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WO1996030012A1 - Procedes de traitement de conditions associees a des excedents d'oxyde d'azote - Google Patents

Procedes de traitement de conditions associees a des excedents d'oxyde d'azote Download PDF

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Publication number
WO1996030012A1
WO1996030012A1 PCT/US1996/003755 US9603755W WO9630012A1 WO 1996030012 A1 WO1996030012 A1 WO 1996030012A1 US 9603755 W US9603755 W US 9603755W WO 9630012 A1 WO9630012 A1 WO 9630012A1
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Prior art keywords
subject
condition
acid
inhibitory agent
selective
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PCT/US1996/003755
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English (en)
Inventor
Francis V. Defeudis
Original Assignee
Defeudis Francis V
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Application filed by Defeudis Francis V filed Critical Defeudis Francis V
Priority to AU53172/96A priority Critical patent/AU5317296A/en
Publication of WO1996030012A1 publication Critical patent/WO1996030012A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof

Definitions

  • Atherosclerosis is a disease which causes thickening and hardening of the arteries, and which is characterized by lesions of raised fibrous plaque formed within the arterial lumen.
  • Atherosclerotic plaque is commonly treated by means of angioplasty through the use of a balloon-tipped catheter.
  • Other devices such as atherosclerectomy instruments which remove obstructions by scraping or shaving plaque from the arterial wall, are also utilized in the treatment of atherosclerosis.
  • laser systems have been proposed for performing angioplasty. In laser angioplasty, a catheter carrying a fiber optic wave guide is passed through a blood vessel, positioned near an obstruction, and then activated to decompose the plaque with laser radiation.
  • Drug therapy is primarily directed toward the control of restenosis using antiplatelet agents, antiproliferative agents, or antimigratory agents.
  • the goal of drug therapy is to reduce smooth muscle cell proliferation by attacking the smooth muscle cells directly, or by affecting processes that promote smooth muscle cell proliferation. (Undoubtedly, most of the drugs under investigation are unproven, with unknown efficiency and side effects.)
  • Certain drugs have been found to be more effective than others in reducing the occurrence of restenosis. These drugs help reduce the necessity of repeating the angioplasty procedure. For instance, there are drugs which show a tendency to inhibit smooth muscle cell growth. Because these drugs can have undesirable side effects, it is not desirable that they be injected as a bolus dose into a peripheral vein and merely allowed to be carried by the bloodstream to the site of the stenotic lesion.
  • Heparin is one such known drug for inhibiting clotting which can be delivered by injection as a bolus and which is known to have disadvantages. For instance, some patients, such as ulcer patients or patients with high blood pressure, are contraindicated by the administration of such large amounts of heparin.
  • angiotensin II and growth factors, including platelet-derived growth factor (PDGF) and basic fibroblast growth factor (FGF) have been implicated in the development of vascular restenosis in vivo.
  • PDGF platelet-derived growth factor
  • FGF basic fibroblast growth factor
  • Angiotensin II receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, alpha-adrenoreceptor antagonists and growth factor antibodies have generally produced only a modest, e.g., between 10% and 50%, reduction of vascular restenosis in such animal models.
  • Clinical studies with ACE inhibitors which showed only a moderate protective effect in animal models of restenosis, have failed to demonstrate a significant efficacy in the prevention of restenosis in humans.
  • angioplasty techniques such as percutaneous transluminal coronary angioplasty (PTCA)
  • PTCA percutaneous transluminal coronary angioplasty
  • the catheter is passed percutaneously through the vascular system to an obstruction site within an artery or vessel and then inflated via an inflation medium to dilate the area of obstruction.
  • PTCA percutaneous transluminal coronary angioplasty
  • the outward compression of the balloon stresses the vessel walls, often resulting in cracking or tearing of the wall and injury to the smooth muscle cells. Consequently, balloon angioplasty procedures may contribute to the occurrence of restenosis in patients within the first year after the intervention.
  • a stent is a device (usually made of metal) that can be placed in the artery at the site of the stenosis.
  • the use of an intracoronary stent for the treatment of restenosis has decreased the incidence of associated myocardial infarction and emergent coronary bypass surgery.
  • the proposed mechanism of action of intracoronary stents and the treatment of acute closure or restenosis is the pinning of the intimal tears formed in the smooth muscle cells of the artery between the stent and the arterial wall, thereby maintaining vessel patency.
  • stents have been shown to be effective in restoring vessel patency and in decreasing myocardial ischemia, the exposure of the metal prosthetic surfaces to circulating blood initiates platelet and coagulation reactions that frequently result in thrombus formation and acute thrombotic occlusions of the stent.
  • the occurrence of thrombosis at the stent site can be a life threatening emergency that usually results in an emergent coronary angioplasty or emergent coronary bypass surgery.
  • the present invention satisfies a need to prevent restenosis following coronary procedures, such as angioplasty, and treats other conditions associated with the presence within the subject of excess nitric oxide (NO).
  • the invention provides an agent that treats conditions associated with excess NO.
  • the present invention is based, at least in part, on the discovery that conditions exist which are associated with excess NO, e.g., that level of NO that exists in the subject in excess of that amount necessary to maintain health and which is endogenously- derived and/or exogenously-acquired.
  • the present invention further provides for the use of selective inhibitory agents to treat such conditions. These agents selectively inhibit the actions and metabolic transformations of excessive amounts of endogenously-derived and/or exogenously-acquired NO which have deleterious effects while protecting that part of the NO generating mechanisms that are maintained intact for normal function.
  • the methods of this invention can be prophylactic and/or therapeutic treatments of a variety of conditions, e.g., inflammation, cancer, and restenosis.
  • the present invention provides methods for using a selective condition inhibitory agent to treat conditions associated with excess NO.
  • the method of the present invention provides advantages in that it allows a physician to adequately treat a variety of conditions that were heretofore difficult to treat or untreatable.
  • the agents employed to treat the conditions associated with the excess NO result in fewer, if any, side effects in the patient being treated.
  • the method of the present invention can be advantageous over conventional procedures since it is easily adaptable to existing treatments and thus can be used in combination therapies.
