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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
  • C07D307/83—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D495/14—Ortho-condensed systems
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  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• This invention is in the area of pharmaceutical compositions and methods for the treatment of inflammatory and immune disorders, and specifically provides novel compounds that have PAF receptor antagonist activity and inhibit the enzyme 5-lipoxygenase.
• Platelet activating factor (PAF, 1-0-alkyl- 2-acetyl-sn-glycerol-3-phosphorylcholine) is a potent inflammatory phospholipid mediator with a wide variety of biological activities.
• PAF was initially identified as a water soluble compound released by immunoglobulin E (IgE)-sensitized rabbit basophils. It is now known that PAF is also generated and released by onocytes, macrophages, polymorphonuclear leukocytes (P Ns) , eosinophils, neutrophils, natural killer lymphocytes, platelets and endothelial cells, as well as by renal and cardiac tissues under appropriate immunological and non-immunological stimulation.
• IgE immunoglobulin E
• PAF causes the aggregation and degranulation of platelets at very low concentrations.
• the potency (active at 10" 12 to 10""M) , tissue level (picomoles) and short plasma half life (2-4 minutes) of PAF are similar to those of other lipid mediators such as thromboxane A 2 , prostaglandins, and leukotrienes.
• PAF mediates biological responses by binding to specific PAF receptors found in a wide variety of cells and tissues.
• PAF receptor antagonists Since then, a number of compounds of diverse chemical structure have been identified as PAF receptor antagonists. Examples of active hetrazepines are disclosed in European Patent Application No. 338 993 A; Ger. Offen. DE 3,936,828; Ger. Offen. DE 4,006,471; Ger. Offen. DE 3,701,344; Ger. Offen. DE 3,724,164;. Ger. Offen. DE 3,724,031; U.S. Patent No. 4,959,361; European Patent Application No. 0 407 955 Al; and European Patent Application No. 0 367 110. A number of imidazo[2.l-a]isoquinolines with PAF receptor antagonist activity are also known, including those disclosed in United States Patent Nos. 4,910,206 and 4,992,428. Pyrrolo[1,2-c]thiazoles with PAF receptor antagonist activity are disclosed, for example, in Lave et al., Drugs of the Future.
• Leukotrienes like PAF, are potent local mediators, playing a major role in inflammatory and allergic responses, including arthritis, asthma, psoriasis, and thro botic disease.
• Leukotrienes are straight chain eicosanoids produced by the oxidation of arachidonic acid by lipoxygenases.
• Arachidonic acid is oxidized by 5-lipoxygenase to the hydroperoxide 5-hydroperoxyeicosatetraenoic acid (5-HPETE) , that is converted to leukotriene A 4 , that in turn can be converted to leukotriene B 4 , C 4 , or D 4 .
• 5-HPETE hydroperoxide 5-hydroperoxyeicosatetraenoic acid
• the slow-reacting substance of anaphylaxis is now known to be a mixture of leukotrienes C 4 , D 4 , and E 4 , all of which are potent bronchoconstrictors.
• Leukotrienes are released simultaneously from leukocytes with PAF, possibly from a common phospholipid precursor such as l-O-hexadecyl-2- arachidonyl-sn-glycero-phosphocholine, and upon cellular activation, act synergistically with PAF in many biological models.
• PAF and leukotrienes have been together associated with disease states such as asthma, arthritis, psoriasis, inflammatory bowel disease, and other inflammatory and immunological disorders.
• n and m are independently 1-4 .
• R 2 is alkyl, alkenyl, alkynyl, alkyaryl, aralkyl, halo lower alkyl, halo lower alkenyl, halo lower alkynyl, -C'- 10 alkyl (oxy) C l -'°alkyl, -C'- I0 alkyl(thio)C M, alkyl, -N(R 3 ) C(0) alkyl, -N(R 3 )C(0) alkenyl, -N(R 3 ) C(O) alkynyl, -N(R 3 )C(0) (alkyl)oxy(alkyl) , -N(R 3 )C(0) (alkyl)thio (alkyl) , -N(R 3 ) C(0)N(alkyl) , -N(R 3 ) C(0)N(alkenyl) , -N(R 3 )C(0)N(alkynyl) , -N
• R- and R 4 are independently alkyl, alkenyl, alkynyl, aryl, aralkyl, alkyaryl, hydrogen, C alkoxy-C,., 0 alkyl, C w alkylthio-C 0 alkyl, and c,. l0 substituted alkyl (wherein the substituent is independently hydroxy or carbonyl, located on any o C M0 ) ;
• R* is H, lower alkyl, or lower alkenyl
• R 9 is H, halogen, lower alkoxy, or lower alkyl
• M is hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group.
• the resulting compounds act as "dual function antagonists" in that they retain PAF receptor antagonist activity and also inhibit the enzyme 5-lipoxygenase.
• the invention described herein provides a novel route to the enhancement of utility of conventional PAF antagonists and
• 5-lipoxygenase activity by adding an iron chelating group such as the above-defined hydroxamate or hydroxyurea groups; or oxalkane, thioalkane, quinolylmethoxy, or amidohydroxyurea moieties to the PAF antagonist at a position on the PAF antagonist molecule that demonstrates "bulk tolerance", i.e., the ability to accommodate functionality without the loss of PAF activity.
