WO2000072799A2 - Methode et compositions permettant de traiter la reponse inflammatoire - Google Patents

Methode et compositions permettant de traiter la reponse inflammatoire Download PDF

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WO2000072799A2
WO2000072799A2 PCT/US2000/014548 US0014548W WO0072799A2 WO 2000072799 A2 WO2000072799 A2 WO 2000072799A2 US 0014548 W US0014548 W US 0014548W WO 0072799 A2 WO0072799 A2 WO 0072799A2
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alkyl
amino
agonist
wrc
formula
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WO2000072799A3 (fr
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Joel M. Linden
Gail W. Sullivan
Ian J. Sarembock
W. Michael Scheld
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The University Of Virginia Patent Foundation
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Priority to AU52941/00A priority Critical patent/AU5294100A/en
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Publication of WO2000072799A3 publication Critical patent/WO2000072799A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to methods and compositions for treating the inflammatory response in mammalian tissue. Discussion of the Background
  • cytokines such as tumor necrosis factor- alpha (TNF ⁇ ) by leukocytes
  • TNF ⁇ tumor necrosis factor- alpha
  • Cytokines stimulate neutrophils to enhance oxidative (e.g., superoxide and secondary products) and nonoxidative (e.g., myeloperoxidase and other enzymes) inflammatory activity.
  • Oxidative e.g., superoxide and secondary products
  • nonoxidative e.g., myeloperoxidase and other enzymes
  • Inappropriate and over-release of cytokines can produce counterproductive exaggerated pathogenic effects through the release of tissue-damaging oxidative and nonoxidative products (Tracey, K. G. et al., J. Exp. Med.. 167, 1211-1227 (1988); and Mannel, D. N. et al., Rev. Infect. Dis. ; 9_ (suppl 5), S602-S606 (1987)).
  • inflammatory cytokines have been shown to be pathogenic in: arthritis (Dinarello, C. A., Semin. Immunol., 4, 133-45 (1992)); ischemia (Seekamp, A. et al., Agents-Actions-Supp.. 41, 137-52 (1993)); septic shock (Mannel, D. N. et al, Rev. Tnfect. Dis. : _ (suppl 5), S602-S606 (1987)); asthma (Cembrzynska Nowak M. et al, Am. Rev. Respir. Dis. r 147. 291-5 (1993)); organ transplant rejection (Imagawa, D. K. et al., Transplantation, 51.
  • adenosine has been shown to inhibit superoxide release from neutrophils stimulated by chemoattractants such as the synthetic mimic of bacterial peptides, f-met-leu-phe (fMLP), and the complement component C 5 a (Cronstein, B. N. et al., J. Trnmunol .. 125, 1366-1371 (1985)).
  • Adenosine can decrease the greatly enhanced oxidative burst of PMNs (neutrophils) first primed with TNF ⁇ (an inflammatory cytokine) and then exposed to a second stimulus such as f-met-leu-phe (Sullivan, G. W. et al., Clin. Res. r 41, 172A (1993)).
  • TNF ⁇ an inflammatory cytokine
  • f-met-leu-phe f-met-leu-phe
  • adenosine can decrease the rate of HIV replication in a T-cell line (Sipka, S. et al., Acta. Biochim. Biopys. Hung. : 23_, 75-82 (1988)).
  • adenosine itself or 5 '-carboxamides of adenosine, such as 5 '-N-ethylcarboxamidoadenosine (NECA)
  • NECA 5 '-N-ethylcarboxamidoadenosine
  • 2-alkylamino substituents increased potency and selectivity, e.g., CV1808 and CGS21680 (Jarvis, M. F. et al, J. Pharmacol, Exp. Ther., 251, 888-893 (1989)).
  • 2-Alkoxy-substituted adenosine derivatives such as WRC-0090 are even more potent and selective as agonists on the coronary artery A 2A receptor (Ukena, M. et al., J. Med. Chem.. 34, 1334-1339 (1991)).
  • the 2- alkylhydrazino adenosine derivatives e.g., SHA 211 (also called WRC-0474) have also been evaluated as agonists at the coronary artery A 2A receptor (Niiya, K. et al, J. Med. Chem., 35, 4557-4561 (1992)).
  • R-PIA and Cl-Ado analogs are actually more potent activators of A, adenosine receptors than of A 2A adenosine receptors and, thus, are likely to cause side effects due to activation of A, receptors on cardiac muscle and other tissues causing effects such as "heart block".
  • Linden et al. (U.S. Pat. No. 5,877,180) is based on the discovery that inflammatory diseases may be effectively treated by the administration of drugs which are selective agonists of A 2A adenosine receptors, preferably in combination with a phosphodiesterase inhibitor.
  • An embodiment of the Linden et al. invention provides a method for treating inflammatory diseases by administering an effective amount of an A 2A adenosine receptor of the following formula:
  • R 4 is a group having the formula:
  • each of R 5 and R 6 independently may be hydrogen, C 3 _ 7 -cycloalkyl, or any of the meanings of R 1 , provided that R 5 and R 6 are not both hydrogen;
  • the Linden et al. invention involves the administration of a Type IV phosphodiesterase (PDE) inhibitor in combination with the A 2A adenosine receptor agonist.
