WO1994004537A2 - Agents a double fonctionnalite anti-inflammatoire et d'immunosuppression - Google Patents

Agents a double fonctionnalite anti-inflammatoire et d'immunosuppression Download PDF

Info

Publication number
WO1994004537A2
WO1994004537A2 PCT/US1993/007728 US9307728W WO9404537A2 WO 1994004537 A2 WO1994004537 A2 WO 1994004537A2 US 9307728 W US9307728 W US 9307728W WO 9404537 A2 WO9404537 A2 WO 9404537A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
methyl
pyridyl
hydroxy
butyl
Prior art date
Application number
PCT/US1993/007728
Other languages
English (en)
Other versions
WO1994004537A3 (fr
Inventor
David M. Goldstein
San-Bao Hwang
Ralph T. Scannell
T. Y. Shen
Original Assignee
Cytomed, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cytomed, Inc. filed Critical Cytomed, Inc.
Priority to AU50167/93A priority Critical patent/AU5016793A/en
Priority to EP93920131A priority patent/EP0656004A1/fr
Publication of WO1994004537A2 publication Critical patent/WO1994004537A2/fr
Publication of WO1994004537A3 publication Critical patent/WO1994004537A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
  • 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-O-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 monocytes, macrophages, polymorphonuclear leukocytes (PMNs), eosinophils, neutrophils, natural killer lymphocytes, platelets and endothelial cells, as well as by renal and cardiac tissues under appropriate immunological and non-immunological stimulation. (Hwang, "Specific receptors of platelet-activating factor, receptor heterogeneity, and signal transduction mechanisms", Journal of Lipid Mediators 2, 123 (1990).) PAF causes the aggregation and degranulation of
  • the potency (active at 10 -12 to 10 -9 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. Structure-activity studies on PAF and its analogs indicate that the ability of PAF to bind to these receptors is highly structure specific and stereospecific. (Shen, et al., "The Chemical and Biological Properties of PAF Agonists, Antagonists, and Biosynthetic Inhibitors", Platelet-Activating Factor and Related Lipid Mediators, F. Snyder, Ed. Plenum Press, New York, NY 153 (1987)). While PAF mediates essential biological responses, it also appears to play a role in pathological immune and inflammatory responses. Many published studies have provided evidence for the involvement of PAF in human diseases, including arthritis, acute inflammation, asthma, endotoxic shock, pain, psoriasis,
  • CV-3988 a phospholipid analog referred to as CV-3988 (rac-3-(N-n-octadecyl-carbamoyloxy- ⁇ -methoxypropyl-2-thiazolioethyl phosphate) was reported to have PMF receptor antagonist properties.
  • CV-3988 rac-3-(N-n-octadecyl-carbamoyloxy- ⁇ -methoxypropyl-2-thiazolioethyl phosphate
  • Leukotrienes like PAF, are potent local mediators, playing a major role in inflammatory and allergic responses, including arthritis, asthma, psoriasis, and thrombotic 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 .
  • 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 1-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
  • European Patent Application Nos. 90117171.0 and 901170171.0 disclose indole, benzofuran, and benzothiphene lipoxygenase
  • 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 1-10 alkyl(oxy)C 1-10 alkyl,
  • R 3 and R 4 are independently alkyl, alkenyl, alkynyl, aryl, aralkyl, alkyaryl, hydrogen, C 1-6 alkoxy-C 1-10 alkyl, C 1-6 alkylthio-C 1-10 alkyl, and C 1-10 substituted alkyl (wherein the substituent is independently hydroxy or carbonyl, located on any of C 1-10 );
  • R 8 is H, lower alkyl, or lower alkenyl
  • R 9 is H, halogen, lower alkoxy, or lower alkyl
  • M is hydrogen, a pharmaceutically
  • 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.
  • an iron chelating group such as the above-defined hydroxamate or hydroxyurea groups
  • 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
  • 5-lipoxygenase inhibiting moiety is optimally oriented for the substrate binding domain of
  • 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 -OR 6 N(R 5 )R 6 -(C 5 H 4 N)R 6 R 7 , -OR 6 N(CO 2 R 5 )
  • 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 pyridinium heterocycle or other quaternary N-heterocycle to the PAF antagonist in many cases enhances the PAF antagonist activity of the compound.
  • 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
  • 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 11 is hydrogen or alkyl.
  • Figure 2 is a schematic illustration of PAF receptor antagonist dimethoxyphenylethyl-phenylimidazo-[2.1-a]isoquinolines modified to exhibit 5-lipoxygenase inhibiting activity.
  • Figure 3 is a schematic illustration of PAF receptor antagonist pyrrolo[1,2]thiazoles modified to exhibit 5-lipoxygenase inhibiting activity.
  • R 12 is H, alkyl, aryl, or aralkyl.
  • FIG. 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 propenylcarboximides modified to exhibit 5-lipoxygenase inhibiting activity.
  • Figure 8 is a schematic illustration of 1,5-dioxabicyclo-[3.3.0]octanes with PAF receptor antagonist and 5-lipoxygenase inhibiting activity.
  • alkyl refers to a saturated
