United States Patent [191
`Yanni et al.
`
`llllll|||l|l||lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`5,475,034
`Dec. 12, 1995
`
`USOO5475034A
`[11] Patent Number:
`[45] Date of Patent:
`
`[54] TOPICALLY ADMINISTRABLE
`COlVIPOSITIONS CONTAINING
`3-BENZOYLPHENYLACETIC ACID
`DERIVATIVES FOR TREATMENT OF
`OPHTHALMIC INFLAMMATORY
`DISORDERS
`
`[75] Inventors: John M. Yanni, Burleson; Gustav
`Graff, Cleburne; Mark R. Hellberg,
`Arlington, all of Tex.
`
`[73] Assignee: Alcon Laboratories, Inc., Fort Worth,
`Tex.
`
`[21] Appl. No.: 254,090
`[22] Filed:
`Jun. 6, 1994
`
`[51] Int. Cl.6 ................................................. .. A61K 31/165
`[52] U.S. Cl. ........................ .. 514/619; 514/535; 514/570;
`514/617; 514/618; 514/621
`[58] Field of Search ........................... .. 564/169; 514/621,
`514/619, 617, 618
`
`[56]
`
`References Cited
`
`7/1987 Poser ..................................... .. 514/539
`4,683,242
`4,783,487 11/1988 Brune ..... ..
`4,851,443
`7/1989 Brune ............. ..
`4,910,225
`3/1990 Ogawa et al. ........................ .. 514/561
`
`FOREIGN PATENT DOCUNIENTS
`
`2071086 9/1981 United Kingdom .
`2093027
`8/1982 United Kingdom .
`
`OTHER PUBLICATIONS
`
`non—steroidal
`“AER-10037, a
`al.,
`et
`Sancillo
`anti—in?ammatory compound of low gastric toxicity,”
`Agents and Actions, 31:ll7—l26 (1990).
`Walsh et al., “Antiin?ammatory Agents. 3. Synthesis and
`Pharmacological
`Evaluation
`of
`2—Amino—3—benzoylphenylacetic Acid and Analogues,” J.
`Med. Chem. 27:1379-1388 (1984).
`Walsh et al., “Antiin?ammatory Agents. 4. Synthesis and
`Biological
`Evaluation
`of Potential
`Prodrugs
`of
`2—Amino—3—benzoylbenzeneacetic
`Acid
`and
`2-Amino-3-(4-chlorobenzoyl)benzeneacetic Acid,” J.
`Med. Chem. 33:2296—2304 (1990).
`Primary Examiner—Shailendra Kumar
`Attorney, Agent, or Firm--Patrick M. Ryan
`
`U.S. PATENT DOCUMENTS
`
`[57]
`
`ABSTRACT
`
`8/1974 Bays et al. ............................ .. 260/469
`3,828,093
`8/1977 Welstead, Jr. et al.
`424/309
`4,045,576
`4,126,635 11/1978 Welstead, Jr. et al. . . . .
`. . . .. 562/441
`4,182,774
`1/1980 Welstead, Jr. et al.
`424/309
`4,254,146
`3/1981 Walsh ............................ .. 424/309
`4,318,949
`2/1982 Shanklin, Jr. et al.
`424/248.56
`
`4,503,073
`4,568,695
`
`3/1985 Walsh et al. . . . . . . .
`. . . .. 514/539
`2/1986 Moran et al. ......................... .. 514/648
`
`Novel ester and amide derivatives of 3'benzoylphenylacetic
`acid are disclosed. The use of these novel derivatives and
`certain known derivatives in topically administrable com
`positions for the treatment of ophthalmic in?ammatory
`disorders is also disclosed.
`
`7 Claims, No Drawings
`
`Page 1 of 10
`
`SENJU EXHIBIT 2007
`METRICS v. SENJU
`IPR2014-01043
`
`