• the R 1 group is added to the PAF receptor antagonist through conventional means, including by appropriate derivatization of amino or carboxylic acid groups positioned such that the 5-LO inhibiting moiety does not significantly affect the PAF receptor antagonist activity of the molecule.
• the 5-lipoxygenase inhibiting moiety is optimally oriented for the substrate binding domain of 5-lipoxygenase.
• the length and lipophilicity of the side chain or spacer (R 2 ) between the aromatic hydrophobic core of the PAF antagonist and the 5-lipoxygenase inhibiting moiety is optimized by conventional means, including by evaluation of standard structure-activity relationships.
• the utility of known PAF receptor antagonists is enhanced by the addition of substituted pyridinium heterocycles or other quaternary N-heterocycles of the formula -0R 6 N(R 5 )R 6 -(C 5 H 4 N)R 6 R 7 , -OR 6 N(C0 2 R 5 ) R 6 -(C 5 H 4 N)R*R 7 , -OR°N(COR 5 )R 6 -(C 5 H 4 N)R 6 R 7 , -OR°OC(0)N(COR 5 )R°-(C 5 H 4 N)R°R 7 , -OR 6 0(CO)N(C0 2 R 6 )R 6 (C 5 H 4 N)R°R 7 , or -R 2 (C 5 H 4 N)R°R 7 , wherein
• R 5 is lower alkyl, lower alkenyl, lower alkynyl, hydroxyl, hydrogen, halo lower alkyl, halo lower alkenyl, halo lower alkynyl, aralkyl, or aryl;
• R 6 is lower alkyl, lower alkenyl, lower alkynyl, aralkyl, halo lower alkyl, halo lower alkenyl, halo lower alkynyl, or aryl;
• R 7 is an organic or inorganic anion. These quaternized heterocycles increase the water solubility of the PAF receptor antagonist, allowing the compound to be administered by injection or infusion intravenously. Further, the addition of the substituted pyridiniu heterocycle or other quaternary N-heterocycle to the PAF antagonist in many cases enhances the PAF antagonist activity of the compound.
• PAF antagonist activity may be restored, or augmented, by the addition of a substituted pyridinium heterocycle or other quaternary N-heterocycle to an appropriate position on the molecule.
• a method to treat disorders mediated by PAF or leukotrienes includes administering an effective amount of one or more of the compounds described herein or a pharmaceutically acceptable salt or derivative thereof, optionally in a pharmaceutically acceptable carrier.
• the compounds disclosed herein can also be used as research tools to study the structure and location of PAF receptors as well as biological pathways involving leukotrienes.
• Figure 1 is a schematic illustration of PAF receptor antagonist hetrazepines modified to exhibit 5-lipoxygenase inhibiting activity.
• R 10 is hydrogen, alkyl, aryl, alkoxy, nitro, halogen, amino, alkylamino, dialkylamino, arylamino, diarylamino, heteroarylamino, diheteroarylamino.
• R n is hydrogen or alkyl.
• FIG. 2 is a schematic illustration of PAF receptor antagonist dimethoxyphenylethyl- phenylimidazo-[2.1-a]isoquinolines modified to exhibit 5-lipoxygenase inhibiting activity. - 9a -
• FIG 3 is a schematic illustration of PAF receptor antagonist pyrrolo[l,2]thiazoles modified to exhibit 5-lipoxygenase inhibiting activity.
• R 12 is H, alkyl, aryl, or aralkyl.
• Figure 4 is a schematic illustration of PAF receptor antagonist thiazolidinecarboxamides
• Figure 5 is a schematic illustration of PAF receptor antagonist dihydropyridines modified to exhibit 5-lipoxygenase inhibiting activity.
• Figure 6 is a schematic illustration of PAF receptor antagonist propenylcarboxi ides modified to exhibit 5-lipoxygenase inhibiting activity.
• Figures 7 and 7a are schematic illustrations of PAF receptor antagonist kadsurenone analogs modified to exhibit 5-lipoxygenase inhibiting activity.
• Figure 8 is a schematic illustration of l,5-dioxabicyclo-[3.3.0]octanes with PAF receptor antagonist and 5-lipoxygenase inhibiting activity.
• alkyl refers to a saturated straight, branched, or cyclic hydrocarbon of c, to C ⁇ 0 .
• lower alkyl refers to a C, to C 6 saturated straight, branched, or cyclic (in the case of C s ⁇ ) hydrocarbon, and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2- dimethylbutyl, and 2,3-dimethylbutyl.
• alkenyl refers to a straight, branched, or cyclic (in the case of C 5 ⁇ ) hydrocarbon of C 2 to C 10 with at least one double bond.
• lower alkenyl refers to - 11 - an alkenyl group of C 2 to c cycles, and specifically includes vinyl, and allyl.
• lower alkylamino refers to an amino group that has one or two lower alkyl substituents.
• alkynyl refers to a C 2 to C 10 straight or branched hydrocarbon with at least one triple bond.
• lower alkynyl refers to a C 2 to C 6 alkynyl group, specifically including acetylenyl and propynyl.
• aryl refers to phenyl or substituted phenyl, wherein the substituent is halo lower alkoxy or lower alkyl.
• alkoxy refers to a moiety of the structure -O-alkyl.
