WO1999040787A1 - Agents modifies, actifs sur le plan pharmacologique, et procedes therapeutiques ameliores et mettant en oeuvre ces agents - Google Patents

Agents modifies, actifs sur le plan pharmacologique, et procedes therapeutiques ameliores et mettant en oeuvre ces agents Download PDF

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Publication number
WO1999040787A1
WO1999040787A1 PCT/US1999/002678 US9902678W WO9940787A1 WO 1999040787 A1 WO1999040787 A1 WO 1999040787A1 US 9902678 W US9902678 W US 9902678W WO 9940787 A1 WO9940787 A1 WO 9940787A1
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Prior art keywords
agents
pharmacologically active
active agent
treatment
inhibitors
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PCT/US1999/002678
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English (en)
Inventor
Ching-San Lai
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Medinox, Inc.
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Application filed by Medinox, Inc. filed Critical Medinox, Inc.
Priority to AU26627/99A priority Critical patent/AU2662799A/en
Publication of WO1999040787A1 publication Critical patent/WO1999040787A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/36—Esters of dithiocarboxylic acids

Definitions

  • the present invention relates to novel modified forms of pharmacologically active agents, and methods for the preparation and use thereof.
  • methods are provided for treating a pathological condition with a modified pharmacologically active agent, which requires administration of reduced levels of the pharmacologically active agent, yet provides prolonged circulating levels thereof .
  • NSAIDs non-steroid anti-inflammatory drugs
  • NSAIDs can cause gastrointestinal ulcers, a side-effect that remains the major limitation to the use of NSAIDs (see, for example, J. L. Wallace, in Gastroenterol. 112:1000-1016 (1997); A. H. Soil et al., in Ann Intern Med. 114:307-319 (1991); and J. Bjarnason et al., in Gastroenterol . 104:1832-1847 (1993)).
  • anthracyclines such as adriamycin are commonly used antitumor agents
  • considerable efforts have also been made to develop strategies for reducing the acute and delayed cardiomyopathies induced by anthracyclines, while maintaining the therapeutic efficacy of these compounds .
  • the molecular mechanism of cardiomyopathy is now attributed to the adriamycin-induced release of iron from intracellular iron proteins, resulting in the formation of an adriamycin-iron complex.
  • adriamycin-iron complex generates reactive oxygen species, causing the scission and condensation of DNA, peroxidation of phospholipid membranes, depletion of cellular reducing equivalents, interference with mitochondrial respiration, and disruption of cell calcium homeostasis (see, for example, Myers et al., in Science 197:165-167 (1977); and Gianni et al . , in Rev. Biochem. Toxicol. 5:1-82 (1983)).
  • adriamycin administration causes cutaneous irritation and alopecia, mucositis (stomatitis and esophagitis) , phlebosclerosis and hematologic toxicities and many other local and systemic toxicities.
  • modified forms of pharmacologically active agents e.g., anti-inflammatory agents
  • pharmacologically active agents e.g., anti-inflammatory agents
  • This not only reduces the cost of drug, it also reduces the level to which the recipient is exposed to potentially harmful agents.
  • invention compounds provide a new class of pharmacologically active agents which cause a much lower incidence of side-effects due to the benefits obtained by modifying the pharmacologically active agents as described herein.
  • compounds comprising a pharmacologically active agent containing a readily cleavable thiocarbonyl sulfide substituent thereon.
  • a pharmacologically active agent containing a readily cleavable thiocarbonyl sulfide substituent thereon.
  • carbon disulfide will be released as a result of cleavage of the bond by which the carbonyl sulfide is linked to said pharmacologically active agent (e.g., by hydrolysis).
  • suitable physiological conditions refers to the physiological conditions at which the desired cleavage occurs.
  • oral administration of a modified pharmacologically active agent according to the invention subjects the linkage by which the carbonyl sulfide is bound to the agent to the acidic conditions of the stomach, which 4 would likely induce hydrolysis of the compound and release of carbon disulfide therefrom.
  • invention compounds allows a protected (i.e., temporarily inactive) form of the active agent to be delivered- -becoming active only when the thiocarbonyl sulfide is cleaved therefrom.
  • Administration of invention compounds also allows concurrent delivery of carbon disulfide along with the pharmacologically active agent, thereby reducing the degree to which the active agent is degraded in the body prior to reaching the desired site of action. This, in turn, allows delivery of reduced loads of the active agent to the recipient . Reduced dosage lessens the propensity of high potency drugs to induce undesirable side reactions.
  • the presence of carbon disulfide allows the active agent to remain in circulation for prolonged periods of time, thereby enhancing the efficacy of the drug.
  • Diseases and conditions contemplated for treatment in accordance with the present invention include inflammatory and infectious diseases, such as, for example, septic shock, hemorrhagic shock, anaphylactic shock, toxic shock syndrome, ischemia, cerebral ischemia, administration of cytokines, overexpression of cytokines, ulcers, inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease), diabetes, arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, cirrhosis, allograft rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis, glomerulonephritis, uveitis, ileitis, inflammation (e.g., liver inflammation, renal inflammation, and the like) , burn, infection (including bacterial, viral, fungal and parasitic infections) , hemodialysis, chronic fatigue syndrome, stroke, cancers
  • cardiopulmonary bypass ischemic/reperfusion injury, 5 gastritis, adult respiratory distress syndrome, cachexia, myocarditis, autoimmune disorders, eczema, psoriasis, heart failure, heart disease, atherosclerosis, dermatitis, urticaria, systemic lupus erythematosus, AIDA, AIDS dementia, chronic neurodegenerative disease, chronic pain, priapism, cystic fibrosis, amyotrophic lateral sclerosis, schizophrenia, depression, premenstrual syndrome, anxiety, addiction, migraine, Huntington's disease, epilepsy, neurodegenerative disorders, gastrointestinal motility disorders, obesity, hyperphagia, solid tumors (e.g., neuroblasto a) , malaria, hematologic cancers, myelofibrosis, lung injury, graft-versus-host disease, head injury, CNS trauma, hepatitis, renal failure, liver disease
  • hepatitis C chronic hepatitis C
  • drug-induced lung injury e.g., paraquat
  • myasthenia gravis MG
  • ophthalmic diseases post-angioplasty, restenosis, angina, coronary artery disease, and the like.
