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EP1091960A1 - Antagonistes bifonctionnels des cascades d'activation des kinases sensibles aux cytokines et technique permettant de les utiliser comme anti-inflammatoires - Google Patents

Antagonistes bifonctionnels des cascades d'activation des kinases sensibles aux cytokines et technique permettant de les utiliser comme anti-inflammatoires

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Publication number
EP1091960A1
EP1091960A1 EP99931893A EP99931893A EP1091960A1 EP 1091960 A1 EP1091960 A1 EP 1091960A1 EP 99931893 A EP99931893 A EP 99931893A EP 99931893 A EP99931893 A EP 99931893A EP 1091960 A1 EP1091960 A1 EP 1091960A1
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EP
European Patent Office
Prior art keywords
carbon atoms
alkyl
compound
constituent
compound according
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP99931893A
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German (de)
English (en)
Inventor
Dennis A. Carson
Howard B. Cottom
Qi Chao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of California
University of California Berkeley
University of California San Diego UCSD
Original Assignee
University of California
University of California Berkeley
University of California San Diego UCSD
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Application filed by University of California, University of California Berkeley, University of California San Diego UCSD filed Critical University of California
Publication of EP1091960A1 publication Critical patent/EP1091960A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
    • 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

  • the invention relates to antagonists of cytokine-sensitive, mitogen- activated protein kinase activation and their use as anti-inflammatory agents.
  • MAPK mitogen activated protein kinase
  • PICs proinflammatory cytokines
  • other stress factors such as ultraviolet light, ionizing radiation, tissue trauma, cytotoxic agents (e.g., anisomycin and arsentine), heat shock and ceramide.
  • JNK c-Jun N-terminal protein kinase
  • SAPK stress-activated protein kinase
  • CSBP protein kinase suppressive anti-inflammatory drug binding protein
  • Activation of JNK and p38 is related to the onset and maintainence of acute and chronic inflammatory conditions such as localized fibrosis, cystic fibrosis, ultraviolet light induced cutaneous immune suppression, cell senescence and apoptosis, gastrointestinal inflammation (e.g., inflammatory bowel disease) and pulmonary inflammation (e.g., chronic bronchitis and asthma).
  • Inhibition of PIC synthesis and/or release by stressed cells can reduce MAPK activation-related inflammation by avoiding initiation of the PIC sensitive MAPK signalling cascades.
  • Different anti-inflammatory agents approach this goal in different ways. For example, pentoxifylline suppresses synthesis of PICs by inhibiting cAMP phosphodiesterase activity.
  • Corticosteroids inhibit transcription of PICs.
  • Cytokine suppressive anti-inflammatory drugs (CS ALDs) are believed to inhibit PIC synthesis by binding a MAPK required for cytokine mRNA translation; these compounds selectively interfere with activation of the p38 signaling cascade. None of the drugs are completely effective in suppressing PIC synthesis or release and many have side- effects that are use-limiting.
  • the invention provides compounds which are bifunctional in that they block PIC initiation of both of the PIC sensitive MAPK activation cascades.
  • the invention combines a novel antagonist of the JNK activation cascade with another PIC inhibitor, most preferably an antagonist of the p38 activation cascade.
  • the components of the resulting "bifunctional activation cascade antagonists" act synergistically to antagonize PIC-sensitive MAPK activation to a greater extent than could be achieved by either compound alone.
  • the bifunctional activation cascade antagonists of the invention inhibit up to 100% of PIC release by stressed cells. In constrast, 70-80% PIC inhibition is the maximum level achievable by known PIC-sensitive MAPK antagonists.
  • bifunctional activation cascade antagonists do not pose the risk of side effects associated with certain anti-inflammatory agents, such as the sleeplessness and anxiety induced by methylxanthine-based cAMP phosphodiesterase inhibitors (e.g., pentoxifylline).
  • the potency of the inventive compounds permits their use at lower dosages than are required by use of their constituents alone.
  • the JNK activation cascade antagonist constituent of the inventive bifunctional activation cascade antagonists consists of heterocyclic molecules with biologically active side chains; specifically, purine, pteridine, thiadiazolopyrimidine, quinalozine and isoquinolone based compounds and water-soluble morpholinoethyl esters thereof. Such compounds and methods for their synthesis are described in detail in commonly owned US Patent Application Serial Nos.08/858,778, 08/367,102 and 08/482,551, the disclosures of which are incorporated herein as though set forth in full.
  • the p38 activation cascade antagonist constituents are any compound which interferes with the initiation or completion of the p38 activation cascade.
  • the p38 activation cascade antagonist is a pyridylimidazole.
  • An especially useful class of pyridylimidazoles for use in the invention are the CSALDs.
  • the JNK and p38 activation cascade antagonist constituents of the bifunctional activation cascade antagonists are preferably conjugated together.
  • the constituents of the bifunctional activation cascade antagonists are conjugated to one another via a bond which is severable in vivo, such as ester, amide or azo linkages.
  • unconjuated JNK and p38 activation cascade antagonist constituents are mixed in a pharmaceutically acceptable carrier.
  • conjugated or unconjugated JNK and p38 constituents of the bifunctional activation cascade antagonists are combined with a delivery vehicle, such as a colloidal dispersion system.