  • the present invention provides a method for treating a condition associated with excess NO in a subject by administering to the subject an effective amount of a selective inhibitory agent to treat the condition.
  • the present invention further pertains to compositions for treating conditions associated with excess NO in a subject.
  • Other aspects of the invention include packaged inhibitory agents that include instructions relating to use, dosage and regimen.
  • the present invention pertains to a method of treating a condition associated with excess nitric oxide (NO) in a subject.
  • the method involves the administration of an effective amount of a selective condition inhibitory agent, as described below, to the subject such that the condition associated with the excess nitric oxide is treated.
  • treating a condition is intended to include preventing, inhibiting, reducing, or delaying the progression of the condition.
  • condition associated with excess NO is intended to include acute or chronic degenerative disorders and/or general and/or injury-induced disease states that are at least partially caused by or exacerbated by having excess NO or metabolites associated with excess NO in the subject.
  • the condition can arise from the presence of excess NO in the subject and/or the presence in the subject of deleterious metabolites, e.g., nitrosamines, of NO formed by the various metabolic transformations involving excess nitric oxide.
  • the condition can include, for example, hyperplasia, atherogenesis, carcinogenesis, neurodegenerative disorders, inflammatory disorders, and auto-immune diseases.
  • a subgenus of the present invention as a method for treating conditions associated with excess NO provided that the condition is not carcinogenesis when the selective inhibitory agent is an ascorbic acid derivative.
  • the term hype ⁇ lasia is intended to include the undesirable and unwanted proliferation of cells or tissue.
  • the undesirable growth can include the growth of neoplasms or the growth of benign cells such as in tissue where the growth is inappropriate.
  • Hype ⁇ lasia is intended to include intimal hype ⁇ lasia, carcinogenesis and artherogenesis.
  • Intimal hype ⁇ lasia preferably includes the internal proliferation of cells of an organ or tissue of the subject, and more preferably the proliferation of vascular smooth muscle cells bordering the inner (luminal) lining of the blood vessel.
  • Atherogenesis preferably includes the formation of stenosis and the development of restenosis in particular.
  • carcinogenesis is intended to include all forms of hype ⁇ lasia of the tumorous as well as nontumorous type.
  • types of cancer covered by the present invention include breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer of the larynx, gallbladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi and kidneys, and leukemia.
  • the tumors associated with the foregoing types of cancer that are treated by the selective condition inhibitory agent of the present invention include basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteosarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hype ⁇ lasia, medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, hype ⁇ lastic corneal nerve tumor, marfanoid habitus tumor, Wilm's tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant
  • the neurodegenerative disorder that is treated by the present invention is intended to include all idiopathic, genetic or trauma-induced disorders. Examples include Alzheimer's disease, Huntington's disease, Parkinson's disease, epilepsy, olivopontocerebellar atrophy, Parkinsonian dementia, amyotrophic lateral sclerosis (ALS) (e.g., Guam ALS), Down's syndrome, Korsakoff s disease, multi-infarct dementia, and HIV-induced dementia.
  • ALS amyotrophic lateral sclerosis
  • Korsakoff s disease multi-infarct dementia
  • HIV-induced dementia HIV-induced dementia.
  • the inflammatory disorders of the present invention include those disorders that result in irritation, injury or infection of various tissues and organs of the subject. Generally, inflammatory disorders are most apparent in the joints and related connective tissue of the subject, and include osteoarthritis, rheumatoid arthritis, tendinitis, bursitis, and like disorders.
  • the auto-immune disorders of the present invention are intended to include those disorders that inhibit an immune response by the subject, and specifically those disease states that involve an immune response during which nitric oxide-producing cells, e.g., macrophages, are activated.
  • Specific auto-immune disorders covered by the present invention include multiple sclerosis (MS), allergic encephalomyelitis, autoimmune hemolytic anemia, sympathetic ophthalmia, chronic immune thrombocytopenic pu ⁇ ura (ITP), atopic dermatitis, systemic lupus erythematosus (SLE), autoimmune deficiency syndrome, myasthenia gravis (MG), and other related disorders that are typically caused by aberrant T cells.
  • MS multiple sclerosis
  • ITP chronic immune thrombocytopenic pu ⁇ ura
  • SLE systemic lupus erythematosus
  • MG myasthenia gravis
  • disorders covered by the present invention include stroke, cataracts, sepsis, thyrotoxicosis, osteoporosis, and asthma.
  • subject is intended to include mammals having or being susceptible to a condition associated with excess NO. Examples of such subjects include humans, dogs, cats, pigs, cows, horses, rats and mice.
  • administering is intended to include all routes of administration which allow the selective condition inhibitory agent to perform its intended function of treating conditions associated with excess NO.
  • routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal, etc.), oral, inhalation, and transdermal.
  • the injection can be bolus injections or can be continuous infusion.
  • catheters and other mechanical drug delivery devices can be employed to introduce the agent into the subject and/or to introduce the agent to a specific site for treatment.
  • Other catheter designs not listed above and representing variations of these catheters is deemed to be within the purview of one of ordinary skill, and thus can also be utilized in the present invention.
  • the stent can introduce the agent into the subject by inco ⁇ orating the agent into the coating that is applied to the stent by known techniques, such as by chemical vapor deposition, ion beam implantation, and plasma deposition.
  • the selective inhibitory agent can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally affect its ability to perform its intended function.
  • a selected material to protect it from natural conditions which may detrimentally affect its ability to perform its intended function.
  • One such example includes the use of liposomes to encapsulate or inco ⁇ orate the agent.
  • the agent can further be encapsulated by a biocompatible and or biodegradable microparticle, e.g., a polymeric matrix, to effectuate a time-controlled release of the bound agent.
  • the selective inhibitory agent can be administered alone, or in conjunction with other suitable agents or with a pharmaceutically acceptable carrier, or both.
  • the inhibitory agent can be administered to the subject prior to the onset of the condition, during the condition, or after the onset of the condition.
  • the selective inhibitory agent can also be administered as a prodrug which is converted to its active form in vivo.
  • pharmaceutically acceptable carrier is intended to include substances capable of being coadministered with the selective inhibitory agent, and which allows it to perform its intended function of treating conditions associated with excess nitric oxide.