  • Pharmacologically active agents contemplated for modification in accordance with the present invention include:
  • NSAIDs such as acetaminophen (Tylenol, Datril, etc.), aspirin, ibuprofen (Motrin, Advil, Rufen, others) , choline magnesium salicylate (Triasate) , choline salicylate (Anthropan) , diclofenac (voltaren, cataflam) , diflunisal (dolobid) , etodolac (Iodine) , fenoprofen calcium (naifon) , flurobiprofen (ansaid) , indomethacin (indocin, indo eth, others) , ketoprofen (orudis, oruvail) , ketorolac tromethamine (toradol) , magnesium salicylate (Doan's, magan, mobidin, others), meclofenamate sodium (meclomen) , mefenamic acid (relafan)
  • beta-adrenergic blocking agents acebutolol, atenolol, betaxolol, cartelol, labetalol, metoprolol, nadolol, penbutolol, pindolol, propranolol, timolol
  • angiotensin converting enzyme inhibitors benazepril, captopril, enalapril, fosinopril, quinoapril, ramimpril, losartan
  • aplha-adrenoceptor blocking agents such as prazosin, terazosin, doxazosin, clonidine, guanabenz, guanfacine, methylodopa, guanethidine, guanethidine monosulfate, reserpine, hydralazine, minoxidil, and the like
  • vasodilators such as prazosin, terazosin, doxazosin, clonidine, guanabenz, guanfacine, methylodopa, guanethidine, guanethidine monosulfate, reserpine, hydralazine, minoxidil, and the like
  • agents such as trimethaphan camsylate, phenoxybenzamine hydrochloride, pargyline hydrochloride, deserpidine, diazoxide, rescinnamine, sodium nitroprusside, rauwolf
  • complement factor inhibitor e.g., CMI-392
  • phosphatidic acid synthesis antagonists e.g., CMI-392
  • phosphatidic acid synthesis antagonists e.g., ebselen, edelfosine, enlimomab, galaptin, platelet activating factor antagonists
  • selectin antagonists e.g., ICAM-4
  • interleukin-10 agonist macrocylic lactone, methoxatone, mizoribine, OX-19
  • peptigen agents PG-27
  • protein kinase C inhibitors phosphodiesterase IV inhibitor
  • single chain antigen binding proteins complement factor inhibitor
  • sialophorin sirolimus
  • spirocyclic lactams 5-hydroxytryptamine antagonist
  • anti-TCR monoclonal antibodies CD5 gelonin and TOK-8801, and the like
  • antimetabolite cytotoxics azathioprine, cyclophosphamide
  • GV-150526 L-695902, L-701324, amantadine derivatives, dizocilpine, benzomorphan derivatives, aptiganel, (S) - ⁇ .-phenyl-2-pyridine ethanamide dihyrochloride and 1-amino- cyclopentanecarboxylic acid) , sodium channel antagonists (e.g., 619C89) , glycine antagonists (e.g., glystasins) , calcium channel antagonists 10
  • 1-azulenesulf onic acid derivatives e.g., 1-azulenesulf onic acid derivatives
  • brain-derived neurotropic factor e.g., 1-azulenesulf onic acid derivatives
  • adrenergic transmitter uptake inhibitor e.g., adrenergic transmitter uptake inhibitor
  • endothelin A receptor antagonists e.g., benzenesulfonamide derivatives, GABA A receptor antagonists (e.g., triazolopyrimidine derivatives and cyclohexaneacetic acid derivatives)
  • GPIIb Ilia receptor antagonists e.g., C68-22
  • platelet aggregation antagonist e.g., 2 (1H) -quinolinone derivatives, lH-pyrrole-1-acetic acid derivatives and coumadin
  • Factor Xa inhibitor CPC-211
  • corticotropin releasing factor agonist e.g., cothrombins, fraxiparine, dermatan sulfate and heparinoid
  • dotarizine e.g., intracellular calcium chelators (e.g., BAPTA derivatives)
  • radical formation antagonists e.g., calcium chelators, calcium chelators (e.g., BAPTA derivatives)
  • radical formation antagonists
  • EPC-K1 3 -pyridinecarboxamide derivatives, superoxide dismutase, raxofelast, lubeluzole, 3H-pyrazol-3-one derivatives, kynurenic acid derivatives, homopiperazine derivatives, and polynitroxyl albumin
  • protein kinase inhibitors 3 -pyridinecarboxamide derivatives, superoxide dismutase, raxofelast, lubeluzole, 3H-pyrazol-3-one derivatives, kynurenic acid derivatives, homopiperazine derivatives, and polynitroxyl albumin
  • nerve growth agonist e.g., floor plate factor-5
  • glutamate 11 antagonist e.g., cyclohexanepropanoic acid, riluzole, NS-409 and acetamide derivatives
  • lipid peroxidase inhibitor e.g., 2, 5-cyclohexadiene-l,4-dione derivatives
  • sigma receptor agonist e.g., cyclopropanemethanamine derivatives and SA-4503
  • thyrotropin releasing hormone agonist e.g., JTP-2942, L-prolinamide and posatirelin
  • prolyl endopeptidase inhibitor e.g., monosialoganglioside GM1, proteolytic enzyme inhibitor (e.g., nafamostat) , neutrophil inhibitory factor, platelet activating factor antagonist (e.g., nupafant)
  • T cell inhibitors such as synthetic leucocyte antigen derived peptides, interleukin-1 receptor antagonist, MG/AnergiX, anti-CD3 monoclonal antibodies, anti-CD23 monoclonal antibodies, anti-CD28 antibodies, anti-CD2 monoclonal antibodies, CD4 antagonists, anti-E selectin antibodies, MHC inhibitors, monogens, mycophenolate mofetil, LRA-1 inhibitors, selectin inhibitors, and the like; antimigraine agents, such as MK-462, 324C91, Phytomedicine, (S) -fluoxetine, calcium channel antagonists
  • 5-HT1 agonists e.g., Sumatriptan/Imitrex, Imigran, GR-85548, 311C, and GR-127607
  • 5-HT1D agonists e.g., Sumatriptan/Imitrex, Imigran, GR-85548, 311C, and GR-127607