• heteroaryl refers to an aromatic moiety that includes at least one sulfur, oxygen, or nitrogen in the aromatic ring.
• Nonlimiting examples are furyl, pyridyl, pyri idyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbozolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnoliny
• halo includes fluoro, chloro, bromo, and iodo.
• halo lower refers to a lower (alkyl, alkenyl, or alkynyl) group in which at least one of the hydrogens in the group has been replaced with a halogen atom.
• aralkyl refers to an aryl group with an alkyl substituent.
• alkaryl refers to an alkyl group that has an aryl substituent.
• organic or inorganic anion refers to an organic or inorganic moiety that carries a negative charge and can be used as the negative portion of a salt, and in particular, an organic salt such as an organic amine, including a quaternary amine.
• pharmaceutically acceptable cation refers to an organic or inorganic moiety that carries a positive charge and that can be administered in association with a pharmaceutical agent, for example, as a countercation in a salt.
• metabolicically cleavable leaving group refers to a moiety that can be cleaved .in vivo from the molecule to which it is attached, and includes but is not limited to an organic or inorganic anion, a pharmaceutically acceptable cation, acyl (for example C(O)-alkyl, ncluding acetyl, propionyl, butryl, and succinyl) alkyl, phosphate, sulfate, and sulfonate.
• acyl for example C(O)-alkyl, ncluding acetyl, propionyl, butryl, and succinyl
• enantiomerically enriched composition or compound refers to a composition or compound that includes at least 95% by weight of a single enantiomer of the compound.
• PAF receptor antagonist refers to a compound that binds to a PAF receptor with a binding constant of 10 ⁇ M or lower. - 13 -
• 5-lipoxygenase inhibitor refers to a compound that inhibits the enzyme at 10 ⁇ M or lower in a broken cell system.
• pharmaceutically active derivative refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the compounds disclosed herein.
• compounds with PAF activity can be modified to impart 5-lipoxygenase activity to the compound by the addition of a group that has a hydroxamic acid function (-N(OH)C(O)-) or a hydroxyurea function (-N(OH)C(0)NH-) .
• the hydroxamic acid or hydroxyurea function can be attached to the PAF antagonist molecule through a wide variety of means known or readily ascertainable to those of skill in the art of organic synthesis.
• amines on the PAF antagonist molecule can be converted to hydroxyureas by known procedures, as described in more detail below.
• Carboxylic acids or carboxylic acid derivatives or precursors can easily be converted into hydroxamic acids.
• PAF antagonist molecule can be converted by standard techniques into amine or carboxylic acid functions that, in turn, can be converted into a hydroxyurea or hydroxamic acid, respectively.
• hydroxamic acid and hydroxyurea moieties can be attached to the PAF antagonist molecule through either end of the moiety; i.e., hydroxamic acids (-N(OH)C(O) -) can be attached through the carbonyl or the nitrogen (referred to - 14 - below as a "reverse" hydroxamic acid), and hydroxyureas (-N(OH)C(O)NH-) can be attached through the N(H) or N(OH) (referred to below as a "reverse" hydroxyurea) moiety.
• a general procedure for preparing a hydroxyurea is:
• R is a PAF receptor antagonist with or without a linking moiety
• R' is a moiety as defined in detail above.
• a general procedure for preparing a reverse hydroxyurea is:
• a general procedure for preparing a hydroxamic acid is: - 15 -
• a general procedure for preparing a reverse hydroxamic acid is:
• compounds with PAF activity can be modified to impart 5-lipoxygenase activity to the compound by the addition of a group that has an amidohydroxyurea moiety such as -N(R 8 )C(0)C(R 8 )N(OM)C(0)NHR 9 , -C(O)N(R 8 ) C(R 8 )N(OM) C(O)NHR 9 , -R 2 N(R 8 ) C(0) C(R 8 )N(OM)C(O)NHR 9 , -R 2 C(0)N(R 8 )C(R 8 )N(OM)C(0)NHR 9 , -NHC(0)N(OM)C(R 8 )C(0)N(R 8 ) 2 ; or -NHC(O)N(OM)C(R 8 )N(R 8 )C(O)R 8 .
• a group that has an amidohydroxyurea moiety such as -N(R 8 )C(0)C(R 8 )N(OM)C
• amidohydroxyurea moiety can be attached to the PAF antagonist molecule through a wide variety of means readily ascertainable to those of skill in the art of organic synthesis.
• the amidohydroxyurea moiety can be attached to the PAF receptor antagonist molecule through a spacer, R 2 , as desired. - 16 -
• a general procedure for preparing amidohydroxyurea moieties is:
• Oxaalkanes and thioalkanes can be prepared as described by Crawley, et al., J. Med. Chem.. 35. 2600-2609 (1992) , and illustrated below, by conversion of the PAF receptor antagonist into a Grignard reagent or lithium salt, followed by reaction with the appropriate cyclic ketone.
• Quinolylmethoxy moieties can be prepared as described by Musser, et al., J. Med. Chem. , 35, 2501-2524 (1992) , and references cited therein, as illustrated below.