  • examples of such carriers include solutions, solvents, dispersion media, delay agents, emulsions and the like.
  • the use of such media for pharmaceutically active substances are well known in the art.
  • Any other conventional carrier suitable for use with the selective condition inhibitory agent also falls within the scope of the present invention.
  • the language "effective amount" of the selective condition inhibitory agent is that amount necessary or sufficient to treat conditions associated with excess nitric oxide in the subject.
  • the effective amount can vary depending on such factors as the type of condition being treated, the location of the condition, the type of selective inhibitory agent employed, the potency of the agent, the residence time of the agent within the subject, the size of the subject, the severity of the condition, the mode of application of the agent, and the particular site of administration.
  • the choice of the inhibitory agent can affect what constitutes an "effective amount”.
  • One of ordinary skill in the art would be able to study the aforementioned factors and make the determination regarding the effective amount of the selective condition inhibitory agent without undue experimentation.
  • in vitro and in vivo assays as described in the Examples below or an assay similar thereto (e.g., differing in choice of condition and inhibitory agent) also can be used to determine an "effective amount" of the inhibitory agent.
  • the ordinarily skilled artisan would select an appropriate amount of the agent for use in the aforementioned in vitro and in vivo assays.
  • the effective amounts used in the foregoing assays result in a reduction in urinary nitrite/nitrate levels to normal levels, or a reduction in the level of exhaled NO to normal levels.
  • the regimen of administration also can affect what constitutes an effective amount.
  • the selective condition inhibitory agent can be administered to the subject prior to, simultaneously with, or after the onset of the particular condition. Further, several divided dosages, staggered dosages, as well as a time-controlled release of the agent in selected dosages, can be administered daily or sequentially, or the dose can be continuously infused depending upon the type of agent employed and the preferred mode of administration to the subject. Further, the dosages of the agent can be proportionally increased or decreased as indicated by the exigencies of the therapeutic situation.
  • selective condition inhibitory agent is intended to include agents that selectively inhibit the actions and metabolic transformations of excessive amounts of endogenously-derived and/or exogenously-acquired NO.
  • the inhibitory agent preferably inhibits the deleterious affects of excess NO in the subject by inhibiting selectively the formation of deleterious metabolites involving excessive NO.
  • the agent can inhibit the selected condition by scavenging excess NO in the subject, scavenging nitrite/nitrate, scavenging NO2, scavenging superoxide anion radicals and/or hydroxyl radicals, and/or "inactivating" the formation or action of metabolites formed in pathways involving NO, such as nitrosamines, preferably by preventing the transformation of the metabolites within the subject into more reactive, e.g., mutagenic or carcinogenic, substances.
  • the selective inhibitory agents are "selective" in that the agents allow for the protection of that part of the NO-generating mechanisms that must be maintained for normal function (via inactivating O2"), while eliminating the excess NO that is deleterious, e.g., via inhibiting the formation of or inactivating nitrosamines.
  • the selective inhibitory agents of this invention include anti-oxidants, nitric oxide trappers, nitrite-scavengers, nitrate- scavengers, reductants, and combinations of these agents, as well as other related agents.
  • anti-oxidants is intended to include those naturally occurring or artificially synthesized organic compounds that are utilized to retard oxidation.
  • the anti- oxidants of the invention include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), gallic acid, esters of gallic acid and benzoic acid, vitamins, sulfur compounds, phosphate compounds, caffeic acid, eugenol, ferulic acid, catechol, chlorogenic acid, nordihydroguaiaretic acid (NDGA), flavonoids, e.g., naturally- occurring and synthetic, diketones such as ⁇ -diketones, cysteine such as L-cysteine, glutathione, reduced glutathione peroxidase, tocopherols, analogues and derivatives of ascorbic acid, ellagic acid, hesperidin, hydroquinone, phenylhydrazine,
  • the preferred ascorbic acid derivative of this invention is encompassed by the formula set forth below:
  • X is selected from the group consisting of N, O, S, NR4, and CR5, where R4 and R5, if present, are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, and aryl;
  • R ⁇ is a moiety selected from the group consisting of hydrogen, hydroxyl, halogen, amino, ester, alkyl, alkenyl, alkynyl, and aryl, haloalkyl, and alkoxyl;
  • R2 and R3 are each independently a moiety selected from the group consisting of hydrogen, hydroxyl, O-R , ester, halogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, and alkoxyl, wherein Rg is selected from the group consisting of alkyl, alkenyl, alkynyl, and aryl.
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), more preferably 20 or fewer, and most preferably 6 or fewer.
  • preferred cycloalkyls have from 4-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • alkyl as used throughout the specification and claims is intended to include both "unsubstituted alkyls" and “substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, a halogen, a hydroxyl, a carbonyl, an alkoxyl, an ester, a phosphoryl, an amine, an amide, an imine, a thiol, a thioether, a thioester, a sulfonyl, an amino, and a nitro moiety.
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amines, imines, amides, phosphoryls (including phosphonates and phosphines), sulfonyls (including sulfates and sulfonates), and silyl groups, as well as ethers, thioethers, selenoethers, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, thioalkyls, aminoalkyls, carbonyl-substituted alkyls, CF3, CN, and the like.
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond respectively.
  • lower hydrocarbons as used herein means an alkyl, alkenyl, and/or an alkynyl group, as defined above, but having from one to three carbons, and more preferably from one to six carbon atoms in its backbone structure.
  • higher hydrocarbons as used herein means an alkyl, alkenyl, and/or an alkynyl group, as defined above, but having from three to thirty carbons, and more preferably from six to twenty carbon atoms in its backbone structure.
  • Examples of lower hydrocarbon groups which may be used in the present invention include methyl, methylene, ethyl, ethylene, ethenyl, ethenylene, ethynl, ethynylene, propyl, propylene, propenyl, propenylene, propynyl, and propynylene.
  • Examples of higher hydrocarbon groups include butyl, t-butyl, butenyl, butenylene, and butynyl, butynylene, nonyl, nonylene, nonenyl, nonenylene, nonynyl, and nonynylene.
  • the alkoxyl and haloalkyl groups are alkyl or alkylene groups substituted with one or more oxygen or halogen atoms.