  • 5-HT1D agonists e.g., Sumatriptan/Imitrex, Imigran, GR-85548, 311C, and GR-127607
  • 5-HT1D agonists e.g., Sumatriptan/Imitrex, Imigran, GR-85548, 311C, and GR-127607
  • 5-HT1D agonists e.g., Sumatriptan/Imitrex, Imigran, GR-85548, 311C, and GR-127607
  • 5-HT1D agonists e.g., Sumatriptan/Imitrex, Imigran, GR-8
  • DHE 45 ® ergotamine tartrate, dolasetron mesilate, dotarizine, flupirtine, histamine-H3 receptor agonist, indobufen, 1-azulenesulfonic acid derivatives, cholinesterase inhibitors,
  • bradykinin antagonists e.g., S-9977
  • nitric oxide reductase inhibitors e.g., BN-52296
  • nitric oxide receptor antagonists e.g., substance P antagonists (e.g., Capsaicin/Na ⁇ ocap)
  • endopeptidase inhibitors e.g., neutral
  • endopeptidase, cloned 20 endopeptidase, cloned) , piperazine derivatives, neurokinin 1 antagonists, metergoline, dopamine D2 antagonist (e.g., metoclopramide + lysine acetyl) , enkephalinase inhibitors (e.g., neutral endopeptidase), 5-HT2 antagonists (e.g.,
  • 5-HT3 antagonists e.g., Dolasetron mesilate/MDL-73147, and 4H-carbazol-4-one derivatives
  • tenosal, tolfenamic acid e.g., cy c 1 ooxygena s e inhibitors (e.g., carbasalate/carbaspirin calcium, and
  • alpha adrenoreceptor antagonists e.g., arotinolol, and dihydroergocryptine
  • opioid agonists e.g., flupirtine/D-9998
  • beta adrenergic antagonists e.g., propranolol
  • valproate semisodium
  • interleukin-2 antagonist e.g., sirolimus
  • phospholipase C inhibitor e.g., neurokinin 1 antagonist
  • neurokinin 1 antagonist e.g., L-733060
  • laflunimus, leflunomide, leucotriene antagonists levamisole, LFA3TIP
  • macrocyclic lactone MHC class II inhibitors
  • mizoribine mycophenolate mofetil
  • NfkB inhibitors oncolysin CD6, peldesine, pidotimod, PKC-RACK inhibitors, PNP inhibitors, reumacon, CD28 antagonist, roquinimex, RWJ-50271, subreum, T7 vector, tacrolimus, VLA antagonist (e.g., TBC-772)
  • transforming growth factor beta agonist methionine synthase inhibitors (e.g., vitamin B12 antagonist), adenosine A2 receptor agonist (e.g., YT
  • 5-lipoxygenase inhibitor e.g., zileuton, tenidap, and ABT-761
  • metalloproteinase inhibitor e.g., XR-168, TNF convertase inhibitors, GI-155704A, AG-3340 and BB-2983
  • nitric oxide synthase inhbitors i.e, ARL-16556
  • phospholipase A2 inhibitor e.g., ARL-67974
  • selectin antagonist e.g., CAM inhibitors
  • leucotriene B4 antagonist e.g., CGS-25019C
  • collagenase inhibitor e.g., GR-129574A
  • nalmefene corticotropin releasing factor antagonist
  • corticotropin releasing factor antagonist e.g., NBI-103, and NBI-104
  • proteolytic enzyme inhibitor e.g., protease nexin-1, and NCY-2010
  • bradykinin antagonist e.g., tachykinin antagonists, and NPC-17731
  • growth hormone antagonist e.g., octreotide
  • phosphodiesterase IV inhibitor e.g., PDEIV 15 inhibitors
  • gelatinase inhibitor e.g., REGA-3G12
  • free radical scavengers e.g., SIDR-1026
  • prostaglandin synthase inhibitors e.g., sulfasalazine
  • phenylbutazone penicillamine
  • salsalate azathioprine
  • indomethacin meclofenamate sodium
  • gold sodium thiomalate keto-2
  • antioxidants e.g., N-acetylcsysteine, Vitamin A, Vitamin C, Vitamin E, ⁇ -carotene, EUK-8, flavonoids, glutathione, ⁇ -lipoic acid, melatonin, retinols, and the like
  • 17 anti-infectives e.g., miconazole, vidarabine, inosine, pranobex, vidarabine, inosine prabonex, cefpimizole sodium
  • bronchodialators e.g., sympathomimetics (e.g., epinephrine hydrochloride, metaproterenol sulfate, terbutaline sulfate, isoe
  • C3 convertase inhibitor e.g., C3 convertase inhibitor
  • C5a release inhibitors e.g., CAB-2.1
  • interleukin 1 antagonists e.g., interleukin 1 receptors
  • interleukin 1 receptor antagonists e.g., anakinra
  • interleukin lb antagonists e.g., interleukin-l ⁇
  • interleukin lbeta converting enzyme inhibitors e.g., ICE-inhibitors
  • SDZ-PMX-622 selectin antagonists (e.g., sulfated glycolipid cell adhesion inhibitors) , thrombin 20 inhibitors (e.g., GS-522) , TNF receptor-Ig, tumor necrosis factor antagonists (e.g., anti-TNF MAbs, MAK-195F, TBP-I, Yeda, rhTNFbp, and CDP-571) , tumor necrosis factor alpha antagonists (e.g., E-5531) , and the like; multiple sclerosis agents, such as 4-aminopyridine, 15 ⁇ deoxyspergualin, ACTH, amantadine, antibody adjuvants (e.g., poly-ICLC, and poly-IC+poly-L-lysine+carboxymethylcellulose) , anti-cytokine MAb (CDP-835) , anti-inflammatory s (e.g., sulfated glycolipid cell adhesion inhibitors) , throm
  • CY-1787, and CY-1503 anti-selectin MAb (e.g., CY-1787)
  • anti-TCR MAb e.g., NBI-114, NBI-115, and NBI-116)
  • bacloten bethanechol chloride, carbamazepine, carbohydrate drugs (e.g., CY-1503) , clonazepam, CNS and immune system function modulators (e.g., NBI-106, and NBI-107) , cyclophosphamide, cyclosporine A, cytokines (e.g., IFN- ⁇ , alfaferone, IFN- ⁇ lb, betaseron, TGF- ⁇ 2, PEG-TGF- ⁇ 2, betakine, IFN- ⁇ /Rebif, frone, interferon- ⁇ , and IFN- ⁇ ) , CD4+T cell inhibitors (e.g., AnergiX) , CD28
  • humanized MAb e.g., anti-IFN- ⁇ MAb, smart anti-IFN- ⁇ MAb, anti-Tac antibody, and smart anti-Tac antibody
  • humanized anti-CD4 MAb e.g., anti-CD4 MAb, centara
  • hydrolase stimulants e.g., castanospermine
  • IFN- ⁇ IFN- ⁇ .
