United States Patent 15) 3,669,956 Borck et al. (45) June 13, 1972 54) 4-SUBSTITUTEDAMNO 260/472, 260/516, 260/518 R, 260/518 A, 260/519, PHENYACETIC ACDS AND 260/556 AR, 260/556 B, 260/558 S, 260/558 A, DERVATIVES THEREOF 260/559 T, 260/559 A, 260/.571, 260/574, 260/.575, (72 Inventors: Joachim Borck; Johann Dahin; Volker 424/244, 424/246, 424/248, 424/250, 424/267, Koppe; Josef Kramer; Gustav Shorre; J. 424/270, 424/272, 424/273, 424/274, 424/304, W. Hermann Hovy; Ernst Schorscher, all 424/309, 424/32 i, 424/324, 424/330 of Darmstadt, Germany 51) int. Cl. ........................................................ C07d 41/04 58) Field of Search........ 260/294X,293.4, 293.47, 239 BF, 73) Assignee: E. Merck A. G., Darmstadt, Germany 260/326.3, 294.3 E (22) Filed: July 22, 1968 56) References Cited (21) Appl. No.: 746,326 UNITED STATES PATENTS (30) Foreign Application Priority Data 3,252,970 5/1966 Huebner................................ 260/239 July 22, 1967 Germany.............................. M 74881 3,385,852 5/1968 Casadio................................. 260/246 Jan. 8, 1968 Germany... ....M 76850 OTHER PUBLICATIONS Feb. 23, 1968 Germany...... ...M 77363 March 1, 1968 Germany.............................. M 77429 Norman et al., J. Chen. Soc. 1963, (Nov.), 5431-6. (52) U.S. Cl................... 260/239 BF, 260/239 A, 260/239 E, Primary Examiner-Henry R. Jiles 260/243 B, 260/246, 260/247. 1, 260/247.2 R, Assistant Examiner-G. Thomas Todd 260/247.2 A, 260/247.2 B, 260/247.5 R, 260/247.7 Attorney-Millen, Raptes & White A, 260/247.7 H, 260/268 C, 260/268 PH, 260/293.62, 260/293.64, 260/293, 67,260/293.68, 57) ABSTRACT 260/293.69, 260/293.71, 260/293.72, 260/293.73, 260/293.75, 260/293.76, 260/293.77, 260/293.79, As a group of extraordinarily active anti-inflammatory agents, 260/293.81, 260/293.82, 260/293.83, 260/293.84, 4-aminophenyl acetic acids substituted at the nitrogen and 260/306.7, 260/306.8 R, 260/307 F, 260/307 H, phenyl positions, and derivatives thereof, e.g., 3-chloro-4- 260/309.7, 260/326.3, 260/326.5 S, 260/326.5 SF, piperidino-o-methyl acetic acid, 3-methyl-4-piperidino-a- 260/326.5 E, 260/326.5 G, 260/326.5 L, 260/326.5 methyl acetic acid, and 4-piperidino-naphthyl acetic acids. N, 260/.465 D, 260/465 E, 260/470,260/471 R, 144 Claims, No Drawings 3,669,956 2 4-SUBSTITUTEDAMNO-PHENYLACETCACDS AND A, A and As represent H; an alkyl or cycloalkyl group DERVATIVESTEREOF which optionally contains one to two C-C unsaturated bonds and/or an OH group and/or an NH group andlor This invention relates to substituted 4-aminophenylacetic which is interrupted by O once to three times and/or in acids and the derivatives thereof. 5 terrupted by Y and/or which is branched, this group being According to an object of one aspect of this invention, there of respectively up to 12 carbon atoms; As-NA; phenyl are provided a novel group of chemical compounds as well as or aralkyl of a total of six to 14 carbon atoms (the processes for their manufacture. residues A, A and As being identical or different); According to an object of another aspect of this invention, A is alkylene of up to six carbon atoms, optionally inter there are provided novel pharmaceutical compositions for ef 10 rupted by O or Y; fecting anti-inflammatory, and other therapeutic activities. As is alkylene of one to six carbon atoms; Upon further study of the specification and claims, other Bois an anion, preferably Hals; objects and advantages of the present invention will become B is OH, esterified OH, OM or Hal; apparent. 15 B is alkyl of one to four carbon atoms substituted by B; To attain these compounds, there are provided compounds D is COO or CONA; of the following formula: E is = NR, e S, s NOR O FN-NRR, R R5 Hal is Cl, Br or I; R R L is a group oxidizable to a carboxyl group, such as, ad N 20 vantageously, CHO, CHOH, CH, 1-alkenyl, 1-alkynyl, R N --AR 1,2-dihydroxyalkyl or 1-oxoalkyl of preferably up to four R3 Rs 1. carbonatoms, respectively; M represents metal, especially alkali metal, preferably Li, In the above formula and in all formulas set out herein Cod-R,Zn-R or MgHal; below, the variables have the following meanings, unless 25 M, is H or metal, advantageously alkali or alkaline earth otherwise expressly indicated in individual formulas: metal, preferably Na or K; R, and R being identical or different, represent H or alkyl Q represents Hor M; of one to four carbon atoms; X represents a residue that can be split off with M as