Polydithiocarbamate-containing macromolecules and the use thereof for therapeutic and diagnostic app

专利摘要:
In accordance with the present invention, a new class of drugs is provided for the therapeutic treatment of indications such as stroke and other ischemia / reperfusion injury. Thus, by the present invention, dithiocarbamates are bound to the surface of macromolecules (eg, albumin proteins) by the use of crosslinking agents or by nonspecific binding to treat symptoms such as stroke and other ischemia / reperfusion injury. Provided are polydithiocarbamate-macromolecule-containing compositions representing a new class of drugs for medical treatment. According to another aspect of the invention, the species inducing the expression of inducible nitric oxide synthase (directly or indirectly) inactivates or inhibits its formation as well as • as a result of NO synthase expression. Multiple therapeutic methods have been developed to reduce the nitric oxide concentrations produced. In accordance with another aspect of the present invention, a magnetic resonance imaging method has been developed for the measurement of brain and heart blood flow and infarct volume in ischemic or heart attack conditions. Such methods utilize iron-containing complexes of compositions comprising dithiocarbamate and macromolecules as contrast agents.
公开号:KR20000035992A
申请号:KR1019997001945
申请日:1997-08-28
公开日:2000-06-26
发明作者:칭-산 라이
申请人:메디녹스, 인크.；
IPC主号:

专利说明:

Polydithiocarbamate-Containing Macromolecules and the Use Thereof for Therapeutic and Diagnostic Applications}
Jolly et al. Demonstrated in 1984 that a combination of peroxide dismutase and catalase can protect reperfused myocardial tissue (eg, Jolly et al., Cir. Res., 57: 277). , 1984). This observation suggests that oxygen-derived free radicals are responsible for reperfusion damage to the hypoxia myocardium. However, it is presently known that the phenomenon of ischemia / reperfusion injury is not limited to the myocardium. Instead, ischemia / reperfusion injury is judged as a result of general injury in any tissue or organ (eg, brain, liver or kidney) that has undergone a dangerous period of perfusion by ischemia followed by oxygenated whole blood.
Therefore, ischemia / reperfusion injury is the result of molecular oxygen reintroduction at the time of organ reperfusion or blood circulation recovery. While the delivery of dissolved molecular oxygen maintains cell viability, it also provides oxygen as a substrate for numerous enzymatic oxidation reactions that produce reactive oxygen species that cause oxidative damage, a phenomenon called "oxygen paradox". (See, eg, Hearse et al., In J. Mol. Cell. Cardiol., 10: 641, 1978). Oxygen, a gaseous substance essential for normal cell metabolism, can be harmful under certain conditions. The cell itself is resistant to oxidative damage through its antioxidant mechanisms including peroxide dismutase (SOD), catalase, glutathione peroxidase, glutathione reductase and cellular antioxidants including glutathione, ascorbate and α-tocopherol (See, eg, Chan, in Stroke, 27: 1124-29, 1996). However, when reactive oxygen species are produced at a rate that exceeds the ability of the cell to defend itself against oxidative stress (eg, ischemia / reperfusion injury) formed, the cells are irreversibly damaged resulting in necrotic cell death or ischemic cell death. Results in:
Although the exact mechanism by which oxygen induces ischemic cell death is not yet clear, it is well known that reactive oxygen species cause extensive tissue damage. The most powerful oxidizer, hydroxyl radical (OH), can initiate lipid peroxidation, resulting in protein oxidation and DNA damage in cells (eg, Lai and Piette, in Biochem. Biophys. Res. Commun., 78 : 51-59, 1977 and Dizdaroglu and Bergtold, in Anal.Biochem., 156: 182, 1986). Although less reactive, peroxide anion radicals (· O ₂ ^_ ) alternatively participate in oxidation reactions that form hydrogen peroxide and hydroxyl radicals as follows:
O ₂ ^_ + O ₂ ^_ → H ₂ O ₂
O ₂ ^_ + H ₂ O ₂ → OH + OH ^_ + O ₂
Scheme 1 is promoted by SOD, while Scheme 2 proceeds rapidly in the presence of trace iron metals (eg, Haber and Weiss, in Proc. R. Soc. Ser. A., 147: 332, 1934). Reference). As shown in Schemes 3 and 4, peroxide anion radicals are known to liberate iron from ferritin (see, eg, Wityk and Stern, in Crit. Care Med., 22: 1278-93, 1994), and it is a property. Further catalyzing the iron catalyzed Fenton reaction in bovine treated tissues results in the formation of harmful hydroxyl radicals (e.g. Halliwell and Gutteridge, in Halliwell and Gutteridge.Free Radicals in Biology and Medicine, 2nd edition Oxford: Clarendon Press, 15-19 (1989):
Fe ³⁺ + O ₂ ^_ → Fe ²⁺ + O ₂
Fe ²⁺ + H ₂ O ₂ → OH + OH ^_ + Fe ³⁺
In addition to reactive oxygen species, reactive nitrogen species, such as nitric oxide (NO), have also been observed to occur excessively in ischemia / reperfusion organs (see, eg, Faraci and Brian, in Stroke, 25: 692-703, 1994). . NO is synthesized from the terminal guanidino nitrogen atom of L-arginine by nitric oxide synthase (NOS). Three different isoforms of NOS, eNOS, nNOS and iNOS, are isolated, cloned, sequenced and expressed (see, eg, Nathan, in FASEB J., 6: 3051-3064, 1992). eNOS (endothelial cell derived) and nNOS (neuronal cell derived) are expressed essentially, and both enzymes require an increase in intracellular calcium for active action.
Under physiological conditions, small amounts of NO are released continuously from eNOS in endothelial cells or from nNOS in neuronal cells. These NO act to dilate blood vessels and work with vasoconstrictor catecholamines to regulate blood flow and blood pressure. On the other hand, large amounts of NO are produced by inducible, calcium independent NOS (iNOS) isoforms upon active action by cytokines or endotoxins (eg Moncada and Higgs, in New Engl. J. Med. , 329: 2002-2012, 1993). iNOS is expressed in a variety of cell types, including endothelial cells, smooth muscle cells, microglia and macrophages. Abnormal high concentrations of nitric oxide have recently been found to be associated with ischemia / reperfusion injury (eg, Kumura et al., In J Cereb. Blood Flow and Metab., 14: 487-491, 1994; Iadecola et al. , J. Cereb. Blood Flow and Metab., 15: 378-384, 1995).
In the central nervous system, nitric oxide has been found to function as both neurotransmitter and neurotoxin (see, eg, Faraci and Brian, supra). It mediates N-methyl-D-aspartate (NMDA) toxicity stimulation. High concentrations of NO in the brain can also be achieved using electron electrodes (e.g., Malinski et al., J Cereb. Blood Flow Metab., 13: 355-358, 1993) and by electron ferromagnetic resonance spin trapping (e.g. See, eg, Sato et al., Biochim. Biophys. Acta, 1181: 195-197, 1993). NO concentrations began to increase within minutes after the onset of ischemia, reflecting perhaps the increased activity of the constituent NO synthase. However, when ischemia continues, the NO concentration decreases slowly but increases again during reperfusion (eg, the recent review by Dawson and Dawson in Cerebrovascular Disease, H. Hunt Batjer, ed., Lippincott-Raven Publishers, Philadelphia , pp. 319-325 (1997). Expression of the iNOS gene was demonstrated to begin 12 hours after cerebral anemia and peak in 48 hours in the rat brain (see Iadecola et al., supra).
NO can have both beneficial and detrimental effects during cerebral anemia. Since NO increases the inhibition of aggregation and adhesion of brain blood flow and platelets or leukocytes, an increase in NO production in ischemia can be prevented (eg, Samdani et al., In Stroke 28: 1283-1288 (1997) Reference). Excessive NO production during reperfusion, on the other hand, becomes cytotoxic after peroxynitrite, either directly or by recombination with peroxide anion radicals, according to Schemes 5-7 as follows:
O ₂ ^_ + NO → ONOO ^_
ONOO ^_ + H ⁺ → ONOOH
ONOOH → [· OH] + · NO ₂
In the cell-free system, peroxide anion radicals have been chemically reacted with nitric oxide to form peroxynitrite, ONOO ^_ , which is a toxic anion (Scheme 5, e.g. Beckman et al., In Proc. Natl. Acad. Sci., USA 87: 1620-1624, 1990). The rate constant for the reaction of nitrogen oxides with superoxide anions is 6.7 x 10 ⁹ M ^-1 S ^-1 (see, for example, Huie and Padmaja, in Free Radical Res. Commun., 18: 195-199, 1993). This is three times faster than for the immobilization change of peroxide anion radical by peroxide dismutase (see, eg, Hassan et al., In Free Radical Biol. Med., 5: 377-385, 1988). ). At physiological pH, peroxynitrite necessarily acquires protons (Scheme 6), which readily degrades to form hydroxyl radical-like species (ie, "[.OH]"), which are potent cytotoxic molecules for cells ( Scheme 7).
Thus, the final pathway leading to ischemia / reperfusion injury may arise from hydroxyl radicals or hydroxyl radical like species produced by peroxynitrite as a result of the simultaneous increase of peroxide anions and nitric oxide. Studies using cultured neurons indicate that NMDA- and glutamate induced neurotoxicity and neuronal damage due to hypoxia may be mediated by NO (eg, Bredt and Snyder, Neuron, 8: 3-11, 1992 and Manzoni et al., Neuron, 8: 653-662, 1992).
Several drugs have been developed and tested in animals and humans aimed at preventing free radical induced reperfusion injury. It can be classified into two main types: inhibitors and scavengers. For example, ganglioside GM-1 (binding calmodulin and inhibiting NOS activity) has been evaluated in acute ischemic attacks (eg Lenzi et al., In Stroke, 5: 1552-1558, 1994). Reference). However, treatment with GM-1 does not appear to alter patient survival. In another embodiment, the newly synthesized benzothiazole compound, Rubelusol, is in Phase II clinical trial for the treatment of acute ischemic attack (see, eg, Diener et al., In Stroke, 27: 76-81, 1996). . The drug suppresses glutamate-induced nitric oxide-related neurotoxicity by adjusting to the underlying mechanism in biochemical cascades that induce ischemic tissue damage. Clinical trials are underway for several other glutamate antagonist drugs, but data are not yet published (see, eg, Meldrum, in Current Opinion in Neurol., 8: 15-23, 1995).