  • the alkoxy and haloalkyl groups may be straight or branched chain and preferably are made up of up to about ten atoms (including carbon, oxygen or halogen), preferably up to about six atoms, and most preferably up to about three atoms.
  • the term halogen is art-recognized and includes chlorine, fluorine, bromine, and iodine. Examples of substituted hydrocarbon groups which are useful within this invention are similar to hydrocarbon groups set forth above except for the inco ⁇ oration of oxygen(s) or halogen(s) into the groups.
  • nitro means -NO2; the term “thiol” means -SH; the term “hydroxyl” means -OH; and the term “sulfonyl” means -SO2-.
  • thioalkyl refers to an alkyl group, as defined above, having a sulfhydryl or thioether group attached thereto.
  • the "thioether” moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2) -R7 > wherein R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle and m is zero or an integer in the range of 1 to 8.
  • carbonyl-substituted alkyl as used herein means an alkyl group, as defined above, having a substituted or unsubstituted carbonyl group attached thereto, and includes aldehydes, ketones, carboxylates and esters.
  • alkoxyl or "alkoxy” as used herein refer to an alkyl group, as defined above, having an oxygen attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons linked by an oxygen. Accordingly, the substituent of an alkyl which renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH2) m -R7, where m and R7 are described above.
  • sulfonate as used herein means a sulfonyl group, as defined above, attached to an alkyl or aryl group.
  • sulfate as used herein, means a sulfonyl group, as defined above, attached to a hydroxy or alkoxy group.
  • Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, alkenylamines, alkynylamines, alkenylamides, alkynylamides, alkenylimines, alkynylimines, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls, alkenoxyls, alkynoxyls, metalloalkenyls and metalloalkynyls.
  • aryl as used herein includes 4-, 5-, 6- and 7-membered single-ring aromatic groups which may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycle”.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or -(CH2) m -R7. -CF3, -CN, or the like.
  • substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ether
  • heterocycle or “heterocyclic group” refer to 4 to 10-membered ring structures, more preferably 5 to 7 membered rings, which ring structures include one to four heteroatoms.
  • Heterocyclic groups include pyrrolidine, oxolane, thiolane, imidazole, oxazole, piperidine, piperazine, mo ⁇ holine.
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or -(CH2) m -R7 > -CF3, -CN, or the like.
  • substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls,
  • polycycle or “polycyclic group” refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or -(CH2) m -R7, -CF3, -CN, or the like.
  • substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers
  • the ascorbic acid derivatives of the present invention are publically available or can be prepared using art-recognized techniques. Examples of such methods and derivatives are described in Hatanaka et al. (U.S. Patent No. 5,008,405), issued April 16, 1991, Suzuki et al. Jpn. J. Cancer Res. 82, 386-389, April 1991), Kato et al. (Journal of Medicinal Chemistrv 31 , 793, 1988) and Kushida et al. rCarcinogenesis Vol. 13, No. 6, pp 913-915, 1992) the contents of each are herein inco ⁇ orated by reference.
  • nitric oxide trappers is intended to include compounds that trap NO. Examples include hemoproteins such as hemoglobin, derivatives of hemoglobin such as oxy hemoglobin, heme, hemin, hematin, ovoglobulin, ovoconalbumin, cytochrome C, cytochrome P450 > polymerized hemoglobin, ovomucin, and lactalbumin.
  • hemoproteins such as hemoglobin
  • derivatives of hemoglobin such as oxy hemoglobin, heme, hemin, hematin, ovoglobulin, ovoconalbumin, cytochrome C, cytochrome P450 > polymerized hemoglobin, ovomucin, and lactalbumin.
  • nitrite/nitrate-scavengers is intended to include compounds that scavenge nitrite/nitrate. Examples include ascorbic acid derivatives, urea, phthaloyl dichloride (PDC), benzene, toluene sulfonyl chloride, and aminosulphonic acid, urea and N- methyl nitroanaline.
  • PDC phthaloyl dichloride
  • benzene toluene sulfonyl chloride
  • aminosulphonic acid urea and N- methyl nitroanaline.
  • reductant is intended to include those compounds that also retard oxidation by either 1) accepting one or more electrons by an atom or ion, 2) removing oxygen from a compound or agent, or 3) adding hydrogen to a compound.
  • the reductant preferably treats the condition associated with excess NO by selectively inhibiting the deleterious metabolites associated with excess nitric oxide.
  • reductants utilized in the present invention include alcohol, ether, ketones, aldehyde, azo and diazo compounds, sulfides, bisulfides, hydrosulfides, hydroquinones, and hydrogen peroxide.
  • the inhibitory agent of the present invention can further be selected according to a list of characteristics that exemplify the preferred functionalities of the agent.
  • the agent can thus be selected on the basis of one or more of the following characteristics: 1) the agent is amphiphilic; 2) the agent is a scavenger of nitrogen dioxide; 3) the agent is an inhibitor of nitrosation; 4) the agent is a scavenger of reactive oxy free radicals; 5) the agent is a scavenger of the superoxide anion radical; 6) the agent is an inhibitor of lipid peroxidation; 7) the agent is a scavenger or trapper of NO; 8) the agent is an inhibitor of the metabolic conversion of nitrosamines into more reactive substances; and 9) the agent has an inherent propensity to act on activated cells.
  • the selective inhibitory agent of the invention can also be selected on the basis of a set of domains.
  • the agent can have a first domain or moiety that is substantially lipophilic and a second domain or moiety that is substantially hydrophilic.
  • excess NO is intended to include both exogenously-acquired and endogenously-derived levels of NO that are above, greater than, or in excess of that level of NO in the subject that is created by both the inducible and constitutive enzymatic pathways and which is necessary for the health and maintenance of the subject.
  • the excess NO can arise from the increased synthesis of endogenous NO, for example, by the induction of an NO-synthesizing enzyme, e.g., NO-synthase, by substances released from cells and/or can arise from the accumulation of exogenous nitric oxide from environmental and/or nutritional sources.
  • NO-synthesizing enzyme e.g., NO-synthase
  • cells that produce NO include macrophages, endothelial cells, astrocytes, neurones neutrophils, hepatocytes, and Kupffer cells.