  • the invention further encompasses the following conjugated bifunctional activation cascade antagonists:
  • n is any number of carbon atoms from 1 to 7, O or N;
  • R court if present, is H, an alkyl, a cyclic alkyl, a heterocyclic alkyl, alkenyl, or aralkyl having less than 7 carbon atoms;
  • R 6 and R 7 are H, OH or ORrent in any combination;
  • Z is N or C;
  • X, where Z is C, is H, halogen, N 3 , NO, NH 2 , NHR , , N(R ,)2 or COR , ; and, A is H, halogen, N 3 , NO, NH 2 , NHR plausible N(R ,)2 or COR ,.
  • FIGURE 1 is a bar graph depicting inhibition of cell growth arrest in 3T3 fibroblasts according to the invention after growth arrest was induced through deprivation of the cells of serum.
  • the cells were incubated and grown to 90% confluence in serum. The medium was then removed and replaced with serum- free medium.
  • an inventive compound no. 37, a pteridine
  • Concentrations of compound no. 37 are indicated by the insert legend while concentrations of ceramide are indicated along the x axis.
  • Inhibitory effects were assessed as a measure of DNA synthesis; [ 3 H] thymidine incorporation detection is indicated along the y axis.
  • FIGURE 2 is a bar graph depicting inhibition of cell apoptosis in human (Jurkat) T lymphocytes according to the invention.
  • the inhibitory activity of two inventive compounds nos. 37 and 6 (a purine) was tested in comparison to like activity of pentoxyfilline and a control compound, Ro 20-1724.
  • Activation of the sphingomyelin signal transduction pathway was stimulated by incubation of the cells with an anti-FAS monoclonal antibody (which binds CD95, a cell surface receptor which triggers cell apoptosis).
  • Percent inhibition was measured as a function of the number of cells which excluded vital dye erythrosin B. Percent inhibition is indicated along the y axis while the concentration of compounds tested is indicated along the x axis.
  • FIGURE 3 is a bar graph depicting inhibition of activity on the part of CaPK in Jurkat cells according to the invention.
  • the inhibitory activity of a compound of the invention (no. 37) was tested in the presence of either ceramide or anti-FAS. Inhibition of CaPK activity was measured as a function of phosphorylation and detected by autoradiography. The compounds the cells were incubated in are indicated along the y axis while the percent control (i.e., inhibition of CaPK) is indicated along the x axis. Shorter bars indicate greater relative inhibition.
  • FIGURES 4 (a) through (g) are copies of spectrographs indicative of absorbance of inventive compounds no. 37, no. 6, no. 37 in combination with no. 6, oxo variants of nos. 37 and 6, as well as, for comparison, PABA (p-amino benzoic acid, a common sunscreen additive) and isoquinolone.
  • inventive compounds no. 37, no. 6, no. 37 in combination with no. 6, oxo variants
  • FIGURES 5(a) and (b) depict, respectively, the results of an enzyme- linked immunosorbent assay (ELISA) for TNF- ⁇ production by bacterial lipopolysaccharide (endotoxin) stimulated human monocytes incubated with the compounds of the invention and a control compound (Ro-1724, that is a known and
  • ELISA enzyme- linked immunosorbent assay
  • each graph shows the amount of each compound tested (in ⁇ M) while the vertical axis shows the IC 50 values for TNF- ⁇ production as a percentage of the production in the
  • FIGURE 6 is a graph depicting the results of an assay for in vivo
  • LPS lipopolysaccharide
  • FIGURE 7 depicts the results of an assay for inhibition by compounds of
  • FIGURE 8 depicts the results of an assay for inhibition by a compound of the invention (no. 37) to prevent the stimulatory effects of C 2 - ceramide or protein kinase C activity in human lymphocyte extracts. Inhibitory effects were assessed as a measure of DNA synthesis; [ 3 H] thymidine incorporation detection is indicated along
  • FIGURE 9 depicts the results of an assay for in vitro TNF- ⁇ production by human macrophages in response to lipopolysaccharide (LPS) and inhibition of that production by pteridine and isoquinolone compounds of the invention (nos. 37 and
  • TNF- ⁇ detected in pg/ml.
  • FIGURE 10 depicts inhibition of PDGF induced fibroblast proliferation
  • FIGURE 11 depicts inhibition of EGF induced fibroblast proliferation among 3T3 fibroblasts in response to the inventive compounds.
  • the compounds tested are identified along the x axis by the numbers assigned to them in Table 1. Inhibitory effects were assessed as a measure of DNA synthesis; [ 3 H] thymidine incorporation detection is indicated along the y axis.
  • FIGURE 11 depicts inhibition of EGF induced fibroblast proliferation among 3T3 fibroblasts in response to the inventive compounds.
  • the compounds tested are identified along the x axis by the numbers assigned to them in Table 1. Inhibitory effects were assessed as a measure of DNA synthesis; [ 3 H] thymidine incorporation detection is indicated along the y axis.
  • FIGURE 11 depicts inhibition of EGF induced fibroblast proliferation among 3T3 fibroblasts in response to the inventive compounds.