  • IFN- ⁇ antagonist e.g., anti-IFN- ⁇ MAb, and smart anti-IFN- ⁇ MAb
  • IL-2 antagonists e.g., tacrolimus, FK-506, FR-900506, Fujimycin, Prograf , IL-2 fusion toxin, and DAB 389 IL-2
  • IL-4 antagonists e.g., IL-4 fusion toxin
  • DAB 389 IL-4) immune-mediated neuronal damage inhibitors (e.g., NBI-114, NBI-115, and BI-116), 21 immunoglobins, immunostimulants (e.g., poly-ICLC, edelfosine, ALP, ET-18-OCH3, ET-18-OME, NSC-24, and poly- IC+poly-L-lysine+carboxymethyl- cellulose) , immunosuppressants (e.g., azathioprine, AI-100 animal protein, rDNA human protein AI-101, peptide, AI-102, castanospermine, tacrolimus, FK-506, FR-900506, Fujimycin, Prograf, anti-leukointegrin MAb, Hu23F2G, primatized anti-CD4 antibody, CE9.1, Galaptin 14-1, GL14-1, Lectin-1, reco binant IML-1, linomide, roquinimex, LS-2616, trans
  • peptide T e.g., peptide T
  • phenoxybenzamine e.g., phospholipase C inhibitors (e.g., edelfosine, ALP, ET-18-OCH3, ET-18-0ME, NSC-24)
  • photodynamic therapies e.g., benzoporphyrin derivative (BPD)
  • plasmapheresis e.g., platelet activating factor antagonists (e.g., ginkgolide B, and BN-52021)
  • potassium channel antagonists e.g., aminodiaquine, and EL-970
  • propranolol prostaglandin synthase inhibitors (e.g., sulfasalazine, salazosulfa-pyridine, PJ-306, SI-88, azulfidine, salazopyrin)
  • protease antagonists e.g., ginkgolide B, and BN-52021)
  • TCR, CD3/Ti, and peptigen TP12 TNF antagonists (e.g., thalidomide, and TNF inhibitors) , tricyclic antidepressants, and the like; organ transplantation agents, such as anti-CD25 MAbs, anti-Tac antibodies, anti-TNF MAb (e.g., CDP571) , apoptosin, azathioprines (e.g., imuran) , BCX-34, CA3, CD28, complement inhibiting factors (e.g., CD59) , CTLA4Ig, cyclosporines (e.g., CsA) , FK-506/rapamycin binding proteins (FKBP) , glucocorticoids, humanized version of OKT3 (e.g., huOKT3-185) , mycophenolate mofetil, hydroorotate dehydrogenase inhibitors (e.g., Brequinar) , orthoclone OKT3
  • immunosuppressants e.g., Rapamycin, AY-22989,
  • Migis (membrane immunoglobulin-isotope specific) antibodies SM-8849, immunophilins, VX-10367, VX-10393, VX-10428, mycophenolate mofetil, ME-MPA, RS-61444, cyclosporine, OL-27-400, Sandimmune, IL-4 fusion toxin, trypanosomal inhibitory factor (TIF) , T-cell receptor, CD3/Ti, Org-4094, anti-TBM, CP 17193, Leflunomide/A-77-1726, ELAM-1, AnergiX, Spanidin, 15-deoxyspergualin, deoxyspurgiline, gusperimus hydrochloride, NSC-356894, NKT-01, Roquinimex,
  • immunotoxins e.g., Zolimomab aritox, 24 xmmly-h65 - rta , xomazyme - lym/CD5 - Plus , OrthoZyme-CD5+, XomaZyme-H65-rta, Xomazyme-CD5 Plus
  • intravenous immunoglobulins e.g., IVIG
  • integrin antagonists e.g., integrin blockers
  • MigisTM antibodies monoclonal antibody therapeutics
  • murine MAb e.g., anti-SLE vaccine, and MAb 3E10
  • primatized anti-CD4 antibodies e.g., CE9.1
  • protease inhibitors e.g., matrix metalloprotease (MMP) inhibitors, and stromelysin
  • protein synthesis antagonists e.g., protein synthesis antagonists
  • Alzheimer's disease agents such as ACh release enhancers
  • acetylcholine release stimulants e.g., DUP-996 and analogues
  • AMPA agonists e.g., AMAlex, and Isoxazole compound series
  • AMPA GluR agonist e.g., IDRA-21 [7-chloro-3-methyl-3 , 4-dihydro-
  • AMPA GluR antagonists e.g., S-18986, and related quinolone derivatives
  • anticholinesterases e.g., E-2020
  • Ca-antagonists e.g., NS-649, spider venom-derived ICM peptides and analogues, and substituted 2-aminoindanes compound series
  • combined anticholinesterase and muscarinic AChR antagonists e.g., PD142676
  • K-channel blockers e.g. , Trans -R-4- (4-methoxyphenyl-methyl) cyclohexylanine and analogues, and margatoxin-based functional and/or structural analogues
  • MI muscarinic receptor agonists 25
  • NMDA antagonists e.g., certain indole derivatives, and (R- (R 1 , S 1 ) ) -o.- (4- hydroxyphenyl) -beta-methyl-4- (phenylmenthyl) -1- piperidinepropanol and analogues)
  • nicotinic AChR agonists e.g., ABT-418 [isoxazole,
  • antiparkinson agents e.g., ethosuximide, and the like
  • psoriasis agents such as 5-LO inhibitors (e.g., Wy-50295,
  • A-64077 5-LO/CO inhibitors (e.g., BF-397, Tenidap, CP-309, and CP-66248) , angiogenesis inhibitors (e.g., platelet factor 4), anticancer antibiotic (e.g., AGM-1470, and TNP-470) , anti-inflammatory cytochrome P450 oxidoreductase inhibitors (e.g., DuP-630, and DuP-983) , antiproliferative compounds (e.g., Zyn-Linker) , arachidonic acid analogues (e.g., CD581, and CD554) , arachidonic acid antagonists (e.g., Lonopalene, RS-43179, triamcinolone acetonide with penetration enhancer Azone, betamethasone dipropionate steroid wipe, G-202, Halobetasol propionate, ultravate, Halometasone, C-48401-Ba,