  • NO2 nitrosation
  • NO2 nitrosating agents
  • NO3 nitrosating agents
  • selected cells such as activated endothelial cells and macrophages.
  • NO2 is formed in vivo by bacterial reduction of NO3" and/or by selected cells, such as activated endothelial cells and macrophages.
  • NO2 is formed in vivo by cells through the enzymatic oxidation of L-arginine to NO, which reacts with oxygen to form nitrogen dioxide ( NO2).
  • NO2 exists in equilibrium with several potent nitrosating agents, e.g., N2O3 and N2O4. Ensuing reactions involving these agents yields nitrosamines, which are deleterious metabolites.
  • the endogenous production of nitrosamines can naturally occur in the subject, such as in the oral cavity, urinary bladder, sigmoid colon, and in the vaginal vault.
  • the present invention further pertains to packaged condition inhibitors containing a selective condition inhibitory agent as described above, packaged with instructions for using the agent as a treatment for conditions associated with excess NO.
  • the instructions would provide selected information such as the appropriate dose of the agent or the appropriate regimen.
  • Example 1 The In Vitro Inhibitory Effect of an Anti-Oxidant On PDGF-NO- nnnr Mediated Growth of Cultured Smooth Muscle Cells from Human Primary Stenosing and Restenosing Lesions
  • the anti-oxidant is administered in this example to illustrate the mitogenic or co-mitogenic effect of nitric oxide (NO) and the effect of an anti-oxidant on the enhanced sensitivity of restenosing cells to growth factors.
  • NO acts as an amplification or progression factor in cell growth.
  • Smooth muscle cells are isolated from human primary stenosing lesions (ps- SMC) and fresh restenosing lesions (re-SMC) after percutaneous transluminal atherectomy of severely stenosed or completely occluded superficial femoral arteries. The cells are isolated and grown in culture, and then subcultured. Cell growth curves and the effects of growth factors are then determined.
  • PDGF platelet-derived growth factors
  • an exogenous NO-donor such as SIN-1 or an endogenous NO-precursor such as L-arginine alone
  • IL-1 ⁇ 0.1 - 30 ng/ml
  • PDGF + NO- donor or L-arginine, and PDGF + NO-donor or L-arginine + IL-1 ⁇ are tested.
  • the preventive o action of 2-O-octadecylascorbic acid (10 to 10 M, since its EC50 for inhibiting lipid peroxidation in rat brain homogenates is 4.3 x 10 M) (see Kato et al, Medical.
  • IL-1 ⁇ is used since PDGF acts as a "competence" factor in the cell proliferation that may be induced by IL-1 ⁇ (Iida et al, Proc. Natl. Acad. Sci. 88, 6560-6564 (1991)).
  • IL-l ⁇ is also considered to be useful since it is a potent inducer of the inducible form of NO-synthase, and therefore favors excessive NO formation.
  • the PDGF is administered to show that re-SMC exhibits enhanced proliferation in response to PDGF, whereas pr-SMC does not respond to PDGF at the concentrations tested.
  • the candidate drug e.g., 2-O-octadecylascorbic acid
  • NO-donor or L-arginine enhances the growth response to PDGF, NO serves as a progression or amplification factor in the sequence of events that follows arterial injury, leading to restenosis.
  • This antioxidant is administered in this example to illustrate the in vivo inhibitory effect of anti-oxidants on a stenosis.
  • Group 1 (control) is treated with only standard food (or the drug vehicle).
  • Group 2 receives 0.01% 2-O-octadecylascorbic acid in their food (low dose), and
  • Group 3 receives 0.1% 2-O-octadecylascorbic acid in their food (high dose).
  • Treatment with the anti-oxidant is started 1 to 2 weeks before balloon injury, e.g., which occurs during the angioplasty procedure, and is continued until at least two weeks after balloon injury.
  • Exogenous NO-donors e.g., nitroglycerin or SI -1
  • L-arginine an endogenous precursor to enzymatically synthesized NO
  • the intimal proliferation of smooth muscle cells that occurs in response to the balloon injury is essentially complete in fourteen (14) days (see Steele et al, Circ. Res. 57, 105-112 (1985)).
  • the animals receive 325 mg aspirin per day to reduce the incidence of acute thrombosis after balloon injury.
  • the foregoing example involves the infliction of the balloon injury after the animals are sedated with a combination of ketamine (25 mg/kg), acepromazine (1.1 mg/kg) and atropine (0.6 mg/kg), administered in combination by intramuscular injection in the right femoral artery (other details concerning methodology and drugs is described in Schneider et al, Circulation 88, 628-637 (1993)).
  • Coronary injuries of the left anterior descending coronary artery (LAD) and the left circumflex artery (LCx) are achieved by stretching the vessel wall with an oversized angioplasty balloon, which is inflated three times and then withdrawn from the artery.
  • the injured coronary artery segments of the LAD and LCx are located with the aid of coronary angiograms, then dissected in block from the heart.
  • Serial 4-mm sections are processed and embedded in paraffin, and then cross-sections (e.g., 4 ⁇ m thick) are stained with hematoxylin-eosin, Verhoeff-van Gieson, and Masson's trichrome stains.
  • Each specimen is then evaluated for the presence of intimal proliferation, luminal encroachment, medial dissection, and alteration of the internal and external elastic lamina using a grading system.
  • Mo ⁇ hometric analysis is performed on the section of each artery with the largest neointimal lesion using a computerized IBM-based system. Data is expressed as maximal
  • intimal thickness in mm
  • intimal area in mm
  • residual lumen defined as luminal to intimal plus luminal ratio
  • Plasma and urinary nitrite/nitrate (N ⁇ 2 ⁇ /N ⁇ 3 ⁇ ) concentrations are measured before the intervention, during the intervention, and fourteen days after the intervention.
  • blood samples are taken and the plasma NO2" concentration is determined by first reducing the NO3" concentration enzymatically using nitrate reductase from Aspergillus species. Briefly, plasma samples are diluted 1 :4 or 1 : 10 with distilled water and incubated with assay buffer (composition, Mm: KH2PO4, 50; NADPH, 0.6; FAD, 5; and NO3" reductase, 20 mu; pH 7.5) for 1 hour at 37° C.