Currently, many pharmaceutical companies are focused on the design and development of substrate or product analogue inhibitors of nitric oxide synthase enzyme NOS to treat overproduction of NO in seizures and other ischemic / reperfusion states. For example, aminoguanidine, an NOS inhibitor, has been shown to improve brain damage in cerebral anemia (see, eg, Zhang et al., In Stroke, 27: 317-323, 1996). Inhibition of NOS by N ^G -nitro-L-arginine reduced lipid peroxidation in Gerbil cerebral anemia (eg Caldwell et al., In Eur. J. Pharmacol., 285: 203-206, 1995 Reference).
However, recent data indicate that inhibition of NOS is detrimental to subjects. For example, rodent studies have shown that inhibition of NO production causes intrauterine growth retardation and Fuji destruction (eg, Diket et al., In Am. J. Obstet.Gynecol., 171: 1243-1250, 1994). In addition, inhibition of NOS has been shown to cause myocardial ischemia in endotoxin mice (see, eg, Avonturr et al., Cir. Res., 76: 418-425, 1995).
In contrast to the inhibition methods described in the prior art, which focus on the problem of free radical overproduction, free radical removal methods have also been chosen to reduce excess reactive oxygen and nitrogen species in vivo. For example, a free radical scavenger, tyrilazad mesylate, has been used in clinical trials for the treatment of seizure patients (see, eg, Haley, in Stroke, 25: 418-423 (1994)).
However, there is still a need in the art for agents that effectively prevent free radical induced reperfusion damage without undesirable side effects.
<Overview of invention>
In accordance with the present invention, a new class of drugs is provided for the therapeutic treatment of stroke and other ischemia / reperfusion injury. Thus, according to the present invention, dithiocarbamates are bound to the surface of macromolecules (eg, albumin proteins) by the use of crosslinking agents or by nonspecific binding to provide therapeutic treatment for stroke and other ischemia / reperfusion injury. There is provided a polydithiocarbamate-macromolecule-containing composition representative of a new class of drugs. Many advantages of the polydithiocarbamate-macromolecule-containing compositions of the invention for ischemia / reperfusion therapy
(i) providing multiple thiol groups which are known to react effectively with reactive oxygen species, such as superoxide anions and hydroxyl radicals, and also reactive nitrogen species, such as nitric oxide, to form S-nitrosothiol derivatives,
(ii) chelate and remove foreign iron ions released from damaged tissue to prevent oxidative damage (eg, caused by iron catalyzed oxygen radical reactions),
(iii) In the case of chelation with iron, there is a formation of a 2 to 1 [(dithiocarbamate) ₂ -Fe] complex on the surface of the macromolecule. The complex also removes excess nitric oxide formed in inflammatory tissues such as cerebral infarction during ischemic attacks.
Simultaneous removal of reactive nitrogen species (eg, nitric oxide) and reactive oxygen species (eg, superoxide anion radicals and hydroxyl radicals) leads to the formation of peroxynitrites, as shown in Scheme 5-7 above. Likewise, it should reduce the incidence of reactive hydroxyl radical-like species and thus interfere with pathways that improve ischemia / reperfusion injury.
According to another aspect of the invention, the species inducing the expression of inducible nitric oxide synthase (directly or indirectly) inactivates or inhibits its production as well as results of NO synthase expression. Combination treatment methods have been developed to reduce the nitric oxide concentrations that have been formed. For example, the combined therapeutic methods of the present invention can be used for the treatment of an infectious and / or inflammatory condition. Thus, the efficacy of many therapeutic agents used for the treatment of infection and / or inflammatory conditions may be enhanced by their co-administration in combination with the dithiocarbamate-containing nitric oxide scavenger (s) described herein. Can be.
Proton Magnetic Resonance Imaging (MRI) technology also provides important information on burns in acute infarct areas in human cerebral anemia (eg, Warach et al., In Neurol., 42: 1717-23, 1992). Reference). MRI techniques have been developed in which contrast agents are used to assess brain perfusion after ischemic injury (see, eg, Fisher et al., In Ann. Neurol., 32: 115-122, 1992). Because of its inherent paramagnetism, the iron-containing complexes of the polydithiocarbamate-macromolecule-containing compositions according to the invention are also used for the measurement of blood perfusion in various organs, including the brain, heart, kidney or other biological organs. And contrast enhancement agents for assessing infarct area and volume of heart attack.
Therefore, magnetic resonance imaging methods have been developed for the measurement of brain and heart blood flow and infarct volume in ischemic or heart attack states according to another aspect of the present invention. Such methods utilize iron-containing complexes of compositions comprising dithiocarbamates and macromolecules as contrast agents. The incorporation of dithiocarbamate and macromolecules as described herein provides a dithiocarbamate-macromolecule-containing composition having the beneficial effects of free radical elimination and vasodilation in the treatment of ischemia / reperfusion injury. Turned out.
The present invention relates to novel dithiocarbamate containing compositions. In one aspect, the present invention relates to a dithiocarbamate-containing composition in which dithiocarbamate is covalently associated with macromolecules. In another aspect, the present invention relates to a dithiocarbamate-containing composition in which dithiocarbamate is covalently crosslinked with a macromolecule. In another aspect, the invention relates to methods of diagnosis and treatment using the novel dithiocarbamate containing compositions described herein.
1 shows infarct volume when ischemic attack rats were treated with bovine serum albumin (BSA) in saline or with a combination of BSA and N-methyl-D-glucamine dithiocarbamate (MGD) according to the present invention. Illustrate the effect.
According to the present invention, there is provided a therapeutic composition comprising dithiocarbamate associated non-covalently with a macromolecule. Such derivatives may form complexes with iron, which complexes may again complex with nitric oxide. Thus, therapeutic derivatives of the iron-dithiocarbamate complex [(dithiocarbamate) ₂ Fe] as well as the therapeutic derivatives of the free dithiocarbamate are provided.
According to another aspect of the present invention, there is provided a therapeutic derivative comprising at least one dithiocarbamate covalently crosslinked with a macromolecule. Such derivatives may form complexes with iron, which complexes may again complex with nitric oxide. Thus, there are provided therapeutic derivatives of the iron-dithiocarbamate complex [(dithiocarbamate) ₂ Fe] as well as another therapeutic derivative of the free dithiocarbamate.
According to another aspect of the present invention, there is provided a method of preparing a therapeutic derivative of the dithiocarbamate. The process of the present invention involves contacting dithiocarbamate and macromolecules in the presence of a crosslinking agent under crosslinking conditions.
In accordance with another aspect of the present invention, a combination therapeutic method is provided for treating various conditions associated with overproduction of nitric oxide by a subject. In one embodiment, the combined therapeutic methods of the present invention comprise directly or indirectly treating the production of species that induce expression of inducible nitric oxide synthase in a subject. The method of the present invention provides a method for the treatment of one or more agents capable of directly or indirectly inactivating said species or inhibiting the production of said species and at least one dithiocarbamate-containing nitric oxide scavenger described herein. Co-administration of an effective amount of the formulation to the subject.
According to another embodiment of the present invention, a combination utilizing an effective amount of at least one therapeutic agent useful for the treatment of an infection and / or inflammatory disease and at least one dithiocarbamate-containing nitric oxide scavenger described herein Treatment methods have been developed. The combination has been found to be more effective in the treatment of infectious and / or inflammatory diseases than when the therapeutic agent is used alone.
Any dithiocarbamate can be used in accordance with the present invention. Dithiocarbamates are a class of low molecular weight sulfur containing compounds that are effective antioxidants and chelating agents. For example, diethyldithiocarbamate (DDT) is used clinically in the treatment of nickel poisoning (see, eg, Sunderman, in Annals Clin. Res., 3: 182-185, 1971). DDC has also been used in the treatment of cancer and in patients with human immunodeficiency virus (HIV) infection (see, eg, Reisinger et al., In Lancet, 335: 679-82, 1990). Recent studies have shown that DDC acts as a direct scavenger of hydroxyl radicals or as an iron chelating agent that inhibits hydroxyl radical generation by binding to iron ions or by both mechanisms (eg Liu et al., in Free Rad.Res., 24: 461-472, 1996). In addition, it is N-methyl-D-glucamine dithiocarbamate (MGD) chelates with ferrous iron as a 2 to 1 [(MGD) ₂ / Fe] complex, the complex again strongly interacts with NO. Acting to form stable water soluble complexes in aqueous solutions, ie [(MGD) ₂ / Fe-No] complexes (eg, Lai and Komarov, in FEBS Letters, 345: 120-124, 1994; Komarov and Lai , in Biochim. Biophys.Acta, 1272: 29-36, 1995). The latter complex results in a sharp three-line spectrum with g _iso = 2.04, which is characteristic of nitrosyl-Fe-dithiocarbamate complexes which can be easily detected by EPR spectroscopy at room temperature.
Preferred dithiocarbamates for use in the present invention include compounds having the formula (I)
(R) ₂ NC (S) -SH
Where
Each R is independently C ₁ to C ₁₈ alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, Aroyl, substituted aroyl, acyl, substituted acyl, and the like, or
The two R groups together may form a 5-, 6- or 7-membered ring comprising N and two R groups, or
One of the R groups is alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, substituted alkenylene, arylene, substituted arylene, alkylene, substituted alkalylene, aralkylene , Substituted aralkylene, aralkenylene, substituted aralkenylene, aralkynylene, substituted aralkynylene, cycloalkylene, substituted cycloalkylene, heterocycloalkylene or substituted heterocycloalkylene A divalent moiety selected from the group, wherein the divalent moiety acts as the same substituent on the two dithiocarbamate structures to bind the structures together to form a bis (dithiocarbamate) species.
"Substituted alkyl" as used herein refers to hydroxy, alkoxy (of lower alkyl), mercapto (of lower alkyl), cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl , Substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, trifluoromethyl, cyano, nitro, nitron, amino, amido, -C (O) H, acyl, Alkyl groups further having one or more substituents selected from oxyacyl, carboxyl, carbamate, sulfonyl, sulfonamide, sulfuryl and the like.
As used herein, "cycloalkyl" refers to a cyclic ring containing group having about 3 to 8 carbon atoms, and "substituted cycloalkyl" means a cycloalkyl group further having one or more substituents as described above.
A "heterocyclic" as used herein refers to a cyclic ring having 3 to 14 carbon atoms (ie, a ring) containing one or more heteroatoms (eg, N, O, S, etc.) as part of the ring structure. Containing) and “substituted heterocyclic” means a heterocyclic group further having one or more substituents as described above.
As used herein, "alkenyl" refers to a straight or branched chain hydrocarbyl group of about 2 to 12 carbon atoms having one or more carbon-carbon double bonds, and "substituted alkenyl" refers to By alkenyl group further having one or more substituents as such.