  • PDE Type IV phosphodiesterase
  • the Type IV phosphodiesterase (PDE) inhibitor can be racemic and optically active 4-(polyalkoxyphenyl)-2- pyrrolidones of the following formula:
  • R 18 and R 19 each are alike or different and are hydrocarbon radicals having up to 18 carbon atoms with at least one being other than methyl, a heterocyclic ring, or alkyl of 1-5 carbon atoms which is substituted by one or more of halogen atoms, hydroxy, carboxy, alkoxy, alkoxycarbonyl or an amino group; amino; R' is a hydrogen atom, alkyl, aryl or acyl; and X is an oxygen atom or a sulfur atom.
  • Rolipram is an example of a suitable Type IV phosphodiesterase or PDE inhibitor included within the above formula.
  • Rolipram has the following structure:
  • the present invention provides a method to protect mammalian tissue from the effects of the inflammatory response.
  • This treatment is achieved by the administration of certain agonists of A 2A adenosine receptors, preferably in combination with rolipram or rolipram derivatives that are Type IV phosphodiesterase or PDE inhibitors.
  • one object of the present invention is to provide a novel and improved method for treating the inflammatory response to pathological agents and conditions, such as trauma.
  • compositions and methods for effectively treating inflammatory conditions by administration of an agonist of an A 2A adenosine receptor optionally, in combination with rolipram or a rolipram derivative that is a Type IV phosphodiesterase (PDE) inhibitor.
  • PDE Type IV phosphodiesterase
  • Figure 1 illustrates the relative potencies of adenosine analogs to modulate TNF ⁇ -primed fMLP-stimulated polymorphonuclear cell (PMN) chemiluminescence as a measure of PMN production of oxidative products (0, no TNF ⁇ ; ⁇ , WRC-0474[SHA 211] + TNF ⁇ ; D, GCS 21680 + TNF ⁇ ; and A, adenosine + TNF ⁇ );
  • Figure 2 illustrates the synergistic effect of WRC-0474[SHA 211 ] and 4-
  • Figure 3 illustrates the synergistic effect of WRC-0474[SHA 211] and rolipram in inhibiting TNF ⁇ -stimulated adherent PMN superoxide release
  • Figure 4 illustrates the effect of WRC-0474[SHA 211] and rolipram on TNF ⁇ -stimulated PMN adherence to a fibrinogen coated surface
  • Figure 5 illustrates synergy between A 2A adenosine receptor agonists and Rolipram in inhibition superoxide release from TNF ⁇ -stimulated adherent human neutrophils
  • Figure 6 illustrates the effects of WRC-0470 and rolipram on the oxidative activity of neutrophils in whole blood
  • Figure 7 illustrates the effects of WRC-0470 and rolipram on the release of TNF ⁇ from adherent human monocytes and that this activity is dependent on binding of the adenosine agonist to A 2A adenosine receptors.
  • Figure 8 illustrates the effect of WRC-0470 on white blood cell pleocytosis in rats.
  • Figure 9 illustrates the effect of WRC-0470 on blood-brain-barrier permeability in rats
  • Figure 10 illustrates the effect of rolipram on white blood cell pleocytosis in rats
  • Figure 11 illustrates the combined effect of WRC-0470 and rolipram on white blood cell pleocytosis in rats.
  • the present invention provides a method comprising treating the inflammatory response in a mammal in need of such treatment by administering an effective amount of a compound of formula (I):
  • aryl groups wherein the aryl groups may be substituted with one or more halogens (fluorine, chlorine, or bromine), C M -alkyl groups, hydroxy groups, amino groups, mono(C ].4 -alkyl)amino groups, or di(C, .4 -alkyl)amino groups); (c) C 6 ., 0 - aryl; or (d) C 6 _ 10 -aryl substituted with one or more halogens (fluorine, chlorine, or bromine), hydroxy groups, amino groups, mono(C -alkyl)amino groups, di(C -alkyl)amino groups, or C -alkyl groups; one of R 2 and R 3 has the same meaning as R 1 and the other is hydrogen; or
  • R 4 is a group having the formula (II)
  • each of R 5 and R 6 independently may be hydrogen, C 3.7 -cycloalkyl, or any of the meanings of R 1 , provided that R 5 and R 6 are not both hydrogen;
  • Z has one of the following meanings: a) C 6 -C 10 aryl, optionally substituted with one to three halogen atoms, C r C 6 alkyl, C r C 6 haloalkyl, C,-C 6 alkoxy, C j -C 6 haloalkoxy, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkoxyalkyl, C,-C 6 alkylthio, thio, CHO, cyanomethyl, nitro, cyano, hydroxy, carboxy, C 2 -C 6 acyl, amino C r C 3 monoalkylamino, C 2 -C 6 dialkylamino, methylenedioxy or aminocarbonyl; b) a group of formula -(CH 2 ) m -Het wherein m is 0 or an integer from 1 to 3 and Het is 5 or 6 membered heterocyclic aromatic or non-aromatic ring, optionally benzocondensed
  • R 10 is hydrogen, methyl or phenyl
  • R 12 is hydrogen, C r C 6 linear or branched alkyl, C 5 -C 6 cycloalkyl or C 3 -C 7 cycloalkenyl, phenyl- - -alkyl or R 10 and R 12 , taken together, form a 5 or 6- membered carbocychc ring or R 3 is hydrogen and R 2 and R 4 , taken together, form an oxo group or a corresponding acetalic derivative; R 11 is OH, NH 2 dialkylamino, halogen, cyano; n is 0 or 1 to 4; or e) C,-C 16 alkyl, optionally comprising 1-2 double bonds, O, S or NY; or a pharmaceutically acceptable salt thereof.
