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US 2004O132766A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0132766A1 Griesgraber (43) Pub. Date: Jul. 8, 2004 (54) 1H-MIDAZO DIMERS Publication Classification (76) Inventor: George W. Griesgraber, Eagan, MN (US) (51) Int. Cl." .................... A61K 31/4745; CO7D 471/02 Correspondence Address: (52) U.S. Cl. ............................................ 514/303; 546/118 3M INNOVATIVE PROPERTIES COMPANY PO BOX 33427 ST. PAUL, MN 55133-3427 (US) (57) ABSTRACT (21) Appl. No.: 10/670,957 (22)22) FileFilled: Sep.ep. ZS,25, 2003 1H-imidazo dimer compounds are useful as immune Related U.S. Application Data response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines (60) Provisional application No. 60/413,848, filed on Sep. and are useful in the treatment of a variety of conditions 26, 2002. including viral diseases and neoplastic diseases. US 2004/O132766 A1 Jul. 8, 2004 1H-MIDAZO DIMERS ing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or CROSS REFERENCE TO RELATED other mechanisms. APPLICATION 0001. This application claims priority to U.S. Provisional SUMMARY OF THE INVENTION Application No. 60/413,848, filed Sep. 26, 2002. 0007. It has now been found that certain 1H-imidazo dimer compounds induce cytokine biosynthesis. In one FIELD OF THE INVENTION aspect, the present invention provides 1H-imidazo dimer 0002 The present invention relates to 1H-imidazo dimers compounds of the Formula (I): and to pharmaceutical compositions containing Such dimerS. In addition this invention relates to the use of these dimers as immunomodulators, for inducing cytokine biosynthesis in (I) animals, and in the treatment of diseases, including viral and NH2 NH2 neoplastic diseases. This invention further provides methods of making the dimerS and intermediates used in their Syn N N N N NN thesis. N / R ls- X- ck l R BACKGROUND OF THE INVENTION 0003) The first reliable report on the 1H-imidazo[4,5-c. R4 N-A. R4 quinoline ring System, Bachman et al., J. Org. Chem. 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy 8-quinolinyl)-2-methyl 1H-imidazo4.5-cquinoline for pos 0008 wherein A, R, R and R are as defined herein. Sible use as an antimalarial agent. Subsequently, Syntheses of various Substituted 1H-imidazo[4,5-cquinolines were 0009. The compounds of Formula I are useful as immune reported. For example, Jain et al., J. Med. Chem. 11, pp. response modifiers (IRMs) due to their ability to induce 87-92 (1968), Synthesized the compound 1-2-(4-piperidyl cytokine biosynthesis (e.g., induce the biosynthesis or pro )ethyl)-1H-imidazo4.5-cquinoline as a possible anticon duction of one or more cytokines) and otherwise modulate Vulsant and cardiovascular agent. Also, Baron et al., Chem. the immune response when administered to animals. This AS. 85,94362 (1976), have reported several 2-oxoimidazo 4.5-cquinolines, and Berenyi et al., J. Heterocyclic Chem. makes the compounds useful in the treatment of a variety of 18, 1537-1540 (1981), have reported certain 2-oxoimidazo conditions Such as Viral diseases, and neoplastic diseases, 4.5-cquinolines. that are responsive to Such changes in the immune response. 0004 Certain 1H-imidazo[4,5-cquinolin-4-amines and 0010. In another aspect, the present invention provides 1- and 2-substituted derivatives thereof were later found to pharmaceutical compositions containing the immune be useful as antiviral agents, bronchodilators and immuno response modifier compounds, and methods of inducing modulators. These are described in, inter ail, U.S. Pat. Nos. cytokine biosynthesis in an animal, treating a viral disease in 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; an animal, and treating a neoplastic disease in an animal, by 5,346,905; and 5,389,640, all of which are incorporated administering an effective amount of one or more com herein by reference. pounds of Formula I and/or pharmaceutically acceptable 0005. Many imidazoquinoline amine, imidazopyridine Salts thereof to the animal. amine, 6,7-fused cycloalkylimidazopyridine amine, 1,2- bridged imidazoquinoline amine, thiazoloquinoline amine, 0011. In addition, the invention provides methods of Oxazoloquinoline amine, thiazolopyridine amine, oxazol Synthesizing the compounds of the invention and interme opyridine amine, imidazonaphthyridine and tetrahydroimi diates useful in the Synthesis of these compounds. dazonaphthyridine amine compounds have demonstrated potent immunostimulating, antiviral and antitumor (includ 0012. As used herein, “a,”“an,”“the,”“at least one,” and ing anticancer) activity, and have also been shown to be “one or more' are used interchangeably. useful as vaccine adjuvants to enhance protective immune 0013 The terms “comprising” and variations thereof do System response to vaccines. Such compounds and methods of making them are disclosed in, for example, U.S. Pat. NoS. not have a limiting meaning where these terms appear in the 4,689,338; 4,929,624, 5,266,575; 5,268,376; 5,352,784; description and claims. 