United States Patent [19]
`Yanni et al.
`
`[54] TOPICALLY ADMINISTRABLE
`COMPOSITIONS CONTAINING
`3-BENZOYLPHENYLACETIC ACID
`DERIVATIVES FOR TREATMENT OF
`OPHTHALMIC INFLAMMATORY
`DISORDERS
`
`[75]
`
`Inventors: John M. Yanni, Burleson; Gustav
`Graft', Cleburne; Mark R. Hellberg,
`Arlington, all of Tex.
`
`[73] Assignee: Alcon Laboratories, Inc., Fort Worth,
`Tex.
`
`[21] Appl. No.: 254,090
`
`Jun. 6, 1994
`
`[22] Filed:
`Int. Cl.6
`................................................... A61K 31/165
`[51]
`[52] U.S. Cl . .......................... 514/619; 514/535; 514/570;
`514/617; 514/618; 514/621
`[58] Field of Search ............................. 5641169; 514/621,
`514/619, 617, 618
`
`[56]
`
`References Cited
`
`lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`US0054 7 5034A
`5,475,034
`[11] Patent Number:
`[45] Date of Patent:
`Dec. 12, 1995
`
`4,683,242
`4,783,487
`4,851,443
`4,910,225
`
`711987 Poser ....................................... 514/539
`11/1988 Brune ...................................... 514/563
`711989 Brune ...................................... 514/563
`3/1990 Ogawa et al ........................... 514/561
`
`FOREIGN PATENT DOCUMENTS
`
`2071086
`2093027
`
`9/1981 United Kingdom.
`8/1982 United Kingdom .
`
`OTHER PUBLICATIONS
`
`non-steroidal
`a
`"AHR-10037,
`al.,
`et
`Sancillo
`anti-inflammatory compound of low gastric toxicity,"
`Agents and Actions, 31:117-126 (1990).
`Walsh et al., "Antiinflammatory Agents. 3. Synthesis and
`Pharmacological
`Evaluation
`of
`2-Arnino-3-benzoylphenylacetic Acid and Analogues," J.
`Med. Chern. 27:1379-1388 (1984).
`Walsh et al., "Antiinflammatory Agents. 4. Synthesis and
`Biological Evaluation
`of Potential Prodrugs
`of
`2-Amino-3-benzoylbenzeneacetic
`Acid
`and
`J.
`2-Amino-3-(4-chlorobenzoyl)benzeneacetic Acid,"
`Med. Chern. 33:2296-2304 (1990).
`
`Pnrnary Exarniner-Shailendra Kumar
`Attorney, Agent, or Firm-Patrick M. Ryan
`
`U.S. PATENT DOCUMENTS
`
`[57]
`
`ABSTRACT
`
`3,828,093
`4,045,576
`4,126,635
`4,182,774
`4,254,146
`4,318,949
`4,503,073
`4,568,695
`
`8/1974 Bays et al. .............................. 260/469
`8/1977 We1stead, Jr. et al. ................. 424/309
`11/1978 Welstead, Jr. et al .................. 562/441
`1/1980 Welstead, Jr. et al. ................. 424/309
`3/1981 Walsh ...................................... 424/309
`211982 Shanklin, Jr. et al ............. 424/248.56
`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(cid:173)
`positions for the treatment of ophthalmic inflammatory
`disorders is also disclosed.
`
`7 Claims, No Drawings
`
`LUPIN EX 1007
`
`Page 1 of 10
`
`

`
`5,475,034
`
`2
`
`1
`TOPICALLY ADMINISTRABLE
`COMPOSITIONS CONTAINING
`3-BENZOYLPHENYLACETIC ACID
`DERIVATIVES FOR TREATMENT OF
`OPHTHALMIC INFLAMMATORY
`DISORDERS
`
`FIELD OF THE INVENTION
`
`This invention relates to topically administrable compo(cid:173)
`sitions for the treatment of inflammatory disorders. In par(cid:173)
`ticular, this invention relates to non-irritating, topically
`administrable compositions containing 3-benzoylphenylace(cid:173)
`tic acid derivatives for the treatment of ophthalmic inflam(cid:173)
`matory disorders.