  • Suitable C 6.10 -aryl groups include phenyl and naphthyl.
  • X is a group of the formula (III)
  • X is a group of the formula (V) -C ⁇ C-Z wherein Z is C 3 -C 16 alkyl, hydroxy C 2 -C 6 alkyl or (phenyl) (hydroxymethyl).
  • H on CH 2 OH can optionally be replaced by ethylaminocarbonyl.
  • WRC-0474[SHA 211] and WRC-0470 are particularly preferred.
  • Such compounds may be synthesized as described in: Olsson et al. (U.S. Pat. Nos. 5,140,015 and 5,278,150); Cristalli (U.S. Pat. No. 5,593,975);
  • Miyasaka et al. U.S. Pat. No. 4,956,357; Hutchinson, A. J. et al., J. Pharmacol.
  • the present method also includes the administration of a Type IV phosphodiesterase (PDE) inhibitor in combination with the compound of formula (I).
  • PDE Type IV phosphodiesterase
  • Examples of Type IV phosphodiesterase (PDE) inhibitors include those disclosed in U.S. Patent No. 4,193,926, and WO 92-079778, and Molnar-
  • PDE Type IV phosphodiesterase
  • R 18 and R 19 each are alike or different and are hydrocarbon radicals having up to 18 carbon atoms with at least one being other than methyl, a heterocyclic ring, or alkyl of 1 -5 carbon atoms which is substituted by one or more of halogen atoms, hydroxy, carboxy, alkoxy, alkoxycarbonyl or an amino group or amino.
  • hydrocarbon R 18 and R 19 groups are saturated and unsaturated, straight-chain and branched alkyl of 1-18, preferably 1-5, carbon atoms, cycloalkyl and cycloalkylalkyl, preferably 3-7 carbon atoms, and aryl and aralkyl, preferably of 6-10 carbon atoms, especially monocyclic.
  • alkyl examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 2-methylbutyl, 2,2-dimethylpropyl, hexyl, heptyl, octyl, nonyl, 1,2-dimethylheptyl, decyl, undecyl, dodecyl and stearyl, with the proviso that when one of R 18 and R 19 is methyl, the other is a value other than methyl.
  • unsaturated alkyl groups are alkenyl and alkynyl, e.g., vinyl, 1- propenyl, 2-propenyl, 2-propynyl and 3-methyl-2-propenyl.
  • cycloalkyl and cycloalkylalkyl which preferably contain a total of 3-7 carbon atoms are cyclopropyl, cyclopropylmethyl, cyclopentyl and cyclohexyl.
  • aryl and aralkyl are phenyl and benzyl, which are preferred, and tolyl, xylyl, naphthyl, phenethyl and 3-phenylpropyl.
  • heterocyclic R 18 and R 19 groups are those wherein the heterocyclic ring is saturated with 5 or 6 ring members and has a single O, S or N atom as the hetero atom, e.g., 2- and 3-tetrahydrofuryl, 2- and 3- tetrahydropyranyl, 2- and 3-tetrahydrofhiophenyl, pyrrolidino, 2- and 3- pyrrolidyl, piperidino, 2-, 3- and 4-piperidyl, and the corres onding N-alkyl- pyrrolidyl and piperidyl wherein alkyl is of 1-4 carbon atoms.
  • heterocyclic rings having fewer or more, e.g., 4 and 7, ring members, and one or more additional hetero atoms as ring members, e.g., morpholino, piperazino and N-alkylpiperazino.
  • substituted alkyl R 18 and R 19 groups preferably of 1-5 carbon atoms, are those mono- or polysubstituted, for example, by halogen, especially fluorine, chlorine and bromine.
  • halogen- substituted alkyl examples include 2-chloroethyl, 3-chloropropyl, 4-bromobutyl, difluoromethyl, trifluoromethyl, l,l,2-trifluoro-2-chloroethyl, 3,3,3- trifluoropropyl, 2,2,3,3,3-pentafluoropropyl and l,l,l,3,3,3-hexafluoro-2-propyl.
  • alkyl groups examples include hydroxy groups, e.g., 2-hydroxyethyl or 3-hydroxypropyl; carboxy groups, e.g., carboxymefhyl or carboxyethyl; alkoxy groups, wherein each alkoxy group contains 1-5 carbon atoms, e.g., ethoxymefhyl, isopropoxymethyl, 2- methoxyethyl, 2-isopropoxyethyl, 2-butyoxyethyl, 2-isobutyoxyethyl, and 3- pentoxypropyl.