As used herein, "alkynyl" refers to a straight or branched chain hydrocarbyl group of about 2 to 12 carbon atoms having one or more carbon-carbon triple bonds, and "substituted alkynyl" refers to By alkynyl groups further having one or more substituents as such.
"Aryl" as used herein means an aromatic group having 6 to 14 carbon atoms, and "substituted aryl" means an aryl group further having one or more substituents as described above.
"Heteroaryl" as used herein means an aromatic group having 3 to 14 carbon atoms containing one or more heteroatoms (eg, N, O, S, etc.) as part of the ring structure, " Substituted heteroaryl "means a heteroaryl group further having one or more substituents as described above.
"Alkylaryl" as used herein means an alkyl substituted aryl group having about 7 to 16 carbon atoms, and "substituted alkylaryl" means an alkylaryl group further having one or more substituents as described above. .
"Arylalkyl" as used herein means an aryl substituted alkyl group having about 7 to 16 carbon atoms, and "substituted arylalkyl" means an arylalkyl group further having one or more substituents as described above. .
As used herein, "arylalkenyl" means an aryl substituted alkenyl group having about 8 to 16 carbon atoms, and "substituted arylalkenyl" means an arylal further having one or more substituents as described above. Means a kenyl group.
"Arylalkynyl" as used herein, means an aryl substituted alkynyl group having about 8 to 16 carbon atoms, and "substituted arylalkynyl" means an arylalky further having one or more substituents as described above. Means a Neyl group.
"Aroyl" as used herein means an aryl-carbonyl species, such as benzoyl, and "substituted aroyl" means an aroyl group further having one or more substituents as described above.
"Acyl" as used herein refers to an alkyl-carbonyl species.
"Halogen" as used herein means fluoride, chloride, bromide or iodide atoms.
"Alkylene" as used herein typically means a saturated divalent straight or branched chain hydrocarbyl group of about 2 to 12 carbon atoms, and "substituted alkylene" means one or more substituents as described above. It means an alkylene group having more.
As used herein, "oxyalkylene" typically means a saturated divalent straight or branched chain hydrocarbyloxy group having about 1 to 12 carbon atoms, and "substituted oxyalkylene" is as described above. It means an oxyalkylene group further having one or more substituents.
"Alkenylene" as used herein means a divalent straight or branched chain hydrocarbyl group, typically having about one to two carbon atoms, having at least one carbon-carbon double bond, and "substituted alkenylene" Means an alkenylene group further having one or more substituents as described above.
"Arylene" as used herein typically means a divalent aromatic group having 6 to 14 carbon atoms, and "substituted arylene" means an arylene group further having one or more substituents as described above.
"Alkylene" as used herein typically means an alkyl substituted divalent aryl group having about 7 to 16 carbon atoms, and "substituted alkylene" refers to an alkali further having one or more substituents as described above. Means a flag.
"Aralkylene" as used herein typically means an aryl substituted divalent alkyl group having about 7 to 16 carbon atoms, and "substituted aralkylene" further has one or more substituents as described above. It means an aralkylene group.
As used herein, "aralkenylene" typically refers to an aryl substituted divalent alkenyl group having about 8 to 16 carbon atoms, and "substituted aralkenylene" further includes one or more substituents as described above. It means an aralkenylene group having.
"Aralkynylene" as used herein typically means an aryl substituted divalent alkynyl group having about 8 to 16 carbon atoms, and "substituted aralkynylene" further includes one or more substituents as described above. It means an aralkynylene group having.
As used herein, "cycloalkylene" means a divalent ring containing group having about 3 to 8 carbon atoms, and "substituted cycloalkylene" means a cycloalkylene group further having one or more substituents as described above. it means.
As used herein, “heterocycloalkylene” is a divalent cyclic having from 3 to 14 carbon atoms (ie, containing one or more heteroatoms (eg, N, O, S, etc.) as part of a ring structure. , Ring-containing), and "substituted heterocycloalkylene" means a heterocycloalkylene group further having one or more substituents as described above.
Preferred dithiocarbamates for the practice of the present invention are those in which one of the R groups is C ₁ to C ₁₂ alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, wherein the substituent is carboxyl , -C (O) H, oxyacyl, phenol, phenoxy, pyridinyl, pyrrolidinyl, amino, amido, hydroxy, nitro or sulfuryl), and other R groups are selected from C ₁ to C ₄ Selected from alkyl or substituted alkyl, or any one of R groups is alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, substituted alkenylene, arylene, substituted arylene, Alkylene, Substituted Alkylene, Aralkylene, Substituted Aralkylene, Aralkenylene, Substituted Aralkenylene, Aralkynylene, Substituted Aralkynylene, Cycloalkylene, Substituted Cycloalkylene, Heterocyclo Consisting of alkylene or substituted heterocycloalkylene Is a divalent moiety selected from the group consisting of: a compound of formula (I) in which the divalent moiety acts as the same substituent for both dithiocarbamate structures, thereby binding the structures together to form a bis (dithiocarbamate) species.
Particularly preferred dithiocarbamates in the practice of the present invention are those wherein one of R groups is C ₂ to C ₁₀ alkyl or substituted alkyl, wherein the substituents are carboxyl, acetyl, pyridinyl, pyrrolidinyl, amino, amido, Selected from hydroxy or nitro), another R group is selected from methyl, ethyl, propyl or butyl, or any one of R groups is alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, Alkenylene, Substituted Alkenylene, Arylene, Substituted Arylene, Alkaylene, Substituted Alkylene, Aralkylene, Substituted Aralkylene, Aralkenylene, Substituted Aralkenylene, Aralkynylene, Substituted A divalent moiety selected from the group consisting of aralkyylene, cycloalkylene, substituted cycloalkylene, heterocycloalkylene or substituted heterocycloalkylene, wherein the divalent moiety is two dithiocarbame By acting as the same substituents for the tree structure is a compound of formula I to form a bis combined with the structure (dithiocarbamate) species.
Most preferred dithiocarbamates for the practice of the present invention are those in which one of the R groups is selected from C ₂ to C ₈ alkyl or substituted alkyl, wherein the substituents are selected from carboxyl, acetyl, amido or hydroxy, The other R group is selected from methyl, ethyl, propyl or butyl, or any one of R groups is alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, cycloalkylene, having from 4 to 11 carbon atoms, A divalent moiety selected from the group consisting of substituted cycloalkylene, heterocycloalkylene or substituted heterocycloalkylene, wherein the divalent moiety acts as the same substituent for both dithiocarbamate structures, thereby joining the structures together Is a compound of formula (I) which forms a bis (dithiocarbamate) species.
Various macromolecules such as polypeptides, polysaccharides, polynucleic acids and the like can be used in the present invention. Macromolecules that can be used in the present invention can be synthetic, natural or modified natural materials.
Polypeptides that can be used in the present invention include natural proteins (e.g., serum albumin, hemocyanin, ovalbumin, etc.), purified protein derivatives (e.g., purified protein derivatives of tuberculin), recombinant proteins, Modified proteins (eg, cationized albumin) and the like.
Preferred proteins that can be used in the present invention are albumin. Albumin proteins present naturally in the blood circulation serve as carriers for metals, ions, fatty acids, amino acids, bilirubin, enzymes, drugs, and the like. In normal adults, the plasma albumin concentration is about 3.5 to 5.0 g / dL (see, eg, Halliwell, in Biochem. Pharmacol., 37: 569-571, 1988). Since the capillary wall is relatively impermeable to proteins in the plasma, the protein (including albumin) exhibits an osmotic pressure (or colloidal osmotic pressure) of about 25 mm Hg across the capillary wall. This force tends to draw water into the blood.
High serum albumin concentrations (within normal range) have been associated with reduced incidence of seizures and coronary heart disease (see, eg, Aptaker et al., In Arch. Phys. Med. Rehabil., 75: 80-84, 1994). ). Naturally, administration of albumin solution has been shown to have some beneficial effects by acting to reduce bulk flow through the ruptured blood transfusion gateway and relieve vasogenic edema in animals and patients with ischemic attacks (e.g., See Matsui et al., In Neurosurgery, 33: 293-300, 1993). Albumin has also been found to act as an antioxidant that reacts and neutralizes reactive oxygen species (Halliwell, supra). In view of the known beneficial effects of albumin, the combination of albumin and dithiocarbamate, which has been shown to confer substantial therapeutic effects individually, provides a very useful diagnostic and therapeutic agent.
Polysaccharides that can be used in the present invention include dextran, chitosan, alginate, polymannuronic acid, polymannuronate, hyaluronic acid, chitin, cellulose, starch, glycogen, guar gum, locust bean rubber, levan, inulin, Cyclodextran, agarose, xanthan gum, carrageenan, heparin, pectin, gellan gum, scleroglucan and the like.
The polynucleic acid that can be used in the present invention includes natural double stranded DNA, single stranded DNA, RNA, synthetic DNA, recombinant DNA, recombinant RNA and the like.
Crosslinking that can be used in the process of the invention can be carried out in a variety of ways. That is, the dithiocarbamate may be crosslinked to the macromolecule by a crosslinking agent through any functional group on the macromolecule. Exemplary functional groups on the macromolecule include amino groups, hydroxy groups, sulfhydryl groups, carboxyl groups and the like.
As a crosslinking agent which can be used for this invention, a photoreactive crosslinking agent, a homobifunctional crosslinking agent, a heterodifunctional crosslinking agent, etc. are mentioned. Examples of the photoreactive crosslinking agent include azido compounds and diazo compounds.
Examples of azido and diazo compounds include sulfosuccinimidyl (4-azidosalicylamido) hexanoate, azidobenzoyl hydrazide, N-5-azido-2-nitrobenzoyloxysuccinimide, N- 4- (p-azido-salicylamido) butyl-3 '-(2'-pyridyldithio) propionamide, p-azidophenylglyoxal monohydrate, 4- (p-azidosalicylamami Fig. 4- (iodoacetamido) butane, bis [(β-4-azidosalicylamido) ethyl] disulfide, N-hydroxysuccinimidyl 4-azidobenzoate, N-hydroxysulf Posuccinimidyl 4-azidobenzoate, N-hydroxysuccinimidyl-4-azidosalicylic acid, N-hydroxysulfosuccinimidyl-4-azidosalicylic acid, p-nitrophenyl-2-diazo -3,3,3-trifluoropropionate, 2-diazo-3,3,3-trifluoropropionyl chloride, N-succinimidyl- (4-azidophenyl) -1,3'- Dithiopropionate, sulfosuccinimidyl- (4-azidophenyldithi Propionate, sulfosuccinimidyl-2- (7-azido-4-methylcoumarin-3-acetamide) ethyl-1,3'-dithiopropionate, sulfosuccinimidyl-7-azido 4-methylcoumarin-3-acetate, sulfosuccinimidyl-2- (m-azido-o-nitrobenzamido) -ethyl-1,3'- dithiopropionate, etc. are mentioned.