`
`BACKGROUND OF THE INVENTION
`
`irritation and discomfort.
`Additionally, the acetic acid compounds taught in the '225
`patent are difficult to formulate in stable aqueous solutions.
`The '225 patent solves this problem by incorporating a
`5 water-soluble polymer and sulfite, 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(cid:173)
`rolidone, carboxypropylcellulose, hydroxyethylcellulose,
`hydroxypropylcellulose, polyvinyl alcohol, sodium salt of
`10 polyacrylic acid and so on. Polyvinyl pyrrolidone is pre(cid:173)
`ferred. The concentration of water soluble polymer is in the
`range of 0.1 to 10 w/w %. Sulfite includes sodium, potas(cid:173)
`sium, magnesium, and calcium sulfite 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-inflammatory agents which are stable,
`non-irritating at therapeutic doses, and at least as potent as
`benzoylphenylacetic acids in suppressing ocular inflamma-
`tion.
`
`15
`
`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-inflammatory compounds for
`treating ophthalmic inflammatory 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
`30 based on the finding that certain 3-benzoylphenylacetic acid
`derivatives which show no significant anti-inflammatory
`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(cid:173)
`sitions suitable for topical ophthalmic administration which
`contain an anti-inflammatory-effective amount of a 3-ben(cid:173)
`zoylphenylacetic acid derivative, and to a method of treating
`ophthalmic inflammatory disorders which comprises topi-
`cally administering to the eye a 3-benzoylphenylacetic acid
`derivative.
`
`50
`
`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(cid:173)
`pounds of the present invention have the following structural
`formula:
`
`R
`
`y
`
`(I)
`
`W=O,H
`R=H, C1.iun)branched alkyl, CF3 , SR4
`
`3-benzoylphenylacetic acid and certain of its derivatives
`are known to possess anti-inflammatory activity. U.S. Pat. 20
`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-inflammatory activity.
`U.S. Pat. No. 4,568,695 teaches 2-arnino-3-benzoylphenyl- 25
`ethyl alcohols having anti-inflammatory activity. U.S. Pat.
`No. 4,313,949
`teaches 2-arnino-3-benzoyl-phenylaceta(cid:173)
`mides having anti-inflammatory 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 35
`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(cid:173)
`venous (in the form of sterile solutions). No topical or local 40
`administration is taught by any of the above-listed patents or
`patent applications.
`Certain derivatives of 2-amino-3-benzoylbenzeneacetic
`acid (amfenac) and 2-arnino-3-(4-chloro-benzoyl)benzene(cid:173)
`acetic acid have also been evaluated by Walsh et al., J. Med. 45
`Chern., 33:2296-2304 (1990), in an attempt to discover
`nonsteroidal anti-inflammatory prodrugs with minimal or no
`gastrointestinal side effects upon oral administration.
`In contrast, U.S. Pat. No. 4,683,242 teaches the transder(cid:173)
`mal administration of 2-arnino-3-benzoylphenylacetic acids,
`salts, and esters, and hydrates and alcoholates thereof to
`control inflammation and alleviate pain.
`U.S. Pat. No. 4,910,225 teaches certain benzoylpheny(cid:173)
`lacetic acids for local administration to control ophthalmic, 55
`nasal or otic inflammation. Only acetic acids are disclosed in
`the '225 patent; no esters or ami des are mentioned or taught
`as anti-inflammatory agents for local administration to the
`eyes, nose and ears.