`

`5,475,034
`
`1
`TOPICALLY ADNHNISTRABLE
`COMPOSITIONS CONTAINING
`3-BENZOYLPHENYLACETIC ACID
`DERIVATIVES FOR TREATMENT OF
`OPHTHALMIC INFLAM'MATORY
`DISORDERS
`
`FIELD OF THE INVENTION
`
`This invention relates to topically administrable compo
`sitions for the treatment of in?ammatory disorders. In par
`ticular, this invention relates to non-irritating, topically
`administrable compositions containing 3-benzoylphenylace
`tic acid derivatives for the treatment of ophthalmic in?am
`matory disorders.
`
`15
`
`BACKGROUND OF THE INVENTION
`
`2
`
`irritation and discomfort.
`Additionally, the acetic acid compounds taught in the ’225
`patent are di?icult to formulate in stable aqueous solutions.
`The ’225 patent solves this problem by incorporating a
`water~soluble polymer and sul?te, and adjusting the pH to
`about 6.0 to 9.0, preferably about 7.5-8.5. Water soluble
`polymers taught by the ’225 patent include polyvinyl pyr
`rolidone, carboxypropylcellulose, hydroxyethylcellulose,
`hydroxypropylcellulose, polyvinyl alcohol, sodium salt of
`polyacrylic acid and so on. Polyvinyl pyrrolidone is pre
`ferred. The concentration of water soluble polymer is in the
`range of 0.1 to 10 w/w %. Sul?te includes sodium, potas
`sium, magnesium, and calcium sul?te salt and so on. The
`concentration is in the range of about 0.1 to 1.0 w/w %.
`What is needed are additional non-steroidal, topically
`administrable anti-in?ammatory agents which are stable,
`non-irritating at therapeutic doses, and at least as potent as
`benzoylphenylacetic acids in suppressing ocular in?amma
`tion.
`
`SUMMARY OF THE INVENTION
`
`It has now been found that certain novel and certain
`known 3-benzoylphenylacetic acid derivatives are useful as
`topically administrable anti-in?ammatory compounds for
`treating ophthalmic in?ammatory disorders. Converting the
`free acetic acid functional group to an ester or an amide
`enhances compound stability by slowing the rate of lactam
`formation. Among other factors, the present invention is
`based on the ?nding that certain 3-benzoylphenylacetic acid
`derivatives which show no signi?cant anti-in?ammatory
`activity in vitro are, in fact, as active or even more active
`than the parent 3-benzoylphenylacetic acids when adminis
`tered topically to the eye.
`Accordingly, the present invention is directed to novel
`derivatives of 3-benzoylphenylacetic acid compounds. The
`present invention is also directed to pharmaceutical compo
`sitions suitable for topical ophthalmic administration which
`contain an anti-in?ammatory-effective amount of a 3-ben
`Zoylphenylacetic acid derivative, and to a method of treating
`ophthalmic in?ammatory disorders which comprises topi~
`cally administering to the eye a 3-benzoylphenylacetic acid
`derivative.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`As used herein, “(un)branched” means optionally
`branched, and “(un)substituted” means optionally substi
`tuted.
`The novel 3-benzoylphenylacetic acid derivative com
`pounds of the present invention have the following structural
`formula:
`
`(I)
`
`3-benzoylphenylacetic acid and certain of its derivatives
`are known to possess anti-in?ammatory activity. U.S. Pat.
`Nos. 4,254,146, 4,045,576, 4,126,635, and 4,503,073, and
`U.K. Patent Application Nos. 2,071,086A and 2,093,027A
`teach various 3-benzoylphenylacetic acids, salts and esters,
`and hydrates thereof, having anti-in?ammatory activity.
`US. Pat. No. 4,568,695 teaches 2-amino-3-benzoylphenyl
`ethyl alcohols having anti-in?ammatory activity. US. Pat.
`No. 4,313,949 teaches 2-amino-3-benzoyl-phenylaceta~
`rnides having anti-in?ammatory activity.
`Each of the above-listed patents or patent applications, all
`of which are assigned in whole or in part to A. H. Robins,
`contains an identical disclosure regarding formulations of
`the 3-benzoylphenylacetic acid or acid derivative. Each of
`the above also contains the same disclosure regarding
`administration routes for the drug formulation. The only
`formulation examples in the A. H. Robins patents or patent
`applications are capsules, tablets and “injectable—2% sterile
`solutions,” and the only administration routes mentioned are
`oral (as in capsules or tablets) parenteral (in the form of
`sterile solutions or suspensions), and, in some cases intra
`venous (in the form of sterile solutions). No topical or local
`administration is taught by any of the above-listed patents or
`patent applications.
`Certain derivatives of 2-amino-3-benzoylbenzeneacetic
`acid (amfenac) and 2-amino-3—(4-chloro-benzoyl)benzene
`acetic acid have also been evaluated by Walsh et al., J. Med.
`Chem, 33:2296-2304 (1990), in an attempt to discover
`nonsteroidal anti—in?ammatory prodrugs with minimal or no
`gastrointestinal side effects upon oral administration.
`In contrast, U.S. Pat. No. 4,683,242 teaches the transder
`mal administration of 2-amino-3-benzoylphenylacetic acids,
`salts, and esters, and hydrates and alcoholates thereof to
`control in?ammation and alleviate pain.
`US. Pat. No. 4,910,225 teaches certain benzoylpheny
`lacetic acids for local administration to control ophthalmic,
`nasal or otic in?ammation. Only acetic acids are disclosed in
`the ’225 patent; no esters or amides are mentioned or taught
`as anti—in?ammatory agents for local administration to the
`eyes, nose and ears.
`Although benzoylphenylacetic acids are effective in sup
`pressing ocular in?ammation, their full anti-in?ammatory
`potential has not yet been approached due to their generally
`slow rate of penetration through the cornea. Relatively high
`concentrations of these drugs are often needed to achieve
`corneal penetration rates su?icient to provide effective
`intraocular drug concentrations. Such high drug concentra
`tions are generally not desirable as they may provoke ocular
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`Page 2 of 10
`
`