The bifunctional crosslinking agents that can be used in the present invention can be further divided into two types, homodifunctional crosslinkers and heterodifunctional crosslinkers.
Examples of homobifunctional crosslinkers include dimethyl adimimidate, dimethyl subimidate, dimethyl pyrimidate, disuccinimidyl glutarate, disuccinimidyl suverate, bis (sulfosuccinimidyl) suverate, Bis (diazobenzidine), ethylene glycobis (succinimidylsuccinate), disuccinimidyl tartrate, disulfosuccinimidyl tartrate, bismaleidohexane, glutaraldehyde, dithiobis (succinimidyl propio ), Dithiobis (succinosuccinimidyl propionate), 1,4-di [3 ', 2'-pyridyldithio (propionamido) butane], N, N'-dicyclohexylcarbodiimide And bis [2- (succinimidyloxycarbonyloxy) ethyl] sulfone, dimethyl 3,3'-dithiobispropionimate and the like.
Examples of heterobifunctional crosslinkers include succinimidyl 4- (N-maleimidomethyl) cyclohexane-1-carboxylate, m-maleimidobenzoyl-N-hydroxysuccinimide ester, succinimidyl-4- (p-maleimidophenyl) butyrate, N- (γ-maleimidobutyryloxy) succinimide ester, N-succinimidyl (4-iodoacetyl) aminobenzoate, 4-succinimidyl oxycarbonyl- α- (2-pyridyldithio) toluene, sulfosuccinimidyl-6- [α-methyl-α- (2-pyridyldithio) toluamido] hexanoate, N-succinimidyl-3- (2-pyridyldithio) propionate, 3- (2-pyridyldithio) propionyl hydrazide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 3- (p -Azido salicylamido) butylamine, 1,5-difluoro-2,4-dinitrobenzene, N-hydroxysuccinimidyl-2,3-dibromo-propionate, etc. are mentioned. .
When a photoreactive crosslinking agent is used, typical crosslinking conditions consist of exposure to ultraviolet radiation for about 0.1 minutes to about 10 minutes at a temperature of about 4 ° C to about 40 ° C.
When a bifunctional crosslinker is used, typical crosslinking conditions are first contacting the crosslinker with dithiocarbamate or macromolecule at a temperature of about 4 ° C. to about 40 ° C. for about 0.1 to about 30 minutes, and then with the intermediate formed Other dithiocarbamate or macromolecule (not used for initial contacting) consists of contacting at a temperature of about 4 ° C. to about 40 ° C. for about 0.1 to about 30 minutes.
According to another embodiment of the present invention, there is provided a method of obtaining an in vivo magnetic resonance image comprising administering an iron-containing contrast composition as described herein to a subject, and then imaging the subject.
Rupture of the blood transfusion gateway is known to occur as a result of stroke. This leads to a significant increase in permeability, allowing the diffusion of macromolecules (eg iron-containing derivatives of the dithiocarbamate-macromolecule-containing compositions of the invention) into infarcted brain tissue. Due to the inherent paramagnetism of such compositions, their distribution in the brain (and volume of infarcted areas) can be readily determined by MRI techniques.
According to another embodiment of the present invention, various disease states and / or signs such as septic shock, ischemia, administration of cytokines, overexpression of cytokines, ulcers, inflammatory bowel disease (eg gastritis, ulcers) Colitis or Crohn's disease), diabetes, arthritis (e.g. rheumatoid arthritis), asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, cirrhosis, allograft rejection (e.g. graft rejection), encephalomyelitis, meningitis, Pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis, glomerulonephritis, ophthalmic diseases (e.g. uveitis, glaucoma, blepharitis, granulomas, allergic eye diseases, corneal ulcers, keratitis, cataracts, retinal disease, senile spot degeneration, optic neuritis Etc.), ileitis, inflammation induced by overproduction of inflammatory cytokines (eg, hepatitis, nephritis, airway inflammation, etc.), hemorrhagic shock, anaphylactic shock, burns, persimmons causing overproduction of inflammatory cytokines Salts (bacterial (eg, E. coli infection), viral (eg, HIV), fungal (eg, candidiasis and histoplasmosis) and parasites (eg, Laishmaniasis) And schistosomiasis)), hemodialysis, chronic fatigue syndrome, seizures, cancer (eg, breast, melanoma, carcinoma, etc.), cardiovascular diseases associated with overproduction of inflammatory cytokines (eg, heart disease, cardiopulmonary bypass) Pass, ischemia / reperfusion injury, etc.), ischemic / reperfusion associated with inflammatory cytokine overproduction, toxic shock syndrome, adult respiratory distress syndrome, cachexia, myocarditis, autoimmune disease, eczema, psoriasis, heart failure, dermatitis, gallbladder, cerebral anemia , Systemic lupus erythematosus, AIDS, AIDS dementia, neurodegenerative disorders (e.g., chronic neurodegenerative disorders), chronic pain, erection, cystic fibrosis, amyotrophic lateral sclerosis, schizophrenia, depression, premenstrual syndrome, Anxiety, addiction, migraine, Huntington's disease, epilepsy, Gastrointestinal motility disorders, obesity, polyphagia, solid tumors (eg neuroblastoma), malaria, blood cancer, myelofibrosis, lung damage, graft-versus-host disease, head injury, CNS damage, hepatitis, kidney failure, liver disease (eg For example, chronic hepatitis C), drug-induced lung injury (eg, paraquat), graft rejection and preservation, increased fertilization rate, bacterial translocation, cyclic shock, traumatic shock, photoaging, photodamage, etc. A method of treating a subject is provided.
Preferred indications for treatment in accordance with the present invention are cardiovascular diseases that can be treated by administering an effective amount of a dithiocarbamate-macromolecule-containing composition as described herein to a subject in need thereof. The term "cardiovascular disease" as used herein includes seizures, heart failure, kidney failure, ischemia / reperfusion injury, head injury, and the like.
As will be readily appreciated by those skilled in the art, the compositions of the present invention may be administered by various modes of administration, such as oral, transdermal, intravenous, intramuscular, topical, nasal administration, and the like. have. Depending on the mode of administration utilized, the dithiocarbamate-macromolecule containing composition can be administered in various pharmaceutically acceptable forms. For example, the compositions can be delivered in the form of solids, solutions, emulsions, dispersions, micelles, liposomes, and the like.
Pharmaceutically acceptable forms of the compositions of the invention include solids, solutions, emulsions, dispersions, micelles, liposomes, and the like, wherein the formulations formed comprise, as an active ingredient, one or more of the compositions of the invention for enteral or parenteral use. With suitable organic or inorganic carriers or excipients. The active ingredient can be combined with general nontoxic pharmaceutically acceptable carriers, for example, for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. Carriers that may be used include, in solid, semisolid or liquid form, glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length Triglycerides, dextran and other carriers suitable for use in the preparation of the formulations. In addition, auxiliaries, stabilizers, thickening and coloring agents and flavorings can be used. The active composition is included in the pharmaceutical formulation in an amount sufficient to produce the desired effect on the process or disease to be treated.
Pharmaceutical formulations containing a composition of the invention are suitable for oral use, for example, as tablets, troches, rosin agents, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. It may be in the form. Formulations for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical formulations, such preparations may be sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint, gingko or cherry oil It may contain one or more agents selected from the group consisting of colorants and preservatives to provide pharmaceutical rich and tasty formulations. Tablets containing the active ingredient together with nontoxic pharmaceutically acceptable excipients may also be prepared by known methods. For example, (1) an inert diluent such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; Excipients such as (3) binders such as tragacanth gum, corn starch, gelatin or gum arabic and (4) lubricants such as magnesium stearate, stearic acid or talc can be used. Tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus have a prolonged action. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used. It may also be coated by the techniques described in US Pat. Nos. 4,256,108, 4,160,452 and 4,265,874 to form osmotic tablets for controlled release.
In some cases, oral formulations may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin. It may also be in the form of soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, for example peanut oil, liquid paraffin or olive oil.
Pharmaceutical formulations may be in the form of sterile injectable suspensions. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a diluent or solvent suitable for nontoxic parenteral use, such as, for example, a solution in 1,3-butanediol. Sterile nonvolatile oils can be conventionally employed as a solvent or suspending medium. For this purpose, any mild non-volatile oil can be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), sesame oil, coconut oil, peanut oil, cottonseed oil, and the like, or synthetic fatty vehicles such as ethyl oleate. Can be. If desired, buffers, preservatives, antioxidants and the like can be included.
The compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug. Such formulations may be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters of polyethylene glycol, which are solid at ordinary temperatures but liquefied and / or dissolved in the rectal cavity.
Since individual subjects may exhibit varying degrees of varying signs and each drug has its own unique therapeutic properties, it is within the ability of one of ordinary skill in the art to ascertain the subject's response to treatment and thus vary the dosage.
Conventional daily dosages are generally in the range of about 80 μg to about 300 mg per kg body weight, preferably in the range of 100 μg to 10 mg per kg body weight, which can be administered up to four times a day. Typical daily IV dosages range from about 10 μg to about 100 mg per kg body weight, preferably from 50 μg to 10 mg per kg body weight.
According to another aspect of the present invention, there is provided a method of treating an iron overload condition, comprising administering to a subject an effective amount of a dithiocarbamate-macromolecule containing composition as described herein. Iron overload includes hemochromatosis, hereditary hemochromatosis, hereditary spherocytosis, hemodialysis, thalassemia, transfusion (or hemosiderin deposition), repeated transfusions, anemia, sickle cell disease, dietary iron absorption, lastrogen iron absorption, muscle Iron dextran, and hemolytic disease of newborns.
According to another aspect of the invention, there is provided a method of treating non-ferrous overload disease and condition, comprising administering to a subject an effective amount of a dithiocarbamate-macromolecule containing composition as described herein. Non-ferrous overload diseases and conditions that require treatment include inflammation, ischemia / reperfusion injury, cancer, malaria, kidney failure, Alzheimer's disease, Parkinson's disease, heart disease, AIDS, liver disease, infection, lung injury, graft-versus-host disease, graft rejection And preservation.