`Although benzoylphenylacetic acids are effective in sup- 60
`pressing ocular inflammation, their full anti-inflammatory
`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 sufficient to provide effective 65
`intraocular drug concentrations. Such high drug concentra(cid:173)
`tions are generally not desirable as they may provoke ocular
`
`Page 2 of 10
`
`

`
`10
`
`15
`
`, CN, OH, 20
`
`30
`
`-(CH2),-Z3-(CH2)
`
`, OR7
`
`, R4
`
`n=2-6
`n'=l-6
`Z=othing, 0, 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 (substi(cid:173)
`tution 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 (substi(cid:173)
`tution as defined by X below), -(CHz)nOR3
`R"=H, OH, OR'
`X and X' independently=H, F, Cl, Br, I, OR', CN, OH,
`, CF3, R4
`S(O)n2R4
`, N02
`R4=C 1_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, C 1_z alkyl
`Y=NR'R"
`R'=H, C1 _6 (un)branched alkyl,-(CH2)nZ(CH2)n.A
`Z=othing, 0, CHOR3
`, NR3
`R3=H
`35 A=H, OH, (un)substituted aryl (substitution as defined by X
`below)
`X and X' independently=H, F, Cl, Br, CN, CF3 , OR', SR4
`R"=H
`40 R4=C 1_4 (un)branched alkyl
`m=0-2
`m'=0-2
`W=H
`45 n=2-4
`n'=0-3
`The most preferred compounds for use in the composi(cid:173)
`tions or method of the present invention are 2-Arnino-3-(4-
`50 fiuorobenzoyl)-phenylacetarnide; 2-Arnino-3-benzoyl-phe-
`nylacetarnide;
`and
`2-Arnino-3-(4-chlorobenzoyl)-
`phenylacetarnide.
`The preparation of the compounds of Formula I, Formula
`55 Vll and Formula IX may be accomplished by the reactions
`outlined in the following scheme:
`
`5,475,034
`
`4
`
`-
`
`3
`Y=OR5
`, NR5R6
`R5= -(CH2),-Z2 -(CH2),.A, -(CH2),-Z3 -(CH2)r A'
`r-=2-6
`r'=0-6
`Z20, C=O, OC(=O), C(=O)NR3, NR3C(=O), 5
`-S(O)r2CH2-, S, CHOR3, NR3
`Z3=othing,-CHR4
`- , -CR4R4
`r=12
`R3=H, C1_6(un)branched alkyl, (un)substituted aryl (substi(cid:173)
`tution as defined by X below), (un)substituted heterocycle
`(substitution as defined by X below)
`A=H, OH, (un)substituted aryl (substitution as defined by X
`below), (un)substituted heterocycle, -(CH2)PR3
`A'=OH, (un)substituted aryl (substitution as defined by X
`below),
`(un)substituted heterocycle (substitution as
`defined by X below), -(CH2),0R3
`R4=C 1_6(un)branched alkyl
`R6=H, OR7
`R7=H, C1_6(un)branched alkyl, (un)substituted aryl (substi(cid:173)
`tution as defined by X below)
`X and X' independently=H, F, Cl, Br, I, OR7
`, CF3, R4
`S(O)n2R4
`, N02
`m=0-3
`m=0-5
`n2=0-2
`The preferred, novel 3-benzoylphenylacetic acid deriva- 25
`tives are those wherein:
`W=H
`R=H, CH3
`Y=NR5R6 -NHOH
`R4=C1_iu~)branched alkyl
`R5=-(CH2),-Z2-(CH2),-A,
`,-A'
`r-=2-4
`r'=0-2
`z2=0
`Z3=othing
`A=H
`A'=(un)substituted aryl (substitution as defined by X below)
`R6=H, OR7
`R7=H, C 1_2 alkyl
`X and X' independently=H, F, Cl, Br, CF3, S(O)n2R4
`m=0-2
`m'=0-3
`n2=0
`The 3-benzoylphenylacetic acid derivative compounds
`useful in the topically administrable ophthalmic composi(cid:173)
`tions of the present invention are represented by the follow(cid:173)
`ing structural formula which includes both known deriva(cid:173)
`tives and the novel derivatives of the present invention:
`
`R
`
