(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2002/0049255 A1
`
`Gamache et al.
`Apr. 25, 2002
`(43) Pub. Date:
`
`US 20020049255A1
`
`METHOD OF TREATING
`NEURODEGENERATIVE DISORDERS OF
`THE RETINA AND OPTIC NERVE HEAD
`
`(22)
`
`Filed:
`
`Aug. 13, 2001
`
`Related US. Application Data
`
`(54)
`
`(75)
`
`Inventors: Daniel A. Gamache, Arlington, TX
`(US); Gustav Grafi', Cleburne, TX
`(US); John M. Yanni, Burleson, TX
`(US); Michael A. Kapin, Arlington, TX
`(US)
`
`Correspondence Address:
`Alcon Universal Ltd.
`
`c/o Alcon Research, Ltd.
`Patrick M. Ryan(Q-148)
`6201 So. Freeway
`Fort Worth, TX 76134-2099 (US)
`
`(73)
`
`Assignee: Alcon Universal Ltd.
`
`(21)
`
`Appl. N0.:
`
`09/929,704
`
`(63)
`
`Non-provisional of provisional
`60/225,132, filed on Aug. 14, 2000.
`
`application No.
`
`Publication Classification
`
`(51)
`
`(52)
`
`(57)
`
`Int. Cl.7 ..................... A61K 31/165; A61K 31/195;
`A61K 31/24
`........................... 514/619; 514/567; 514/534
`
`US. Cl.
`
`ABSTRACT
`
`The use of 3-benzolphenylacetic acids and derivatives,
`including nepafenac, to treat neurodegenerative retinal dis-
`orders is disclosed.
`
`Page 1 of 5
`
`LUPIN EX 1034
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`LUPIN EX 1034
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`Page 1 of 5
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`

`

`US 2002/0049255 A1
`
`Apr. 25, 2002
`
`METHOD OF TREATING NEURODEGENERATIVE
`DISORDERS OF THE RETINA AND OPTIC NERVE
`HEAD
`
`[0001] This application claims priority to US. Provisional
`Application, Serial No. 60/225,132, filed Aug. 14, 2000.
`
`FIELD OF THE INVENTION
`
`[0002] This invention relates to the treatment of retinopa-
`thy. In particular, this invention relates to the use of certain
`3-benzoylphenylacetic acids and derivatives to treat or pre-
`vent neurodegenerative disorders of the retina and optic
`nerve head.
`
`BACKGROUND OF THE INVENTION
`
`its
`3-benzoylphenylacetic acid and certain of
`[0003]
`derivatives are known to possess anti-inflammatory activity.
`US. Pat. 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-inflam-
`matory activity. US. Pat. No. 4,568,695 discloses 2-amino-
`3-benzoylphenylethyl alcohols having anti-inflammatory
`activity. US. Pat. No. 4,313,949 discloses 2-amino-3-ben-
`zoyl-phenylacetamides having anti-inflammatory activity.
`
`[0004] Certain derivatives of 2-amino-3-benzoylbenzene-
`acetic acid (amfenac) and 2-amino-3-(4-chloro-benzoyl)
`benzeneacetic acid have also been evaluated by Walsh et al.,
`J. Med Chem., 33:2296-2304 (1990),
`in an attempt
`to
`discover nonsteroidal anti-inflammatory prodrugs with
`minimal or no gastrointestinal side effects upon oral admin-
`istration.
`
`[0005] US. Pat. 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.
`
`[0006] US. Pat. No. 4,910,225 teaches certain ben-
`zoylphenylacetic 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 men-
`tioned or taught as anti-inflammatory agents for local admin-
`istration to the eyes, nose and ears.
`
`[0007] US. Pat. No. 5,475,034 discloses topically admin-
`istrable compositions containing certain amide and ester
`derivatives
`of 3-benzyolphenylacetic
`acid,
`including
`nepafenac, useful for treating ophthalmic inflammatory dis-
`orders 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.”
`
`[0008] US. Pat. No. 6,066,671 discloses the topical use of
`certain amide and ester derivatives of 3-benzoylphenylacetic
`acid, including nepafenac, for treating GLC1A glaucoma.
`
`SUMMARY OF THE INVENTION
`
`It has now been found that certain 3-benzoylphe-
`[0009]
`acids
`and derivatives,
`including nepafenac
`nylacetic
`(2-amino,3-benzoyl-phenylacetamide), are useful in treating
`neurodegenerative disorders of the retina and optic nerve
`head.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0010] The 3-benzoylphenylacetic acids and derivatives
`useful in the methods of the present invention are those of
`formula (1) below.
`
`(I)
`
`
`
`[0011] R=H, C1_4 (un)branched alkyl, CF3, SR4
`
`[0012] Y=OR', NR"R';
`
`[0013] R'=H, C1_10 (un)branched alkyl, (un)substi-
`tuted (substitution as defined by X below), (un)sub-
`stituted heterocycle (substitution as defined by X
`below), —(CH2)DZ(CH2)UVA;
`
`[0014]
`
`n=2-6;
`
`[0015]
`
`n'=1-6;
`
`[0016] Z=nothing, O, C=O, OC(=O), C(=O)O,
`C(=O)NR3, NR3C(=O), S(O)n2, CHOR3, NR3;
`
`[0017]
`
`n2=0-2;
`
`[0018] R3=H, C1_6 (un)branched alkyl, (un)substi-
`tuted 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)sub-
`stituted heterocycle (substitution as defined by X
`below), —(CH2)DOR3;
`
`[0019] R"=H, OH, OR‘
`
`[0020] X and X' independently=H, F, Cl, Br, I, OR',
`CN, OH, S(O)n2R4, CF3, R4, N02;
`
`[0021] R4=C1_6 (un)branched alkyl;
`
`[0022] m=0-3;
`
`[0023] m'=0-5;
`
`[0024] W=O, H.
`
`[0025] As used herein, the acid (Y=OH) includes phar-
`maceutically acceptable salts as well.
`
`[0026] Preferred compounds for use in the methods of the
`present invention are those of Formula I wherein:
`
`[0027] R=H,C1_2 alkyl;
`
`[0028] Y=NR‘R";
`
`CM
`[0029] R‘=H,
`—(CH2)nZ(CH2)n'A;
`
`(un)branched
`
`alkyl,
`
`[0030] Z=nothing, O, CHOR3, NR3;
`
`Page 2 of 5
`
`Page 2 of 5
`
`