`

`3
`
`5,475,034
`
`R3=H, C1_6(un)branched alkyl, (un)substituted aryl (substi
`tution as de?ned by X below), (un)substituted heterocycle
`(substitution as de?ned by X below)
`A=H, OH, (un)substituted aryl (substitution as de?ned by X
`below), (un)substituted heterocycle, —(CH2),OR3
`A'=OH, (un)substituted aryl (substitution as de?ned by X
`below), (un)substituted heterocycle (substitution as
`de?ned by X below), —(CH2),OR3
`
`10
`
`R7=H, C1_6(un)branched alkyl, (un)substituted aryl (substi
`tution as de?ned by X below)
`X and X‘ independently=H, F, Cl, Br, 1, CR7, CN, OH,
`S(O),,2R4, CF3, R4, NO2
`
`n2=O—2
`The preferred, novel 3-benzoylphenylacetic acid deriva- 25
`tives are those wherein:
`
`—(CH2),—Z3——(CH2)
`
`r=2—4
`r‘=O-2
`22:0
`Z3=nothing
`A=H
`A'=(un)substituted aryl (substitution as de?ned by X below)
`R6=H, OR7
`R7=H, CL2 alkyl
`X and X' independently=H, F, Cl, Br, CF3, S(O),,2R4, OR7
`m=0—2
`m'-—-0—3
`n2=0
`The 3-benzoylphenylacetic acid derivative compounds
`useful in the topically adrninistrable ophthalmic composi
`tions of the present invention are represented by the follow
`ing structural formula which includes both known deriva
`tives and the novel derivatives of the present invention:
`
`30
`
`35
`
`40
`
`50
`
`R3=H, C1_6 (un)branched alkyl, (un)substituted aryl (substi
`tution as de?ned by X below), (un)substituted heterocycle
`(substitution as de?ned by X below)
`A=H, 0H, optionally (un)substituted aryl (substitution as
`de?ned by X below), (un)substituted heterocycle (substi
`tution as de?ned by X below), —(CH,),IOR3
`
`X and X' independently=H, F, Cl, Br, I, OR’, CN, OH,
`S(O),,2R"’, CF3, R4, NO2
`R"'=C1_6 (un)branched alkyl
`m=0—3
`m'=0-5
`W=O,H
`Preferred compounds for use in the pharmaceutical com
`positions or method of the present invention are those of
`Formula I wherein:
`R=H, C1_2 alkyl
`Y=NR‘R"
`R'=H, CL6 (un)branched alkyl,—(CH2),,Z(CH2)n.A
`Z=nothing, O, CHOR3, NR3
`R3=H
`A=H, OH, (un)substituted aryl (substitution as de?ned 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-—-O—2
`m'=O-2
`W=H
`n=2—4
`n'=O-3
`The most preferred compounds for use in the composi
`tions or method of the present invention are 2-Amino-3-(4
`?uorobenzoyl)-phenylacetamide; 2-Amino-3-benzoyl-phe
`nylacetamide;
`and
`2-Amino-3-(4-chlorobenzoyl)
`phenylacetamide.
`The preparation of the compounds of Formula I, Formula
`VII and Formula IX may be accomplished by the reactions
`outlined in the following scheme:
`
`R=H, c,_4 (un)branched alkyl, CF3, SR4
`
`R'=H (except when Y=OR'), C1_10 (un)branched alkyl,
`(un)substituted (substitution as de?ned by X below), 65
`(un)substituted heterocycle (substitution as de?ned by X
`below), —(CHQ,,Z(CH2)"'A
`
`Page 3 of 10
`
`

`

`5,475,034
`
`5
`
`_continued
`
`R ‘I’
`
`NRSRf
`
`NHz
`
`6
`
`-continued
`
`(X)m
`
`IX
`
`wherein X, Y, R, R4, R5, R6, m, m', and W are as de?ned
`above. The general method for the preparation for com—
`pounds of Formula I and Formula IV where Y is such that
`the compound is an amide derivative and W is hydrogen are
`detailed in U.S. Pat. No. 4,313,949 assigned to A. H. Robins.
`The general method for preparing compounds of Formula V
`and detailing the conversion of compounds of Formula V
`into compounds of the Formula VII are described in U.S.
`Pat. Nos. 4,045,576, 4,503,073, 4,182,774, and 4,126,635 all
`assigned to A. H. Robins, and by the methods of Walsh et al.,
`(J. Medicinal Chemistry, volume 27, 1984, pages l379~88
`and J. Medicinal Chemistry, volume 33, 100, pages
`2296—2304). Compounds of Formula VI where X‘ is a
`suitable leaving group such as Cl, Br, I, or organic sulfonate
`(mesylate, tosylate) and R5 is as described above, may be
`prepared by one skilled in the art. Arnides of Formula IX
`may be formed by reacting esters of Formula VII (preferably
`ethyl or methyl esters) with the appropriate amine of For
`mula VIII either neat or in the presence of a solvent such as
`dimethyl formamide, dimethyl sulfoxide or acetonitrile at
`temperatures between 0° and 150° C. Amines of Formula
`VIII, may be prepared by one skilled in the art.
`The synthesis of compounds of Formula I and the car
`boxylic acid of Formula X where W is oxygen is detailed in
`U.S. Pat. No. 4,254,146 assigned to A. H. Robins and is
`outlined below. The required amine or alcohol (Formula X1)
`is commercially available or can be readily prepared by one
`skilled in the art.
`
`(X)m
`
`R o
`|
`
`Y 1 SOClg
`2_ HY
`X1
`
`NW2
`
`(X)m
`
`(X)m'
`
`00m
`
`NW2
`
`\ 0
`
`(X)m'
`
`I
`
`R
`
`I
`
`ONa
`
`NI-Ig
`
`+ X—R5*—'>
`V1
`
`\ 0
`
`v
`
`20
`
`25
`
`30
`
`35
`
`40
`
`001"
`
`R o
`1
`
`OR5
`
`NH;
`
`45
`
`(X)m'
`
`\ o
`
`v11
`
`R o
`I
`
`OR5
`
`Nl‘lz
`
`+ R5R6NH%
`VIII
`
`(X)m
`
`(X)m
`
`\
`0
`
`V11
`
`50
`
`55
`
`60
`
`65
`
`Page 4 of 10
`
`