  • lower alkyl refers to a C 1 to C 6 saturated straight, branched, or cyclic (in the case of C 5-6 ) 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 as referred to herein, and unless otherwise specified, refers to a
  • lower alkenyl refers to an alkenyl group of C 2 to C 6 , and specifically incNudes vinyl, and allyl.
  • lower alkylamino refers to an amino group that has one or two lower alkyl
  • 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
  • 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, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl,
  • halo as used herein, includes fluoro, chloro, bromo, and iodo.
  • halo lower refers to a lower (alkyl, alkenyl, or alkynyl) group in which at least one of the
  • 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
  • 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.
  • metabolically 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.
  • 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
  • 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 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:
  • 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
  • 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
  • amidohydroxyurea moieties is:
  • Oxaalkanes and thioalkanes can be prepared as described by Crawley, et al., J. Med. Chem.. 35, 22600-2609 (1992), and illustrated below, by
  • 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
  • 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-1,3-dioxolanes; 2,4-diaryl-1,3-oxathiolanes; 2,5-diaryl-1,3-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.
  • receptor antagonists is available and can be used to identify bulk tolerating areas.
  • the invention is not limited to the
  • 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
  • PAF antagonists can also be modified by the addition of oxalkane, thioalkane, quinolylmethoxy, or
  • Figure 1 is an illustration of the chemical structures of nonlimitin, examples of hetrazepines modified to include hydroxamate and hydroxyurea moieties. Starting from the known thienotriazolodiazepine 1 both hydroxamate and hydroxyurea moieties can be incorporated onto an area o the molecule where a great variety of functionalization has clearly been shown to be tolerated. Thus, as shown in scheme 1 below, ester 1 is saponified to carboxylic acid 2 with hydroxide. Conversion of
  • hydroxamate 3 is converted into a hydroxyurea by sequential reaction with triphosgene and methyl hydroxylamine to furnish 5.
  • hydroxamates and hydroxyurea containing hetrazepines are synthesized with modified spacer groups between the thiophene ring and the iron chelating moiety.
  • Example 2 Preparation of Dimethoxyphenyl- ethylphenylimidazo[2.1-a]isoquinolines with PAF and 5-Lipoxygenase Inhibiting Activity.
  • a number of imidazo[2.1-a]isoquinolines with PAF receptor antagonist activity are also known.
  • Nonlimiting examples of imidazo- [2.1-a]isoquinolines PAF receptor antagonists that can be modified according to the present invention to exhibit 5-lipoxygenase inhibiting activity are disclosed in United States Patent Nos. 4,910,206 and 4,992,428.
  • FIG. 2 is an illustration of the chemical structures of nonlimiting examples of imidazo- [2.1-a]isoquinolines modified to include
  • 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
  • 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.
  • Nonlimiting examples of dual function imidazo[ 2.1-a] isoquinolines that can be prepared according to this process are:
  • Pyrrolo[1,2-c]thiazoles with PAF receptor antagonist activity can also be modified using the disclosed process to impart 5-lipoxygenase
  • 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 A1.
  • Figure 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.
  • triphosgene followed by methyl hydroxylamine hydrochloride gives the hydroxyurea 22.
  • a second pathway treatment of the carboxylic acid 19 with oxalyl chloride followed by a nitroaniline gives the amide 23. Reduction of the nitro group with sodium dithionite then yields the aniline 24. Treatment with triphosgene and then with a
  • hydroxylamine such as methyl hydroxylamine
  • pyrrolo[1,2-c]carboxylic acid 19 is treated with oxalyl chloride followed by a hydroxylamine to provide the pyrrolo[1,2-c]thiazole hydroxamic acid 26.
  • Reverse Hydroxyurea of Compound 22 7-(N-hydroxyureidyImethyl)-3-(3-pyridyl)-1H,3H- pyrrolo[1,2-c]thiazole; 7-(N'-benzyl-N-hydroxyureidyImethyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole;
  • 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.
  • 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 treated with methyl hydroxylamine to provide the hydroxamic acid 33.
  • Nonlimiting examples of dual function thiazolidinecarboxamides that can be prepared according to this process are:
  • Dihydropyridines with PAF receptor antagonist activity including those disclosed in UK Patent Application No. 2 233 974 A and WO
  • Pathways two and three of Scheme 5 illustrate methods for the preparation of hydroxamidophenyldihydropyridine and hydroxamidodihydropyridine.
  • the hydroxamidophenyldihydropyridine 46 is prepared as described above from the ketoamide 44, ketoester 40 and 2-chlorobenzaldehyde.
  • the hydroxamidodihydropyridine 50 can be prepared from the ketoesters 47 and 40 along with 2-chlorobenzaldehyde.