  • assay buffer composition, Mm: KH2PO4, 50; NADPH, 0.6; FAD, 5; and NO3" reductase, 20 mu; pH 7.5
  • a standard curve for NO3" is constructed and the resultant NO2" concentrations are determined by chemiluminescence (see Rees et al, Br. J. Pharmacol. 114, 689-693 (1995)).
  • Urinary NO2VNO3- levels are measured by an automated procedure (see Kanno et al, Clin. Exp. Pharmacol. Physiol. 19, 619-625 (1992)).
  • Inducible NO synthase activity is determined in various tissues (e.g., macrophages, spleen, liver, heart, injured and normal coronary arteries) upon sacrifice of the control and the anti-oxidant-treated animals to provide estimates of NO generation.
  • Exhaled NO is measured before, during, and after balloon injury (at designated time intervals) using a chemiluminescence analyzer sensitive to NO (2 to 4000 p.p.b., by volume), adapted for on-line recording of NO concentration (see Kharitonov et al., Lancet 343, 133-135 (1994)).
  • the anti-oxidant is administered in this example to illustrate the ex vivo inhibitory effects of anti-oxidants on restenosis.
  • Balloon-injury via angioplasty procedures to rat carotid arteries induced the production of NO (in 6 and 24 hours) by increasing the NO-synthase activity in the blood vessel wall.
  • This effect is enhanced by the administration of IL-l ⁇ (30 IU/ml) to the subject.
  • the increased NO-synthase activity is correlated with decreased reactivity of the blood vessel to phenylephrine and with an accumulation of cyclic-GMP.
  • vascular smooth muscle cells contain a system that generates NO and this system is activated following vascular injury in vivo.
  • IL-1 ⁇ mediates the induction of NO-synthase in the injured blood vessel wall.
  • IL-l ⁇ , PDGF and excess NO are all involved in mediating the cell proliferative response to injury that eventually leads to restenosis.
  • the anti-oxidant is administered in this example to show that excess NO mediates the formation of restenosis, and that cyclic-GMP (the "NO receptor") mediates the early growth-programming events that eventually lead to restenosis.
  • cyclic-GMP the "NO receptor”
  • balloon-injured arteries show an increase in sensitivity to IL-l ⁇ .
  • rats are pretreated with a candidate drug, such as the anti-oxidant 2-O- octadecylascorbic acid at doses of 0.05%, 0.1% or 1.0% in food (see Konishi et al, s. Second Joint Meeting of the AACR/JCA February 10-14 (1992)), or 1-100 mg/kg p.o., or 0.3-30 mg/kg i.p. (based on pharmacokinetic data for rats given by Terao S., Medical. Biochemical and Chemical Aspects of Free Radicals. 477-480 (1989)), and the measurements of NO synthase activity, cyclic-GMP formation and responses to IL-l ⁇ are compared with the control (basal diet or vehicle-treated) animals.
  • a candidate drug such as the anti-oxidant 2-O- octadecylascorbic acid at doses of 0.05%, 0.1% or 1.0% in food (see Konishi et al, s. Second Joint Meeting of the AACR/J
  • the anti-oxidant is administered in this example to illustrate the capacity of anti-oxidants to treat in vitro inflammatory disorders.
  • Nitrosation of secondary amines typically occurs in stimulated macrophages, a major cell type involved in inflammatory reactions and in the process of "accelerated atherogenesis” (e.g., restenosis).
  • Immunostimulated (activated) macrophages are involved in inflammatory reactions and in responses to injury.
  • Miwa et al, Carcinogenesis 8, 955-958 (1987) showed that macrophages (cultured cell lines and freshly-isolated macrophages) produced NO2" and N-nitrosomo ⁇ holine when they were immunostimulated with Escherichia coli lipopolysaccharide (LPS) in the presence of mo ⁇ holine (a secondary amine).
  • LPS Escherichia coli lipopolysaccharide
  • mo ⁇ holine a secondary amine
  • Several other secondary amines are also N-nitrosated. The secondary amines act to "tap out" some intermediate in the pathway from the precursor to the final products, NO2" and NO3-.
  • This example assesses the abilities of anti-oxidants to inhibit the in vitro formation of nitrosamines which, upon further metabolic transformation, are involved in the formation of mutagenesis, carcinogenesis, atherogenesis and inflammation disorders.
  • Macrophage cell lines e.g., J774.1, PU5-1.8, WEHI-3 or RAW264 and freshly isolated macrophages from C3H/ ⁇ e mice. These cells are cultured in
  • Nitrosamines are extracted from the cells with dichloromethane and the extracts are analyzed by a gas-chromatography-thermal energy analyzer (see Miwa et al, cited supra). Under these conditions, the cells mentioned above produce NO2" and N- nitrosomo ⁇ holine, with LPS being required for both processes.
  • the candidate anti-oxidant, 2-O-octadecylascorbic acid is tested by adding it to the culture medium over a concentration range of 10 to 10 M. The formation of N-nitrosomo ⁇ holine and NO2" by the cells is monitored for the incubation periods 0-12 hours, 24-36 hours and 48-60 hours.
  • the anti-oxidant is administered in this example to show that NO2" and NO3- synthesis is a general property of "activated" macrophages, and provides evidence that the formation of NO2", NO3" and N-nitrosamines are inhibited by 2-O-octadecylascorbic acid. Consequently, the deleterious effects of excess NO, one of which is nitrosamine formation (see Tannenbaum et al., Am. J. Clin. Nutr. 53, 247S-250S (1991)), are inhibited by the candidate anti-oxidant.
  • the anti-oxidant is administered in this example to illustrate the capacity of anti-oxidants to treat in vivo inflammatory disorders.
  • adjuvant-induced arthritis which involves a T-lymphocyte-mediated delayed hypersensitivity reaction (see Cohen I. R., Annu. Rev. Pharmacol. 9, 567-589 (1991)), is widely used as a model for studying the anti- inflammatoiy /anti-rheumatic properties of compounds.
  • adjuvant arthritis induced in rats by M. tuberculosis is exacerbated by L-arginine (an NO precursor) and suppressed by N -nitro-D-arginine methyl ester (L-NAME; an NO synthase inhibitor).