`

`7
`
`-continued
`
`(70”:
`
`5,475,034
`
`R O
`l
`
`Y
`
`5
`
`NW2
`
`8
`
`-continued
`
`H
`N\/\
`OCH3
`
`/
`s
`
`0
`NH2
`\ 0
`
`G0,",
`
`\ 0
`
`10
`
`Compound 5
`2-Amino-3-(4-?uorobenzoyD-ot-(methylthio)~N-(2-metl1oxy)ethyl
`acetarnide
`
`The manipulation of suitable protecting groups and depro- 15
`tecting steps as employed by one skilled in the art may be
`necessary for the preparation of compounds of Formula 1,
`Formula IV, Formula VIII, Formula IX and required inter
`mediates.
`The invention will be further illustrated by the following
`examples which are intended to be illustrative, but not
`limiting
`
`20
`
`/\/
`S
`
`NH;
`
`0
`NH2
`
`\ O
`
`25
`
`30
`
`Compound 1
`2-Amino-3-(4-fluorobenzoyD-ot-(n-propylthioyphenylacetamide
`
`35
`
`S
`
`NH:
`
`O
`NH;
`\ 0
`
`Compound 2
`2-Amino-3-benzoyl-ot-(n-propylthio)-phenylacetamide
`
`S
`
`NH;
`
`0
`NHZ
`
`\ 0
`
`c1
`Compound 3
`2-Amino-3-(4-chlorobenzoyl)-ot-(n-propylthio)-phenylacetamide
`
`/
`S
`
`c1
`
`NH2
`
`0
`NH;
`
`\ 0
`
`Compound 4
`2-Amino-3-benzoyl-5-chloro-tx-(methylthio)-pl1eny1acetamide
`
`40
`
`45
`
`so
`
`55
`
`60
`
`/
`S
`
`OMe
`
`H
`NW OMB
`
`0
`NH;
`\ 0
`
`Compound 6
`2'Amm‘_"3‘(4‘?“°r°bsnz°yl)'o"(melhyllhi°)‘¥‘l‘
`3-(3,4-d1methoxyphenyl)propyl phenylacetamide
`
`0 NH;
`NHZ
`\
`O
`
`Compound7
`2-Amino-3-(4-?uorobenzoyD-phenylacetamide
`
`NH
`2
`
`0
`N'HZ
`\ 0
`
`Compound 8
`2-Arnino-3-benzoyl-phenylacetamide
`
`NH:
`
`O
`NHz
`\ 0
`
`c1
`
`‘
`
`Compound 9
`2-Arnino-3-(4-ch1orobenz0y1)-phenylacetarnide
`
`Cl
`
`NH2
`
`0
`NH;
`\ 0
`
`Compound 10
`2-Amino-3-benzoyl-S-chlorophenylacetamide
`H
`
`N\/\
`OMe
`
`0
`NH1
`
`\
`0
`
`Compound 11
`2-Arnino-3-(4-?uorobenzoyl)-N
`@metlmykmyl Phmylacmmid6
`
`Page 5 of 10
`
`