  • the compounds tested are identified along the x axis by the numbers assigned to them in Table 1. Inhibitory effects were assessed as a measure of DNA synthesis; [ 3
  • FIGURE 12 depicts data indicative of the apoptopic protective characteristics of the compounds of the invention as represented by compounds 1C-
  • FIGURES 13(a) through (c) show the structure of commercially available isoquinoline structures whose inhibitory effect with respect to production of TNF- ⁇ by human monocytes prior to modification to add side chain substituents according to
  • bifunctional activation cascade antagonists comprise a JNK activation cascade antagonist constituent as described in commonly owned US Patent
  • JNK and p38 activation cascade Each constituent inhibits PIC production, especially production of TNF ⁇ .
  • JNK and p38 activation cascade antagonists are identified in Table I and compared to other anti-inflammatory agents.
  • Table I the CSAID compounds which begin with “SK&F” or “SB” are manufactured by Smith-Kline Beecham Pharmaceuticals, USA.
  • the "FR” compound is manufactured by Fuji Laboratories, Japan.
  • the "SR” compound is manufactured by Sanofilich,
  • CSAID is used in this disclosure as a generic term for p38 activation cascade antagonists, especially pyridylimidazole compounds. However, it is acknowledged that CSALD is also used as a trademark by
  • CSAIDs antagonize p38 activation.
  • Such compounds are included in, but do not exclusively comprise, the class of compounds referred to herein as "CSAIDs".
  • NSAIDs and PDE inhibitors have, respectively, undesirable PIC stimulatory activity and side-effects.
  • corticosteroids pose the risk of certain undesirable side-effects and are not as specific in their PIC inhibitory activity as CSAIDs.
  • pyridylimidazole compounds, especially CSAIDs are the compounds of choice for use as partners to JNK activation cascade antagonists to form the bifunctional
  • activation cascade antagonists of the invention which may be administered alone or together with other anti-inflammatory agents and medicaments as indicated.
  • CSAIDs Administered alone, CSAIDs inhibit 70-80% or less of TNF ⁇ release in an art-accepted model of stress-induced inflammation (Example 2). CSAIDs predominantly antagonize activation of p38 kinase, but do not affect JNK activation to a signficant degree. Conversely, the activity of the JNK activation cascade antagonist constituents of the bifunctional activation cascade antagonists of the invention is predominantly directed toward inhibition of PIC-stimulated JNK activation.
  • constituents of the inventive compounds have little impact on p38 activation.
  • the JNK activation cascade antagonist and CSAID constituents of the bifunctional activation cascade antagonists of the invention antagonize activation of different MAPK pathways in a non-overlapping manner. While the invention is not to
  • bifunctional activation cascade antagonists of the invention exert synergistically
  • the compounds can provide greater anti-inflammatory potency, with relatively low risk of additive toxicity, than would be expected from a
  • CSAID SB 203580 inhibits inflammation in several animal models; Badger, et al. .Pharmacol.Exp.Ther., 3:1453-1461, 1996) and SB 210313 (Boehm, et al., J.Med.Chem., 39:3929-3927, 1996).
  • Particularly potent JNK activation cascade
  • antagonist constituents are compounds 54 and 54a (morpholinyl esters of Compound 52, described in Example XVII; isoquinilones), compound 6 (a purine) or compound
  • R 2 is (CH 2 ) 3 COOEt
  • the constituents of the bifunctional activation cascade antagonists may be co-administered as separate compounds. However, to ameliorate their systemic activity, the constituents may be conjugated to one another by a bond which is
  • Suitable conjugation means include amide, ester and aso linkages, which
  • a particularly useful conjugation bond that is cleavable in vivo is a tertiary N acyloxymethyl amide bond (Moreira, et al., Tetrahedron Lett., 35:7107-7110 (1994),
  • tertiary N acyloxymethyl amide bonds are formed to stabilize carboxylic acid or secondary amide moities on prodrugs (i.e., drugs bound to inert carriers by a bond which is separable in vivo).
  • the bonds involve direct coupling of a R, CoNR 2 CH 2 (secondary amide) moiety to an R 3 CO 2 H drug.
  • bifunctional activation cascade antagonists bound by ester- linkages are:
  • n is any number of carbon atoms from 1 to 7,
  • R is H, an alkyl, a cyclic alkyl, a heterocyclic alkyl, alkenyl, or aralkyl having less than 7 carbon atoms;
  • R 6 and R 7 are H, OH or OR,, in any combination;
  • Z is N or C
  • A is H, halogen, N 3 , NO, NH 2 , NHR réelle N(R,)2 or COR,.
  • the bifunctional activation cascade antagonists of the invention may be
  • Aqueous carriers preferred for use with the bifunctional activation cascade antagonists of the invention may include sterile aqueous of non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/ aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, antioxi-
  • a composition of bifunctional activation cascade antagonists may also be lyophilized using means well known in the art, for subsequent reconstit ⁇ tion and use according to the invention.
  • Absorption promoters, detergents and chemical irritants can enhance transmission of a bifunctional activation cascade antagonist to a target tissue.
  • chemical irritants e.g., keritinolytic agents
  • Suitable nasal absorption promoters in particular are set forth at Chien, supra at Ch. 5, Tables 2 and 3; milder agents are preferred.
