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United States Patent (19) (11 3,946,035 Jacquet Et Al

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United States Patent (19) (11 3,946,035 Jacquet Et Al United States Patent (19) (11 3,946,035 Jacquet et al. (45) Mar. 23, 1976 (54) ANTI-INFLAMMATORY POLYMERS, 51) Int. Cl......................................... C07D 209/18 PHARMACEUTICAL COMPOSITIONS 58) Field of Search......... 260/326.13 R, 85.7, 88.3, CONTAINING THE SAME AND PROCESS 260/326.13 FOR PRODUCING SAD POLYMERS 56) References Cited 75) Inventors: Bernard Jacquet, Antony; Christos Papantoniou, Epinay-sur-Seine; UNITED STATES PATENTS Pierre Dufaure; Claude Mahieux, 3,535,337 10/1970 Chemerda et al............. 260/326. 16 both of Paris, all of France 3,798,235 3/1974 Yamamoto et al............ 260/326.13 (73) Assignee: L'Oreal, Paris, France Primary Examiner-Elbert L. Roberts 22 Filed: June 27, 1973 Attorney, Agent, or Firm-Cushman, Darby & (21) Appl. No. 374,060 Cushman 57 ABSTRACT 30) Foreign Application Priority Data A polymer has on its macromolecular chains in the form of a lateral branching an anti-inflammator resi June 29, 1972 Luxemburg............................ 65622 due having a carboxylic acid function chemically June 29, 1972 Luxemburg............................ 65621 linked to the macromolecular chains by an intermedi 52 U.S. Cl............... 260/243 A; 260/85.7; 424/78; ate covalent function. 260/295 R; 260/302 R; 260/326.13 R; 13 Claims, No Drawings 260/326.2 3,946,035 1. 2 When taken or administered topically to a human, ANTI-INFLAMMATORY POLYMERS, the activity manifests itself in the same order of magni PHARMACEUTICAL COMPOSITIONS tude, and the polymers exhibit essentially no undesir CONTAINING THE SAME AND PROCESS FOR able side effects, whereas the same anti-inflammatory PRODUCING SAD POLYMERS material alone, when applied topically, has at times been found to produce a significant mortality rate in The present invention relates to new polymers use laboratory animals. fully employed in the field of pharmaceuticals, to a The present invention thus relates to a polymer hav process for preparing these polymers and to a composi ing in its macromolecular chains in the form of a lateral tion containing the same. O branching, the residue of an anti-inflammatory material Heretofore it has been proposed to use, as a medi having a carboxylic acid function which residue is cine, certain polymers having in their macromolecular linked chemically to said macromolecular chains by an chains, residues or moieties of a therapeutically active intermediate covalent function. The new polymers material, in an effort to obtain a delayed and prolonged according to the invention have an average molecular action of this active material, i.e. to achieve a progres 15 weight between about 2,000 and 1,000,000. The mac sive liberation or absorption of the material in the romolecular chains of the polymers according to the body. Although many diverse types of polymers have present invention can be homopolymers, that is, they been studied in a number of therapeutic areas, until can result from the polymerization of but one monomer now these studies have not, essentially, provided a truly or they can be copolymers, such as bipolymers, terpoly commercially acceptable product. It has been ob 20 mers, etc. that is they can result from the polymeriza served, for instance, that certain of these polymers tion of at least two ethylenically unsaturated mono characterized by having the active material or residue mers. In copolymers which are formed from at least in branched relationship to the polymer chain exhibit two different monomers, only one of the monomeric essentially no activity even over prolonged periods of units carries as a branched substituent the residue of time or exhibit an activity lower than that of the active 25 the anti-inflammatory material. material employed alone, i.e. not in combination with The other monomer, or monomers, in this embodi the polymer. ment where the macromolecular chains are constituted Accordingly these polymers, often called “anti-in from more than two monomers, is generally selected flammatory polymers', i.e. polymers having in the form depending upon the desired use of the resulting poly of a branching relative to the main polymer chain a 30 e. known anti-inflammatory active material, have not It is thus possible to impart to the polymers of this until now proved to be of any sustantial therapeutic invention different properties which can depend only significance. on the nature of the one or another of monomers con Among the numerous active anti-inflammatory mate stituting the macromolecular chains of these copoly rials currently known and used in the field of therapeu 35 e.S. tics, certain ones exhibit quite remarkable activity. Representative monomers usefully employed in the However, their use is often accompanied by a number present invention include: of disadvantages, which seriously limit their use. vinyl esters of fatty acids having 8-18 carbon atoms, This is particularly true with respect to such anti-in such as vinyl stearate, vinyl octanoate, vinyl