`

`5,475,034
`
`—continued
`
`H
`N
`
`O
`NH:
`
`OMe
`
`OMe
`
`Compound 12
`2~Amino-3-(4-?uorobenzoyD-N-3-(3,4~dimethoxyphenyl)
`propyl phenylacetarnide
`
`H
`N
`
`OMe
`
`0MB
`
`0
`N02
`\ 0
`
`Compound 13
`3-Benzoy1-2~nitrophenyl-N-3-(3,4-dimethoxyphenyl)
`propyl acetamide
`
`O
`\/
`
`O
`NHz
`\ 0
`
`Br
`Compound 14
`Ethyl 2-arnino-3—(4'bromobenzoyD-benzene acetate
`
`NI-IZ
`
`O
`NHZ
`\ 0
`
`Br
`Compound 15
`2~Amino-3-(4-bromobenzoyl)-phenylacetamide
`
`NHMe
`
`O
`NH;
`\ 0
`
`Br
`Compound 16
`2—Amino-3~(4~bromobenzoyl)-N-methyl-phenylacetamide
`
`PREPARATION I
`
`2-Amino-3—(4-?uorobenzoyl)-ot—(n-propylthio)
`phenylacetamide, Compound 1
`
`A solution of 21.5 g (0.1 mole) of 4’~?uoro-2-aminoben
`zophenone in 400 mL of methylene chloride was cooled to
`—70° C. and 11.5 g (0.1 mole) of 95% t-butylhypochlorite
`was added over a period of 15 min, keeping the temperature
`below —66° C. To this solution was added a solution of 13.3
`g of 2-n-propylthioacetarnide in 50 mL of methylene chlo
`ride over a 10 min period. The solution was stirred for 1 h
`at —65° to —70° C. and then allowed to warm to 0° C. at
`which point 10.2 g (0.1 mole) of triethylarnine was added.
`The solution was stirred for 10 min and then washed with
`water. The organic solution was dried over magnesium
`sulfate. After concentrating under reduced pressure, the
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`55
`
`60
`
`65
`
`10
`residue was crystallized from isopropyl alcohol and dried to
`give 19.5 g (56%) of yellow crystals melting at l40°-l42°
`C.
`Analysis: Calculated for C18H19N2O2SF: C, 62.41; H,
`5.53; N, 8.09. Found: C, 62.34; H, 5.58; N, 8.04.
`
`PREPARATION II
`
`2-Arnino-3—benzoyl-ot-(n-propylthio)—phenylacetamide,
`Compound 2
`
`In the same manner as given in Preparation 1,2-arnino
`3—benzoyl—ot-(n-propylthiophenylacetarnide, Compound 2,
`is prepared from Z-aminobenzophenone, t-butylhypochlorite
`and 2-n-propylthioacetarnide.
`
`PREPARATION HI
`
`2-Amino-3—(4-chlorobenzoyD-ot-(n—propylthio)
`phenylacetamide, Compound 3
`
`In the same manner as given in Preparation 1,2-amino
`3-(4-chlorobenzoyl)_ot-(n-propylthio)—phenylacetamide,
`Compound 3, is prepared from 4'-chloro-2eaminobenzophe
`none t~butylhypochlorite and Z-npropylthioacetamide.
`
`PREPARATION IV
`
`2-Amino-3—benzoyl-S-chloro-ot-(methylthio)—
`phenylacetarnide, Compound 4
`
`To a cold (—70° C.) solution of 12.77 g (0.055 mole) of
`2-arnino-5-chlorobenzophenone in 300 mL of methylene
`chloride, under nitrogen atmosphere, was added 6.0 g (0.552
`mole) of t-butylhypochlorite in 20 mL of methylene chlo
`ride. After the reaction was stirred for an additional 15 min,
`a suspension of 5.8 g (0.055 mole) of ot-(methylthio)aceta
`mide in 150 mL of methylene chloride was added. The
`mixture was stirred at —65° C. for l h. Triethylamine (5.6 g,
`0.055 mole) was added and the solution was allowed to
`warm to room temperature. The reaction mixture was
`extracted with water and the organic layer dried over mag
`nesium sulfate. The volume of the solution was reduced in
`vacuo to about 200 mL and the product crystallized as a
`yellow solid, mp. l73.5°—174.5° C. Yield was 6.86 g
`(37.3%).
`Analysis: Calculated for CIGHISNZOZSCI: C, 57.40; H,
`4.52; N, 8.36. Found C, 57.38; H, 4.50; n, 8.51
`
`PREPARATION V
`
`2-Amino-3-(4-?uorobenzoyl)-oz(methylthio
`)-N-(2-methoxy )ethylacetamide, Compound 5
`
`To a solution of 21.5 g (0.1 mole) of 2-amino-4'-?uoro
`benzophenone in 400 mL of methylene chloride cooled to
`—70° C. is added ll.5 g (0.1 mole) of 95% t-butylhypochlo
`rite over 15 min, keeping the temperature below —66° C. To
`this solution is added a solution of ot-(methylthio)-N—(2
`methoxyethyl)acetarnide (0.1 mole) in 50 mL of methylene
`chloride over a ten minute period. The solution is stirred for
`1 h at —65° to —70° C. and then is allowed to warm to 0° C.
`Triethylamine (0.1 mole) is added and the resulting solution
`is washed with water. The organic solution is dried with
`magnesium sulfate, and concentrated in vacuo. The product
`is isolated using standard conditions.
`
`Page 6 of 10
`
`