  • Suitable agents for use in the method of this invention for mucosal/nasal delivery are also described in Chang, et al, Nasal Drug Delivery, “Treatise on Controlled Drug Delivery", Ch. 9 and Table 3-4B thereof, (Marcel Dekker, 1992).
  • Suitable agents which are known to enhance absorption of drugs through skin are described in Sloan, Use of Solubility Parameters from Regular Solution Theory to Describe Partitioning-Driven Processes. Ch. 5, "Prodrugs: Topical and Ocular Drug Delivery” (Marcel Dekker, 1992), and at
  • a colloidal dispersion system may be used for targeted delivery of the
  • systems include macromolecule complexes, nanocapsules, microspheres, beads, and
  • lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and
  • liposomes are particularly convenient and effective colloidal system.
  • a particularly convenient and effective colloidal system is a liposome.
  • Liposomes are artificial membrane vesicles which are useful as delivery
  • LUV large unilamellar vesicles
  • aqueous buffer containing large macromolecules.
  • Compounds can be encapsulated within the aqueous interior and be delivered to cells in an active form.
  • liposomes have been used for delivery of polynucleotides in plant
  • yeast and bacterial cells are yeast and bacterial cells.
  • composition of a liposome is usually a combination of phospholipids
  • phospholipids especially high-phase-transition-temperature phospholipids, usually in combination with steroids, especially cholesterol.
  • steroids especially cholesterol.
  • Other phospholipids or other lipids may also be
  • liposomes depend on pH, ionic strength, and the
  • phosphatidyl compounds such as phosphatidylglycerol, phosphatidylcholine,
  • phosphatidylserine phosphatidylethanolamine
  • sphingolipids cerebrosides
  • gangliosides particularly useful are diacylphosphatidylglycerols, where the lipid
  • moiety contains from 14-18 carbon atoms, particularly from 16-18 carbon atoms, and
  • Illustrative phospholipids include egg phosphatidylcholine,
  • dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine.
  • the targeting of liposomes can be classified based on anatomical and
  • Anatoxnical classification is based on the level of selectivity, for
  • Mechanistic targeting can be distinguished based upon whether it is passive or active. Passive targeting
  • RES endothelial system
  • targeting involves alteration of the liposome by coupling the
  • liposome to a specific ligand such as a monoclonal antibody, sugar, glycolipid, or
  • the surface of the targeted delivery system may be modified in a variety of ways.
  • lipid groups can be incorporated into the lipid bilayer of the liposome in order to maintain the targeting
  • lipid chains can be used for joining the lipid chains to the targeting ligand (see, e.g.,
  • ligands are receptor ligands, antigens, enzymes and monoclonal antibodies.
  • targeting ligands can be prepared according to conventional techniques (e.g., peptide
  • JNK activation cascade antagonist constituents useful in the invention are JNK activation cascade antagonist constituents useful in the invention.
  • JNK activation cascade antagonists of the invention generally comprise
  • Purines JNK activation cascade antagonists have the general formula (8):
  • Z is N or CH and R, is (CH 2 ) n A, where:
  • A is NH 2 , acyloxy, SO 3 H, PO 4 H 2 , NNO(OH), SO 2 NH 2 , PO(OH)NH 2 , SO 2 R, or COOR where R is H, an alkyl having from 1 to 4 carbon atoms, an alkenyl having from 1 to 4 carbon atoms, tetrazolyl or benzyl;
  • n is any number of atoms from 1 to 7 having saturated and/or unsaturated
  • R is a ⁇ -carboxyalkyl, ⁇ -carboxyalkenyl, or ⁇ -
  • R 2 is H, an alkyl (including aliphatic and alicyclic, and heteroalicyclic forms), alkenyl, aralkyl having 1 to 7 carbon atoms or a ⁇ -hydroxyalkyl having from 1 to 7 carbon atoms;
  • R 3 is the same as R 2 ;
  • X is H, any halogen, OH, SH, OR , or SR , where R ' is an alkyl, alkenyl, phenyl or benzyl having from 1 to 4 carbon atoms.
  • R 2 CH,COOEt theobromine
  • R 2 (CH 2 ) 2 COOEt
  • R 2 (CH 2 ) 3 COOEt 2
  • R 2 ⁇ CH 2 )3COOH
  • R 2 (CH 2 ) 4 COOEt
  • R 2 (CH 2 ) 3 COOEt
  • This method is essentially based on the Traube purine synthesis protocol
  • the above method was utilized to prepare the N-3 propylpurines.
  • the starting material used was n-propyl urea condensed with ethyl cyanoacetate in the
  • Ring closure was accomplished as described in method A, except that diethoxymethyl acetate was used as the source of carbon in the ring closure step. Sequential alkylations were then performed using alkyl halides to yield the final compound 31 (ethyl 4-(2,3,6,7-tetrahydro-2,6-dioxo-7-methy 1-3 -n-propyl- lH-purin-1- yl)butonoic acid). A detailed description of this protocol is provided in the Examples.