`y
`
`(I)
`
`60
`
`R=H, C1 _4 (un)branched alkyl, CF3, SR4
`Y=OR', NR"R'
`R'=H (except when Y=OR'), C 1_10 (un)branched alkyl,
`(un)substituted (substitution as defined by X below), 65
`(un)substituted heterocycle (substitution as defined by X
`below), -(CHz)nZ(CH2)n.A
`
`(X)m'
`
`(X)m
`
`II
`
`III
`
`Page 3 of 10
`
`

`
`6
`
`-continued
`
`(X)m
`
`(X)m'
`
`IX
`
`R
`
`NHz
`
`NR5R6
`
`5,475,034
`
`5
`
`-continued
`
`(X)m
`
`NWz
`
`y
`
`5
`
`10
`
`(X)m'
`
`(X)m
`
`(X)m'
`
`R
`
`IV t
`
`R
`
`y
`
`20
`
`25
`
`15 wherein X, Y, R, R4
`, R6
`, R5
`, m, m', and W are as defined
`above. The general method for the preparation for com-
`pounds of Formula I and Formula N 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 eta!.,
`(J. Medicinal Chemistry, volume 27, 1984, pages 1379-88
`30 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
`+X-R5~ 35 prepared by one skilled in the art. Amides of Formula IX
`VI
`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
`40 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-
`45 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 XI)
`is commercially available or can be readily prepared by one
`50 skilled in the art.
`
`ON a
`
`(X)m
`
`(X)m'
`
`v
`
`(X)m
`
`(X)m'
`
`R
`
`NHz
`
`OR5
`
`(X)m
`
`CXlm'
`
`R
`
`VII
`
`OR5
`
`55
`
`(X)m
`
`R
`
`NWz
`
`y
`
`1 SOC)z :;,.
`2.HY
`XI
`
`+R5R6NH~
`VIII
`
`60
`
`(X)m'
`
`VII
`
`X
`
`65
`
`Page 4 of 10
`
`

`
`5,475,034
`
`7
`
`-continued
`
`(X)m
`
`(X)m'
`
`R
`
`NWz
`
`y 5
`
`10
`
`8
`
`I
`s
`
`-continued
`
`H
`N
`~OCH3
`
`CompoundS
`2-Amino-3-(4-fluorobenzoyl)-a.-(methylthio)-N-(2-methoxy)ethyl
`acetamide
`
`OMe
`
`I
`s H~ N
`
`-
`~ !J
`
`OMe
`
`The manipulation of suitable protecting groups and depro- 15
`tecting steps as employed by one skilled in tbe art may be
`necessary for tbe preparation of compounds of Formula I,
`Formula IV, Formula VIII, Formula IX and required inter-
`mediates.
`The invention will be further illustrated by tbe following
`examples which are intended to be illustrative, but not
`limiting.
`
`20
`
`J-1
`s
`
`NHz
`
`Compound I
`2-Amino-3-(4-fluorobenzoyl)-a.-(n-propylthio)-phenylacetamide
`
`J-1
`s
`
`NHz
`
`Compound2
`2-Amino-3-benzoyl-a.-(n-propylthio)-phenylacetamide
`
`J-1
`s
`
`NHz
`
`Compound3
`2-Amino-3-(4-chlorobenzoyl)-a.-(n-propylthio)-phenylacetamide
`
`I
`s
`
`NHz
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`Compound6
`2-Amino-3-(4-fluorobenzoyl)-a.-(methylthio)-N-
`3-(3,4-dimethoxyphenyl)propyl phenylacetamide
`
`Compound?
`2-Amino-3-(4-fluorobenzoyl)-phenylacetamide
`
`NHz
`
`CompoundS
`2-Amino-3-benzoyl-phenylacetamide
`
`NHz
`
`Compound 9
`2-Amino-3-(4-chlorobenzoyl)-phenylacetamide
`
`NHz
`
`Compound 10
`2-Amino-3-benzoyl-5-chlorophenylacetamide
`
`H
`N
`~OMe
`
`Compound4
`2-Amino-3-benzoyl-5-chloro-a.-(methylthio)-phenylacetamide
`
`Compound 11
`2-Amino-3-(4-fluorobenzoyl)-N(cid:173)
`(2-methoxy)ethyl phenylacetamide
`
`Page 5 of 10
`
`

`
`5,475,034
`
`9
`
`-continued
`
`OMe
`
`~~OMe
`
`10
`residue was crystallized from isopropyl alcohol and dried to
`give 19.5 g (56%) of yellow crystals melting at 140°-142°
`c.