  • hydroxy groups e.g., 2-hydroxyethyl or 3-hydroxypropyl
  • carboxy groups e.g., carboxymefhyl or carboxyethyl
  • alkoxy groups wherein each alkoxy group contains 1-5 carbon atoms, e.g., ethoxymefhyl, isopropoxymethyl, 2- methoxyethyl, 2-isopropoxyethyl,
  • alkoxycarbonyl of 1-5 carbon atoms in the alkoxy group are alkoxycarbonyl substituted alkyl-groups.
  • alkoxycarbonyl substituted alkyl-groups are ethoxycarbonylmethyl and 2-butoxycarbonylethyl.
  • Alkyl groups of 1-5 carbon atoms can also be substituted, e.g., in the ⁇ , T and preferably terminal position with amino groups wherein the nitrogen atom optionally is mono- or disubstituted by alkyl, preferably of 1-5 carbon atoms, or is part of a 4- to 7- membered ring.
  • Rolipram and its analogues are specific examples of preferred Type IV phosphodiesterase inhibitors.
  • inflammatory responses that can be treated (including inhibited, blocked or treated prophylactically) with a compound of formula (I), optionally with a Type IV PDE inhibitor, are inflammation due to
  • autoimmune stimulation autoimmune diseases
  • autoimmune diseases such as lupus erythematosus, multiple sclerosis, infertility from endometriosis, gout, type I diabetes mellitus including the destruction of pancreatic islets leading to diabetes and the inflammatory consequences of diabetes, including leg ulcers, Crohn's disease, ulcerative colitis, inflammatory bowel disease, osteoporosis and rheumatoid arthritis;
  • allergic diseases such as asthma, hay fever, rhinitis, vernal conjunctivitis and other eosinophil-mediated conditions
  • skin diseases such as psoriasis, contact dermatitis, eczema, infectious skin ulcers, open wounds, cellulitis
  • infectious diseases including sepsis, septic shock, encephalitis, infectious arthritis, endotoxic shock, gram negative shock, Jarisch-Herxheimer reaction, shingles, toxic shock, cerebral malaria, bacterial meningitis, acute respiratory distress syndrome (ARDS), lyme disease, HIV infection, (TNF ⁇ - enhanced HIV replication, TNF ⁇ inhibition of reverse transcriptase inhibitor activity);
  • wasting diseases cachexia secondary to cancer and HIV
  • organ, tissue or cell transplantation e.g., bone marrow, cornea, kidney, lung, liver, heart, skin, pancreatic islets
  • transplant rejection graft versus host disease
  • adverse effects from drug therapy including adverse effects from amphotericin B treatment, adverse effects from immunosuppressive therapy, e.g., interleukin-2 treatment, adverse effects from OKT3 treatment, adverse effects from GM-CSF treatment, adverse effects of cyclosporine treatment, and adverse effects of aminoglycoside treatment, stomatitis and mucositis due to immunosuppression;
  • cardiovascular conditions including circulatory diseases induced or exacerbated by an inflammatory response, such as ischemia, atherosclerosis, peripheral vascular disease, restenosis following angioplasty, inflammatory aortic aneurysm, vasculitis, stroke, spinal cord injury, congestive heart failure, hemorrhagic shock, ischemia/reperfusion injury, vasospasm following subarachnoid hemorrhage, vasospasm following cerebrovascular accident, pleuritis, pericarditis, and the cardiovascular complications of diabetes; and (i) dialysis, including pericardit
  • inflammatory responses due to organ, tissue or cell transplantation i.e., the transplantation of allogeneic or xenogeneic tissue into a mammalian recipient, inflammation due to autoimmune diseases and inflammatory responses due to circulatory pathologies such as ischemia, and the treatment thereof, including angioplasty, stent placement, shunt placement or grafting.
  • the invention also includes a method for binding a compound of formula (I) to designated A 2A adenosine receptor sites comprising said receptors, in vivo or in vitro, with an amount of a compound of formula (I) effective to bind to said receptors.
  • Tissue or cells comprising ligand bound receptor sites can be used to measure the selectivity of test compounds for specific receptor subtypes, or can be used as a tool to identify potential therapeutic agents for the treatment of diseases or conditions associated with receptor site activation, by contacting said agents with said ligand-receptor complexes, and measuring the extent of displacement of the ligand and/or binding of the agent.
  • the exact dosage of the compound of formula (I) to be administered will, of course, depend on the size and condition of the patient being treated, the exact condition being treated, and the identity of the particular compound of formula (I) being administered.
  • a suitable dosage of the compound of formula (I) is 0.5 to 100 ⁇ g/kg of body weight, preferably 1 to 10 ⁇ g/kg of body weight.
  • the compound of formula (I) will be administered from 1 to 8, preferably 1 to 4, times per day.
  • the preferred mode of administration of the compound of formula (I) may also depend on the exact condition being treated. However, most typically, the mode of administration will be oral, topical, intravenous, parenteral, subcutaneous, or intramuscular injection. Of course, it is to be understood that the compound of formula (I) may be administered in the form of a pharmaceutically acceptable salt. Examples of such salts include acid addition salts.
  • Preferred pharmaceutically acceptable addition salts include salts of mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid, and the like; salts of monobasic carboxylic acids, such as, for example, acetic acid, propionic acid, and the like; salts of dibasic carboxylic acids, such as maleic acid, fumaric acid, oxalic acid, and the like; and the salts of tribasic carboxylic acids, such as, carboxysuccinic acid, citric acid, and the like.