5,389,640; 5,482.936; 5,494,916; 6,110,929; 6,194,425; 0014. The above summary of the present invention is not 6,331,539; 6,376,669; 6,451,810; 6,541,485; 6,573,273; intended to describe each disclosed embodiment or every 6,545,016; 6,545,017; and 6,525,064, and PCT Publications implementation of the present invention. The description WO 02/46188, WO 02/46189; WO 02/46190; WO 02/46191; WO O2/46192; and WO 02/46193, the disclosures that follows more particularly exemplifies illustrative of which are specifically incorporated by reference herein. embodiments. Guidance is also provided herein through lists of examples, which can be used in various combinations. In 0006 Despite these recent discoveries of compounds that each instance, the recited list Serves only as a representative are useful as immune response modifiers, there is a continu group and should not be interpreted as an exclusive list. US 2004/O132766 A1 Jul. 8, 2004 DETAILED DESCRIPTION OF THE 0.042 straight or branched chain Co alky INVENTION nylene, 0.015. In one aspect, the present invention provides 0.043 straight or branched chain perfluoro Co 1H-imidazo dimer compounds of the Formula (I): alkylene, 0044 C- alkylene-O-C alkylene; (I) 0045 –C(O)-; NH2 NH2 0046 -S(O) ; N N N N NN 0047 –OC(O)O-; - Y-R,y- a -(K. 2 0048 -N(R)C(O)N(R)-; R R Y 7 o R4 N-A. R4 0016 wherein: 0017 A is a divalent linking group selected from the group consisting of 0018 straight or branched chain Co alkylene; 0019 straight or branched chain Coalkenylene; 0020 straight or branched chain Co alky 0049) 1.5-naphthylene; nylene, and 0050 2,6-pyridinylene; 0051 12-cyclohexylene; 0022 each Z is independently selected from the 0052) 1,3-cyclohexylene; group consisting of 0053 14-cyclohexylene; 0023 straight or branched chain Co alkylene; 0.054 trans-1,4-cyclohexylene; 0024) Straight or branched chain Coalkenylene; and 0025 straight or branched chain Co alky nylene; 0026 any of which may be optionally interrupted by -O-, -N(R)-, or -S(O) ; 0027 each Y is independently selected from the 0055) and group consisting of 0056 trans-5-norbornen-2,3-diyl; 0057 wherein n is 0-4; each R is independently Selected from the group consisting of C alkyl, C, alkoxy, and halogen; and Q is selected from the group consisting of a bond, -CH2-, and -O-, 0.058 R is selected from the group consisting of: 0059 -hydrogen; 0060) -alkyl; 0061 -alkenyl; 0062 -aryl; 0063) -substituted aryl; 0064 -heteroaryl; 0039 W is selected from the group consisting of: 0065 -substituted heteroaryl; 0040 straight or branched chain Co alkylene; 0.066 -alkyl-X-alkyl; 0041 Straight or branched chain Coalkenylene; 0067 -alkyl-X-aryl; US 2004/O132766 A1 Jul. 8, 2004 0068) -alkyl-X- alkenyl; and to 2 heteroatoms and unsubstituted or substituted by one or more Substituents Selected from the group 0069 -alkyl or alkenyl substituted by one or more consisting of: Substituents Selected from the group consisting of: -halogen; 0070) -OH: 01.06) 0071 -halogen; 01.07 -alkyl, -alkenyl, 0.072 -N(R); 0108) 0.073 –C(O)-N(R); 01.09) -X-alkyl; and 0.074 –C(S)-N(R); 0110 -N(R), 0111 each Rs is independently selected from the 0075) -S(O)-N(R); group consisting of 0076 -N(R)-C(O)-Co alkyl; 0112 hydrogen; 0077 -N(R)-C(S)-Co alkyl; 0113) Ce alkyl, 0078 -N(R)-S(O)-Co alkyl; 0114 C-7 cycloalkyl, and 0079 –C(O)-Co alkyl; 0115) benzyl; or 0080 -C(O)-O-C alkyl; 0116 when Y is -N(Rs)C(O)-, -C(O)N(Rs), 0081 -N: -N(R)C(O)N(R)-, -N(R)S(O), 0082) -aryl; -S(O)N(R)-, -N(Rs)C(O)O-, or -OC(O)N(R)- and the nitrogen of the N(Rs) 0083) -substituted aryl; group is bonded to Z, then Rs can join with Z to form 0084 -heteroaryl; a ring having the Structure 0085 -substituted heteroaryl; 0.086 -heterocyclyl; 0087 -substituted heterocyclyl; -O-M R7 0088 –C(O)-aryl; 0089 –C(O)-(substituted aryl); 0117) each R is independently hydrogen or Co 0090 –C(O)-heteroaryl; and alkyl, 0.091 –C(O)-(substituted heteroaryl); 0118 R, is Cls alkylene; and 0092 R and R are each independently selected 0119 X is -O- or -S-; from the group consisting of: 0120 with the proviso that if Wis-C(O)-, -S(O), 0093 -hydrogen; -OC(O)O-, or -N(R)C(O)N(R)- then each Y is a 0094) -halogen; bond; 0095) -alkyl; 0121 or a pharmaceutically acceptable salt thereof.