  • Pteridine JNK activation cascade antagonists have the general formula (9):
  • R is (CH 2 ) n A, where:
  • A is NH 2 , acyloxy, SO 3 H, PO 4 H 2 , NNO(OH), SO 2 NH 2 , PO(OH)NH 2 , SO 2 R, or COOR where R is H, an alkyl having from 1 to 4 carbon atoms, an alkenyl having from 1 to 4 carbon atoms, tetrazolyl or benzyl;
  • n is any number of atoms from 1 to 7 having saturated and/or unsaturated carbon to carbon bonds, which atoms may include an oxygen or nitrogen atom in place of a carbon atom to form, respectively, ether or amino linkages;
  • R is a ⁇ -carboxyalkyl, ⁇ -carboxyalkenyl, or ⁇ - carboxyaryl having from 1 to 8 carbon atoms, wherein the aromatic group further has as a substituent A (as defined above);
  • R 2 is H, an alkyl (including aliphatic and alicyclic, and heteroalicyclic
  • alkenyl aralkyl having 1 to 7 carbon atoms or a ⁇ -hydroxyalkyl having from 1 to 7 carbon atoms;
  • R 4 is the same as R 2 , OH or an O-alkyl having from 1 to 5 carbon atoms;
  • R 5 is the same as R 2 , OH or an O-alkyl having from 1 to 5 carbon atoms; and,
  • Method C (above) was chosen as a convenient method to produce N-alkyls in preference to O-alkyls in this group. Method C was modified to this end as follows:
  • R is (CH 2 ) n A, where:
  • A is NH 2 , acyloxy, SO 3 H, PO 4 H 2 , NNO(OH), SO 2 NH 2 , PO(OH)NH 2 ,
  • alkenyl having from 1 to 4 carbon atoms, tetrazolyl or benzyl
  • n is any number of atoms from 1 to 7 having saturated and/or unsaturated
  • R is a ⁇ -carboxyalkyl, ⁇ -carboxyalkenyl, or ⁇ -
  • R 2 is H, an alkyl (including aliphatic and alicyclic, and heteroalicyclic
  • alkenyl aralkyl having 1 to 7 carbon atoms or a ⁇ -hydroxyalkyl
  • Isoquinolone JNK activation cascade antagonists have the general formula
  • R 2 is (CH 2 ) n A, where:
  • A is NH 2 , acyloxy, SO 3 H, PO 4 H 2 , NNO(OH), SO 2 NH 2 , PO(OH)NH 2 , SO 2 R, or COOR where R is H, an alkyl having from 1 to 4 carbon atoms, an alkenyl having from 1 to 4 carbon atoms, tetrazolyl or benzyl;
  • n is any number of atoms from 1 to 7 having saturated and/or unsaturated carbon to carbon bonds, which atoms may include an oxygen or nitrogen atom in place of a carbon atom to form, respectively, ether or amino linkages; and, preferably, R 2 is a ⁇ -carboxyalkyl, ⁇ -carboxyalkenyl, or ⁇ - carboxyaryl having from 1 to 8 carbon atoms, wherein the aromatic group further has as a substituent A (as defined above); and
  • R 3 is H, an alkyl (including aliphatic and alicyclic, and heteroalicyclic forms), alkenyl, aralkyl having 1 to 7 carbon atoms or a ⁇ -hydroxyalkyl having from 1 to 7 carbon atoms;
  • R 4 is H, OH, NH 2 or O-alkyl having from 1-7 carbon atoms;
  • R 5 is H, OH, NO, NO 2 , NH 2 an O-alkyl having from 1-4 carbon atoms, or X where;
  • X is H, any halogen, OH, SH, OR ' , or SR ' , where R ' is an alkyl, alkenyl, phenyl or benzyl having from 1 to 4 carbon atoms; and,
  • R 7 is H, OH, NO, NO 2 , NH 2 an O-alkyl having from 1-7 carbon atoms, or
  • X is H, any halogen, OH, SH, OR, or SR, where R ' is an alkyl, alkenyl, phenyl or benzyl having from 1 to 7 carbon atoms.
  • the starting material for this protocol was N-methyl isatoic anhydride. A detailed description of this protocol is provided in the examples.
  • ester increases the water solubility of the compounds.
  • aminoalkyl esters Particular substituents that increase the water solubility of the compounds effectively are aminoalkyl esters.
  • the amino group of the aminoalkyl ester preferably is a secondary or tertiary amino group.
  • the amino substituents have between 1 and 6
  • aminoalkyl is a tertiary amine and the amino substituents are preferably are
  • the most preferred aminoalkyl is N-morpholinoethyl.
  • the carboxylic acid is N-morpholinoethyl.
  • CSAIDs are available from, for example, the sources listed in the legend to
  • Patent No. 4,778,806 Published PCT Application No. WO9725045; Published PCT
  • SB 210313 1 -[3-(4-morpholinyl)propyl]-4-(4-fluorophenyl-5-(4-
  • SK&F 105561 2-(4-methylthiophenyl)-3-(4-pyridyl)-6,7-dihydro- [5H]-pyrrolo[l ,2-a] imidazole
  • SB 203580 4-(4-fluorophenyl)-2-(4-methylsulf ⁇ nyl)-5-(4-
  • SK&F 86002 5-(4-pyridyl)-6(4-flurophenyl)-2,3- dihydroimidazole(2,l-b)thia zol
  • a representative CSAID synthesis scheme (shown for SB 210313) is:
  • kits are also provided by the same.