  • mineral acids for example, hydrochloric acid, sulfuric acid, nitric acid, and the like
  • salts of monobasic carboxylic acids such as, for example, acetic acid, propionic acid, and the like
  • salts of dibasic carboxylic acids such as maleic acid, fumaric acid, oxalic acid, and the like
  • tribasic carboxylic acids such as, carboxysuccinic acid, citric acid, and the like.
  • the salt may be derived by replacing the acidic proton of the -CO 2 H group with a cation such as Na + , K + , NH + 4 mono-, di-, tri-, or tetra(C j _ 4 -alkyl)ammonium, or mono-, di-, tri-, or tetra(C 2.4 alkanol) ammonium.
  • a cation such as Na + , K + , NH + 4 mono-, di-, tri-, or tetra(C j _ 4 -alkyl)ammonium, or mono-, di-, tri-, or tetra(C 2.4 alkanol) ammonium.
  • Preferred pharmaceutically acceptable addition salts include salts of mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid, and the like; salts of monobasic carboxylic acids, such as, for example, acetic acid, propionic acid, and the like; salts of dibasic carboxylic acids, such as maleic acid, fumaric acid, oxalic acid, and the like; and salts of tribasic carboxylic acids, such as, carboxysuccinic acid, citric acid, and the like.
  • mineral acids for example, hydrochloric acid, sulfuric acid, nitric acid, and the like
  • salts of monobasic carboxylic acids such as, for example, acetic acid, propionic acid, and the like
  • salts of dibasic carboxylic acids such as maleic acid, fumaric acid, oxalic acid, and the like
  • salts of tribasic carboxylic acids such as, carboxysuccinic acid, citric acid, and the like.
  • the compounds of formula (I) can be administered orally, for example, with an inert diluent with an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets.
  • the compounds can be incorporated with excipients and used in the form of tablets, troches, capsules, elixers, suspensions, syrups, waters, chewing gums, and the like.
  • These preparations should contain at least 0.5% by weight of the compound of formula (I), but the amount can be varied depending upon the particular form and can conveniently be between 4.0% to about 70% by weight of the unit dosage.
  • the amount of the compound of formula (I) in such compositions is such that a suitable dosage will be obtained.
  • Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between about 30 ⁇ g and about 5 mg, preferably between 50 to 500 ⁇ g, of active compound.
  • Tablets, pills, capsules, troches, and the like can contain the following ingredients: a binder, such as microcrystalline cellulose, gu ⁇ ; ⁇ tragacanth or gelatin; an excipient, such as starch or lactose; a disintegrating agent, such as alginic acid, Primogel, corn starch, and the like; a lubricant, such as magnesium stearate or Sterotes; a glidant, such as colloidal silicon dioxide; a sweetening agent, such as sucrose, saccharin or aspartame; or flavoring agent, such as peppermint, methyl salicylate, or orange flavoring.
  • a liquid carrier such as a fatty oil.
  • dosage unit forms can contain other materials that modify the physical form of the dosage unit, for example, as coatings.
  • tablets or pills can be coated with sugar, shellac, or other enteric coating agents.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and preservatives, dyes, colorings, and flavors. Materials used in preparing these compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • the compounds of formula (I) can be incorporated into a solution or suspension. These preparations should contain at least 0.1 % of the aforesaid compound, but may be varied between 0.5% and about 50% of the weight thereof. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 30 ⁇ g to 5 mg, preferably between 50 to 500 ⁇ g, of the compound of formula (I).
  • Solutions or suspensions of the compounds of formula (I) can also 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.
  • 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
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Effective amounts of the Type IV phosphodiesterase inhibitor can be administered to a subject by any one of various methods, for example, orally as in a capsule or tablets, topically, or parenterally in the form of sterile solutions.
  • the Type IV phosphodiesterase inhibitors while effective themselves, can be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility, and the like.
  • the Type IV phosphodiesterase may be administered in the form of a pharmaceutical composition similar to those described above in the context of the compound of formula (I). While dosage values will vary with the specific disease condition to be alleviated, good results are achieved when the Type IV phosphodiesterase inhibitor is administered to a subject requiring such treatment as an effective oral, parenteral or intravenous dose as described below.
  • the amount of active agent per oral dosage unit usually is 0.1-20 mg, preferably 0.5-10 mg.
  • the daily dosage is usually 0.1- 50 mg, preferably 1-30 mg p.o.
  • the amount of active agent per dosage unit is usually 0.005-10 mg, preferably 0.01-5 mg.
  • the daily dosage is usually 0.01-20 mg, preferably 0.02-5 mg i.v. or i.m.
  • dosage levels and their related procedures would be consistent with those known in the art, such as those dosage levels and procedures described in U.S. Patent No. 5,565,462 to Eitan et al., which is incorporated herein by reference. It is to be understood, however, that for any particular subject, specific dosage regimens should be adjusted to the individual need and the professional judgment of the person administering or supervising the administration of the Type IV phosphodiesterase inhibitor. In some cases, the compound of formula (I) will be administered for an extended period of time following the inflammatory insult, even chronically. It is to be further understood that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of the present invention.