• RCO 2 R" RCH 2 OH R" is H or ester
• Any compound that has PAF receptor antagonist activity can be modified according to the present invention to impart 5-lipoxygenase inhibiting activity to that compound. It is generally known that there are locations on biologically active molecules, including PAF receptor antagonists active, that cannot be modified without compromising the desired biological activity. It is also generally known that there are locations on biologically active compounds that can tolerate the addition of moieties without significant loss of the desired biological activity. These areas of the compounds are referred to as "bulk tolerating" locations.
• the invention is a method to impart 5-lipoxygenase inhibiting activity to PAF receptor antagonists other than 2,4-diaryl- 1, 3-dithiolanes; 2 , 4-diaryl-l, 3-dioxolanes; 2,4- diaryl-1, 3-oxathiolanes; 2 , 5-diaryl-l, 3- oxathiolanes; 2,5-diaryl tetrahydrothiophenes, tetrahydrofurans, and pyrrolidines; 1,3-diaryl cyclopentanes; and 2,4-diaryl tetrahydrothiophenes, tetrahydrofurans and pyrrolidines.
• R 1 groups are added to PAF receptor antagonists at bulk tolerating locations on the molecule.
• the bulk tolerating areas are easily identified by analysis of the PAF receptor antagonist activity of the compound of interest, and the compound as modified by the addition of chemical moieties at various locations on the molecule.
• a large amount of information available regarding structure- activity relationships for a variety of PAF receptor antagonists is available and can be used to identify bulk tolerating areas.
• the invention is not limited to the modification of specific PAF receptor antagonists, but is instead a general method.
• Examples 1-7 provide detailed descriptions for methods to convert conventional PAF receptor antagonists into dual function antagonists through the addition of hydroxamate or hydroxyurea moieties to the compounds.
• these PAF antagonists can also be modified by the addition of oxalkane, thioalkane, quinolylmethoxy, or amidohydroxyurea moieties. Given these detailed instructions, one of ordinary skill in the art will be able to modify other PAF antagonist molecules in a similar fashion. All modifications of PAF antagonists at bulk tolerating areas with the disclosed 5-lipoxygenase inhibiting moieties are considered within the scope of this invention.
• hetrazepines with PAF receptor antagonist activity are known.
• Nonlimiting examples of active hetrazepines that can be modified using the disclosed method are disclosed in European Patent Application No. 338 993 A; Ger.
• FigU re 1 is an illustration of the chem i cal structures of nonli-itin, examples of hetra-ep i nes .edifie d to inclu d e hy d roxamate and hy d roxyurea moieties.
• Starting from the known thienot ⁇ - azolodiazepine 1 b oth hydroxamate and hy d roxyurea P ieties can b e incorporated onto an area o the molecule where a great has clearly been shown to be tolerated.
• ester 1 is ..pen-*--- to car b oxylic aci d 2 with hydroxide.
• hydroxamates and hydroxyurea containing hetrazepines are synthesized with modified spacer groups between the thiophene ring and the iron chelating moiety.
• Compound 8 6-(2-chlorophenyl)-3-N-(N'-hydroxy-N'-methyl- carboxamido)-11-methy1-2,3,4-dihydropyrollo-[4,3:4, 5]thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]- diazepine;
• Example 2 Preparation of Dimethoxyphenyl- ethylphenylimidazo[2.1-a]isoquinolines with PAF and 5-Lipoxygenase Inhibiting Activity.
• imidazo[2.1-a]isoquinolines with PAF receptor antagonist activity are also known.
• Figure 2 is an illustration of the chemical structures of nonlimiting examples of imidazo- [2.1-a]isoquinolines modified to include hydroxamate and hydroxyurea moieties. These compounds can be prepared as described in detail in Scheme 2 below. 29 -
• the dihydroimidazole 10 is condensed with the nitro ester 11 to give the dihydroimidazo- [1,2-a] isoquinoline 12.
• Reduction of the nitro group to the amine with zinc metal yields the amino heterocycle 13 which is treated first with triphosgene and then with a hydroxylamine (methyl hydroxylamine was used in this example but any substitution is possible) to give the hydroxyurea 14.
• the hydroxamic acid can be prepared starting from the dihydroimidazole 10 and the cyano ester 15.
• the resultant dihydroimidazoquinoline can then be hydrolyzed to the acid 17 which is converted via its acid chloride to the hydroxamic acid 18.
• the reverse hydroxyurea of compound 14 can be prepared by reduction of the nitro ester 12 to the corresponding hydroxylamine, that is reacted with CH 3 NCO to provide the product hydroxyurea.
• dual function imidazo[2.1-a] isoquinolines that can be prepared according to this process are:
• Reverse Hvdroxyurea of Compound 14 5-[4 -(3-(N -methyl-N-hydroxyureidyl)-4,5-dimeth- oxyphenylethy1)phenyl]-2,3-dihydro-imidazo[2, l-a]- isoquinoline;
• Reverse hvdroxyurea 14 5-[4'-(3-(N-hydroxyureidyl) -4,5-dimethoxyphenyl- ethyl)phenyl]-2,3-dihydro-imidazo[2,1-a]- isoquinoline;
• Hydroxamic acid 18 5-[4'-(3-(N-hydroxycarboxamido)-4,5-dimethoxy- pheny1-ethy1)-phenyl]-2,3-dihydro-imidazo[2, 1-a]- isoquinoline;
• Pyrrolo[l,2-c]thiazoles with PAF receptor antagonist activity can also be modified using the disclosed process to impart 5-lipoxygenase inhibiting activity to the molecules.