`

`11
`PREPARATION v1
`
`12
`PREPARATION x1
`
`5,475,034
`
`2-Amino-3-(4-fluorobenzoyl)-ot(methylthio)-N-3-(3,4
`dirnethoxyphenyl)propyl acetamide,
`Compound 6
`
`To a solution of 21.5 g (0.1 mole) of 2-arnino- 4'-?uoro- .
`benzophenone in 400 mL of methylene chloride, cooled to
`—70° C. is added 11.5 g (0.1 mole) of 95% t-butylhypochlo
`rite over 15 min, keeping the temperature below —66° C. To
`this solution is added a solution of ot-(methylthio)-N-3-(3,
`4-dimethoxyphenyl)propylacetamide (0.1 mole) in 50 mL of
`methylene chloride over a ten minute period. The solution is
`stirred for 1 h at —65° to —70° C. and then is allowed to warm
`to 0° C. Triethylamine (0.1 mole) is added and the resulting
`solution is washed with water. The organic solution is dried
`with magnesium sulfate, and concentrated in vacuo. The
`product is isolated using standard conditions.
`
`10
`
`PREPARATION VII
`
`2-Arnino-3-(4-fluorobenzoyl)-phenylacetamide,
`Compound 7
`
`A solution of 24.2 g (0.07mole) of 2-amino-3-(4-?uo~
`robenzoyl)-ot-(n-propylthio)phenylacetamide in 300 mL of
`tetrahydrofuran was treated with an excess of wet Raney
`nickel (washed three times with water and three times with
`tetrahydrofuran). The mixture was stirred for 1 h and ?l
`tered. The ?ltrate was concentrated under reduced pressure
`and the residue was crystallized from 95% ethanol to aiford
`14.8 g (78%) of yellow needles melting at 184°—l86° C.
`Analysis: Calculated for C15H13N2O2F: C, 66.17; H,
`4.81; N, 10.29. Found: C, 66.32; H, 4.81;N, 10.48.
`
`PREPARATION VH1
`
`2-Arnino-3-benzoyl-phenylacetamide, Compound 8
`
`In the same manner as given in Preparation VII, 2-amino
`3-benzoylphenylacetamide is prepared from 2-amino-3-ben
`zoyl-ot-(n-propylthio)phenylacetarnide.
`
`25
`
`30
`
`35
`
`PREPARATION IX
`
`2-Amino-3-(4-chlorobenzoyl)-phenylacetamide,
`Compound 9
`
`45
`
`In the same manner as given in Preparation VII, Z-amino
`3-(4-chlorobenzoyl)phenylacetamide is prepared from
`2-amino-3-(4-chlorobenzoyl)-0t-(n-propylthio)phenylaceta
`mide.
`
`50
`
`2-Amino-3-(4-?uorobenzoyl)-N-(2-methoxy)ethyl
`phenylacetamide, Compound 11
`A mixture of 0.07 mole of 2-arnino-3-(4-?uorobenzoy1)
`ot-(methylthio)-N-(2-methoxy)ethylacetamide in 300 mL of
`tetrahydrofuran is treated with an excess of wet Raney
`nickel (washed three times with water and three times with
`tetrahydrofuran). The mixture is stirred for 1 h and ?ltered.
`The ?ltrate is concentrated under reduced pressure and the
`residue is puri?ed by standard procedures to give the prod
`uct.
`
`PREPARATION XII
`2-Amino-3-(4-?uorobenzoyl)-N-3-(3,4-dimethoxyphe
`nyl)propyl phenylacetamide, Compound 12
`A mixture of 0.07 mole 2-amino-3-(4-?uorobenzoyl)-ot
`(methylthio)-N-3-(3,4-dimethoxyphenyl) propylacetamide
`in 300 mL of tetrahydrofuran is treated with an excess of wet
`Raney nickel (washed three times with water and three times
`with tetrahydrofuran). The mixture is stirred for 1 h and
`?ltered. The ?ltrate is concentrated under reduced pressure
`and the residue is puri?ed by standard procedures to give the
`product.
`
`PREPARATION XIII
`
`3-Benzoyl-2-nitrophenyl-N-3-(3,4~
`dimethoxyphenyDpropyl acetamide, Compound 13
`A mixture of 0.028 mole of 3-benzoyl-2-nitrobenzene
`acetic acid, 50 mL of thionyl chloride and 50 mL of benzene
`is heated at re?ux. The dark solution is concentrated under
`vacuum. The residue is diluted with benzene and concen
`trated under vacuum (twice). A portion of the acid chloride
`(0.01 3 mole) in tetrahydrofuran is added to a solution of
`3-amino (3,4-dimethoxyphenyl)propane (0.015 mole). The
`mixture is stirred at room temperature and then added to 200
`mL of cold water. The resulting mixture is extracted with
`diethyl ether. The combined extracts are washed with water,
`dried over sodium sulfate and concentrated under reduced
`pressure. The residue is puri?ed using standard procedures
`to give the product.
`
`PREPARATION XIV
`
`PREPARATION X
`
`2-Amino-3-benzoyl-S-chlorophenylacetamide,
`Compound 10
`
`55
`
`Ethyl-2-Amino-3-(4-bromobenzoyl)benzene acetate,
`Compound 14
`
`A mixture of 21.34 g (0.0639 mole) of 2-amino-benzoyl
`5-chloro-ot-(methylthio)phenylacetamide and excess Raney
`nickel in a mixture of 900 mL absolute ethanol, and 200 mL
`60
`dimethylforrnamide was stirred at room temperature for 45
`min. The mixture was ?ltered through celite to remove
`Raney nickel. The solvent was removed under reduced
`pressure to give a yellow solid which was recrystallized to
`give a solid, mp. 213.5°—215.0° C. (d).
`Analysis: Calculated for C15H13N2O3Cl: C, 62.40; H,
`4.54; N, 9.70. Found: C, 62.35; H, 4.58; N, 9.74.
`
`65
`
`A slurry of 35.6 g (0.1 mole) of 2-amino-3-(bromoben
`zoyl)benzeneacetic acid in 500 mL of dimethylforrnarnide
`was treated with 32.0 g (0.2 mole) of ethyl iodide and stirred
`at ambient temperature for 24 h. The mixture was ?ltered
`and the ?ltrate was poured into 3.5 l of water. The solid
`which precipitated was collected by ?ltration, washed with
`water and recrystallized from absolute ethanol to give 26.8
`g (74%) of the title compound, as gold needles, mp.
`107°—109° C.
`Analysis: Calculated for C17H16 BrNO3: C, 56.37; H,
`4.45; N, 3.87. Found: C, 56.22; H 4.42; N, 3.87.
`
`Page 7 of 10
`
`