  • Test compounds are dissolved in the animals' drinking water, or given with food (for 2-O-octadecylascorbic acid). Two groups are given tap water, one without any treatment for recording normal values of parameters (naive group), the other to serve as control of the adjuvant arthritis.
  • L-arginine (30 mg/ml) is given in the drinking water from Day 7 to Day 35.
  • 2-O-Octadecylascorbic acid (0.05%-l .0% in food) is administered during the total course of this regimen to the control arthritic animals and to the animals treated with L-arginine.
  • adjuvant arthritis is induced in all rats except the naive group by a single intradermal injection (0.1 ml) into the right foot pad of 0.3 mg heat-killed M. tuberculosis in Freund's incomplete adjuvant.
  • the inflammatory response is evaluated by measuring the volume of the contralateral (non-injected) hind paw (secondary lesion). Paw volume is determined by plethysmometry immediately after immunization and every seven days for a total period of thirty-five days. Weight gain is also measured on these days (reduced weight gain is a feature of adjuvant arthritis).
  • T-lymphocyte proliferation assays are carried out (in microwell plates) in which the cells (10 cells/well) are stimulated with M. tuberculosis (final cone: 5 ⁇ g/ml) and incubated for seven days at 37° C in 5% CO2 humidified air.
  • M. tuberculosis final cone: 5 ⁇ g/ml
  • peritoneal macrophages are isolated and plated in 24-well culture plates at a concentration of 2.5 x 10 cells/ml and incubated for 24 hours. Aliquots of the medium are then taken for assay of NO2" and acid phosphatase activity (see lalenti et al. , cited supra).
  • the anti-oxidant is administered to show that the candidate anti-oxidant reverses the pro-inflammatory and other effects (i.e., reduced weight gain, enhanced proliferation of T-lymphocytes, increased production of NO2" by macrophages, and increased release of acid phosphatase from macrophages) of L-arginine since these changes are caused by the excessive formation of NO.
  • An exogenous NO-donor also acts like L- arginine in exacerbating adjuvant arthritis, and such an effect is opposed by the candidate anti-oxidant.
  • the anti-oxidant is administered in this example to illustrate the capacity of anti-oxidants to treat in vivo inflammatory disorders.
  • the concentration of exhaled NO is increased in patients with asthma (see Kharitonov et al, Lancet 343, 133-135 (1994); and Persson et al, Lancet 343, 146-147 (1994)) and bronchiectasis (chronic dilatation of bronchii and bronchioles) (see Kharitonov et al, Clin. Sci. 88, 135-139 (1995)).
  • This increase is caused by the increased expression of inducible NO-synthase in the inflamed lower respiratory tract, which is supported by the findings that asthmatic patients who are treated with inhaled steroids have normal levels of exhaled NO (see Kharitonov et al, 1994 cited supra).
  • Example 7 The In Vitro Inhibitory Effect of Anti-Oxidants On Carcinogenesis
  • the anti-oxidant is administered in this example to illustrate that anti-oxidants inhibit in vitro the mutagenic effects and responses of excess NO.
  • NO and NO-donors e.g., spermine-NO complex and nitroglycerin
  • Salmonella typhimurium strain TA1535 reversion of histidine dependence of the cells back to prototrophy mainly via C — * > T transitions in the bisG46 (CCC) target codon, consistent with a cytosine-deamination mechanism
  • CCC bisG46
  • NO nitrogen oxides
  • the mutagenic activity of NO is effectively blocked by ⁇ -carotene, tocopherols, and the amphiphilic anti-oxidant 2-O-octadecylascorbic acid, whereas BHT, dimethyl- ⁇ -carotene and mannitol also block the mutagenic effects of NO x but are less effective.
  • Ascorbic acid is ineffective (all measured by assessing the frequency of reversion to histidine prototrophy in Salmonella typhimurium TA1535 as an indicator of reversal of NO" or NO2" induced genetic damage).
  • the anti-oxidant is administered in this example to illustrate that anti-oxidants inhibit in vivo the mutagenic effects and responses of excess NO.
  • Transplantable subcutaneous tumors such as C-3 fibrosarcoma or melanoma
  • the groups are broken up into three separate groups.
  • Group 1 control
  • group 2 low dose
  • group 3 high dose
  • Each group is further divided into two groups, the first group receiving L-arginine and the second group receiving an exogenous NO-donor, such as molsidomine or its active metabolite 3-mo ⁇ holino-sydnonimine (SIN-l) or nitroglycerin.
  • NO-donor and L-arginine are administered to the rats to determine if they are possible enhancers of carcinogenesis.

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Abstract

Cette invention concerne l'utilisation d'un agent sélectif inhibiteur destiné au traitement prophylactique et/ou thérapeutique d'états associés à un excédent d'oxyde d'azote (NO). La présente invention propose également des procédés d'utilisation de l'agent sélectif inhibiteur destiné au traitement d'états associés à un excédent d'oxyde d'azote. Cette invention s'appuie, au moins en partie, sur la découverte que les agents sélectifs inhibiteurs peuvent traiter des états associés à un excédent d'oxyde d'azote, par exemple quand le niveau de NO chez un sujet dépasse celui que l'on observe chez un sujet en bonne santé, le NO étant dérivé de manière endogène et/ou acquis de manière exogène. La présente invention, enfin, concerne l'utilisation d'agents inhibiteurs sélectifs, c'est-à-dire d'agents qui permettent d'inhiber de façon sélective des effets et des transformations métaboliques de quantités excessives de NO dérivé de manière endogène et/ou acquis de manière exogène, lors de traitements prophylactiques et/ou thérapeutiques de diverses conditions, par exemple d'athérogenèse telle que la resténose, l'hyperplasie, les inflammations et les troubles neurodégénératifs.