• Nonlimiting examples of pyrrolo[1,2-c]thiazoles that can be converted into dual function antagonists are described, for example, in Lave et al., Drugs of the Future. 14(9) . 891 (1989); European Patent Application No. 388 309 A2; and European Patent Application No. 0 252 823 Al.
• FIG. 3 is an illustration of nonlimiting examples of pyrrolo[1,2-c]thiazoles modified through the addition of hydroxamate or hydroxyurea groups to impart 5-lipoxygenase inhibiting activity to the compound.
• These compounds can be synthesized as illustrated in Scheme 3 below, using pyrrolofl,2-c]thiazole carboxylic acid 19 as the starting material.
• the carboxylic acid 19 is - 36 - converted to the amide 20 by treatment with oxalyl chloride followed by ammonia. Reduction of the amide with lithium aluminum hydride provides the amine 21.
• Treatment of the amine 21 with triphosgene followed by methyl hydroxylamine hydrochloride gives the hydroxyurea 22.
• pyrrolo[l,2-c]carboxylic acid 19 is treated with oxalyl chloride followed by a hydroxylamine to provide the pyrrolo[l,2-c]thiazole hydroxamic acid 26.
• Reverse Hydroxyurea of Compound 22 7-(N-hydroxy-N'-methylureidyImethyl)-3-(3-pyridyl)- lH,3H-pyrrolo[l,2-c]thiazole;
• Reverse Hvdroxyurea 25 N-(4-(N-hydroxy-N'-methylureidylphenyl)-3-(3- pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7- carboxamide; - 42 -
• hydroxamic acid 26 3-(3-pyridyl)-lH,3H-pyrrolo[l,2-c]thiazole-7-N- ethy1-N-hydroxycarboxamide;
• Nonlimiting examples of thiazolidine- carboxamides with PAF receptor antagonist activity that can be modified to exhibit 5-lipoxygenase inhibiting activity are disclosed in U.S. Patent No. 4,987,132.
• Illustrative examples of thiazolidinecarboxamides modified to have 5-lipoxygenase inhibiting activity are illustrated in Figure 4. These compounds can be prepared as exemplified in Scheme 4 below.
• the alkyl amine 30 is treated with triphosgene and methyl hydroxylamine to provide the hydroxyurea 31. Reaction of the hydroxyurea with carbe- thoxypiperazine under basic conditions gives the alkyl piperazine 34. Esterification of thiazolidine 36 with the piperazine 34 gives the dual function antagonist 37.
• the preparation of the hydroxamic acid dual function antagonist 38 starts with the carboxylic acid 32 which is converted to the acid chloride and - 46 - treated with methyl hydroxylamine to provide the hydroxamic acid 33.
• Treatment of 33 with carbethoxypiperazine under basic conditions yields the alkyl piperazine 35.
• Esterification of the thiazolidine carboxylic acid 36 with the piperazine 35 yields the dual function antagonist 38.
• Nonlimiting examples of dual function thiazolidinecarboxamides that can be prepared according to this process are:
• Hvdroxyurea 37 l-(3-(4'-N-hydroxylureidylphenyl)propyl)-4-[2-(3- pyridyl)-thiazolidine-4-yl-carbonyl]piperazine;
• Dihydropyridines with PAF receptor antagonist activity can be modified to exhibit 5-lipoxygenase inhibiting activity.
• Nonlimiting examples of dihydropyridines modified to exhibit 5-lipoxygenase inhibiting activity are illustrated in Figure 5.
• Scheme 5 below illustrates three pathways for the preparation of dual function dihydropyridines. The first pathway sets out the preparation of the hydroxyureidylphenyl dihydropyridine 43. Reaction of the ketoa ide 39 with the ketoester 40 and 2-chlorobenzaldehyde gives the nitroa ide 41. Reduction of the nitroamide with zinc yields the aminoamide 42. Reaction of the aminoamide with triphosgene and methyl hydroxylamine gives the dual function antagonist 43.
• the hydroxamidodi- hydropyridine 50 can be prepared from the ketoesters 47 and 40 along with 2-chloro- benzaldehyde.
• Nonlimiting examples of dual function dihydropyridines that can be prepared according to this process are:
• hydroxamic acid 43 4-(2-chlorophenyl) -3-ethoxycarbonyl-5-[ (4-N- hydroxyureidylpheny1) -aminocarbony1]-6-methy1-2-[4- (2-methylimidazo[4 , 5-c]pyrid-l-yl)phenyl]-1, 4- dihydropyridine;
• Reverse hydroxyurea of Compound 43 4-(2-chlorophenyl) -3-ethoxycarbonyl-5-[ (4-N- hydroxy-N'-methylureidylphenyl) -aminocarbonyl]-6- methyl-2-[4-(2-methylimidazo[4 , 5-c]pyrid-l-yl) - phenyl]-1,4-dihydropyridine;
• Hydroxamic acid 46 4-(2-chlorophenyl) -3-ethoxycarbonyl-5-[ (4-N- hydroxycarboxamidophenyl) aminocarbonyl]-6-methyl-2- [4-(2-methylimidazo[4 , 5-c]pyrid-l-yl) phenyl]-l, 4- dihydropyridine;
• Reverse Hydroxamic Acid of Compound 46 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-[ (4-N-acetyl- N-hydroxyaminophenyl)-aminocarbonyl]-6-methyl-2-[4- (2-methylimidazo[4,5-c]pyrid-l-yl)phenyl]-1,4- dihydropyridine;
• Hydroxamic Acid 50 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-[4-N-hydroxy- carboxamido]-6-methyl-2-[4-(2-methylimidazo[4,5-c]- pyrid-l-yl)phenyl]-l,4-dihydropyridine;
• Example 6 Preparation of Propenyl Carboxamide Hydroxyurea and Hydroxamic acid Derivatives with PAF Receptor Antagonist Activity and 5-Lipoxygenase Inhibiting Activity.