  • Nonlimiting examples of dual function dihydropyridines that can be prepared according to this process are:
  • 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.
  • R is a nitro group as in 59, it is reduced with zinc metal to the amine and then converted to the hydroxyurea 61 with triphosgene and methyl hydroxylamine.
  • R is halogen as in 62 the aromatic ring can be metalated and carboxylated to produce the acid 63.
  • 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.
  • 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- lipoxygenase activity according to the present invention are illustrated in Figures 7 and 7a.
  • 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:
  • 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: rac-trans-2-[3',4'-dimethoxy-5'-(N-hydroxy-N- methylureidyl)phenyl]-6-(3",4",5"-trimethoxyphenyl)-1,5-dioxabicyclo[3.3.0]octane; rac-trans-2-[3',4'-dimethoxy-5'-(N-hydroxy-N-phenylureidyl)phenyl]-6-(3",4",5"-trimethoxyphenyl)-1,5-dioxabicyclo-[3.3.0]octane; rac-trans-2-[3',4'-dimethoxy-5'-(N-cyclopropyl-N-hydroxyureidyl)phenyl]-6-(3",4",5"-trimethoxyphenyl)-1,5-dioxabicyclo[3.3.
  • quinolylmethyloxy, and amidohydroxyurea moieties a wide variety of dual function antoagonists can be prepared that have both PAF receptor antagonist activity and 5-lipoxygenase inhibiting activity.
  • the PAF receptor antagonist that is used as the starting material for the dual function is listed below.
  • 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.
  • 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
  • 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
  • PAF is known to induce hemoconcentration and increased permeability of 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
  • 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 cytosol 5-lipoxygenase of rat basophilic leukemia cells has been widely utilized in studies on leukotriene biosynthesis.
  • Compounds that inhibit 5-lipoxygenase decrease the levels of leukotrienes.
  • arachidonic- acid a pharmacological model of inflammation induced by 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 ⁇ 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 B) are collected separately.
  • [ 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 [ 3 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 [ 3 H]PAF is then separated through a Whatman GF/C glass fiber filter under vacuum. No
  • 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 IC 50 is calculated as the concentration of the inhibitor necessary to obtain 50% inhibition of the specific [ 3 H]PAF binding and is calculated by a nonlinear regression computer software program, GraphPad Inplot, version 3.0 (GraphPad software, San Diego, CA).
  • Example 11 Effect of Compound on PAF-induced
  • mice Female CD-1 mice, weighing 16-20 grams, can be obtained from Charles River Laboratory (Wilmington, MA) . Tap water and rodent laboratory chow (5001,
  • PAF (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, Sigma Chemical Co.) is dissolved in 0.25% bovine serum albumin (BSA) in 0.9% NaCl solution. Except for dose-response studies, 10 ⁇ g (10 ml/kg) of PAF solution is injected into the tail vein. Test compounds are dissolved in 0.5
  • 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
  • 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
  • Washed rat RBL cells (4 ⁇ 108) 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 ⁇ g for 10 minutes, followed by further
  • 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
  • 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
  • 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, naphthalenedisulfonic acid, and polygalacturonic acid; (b) base 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
  • polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with an organic cation formed from N,N-dibenzylethylene-diamine, D-glucosamine, ammonium, tetraethylammonium, or ethylenediamine; or (c) combinations of (a) and (b); e.g., a zinc tannate salt or the like.
  • 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.
  • 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 any substance that is selected from the group consisting of:
  • the active compound 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, 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,
  • compositions and that the concentration ranges set forth herein are exemplary only and are not
  • 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 any active compound.
  • 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 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
  • 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. In addition, 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,
  • 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.
  • 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 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
  • Liposomal suspensions may also be used.
  • 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
  • diphosphate, and/or triphosphate derivatives are then introduced into the container.
  • the container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal

Abstract

Antagonistes du récepteur du facteur d'activation des plaquettes présentant des structures diverses et possédant une efficacité de 5-lipoxygénase par apport d'une fraction, telle qu'un hydroxamate, hydroxyurée, oxalcane, thioalkane, quinolylméthoxy, ou amidohydroxyurée, à l'antagoniste du récepteur du facteur d'activation des plaquettes (PAF) au niveau d'une position située sur la molécule de l'antagoniste de PAF démontrant une tolérance 'en masse', c'est-à-dire la possibilité d'intégrer une fonctionnalité sans perte importante de l'activité de PAF.
PCT/US1993/007728 1992-08-20 1993-08-16 Agents a double fonctionnalite anti-inflammatoire et d'immunosuppression WO1994004537A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU50167/93A AU5016793A (en) 1992-08-20 1993-08-16 Dual functional anti-inflammatory and immunosuppressive agents
EP93920131A EP0656004A1 (fr) 1992-08-20 1993-08-16 Agents a double fonctionnalite anti-inflammatoire et d'immunosuppression

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US93339592A 1992-08-20 1992-08-20
US07/933,395 1992-08-20

Publications (2)

Publication Number Publication Date
WO1994004537A2 true WO1994004537A2 (fr) 1994-03-03
WO1994004537A3 WO1994004537A3 (fr) 1994-10-27

Family

ID=25463868

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/007728 WO1994004537A2 (fr) 1992-08-20 1993-08-16 Agents a double fonctionnalite anti-inflammatoire et d'immunosuppression

Country Status (5)