  • kits may include any or all of the following: a bifunctional activation cascade antagonist; a pharmaceutically acceptable carrier (may be pre-mixed with the bifunctional activation cascade antagonist) or suspension base for reconstituting
  • medicament if any, or a single vial for mixtures thereof; device(s) for use in
  • composition delivering the composition to a host; assay reagents for detecting indicia that the anti-
  • bifunctional activation cascade antagonists of the invention may be
  • the methods of the invention are expected to be of particular use in providing protection against inflammation and associated excess formation of fibrotic tissue.
  • efficacy for the JNK activation cascade
  • bifunctional activation cascade antagonists of the invention are administered to a host using any available method and route suitable for drug delivery,
  • delivery methods and routes which target the skin e.g., for
  • mucosa e.g., for respiratory, ocular,
  • Intranasal administration means are particularly useful in addressing respiratory inflammation, particularly inflammation mediated by antigens transmitted from the nasal passages into the trachea or broncheoli.
  • Such means include inhalation of aerosol suspensions or insufflation.
  • Nebulizer devices suitable for delivery of drug compositions to the nasal mucosa, trachea and bronchioli are well-known in the art and will therefore not be described in detail here.
  • Chien, Novel Drug Delivery Systems, Ch. 5 Marcel Dekker, 1992).
  • Dermal routes of administration are useful in addressing allergic reactions and inflammation in the skin.
  • Examples of means for delivering drugs to the skin are topical application of a suitable pharmaceutical preparation, transdermal transmission, injection and epidermal administration.
  • absorption promoters or iontophoresis are suitable methods.
  • those of ordinary skill in the art may wish to consult Chien, supra at Ch. 7.
  • Iontophoretic transmission may be accomplished using commercially available "patches" which deliver their product continuously via electric pulses through unbroken skin for periods of several days or more. Use of this method allows for controlled transmission of pharmaceutical compositions in relatively great concentrations, permits infusion of combination drugs and allows for contemporaneous use of an absorption promoter.
  • An exemplary patch product for use in this method is the LECTRO
  • Opthalmic administration involves invasive or topical application of a pharmaceutical preparation to the eye.
  • Eye drops, topical cremes and injectable liquids are all examples of suitable mileaus for delivering drugs to the eye.
  • Systemic administration involves invasive or systemically absorbed topical administration of pharamaceutical preparations. Topical applications as well as intravenous and intramuscular injections are examples of common means for systemic administration of drugs .
  • the compounds of the invention vary in potency.
  • CSAIDs The relative potencies of other antiinflammatory constituents, including CSAIDs, are known in the art.
  • IC 50 level at which 50% of TNF ⁇ release is inhibited
  • Dosages of the compounds of the invention will vary depending on the age, weight and presenting condition of the host to be treated, as well as the potency of the particular compound administered. Such variables will readily be accounted for by those of ordinary skill in the clinical art. In particular, dosages will be adjusted upward or downward for each recipient based on the severity of the condition to be treated and accessibility of the target cells to the pharmaceutical formulations of the invention. Where possible, it will be preferable to administer the pharmaceutical formulations of the
  • dosages will also vary depending on the route of administration and the extent to which the formulations of the invention are expected to reach target cells before dilution or clearance of the formulation.
  • bifunctional activation cascade antagonists are administered in lower dosages (e.g., at about a 10-40% lower dosage).
  • Those of ordinary skill in the clinical arts will be able to determine medically sound dosing schedules for patients with particular presenting conditions, taking into account the severity of the condition, the patient's overall health, patient age and weight, and other clinically relevant factors. These dosages may be combined with other conventional pharmaceutical therapies for inflammation and fibrosis; e.g., corticosteroids.
  • lymphocytes, monocytes, neutrophils, intracellular components such as microsomes or immunologically naive animals are exposed to a PIC and the candidate therapeutic compound.
  • a control is incubated with a known amount of the inflammatory or fibroblast proliferation inducing agent.
  • Treatment groups are exposed to the same amount of inflammatory or fibroblast proliferation inducing agent as well as aliquots of the candidate therapeutic compound.
  • Inflammatory responses or fibroblast proliferation in each group are detected by conventional means known to those of skill in the art (such as the assay steps described in the examples) and compared.
  • mp refers to melting point
  • PBMC peripheral blood monocyte cells
  • PIC-sensitive-MAPK activator namely lipopolysaccharide (LPS, Sigma).
  • TNF ⁇ production was measured as the hallmark of MAPK cascade activation
  • the PBMC were isolated from heparinized normal human blood by ficoll-
  • the cells were plated in 96 well plates with a JNK
  • SB210313 is l-[3-(4-morpholinyl)propyl]-4-(4-flurophenyl)-5-
  • the plated cells were suspended in RPMI 1640
  • compound 54 achieved 50% inhibition (IC 50 )
  • the IC 50 for compound 37 was achieved at 20-25 ⁇ m.
  • the IC 50 for compound 37 was achieved at 20-25 ⁇ m.
  • SB210313 one of the most potent CSAIDs, was achieved at 1.6 to 3.2 ⁇ m. However, the maximal level of inhibition achieved by any of the compounds was only 70-80%.