  • ICAM interleukin-1 kinase
  • cell adhesion inhibitors e.g., selectin inhibitor, GM-1930
  • cellular aging inhibitors e.g., cell adhesion inhibitors, cell adhesion inhibitors, cell adhesion inhibitors, cell adhesion inhibitors (e.g., selectin inhibitor, GM-1930)
  • cell adhesion inhibitors e.g., selectin inhibitor, GM-1930
  • dihydrofolate reductase inhibitors e.g., G-301, dichlorobenzoprim, 26 methotrexate, and methotrexate in microsponge delivery system
  • E-selectin inhibitors e.g.,
  • fibroblast growth factor antagonists e.g., Saporin mitotoxin, and Steno-Stat
  • G-proteins and signal transduction compounds e.g., CPC-A
  • gel formulations for acne e.g., nicotinamide, N-547, and Papulex
  • growth hormone antagonists e.g.,
  • Octreotide, Sandostatin, Lanreotide, angiopeptin, BIM-23014, and Somatuline e.g., humanized antibodies (e.g., anti-CD4 antibody), hydroorotate dehydrogenase inhibitors (e.g., Brequinar sodium, bipenquinate, and DuP-785) , ICAM-1 inhibitors
  • IL-1 and other cytokine inhibitors e.g., Septanil
  • IL-1 converting ezyme inhibitors IL-1 receptor antagonists
  • IL-2 antagonists e.g., Tacrolimus, Prograf, and FK-506
  • DRB389IL-22 IL-2 receptor-targeted fusion toxins
  • IL-8 receptors IL-8 receptors
  • immunostimulants e.g., IL-8 receptors, immunostimulants (e.g.,
  • FK-506, and FK-507 immunosuppressive agents targeting FK506 (e.g., immunophilins, VX-10367, and VX-10428) , immunotoxins MAb directed against CD antigen (e.g., XomaZyme-CD5 Plus), leukotriene antagonists (e.g., Sch-40120, Wy-50295, and Wy-49232) , leukotriene B4 antagonists (e.g., SC-41930, SC-50605, SC-48928, ONO-4057, LB-457, LY-255283, LY-177455, LY-223982, LY-223980, and LY- 255253) , leukotriene synthesis inhibitors
  • lipase clearing factor inhibitors e.g., 1-docosanol, and lidakol
  • 27 lipid encapsulated reducing agent e.g., Dithranol
  • liposomal gel e.g., Dithranol
  • LO inhibitors e.g., CD581, CD554, Masoprocol, and Actinex
  • lithium succinate ointments e.g., lithium salts, and Efalith
  • membrane integrity agonists e.g., lithium salts, and Efalith
  • microtubule inhibitors e.g., Posophyliotoxin-containing compound, and Psorex
  • octapeptide somatostatin analogues e.g.,
  • oligonucleotides e.g., ISIS 4730, ISIS 3801, ISIS 1939, and IL-1 inhibitors
  • peptide agonists e.g., octapeptide, and peptide T
  • PKC inhibitors e.g., phospholipase A2 compounds, pospholipase D compounds
  • photodynamic anticancer agents e.g., 5-aminolevulinic acid, and 5-ALA
  • photodynamic therapies e.g., benzoporphyrin derivative, synthetic chlorins, synthetic porphyrins, and EF-9
  • photosensitizer e.g.,
  • PKC inhibitors e.g., Safingol, and Kynac
  • platelet activating factor antagonists e.g., TCV-309
  • platelet aggregation inhibitors e.g., CPC-A
  • prodrug NSAIDs e.g., G-201
  • prostaglandin agonist e.g., eicosapentaenoic acid + gamma-linolenic acid combination, and Efamol Marine
  • protein inhibitors e.g., SPC-103600, and SPC-101210
  • PKC protein kinase C
  • PKC protein kinase C
  • protein synthesis antagonists e.g., Calcitriol, Du-026325, LG-1069, LG-1064, AGN-190168, Namirotene, and CBS-211A
  • purine nucleoside phosphorylase e.g., purine nucleoside phosphorylase
  • FKBP immunophilins
  • VX-10367 immunophilins
  • VX-104248 second generation monoaromatic retinoids (e.g., Acitretin, and Neotigason) , soluble IL-1, IL-4 and IL-7 receptors, somatostatin and somatostatin analogues (e.g.,
  • streptomyces anulatus isolates e.g., epocarbazolin-A
  • superoxide dismutase e.g., superoxide dismutase
  • vitamin D 3 analogues e.g., Tacalcitol, Bonealfa, TV-02 ointment
  • vitamin D 3 derivatives e.g., 1, 2-diOH-vitamin D 3
  • diabetes agents such as ACE inhibitors (e.g., captopril)
  • amylin, amylin agonists and antagonists e.g.,
  • NormylinTM AC137, GC747, AC253, and AC625)
  • autoimmune compounds e.g., AI-401
  • capsaicins e.g., capsaicins
  • nerve growth factors e.g., Genentech compounds
  • oral hypoglycemics e.g., AS-6, glimepiride, Amaryl, CL 316,243, acarbose, miglitol, recombinant yeast glucagon, GlucaGenTM, NovoNormTM, glipizide, insulinotropin, and CI - 991/CS - 045
  • platelet-derived growth factors e.g., Zymo
  • T cell approaches e.g., anergize, AnergiXTM, Procept compounds, and T cell Sciences compounds
  • tolrestats e.g., Alredase ® , and ARI-509
  • activin somatostatin
  • stroke agents such as 5-HT antagonists (e.g., Piperazine derivative), 5-HT reuptake inhibitors (e.g.,
  • 5-HT 3 agonists e.g., SR-57746A, and SR-57746 .