  • the compound of formula (I) and the Type IV phosphodiesterase inhibitor are coadministered together in a single dosage unit.
  • the compound of formula (I) and the Type IV phosphodiesterase inhibitor may be administered in the same type of pharmaceutical composition as those described above in the context of the compound of formula (I).
  • the dosage of the A 2A adenosine receptor agonist may be reduced by a factor of 5 to 10 from the dosage used when no Type IV phosphodiesterase inhibitor is administered. This reduces the possibility of side effects.
  • the present studies establish that anti-inflammatory doses have no toxic effects in animals; the effect of WRC-0470 to inhibit neutrophil activation is synergistic with rolipram; and intravenous infusion of WRC-0470 profoundly inhibits extravasation of neutrophils in an animal model of inflammation, an action also synergistic with rolipram. Further, the present studies establish that activation of A 2A receptors on human monocytes strongly inhibits TNF ⁇ (an inflammatory cytokine) release. This mechanism further contributes to the anti- inflammatory action of the A 2A adenosine receptor agonists of the present invention.
  • f-Met-Leu-Phe(fMLP), luminol, and trypan blue were from Sigma Chemical.
  • Ficoll-Hypaque was purchased from Flow Laboratories (McLean, A) and Los Alamos Diagnostics (Los Alamos, NM).
  • Hanks balanced salt solution (HBSS), and limulus amebocyte lysate assay kit were from Whittaker Bioproducts (Walkersville, MD).
  • Human serum albumin (HSA) was from Cutter Biological (Elkhart, IN). Recombinant human tumor necrosis factor-alpha was supplied by Dianippon Pharmaceutical Co. Ltd. (Osaka, Japan).
  • ZM241385 was a gift of Dr. Simon Poucher, Zeneca Pharmaceuticals (Chesire, England).
  • Leukocyte Preparation Purified PMN (-98% PMN and >95% viable by trypan blue exclusion) containing ⁇ 1 platelet per 5 PMN and ⁇ 50 pg/ml endotoxin (limulus amebocyte lysate assay) were obtained from normal heparinized (10 Units/ml) venous blood by a one-step Ficoll-Hypaque separation procedure (Ferrante, A. et al, J. Immunol. Meth., 16, 109 (1980)). Residual RBC were lysed by hypotonic lysis with iced 3 ml 0.22%) sodium chloride solution for 45 seconds followed by 0.88 ml of 3% sodium chloride solution.
  • Luminol-enhanced chemiluminescence a measure of neutrophil oxidative activity, is dependent upon both superoxide production and mobilization of the granule enzyme myeloperoxidase. The light is emitted from unstable high-energy oxygen species generated by activated neutrophils.
  • Purified PMN (5 x lOVml) were incubated in HBSS containing 0.1 % human serum albumin (1 ml) with or without adenosine, adenosine analogs, and TNF ⁇ (1 U/mL) for 30 minutes at 37°C in a shaking water bath.
  • the wells were then filled with 1 ml of HBSS-0.1% human serum albumin containing PMN (1 x 10 6 /ml) with and without rhTNF ⁇ (1 U/ml), adenosine deaminase (ADA) (1 U/ML), WRC- 0474[SHA 211] (10 nM), CGS21680 (30 nM), adenosine (100 nM) and rolipram (100 nM) .
  • the plates were incubated for 90 minutes at 37 ° C in 5 % CO 2 .
  • test compounds WRC- 0474[SHA 211], WRC-0470, WRC-0090 and WRC-0018 were evaluated according to the following method modified from Sullivan, G. W. et al., Int. I. Tmmunopharmacol. 17, 793-803 (1995).
  • Neutrophils (1 x lOVml from Ficoll- Hypaque separation were incubated for 90 minutes in 1 ml of Hanks balanced salt solution containing 0.1% human serum albumin, cytochrome c (120 ⁇ M) and catalase (0.062 mg/ml) in the presence and absence of rhTNF ⁇ (1 U/ml), WRC-0474[SHA 211], WRC-0470, WRC-0090 and WRC-0018 (3-300 nM), and rolipram (100 nM) in a tissue culture well which had been coated overnight with human fibrinogen.
  • Hanks balanced salt solution containing 0.1% human serum albumin, cytochrome c (120 ⁇ M) and catalase (0.062 mg/ml) in the presence and absence of rhTNF ⁇ (1 U/ml), WRC-0474[SHA 211], WRC-0470, WRC-0090 and WRC-0018 (3-300 nM), and rolipram (100 nM
  • SOD superoxide dismutase
  • Figure 5 shows synergy between A2A adenosine agonists and rolipram in inhibiting TNF ⁇ -stimulated adherent PMN oxidative activity (p ⁇ 0.05).
  • WRC- 0474[SHA 211] (30-300 nM), WRC-0470 (300 nM), WRC-0090 (300 nM) and WRC-0018 (300 nM) combined with rolipram synergistically decreased superoxide release (p ⁇ 0.05). All four compounds had some activity in the presence of rolipram.
  • WRC-0474[SHA 211] and WRC-0470 were the most active. Nanomolar concentrations of WRC-0474[SHA 211] resulted in biphasic activity. All compounds were synergistic with rolipram to decrease TNF ⁇ - stimulated adherent PMN oxidative activity.
