, C1.2 alkyl;
`
`Y = NR'R";
`
`10
`
`R' = H, C1-5 (un)branched alkyl, ~(CH2)nZ(CH2 )n'A;
`
`' z = nothing, 0, CHOR3, NR3;
`
`R3 = H;
`
`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;
`
`15
`
`R" = H;
`
`R4 = 01-4 (un)branched alkyl;
`
`20
`
`25
`
`30
`
`m = 0-2;
`
`m' = 0—2;
`
`W = H;
`
`n = 2-4;
`
`n’ = 0-3.
`
`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.
`
`According to the present invention, a therapeutically effective amount of
`
`a compound of formula (l) is administered topically, locally or systemically to
`
`treat or prevent neurodegenerative disorders of the retina and optic nerve head.
`
`Such disorders include, but are not limited to atrophic macular degeneration;
`
`retinitis pigmentosa;
`
`iatrogenic retinopathy;
`
`retinal tears and holes; diabetic
`
`retinopathy; sickle cell retinopathy; retinal vein and artery occlusion; and optic
`
`4
`
`Page 5 of 13
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`PCT/US01/25319
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`neuropathy. Certain ophthalmic disorders, such as sickle cell retinopathy and
`
`retinal vein or artery occlusion, can be characterized by both angiogenesis and
`
`neurodegenerative components.
`
`According to the present
`
`invention, a
`
`compound of
`
`formula (I)
`
`is administered to treat or prevent disorders
`
`characterized, at least in part, by neurodegeneration.
`
`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
`
`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
`
`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 ointments.
`
`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
`
`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,
`
`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.
`
`10
`
`15
`
`20
`
`25
`
`30
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`The doses of the compounds of formula (i) used in the treatment or
`
`prevention of neurodegenerative disorders of the retina and optic nerve head
`
`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 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 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).
`
`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
`
`compositions useful in the present invention.
`
`Formulation 1
`
`Compound of formula (I)
`
`Polysorbate 80
`
`0.01 — 0.5%
`
`0.01%
`
`Benzalkonium Chloride
`
`0.01% + 10% excess
`
`Disodium EDTA
`
`Monobasic Sodium Phosphate
`
`Dibasic Sodium Phosphate
`
`0.1%
`
`0.03%
`
`0.1 %
`
`Sodium Chloride
`
`q.s. 290-300 mOsm/Kg
`
`pH adjustment with NaOH and/or HCl
`
`pH 4.2 — 7.4
`
`Water
`
`q.s. 100%
`
`1D
`
`15
`
`20
`
`25
`
`30
`
`6
`
`Page 7 of 13
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`W0 02/13805
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`PCT/USOl/25319
`
`Formulation 2
`
`Compound of formula (I)
`
`Hydroxypropyl Methylcellulose
`
`Polysorbate 80
`
`0.01 — 0.5%
`
`0.5%
`
`0.01 %
`
`Benzalkonium Chloride
`
`0.01% + 5% excess
`
`Disodium EDTA
`
`Dibasic Sodium Phosphate
`
`Sodium Chloride
`
`0.01%,
`
`0.2%
`
`q.s. 290-300 mOsm/Kg
`
`pH adjustment with NaOH and/or HCI
`
`pH 4.2 — 7.4
`
`Water
`
`q.s. 100%
`
`Formulation 3
`
`10
`
`15
`
`Nepafenac
`
`Carbopol 974P
`
`Tyloxapol
`
`Glycerin
`
`‘20
`
`Disodium EDTA ‘
`
`Benzalkonium Chloride
`
`0.1 + 6% excess
`
`0.08%
`
`0.01%
`
`2.4%
`
`0.01%
`
`0.01%
`
`pH adjustment with NaOH and/or HCI
`
`pH 7.5 i 0.2
`
`Water
`
`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
`
`so
`
`considered to be illustrative in all respects and not restrictive, the scope of the
`
`invention being indicated by the appended claims rather than by the foregoing
`
`description.
`
`Page 8 of 13
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`WO 02/13805
`
`We Claim:
`
`PCT/US01/25319
`
`1.
`
`A method of treating or preventing a neurodegenerative disorder of the
`
`retina or optic nerve head in a patient suffering from or predisposed to such a
`
`5
`
`disorder which comprises administering to the patient a therapeutically effective
`
`amount of 3-benzoylphenylacetic acid or derivative of the formula:
`
`
`
`wherein
`
`10
`
`R = H, C14(un)branched alkyl, CF3, SR4,
`
`Y = OR', NR"R';
`
`R' = H, 01-10 (un)branched alkyl, (un)substituted (substitution as defined by X
`
`below), (un)substituted heterocycle (substitution as defined by X below),
`
`-(CH2),Z(CH2),’A;
`
`15
`
`n = 2-6;
`
`n'= 1-6;
`
`Z = nothing, 0, 0:0, OC(=O), C(=O)O, C(=O)NR3, NR3C(=O), 8(0),,2,
`
`CHOR3, NR3;
`
`n2 = 0-2;
`
`20
`
`R3 = H, C143 (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';
`
`25
`
`x and X' independently = H, F, Cl, Br, l, OR', CN, OH, 3(0),,2R4, CFg, R4,
`
`N02;
`
`Page 9 of 13
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`PCT/US01/25319
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`R4 = C1-6 (un)branched alkyl;
`
`m = 0-3;
`
`m' = 0-5; and
`
`W = O, H.