As will be readily understood by those skilled in the art, various agents and / or conditions induce the expression of inducible nitric oxide synthase, and the potential negative effects of such exposure are determined by the complex methods described herein. Can be alleviated. Thus, for example, cytokines, cytokine receptors, endotoxins, platelet activating factors, bradykinin, bradykinin receptors, bacteria, parasites, viruses, coagulation factors, arachidonate metabolites, nitric oxide synthase, nuclear factor kappa B, Exposure to ultraviolet light, gamma radiation, high temperatures, oxygen radicals, and the like can be advantageously protected by the complex methods described herein.
The expression of inducible nitric oxide synthase and thus the induction of nitric oxide production can lead to various disease states and / or signs, such as septic shock, hemorrhagic shock, anaphylactic shock, toxic shock syndrome, ischemia, cerebral anemia , Administration of cytokines, overexpression of cytokines, ulcers, inflammatory bowel disease (eg gastritis, 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, ophthalmic diseases (e.g. uveitis, glaucoma, blepharitis, granulomas, allergic eye diseases, corneal ulcers, keratitis, cataracts, retinal diseases , Senile spot degeneration, optic neuritis, etc.), ileitis, inflammation (e.g., hepatitis, nephritis, airway inflammation, etc.), burns, infections (e.g., E. coli infection), viral (e.g., HIV) Jean Sex (eg, candidiasis and histoplasmosis) and parasites (eg, Leishmaniasis and Schistosomiasis) infections, hemodialysis, chronic fatigue syndrome, seizures, cancer (eg, breasts, melanoma) , Carcinoma, etc.), cardiovascular diseases associated with inflammatory cytokine overproduction (eg, heart disease, cardiopulmonary bypass, ischemia / reperfusion injury, etc.), ischemic / reperfusion associated with inflammatory cytokines overproduction, adult respiratory distress syndrome , Cachexia, myocarditis, autoimmune disease, eczema, psoriasis, heart failure, atherosclerosis, dermatitis, gallbladder, systemic lupus erythematosus, AIDS, AIDS dementia, neurodegenerative disorders (e.g. chronic neurodegenerative disorders), chronic pain, Persistence, cystic fibrosis, amyotrophic lateral sclerosis, schizophrenia, depression, premenstrual syndrome, anxiety, intoxication, migraine, Huntington's disease, epilepsy, gastrointestinal motility disorders, obesity, polyphagia, solid tumors (e.g. nerve Blastoma ), Malaria, blood cancer, myeloid fibrosis, lung damage, graft-versus-host disease, head injury, CNS injury, hepatitis, renal failure, liver disease (eg chronic hepatitis C), drug-induced lung injury (eg , Paraquat), myasthenia gravis (MG), graft rejection and preservation, increased fertility, bacterial translocation, cyclic shock, traumatic shock, photoaging, photodamage.
Treatment of such diseases can be accomplished by various agents, for example inhibitors of cytokine synthesis / release (e.g., anticytokine antibodies, anticytokine receptor antibodies, etc.), anti-endotoxin antibodies, bradykinin antagonists, synthetic peptide blocking bradykinin receptors, Fungicides / permeability increasing proteins, inhibitors of coagulation cascades (eg, antibodies to platelet activating factors), inhibitors of complement activity, arachidonate metabolism inhibitors, inhibitors of nitric oxide synthase enzymes, immunosuppressants, diabetes treatments, Anti-inflammatory drugs, preparations for seizure therapy, preparations for asthma therapy, preparations for cirrhosis therapy, anticancer drugs, antimicrobial drugs, antifungal drugs, antiretroviral drugs, preparations for the treatment of opportunistic infections and malignancies, red Useful preparations for the treatment of reflective lupus, preparations for the treatment of uveitis, thrombolytics, antispasmodics, rituals, constipation Useful formulations can be carried out by antihistamines useful in the treatment of Parkinson's disease agents, useful therapeutic agents in Crohn's disease therapy, antioxidants, etc.
Such formulations, used alone or as part of any two or more combinations thereof, may be advantageously combined with the dithiocarbamate-containing nitric oxide scavengers described herein, and may be in various states, such as
Anti-endotoxin therapy (eg, with antibodies to endotoxins, antibodies to LPS-binding proteins, soluble CD14 proteins, fungicides / permeability increasing proteins, polymyxin B, etc.),
Inhibition of cytokine synthesis / release (eg, using phosphodiesterase inhibitors, IL-4, IL-10, IL-13, TGF-β, corticosteroids, etc.),
Anticytokine therapy (eg, antibodies to TNF, soluble TNF receptors, IL-1 receptor antagonists, antibodies to IL-1 receptors, antibodies to IL-6, antibodies to interferon-γ, soluble interferon-γ Receptors, etc.),
Inhibition of coagulation cascade (and using agents such as inhibition of complement activity, anti-factor XII antibodies, antibodies to C5a, C1-esterase inhibitors, soluble Cr1, etc.),
Inhibition of platelet activating factor (PAF) (using agents such as PAF receptor antagonists),
Inhibition of arachidonate metabolism (eg, using agents such as cyclooxygenase inhibitors, lipoxygenase inhibitors, leukotriene inhibitors, thromboxane A ₂ inhibitors, prostaglandins, etc.),
Inhibition of nitric oxide synthase enzymes (e.g., arginine analogs (e.g., LN ^G -methyl arginine, LN ^G -nitroarginine, LN ^G -aminoarginine, L-iminoethylornithine, ε-N-imine) Noethyl-L-lysine, LN ^G -nitroarginine methyl ester, LN ^G -hydroxyl-N ^G -methylarginine, LN ^G -methyl-N ^G -methylarginine, L-thiocitrulline, LS-methylthiocitrulline, LS Ethylisothiocitrulline, S-ethylisothiocitrulline, aminoguanidine, S-methylisothiourea sulfate, etc.), heme ligands (e.g., 7-nitroidazole, 7,7,8,8-tetramethyl- o-quinomimethane, imidazole, 1-phenylimidazole, 2-phenylimidazole, etc.), calmodulin antagonists (e.g., chlorpromazine, W-7, etc.),
Immunosuppression (eg, cyclosporin A, OKT3, FK506, mycophenolate mofetil (MMF), azathioprine, corticosteroids (eg prednisone), anti- lymphocyte globulins, anti-thymocyte globulins, etc. Using the formulation),
Diabetes therapy (e.g., free pancreatic islets, encapsulated pancreatic islets, oral insulin, intravenous insulin, amylin hormones, etc.) using one or more agents such as dihydropyridine calcium channel blockers (e.g., nifedipine, nitrendipine, Using a preparation such as nisoldipine), acetohexamide, chlorpropamide, glyburide, glyphide, metformin, tolbutamide, tolazamide, etc.),
Inflammatory disease therapy (e.g., disease improving agents (e.g., antimalarial agents, methotrexate, sulfasalazine, mesalamine, azathioprine, 6-mercaptopurine, metronidazole, injectable and oral gold, D-penicila) Min et al.), Corticosteroids, nonsteroidal anti-inflammatory drugs (e.g., acetominophene, aspirin, sodium salicylate, magnesium salicylate, magnesium choline salicylate, salicylic salicylic acid, ibuprofen, naproxen, diclofenac, diflunisal, etodollac, Phenopropene Calcium, Fluriprofen, Pyroxycamp, Indomethacin, Ketoprofen, Ketorolac Tromethamine, Meclofenamate, Meclofenamate Sodium, Mefenamic Acid, Nabumethone, Oxaprozin , Phenyl butyl nitron (PBN), sulindac, tolmetin, etc.),
Leukocyte adhesion molecules (e.g., using one or more agents, such as seizure therapy (e.g., fibrinolytic agents (e.g., streptokinase, acylated plasminogen-streptokinase complex, urokinase, tissue plasminogen activator, etc.) For example, using monoclonal antibodies against intercellular adhesion molecule-1 (ICAM-1, CD18, etc.), blood dilution therapy (using a modified hemoglobin solution such as diaspirin crosslinked hemoglobin), growth factors (eg For example, glutamate antagonists (eg, lamotrigine, dissolsilpin maleate (MK 801), BW619C89, BW1003C87, using basic fibroblast growth factor (bFGF), transforming growth factor-beta 1 (TGF-β1), etc.) Etc.), using NMDA antagonists (e.g., CGS 19755 (Celportel), Aptiganel hydrochloride, dextropar, d-CPPene, etc.), and GABA agonists (e.g., mussimol). ), Using a free radical scavenger For example, allopurinol, S-PBN, 21-aminosteroid, tocopherol, peroxide dismutase, dexanabinol (HU-211), selenium, carotenoids, etc.), idebenone, ticlopidine, lovastatin, citcholine, etc.) ,
Asthma therapy (e.g., bronchodilators (e.g., albuterol, salmeterol, metaprothenol, bitolterol, pybuterol, terbutalin, isoproterenol, epinephrine, etc.), theophylline (e.g. , Theophylline, aminophylline, etc.), corticosteroids (e.g., beclomethasone, prednisone, etc.), antimodulators (e.g., chromoline sodium, nedocromyl sodium, etc.),
Cirrhosis therapy (e.g., diuretics (e.g. spironolactone), opiate antagonists (e.g. naloxone), cholestyramine, colchicine, cholestipol, methotrexate, rifampin, ursodeoxycholine acid, etc. ),
Anticancer therapy (e.g., alkylating agents (e.g., mechlorethamine, chlorambucil, ifosfamide, melphalan, busulfan, carmustine, lomustine, procarbazine, dacarbazine, cisplatin, carbople Latin, etc.), antimetabolites (e.g. methotrexate, mercaptopurine, thioguanine fluorouracil, cytarabine, etc.), hormonal agents (e.g. testosterone propionate, fluoxymesterone, flutamide, Diethylstilbestrol, ethynyl estradiol, tamoxifen, hydroxyprogesterone caproate, hydroxyprogesterone, megestrol acetate, etc., adrenocorticosteroids (e.g. prednisone), aromatase inhibitors (e.g. , Amino glutetimides), leuprolide, goserelin acetate, biological response modifiers (e.g., interferon-α2a, interferon-α2b, interleukin-2, etc.), peptides Hormone inhibitors (eg octreotide acetate), natural products (eg vinblastine, vincristine, vinorelbine, paclitaxel, dactinomycin, daunorubicin, idarubicin, doxorubicin, etoposide, Plicamycin, mitomycin, mitoxantrone, bleomycin, hydroxyurea, mitotan, fludarabine, cladribine, etc., support agents (e.g., allopurinol, mesna, leucovorin, erythropoi) Using one or more agents, such as ethyne, filgrastim, sargramostim, etc.),
Antibacterial therapy (e.g., selftriaxone, TMP-SMZ, penicillin, aminoglycosides, vancomycin, gentamicin, rifampin, imipenem, clindamycin, metronidazole, tetracycline, erythromycin, sulfonamide, streptomycin, ampicillin, Using one or more agents such as isoniazid, pyrazinamide, etambutol, etc.),
Antifungal therapy (e.g., amphotericin B, griseofulvin, miastatin, flucitocin, natamycin, antifungal imidazoles (e.g. clotrimazole, myconazole, ketoconazole, fluconazole, itraconazole, etc.) Using the formulation),
Antiretroviral therapy (e.g., using agents such as protease inhibitors (e.g., invirase, ritonavir, crycivan, etc.), zidovudine, didanosine, zalcitabine, stavudine, viramun, etc.),
Treatment of opportunistic infections and malignancies (eg anti-AIDS treatment, pentamidine, trimetaprim / sulfamethoxazole, primaquine, atobacon, clarithromycin, clofazimin, etabutol, rifampin, amikacin Using agents such as ciprofloxacin, pyrimethamine, amphotericin B, gancyclovir, foscarnet, fluconazole, ketoconazole, acyclovir, etc.),
Lupus erythematosus (using agents such as, for example, hydroxychloroquinine sulfate, chloroquinine sulfate, quinacrine, dapsone, isotretinoin, etc.),
Uveitis therapy (e.g., using agents such as corticosteroids, azathioprine, cyclosporin, etc.),
Thrombolytic therapy for acute myocardial infarction (e.g., using agents such as streptokinase, tissue plasminogen activator (t-PA), anistreplase, etc.),
Antispasmodic therapy (using agents such as, for example, dicyclomin, hydroxyamine, propanetelline, etc.),
Ritual therapy (using agents such as loperamide, diphenoxylate with atropine, etc.),
Anticonstipation therapy (using agents such as, for example, siarium, methylcellulose, polycarbophil, cisapride, fiber supplements including chaff),
Antihistamine therapy (e.g. ethanolamine (e.g. diphenhydramine, clemastine, etc.), ethylenediamine (e.g. brompheniramine, chlorpheniramine, triprolidine, etc.), phenothiazine (e.g. For example, hydroxyzine), piperidine (e.g., using agents such as terfenadine, astemisol, azatadine, ciproheptadiene, loratidine, etc.),
Anti-Parkinson therapy (using agents such as benztropin mesylate, biferidene, chlorphenoxamine, cyclmine, orfenadrin, procclidine, trihexifenidyl, etc.)