MX, R represents F, Hal, CFs, OH, NO, CN, R, OR, SH, SR, and is preferably Hal or a sulfuric or sulfonic acid residue, NR-COR, N.R.R., SONRR, SOR or SOR; and 30 X is a residue substitutable by an amino group, especially under special circumstances, Rs can represent H; Hal, OH, acyloxy, a secondary or tertiary amino group, a R. R. and Rs represent H; with the provisions that one each sulfuric acid residue, an alkylsulfuric acid residue of these residues can also represent F, Hal, R, OR or (wherein the alkyl group is of preferably one to four car SR; and the residues R and Rs together can also bonatoms), or a sulfonic acid residue; represent a tetramethylene optionally containing one to 35 X, represents Hal, OH, acyloxy or alkoxy of preferably two double bonds; the latter special case wherein R and respectively up to four carbon atoms, a sulfuric acid R represent tetramethylene optionally containing one to residue or a sulfonic acid residue; two double bonds, Rs can also be H and Rs can represent X is OH, SH, O-acyl or S-acyl of preferably up to four car H, F, Hal, CF, OH, NO, CN, R, OR, SR, NR-COR, bonatoms each, or X; NRR, SONRR, SOR or SOR; 40 X, and Xs represent each ORs, SRs, NRRe, or together R and Rs represent linear or branched alkyl of one to seven also O or E (the residues X and Xs being identical or dif carbon atoms, or together a linear or branched alkylene ferent); chain of two to 14 carbon atoms which chain can op Xs represents a residue which can be split off with Has HXa, tionally be interrupted by an oxygen or sulfur atom, the especially Hal; or OH, SH or NH optionally substituted residue RandR, being identical or different; 45 by alkyl, acyl, alkysulfonyl or alkoxysulfonyl of respec R represents alkyl of one to four carbon atoms; tively up to four carbon atoms; Ro is acyl (preferably acetyl) or a hydrocarbon residue X and X represent Hal or OH optionally substituted by al (preferably methyl or phenyl); kyl, acyl, alkylsulfonyl or alkoxysulfonyl of preferably R represents 50 respectively up to four carbon atoms (the residues X and Xs being identical or different); Y represents S, NH, N-alkyl of one to six carbon atoms op tionally substituted by OH, N-phenyl or N-phenyl-alkyl of - . seven to 10 carbon atoms; R represents alkylidene of one to seven carbon atoms; and 55 R R Rs represents alkyl of one to seven carbon atoms, wherein the residues R and/or Rs can contain one or more addi 2 is R7RN u tional C = C (double) bonds or CEC (triple) bonds, and wherein these residues can also be connected with 60 R. R. each other in the form of a ring directly or by way of an oxygen or sulfur atom; R R. R is an optionally substituted hydrocarbon residue Z is -CRR-A (preferably alkyl of one to four carbon atoms); Rs and Rs represent H or an optionally substituted 65 3 Ri hydrocarbon residue (preferably alkyl of one to four car bon atoms or phenyl; the residues Ris and Rus being R R. identical or different); 2 is RRN -CRR-e-Z-CRR R is a -(CH)-CHXXs group which can, if desired, contain an additional double bond; a -(CH)-X group 70 R R. which can, if desired, contain one or two additional dou ble bonds; or 3-butenyl, 3-butynyl, 1,3-butadienyl or 1 It has been discovered that substituted 4-aminophenylacetic buten-3-ynyl; acids and the derivatives thereof, of Formula 1, as well as the A represents COOA, CONAAs, CONA, C( = NOH)OH salts thereof with acids or bases, the quaternary ammonium or C(OR)s; 75 salts thereof and the anhydrides thereof exhibit dutstanding 0.1040 O3S 3,669,956 3 4. anti-inflammatory activities, as well as good analgesic and Kaolin edema test: anti-pyretic activities, all the compounds being also physiolog Ann. N.Y. Acad. Sci. 86,263 (1960). ically compatible. In addition, these compounds also exhibit Generally, the compounds of the present invention can be bacteriostatic, bactericidal, antiprotozoal, diuretic, blood used in all instances where it is customary to employ Ibufenac sugar-lowering, choleretic, cholesterol-level-lowering, and 5 or Indomethacin. More specifically, diseases such as in radiation-protective effects. flammatory states of the joints and the muscular system, rheu Thus, the following effect relationships resulted with matic fever, chronic rheumatic arthritis, periarthritis, and neu respect to several of the compounds of the present invention ritis, can successfully be treated with the compounds of this in as compared, for example, with the compound bufenac (p- vention.