• Propenyl carboxamides with PAF receptor antagonist activity can be modified into dual function antagonists with 5-lipoxygenase inhibiting activity, including those disclosed in Gutherie, G. L., et al., J. Med. Chem.. 33. 2857 (1990); and European Patent Application No. 298466 A2.
• Examples of propenyl carboxamides with dual function PAF receptor antagonism and 5-LO inhibiting activity are illustrated in Figure 6. These compounds can be synthesized as illustrated in Scheme 6 below.
• the nitro or halogenoaniline 51 is reacted with the nitrile 52 to give the aniline 53. Ring closure under acidic conditions then gives the indole 54.
• benzothiophene II can be converted to the following hydroxamates and hydroxyureas.
• thiophene analogues can be prepared as shown in 65 through 69. These in turn can be converted to the hydroxyureas such as 70 or the hydroxamic acids such as 71.
• hydroxyureas such as 70
• hydroxamic acids such as 71.
• dual function propenyl carboxamides that can be prepared according to this process are:
• Kadsurenone derivatives with PAF receptor antagonist activity including those reported in Shen, et al., Proc. Natl. Acad. Sci. U.S.A.. 82. 672(1985) and Ponpipom, et al., J. Med. Chem.. 30, 136 (1987) can be converted into dual function antagonists by the addition of R 1 groups at bulk tolerating areas on the molecule.
• Examples of kadsurenone derivatives modified to exhibit 5- lipoxygena ⁇ e activity according to the present invention are illustrated in Figures 7 and 7a. Processes for the preparation of compounds illustrated in Figures 7 and 7a are set out in Schemes 7 and 7a, respectively, below.
• kadsurenone derivative 81 is prepared from allylic alcohol 74 and phenol 75 to give the diaryl ether 76.
• kadsurenone derivative 88 is prepared from the allylic alcohol 82 and the phenol 83 as illustrated.
• Nonlimiting examples of dual function kadsurenone derivatives that can be prepared according to this process are:
• Hydroxyurea 88 rac-5-allyl-3A-methoxy-3-methyl-2-[3 -(N-hydroxy-N- propylureidy1) -4 '-methoxypheny1]-2,3 3A,6- tetrahydro-6-oxobenzofuran;
• hvdroxyurea 81 rac-5-allyl-3A-methoxy-3-methyl-2-[3 '- (N-hydroxy-N- propylureidylethoxy) -4'-methoxypheny1]-2 , 3 , 3A, 6- tetrahydro-6-oxobenzofuran;
• Dioxabicyclo[3.3.0]octanes with PAF receptor antagonist activity can be modified to exhibit 5-lipoxygenase inhibiting activity by the addition of an R 1 group to a bulk tolerating location on the molecule.
• Nonlimiting examples of dual function dioxabicyclo[3.3.0]octanes are illustrated in Figure 8.
• Nonlimiting examples of specific dioxabicyclo[3.3.0]octanes include: - 94 - rac-trans-2-[3' ,4'-dimethoxy-5'-(N-hydroxy-N- methylureidyl)phenyl]-6-(3",4",5"-tri ⁇ methoxyphenyl)-1,5-dioxabicyclo[3.3.0]octane;
• dual function antoagonists can be prepared that have both PAF receptor antagonist activity and 5-lipoxygenase inhibiting activity. Specific nonlimiting examples are listed below.
• the PAF receptor antagonist that is used as the starting material for the dual function antagonist follows the compound name in parenthesis.
• 5-[4-(3-(2-quinolylmethoxymethyl) -4,5- dimethoxyphenylethy1) phenyl]-2 , 3-dihydroimidazo- [2, 1-a] iscoquinoline (from compound 17) .
• Amidohydroxyureas can be prepared, for example, from amine compounds numbered 4, 13, 72, 24, 60, and 87.
• one or more enantiomers of a biologically active compound is more active, and perhaps less toxic, than other enantiomers of the same compound.
• Such enantiomerically enriched compounds are often preferred for pharmaceutical administration to humans.
• trans-2,5-diaryl tetrahydrothiophene and trans-2,5- diaryl tetrahydrofuran are often more active PAF receptor antagonists than their cis counterparts.
• Nonlimiting examples of chiral acids include malic acid, mandelic acid, dibenzoyl tartaric acid, 3- bromocamphor-8-sulfonic acid, 10-camphorsulfonic acid, and di-p-toluoyltartaric acid.
• acylation of a free hydroxyl group with a chiral acid also results in the formation of diastereomeric mixtures whose physical properties may differ sufficiently to permit separation.