As well as other conditions, including the induction of nitric oxide synthase, which can be readily identified by those skilled in the art:
In addition, in the present invention, simultaneous administration of a combination of a therapeutic agent suitable for the treatment of various diseases and conditions and the dithiocarbamate-containing nitric oxide scavenger (s) described herein may be made. For example, the dithiocarbamate-containing nitric oxide scavenger (s) of the invention may be immunosuppressive agents such as glucocorticoids (methylprednisolone), myelin based proteins (eg 7-capacone), anti -Fc receptor monoclonal antibodies, hydroorotate dehydrogenase inhibitors, anti-IL2 monoclonal antibodies (e.g., multiclicksimab), buspyron, castanospermine, CD-59 (complement factor inhibitors) ), 5-lipoxygenase inhibitors, phosphatidic acid synthetic antagonists, ebselene, edelfosine, enlimab, galactin, platelet activator antagonists, selectin antagonists, interleukin-10 agonists, macrocyclic lactones, methoxides It is advantageously used with the administration of satone, mizoribin, protein kinase C inhibitors, phosphodiesterase IV inhibitors, sialoporins, sirolimus, spirocyclic lactams, 5-hydroxytrytamine antagonists and the like.
Other therapies in which the dithiocarbamate-containing nitric oxide scavenger (s) of the present invention are advantageously used in conjunction with the main therapeutic agent are anti-metabolites cytotoxins (eg, azathioprine, cyclophosphamide), C5a Release inhibitors, benzidamine, feldscein, pentostatin, thalidomide, benzoporphyrin derivatives, arachidonate antagonists (e.g., halomethasone, halobetasol propionate), corticosteroids (clobetasol propio Nate), growth hormone antagonists (octapeptide somatostatin analogs, lanreotide, angiopeptin and dermopeptin), thymopentin and the like.
Another therapy in which the dithiocarbamate-containing nitric oxide scavenger (s) of the present invention is advantageously used in conjunction with the main therapeutic agent is a neuroprotective agent, for example α-adrenoceptor antagonist (eg, α- Dihydroergocriptine), NMDA antagonists (e.g., remasemid, 2-piperazincarboxylic acid, N-indologlycinamide derivatives, spiro [benzo (b) thiophene-4 (5H)] derivatives , Elliprodyl, dexanbinol, amantadine derivatives, dizocilpin, benzomorphan derivatives, aptiganel, (S) -α-phenyl-2-pyridine ethaneamide dihydrochloride, 1-amino-cyclopentanecarboxylic acid Etc.), sodium channel antagonists, glycine antagonists (e.g., glycascin), calcium channel antagonists (e.g., 3,5-pyridinedicarboxylic acid derivatives, coopeptides, 1-piperazinethanol, Thieno [2,3-b] pyridine-5-carboxylic acid derivative, nilvadipine, nisoldipine, tyrilazad mesylate, 2H-1- Zopyran-6-ols, nitron spin traps, iasidipine, iomerazine hydrochloride, remildipine, liparizine, eponidipine, piperazine derivatives, etc., calpine inhibitors, fibrinogen antagonists (e.g. , Ankrod), integrin antagonist (eg antren), thromboxane A ₂ antagonist (eg 9H-carbazole-9-propanoic acid derivative, 5-heptenone acid derivative, 1-azulene -Sulfonic acid derivatives, etc.), brain-induced neurotrophic factors, adrenergic propagation inhibitors (e.g., 1-butanamine), endothelin A receptor antagonists (e.g., benzenesulfonamide derivatives), GABA A receptor antagonists Vagina (eg, triazolopyrimidine derivatives, cyclohexaneacetic acid derivatives, etc.), GPIIb IIIa receptor antagonists, platelet aggregation antagonists (eg, 2 (1H) -quinolinone derivatives, 1H-pyrrole-1- Acetic acid derivatives, coumadine, etc.), factor Xa inhibitors, corticotropin release factor Vagina, thrombin inhibitors (eg, proxiparin, dermatan sulfate, heparinoids, etc.), dotarizine, intracellular calcium chelating agents (eg, BAPTA derivatives), radical forming antagonists (eg, EPC- K1, 3-pyridinecarboxamide derivatives, peroxide dismutase, lacsofelast, rubelazole, 3H-pyrazol-3-one derivatives, kynurenic acid derivatives, homopiperazine derivatives, polynitroxyl albumin, etc.), protein kinases Inhibitors (e.g., 1H-1,4-diazepine), nerve growth agonists, glutamate antagonists (e.g., cyclohexanepropanoic acid, rilusol, acetamide derivatives, etc.), lipid peroxidase inhibitors (e.g. For example, 2,5-cyclohexadiene-1,4-dione derivatives), sigma receptor agonists (eg cyclopropanemethanamine derivatives), tyrotropin-releasing hormone agonists (eg L-proline Amides, posatyrrelin, etc.), prolyl endopeptide Anase inhibitors, monosialoganglioside GM1, proteolytic enzyme inhibitors (e.g., napamosat), neutrophil inhibitors, platelet activator antagonists (e.g., nupapant), monoamine oxidase B inhibitors ( For example, parafluoroselegiline, benzonitrile derivatives, etc.), PARS inhibitors, angiotensin I converting enzyme inhibitors (e.g., perindopril, ramipril, etc.), acetylcholine agonists (e.g., pramiracetam) Protein synthesis antagonists (e.g., prostains), phosphodiesterase inhibitors (e.g., propentophylline), opioid kappa receptor agonists (e.g., 10H-phenothiazine-2-carboxamine Derivatives), somatomedin-1, carnitine acetyltransferase stimulant (e.g., acetylcarnitine), and the like.
Another therapy in which the dithiocarbamate-containing nitric oxide scavenger (s) of the present invention is advantageously used in conjunction with the main therapeutic agent is a T cell inhibitor such as a synthetic leukocyte antigen induced peptide, an interleukin-1 receptor antagonist. , MG / AnergiX, anti-CD3 monoclonal antibody, anti-CD23 monoclonal antibody, anti-CD28 antibody, anti-CD2 monoclonal antibody, CD4 antagonist, anti-E selectin antibody, MHC inhibitor, mycophenolate Administration of mofetil and the like.
Another therapy in which the dithiocarbamate-containing nitric oxide scavenger (s) of the present invention is advantageously used in conjunction with the main therapeutic agent is an antimigraine agent such as naratriptan, zolmitriptan, riztriptan, Quetiapine, phytomedin, (S) -fluoxetine, calcium channel antagonists (e.g., nimodipine / nimotope), flunarizine, dotarizine, isomerizine HCl, etc., α-dihydroergocryptin , 5-HT1 agonist (eg sumatriptan / immitrex, imigrand, etc.), 5-HT1D agonist, 5-HT1A antagonist, 5-HT1B antagonist, 5-HT1D antagonist (eg, 1H-indole-5-ethanesulfonamide derivatives, 1H-indole-5-methanesulfonamide, etc.), 2-thiophenecarboxamide, 3-piperidinamine, diclofenac potassium, dihydroergotamine, dolacetron mesylate Dotarizine, flupyrithin, histamine-H3 receptor agonist, indobufen, 1-azulenesulfonic acid derivative, cholinesterase inhibitor, brady Nin antagonists, substance P antagonists (e.g. capsaicin / nasocap), piperazine derivatives, neurokinin 1 antagonists, metgoline, dopamine D2 antagonists (e.g. metoclopramide + lysine acetyl ), Enkephalinase inhibitors (eg, neutral endopeptidase), 5-HT2 antagonists, 5-HT3 antagonists (eg, dolasetron mesylate, 4H-carbazol-4-one derivatives, etc.) , Tenosal, tolphenamic acid, cyclooxygenase inhibitors (e.g. carbasalate / carbaspirin calcium, tenosal, etc.), alpha adrenoreceptor antagonists (e.g. arotinol, dihydroergo Kryptin and the like), opioid antagonists (eg flupyrutin), beta adrenergic antagonists (eg propranolol), valproate semisodium, and the like.