`Analysis: Calculated for C18H19N20 2SF: C, 62.41; H,
`5 5.53; N, 8.09. Found: C, 62.34; H, 5.58; N, 8.04.
`
`Compound 12
`2-Arnino-3-(4-fluorobenzoyl)-N-3-(3,4-dimethoxyphenyl)
`propyl phenylacetamide
`
`OMe
`
`~~OMe
`
`Compound 13
`3-Benzoyl-2-nitrophenyl-N-3-(3,4-dimethoxyphenyl)
`propy 1 acetamide
`
`o-..........--
`
`Br
`
`Compound 14
`Ethyl 2-amino-3-(4-bromobenzoyl)-benzene acetate
`
`NHz
`
`Br
`
`Compound 15
`2-Amino-3-(4-bromobenzoyl)-phenylacetamide
`
`NHMe
`
`Br
`
`Compound 16
`2-Amino-3-(4-bromobenzoyl)-N-methyl-phenylacetamide
`
`PREPARATION I
`
`2-Amino-3-( 4-fiuorobenzoy 1)-a-(n-propylthio )(cid:173)
`phenylacetamide, Compound l
`
`PREPARATION II
`
`10
`
`2-Amino-3-benzoyl-a-(n-propylthio)-phenylacetamide,
`Compound 2
`
`In the same manner as given in Preparation 1,2-amino-
`3-benzoyl-a-(n-propylthiophenylacetamide, Compound 2,
`is prepared from 2-aminobenzophenone, t-butylhypochlorite
`l5 and 2-n-propylthioacetamide.
`
`PREPARATION III
`
`20
`
`2-Amino-3-( 4-chlorobenzoy 1)-a-(n-propylthio )-
`phenylacetamide, Compound 3
`
`In the same manner as given in Preparation 1,2-amino-
`3-(4-chlorobenzoyl)-a-(n-propylthio)-phenylacetamide,
`Compound 3, is prepared from 4'-chloro-2-aminobenzophe-
`25 none t-butylhypochlorite and 2-n-propylthioacetamide.
`
`PREPARATION IV
`
`2-Arnino-3-benzoy 1-5-chloro-a-(methy lthio )(cid:173)
`phenylacetamide, Compound 4
`
`To a cold (-70° C.) solution of 12.77 g (0.055 mole) of
`2-amino-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(cid:173)
`ride. After the reaction was stirred for an additional 15 min,
`a suspension of 5.8 g (0.055 mole) of a-(methylthio)aceta(cid:173)
`mide in 150 mL of methylene chloride was added. The
`mixture was stirred at -65° C. for 1 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(cid:173)
`nesium sulfate. The volume of the solution was reduced in
`vacuo to about 200 mL and the product crystallized as a
`yellow solid, m.p. 173.5°-174.5° C. Yield was 6.86 g
`(37.3%).
`Analysis: Calculated for C16H15N20 2SCI: 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-fiuorobenzoyl)-a(methylthio
`)-N-(2-methoxy )ethylacetamide, Compound 5
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`A solution of 21.5 g (0.1 mole) of 4'-fiuoro-2-aminoben(cid:173)
`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 60
`g of 2-n-propylthioacetamide in 50 mL of methylene chlo(cid:173)
`ride over a 10 min period. The solution was stirred for 1 h
`at -65° to -70° C. and then allowed to warm to oo C. at
`which point 10.2 g (0.1 mole) of triethylamine was added.