`

`US 2002/0049255 A1
`
`Apr. 25, 2002
`
`[0031] R3=H;
`
`[0032] A=H, OH, (un)substituted aryl (substitution as
`defined by X below);
`
`[0033] X and X' independently=H, F, Cl, Br, CN,
`CF3, OR', SR4, R4;
`
`[0034] R"=H;
`
`[0035] R4=C1_4 (un)branched alkyl;
`
`[0036] m=0-2;
`
`[0037] m'=0-2;
`
`[0038] W=H;
`
`[0039]
`
`n=2-4;
`
`[0040]
`
`n‘=0-3.
`
`[0041] 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.
`
`[0042] According to the present invention, a therapeuti-
`cally effective amount of a compound of formula (I) 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; iatro-
`genic retinopathy; retinal tears and holes; diabetic retinopa-
`thy; sickle cell retinopathy; retinal vein and artery occlusion;
`and optic neuropathy. Certain ophthalmic disorders, such as
`sickle cell retinopathy and retinal vein or artery occlusion,
`can be characterized by both angiogenesis and neurodegen-
`erative components. According to the present invention, a
`compound of formula (I) is administered to treat or prevent
`disorders characterized, at least in part, by neurodegenera-
`tion.
`
`[0043] 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 admin-
`istered systemically, such as orally or intravenously. Suitable
`pharmaceutical vehicles or dosage forms for injectable com-
`positions, 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.
`
`[0044] Pharmaceutical compositions comprising a com-
`pound 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 chlo-
`ride; 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 car-
`boxy vinyl polymers, including those known as carbomers,
`hydroxyethylcellulose, or polyvinyl alcohol.
`
`[0045] 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 admin-
`istration. 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.
`
`therapeutic agents may be added to
`[0046] Additional
`supplement the compounds of formula (I).
`
`[0047] 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
`
`[0048] The following formulations are representative of
`the topical compositions useful in the present invention.
`
`Formulation 1
`
`Compound of formula (I)
`Polysorbate 80
`Benzalkonium Chloride
`Disodium EDTA
`Monobasic Sodium Phosphate
`Dibasic Sodium Phosphate
`Sodium Chloride
`pH adjustment with NaOH and/or HCl
`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%
`
`[0049]
`
`Formulation 2
`
`Compound of formula (I)
`Hydroxypropyl Methylcellulose
`Polysorbate 80
`Benzalkonium Chloride
`Disodium EDTA
`Dibasic Sodium Phosphate
`Sodium Chloride
`pH adjustment with NaOH and/or HCl
`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%
`
`Page 3 of 5
`
`Page 3 of 5
`
`