  • bifunctional activation cascade antagonists of the invention achieve synergy between
  • MOLT-4 human lymphoblastoid cells were used as models of JNK
  • MOLT-4 cells were preincubated with compound 54 to demonstrate the
  • buffered saline and provided to the cells in concentrations of 50 ⁇ m or lO ⁇ m.
  • PBS served as a control and, for comparison, one group of cell samples were exposed
  • the IC 50 s for compound 54 varied from 10-50 ⁇ m, depending on the
  • antagonists of the invention provide the activity of each antagonistic constituent in a
  • bifunctional activation cascade antagonists provide the same activity of each constituent alone at greater potency.
  • Lymphocyte and monocyte extracts were prepared under similar conditions
  • cascade antagonists of the invention antagonize activation of different MAPK
  • antagonists of the invention provide the activity of each antagonistic constituent in a
  • bifunctional activation cascade antagonists provide the bifunctional activation cascade antagonists
  • JNK activation cascade antagonists in this context are provided.
  • 3T3 fibroblast cells were seeded in 96 well microtiter plates in DMEM in
  • the medium was removed, the cells washed and reincubated in serum-free
  • the bifunctional activation cascade antagonists of the invention provide the activity of each antagonistic constituent in a synergistic manner.
  • the bifunctional activation cascade antagonists provide the same activity of each constituent alone at greater potency.
  • DX2 is a functional anti-FAS (CD95) antibody which will, on binding of CD95, activate the Smase catalysis of sphingomyelin hydrolysis and production of ceramide (see, re DX2, Cifone, et al. , J. Exp. Med, 177 : 1547- 1552, 1993, the disclosure of which is incorporated herein by reference for use in accessing the DX2 antibody).
  • CD95 functional anti-FAS
  • human T lymphoblasts (Jurkat) were suspended at 2xl0 6 cells per ml in RPMI-1640 supplemented with insulin, transferrin, selenium and glutamine. After incubation for 2 hrs. at room temperature with either compound no. 37, compound no. 6, pentoxifylline or a control compound (Ro-1724), 25 ng/ml of anti-FAS antibody was added to each suspension. After another 2 hrs., cell apoptosis was measured as a function of the number of cells (counted by hemocytometer) that excluded the vital dye erythrosin B.
  • the results of the experiment are shown in FIGURE 2 and establish the apoptosis inhibitory efficacy of the compounds of the invention (as represented by compounds nos. 6 and 37, particularly the latter).
  • the bifunctional activation cascade antagonists of the invention provide the activity of each antagonistic constituent in a synergistic manner.
  • the bifunctional activation cascade antagonists provide the same activity of each constituent alone at greater potency.
  • JNK activation cascade antagonists in this context are provided.
  • Ceramide-activated protein kinase is a 97 kDa protein which is exclusively membrane-bound and is believed to serve a role in the sphingomyelin signal transduction pathway.
  • CaPK is believed to mediate phosphorylation of a peptide derived from the amino acid sequence surrounding Thr 669 of the epidermal
  • membrane fraction was isolated from each test sample of treated cell homogenate by
  • antagonists of the invention provide the activity of each antagonistic constituent in a synergistic manner.
  • the bifunctional activation cascade antagonists provide the same activity of each constituent alone at greater potency.
  • Radiation is a major cause of skin damage (including apoptosis) in humans.
  • the sphingomyelin signal transduction pathway is believed to be involved in at least the early stages of development of radiation induced dermatoses (including radiation dermatitis, sunburn and UVB induced immune suppression from radiation damage to Langerhans cells in the skin- see, e.g., Haimovitz-Friedman, et al, J.Exp.Med, 180:525-535, 1994 (cellular responses to ionizing radiation); and, Kurimoto and Streilein, J.Immunol. , 145:3072-3078, 1992 (cutnaceous immune suppression from UVB exposure)).
  • a compound which will inhibit cell responses to stimulus of the sphingomyelin signal transduction pathway by radiation and can be administered topically at the site of exposure would be of great benefit in retarding the damage associated with radiation exposure (e.g., through exposure to sunlight or radiation).
  • the ultraviolet spectra of compounds of the invention were evaluated and compared to those of a commercially available sunscreen additive (PABA) and isoquinoline.
  • PABA sunscreen additive
  • the spectra were identified using a KONTRON analytical instrument.
  • the compounds of the invention as represented by compounds nos. 6 and 37
  • absorbed through most of the UVB region indicating efficacy in absorbing radiation.
  • a mixture of compound nos. 6 and 37 proved to absorb throughout the UVB region.
  • lengths from 2-5 carbons are especially useful in inhibiting TNF- ⁇ production in vitro
  • N-1 chain lengths of about 4 carbons appear to be
  • esterified compounds were significantly more effective inhibitors of TNF- ⁇
  • Peripheral blood mononuclear cells were isolated from normal human
  • test compounds (FIGURE 10) were added to the plated cells in a volume of 100 ⁇ l and incubated for 1
  • the sensitivity of the assay ranged from 10-
  • antagonists of the invention provide the activity of each antagonistic constituent in a synergistic manner.
  • the bifunctional activation cascade antagonists provide the same activity of each constituent alone at greater potency.
  • the compounds of the invention effectively reduce cellular response to LPS, a known inducer of TNF- ⁇ production.