`

`5,475,034
`
`13
`PREPARATION XV
`
`2-Amino-3-(4~brom0benzoyl)-phenylacetamide,
`Compound 15
`
`Ammonia is condensed in a tube containing 2-amino-3
`(4-bromobenzoyl)benzeneacetic acid, ethyl ester. The tube is
`sealed and the reaction mixture is warmed. The sealed tube
`was cooled and opened. Solvent was evaporated and the
`residue was puri?ed by standard methods to give Compound
`15.
`
`PREPARATION XVI
`
`2-Amino-3~(4-bromobenzoyl)-N-methyl
`phenylacetamide, Compound 16
`
`15
`
`In the same manner as Preparation XV, 2-arnino-3-(4
`bromobenzoyl)-N-methyl phenylacetamide, Compound 16
`is prepared from 2-amino~3-(4-bromobenzoyl)benzeneace
`tic acid, ethyl ester and methylarnine.
`
`20
`
`Anti-In?ammatory Tests
`
`25
`
`1. In vitro Anti-In?ammatory Test
`In vitro anti-in?ammatory activity of 2-amino-3-benzoyl
`benzeneacetic acid analogues was tested by polarographi
`cally monitoring the inhibition in the rate of oxygen con
`sumption (Cook H. W., Ford 6., and Lands WEM, Anal.
`Biochem. 96:341, 1979) in the conversion of arachidonic
`acid to prostaglandin H2 by prostaglandin H synthase
`(cyclooxygenase). cyclooxygenase enzyme was prepared
`by solubilizing 20 mg of lipid-depleted sheep vesicular
`gland rnicrosomal powder (Gra? G., Stephenson J. H., et al.,
`J. Biol. Chem. 25317662, 1978) in 1.0 mL of buffer con
`taining 50 mM phosphate, 5 mM diethyldithiocarbamic
`acid, and 2 uM hematin (pH 7.4). Incubations were carried
`out at 30° C. with a YSI-oxygen monitor (Model 53) in 50
`mM phosphate/0.5 mM phenol buffer (pH 7.4) as described
`elsewhere (Graff G., and Anderson L. A., Prostaglandins
`38:473, 1989).
`11. Ex Vivo Anti—ln?ammatory Test
`Ex vivo anti-in?ammatory activity of 2-amino-3~benzoyl
`benzeneacetic acid analogues was evaluated in naive New
`Zealand Albino (NZA) rabbits. In this test animals were
`dosed bilaterally with a single 50 uL aliquot of a 0.1%
`solution/suspension of vehicle, formulated test or reference
`compound. After 60 minutes of treatment, animals were
`euthanized, iris/ciliary body (ICB) quickly excised and
`placed into ice-cold PBS buffer (pH 7.4). The tissue was
`then weighed, homogenized in ice-cold 50 mM phosphate/
`0.5 mM phenol buffer (pH 7.4) and incubated for 10 minutes
`at 37° C. with 10 M of [l-l4Cl-2Oz4. Upon termination of
`the incubations, reaction products (prostaglandins) were
`isolated by organic solvent extraction (Bligh, E. G. and
`Dyer, W. J., Can. J. Biochem. Physiol. 37:911, 1959) and
`quanti?ed by C18-HPLC (Powell, W. 5., Anal. Bio
`chem.l48:59 1985).
`HI. In Vivo Anti~In?ammatory Test
`In vivo anti-in?ammatory activity of 2~amino-3-benzoyl
`benzeneacetic acid analogues was evaluated in the model of
`
`35
`
`40
`
`45
`
`50
`
`55
`
`14
`trauma-induced breakdown of the blood-aqueousabarrier in
`New Zealand Albino (NZA) rabbits. Animals were anesthe
`tized prior to bilateral administration of a single topical 50
`pL dose of a 0.1% solution/suspension of formulated test or
`reference compound. After 45 minutes of treatment ocular
`trauma was induced by paracentesis. Thirty minutes post
`paracentesis animals were euthanized, and aqueous humor
`was removed for protein (Bradford, M. M., Anal. Biochem.
`72:248, 1976) and PGE2 analysis (Radio immune assay,
`NEN-Research Products, E. I. Du Pont de N emours, Boston,
`Mass).
`
`Results
`
`The results from in vitro, ex vivo and in vivo anti~
`in?ammatory tests are surmnarized in Table l. Non-haloge
`nated and halogenated 2-amin0-3-benzoylbenzeneacetic
`acid analogues with free carboxylic acid functional groups,
`including the reference compound diclofenac, were potent in
`vitro inhibitors of sheep vesicular gland cyclooxygenase
`activity with IC5o values ranging from 0.029 to 0.250 M.
`When tested in vivo, they effectively inhibited trauma
`induced accumulation of PGE2 (298%) and plasma protein
`in?ux into the aqueous humor in vivo. Similar results were
`obtained with the reference compound, diclofenac, which
`was somewhat less effective both in vitro and in vivo than
`the chloro- or bromo- substituted 2-a1nino-3‘benzoylbenze
`neacetic acids.
`In contrast, unsubstituted and mono-substituted amide
`analogues of 2-amino- 3-benzoylbenzeneacetic acid (Com
`pounds 7, 8, 9, l5 and 16) were 23 orders of magnitude less
`effective inhibitors of cyclooxygenase activity in vitro with
`IC5O values ranging from 16 to >133 pM. Despite their weak
`inhibitory e?ects on cyclooxygenase activity in vitro, they
`were as effective as, or in one instance (Compound 7) more
`effective than, free carboxylic acid analogues in inhibiting
`plasma protein in?ux into the anterior chamber (62 to 72%)
`and aqueous humor PGE2 accumulation (>93%). Interest
`ingly, the dimethyl substituted amide analog was inactive in
`both in vitro and in vivo tests.
`Although the in vitro potency was clearly enhanced by
`halogenation of the 4-position of the benzoyl ring of
`2—amino-3-benzoylbenzeneacetic acid, there was little evi
`dence for such a structure related effect in vivo.
`When tested for ex vivo anti-in?ammatory activity, Com
`pound 8 was the most effective inhibitor of iris/ciliary body
`prostaglandin synthesis. The synthesis of all prostaglandins
`produced by the iris/ciliary body was inhibited to a similar
`extent. This spectrum of inhibition is in contrast to the
`effects of 2-amino-3-benzoylbenzeneacetic acid analogs
`with free carboxylic acid functional groups which predomi
`nately inhibited PGE2 production.
`Conversion of the free carboxylic acid functional group of
`Bromfenac to an ethyl ester (Compound 14) also resulted in
`a >3 orders of magnitude decline in in vitro cyclooxygenase
`inhibitory activity. However, when tested for topical ocular
`anti-in?ammatory activity the ethyl ester showed signi?cant
`inhibitory activity by reducing plasma protein extravasation
`into the aqueous humor by 60%.
`
`Page 8 of 10
`
`