  • PMN degranulation (adherent cells). The following methods were adapted from Sullivan, G. W. and G. L. Mandell, Tnfect. miimun.. 3-D, 272-280 (1980). Neutrophils (3.1 ⁇ 10 6 /ml) from Ficoll-Hypaque separation were incubate for 120 minutes in 1 ml of Hanks balanced salt solution containing 0.1% human serum albumin, ⁇ rh TNF ⁇ (10 U/ml), ⁇ WRC-0470 (3-300 nM), and ⁇ rolipram (30 nM) in a tissue culture well which had been coated overnight with human fibrinogen.
  • WRC-0470 in addition to decreasing TNF ⁇ -stimulated PMN adherent and the oxidative burst of these adherent neutrophils, WRC-0470 also decreases degranulation activated PMN adhering to a biological surface. PMN oxidative activity in whole blood. The following methods were adapted from Rothe, G. A. et al, I. Trnmunol. Mefh.. US, 133-135 (1991).
  • Heparinized whole blood (0.8 ml) was incubated (37°; 30 min) with adenosine deaminase (ADA, 1 U/ml), catalase (14,000 U/ml), ⁇ dihydrorhodamine 123, ⁇ WRC-0470 (3-300 nM), ⁇ rolipram (300 nM) and ⁇ TNF ⁇ (10 U/ml).
  • the primed blood samples were stimulated with fMLP (15 min), then iced, the red blood cells lysed with FACS lysing solution (Becton-Dickinson, San Jose, CA), washed and the leukocytes resuspended in phosphate-buffered saline (PBS).
  • PBS phosphate-buffered saline
  • WRC-0470 decreased oxidative activity of TNF ⁇ -primed fMLP-stimulated neutrophils in whole blood and acted synergistically with rolipram.
  • WRC-0470 (30-300 nM) decreased neutrophil oxidative activity synergistically with rolipram (300 nM) in samples stimulated with fMLP and in blood samples primed with TNF ⁇ and then stimulated with fMLP.
  • a monocyte rich monolayer (> 95% monocytes) was prepared by incubating 1 ml of the mononuclear leukocyte fraction (5 x lOVml) from a Ficoll-Hypaque separation in wells of a 24 well tissue culture plate (1 hr; 37°C; 5%> CO 2 ).
  • the non-adherent leukocytes were removed by washing and culture medium added to the wells (1 ml RPMI 1640 containing 1.5 mM HEPES-1%> autologous serum with penicillin and streptomycin (250 U/ml and 250 ⁇ g/ml, respectively) and ADA (1 U/ml) ⁇ WRC-0470 (30-100 nM), ⁇ endotoxin (10 ng/ml), ⁇ rolipram (300 nM) and ⁇ the adenosine A 2A selective antagonist 4-(2-[7-amino-2-(2- furyl)[l,2,4]-triazolo[2,3a]-[l,3,5]trazinyl-amino]ethyl)-phcuol (ZM241385) (50 nM).
  • TNF ⁇ was assayed in the cell-free supernatants by an ELISA kit (Cistron Biotechnology, Pine Brook, NJ). As shown in Figures 7A and 7B, WRC-0470 ⁇ rolipram decreased endotoxin-stimulated adherent monocyte production of TNF ⁇ (P ⁇ 0.050).
  • WRC-0470 affects TNF ⁇ -stimulated neutrophil activity and decreases endotoxin-stimulated TNF ⁇ production by monocytes.
  • % BBBP blood-brain barrier permeability
  • WBC white blood cell
  • Figure 10 shows the effect of rolipram on CSF pleocytosis in a range of 0-0.01 ⁇ g/kg/hr with 0.01 ⁇ g/kg/hr inhibiting 99% of the pleocytosis (p ⁇ 0.05).
  • Rolipram at either 0.01 or 0.005 ⁇ g/kg/hr showed significant inhibition of alterations of BBBP (p ⁇ 0.05), while a dose of 0.002 ⁇ g/kg/hr had no significant effect.
  • Balloon angioplasty is commonly used to treat coronary artery stenosis. Restenosis following balloon angioplasty (BA) occurs in up to 40%> of coronary interventions. Holmes et al., American Journal of Cardiology, 51, 77C-81C (1984). (40%).
  • Restenosis results from a complex interaction of biologic processes, including (i) formation of platelet-rich thrombus; (ii) release of vasoactive and mitogenic factors causing migration and proliferation of smooth muscle cells (SMC); (iii) macrophage and other inflammatory cell accumulation and foam cell (FC) formation; (iv) production of extracellular matrix; and (v) geometric remodeling.
  • SMC smooth muscle cells
  • FC macrophage and other inflammatory cell accumulation and foam cell

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Abstract

Des agonistes de récepteurs d'adénosine A2A, éventuellement combinés à un inhibiteur de phosphodiestérase (PDE) de type IV, sont efficaces pour le traitement de la réponse inflammatoire de tissus de mammaliens.