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    USOOS214147A United States Patent (19) 11) Patent Number: 5,214,147 Kazmierczak et al. 45) Date of Patent: May 25, 1993 54 PROCESS FOR PREPARING REACTIVE 4,993,392 3/1991 Cantatore et al. .................. 54.6/190 HINDERED AMNE LIGHT STABILIZERS 5,017,721 5/1991 Messina et al. ..................... S46/244 75 Inventors: Robert T. Kazmierczak; Ronald E. FOREIGN PATENT DOCUMENTS MacLeay, both of Williamsville, 226700 5/1986 Czechoslovakia . N.Y. 22997 1/1981 European Pat. Off. 0022997 1/1981 European Pat. Off. (73) Assignee: Elf Atochem North America, Inc., 54-95649 7/1979 Japan. Philadelphia, Pa. 54-103461 8/1979 Japan. (21) Appl. No.: 805,719 2197318 5/1988 United Kingdom ................ 54.6/190 (22 Filed: Dec. 6, 1991 OTHER PUBLICATIONS Gala et al. Can. Jour. Chem. vol. 60, pp. 710-715 (1982). Related U.S. Application Data "Anionic Polymerization to Cationic Polymerization,' 60 Division of Ser. No. 619,287, Nov. 27, 1990, Pat, No. Encyclopedia of Polymer Science and Engineering, vol. 2, 5,101,033, which is a division of Ser. No. 310,408, Feb. pp. 83, 84 (John Wiley & Sons). 13, 1989, Pat. No. 4,983,738, which is a continuation-in Wilson B. Lutz et al., "New Derivatives of 2,26,6-Tet part of Ser. No. 84,602, Aug. 12, 1987, abandoned. ramethylpiperidine,' pp. 1695-1703 (May 1962). 51) Int. C. ............................................ CO7D 211/30 Primary Examiner-Donald G. Daus 52) U.S.C. .................................... 54.6/190; 546/224; Attorney, Agent, or Firm-Panitch Schwarze Jacobs & 546/244 Nadel 58) Field of Search ................ 54.6/190, 191, 224, 244 (57) ABSTRACT (56) References Cited N-(2,26,6-tetraalkyl-4-piperidinyl)amide-hydrazides of U.S.
  • Synthesis and Applications of Cellulose Derivatives for Drug Delivery

    Synthesis and Applications of Cellulose Derivatives for Drug Delivery

    Synthesis and Applications of Cellulose Derivatives for Drug Delivery Joyann Audrene Marks Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Macromolecular Science and Engineering Kevin J. Edgar, Chair Maren Roman Lynne S. Taylor Judy S. Riffle S. Richard Turner August 5, 2015 Blacksburg, VA Keywords: pairwise blends, amorphous solid dispersion, oral drug delivery, cellulose esters, bioavailability, cationic cellulose, extrusion Copyright © 2015 by Joyann A. Marks Synthesis and Applications of Cellulose Derivatives for Drug Delivery Joyann Audrene Marks ABSTRACT In an effort to produce new derivatives of cellulose for drug delivery applications, methods were developed to regioselectively modify C-6 halo cellulose esters to produce cationic derivatives via nucleophilic substitution. Reaction of C-6 substituted bromo and iodo cellulose with trialkylated amines and phosphines produced new cationic ammonium and phosphonium cellulose derivatives which can be explored as delivery agents for nucleic acids, proteins and other anionic drug molecules. It was anticipated that these new derivatives would not only be capable of complexing anionic drug molecules but would have greatly improved aqueous solubility compared to their precursors. The phosphonium derivatives described in this work are an obvious example of such improved solubility properties. Given the importance of cellulose derivatives in making amorphous dispersions with critical drugs, it has also been important to analyze commercially available polymers for the potential impact in oral drug delivery formulations. To do so pairwise blends of cellulosics and synthetic polymers commonly used as excipients were tested for miscibility using techniques such as DSC, mDSC, FTIR and film clarity.