`

`16
`
`15
`
`5,475,034
`
`TABLE 1
`
`Y
`
`O
`
`NH:
`
`X
`
`0
`
`SUMMARY OF ANT I-INFLAMMATORY TEST RESULTS
`
`In Vitro
`Cyclooxygenase
`Inhibition
`
`Ex Vivo
`Iris/Ciliary Body
`Total Prostaglandin
`Synthesis
`
`Substituent
`
`In Vivo
`Aqueous Humor
`PGE2 Accumulation
`
`In Vivo
`Paracentesis
`Protein Extravasation
`
`Compound
`
`X
`
`Y
`
`IC50 (uM)
`
`Inhibition (%)***
`
`Inhibition
`
`Inhibition (%)*
`
`Diclofenac** —
`Amfenac
`4'-H
`
`—
`OH
`
`—
`—
`Bromfenac
`#15
`#16
`——
`#8
`#7
`#9
`#15
`#14
`
`OH
`4'~F
`OH
`4'-Cl
`OH
`4'-Br
`N1-I2
`4"Br
`NHC1-l3
`4'-Br
`N(CH3)2
`4'-Br
`NPR
`H
`NI-I2
`4'-F
`NI-I2
`4'-Cl
`NH2
`4'-Br
`4'aBr OCH2CH3
`
`0.120
`0.25
`
`0.171
`0.070
`0.029
`19
`16
`>>100
`64
`133
`>>l00
`19
`>>25
`
`50
`—
`
`—
`—
`44
`—
`48
`-
`81
`27
`29
`23
`33
`
`97
`—
`
`-—
`99
`98
`97
`93
`—27
`98
`98
`98
`97
`—
`
`*Single topical dose of a 0.1% drug solution/suspension 45 minutes prior to paracentesis
`**Diclofenac, also known as Voltaren Opthalmic (TM), is used as a reference standard
`***Single topical dose of 0.1% drug solution/suspension 60 minutes prior to iris/ciliary body isolation
`
`54
`41
`
`42
`72
`62
`64
`62
`2
`61
`72
`65
`64
`60
`
`The 3-benzoylphenylacetic acid derivative compounds of
`this invention are useful for controlling ophthalmic in?am
`matory disorders and ocular pain. Such disorders include,
`but are not limited to uveitis, scleritis, episcleritis, keratitis,
`surgically-induced in?ammation and endophthalmitis.
`The 3-benzoylphenylacetic acid derivatives may be for
`mulated into a variety of topically administrable ophthalmic
`compositions, such as solutions, suspensions, gels or oint
`ment.
`Pharmaceutical compositions comprising compounds of
`Formula 1 in aqueous solution, optionally containing a
`preservative for multidose use and other conventionally
`employed ophthalmic adjuvants, including a salt entity to
`adjust the tonicity of solutions, can be employed. The most
`preferred form of delivery is by eye drops; however, for
`mulations wherein the ?nal specialty form is a gel or
`ointment can also be employed and formulated according to
`conventional technology. The ophthalmic compositions of
`the present invention will typically contain one or more
`compounds of Formula 1 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).
`Further, additional therapeutic agents including steroids,
`such as, dexamethasone; antibiotics, such as gentamicin;
`anti-infectives, such as sulfonarnides; and antioallergics,
`such as antihistamines, may be added to supplement the
`ophthalmic compositions of the present invention.
`The compositions may contain preservatives such as
`thimerosal, chlorobutanol, benzalkonium chloride, Onamer
`M,