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GB2372742A (en) * 2001-03-03 2002-09-04 Univ Leiden C2,5'-Disubstituted and N6,C2,5'-trisubstituted adenosine derivatives and their different uses
WO2002094273A2 (fr) * 2001-05-25 2002-11-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Combinaison d'agoniste vis-a-vis du recepteur de l'adenosine a2a-et de tiotropium ou de derive de cette substance, pour le traitement de l'obstruction des voies respiratoires
WO2003086408A1 (fr) * 2002-04-10 2003-10-23 University Of Virginia Patent Foundation Utilisation d'agonistes du recepteur d'adenosine a2a dans le traitement de maladies inflammatoires
WO2005111053A2 (fr) * 2004-05-17 2005-11-24 Can-Fite Biopharma Ltd. Compositions pharmaceutiques présentant une activité anti-inflammatoire
WO2006048884A1 (fr) * 2004-11-08 2006-05-11 Can-Fite Biopharma Ltd. Traitement therapeutique de resorption osseuse acceleree
US7112574B2 (en) * 2001-03-03 2006-09-26 Universiteit Leiden C2,8-disubstituted adenosine derivatives and their different uses
US7214665B2 (en) 2001-10-01 2007-05-08 University Of Virginia Patent Foundation 2-propynyl adenosine analogs having A2A agonist activity and compositions thereof
US7378400B2 (en) 1999-02-01 2008-05-27 University Of Virginia Patent Foundation Method to reduce an inflammatory response from arthritis
US7442687B2 (en) 2004-08-02 2008-10-28 The University Of Virginia Patent Foundation 2-polycyclic propynyl adenosine analogs having A2A agonist activity
US7576069B2 (en) 2004-08-02 2009-08-18 University Of Virginia Patent Foundation 2-polycyclic propynyl adenosine analogs having A2A agonist activity
US7605143B2 (en) 2004-08-02 2009-10-20 University Of Virginia Patent Foundation 2-propynyl adenosine analogs with modified 5′-ribose groups having A2A agonist activity
EP2274007A2 (fr) * 2008-03-10 2011-01-19 Cornell University Modulation de la perméabilité d'une barrière hématoencéphalique
US9415016B2 (en) 2008-04-03 2016-08-16 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
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US9499546B2 (en) 2004-11-05 2016-11-22 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines
US9505796B2 (en) 2006-03-21 2016-11-29 Crozet Medical Gmbh Phosphorylated A2A receptor agonists
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US9526730B2 (en) 2012-05-14 2016-12-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
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US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
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US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
US11033552B2 (en) 2006-05-04 2021-06-15 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US11911387B2 (en) 2010-11-15 2024-02-27 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
US11911388B2 (en) 2008-10-16 2024-02-27 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug

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US7084127B2 (en) 2001-03-03 2006-08-01 Universiteit Leiden C2,5′-disubstituted and N6, C2,5′-trisubstituted adenosine derivatives and their different uses
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US7189706B2 (en) 2001-03-03 2007-03-13 Universiteit Leiden C2,5′-disubstituted and N6,C2,5′-trisubstituted adenosine derivatives and pharmaceutical compositions containing them
US7112574B2 (en) * 2001-03-03 2006-09-26 Universiteit Leiden C2,8-disubstituted adenosine derivatives and their different uses
WO2002094273A2 (fr) * 2001-05-25 2002-11-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Combinaison d'agoniste vis-a-vis du recepteur de l'adenosine a2a-et de tiotropium ou de derive de cette substance, pour le traitement de l'obstruction des voies respiratoires
WO2002094273A3 (fr) * 2001-05-25 2003-12-11 Boehringer Ingelheim Pharma Combinaison d'agoniste vis-a-vis du recepteur de l'adenosine a2a-et de tiotropium ou de derive de cette substance, pour le traitement de l'obstruction des voies respiratoires
US7214665B2 (en) 2001-10-01 2007-05-08 University Of Virginia Patent Foundation 2-propynyl adenosine analogs having A2A agonist activity and compositions thereof
WO2003086408A1 (fr) * 2002-04-10 2003-10-23 University Of Virginia Patent Foundation Utilisation d'agonistes du recepteur d'adenosine a2a dans le traitement de maladies inflammatoires
US9556175B2 (en) 2002-08-21 2017-01-31 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and thier use as pharmaceutical compositions
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WO2005111053A3 (fr) * 2004-05-17 2006-02-09 Can Fite Biopharma Ltd Compositions pharmaceutiques présentant une activité anti-inflammatoire
WO2005111053A2 (fr) * 2004-05-17 2005-11-24 Can-Fite Biopharma Ltd. Compositions pharmaceutiques présentant une activité anti-inflammatoire
US7605143B2 (en) 2004-08-02 2009-10-20 University Of Virginia Patent Foundation 2-propynyl adenosine analogs with modified 5′-ribose groups having A2A agonist activity
US7576069B2 (en) 2004-08-02 2009-08-18 University Of Virginia Patent Foundation 2-polycyclic propynyl adenosine analogs having A2A agonist activity
US7442687B2 (en) 2004-08-02 2008-10-28 The University Of Virginia Patent Foundation 2-polycyclic propynyl adenosine analogs having A2A agonist activity
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WO2006048884A1 (fr) * 2004-11-08 2006-05-11 Can-Fite Biopharma Ltd. Traitement therapeutique de resorption osseuse acceleree
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