`
`2.
`
`The method of Claim 1 wherein
`
`R = H, C1-2 alkyl;
`
`Y = NR'R";
`
`R' = H, C14; (un)branched alkyl, ——(CH2),,Z(CH2 )n:A;
`
`z = nothing, 0, CHOR3, NR3;
`
`R3 = H;
`
`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;
`
`R4 = 01-4 (un)branched alkyl;
`
`10
`
`15
`
`m = 0-2;
`
`m' = 0-2;
`
`W = H;
`
`n = 2-4; and
`
`20
`
`n' = 0-3.
`
`3.
`
`The method of Claim 2 wherein the 3-benzoylphenylacetic acid or
`
`derivative is selected from the group consisting of 2—Amino-3—(4-
`
`fluorobenzoyl)-phenylacetamide; 2—Amino-3-benzoyl-phenylacetamide; and
`
`25
`
`2-Amino-3-(4-chlorobenzoyl)-phenylacetamide.
`
`4.
`
`The method of Claim 1 wherein the 3—benzoylphenylacetic acid or
`
`derivative is topically administered to the eye.
`
`5.
`
`The method of Claim 4 wherein the therapeutically effective amount of
`
`3-benzoylphenylacetic acid or derivative is from about 0.001 to about 4.0%
`
`(w/v).
`
`Page 10 of13
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`Page 10 of 13
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`

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`WO 02/13805
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`PCT/US01/25319
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`6.
`
`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.
`
`'7.
`
`A method of treating or preventing a disorder of the retina or optic nerve
`
`head in a patient suffering from or predisposed to such a disorder which
`
`comprises administering to the patient a therapeutically effective amount of 3-
`
`benzoylphenylacetic acid or derivative of the formula:
`
`10
`
`
`
`wherein
`
`R = H, 01-4 (un)branched alkyl, CF3, SR4;
`
`Y = OR', NR"R';
`
`15
`
`R' = H, 01-10 (un)branched alkyl, (un)substituted (substitution as defined by X
`
`below), (un)substituted heterocycle (substitution as defined by X below),
`
`-(CH2),Z(CH2),:A;
`
`n = 2-6;
`
`n'= -6;
`
`20
`
`z = nothing, 0, 0:0, oc<=0), C(=O)O, C(=O)NR3, NR3C(=O), 8(0),,2,
`CHOR3, NR3;
`‘
`V
`
`rr2 = 0-2;
`
`R3 = H, 01-5 (un)branched alkyl, (un)substituted aryl (substitution as defined
`
`by X below), (un)substituted heterocycle (substitution as defined by X below);
`
`25
`
`A = H, OH, optionally (un)substituted aryl (substitution as defined by X below),
`
`(un)substituted heterocycle (substitution as defined by X below), —(CH2),.OR3;
`
`10
`
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`R" = H, OH, OR';
`
`x and x' independently = H, F, Cl, Br, I, OR', CN, OH, S(O)n2R4, CF3, R4,
`
`N02;
`
`R4 = 01—6 (un)branched alkyl;
`
`m = 0—3;
`
`m' = 0-5; and
`
`W = O, H;
`
`wherein the disorder is selected from the group consisting of atrophic macular
`
`degeneration; retinitis pigmentosa; iatrogenic retinopathy; retinal tears and
`
`holes; diabetic retinopathy; sickle cell retinopathy; retinal vein and artery
`
`occlusion; and optic neuropathy.
`
`8.
`
`The method of Claim 7 wherein
`
`R = H, 01-2 alkyl;
`
`Y = NR'R";
`
`R' = H, 01-5 (un)branched alkyl, ——(CH2)nZ(CH2 )n’A;
`
`z = nothing, 0, CHORS, NR3;
`
`R3 = H;
`
`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;
`
`10
`
`15
`
`20
`
`R4 = C14 (un)branched alkyl;
`
`m = 0—2;
`
`m' = 0-2;
`
`25
`
`W = H;
`
`n = 2—4; and
`
`n' = 0-3.
`
`9.
`
`The method of Claim 8 wherein the 3-benzoylphenylacetic acid or
`
`30
`
`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.
`
`11
`
`Page 12 of 13
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`10.
`
`The method of Claim 7 wherein the 3-benzoylphenylacetic acid or
`
`derivative is topically administered to the eye.
`
`11.
`
`The method of Claim 10 wherein the therapeutically effective amount of
`
`5
`
`3-benzoylphenylacetic acid or derivative is from about 0.001 to about 4.0%
`
`(WM.
`
`12.
`
`The method of Claim 7 wherein the 3-benzoylphenylacetic acid or
`
`derivative is administered orally, intravenously, in a subconjunctival injection
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`10
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`or implant, in a sub-Tenon’s injection or implant, in an intravitreal injection or
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`implant, or in a surgical irrigating solution.
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`12
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`Page 13 of13
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`Page 13 of 13
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