Country Link
EP (1) EP0656004A1 (fr)
CN (1) CN1090284A (fr)
AU (1) AU5016793A (fr)
MX (1) MX9305063A (fr)
WO (1) WO1994004537A2 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0624588A1 (fr) * 1993-05-07 1994-11-17 J. URIACH & CIA. S.A. Dérivés de quinoline à activité pharmacologique
WO1995018610A1 (fr) * 1994-01-06 1995-07-13 Cytomed, Inc. Composes et methodes de traitement de troubles a caractere cardio-vasculaire, inflammatoire et immunitaire
US5639782A (en) * 1992-03-04 1997-06-17 Center For Innovative Technology Neolignan derivatives as platelet activating factor receptor antagonists and 5-lipoxygenase inhibitors
US5681966A (en) * 1994-06-27 1997-10-28 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5703093A (en) * 1995-05-31 1997-12-30 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5750565A (en) * 1995-05-25 1998-05-12 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5856323A (en) * 1992-07-13 1999-01-05 Cytomed, Inc. Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase
US6294574B1 (en) 1992-07-13 2001-09-25 Cytomed, Inc. Compounds and methods for the treatment of inflammatory and immune disorders
US6555543B2 (en) 2000-08-04 2003-04-29 Dmi Biosciences, Inc. Method of using diketopiperazines and composition containing them
US9623072B2 (en) 2011-10-10 2017-04-18 Ampio Pharmaceuticals, Inc. Treatment of degenerative joint disease
US9707227B2 (en) 2003-05-15 2017-07-18 Ampio Pharmaceuticals, Inc. Treatment of T-cell mediated diseases
US9808454B2 (en) 2013-03-15 2017-11-07 Ampio Pharmaceuticals, Inc. Compositions for the mobilization, homing, expansion and differentiation of stem cells and methods of using the same
US9925300B2 (en) 2011-10-10 2018-03-27 Ampio Pharmaceuticals, Inc. Implantable medical devices with increased immune tolerance, and methods for making and implanting
US9956217B2 (en) 2014-08-18 2018-05-01 Ampio Pharmaceuticals, Inc. Treatment of joint conditions
US10881710B2 (en) 2011-10-28 2021-01-05 Ampio Pharmaceuticals, Inc. Treatment of rhinitis
US11389512B2 (en) 2015-06-22 2022-07-19 Ampio Pharmaceuticals, Inc. Use of low molecular weight fractions of human serum albumin in treating diseases
WO2023012130A1 (fr) 2021-08-02 2023-02-09 F. Hoffmann-La Roche Ag Nouveaux dérivés de cyclopenta-thiéno-diazépine utilisés en tant que gaba a gamma1 pam

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5856843B2 (ja) 2008-05-27 2016-02-10 アンピオ ファーマシューティカルズ，インコーポレイテッド ジケトピペラジンを用いた医薬組成物
CA2810844C (fr) 2010-09-07 2017-03-21 Dmi Acquisition Corp. Compositions de diketopiperazine destinees au traitement de syndrome metabolique et de troubles associes

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0217204A1 (fr) * 1985-09-13 1987-04-08 Merck & Co. Inc. Trans-2-(3,4,5-trimethoxyphenyl)-5-(5,6-dimethoxy-3-pyridyl)-tétrahydrothiophène, un antagoniste du FAP
EP0222961A1 (fr) * 1985-09-17 1987-05-27 Ciba-Geigy Ag Ethers de résorcinol
EP0299761A1 (fr) * 1987-07-15 1989-01-18 The Wellcome Foundation Limited Dérivés aryliques anti-inflammatoires
EP0194416B1 (fr) * 1985-01-25 1989-04-26 Boehringer Ingelheim Kg Thiéno-triazolo-1,4-diazépino-2-carboxamides, leur procédé de préparation et composition pharmaceutique
EP0351214A1 (fr) * 1988-07-14 1990-01-17 The Wellcome Foundation Limited Dérivés aryliques anti-inflammatoires
FR2653119A1 (fr) * 1989-10-18 1991-04-19 Lipha Nouveaux aryloxy alcoyl benzenes, leurs procedes de preparation et les compositions pharmaceutiques en renfermant.
EP0441515A1 (fr) * 1990-02-07 1991-08-14 Pfizer Inc. Dérivés de tétraline et chromane pour le traitement de l'asthme, de l'arthrite et des maladies similaires
WO1991017163A1 (fr) * 1990-05-09 1991-11-14 Pfizer Inc. IMIDAZO (4,5-c) PYRIDINES PRESENTANT UNE ACTIVITE ANTAGONISTE DU FAP
EP0475204A2 (fr) * 1990-08-30 1992-03-18 Boehringer Ingelheim Kg Amides hétéroazépinoides
WO1992010498A1 (fr) * 1990-12-13 1992-06-25 Smithkline Beecham Corporation Nouveaux medicaments anti-inflammatoires suppresseurs de cytokine