`The solution was stirred for I 0 min and then washed with 65
`water. The organic solution was dried over magnesium
`sulfate. After concentrating under reduced pressure, the
`
`To a solution of 21.5 g (0.1 mole) of 2-amino-4'-fiuoro(cid:173)
`benzophenone in 400 mL of methylene chloride cooled to
`-70° C. is added 11.5 g (0.1 mole) of95% t-butylhypochlo(cid:173)
`rite over 15 min, keeping the temperature below -66° C. To
`this solution is added a solution of a-(methylthio)-N-(2-
`methoxyethyl)acetamide (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 oo 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 VI
`
`12
`PREPARATION Xl
`
`5,475,034
`
`2-Amino-3-(4-fluorobenzoyl)-a(methylthio)-N-3-(3,4-
`dimethoxyphenyl)propyl acetamide,
`Compound 6
`
`5
`
`2-Amino-3-(4-fiuorobenzoyl)-N-(2-methoxy)ethyl
`phenylacetarnide, Compound 11
`
`A mixture of 0.07 mole of 2-arnino-3-(4-fiuorobenzoyl)(cid:173)
`a-(methylthio)-N-(2-methoxy)ethylacetamide in 300 mL of
`tetrahydrofuran is treated with an excess of wet Raney
`10 nickel (washed three times with water and three times with
`tetrahydrofuran). The mixture is stirred for 1 h and filtered.
`The filtrate is concentrated under reduced pressure and the
`residue is purified by standard procedures to give the prod(cid:173)
`uct.
`
`To a solution of 21.5 g (0.1 mole) of 2-amino- 4'-fiuoro(cid:173)
`benzophenone in 400 mL of methylene chloride, cooled to
`-70° C. is added 11.5 g (0.1 mole) of95% t-butylhypochlo(cid:173)
`rite over 15 min, keeping the temperature below -66° C. To
`this solution is added a solution of a-(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 15
`solution is washed with water. The organic solution is dried
`with magnesium sulfate, and concentrated in vacuo. The
`product is isolated using standard conditions.
`
`PREPARATION VII
`
`20
`
`2-Amino-3-( 4-fiuorobenzoyl)-phenylacetamide,
`Compound 7
`
`A solution of 24.2 g (0.07mole) of 2-amino-3-(4-fiuo(cid:173)
`robenzoyl)-a-(n-propylthio)phenylacetamide in 300 mL of 25
`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 fii(cid:173)
`tered. The filtrate was concentrated under reduced pressure
`and the residue was crystallized from 95% ethanol to afford 30
`14.8 g (78%) of yellow needles melting at 184°-186° C.
`Analysis: Calculated for C15H 13N20 2F: C, 66.17; H,
`4.81; N, 10.29. Found: C, 66.32; H, 4.81;N, 10.48.
`
`PREPARATION XII
`
`2-Amino-3-( 4-fiuorobenzoyl)-N-3-(3 ,4-dimethoxyphe(cid:173)
`nyl)propyl phenylacetamide, Compound 12
`A mixture of 0.07 mole 2-amino-3-(4-fiuorobenzoyl)-a(cid:173)
`(methylthio )-N-3-(3,4-dimethoxyphenyl) propyl acetamide
`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
`filtered. The filtrate is concentrated under reduced pressure
`and the residue is purified by standard procedures to give the
`product.
`
`PREPARATION XIII
`
`3-Benzoyl-2-nitrophenyl-N-3-(3,4-
`dimethoxyphenyl)propyl acetamide, Compound 13
`
`PREPARATION VIII
`
`2-Amino-3-benzoyl-phenylacetarnide, Compound 8
`
`35
`
`In the same manner as given in Preparation VII, 2-amino-
`3-benzoylphenylacetamide is prepared from 2-arnino-3-ben- 40
`zoyl-a-(n-propylthio)phenylacetarnide.
`
`PREPARATION IX
`
`2-Amino-3-(4-chlorobenzoyl)-phenylacetamide,
`Compound 9
`
`In the same manner as given in Preparation VII, 2-amino-
`3-(4-chlorobenzoyl)phenylacetarnide
`is prepared
`from
`2-arnino-3-( 4-chlorobenzoy 1)-a-(n-propylthio )pheny laceta- 50
`mide.