• a wide variety of biological assays have been used to evaluate the ability of a compound to act as a PAF receptor antagonist, including the ability of the compound to bind to PAF receptors, and the effect of the compound on various PAF mediated pathways. Any of these known assays can be used to evaluate the ability of the compounds disclosed herein to act as PAF receptor antagonists.
• PAF is known to induce hemoconcentration and increased permeability of - 99 - microcirculation leading to a decrease in plasma volume.
• PAF mediated acute circulatory collapse can be used as the basis of an assay to evaluate the ability of a compound to act as a PAF antagonist, by analyzing the effect of the compound on PAF induced decreased plasma volume in an animal model such as mouse.
• Endotoxemia causes the release of chemical mediators including eicosanoids, PAF, and tumor necrosis factor (TNF) that stimulate a variety of physiologic responses including fever, hypotension, leukocytosis, and disturbances in glucose and lipid metabolism. Endotoxemia can result in severe shock and death. Endotoxin-induced mouse mortality is a useful animal model to evaluate the pharmacological effect of compounds on endotoxic shock.
• chemical mediators including eicosanoids, PAF, and tumor necrosis factor (TNF) that stimulate a variety of physiologic responses including fever, hypotension, leukocytosis, and disturbances in glucose and lipid metabolism.
• Endotoxemia can result in severe shock and death. Endotoxin-induced mouse mortality is a useful animal model to evaluate the pharmacological effect of compounds on endotoxic shock.
• a wide variety of biological assays have also been used to evaluate the ability of a compound to inhibit the enzyme 5-lipoxygenase.
• a cytosol 5-lipoxygenase of rat basophilic leukemia cells (RBL) has been widely utilized in studies on leukotriene biosynthesis.
• Compounds that inhibit 5-lipoxygenase decrease the levels of leukotrienes.
• 5-lipoxygenase Another biological assay used to evaluate the ability of a compound to inhibit the enzyme 5-lipoxygenase is based on the classic pharmacological model of inflammation induced by - 100 - the topical application of arachidonic- acid to the mouse ear.
• arachidonic acid is converted by 5-lipoxygenase to various leukotrienes (and other mediators) , which induce changes in blood flow, erythema, and increase vasodilation and vasopermeability.
• the resulting edema is measured by comparing the thickness of the treated ear to a control ear.
• Agents that inhibit 5-lipoxygenase reduce the edematous response, by lowering the amounts of biochemical mediators formed from arachidonic acid.
• Human platelet membranes can be prepared from platelet concentrates obtained from the
• the lysed membrane suspension is layered over the top of a discontinuous sucrose density gradient of 0.25, 1.03, and 1.5 M sucrose prepared in 10 mM MgCl 2 , 10 mM Tris and 2 mM EDTA, pH 7.0, and centrifuged at 63,500 x g for 2 hr.
• the membrane fractions banding between 0.25 and 1.03 M (membrane A) and between 1.03 and 1.5 M (membrane - 101 -
• B) are collected separately.
• the protein concentration of the membrane preparations is determined by Lowry's method with bovine serum albumin (BSA) as the standard.
• BSA bovine serum albumin
• [ 3 H]PAF The ability of [ 3 H]PAF to bind to specific receptors on human platelet membranes is evaluated at optimal conditions at pH 7.0 and in the presence of 10 mM MgCl 2 .
• Membrane protein 100 ug is added to a final 0.5 ml solution containing 0.15 pmol (0.3 nM concentration) of [ H]PAF and a known amount of unlabeled PAF or PAF receptor antagonist in 10 mM MgCl 2 , 10 mM Tris and 0.25% BSA at pH 7.0. After incubation for four hours at 0°C, the bound and unbound [H]PAF is then separated through a Whatman GF/C glass fiber filter under vacuum.
• the nonspecific binding is defined as the total binding in the presence of excess unlabeled PAF (1 mM) where no further displacement is found with higher concentrations of either unlabeled PAF or PAF analogs or PAF receptor antagonists.
• the specific binding is defined as the difference between total binding and nonspecific binding.
• [ 3 H]PAF binding in the presence of inhibitors is normalized in terms of percent inhibition by assigning the total binding in the absence of inhibitors as 0% inhibition and the total binding in the presence of 1 mM unlabeled PAF as 100%.
• the percent inhibition by the compound can be calculated by the formula expressed below: - 102 -
• % inhibition [ (Total binding - total binding in the presence of compound) /nonspecific binding] x 100%
• the IC,137 is calculated as the concentration of the inhibitor necessary to obtain 50% inhibition of the specific [ H]PAF binding and is calculated by a nonlinear regression computer software program, GraphPad Inplot, version 3.0 (GraphPad software, San Diego, CA) .
• mice Female CD-I mice, weighing 16-20 grams, can be obtained from Charles River Laboratory (Wilmington, MA) . Tap water and rodent laboratory chow (5001,
• PAF l-0-alkyl-2-acetyl-sn-glyceryl-3- pho ⁇ phorylcholine, Sigma Chemical Co.
• BSA bovine serum albumin
• 10 ⁇ g (10 ml/kg) of PAF solution is injected into the tail vein.