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4757084A (en) * 1984-02-29 1988-07-12 Merck & Co., Inc. 2,5-diaryl tetrahydrothiophenes and analogs thereof as PAF-antagonists
EP0194416B1 (fr) * 1985-01-25 1989-04-26 Boehringer Ingelheim Kg Thiéno-triazolo-1,4-diazépino-2-carboxamides, leur procédé de préparation et composition pharmaceutique
EP0217204A1 (fr) * 1985-09-13 1987-04-08 Merck & Co. Inc. Trans-2-(3,4,5-trimethoxyphenyl)-5-(5,6-dimethoxy-3-pyridyl)-tétrahydrothiophène, un antagoniste du FAP
EP0222961A1 (fr) * 1985-09-17 1987-05-27 Ciba-Geigy Ag Ethers de résorcinol
EP0299761A1 (fr) * 1987-07-15 1989-01-18 The Wellcome Foundation Limited Dérivés aryliques anti-inflammatoires
EP0351214A1 (fr) * 1988-07-14 1990-01-17 The Wellcome Foundation Limited Dérivés aryliques anti-inflammatoires
FR2653119A1 (fr) * 1989-10-18 1991-04-19 Lipha Nouveaux aryloxy alcoyl benzenes, leurs procedes de preparation et les compositions pharmaceutiques en renfermant.
EP0441515A1 (fr) * 1990-02-07 1991-08-14 Pfizer Inc. Dérivés de tétraline et chromane pour le traitement de l'asthme, de l'arthrite et des maladies similaires
WO1991017163A1 (fr) * 1990-05-09 1991-11-14 Pfizer Inc. IMIDAZO (4,5-c) PYRIDINES PRESENTANT UNE ACTIVITE ANTAGONISTE DU FAP
EP0475204A2 (fr) * 1990-08-30 1992-03-18 Boehringer Ingelheim Kg Amides hétéroazépinoides
WO1992010498A1 (fr) * 1990-12-13 1992-06-25 Smithkline Beecham Corporation Nouveaux medicaments anti-inflammatoires suppresseurs de cytokine

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ARZNEIM.-FORSCH./DRUG. RES., vol.39 (II), no.10, 1989 pages 1242 - 1245 C. BONNE ET AL. '2-(2-Hydroxy-4-methylphen yl)aminothiazole Hydrochloride as a Dual Inhibitor of Cyclooxygenase/Lipoxygenase and a Free Radical Scavenger' *
BR. J. PHARMACOL., vol.107, no.4, 1992 pages 1108 - 1115 C.M. HERD ET AL. 'Effect of a 5-lipoxygenase inhibitor and leukotriene antagonist (PF 5901) on PAF-induced airway responses in neonatally immunized rabbits' *
BR. J. PHARMACOL., vol.94, no.4, 1988 pages 1115 - 1122 G. ANDERSON, M. FENNESSY 'Effects of REV 5901, a 5-lipoxygenase inhibitor and leukotriene antagonist, on pulmonary responses to platelet activating factor in the guinea-pig' *
EUR. J. PHARMACOL., vol.142, no.2, 1987 pages 197 - 205 J. CHANG ET AL. 'The antiinflammatory action of guanabenz is mediated through 5-lipoxygenase and cyclooxygenase' *
JAPAN. J. PHARMACOL., vol.38, 1985 pages 267 - 272 T. HIDAKA ET AL. 'Inhibition of Polymorphonuclear Leukocyte 5-Lipoxygenase and Platelet Cyclooxygenase by alpha-(3,5- Di-Tert-Butyl-4-Hydroxybenzylidene)-gamma- Butyrolactone (KME-4), a New Antiinflammatory Drug' *
MED. CHEM. RES., vol.2, no.7-8, 1992 pages 443 - 450 D.M. GOLDSTEIN, T.Y. SHEN 'Dual Inhibitors of Platelet Activating Factor and 5-Lipoxygenase I. 2,4-Diaryl-1,3-dithiolanes' *
MED. CHEM. RES., vol.2, no.7-8, 1992 pages 451 - 456 D.M. GOLDSTEIN, T.Y. SHEN 'Dual Inhibitors of Platelet Activating Factor and 5-Lipoxygenase II. Novel 2,4-Diaryl-1,3-dithiolanes with Iron-chelating Functionalities' *
PHARMACOL. COMM., vol.1, no.4, 1992 pages 329 - 335 R.N. WILLETTE ET AL. 'SK&F 86002, a dual lipoxygenase/cyclooxygenase inhibitor prevents changes in body weight and serum tumor necrosis factor elicited by lipopolysaccharide and platelet activating factor' *