Another therapy in which the dithiocarbamate-containing nitric oxide scavenger (s) of the invention is advantageously used in conjunction with the main therapeutic agent is an anti-arthritis agent such as an anti-CD4 monoclonal antibody, phospholipase A1 inhibitor , Combination of loteprednol, tobramycin, loteprednol and tobramycin, salasedine, amiprilos, anakinra, anergiX, anti-B7 antibody, anti-CD3H, anti-gp39, anti-MHC MAbs, antirheumatic peptides, anti-Tac (Fv) -PE40, AP-1 inhibitors, purine nucleotide phosphorylase inhibitors, bindarit, CD2 antagonist, campath-1H, CD4 antagonist, tumor necrosis factor antagonist (Eg, p80 TNFR, rhTNFbp, peptide T, CenTNF, thalidomide, etc.), cobra venom factor, interleukin 1a agonists (eg cytogenin), interleukin 2 receptor antagonists (eg, multiple clicks) Shimab), ICAM 1 antagonist (e.g., Enrimabab), interleukin 1 beta conversion enzyme inhibition (Eg, ICE-inhibitors), interferons, interleukin-10, interleukin-1 antagonists, interleukin-2 antagonists (eg sirolimus), phospholipase C inhibitors, neurokinin 1 antagonists, Laflunimus, leflunomide, leukotriene antagonist, levamisol, LFA3TIP, macrocyclic lactones, MHC class II inhibitors, myzoribin, mycophenolate mofetil NfkB inhibitors, feldscein, pydotimod, PNP inhibitor, rheumacon , CD28 antagonist, lokinimex, subreum, tacrolimus, modified growth factor beta agonists, methionine synthase inhibitors (eg vitamin B12 antagonists), adenosine A2 receptor agonists, CD5 antagonists (eg For example, zolimob), 5-lipoxygenase inhibitors (e.g., zileuton, tenidab, etc.), cyclooxygenase inhibitors (e.g., tenoxycam, talmetacin, pyroxamcin cinnamate, Oxaprozin, mopezolac, nabumetone, flurbiprofen, acecle Fenac, diclofenac, dexibuprofen, etc.), metalloproteinase inhibitors (eg, TNF invertase enzyme inhibitors), phospholipase A2 inhibitors, leukotriene B4 antagonists, collagenase inhibitors, cyclooxygenase 2- Inhibitors (e.g. meloxycam), thromboxane synthase inhibitors (e.g. curcumin), cysteine protease inhibitors, metalloproteinase inhibitors, lipocortins synthetic agonists (e.g. Donisolone 21-farnesylate, deplazacort, etc.), chelating agents (e.g., diacerane), elastase inhibitors, nitric oxide antagonists (e.g., hydroxylcobalamine), stromelli Renal inhibitors, prostaglandin E1 agonists (eg, misoprostol, misoprostol + diclofenac, etc.), dihydrofolate reductase inhibitors (eg, trimetrexate), opioid antagonists ( For example, nalmefene), corticotropin releasing factor antagonist, protease inhibitors (eg protease nexin-1), bradykinin antagonists (eg tachykinin antagonists), growth hormone antagonists (Eg, octreotide), phosphodiesterase IV inhibitors, gelatinase inhibitors, prostaglandin synthase inhibitors (eg sulfasalazine), and the like.
Another therapy in which the dithiocarbamate-containing nitric oxide scavenger (s) of the invention is advantageously used in conjunction with the main therapeutic agent is an agent useful for the treatment of septic shock, such as angiogenesis inhibitors, bradykinin antagonists. , Complement factor inhibitors (e.g. C3 invertase enzyme inhibitors), C5a release inhibitors, dopamine agonists (e.g. dopexamine), elastase inhibitors, E selectin antagonists, farnesyltransferase inhibitors (e.g. For example, RBE limonene), immunostimulating agents (e.g., lipid A vaccine, Edobacoma, Nevakumab, StaffGAM, Diabody, etc.), immunosuppressive agents (e.g., transcyclopentanyl purine analogs), interleukin 1 Antagonists (eg interleukin 1 receptor), interleukin 1 receptor antagonists (eg anakinra), interleukin 1b antagonists (eg interleukin-1β), interleukin-1β inverting enzyme inhibitors (eg , ICE-inhibitor) Terleukin 8 antagonist (e.g. IL-8 receptor), interleukin 13 agonist (e.g. interleukin-13), lipase washing factor inhibitor, membrane permeability enhancer (e.g. fungicide permeability increasing protein / BPI ), Nitric oxide synthase inhibitors (eg, L-NMMA, α-methyl-N-iminoethyl-ornithine, etc.), P2 receptor stimulants (eg, ATP analogues), phosphatidic acid synthetic antagonists ( For example, lysophilin), phospholipase A2 inhibitors (e.g., acylpyrrole-alkanoic acid derivatives, indoreacetic acid derivatives, etc.), platelet activating factor antagonists (e.g., (2RS, 4R) -3- (2- (3-pyridinyl) thiazolidine-4-yl) indole), prostacyclin agonists (eg taprosten), protein kinase C inhibitors, selectin antagonists (eg sulfuric acid Glycolipid Cell Adhesion Inhibitors), TNF Receptor-Ig, Tumor Necrosis Factor Antagonist (eg, Anti-TNF MAbs), Tumor Necrosis Factor Alpha It includes the administration of such hangjil.
Another therapy in which the dithiocarbamate-containing nitric oxide scavenger (s) of the present invention is advantageously used in conjunction with the main therapeutic agent is a therapeutic agent for multiple sclerosis, for example 4-aminopyridine, deoxyspergualin, ACTH, amantadine, antibody adjuvant (e.g., poly-ICLC), anti-cytokine monoclonal antibody, anti-inflammatory, baclothene, betacol chloride, carbamazepine, carbohydrate drug, clonazepam , CNS and immune system modulators, cyclophosphamide, cyclosporin A, cytokines (e.g. IFN-α, alphaferon, IFN-β 1b, betacerone, TGF-β2, PEG-TGF-β2, betakin , IFN-β / Lviv, pron, interferon-β, IFN-β, etc., CD4 + T cell inhibitors (eg, AnergiX), CD28 antagonists, growth factors (eg, glial growth factor, GGF, Nerve growth factor, TGF-β2, PEG-TGF-β2, betakin, etc., humanized MAb (eg, anti-IFN-γMAb, smart anti-IFN-γMAb, anti-Tac antibody, Mat anti-Tac antibodies, etc.), humanized anti-CD4 MAbs (e.g., anti-CD4 MAb, Centara, etc.), hydrolase stimulants (e.g., castanospermine), IFN-α, IFN-γ Antagonists (eg anti-IFN-γMAb, smart anti-IFNγMAb, etc.), IL-2 antagonists (eg tacrolimus, fuzimycin, prograph, IL-2 fusion toxin, DAB ₃₈₉ IL- 2), IL-4 antagonists (eg, IL-4 fusion toxins, DAB ₃₈₉ IL-4, etc.), immune mediated neuronal damage inhibitors, immunoglobulins, immunostimulants (eg, poly-ICLC, edel) Gun barrel, ET-18-OCH3, ET-18-OME, etc.), immunosuppressive agents (e.g., azathioprine, castanospermine, tacrolimus, FK-506, Fujimycin, prograph, anti-leucointegrin MAb, primate anti-CD4 antibody, linomide, loquinimex, transcyclo-pentanyl purine analog, spanidine, 15-deoxyspergualline, deoxyspurgiline, gusperimus HCl, cyclosporine, sandimmune , IL-10, anti -TCR MAbs, anti-CD4 MAb, cantara, immunophilin, cyclophosphamide, etc., integrin antagonists (eg anti-integrin monoclonal antibodies), interferon agonists, interferon-β-1b, Isoprinosine, IV methylprednisolone, macrolide, MAO B inhibitors (e.g., selegiline, parkinyl, etc.), methotrexate, mitoxantrone, muscarinic antagonist, oxybutynin chloride, oxygen free radical antagonist ( For example, tetrandrine, biobenzylisoquinoline alkaloids, etc.), phenoxybenzamine, phospholipase C inhibitors, photodynamic therapy (e.g., benzoporphyrin derivatives (BPD)), platelet activating factor antagonists (e.g. For example, gingkolide B), potassium channel antagonists (e.g. aminodiaquine), propranols, phosphaglandin synthase inhibitors (e.g. sulfasalazine, salazulfa-pyridine, azupidine, salazoprine Etc.), protease antagonists (eg , Gingcolide B), recombinant soluble IL-1 receptor, spherugalin analogs (eg, spanidine, 15-deoxyspergualin, deoxyspurgiline, gusperimus HCl, etc.), selectin antagonists Administration of the vagina (eg lectin-1, recombinant IML-1, etc.), soluble TNF receptor I, TNF antagonists (eg thalidomide, TNF inhibitors, etc.).
Another therapy in which the dithiocarbamate-containing nitric oxide scavenger (s) of the present invention is advantageously used in conjunction with the main therapeutic agent is an organ transplant agent such as anti-CD25 MAbs, anti-Tac antibodies, anti-TNF MAb, apoptocin, azathioprine (eg immunoran), complement inhibitory factor (eg CD59), cyclosporin (eg CsA), FK-506 / rapamycin binding protein (FKBP), Glucocorticoids, humanized modifications of OKT3 (eg, huOKT3-185), hydroorotate dehydrogenase inhibitors (eg, Brequinar), orthoclonal OKT3 (eg, IgG2a anti-T cell mice Monoclonal antibodies, muromonab-CD3, etc.), rapamycin, streptomyces isolates and the like.