  • 5-HT 4 antagonists e.g., SR-572257
  • 5-HT 4 antagonists e.g., 5-HT 4 antagonists
  • 5-lipoxygenase inhibitors e.g., low MW dual
  • ACh agonists e.g., Pramiracetam, Choline-L- alfoscerate, L-alpha-glycerylphosphoryl-choline, and Delecit
  • adenosine agonists e.g., GP-1-4683, ARA-100, and arasine analogs
  • adenosine Al receptor agonists e.g., Azaisotere, 2-chloro-N- [4 (phenylthio) -1-piperidinyl] adenosine, and 2120136
  • adenosine reuptake inhibitors e.g., Diphenyloxazole derivatives
  • aldose reductase inhibitors e.g., 30
  • alpha antagonists e.g., Drotaverine acephyllinate, and Depogen
  • alpha 2 agonists e.g., SNAP-5083, SNAP-5608, and SNAP-5682
  • AMPA receptor agonists 5 e.g., heterocyclic compound SYM-1207, and heterocyclic compound SYM-1252
  • AMPA receptor antagonists e.g., LY-293558, and LY-215490
  • Ancrod/Arvin aspirin, benzothiazoles (e.g., Lubeluzole, and R87926) , benzodiazepine receptor
  • C5a release inhibitors e.g., protein derivative CMI-46000
  • calcium antagonists e.g., Lemildipine, NB-818, NPK-1886, Trimetazidine derivative, Iomerizine KP-2796, Diltiazem analog clentiazem maleate, and TA-3090
  • calcium channel e.g., Lemildipine, NB-818, NPK-1886, Trimetazidine derivative, Iomerizine KP-2796, Diltiazem analog clentiazem maleate, and TA-3090
  • nitrendipine-like compound diperdipine YS-201, U-92032, Diltiazem derivative, 1058, SM-6586, KP-840, F-0401, D-31-D, Tetrahydronaphthalene derivatives, fasudil, AT-877, H-7, HA-1044, HA-1077, Eril,
  • palmitoyl-transferase inhibitors carvedilol
  • cerebral calcium antagonist vasodilators e.g., Nimodipine, and Nimotop
  • cholinesterase inhibitors e.g., indole and indazole derivatives, and Tacrine analog
  • 35 factor inhibitors e.g., TK9C, protein derivative
  • TP16 compinact A, compinact C, Factor D inhibitors, and soluble, recombinant MCP-based 31 complement inhibitors
  • complement inhibitors e.g., sCRI/BRL-55730, and YM-203
  • coronary vasodilators e.g., Nicorandil, RP-46417, SG-75, and Adancor
  • CPC-111 cytidyl diphosphocholine/citicholines
  • cytokines e.g.,
  • NBI-117 Dexanabiol, dopamine agonists, EAA receptors, endothelin antagonists (e.g., SB 209670) , endothelin receptor antagonists, excitatory amino acid agonists (e.g., acylated polyamine analogs, and N- (4-hydroxyphenylpropa- nonyl) -spermine analog) , excitatory amino acid antagonists (e.g., Tryptophan, 4, 6-disubstituted stroke & kynurenine derivatives, NPC-17742, CPC-701, and CPC-702) , glutamate antagonists (e.g., Kainate quisqualate NNC-07-9202,
  • glycine e.g., Araxin compounds, Quinoxaline derivative, YM-90K, and YM-900
  • glycine antagonists e.g., Araxin compounds, Quinoxaline derivative, YM-90K, and YM-900
  • NMDA agonists e.g., 3-hydroxy-2, 5-dioxo- lH-benz [b] azepines
  • glycine NMDA associated antagonists e.g., 5, 6-dihydro-lH-pyrrolo
  • NMDA receptor L-687414 Glystasins, ACEA-2011, ACEA-3031, AC-1021, ACPC, and eliprodil
  • growth factor antagonists e.g., non-peptide indolocarbazole neutrophic molecules, and CEP-075
  • GPIIb/IIIa antagonists e.g., Peptide
  • hemorheological agents e.g., Drotaverine acephyllinate, and Depogen
  • heparin hydroxyl radical formation inhibitors
  • hypocalcemic agents e.g., calcitonin peptide, related to hCGRP peptide
  • hypothermic agents/BMY-20862 ICAM-1 compounds (e.g., Enlimomab)
  • 32 immunosuppressants e.g., small molecule compounds, and NBI-117
  • integrin general antagonists e.g., monoclonal antibody AN-100225, and monoclonal antibody AN-100226)
  • Interleukin-1 antagonists e.g., cyclic nitrones
  • iron-dependent lipid peroxidation inhibitors e.g., 2- (amino-methyl) chromans
  • lactic acid accumulation/inhibitors e.g., small molecule CPC
  • lipid peroxidase inhibitors e.g., Idebenone, and Avan
  • low molecular weight small molecules e.g., methyltransferase stimulants (e.g., 4-methyl benzenesulfonate, ademetionine sulfate tosilate, FO-156, and Ceritan)
  • monoamine oxidase e.g., 4-methyl benzenesulfonate, ademetionine sulfate tosilate, FO-156, and Ceritan
  • B inhibitors e.g., MD-280040, MD-200243, MD-280080, Lazabemide, and Ro-19-6327
  • MS-153, MS-424, /Na + /H + Na + /Li + exchange inhibitors e.g., Pyrazine derivatives
  • nadroparin e.g., Fraxiparin
  • nafronyl/naftidrofuryl e.g.,
  • Praxilene nerve growth factor agonists (e.g., small molecule compounds, CNTF, BDNF, 2.5S NGF, monosialoganglioside GM1, and Sigen/Sygen) , neuronal calcium channel blockers (e.g., CPC-304, and CPC-317) , neuronal differentiation compounds
  • nerve growth factor agonists e.g., small molecule compounds, CNTF, BDNF, 2.5S NGF, monosialoganglioside GM1, and Sigen/Sygen
  • neuronal calcium channel blockers e.g., CPC-304, and CPC-317
  • neuronal differentiation compounds e.g., CPC-304, and CPC-317
  • neuropeptide agonists e.g., F-spondin
  • Neurotrophic Peptide Trofexin e.g., neutrophil inhibitory factors (e.g., small molecule compounds), nitric oxide agonists (e.g., hydroxy derivative N-3393, hydroxy derivative N-3398, nicorandil, and Therapicon) , nitric oxide antagonists, NMDA antagonists (e.g., Spiroisoindoles/dizocilpine derivatives, Oxindole compound, CP-112116, LY-104658, LY-235959, FR-115427, Sialic acid derivative,
  • neutrophil inhibitory factors e.g., small molecule compounds
  • nitric oxide agonists e.g., hydroxy derivative N-3393, hydroxy derivative N-3398, nicorandil, and Therapicon
  • NMDA antagonists e.g., Spiroisoindoles/dizocilpine derivatives, Oxindole compound, CP-112116
  • N-palmitoyl-Betaethylglycoside neuraminic acid ND-37, Ro-01-6794, 706, Dextrorphan, Ifenprodil 33 analogue eliprodil, SL-82.0715, Lipophilic molecules, HU-211, Remacemide, 934-423, 12495, 12859, 12942AA, Selfotel, CGS-19755, SDZ-EAA-494, CGP-40116, CGP-37849, CGP-39551, and CGP-43487) , 5 NMDA antagonist-partial agonists (e.g.,
  • Conantokin G peptide SYM-1010) NMDA channel blockers (e.g., Aptiganel, CERESTAT, and CNS 1102) , NMDA receptor antagonists, NMDA receptor subtypes (e.g., Kainate quisqua-late
  • non-ionic copolymer RheothRx e.g., FPL-15896
  • nootropic/acetylcholine agonists e.g., FPL-15896
  • N-type calcium channel antagonists e.g., NS-626, and NS-638
  • opioid antagonists e.g., Nalmefene, nalmetrene, JF-1, ORF-11676, Cervene, and Incystene
  • opioid kappa receptor agonists e.g., acrylacetamide enadoline, and CI-997
  • organoselenims e.g., Ebselen, DR-3305, PZ-25,
  • oxygen scavengers e.g., Tirilazad mesylate, Lazaroids, and Freedox
  • PA2 inhibitors e.g., phospholipase A2 inhibitor
  • PAF antagonists e.g., nupafant
  • ACPC ACPC
  • peptide/ GPIIb/IIIa antagonists e.g., Integrelin
  • peptidic neuron-specific calcium channel antagonists e.g., SNX-111
  • phosphodiesterase inhibitors e.g., Xanthine
  • Hextol Hextol
  • phospholipase A2 inhibitors e.g., small organic molecule CEP-217
  • plasminogen activators e.g., plasminogen activators
  • r-ProUK recombinant pro-urokinase
  • platelet-activating factor antagonists e.g., r-ProUK (recombinant pro-urokinase)
  • Peptide e.g., cilostazol, peptide agents, GPHb-IIIA inhibitor, 34 and TP-9201
  • platelet aggregation inhibitors e.g., Diaminoalkanioic acid derivatives
  • potassium channel agonists e.g., Nicorandil, RP-46417, SG-75, and Adancor
  • prolyl endopeptidase (PEP) inhibitors e.g., JTP-4819
  • protein kinase C inhibitors e.g., monosialoganglioside derivative Liga-20
  • proteolytic enzyme inhibitors e.g., Protease nexin-1, Incyte, PN-1, PN-2, Nafamostat, FUT-175, Duthan, and Futhan
  • pyrimidine derivatives e.g., Protease nexin-1, Incyte, PN-1, PN-2, Nafamostat, FUT-175, Duthan,
  • Quinolizine derivatives e.g., KF-17329, and KF-19863
  • radical formation antagonists e.g., EPC-K1
  • recombinant tissue plasminogen activators e.g., alteplase, and Activase
  • Schwann cell derived molecules/promoters e.g., Sigma ligand
  • sigma antagonists e.g., Sigma ligand
  • sigma receptor antagonists e.g., tetrahyropyridinyl- isoxazolines and isoxazoles PD-144418
  • sodium/calcium channel modulators e.g., Lifarizine, and RS-87476)
  • sodium channel antagonists e.g., streptokinase (e.g., Streptase)
  • substituted guanadine e.g., small molecule CNS-1237
  • superoxide dismutase stimulants e.g.