• Test compounds are dissolved in 0.5
• DMSO saline solution and intravenously injected at 3 mg/kg body weight 15 minutes prior to PAF challenge. Thirty to fifty ⁇ L blood is collected by cutting the tail end into a heparinized micro-hematocrit tube (O.D. 1.50 mm) 15 minutes after PAF administration. - 103 -
• Example 12 Effect of Compounds on Arachidonic Acid-induced Mouse Ear Edema a) Animals The animals are obtained and treated as in
• Arachidonic acid is applied to both ears of mice in 0.025 ml of freshly prepared vehicle (acetone:pyridine:water (97:2:1 v/v/v) and dried under a Sun-Lite Hitensity bulb. Except for dose-response studies, 0.5 mg of arachidonic acid is used for all applications. All test compounds are dissolved in 0.5% DMSO saline solution and intravenously injected at 3 mg/kg body weight 15 minutes prior to arachidonic acid treatment. Animals are sacrificed by cervical dislocation at 1 hour after topical application of arachidonic acid. A 7 mm-diameter disc of tissue is removed from each ear by means of a metal punch. Edema is measured by the average wet weight of the both ear tissues.
• mice are obtained and treated as in
• Endotoxin E. coli serotype 0127:B8, lipopolysaccharide, Sigma Chemical Co. St. Louis, is freshly dissolved in 0.9% NaCl solution. Except for dose-response studies, endotoxin at 50 mg/kg is injected into the tail vein. Test compounds are dissolved in 0.5% DMSO saline solution and intravenously injected at 3 mg/kg body weight 15 minutes prior to PAF challenge. Death occurs - 104 - typically within 12-36 hours. Mortality is recorded 48 hours after endotoxin challenge, as death rarely occurs after 48 hr. The extent of mouse mortality in response to varying concentrations of endotoxin within 48 hours after intravenous injection of endotoxin is evaluated.
• Washed rat RBL cells (4x108) are suspended in 20 ml of 50 M potassium phosphate buffer at pH 7.4 containing 10% ethylene glycol/1 mM EDTA (Buffer A) .
• the cell suspension is sonicated at 20 KHz for 30 seconds, and the sonicate centrifuged at 10000 x g for 10 minutes, followed by further centrifugation at 105000 x g for 1 hr.
• the supernatant solution (cytosol fraction) containing 5-lipoxygenase is stored at - 70°C. Protein concentration is determined according to the procedure of Bradford (Bradford Dye Reagent) with bovine serum albumin as a standard.
• the mixture should contain 50 mM potassium phosphate buffer at pH 7.4, 2 mM CaCl 2 , 2 mM ATP, 25 M arachidonic acid (0.1 Ci) and enzyme (50-100 mg of protein) in a final volume of 200 L.
• the reaction is carried out at 24°C for 3 minutes.
• the mixture is extracted with 0.2 ml of an ice-cold mixture of ethyl ether:methanol: 0.2 M citric acid (30:4:1) .
• the extract is subjected to thin-layer chromatography at -10°C in a solvent system of petroleum ether:ethyl ether:acetic acid (15:85:0.1) .
• the silica gel zones corresponding to authentic - 105 - arachidonic acid and its metabolites are scrapped into scintillation vials for counting.
• the enzyme activity is expressed in terms of the amount of arachidonic acid oxygenated for 3 minutes.
• Humans, equine, canine, bovine and other animals, and in particular, mammals, suffering from disorders mediated by PAF or products of 5- lipoxygenase can be treated by administering to the patient an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable derivative or salt thereof in a pharmaceutically acceptable carrier or diluent.
• the active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid, cream, gel or solid form.
• salts or complexes refers to salts or complexes that retain the desired biological activity of the above-identified compounds and exhibit minimal undesired toxicological effects.
• Nonlimiting examples of such salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like) , and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisul onic acid, and polygalacturonic acid; (b) base addition salts formed with polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, - 106 - cobalt, nickel, cadmium
• the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated.
• a preferred dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day.
• a typical topical dosage will range from 0.01 - 3% wt/wt in a suitable carrier.
• the effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
• the compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing 1 to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form.
• a oral dosage of 25-250 mg is usually convenient.
• the active ingredient should be administered to achieve peak plasma concentrations of the active compound of about 0.01 -30 ⁇ M, preferably about 0.1-10 ⁇ M. This may be achieved, for example, by the intravenous injection of a solution or formulation of the active ingredient, - 107 - optionally in saline, or an aqueous medium or administered as a bolus of the active ingredient.
• the concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
• the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
• Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
• the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules.
• Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
• the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic - 108 - acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
• a binder such as microcrystalline cellulose, gum tragacanth or gelatin
• an excipient such as starch or lactose, a disintegrating agent such as alginic - 108 - acid, Primogel, or corn starch
• a lubricant such as magnesium stearate or Sterotes
• a glidant such
• dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
• dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.
• the active compound or pharmaceutically acceptable salt or derivative thereof can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
• a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
• the active compound or pharmaceutically acceptable derivatives or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, antiinflammatories, or antiviral compounds.
• Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers - 109 - such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
• the parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
• preferred carriers are physiological saline or phosphate buffered saline (PBS) .
• the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
• a controlled release formulation including implants and microencapsulated delivery systems.
• Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
• Liposomal suspensions may also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety) .
• liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container.
• appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol
• aqueous solution of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives are then introduced into the container.
• the container - 110 - is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.

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