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5639782A (en) * 1992-03-04 1997-06-17 Center For Innovative Technology Neolignan derivatives as platelet activating factor receptor antagonists and 5-lipoxygenase inhibitors
US5856323A (en) * 1992-07-13 1999-01-05 Cytomed, Inc. Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase
US5463083A (en) * 1992-07-13 1995-10-31 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US6294574B1 (en) 1992-07-13 2001-09-25 Cytomed, Inc. Compounds and methods for the treatment of inflammatory and immune disorders
US5741809A (en) * 1992-08-24 1998-04-21 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular inflammatory and immune disorders
EP0624588A1 (fr) * 1993-05-07 1994-11-17 J. URIACH & CIA. S.A. Dérivés de quinoline à activité pharmacologique
WO1995018610A1 (fr) * 1994-01-06 1995-07-13 Cytomed, Inc. Composes et methodes de traitement de troubles a caractere cardio-vasculaire, inflammatoire et immunitaire
US6420392B1 (en) 1994-01-06 2002-07-16 Millennium Pharmaceuticals, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5681966A (en) * 1994-06-27 1997-10-28 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5792776A (en) * 1994-06-27 1998-08-11 Cytomed, Inc., Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5780503A (en) * 1994-06-27 1998-07-14 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5750565A (en) * 1995-05-25 1998-05-12 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US6569895B1 (en) 1995-05-25 2003-05-27 Millennium Pharmaceuticals, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5703093A (en) * 1995-05-31 1997-12-30 Cytomed, Inc. Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US6555543B2 (en) 2000-08-04 2003-04-29 Dmi Biosciences, Inc. Method of using diketopiperazines and composition containing them
US10039760B2 (en) 2000-08-04 2018-08-07 Ampio Pharmaceuticals, Inc. Method of using diketopiperazines and composition containing them
US9707227B2 (en) 2003-05-15 2017-07-18 Ampio Pharmaceuticals, Inc. Treatment of T-cell mediated diseases
US9730924B2 (en) 2003-05-15 2017-08-15 Ampio Pharmaceuticals, Inc. Treatment of T-cell mediated diseases
US11369598B2 (en) 2003-05-15 2022-06-28 Ampio Pharmaceuticals, Inc. Treatment of T-cell mediated diseases
US10828296B2 (en) 2003-05-15 2020-11-10 Ampio Pharmaceuticals, Inc. Treatment of T-cell mediated diseases
US9623072B2 (en) 2011-10-10 2017-04-18 Ampio Pharmaceuticals, Inc. Treatment of degenerative joint disease
US10842847B2 (en) 2011-10-10 2020-11-24 Ampio Pharmaceuticals, Inc. Treatment of degenerative joint disease
US10251930B2 (en) 2011-10-10 2019-04-09 Ampio Pharmaceuticals, Inc. Treatment of degenerative joint disease
US11058798B2 (en) 2011-10-10 2021-07-13 Ampio Pharmaceuticals, Inc. Implantable medical devices with increased immune tolerance, and methods for making and implanting
US10471178B2 (en) 2011-10-10 2019-11-12 Ampio Pharmaceuticals, Inc. Implantable medical devices with increased immune tolerance, and methods for making and implanting
US9925300B2 (en) 2011-10-10 2018-03-27 Ampio Pharmaceuticals, Inc. Implantable medical devices with increased immune tolerance, and methods for making and implanting
US10881710B2 (en) 2011-10-28 2021-01-05 Ampio Pharmaceuticals, Inc. Treatment of rhinitis
US11026940B2 (en) 2013-03-15 2021-06-08 Ampio Pharmaceuticals, Inc. Compositions for the mobilization, homing, expansion and differentiation of stem cells and methods of using the same
US9808454B2 (en) 2013-03-15 2017-11-07 Ampio Pharmaceuticals, Inc. Compositions for the mobilization, homing, expansion and differentiation of stem cells and methods of using the same
US9956217B2 (en) 2014-08-18 2018-05-01 Ampio Pharmaceuticals, Inc. Treatment of joint conditions
US10342793B2 (en) 2014-08-18 2019-07-09 Ampio Pharmaceuticals, Inc. Treatment of joint conditions
US11090301B2 (en) 2014-08-18 2021-08-17 Ampio Pharmaceuticals, Inc. Treatment of joint conditions
US11389512B2 (en) 2015-06-22 2022-07-19 Ampio Pharmaceuticals, Inc. Use of low molecular weight fractions of human serum albumin in treating diseases
WO2023012130A1 (fr) 2021-08-02 2023-02-09 F. Hoffmann-La Roche Ag Nouveaux dérivés de cyclopenta-thiéno-diazépine utilisés en tant que gaba a gamma1 pam