  • urokinase e.g., Abbokinase
  • w-conopeptide e.g., SNX-111
  • warfarin e.g., Coumadin
  • agents useful for the treatment of carcinomas e.g., adriamycin, taxol, interleukin-1, interleukin-2 35
  • LHRH analogs such as nafarelin acetate
  • prostatic carcinoma agents useful for the treatment of prostatic carcinoma
  • agents useful for the treatment of endometriosis e.g., LHRH analogs
  • agents useful for the treatment of uterine contraction e.g., oxytocin
  • agents useful for the treatment of diuresis e.g., vasopressin
  • agents useful for the treatment of cystic fibrosis e.g., Dnase (i.e., deoxyribonuclease) , SLPI, and the like
  • agents useful for the treatment of neutropenia e.g., GCSF
  • agents useful for the treatment of lung cancer e.g., beta 1-interferon
  • agents useful for the treatment of respiratory disorders e.g., superoxide dismutase
  • N ( - (iminoethyl) -L-ornithine, thiocitrulline and other citrulline derivatives N ⁇ -nitro-L- arginine, N ⁇ -nitro-L-arginine methyl ester, N ⁇ -amino-L-arginine, and other arginine derivatives, isothiourea and its derivatives, and the like, as well as a variety of other agents, such as acyclovir, alendronate sodium, amlodipine, ampicillin, azelaic acid, azithromycin, beclomethasone, betamethasone, bicalutamide, buspirone, carisoprodol, carvedilol, cefaclor, cefadroxil, cefixime, cefprozil, ceftibuten, cefuroxime axetil, cephalexin, cetirizine hydrochloride, cimetidine, 36 ciprofloxacin, cisapri
  • the thiocarbonyl sulfide component and the pharmacalogically active agent of invention compounds can be covalently attached employing a variety of linkages, 37 e.g., disulfide linkages, thioamide linkages, thioether linkages, thioimide linkages, S-glycosidic linkages, and the like.
  • linkages can be accomplished using standard synthetic techniques as are well known by those of skill in the art, either by direct reaction of the starting materials, or by incorporating a suitable functional group on the starting material, followed by coupling of the reactants .
  • a method for the preparation of protected forms of pharmacologically active agents comprising covalently attaching a thiocarbonyl sulfide substituent to said pharmacologically active agent, wherein said covalent attachment is susceptible to cleavage under selected physiological conditions .
  • the resulting modified agent provides a latent form of the pharmacologically active agent, releasing the biological activity thereof only when the covalent bond linking the thiocarbonyl sulfide to said pharmacologically active agent is cleaved (e.g., by an esterase, amidase or other suitable enzyme) .
  • Cleavage of the covalent bond linking the thiocarbonyl sulfide to said pharmacologically active agent also releases free carbon disulfide, which imparts a drug sparing effect (i.e., reduces the amount of drug required to achieve a therapeutic effect) .
  • Release of free carbon disulfide also provides a protective effect on the liver by reducing the amount of active agent which is cleared by the liver.
  • pharmacologically active agent s
  • said method comprising covalently attaching a thiocarbonyl sulfide substituent to said pharmacologically active agent (s) prior to administration to said subject, wherein said covalent 38 attachment is susceptible to cleavage under selected physiological conditions.
  • pharmacologically active agent comprising covalently attaching a thiocarbonyl sulfide to said pharmacologically active agent, wherein said covalent attachment is susceptible to cleavage under selected physiological conditions.
  • improved methods for the administration of pharmacologically active agent (s) to a subject for the treatment of a pathological condition comprising covalently attaching a thiocarbonyl sulfide to said pharmacologically active agent prior to administration of said pharmacologically active agent to said subject, wherein said covalent attachment is susceptible to cleavage under selected physiological conditions, thereby releasing a therapeutically effective amount of carbon disulfide.
  • pharmacologically active agent s
  • said methods comprising covalently attaching a thiocarbonyl sulfide substituent to said pharmacologically active agent prior to administration to said subject, wherein said covalent attachment is susceptible to cleavage under selected physiological conditions.
  • methods for enhancing circulating levels of pharmacologically active agent (s) upon administration to a subject comprising covalently attaching a thiocarbonyl sulfide substituent to said pharmacologically active agent prior to administration thereof to said subject, wherein said covalent attachment is susceptible to cleavage under selected physiological conditions.
  • modified pharmacologically active agents described herein can be delivered in a variety of ways, such as, for example, orally, intravenously, subcutaneously, parenterally, rectally, by inhalation, and the like.
  • the modified pharmacologically active agents contemplated for use herein can be delivered in a variety of pharmaceutically acceptable forms.
  • the active agent can be delivered in the form of a solid, solution, emulsion, dispersion, micelle, liposome, and the like.