`
`A mixture of 0.028 mole of 3-benzoyl-2-nitrobenzene(cid:173)
`acetic acid, 50 mL of thionyl chloride and 50 mL of benzene
`is heated at reflux. 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-arnino (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
`45 diethyl ether. The combined extracts are washed with water,
`dried over sodium sulfate and concentrated under reduced
`pressure. The residue is purified using standard procedures
`to give the product.
`
`PREPARATION XIV
`
`PREPARATION X
`
`2-Amino-3-benzoyl-5-chlorophenylacetarnide,
`Compound 10
`
`A mixture of 21.34 g (0.0639 mole) of 2-amino-benzoyl-
`5-chloro-a-(methylthio)phenylacetarnide and excess Raney
`nickel in a mixture of 900 mL absolute ethanol, and 200 mL
`dimethylformarnide was stirred at room temperature for 45
`min. The mixture was filtered 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, m.p. 213.5°-215.0° C. (d).
`Analysis: Calculated for C15H13N20 3Cl: C, 62.40; H,
`4.54; N, 9.70. Found: C, 62.35; H, 4.58; N, 9.74.
`
`Ethyl-2-Amino-3-(4-bromobenzoyl)benzene acetate,
`Compound 14
`
`55
`
`A slurry of 35.6 g (0.1 mole) of 2-amino-3-(bromoben(cid:173)
`zoyl)benzeneacetic acid in 500 mL of dimethylformarnide
`was treated with 32.0 g (0.2 mole) of ethyl iodide and stirred
`60 at ambient temperature for 24 h. The mixture was filtered
`and the filtrate was poured into 3.5 1 of water. The solid
`which precipitated was collected by filtration, washed with
`water and recrystallized from absolute ethanol to give 26.8
`g (74%) of the title compound, as gold needles, m.p.
`65 107°-109° c.
`Analysis: Calculated for C17H16 BrN03 : 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
`
`5
`
`14
`trauma-induced breakdown of the blood-aqueous-barrier in
`New Zealand Albino (NZA) rabbits. Animals were anesthe(cid:173)
`tized prior to bilateral administration of a single topical 50
`~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(cid:173)
`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,
`10 NEN-Research Products, E. I. DuPont de Nemours, Boston,
`Mass.).
`
`Results
`
`13
`PREPARATION XV
`
`2-Amino-3-(4-bromobenzoyl)-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 purified by standard methods to give Compound
`15.
`
`PREPARATION XVI
`
`2-Amino-3-( 4-bromobenzoyl)-N-me thy 1
`phenylacetamide, Compound 16
`
`In the same manner as Preparation XV, 2-amino-3-(4-
`bromobenzoyl)-N-methyl phenylacetamide, Compound 16
`is prepared from 2-amino-3-(4-bromobenzoyl)benzeneace(cid:173)
`tic acid, ethyl ester and methylamine.
`
`Anti-Inflammatory Tests
`
`15
`
`20
`
`25
`
`The results from in vitro, ex vivo and in vivo anti(cid:173)
`inflammatory tests are summarized in Table 1. Non-haloge(cid:173)
`nated and halogenated 2-amino-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 IC50 values ranging from 0.029 to 0.250 f.!M.
`When tested in vivo, they effectively inhibited trauma(cid:173)
`induced accumulation of PGE2 (~98%) and plasma protein
`influx 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-amino-3-benzoylbenze(cid:173)
`neacetic acids.
`In contrast, unsubstituted and mono-substituted amide
`analogues of 2-amino- 3-benzoylbenzeneacetic acid (Com(cid:173)
`pounds 7, 8, 9, 15 and 16) were ~3 orders of magnitude less
`effective inhibitors of cyclooxygenase activity in vitro with
`IC50 values ranging from 16 to> 133 f.!M. Despite their weak
`inhibitory effects 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 influx 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-
`45 dence for such a structure related effect in vivo.