`

`US 2002/0049255 A1
`
`Apr. 25, 2002
`
`[0050]
`
`Formulation 3
`
`Nepafenac
`Carbopol 974P
`Tyloxapol
`Glycerin
`Disodium EDTA
`Benzalkonium Chloride
`pH adjustment with NaCH and/or HCl
`Water
`
`0.1 + 6% excess
`0.08%
`0.01%
`2.4%
`0.01%
`0.01%
`pH 7.5 1 0.2
`q.s. 100%
`
`[0051] This invention has been described by reference to
`certain preferred embodiments; however, it should be under-
`stood 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 invention being indicated by
`the appended claims rather than by the foregoing descrip-
`tion.
`
`We claim:
`
`1. Amethod of treating or preventing a neurodegenerative
`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 deriva-
`tive of the formula:
`
`
`
`wherein
`
`R=H, C1_4 (un)branched alkyl, CF3, SR4;
`
`Y=OR', NR"R';
`
`R‘=H, C1_10 (un)branched alkyl, (un)substituted (substi-
`tution as defined by X below), (un)substituted hetero-
`cycle
`(substitution
`as
`defined
`by X below),
`—(CH2)nZ(CH2)nvA;
`
`n=2-6;
`
`n'=1-6;
`
`Z=nothing, o, C=O, OC(=O), C(=O)O, C(=O)NR3,
`NR3C(=O), S(O)n2, CHOR3, NR3;
`
`n2=0-2;
`
`R3=H, C1_6 (un)branched alkyl, (un)substituted aryl (sub-
`stitution as defined by X below), (un)substituted het-
`erocycle (substitution as defined by X below);
`
`Page 4 of 5
`
`A=H, OH, optionally (un)substituted aryl (substitution as
`defined by X below), (un)substituted heterocycle (sub-
`stitution as defined by X below), —(CH2)DOR3;
`
`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; and
`
`W=O, H.
`2. The method of claim 1 wherein
`
`R=H, C1_2 alkyl;
`
`Y=NR'R";
`
`R‘=H, C1_6 (un)branched alkyl, —(CH2)HZ(CH2)D.A;
`
`Z=nothing, O, 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;
`
`R"=H;
`
`R4=C1_4 (un)branched alkyl;
`
`m=0-2;
`
`m'=0-2;
`
`W=H;
`
`n=2-4; and
`
`n‘=0-3.
`
`3. The method of claim 2 wherein the 3-benzoylpheny-
`lacetic acid or derivative is selected from the group consist-
`ing
`of
`2-Amino-3-(4-fiu0robenzoyl)-phenylacetamide;
`2-Amino-3-benzoyl-phenylacetamide; and 2-Amino-3-(4-
`chlorobenzoyl)-phenylacetamide.
`4. The method of claim 1 wherein the 3-benzoylpheny-
`lacetic 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 deriva-
`tive is from about 0.001 to about 4.0% (w/v).
`6. The method of claim 1 wherein the 3-benzoylpheny-
`lacetic acid or derivative is administered orally,
`intrave-
`nously,
`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 administer-
`ing to the patient a therapeutically effective amount of
`3-benzoylphenylacetic acid or derivative of the formula:
`
`Page 4 of 5
`
`

`

`US 2002/0049255 A1
`
`Apr. 25, 2002
`
`
`
`wherein
`
`R=H, C1_4 (un)branched alkyl, CF3, SR4;
`Y=OR', NR"R';
`
`R‘=H, C1_10 (un)branched alkyl, (un)substituted (substi-
`tution as defined by X below), (un)substituted hetero-
`cycle
`(substitution
`as
`defined
`by X below),
`—(CH2)UZ(CH2)nvA;
`
`n=2-6;
`
`n'=1-6;
`
`Z=nothing, o, C=O, OC(=O), C(=O)O, C(=O)NR3,
`NR3C(=O), S(O)n2, CHOR3, NR3;
`
`n2=0-2;
`
`R3=H, C1_6 (un)branched alkyl, (un)substituted aryl (sub-
`stitution as defined by X below), (un)substituted het-
`erocycle (substitution as defined by X below);
`
`A=H, OH, optionally (un)substituted aryl (substitution as
`defined by X below), (un)substituted heterocycle (sub-
`stitution as defined by X below), —(CH2)DOR3;
`R"=H, OH, OR';
`
`X and X' independently=H, F, Cl, Br, I, OR', CN, OH,
`S(O)n2R4> CF33 R4) N02;
`
`R4=C1_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, C1_2 alkyl;
`
`Y=NR‘R";
`
`R‘=H, C1_6 (un)branched alkyl, —(CH2)nZ(CH2)n,A;
`
`Z=nothing, O, 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;
`
`R"=H;
`
`R4=C1_4 (un)branched alkyl;
`m=0-2;
`
`m'=0-2;
`
`W=H;
`
`n=2-4; and
`n‘=0-3.
`
`9. The method of claim 8 wherein the 3-benzoylpheny-
`lacetic acid or derivative is selected from the group consist-
`ing
`of
`2-Amino-3-(4-fiuorobenzoyl)-phenylacetamide;
`2-Amino-3-benzoyl-phenylacetamide; and 2-Amino-3-(4-
`chlorobenzoyl)-phenylacetamide.
`10. The method of claim 7 wherein the 3-benzoylpheny-
`lacetic acid or derivative is topically administered to the eye.
`11. The method of claim 10 wherein the therapeutically
`effective amount of 3-benzoylphenylacetic acid or deriva-
`tive is from about 0.001 to about 4.0% (w/v).
`12. The method of claim 7 wherein the 3-benzoylpheny-
`lacetic acid or derivative is administered orally,
`intrave-
`nously,
`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.
`*
`*
`*
`*
`*
`
`Page 5 of 5
`
`Page 5 of 5
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`