  • physiologically active composition comprising modified pharmacologically active agents as described herein in a suitable vehicle rendering said compound (s) amenable to oral delivery, transdermal delivery, intravenous delivery, intramuscular delivery, topical delivery, nasal delivery, and the like.
  • compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a micelle, a liposome, and the like, wherein the resulting composition contains one or more of the compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications .
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form.
  • auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
  • the active compound(s) is (are) included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and 41 palatable preparations.
  • Tablets containing the active ingredient in admixture with non- toxic pharmaceutically acceptable excipients may also be manufactured by known methods.
  • the excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874, to form osmotic therapeutic tablets for controlled release.
  • formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin.
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • the pharmaceutical compositions may be in the form of a sterile injectable suspension.
  • This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol .
  • Sterile, fixed oils are 42 conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid) , naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
  • compositions contemplated for use in the practice of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • suppositories for rectal administration of the drug.
  • These compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
  • the dosage of nitric oxide scavenger- containing conjugate of the invention employed as described herein falls in the range of about 0.01 mmoles/kg body weight of the subject/hour up to about 0.5 mmoles/kg/hr .
  • Typical daily doses lie within the range of from about 1 ⁇ g up to about 50 mg per kg body weight, and, preferably within the range of from 10 ⁇ g to 10 mg per kg body weight and can be administered up to four times daily.
  • the daily IV dose lies within the range of from about 1 ⁇ g to about 100 mg per kg body weight, and, preferably, within the range of from 10 ⁇ g to 10 mg per kg body weight. 43
  • invention method for the treatment of a subject afflicted with a pathological condition comprises administering to a subject an effective amount of a modified pharmacologically active agent, wherein said pharmacologically active agent is effective for treatment of said condition, and wherein said pharmacologically active agent has been modified by the covalent attachment thereto of a thiocarbonyl sulfide.
  • Wistar rats (200-250 grams, male) are fasted overnight but allowed free access to water. Ten rats in each group are given ibuprofen alone or ibuprofen modified according to the invention orally at doses of 10, 20 or 50 mg/kg. The rats are sacrificed five hours later and visible gastric damage is assessed by examining under microscope and histological evaluation. 44
  • White New Zealand rabbits male, about 1 kg are given subcutaneously ibuprofen alone or ibuprofen modified according to the invention at a dose of 30 mg/kg for every 12 hours.
  • the animals are sacrificed on day 4 (after the 7th dose) and the visible ulcers in the stomach are examined and measured with calipers.
  • the tissue samples are fixed in neutral buffered formalin and processed for histological evaluation.
  • Wistar rats male, 200-250 g are_ fasted overnight but allowed to free access to drinking water.
  • Ibuprofen alone or ibuprofen modified according to the invention is given orally at a dose of 1, 10, or 30 mg/kg (6 animals each group) .
  • the rats are anesthetized and 0.1 ml of lambda carrageenan (0.1% solution) is injected into the right hind foot pad. The volume of the pad is measured by hydroplethysmometry every hour for the next five hours.
  • Wistar rats male, 200-250 g are fasted overnight but allowed free access to drinking water. The rats are anesthetized and their backs are shaved. After an incision to the back, a sponge (2.5 x 1 x 0.5 cm) soaked with 2 ml of 0.5% carrageenan is implanted. Five hours later, the rats (6 animals in each group) are given orally 45 either ibuprofen alone or ibuprofen modified according to the invention at a dose of 30 mg/kg or vehicle control. One hour later, the rat is sacrificed and the sponge is carefully removed. The exudate is recovered from the sponge and the prostaglandin E2 level in the exudate is measured by enzyme-linked immunosorbent assay.
  • mice Male, 20-25 g are fed a standard diet and allowed free access to drinking water.
  • the mice are anesthetized and the telemetry system consisting of implantable transmitters, a telemetry receiver and analog ECG adapter is implanted in the peritoneal cavity of each mouse. After surgery, the mice are allowed to recover for two weeks .
  • the mice are given intravenously either adriamycin alone or adriamycin modified according to the invention at a dose of 4 mg/kg through the tail vein.
  • the treated mice are observed for two weeks.
  • the body weight, ECG and heart rate are recorded daily. At the end of the study, the animals are sacrificed and the hearts are processed for histological evaluation.

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Abstract

Selon la présente invention, des formes modifiées d'agents actifs sur le plan pharmacologique (par exemple des agents anti-inflammatoires) apportent des concentrations circulatoires accrues/à effet prolongé de l'agent actif, permettant ainsi d'administrer des concentrations réduites de cet agent à un receveur, ce qui diminue non seulement le coût du médicament mais également la concentration en agents potentiellement nocifs, à laquelle le receveur est exposé. Les composés de l'invention constituent une nouvelle classe d'agents actifs, sur le plan pharmacologique, provoquant une fréquence moins grande d'effets secondaires, par suite de l'effet bénéfique obtenu par modification pharmacologique de ces agents actifs.
PCT/US1999/002678 1998-02-13 1999-02-08 Agents modifies, actifs sur le plan pharmacologique, et procedes therapeutiques ameliores et mettant en oeuvre ces agents WO1999040787A1 (fr)

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US6759430B2 (en) 1998-01-22 2004-07-06 Oxon Medica Inc. Piperidine and pyrrolidine derivatives comprising a nitric oxide donor for treating stress
US6455542B1 (en) 1998-01-22 2002-09-24 Oxon Medica Inc. Piperidine and pyrrolidine derivatives comprising a nitric oxide donor for treating stress
US6448267B1 (en) 1998-01-22 2002-09-10 Oxon Medica, Inc. Piperidine and pyrrolidine derivatives comprising a nitric oxide donor for treating stress
EP2261200A3 (fr) * 2000-06-23 2010-12-29 Medinox, Inc. Formes modifiée d'agents à activitée pharmacologique et leurs usages
JP2004517037A (ja) * 2000-06-23 2004-06-10 メデイノックス，インコーポレイテッド 修飾された形の薬理活性薬物およびそれらの用途
US7378438B2 (en) 2002-04-19 2008-05-27 Yissum Research Development Company Of The Hebrew University Of Jerusalem Beta-agonist compounds comprising nitric oxide donor groups and reactive oxygen species scavenger groups and their use in the treatment of respiratory disorders
US8679481B2 (en) 2003-05-16 2014-03-25 Acorda Therapeutics, Inc. Methods of reducing extravasation of inflammatory cells
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US20090238876A1 (en) * 2005-02-17 2009-09-24 Haim Danenberg Bisphosphonates for treating endometriosis
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