  • the inhibitory activity of the compounds of the invention on LPS induced leukopenia was enhanced (FIGURE 6).
  • the inhibitory activity of the compounds of the invention was essentially unaffected by diacylglycerol (FIGURE 7), indicating that the mode of action of the compounds of the invention are not dependent on hydrolysis of phosphatidic acid.
  • the leukopenia inhibitory capacity of the test compounds was determined by intraperitoneal administration of 0.5 ⁇ g of LPS in saline to ICR female mice (age 6-8 weeks; weight 19-23 g). One hour before receiving the LPS, the mice received the test compound by intraperitoneal injection at a dose of 50 mg/kg (in isotonic saline). Two hours after injection of LPS, 200 ⁇ l of blood was collected from each mouse into a
  • heparinized tube and the total count of nucleated cells determined in a hemocytometer.
  • An isoquinoline compound of the invention (compound 52) was also tested in vitro for its inhibitory efficacy with respect to LPS induced TNF- ⁇ production in human cells.
  • the bifunctional activation cascade antagonists of the invention provide the activity of each antagonistic constituent in a
  • bifunctional activation cascade antagonists provide the bifunctional activation cascade antagonists
  • antagonists of the invention provide the activity of each antagonistic constituent in a
  • bifunctional activation cascade antagonists provide the bifunctional activation cascade antagonists
  • Mouse fibroblast line 3T3 cells (American Type Culture Collection #CCL 92) were seeded into 96 well plates in complete medium and allowed to grow to confluence. The medium was then replaced with medium-free serum and the cells incubated for 24 hrs.
  • test compounds were then incubated with the cells for 1 hr before addition of 5 ng/ml human PDGF or EGF was added to each well. After another 24 hrs, 1 ⁇ Ci of [ 3 H] -thymidine was added to each well. 4 hrs later the cells were harvested onto glass fiber filters and the cellular incorporation of [ 3 H] -thymidine was measured by liquid scintillation counting (FIGURES 10 and 11).
  • the bifunctional activation cascade antagonists of the invention provide the activity of each antagonistic constituent in a synergistic manner.
  • the bifunctional activation cascade antagonists provide the same activity of each constituent alone at greater potency.
  • Theobromine or 8-bromotheobromine (2 mmol) was combined with anhydrous K 2 CO 3 (2.5 mmol) and dry DMF (15 mL) and the mixture was brought to 75 °C.
  • the appropriate alkyl halide (2.5 mmol) was added and the mixture was stirred at 75 °C for 2-18 h.
  • the reaction mixture was cooled, poured into water (125 mL) and extracted with ethyl acetate (2 x 75 mL). The organic layer was dried over magnesium sulfate and evaporated to yield a colorless oil or white solid which was triturated with ethyl ether.
  • the 5-nitrosopyrimidine (15 mmol) was suspended in water (50 mL) and
  • the orthodiamine 28 or 33 (2 mmol) was suspended in water (20 mL) and
  • nitrosopyrimidine 32 (220 mg, 1.28 mmol) was mixed thoroughly
  • N-methylisatoic anhydride 3.5 g, 19.8 mmol
  • 4-aminobutyric acid 2.5 g, 24.3 mmol
  • TLC indicated reaction to be complete and the DMF was removed in vacuo.
  • the residue was used directly for esterification which was accomplished by dissolving the residue in 100%) ethanol (50 mL) and adding chlorotrimethyl silane (2.5 mL, 20 mmol).
  • the mixture was heated at 65 °C for 6 h and then evaporated to yield a brown syrup. Crude yield 87%) from isatoic anhydride.

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Abstract

L'invention concerne des composés antagonistes bifonctionnels de certaines cascades d'activation, qui inhibent les réponses inflammatoires associées au TNF-α et la prolifération des fibroblastes in vivo et in vitro en bloquant l'activation des kinases c-Jun et p38. Les composés de l'invention possèdent davantage qu'une activité additionnelle par rapport aux différents constituants de chaque composé. Un de ces constituants bloque l'activation de la kinase c-Jun, tandis que l'autre bloque l'activation de la kinase p38, sans que ces activités se chevauchent. Les composés de l'invention n'inhibent de manière appréciable ni l'activité de l'AMPc phosphodiestérase, ni l'hydrolyse de l'acide phosphatidique, et ils ne sont ni cytotoxiques ni cytostatiques. L'invention concerne également des techniques qui permettent d'utiliser ces nouveaux composés comme anti-inflammatoires. Ces techniques sont censées protéger un vertébré hôte des réponses inflammatoires (par exemple après angioplastie) ou atténuer chez lui lesdites réactions, limiter la fibrose (par exemple dans la cirrhose du foie), et inhiber la sénescence cellulaire, l'apoptose cellulaire et l'immunosuppression cutanée induite par les ultraviolets.
EP99931893A 1998-06-29 1999-06-24 Antagonistes bifonctionnels des cascades d'activation des kinases sensibles aux cytokines et technique permettant de les utiliser comme anti-inflammatoires Withdrawn EP1091960A1 (fr)

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WO2003106426A1 (fr) 2002-06-14 2003-12-24 Cytokinetics, Inc. Composes, compositions et procedes
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