dodecano flammatory materials as 1-(p-chlorobenzoyl)-5- 40 ate and vinyl decanoate; methoxy-2-methyl 3-indole acetic acid (indometha acrylates and methacrylates of fatty alcohols having cine), 3'-trifluoromethyl-2-diphenylamine carboxylic 8-18 carbon atoms, such as octyl, dodecyl or octadecyl acid (flufenamic acid), 2’, 3'-dimethyl 2-diphenyla acrylate and methacrylate, mine caroxylic acid (mefenamic acid), 2-(10-methyl-2 allylic and methallylic esters of an acid having 2-18 phenothiazinyl) acetic acid or (methiazinic acid) and 45 carbon atoms such as allyl and methallyl acetates, pro 3'-trifluoromethyl-2-phenylamino 3-pyridine carbox pionates, butyrates, hexanoates, octanoates, decano ylic acid (niflamic acid) all of which, while exhibiting ates, dodecanoates, octadeconoates and eicosanoates, rapid anti-inflammatory activity after absorption by or the acrylates and methacrylates of N,N-dialk topical application onto the body, nonetheless also ylaminoalkyls such as dimethylaminoethyl methacryl exhibit relatively high toxicity characteristics. It has 50 ate or diethylaminoethyl methacrylate which can op been observed that numerous ones of known active tionally be quaternized, and materials of this type are ulcerative and accordingly vinyl heterocycles such as N-vinyl pyrrolidone and their use is not without certain risks. Consequently a the N-acryloyl and methacryloyl D-glucosamines. great number of patients cannot be treated with strong Certain of these monomers, such as N-vinyl pyrrol anti-inflammatory agents and often there is no substi 55 idone, increase the solubility of the resulting polymer in tute which can be prescribed. aqueous solutions while others of these monomers hav It has now been found, however, that it is possible to ing fatty chains increase the solubility of the resulting obtain a delayed and prolonged action of an active polymer in an oil vehicle. anti-inflammatory material and to reduce considerably Thus it can be seen that by judiciously selecting one its toxicity and the ulcertative action by using as the 60 or more monomers, it is possible with the use of but one anti-inflammatory active compound certain polymers anti-inflammatory material to produce either an aque having in branched relationship to their main chain ous composition or in oily compositions, a feature residues of certain known active anti-inflammatory which heretofore was not always possible with the anti materials. inflammatory materials alone, that is, not fixed on poly Further, when taken orally by a human the activity of 65 mer chains. the anti-inflammatory polymers of this invention is, in As indicated above, the residue of the anti-inflamma most instances, greater than that of the anti-inflamma tory material is linked to the macromolecular chains of tory material alone, i.e. not linked to a polymer. the polymer by an intermediate covalent function. 3,946,035 3 4 According to a first embodiment of the present in wherein: vention, the polymers are homopolymers, that is they R" represents hydrogen or methyl, are constituted by repeating units selected from the R", is hydrogen or methyl group consisting of: R represents a member selected from the group consisting of (a)--CH-CH 2. O wherein Ra represents a saturated hydrocarbon chain C O having 8-18 carbon atoms, k 15 b. (b) C H mo I -o-, 20 O wherein R represents either a saturated hydrocarbon H - O -- C X chain having 8-18 carbon atoms, or N,N'-dialk 25 ylaminoethyl wherein said alkyl moieties have 1-3 car bon atoms, C. II O 30 -ch-o-R, wherein Rs is a saturated hydrocarbon having 2-18 35 carbon atoms, (d) - and V o? 40 (e) -9-glucosamine, and and 45 R represents a member selected from the group consisting of (a) oc, O-C-X, 50 J (b) -CH2-O-C-CH-O-C-X, wherein: n is 1-10, preferably 1-3 inclusive, 55 R represents hydrogen or methyl, (c) -CH2-NH-9-CH-O-9-X, r and r" represent alkyl having 1-3 carbon atoms, O Y represents chlorine or bromine, and X represents aryl, alkaryl or aromatic heterocycle O O residue derived from an anti-inflammatory mate 60 (d) --NH-CH-NH lich,-o-x and rial. O O According to a second embodiment of the present -- invention, the polymers are bipolymers having repeat (e) -O-C-CH-N-(CH2)-O-C-X, Y r ing units of the formula 65 r r R" R -ch (VI) wherein ch r and r" represent alkyl having 1-3 carbon atoms, R R 3,946,035 S Y represents chlorine or bromine, n is 1-10, preferably 1-3 and X is aryl, alkaryl or aromatic heterocycle residue derived from an anti-inflammatory material. In accordance with the present invention, the residue 5 of anti-inflammatory material, X, which is fixed onto the macromolecular chains can be selected from the group consisting of (1) (H3 10 w In -a, - 15; (2) --O- 20 (3) O NH - CH 3 25 30 wherein each R", independently is selected from the group consisting of hydrogen, chlorine, methyl and methoxy and R's is selected from the group consisting of hydrogen, methyl, methoxy and trifluoromethyl, 35 (14) S NH - C ) s 40 R (15) NH CF wherein R', R', and R's each independently represent -S alkyl having 1-3 carbon atoms, Cl, Br, F or I, 45 " (6) (16) C -NH--: CF 50 ..
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