Also Published As

Publication number Publication date
CN1090284A (zh) 1994-08-03
EP0656004A1 (fr) 1995-06-07
MX9305063A (es) 1994-04-29
WO1994004537A3 (fr) 1994-10-27
AU5016793A (en) 1994-03-15

Similar Documents

Publication Publication Date Title
US5856323A (en) Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase
WO1994004537A2 (fr) Agents a double fonctionnalite anti-inflammatoire et d'immunosuppression
US5358938A (en) Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase
US5792776A (en) Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
CA2194064C (fr) Composes et procedes pour le traitement des troubles cardio-vasculaires, inflammatoires et immunitaires
US6420392B1 (en) Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US6025384A (en) Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US5648486A (en) Compounds and methods for the treatment of inflammatory and immune disorders
WO1988009333A1 (fr) Compose a base de thieno(triazolo)diazepine et applications medicales de ce compose
WO1997013766A1 (fr) Derives heteroaromatiques substitues
US5703093A (en) Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
FR2981935A1 (fr) Nouveaux composes di-substitues de la diamino-3,4-cyclobutene-3-dione-1,2 utiles dans le traitement de pathologies mediees par des chimiokines.
US6294574B1 (en) Compounds and methods for the treatment of inflammatory and immune disorders
DE4107521A1 (de) Neue acylaminosubstituierte hetrazepine
FR2981936A1 (fr) Nouveaux composes di-substitues de la diamino-3,4-cyclobutene-3-dione-1,2 utiles dans le traitement de pathologies mediees par des chimiokines.
US5011847A (en) 2,5-diaryl tetrahydrofurans and analogs thereof as PAF antagonists
US5565463A (en) 9-subtituted-8-unsubstituted-9-deazaguanines
WO1994006790A1 (fr) 2,4-diaryl-1,3-dithiolanes; 2,4-diaryl-1,3-dioxolanes; 2,4-diaryl-1,3-oxathiolanes et 2,5-diaryl-1,3-oxathiolanes utilises en tant qu'inhibiteurs des recepteurs du facteur d'activation plaquettaire
US5530141A (en) 2,4-diaryl-1,3-dithiolanes; 2,4-diaryl-1,3-dioxolanes; 2,4-diaryl-1,3-oxathiolanes; and 2,5-diaryl-1,3-oxathiolanes for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase
EP0475204A2 (fr) Amides hétéroazépinoides
DE60003550T2 (de) Substituierte 3-pyridyl-4-arylpyrrole und deren einsatz in verfahren zur therapeutischen und prophylaktischen behandlung
US6201016B1 (en) Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
JP4446123B2 (ja) 心・血管の、炎症性の、及び免疫性の疾患の治療のための化合物及び方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AU CA FI HU JP KR

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AU CA FI HU JP KR

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

WWE Wipo information: entry into national phase

Ref document number: 1993920131

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1993920131

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1993920131

Country of ref document: EP

NENP Non-entry into the national phase in:

Ref country code: CA