`When tested for ex vivo anti-inflammatory activity, Com(cid:173)
`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(cid:173)
`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-inflammatory activity the ethyl ester showed significant
`inhibitory activity by reducing plasma protein extravasation
`into the aqueous humor by 60%.
`
`35
`
`40
`
`I. In vitro Anti-Inflammatory Test
`In vitro anti-inflammatory activity of 2-amino-3-benzoyl(cid:173)
`benzeneacetic acid analogues was tested by polarographi(cid:173)
`cally monitoring the inhibition in the rate of oxygen con(cid:173)
`sumption (Cook H. W., Ford G., and Lands WEM, Anal.
`Biochem. 96:341, 1979) in the conversion of arachidonic
`acid to prostaglandin H2 by prostaglandin H synthase 30
`(cyclooxygenase). Cyclooxygenase enzyme was prepared
`by solubilizing 20 mg of lipid-depleted sheep vesicular
`gland microsomal powder (Graff G., Stephenson J. H., et al.,
`J. Biol. Chern. 253:7662, 1978) in 1.0 mL of buffer con(cid:173)
`taining 50 mM phosphate, 5 mM diethyldithiocarbamic
`acid, and 2 f.!M 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).
`IT. Ex Vivo Anti-Inflammatory Test
`Ex vivo anti-inflammatory activity of 2-amino-3-benzoyl(cid:173)
`benzeneacetic acid analogues was evaluated in naive New
`Zealand Albino (NZA) rabbits. In this test animals were
`dosed bilaterally with a single 50 ~ 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/ 50
`0.5 mM phenol buffer (pH 7.4) and incubated for 10 minutes
`at 37° C. with 10 f.!M of [l- 14C]-20:4. 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 55
`quantified by C18-HPLC (Powell, W. S., Anal. Bio(cid:173)
`chem.l48:59 1985).
`Ill. In Vivo Anti-Inflammatory Test
`In vivo anti-inflammatory activity of 2-amino-3-benzoyl(cid:173)
`benzeneacetic acid analogues was evaluated in the model of
`
`Page 8 of 10
`
`

`
`5,475,034
`
`TABLE 1
`
`y
`
`16
`
`15
`
`X
`
`SUMMARY OF ANTI-INFLAMMATORY TEST RESULTS
`
`Io Vitro
`Cyclooxygenase
`Inhibition
`
`Ex Vivo
`Iris/Ciliary Body
`Total Prostaglandin
`Synthesis
`
`Substituent
`
`Io Vivo
`Aqueous Humor
`PGE2 Accumulation
`
`In Vivo
`Paracentesis
`Protein Extravasation
`
`Compound
`
`X
`
`y
`
`IC50 (uM)
`
`Inhibition (% )***
`
`Inhibition
`
`Inhibition (% )*
`
`Diclofenac**
`Amfenac
`
`Bromfenac
`#15
`#16
`
`#8
`#7
`#9
`#15
`#14
`
`4'-H
`OH
`OH
`4'-F
`4'-Cl
`OH
`4'-Br
`OH
`NH2
`4'-Br
`NHCH3
`4'-Br
`4'-Br N(CH3)2
`NH2
`H
`4'-F
`NH2
`4'-Cl
`NH2
`4'-Br
`NH2
`4'-Br OCH2CH3
`
`0.120
`0.25
`0.171
`0.070
`0.029
`19
`16
`»100
`64
`133
`»100
`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 35
`this invention are useful for controlling ophthalmic inflam(cid:173)
`matory disorders and ocular pain. Such disorders include,
`but are not limited to uveitis, scleritis, episcleritis, keratitis,
`surgically-induced inflammation and endophthalmitis.
`The 3-benzoylphenylacetic acid derivatives may be for- 40
`mulated into a variety of topically administrable ophthalmic
`compositions, such as solutions, suspensions, gels or oint(cid:173)
`ment.
`Pharmaceutical compositions comprising compounds of
`Formula 1 in aqueous solution, optionally containing a 45
`preservative