PCT/US1996/003755 1995-03-24 1996-03-21 Procedes de traitement de conditions associees a des excedents d'oxyde d'azote WO1996030012A1 (fr)

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JPH11255655A (ja) * 1997-12-09 1999-09-21 Hayashibara Biochem Lab Inc 神経機能調節剤
WO1999037294A3 (fr) * 1998-01-26 2000-04-06 Mitokor Agents protegeant les mitochondries et utilises dans le traitement des maladies associees aux mitochondries
FR2791571A1 (fr) * 1999-04-02 2000-10-06 Sod Conseils Rech Applic Association inhibiteur(s) de no synthase et antioxydant(s) metabolique(s)
WO2001019341A1 (fr) * 1999-09-10 2001-03-22 Institut Molekulyarnoi Genetiki Rossiiskoi Akademii Nauk (Img Ran) Procede pour moduler le metabolisme des oxydes d'azote, composition correspondante et ses variantes et procede pour agir sur l'organisme d'un patient necessitant une correction du metabolisme des oxydes d'azote
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FR2825922A1 (fr) * 2001-06-15 2002-12-20 Oreal 2-hexadecanoate d'ascorbyle comme inhibiteur de no-synthase et utilisations
FR2825920A1 (fr) * 2001-06-15 2002-12-20 Oreal Desferal comme inhibiteur de no-synthase et utilisations
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US6518261B2 (en) * 2000-03-17 2003-02-11 Oncology Sciences Corporation Use of eugenol in combination with other chemopreventative agents as prophylaxis for cancers
WO2003075905A1 (fr) * 2002-03-14 2003-09-18 Bobel 246, S.L. Utilisation de derives de phenols 2,4-disubstitues comme inhibiteurs de l'expression des l-selectines et de l'isoforme inductible de l'oxyde nitrique synthase
EP1094712A4 (fr) * 1998-07-09 2004-09-08 Cv Technologies Inc Hypericine et extrait d'hypericum: agents bloquant les canaux de calcium de type c et leur utilisation comme agents therapeutiques diriges contre le canal de calcium de type t
EP1588705A1 (fr) * 2004-04-21 2005-10-26 INTE:LIGAND Software-Entwicklungs und Consulting GmbH Utilisation de dérivés de la coumarine
WO2008090717A1 (fr) * 2007-01-26 2008-07-31 Shiseido Company, Ltd. Inhibiteur de l'adam
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JPH11255655A (ja) * 1997-12-09 1999-09-21 Hayashibara Biochem Lab Inc 神経機能調節剤
US6498191B2 (en) 1998-01-26 2002-12-24 Mitokor Mitochondria protecting agents for treating mitochondria associated diseases
WO1999037294A3 (fr) * 1998-01-26 2000-04-06 Mitokor Agents protegeant les mitochondries et utilises dans le traitement des maladies associees aux mitochondries
US6511966B2 (en) 1998-01-26 2003-01-28 Mitokor Mitochondria protecting agents for treating mitochondria associated diseases
EP1094712A4 (fr) * 1998-07-09 2004-09-08 Cv Technologies Inc Hypericine et extrait d'hypericum: agents bloquant les canaux de calcium de type c et leur utilisation comme agents therapeutiques diriges contre le canal de calcium de type t
FR2791571A1 (fr) * 1999-04-02 2000-10-06 Sod Conseils Rech Applic Association inhibiteur(s) de no synthase et antioxydant(s) metabolique(s)
WO2000059448A3 (fr) * 1999-04-02 2001-03-08 Sod Conseils Rech Applic Association d'inhibiteur(s) de no synthase et d'antioxydant(s) metabolique(s)
WO2001019341A1 (fr) * 1999-09-10 2001-03-22 Institut Molekulyarnoi Genetiki Rossiiskoi Akademii Nauk (Img Ran) Procede pour moduler le metabolisme des oxydes d'azote, composition correspondante et ses variantes et procede pour agir sur l'organisme d'un patient necessitant une correction du metabolisme des oxydes d'azote
US6518261B2 (en) * 2000-03-17 2003-02-11 Oncology Sciences Corporation Use of eugenol in combination with other chemopreventative agents as prophylaxis for cancers
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WO2002102342A1 (fr) * 2001-06-15 2002-12-27 L'oreal Inhibiteur de no-synthase et utilisations
WO2002102343A1 (fr) * 2001-06-15 2002-12-27 L'oreal - D.I.P.I. 2-hexadecanoate d'ascorbyle comme inhibiteur de no-synthase
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WO2002102344A3 (fr) * 2001-06-15 2003-03-20 Oreal Inhibiteur de no-synthase et utilisations
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WO2003075905A1 (fr) * 2002-03-14 2003-09-18 Bobel 246, S.L. Utilisation de derives de phenols 2,4-disubstitues comme inhibiteurs de l'expression des l-selectines et de l'isoforme inductible de l'oxyde nitrique synthase
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WO2005102316A3 (fr) * 2004-04-21 2006-03-30 Inte Ligand Utilisation de derives de coumarine
WO2008090717A1 (fr) * 2007-01-26 2008-07-31 Shiseido Company, Ltd. Inhibiteur de l'adam
JP2008184387A (ja) * 2007-01-26 2008-08-14 Shiseido Co Ltd Ａｄａｍ阻害剤
CN103079556A (zh) * 2010-09-03 2013-05-01 布瑞恩州比亚有限公司 一种用于预防或治疗神经退行性脑功能紊乱的药物组合物
JP2013536258A (ja) * 2010-09-03 2013-09-19 ブレイントロピア カンパニー リミテッド 退行性神経系脳疾患の予防又は治療用医薬組成物
EP2612668A4 (fr) * 2010-09-03 2014-03-19 Braintropia Co Ltd Composition pharmaceutique destinée à la prévention ou au traitement de troubles cérébraux neurologiques dégénératifs
AU2011296802B2 (en) * 2010-09-03 2014-09-25 Braintropia Co., Ltd. Pharmaceutical composition for prevention or treatment of degenerative neurological brain disorders
US9040580B2 (en) 2010-09-03 2015-05-26 Braintropia Co., Ltd. Method for prevention or treatment of degenerative neurologial brain disorders
FR3080040A1 (fr) * 2018-04-13 2019-10-18 International Lacquers Composition anhydre pour vernis a ongles
CN113616638A (zh) * 2021-08-27 2021-11-09 广州医科大学附属第二医院 杨梅素在制备转化生长因子β受体1抑制剂中的应用

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