Another therapy in which the dithiocarbamate-containing nitric oxide scavenger (s) of the invention is advantageously used in conjunction with the main therapeutic agent is a therapeutic agent for systemic lupus erythematosus (SLE), for example androgen derived steroids, anti- CD4 humanized antibodies, CD2 antagonists, cyclosporin (e.g., sandimmune, cyclosporin analogues, cyclosporin-G, NVal-CyA, etc.), cytokines (e.g., IL-4 fused toxins), cytokine receptors Antagonists (e.g. immunomodulatory cytokines), E-selectin antagonists (e.g. anti-ELAM), FK506 / tacrolimus (e.g. prograpes), hypercalcemia agents, IFN-γ Antagonists (eg anti-IFN-γ MAb, smart anti-IFN-γ MAb, etc.), IL-1β invertase enzyme inhibitor (ICE), E. IL-2 (e.g., Selmoleukin, IL-2, Selleuk, etc.), immunoglobulin (e.g., anti-ELAM), immunostimulant (e.g., thymotrinan), immunized by Coli Inhibitors (eg rapamycin, anti-CD4, T-cell inhibitors, anti-tac MAb, immunophilin, mycophenolate mofetil, IL-4 fusion toxin, tripanosoma inhibitory factor (TIF), lefluno Mead, spanidine, 15-deoxyspergualin, deoxyspurgiline, gusperimus hydrochloride, loquinimex, linomide, etc.), immunotoxins (e.g., zolimob aritox, jomajim (Xomazyme) -CD5 plus, etc.), intravenous immunoglobulins, integrin antagonists (eg, integrin blockers), Migis® antibodies, monoclonal antibody therapeutics, mouse MAb (eg, Anti-SLE vaccine, MAb 3E10, etc.), primate anti-CD4 antibodies (eg CE9.1), protease inhibitors (eg matrix metalloproteases) (MMP) inhibitors, stromelysin and the like), protein synthesis antagonists (e.g., anti-CD6-bR, anti-T12-bR, oncorycin CD6, etc.), purine nucleoside phosphorylase inhibitors, selectin Antagonists (e.g., lexicins), sperguline analogs (e.g., spanidine, 15-deoxyspergualin, deoxyspurgiline, gusperimus hydrochloride, etc.), T cell inhibitors (Eg, anergy X), tumor necrosis factor (TNF) antagonists, and the like.
Another therapy in which the dithiocarbamate-containing nitric oxide scavenger (s) of the present invention is advantageously used in conjunction with the main therapeutic agent is a therapeutic agent for Alzheimer's disease, such as an ACh release increasing agent (eg, benzothiophene). Derivatives), acetylcholine release stimulants, AMPA agonists (e.g., AMAlex, a series of isoxazole compounds, etc.), AMPA GluR agonists (e.g., IDRA-21 [7-chloro-3-methyl-3,4 -Dihydro-2H-1,2,4-benzothiadiazinine)), anticholinesterases, Ca-antagonists (eg spider venom induced ICM peptides and analogues, a series of substituted 2-aminoindane compounds) ), K-channel blockers (e.g., trans-R-4- (4-methoxyphenylmethyl) cyclohexylanine and analogues, functional and / or structural analogues based on margatoxins, etc.), muscarinic receptor action Vagina (eg Xanomeline), NMDA antagonist (eg any indole derivative, (R- (R ¹ , S ¹ ))-α- (4- Hydroxyphenyl) -beta-methyl-4- (phenylmentyl) -1-piperidinepropanol and the like and the like), nicotine AChR agonists (eg, ABT-418 [isoxazoles, 3-meth-5) -(1-meth-2-pyrrolidinyl)], and the like.
Another therapy in which the dithiocarbamate-containing nitric oxide scavenger (s) of the present invention is advantageously used in conjunction with the main therapeutic agent is a therapeutic agent for psoriasis, for example a 5-LO inhibitor (e.g. ronaphalene, zileuton). , Epocarbazoline-A, etc.), 5-LO / CO inhibitors (e.g. Tennyb), angiogenesis inhibitors (e.g. platelet factor 4), anticancer, antibiotic, anti-inflammatory cytochrome P450 oxidoreductase Inhibitors, antiproliferative compounds (e.g. Zyn-linkers), arachidonic acid analogues, arachidonic acid antagonists (e.g. lonophalene, triamcinolone acetonide with penetration enhancer azone, betamethasone dipropionate steroid wipes, Halobetasol propionate, ultrabate, halomethasone, cycorten, etc.), beta-glucan receptor antagonists, betamethasone steroid wipes, calcium metabolism reducers (e.g., tacalcitol, bonalpha, calcipotriol, Degree Nex et al.), CD4 binding inhibitors, cell adhesion inhibitors (e.g. selectin inhibitors), cell aging inhibitors (e.g. Factor X), corticosteroids (e.g. halobetasol propionate, ultrabate, halo Metasonone, cycortene, etc.), dihydrofolate reductase inhibitors (e.g. dichlorobenzoprim, methotrexate, methotrexate in microsponge delivery systems, etc.), E-selectin inhibitors, endogenous active forms of vitamin D ₃ (e.g. For example, saporin mitotoxin, steno-start, etc.), fumagillin analogues, G-protein and signal transducing compounds, gel preparations for acne (eg, nicotinamide, populex, etc.), growth hormone antagonists ( For example, octreotide, sandostatin, lanreotide, angiopeptin, somatulin, etc., humanized antibodies (eg, anti-CD4 antibodies), hydroorotate dehydrogenase inhibitors (eg, Cotton, Brequinar sodium, bifenquinate, etc.), ICAM-1 inhibitors, IL-1 and other cytokine inhibitors (eg septanyl), IL-1 invertase enzyme inhibitors, IL-1 receptor antagonists (eg For example, anthryl), IL-2 antagonists (eg tacrolimus, progra, FK-506, etc.), IL-2 receptor targeted fusion toxins, IL-8 receptors, immunostimulants (eg , Thymopentin, Timunox, etc.), immunosuppressive agents (e.g. cyclosporine, sandim 샌드, anti-CD11, tacrolimus, prograph, FK-506, FK-507, etc.), leukotriene antagonists, leukotriene B4 antagonists Vaginal, leukotriene synthesis inhibitors, lipase washing factor inhibitors (e.g., 1-docosanol, lidacol, etc.), lipid encapsulated reducing agents (e.g., ditanol), liposome gels (e.g., ditranol) , Lithium succinate ointment (e.g., lithium salt, epaliz, etc.), octapeptide somatostatin analogs (e.g., lanreotide, angiopeptin , Somatulin, etc.), PKC inhibitors, phospholipase A2 compounds, photodynamic anticancer agents (eg, 5-aminoleubulinic acid), photodynamic therapy (eg, benzoporphyrin derivatives, synthetic choline, synthetic porphyrins, etc.) , PKC inhibitors (e.g. sapgol, tinac, etc.), platelet activator antagonists, platelet aggregation inhibitors (e.g. CPC-A), prostaglandin agonists (e.g. eicosapentaenoic acid + gamma- Linolenic acid blends, efamol marine, etc.), protein kinase C (PKC) inhibitors, protein synthesis antagonists (e.g. calcitriol, namirotene, etc.), purine nucleoside phosphorylase inhibitors, radical forming agonists (e.g. For example, benzoporphyrin derivatives), recombinant anti-leucoproteinases, retinoids, retinoid derivatives, rapamycin binding protein (FKBP) (e.g. immunophilin), second generation unidirectional retinoids (e.g. acitretin, Neoti Hands, etc.), soluble IL-1, IL-4 and IL-7 receptors, somatostatin analogs (eg, octreotide, acidstatin, etc.), peroxide dismutase, thymidylate synthase inhibitors, transglutaminaa Administration of an inhibitor, a tyrphostin EGF receptor kinase blocker, a VCAM-1 inhibitor, and the like.
Another therapy in which the dithiocarbamate-containing nitric oxide scavenger (s) of the present invention is advantageously used in conjunction with the main therapeutic agent is a therapeutic agent for diabetes, for example an ACE inhibitor (eg captopril), amylin Agonists and antagonists (e.g. Normylin®), autoimmune compounds, capsaicin (e.g. Jostrix-HP), domperidone (e.g. Motilium) Fluvastatin (e.g. rescol), iloprost, insulin analogues (e.g., Nu-insulin compound, humulin, eletin, Humalog (registered trademark)), Lys-Pro, Amaryl, etc.), insulin type growth factor, insulinotropin, nerve growth factor, oral hypoglycemic drugs (e.g., glymepiride, amaryl, acarbose, miglitol, recombinant yeast glucagon, glucagen (GlucaGen) (Registered trademark), Novornorm (registered trademark)), glyphide, insulinotropin, etc.) , Platelet induced growth factors (e.g., geogenetics / novonordisk compounds), sulfonylureas (e.g., tolbutamide, acetohexamide, tolazamide, chlorpropramide, etc.), T cell methods (E.g., anergy, procept compounds, T cell science compounds, etc.), tolesat (e.g., Alredase®, etc.).
Another therapy in which the dithiocarbamate-containing nitric oxide scavenger (s) of the invention is advantageously used in conjunction with the main therapeutic agent is a therapeutic agent for seizures, such as ankrod, a 5HT antagonist (eg piperazine). Derivatives), 5-HT reuptake inhibitors (e.g., milnacipran, dalcifrane, etc.), 5-HT agonists, 5-lipoxygenase inhibitors, ACH agonists (e.g., pramiracetam, choline- L-alphaphosphate, L-alpha-glycerylphosphorylcholine, delexit, etc., adenosine agonists (eg arasine analogues), adenosine A1 receptor agonists (eg azaisoteres, 2- Chloro-N- [4- (phenylthio) -1-piperidinyl] adenosine and the like), adenosine reuptake inhibitors (e.g. diphenyloxazole derivatives), adrenergic propagator reuptake inhibitors (e.g. Melan, alnert, selport, etc.), aldose reductase inhibitors (eg, spiro-3 'pyrroline induction) ), Alpha antagonists (e.g., drotaberin acepilinate, defogen, etc.), alpha 2 agonists, ancrode / arbin, aspirin, benzothiazole (e.g., ruvelazole, etc.), benzodiazepine receptor Antagonists (e.g. 3-oxadiazolyl-1,6-naphthyridine derivatives, tetracyclic imidazodiazepine-based imidazenyls, etc.), blood substitutes, bradykinin antagonists (e.g., Bradycor, pepti KOR et al.), C5a release inhibitors (e.g., protein derivatives), calcium antagonists (e.g. remildipine, trimetazidine derivatives, iomerizin, diltiazem analogs such as clentiazem maleate), calcium channels Antagonists (e.g. nitridypine-like compounds diferdipine, diltiazem derivatives, tetrahydronaphthalene derivatives, fasudil, aryl, darodipine, dazodipine, dihydropyridine, laccidipine, nilvadipine Calpine inhibitors, carnitine, palmitoyl-transferase Preparations, carvedilol, cell adhesion molecule technology, brain calcium antagonist vasodilators (e.g., nimodipine, nimotope, etc.), cholinesterase inhibitors (e.g., indole and indazole derivatives, tacrine analogs, etc.), Complement factor inhibitors (e.g., protein derivative TP16, Compactact A, Compactact C, Factor D inhibitors, soluble, recombinant MCP based complement inhibitors, etc.), complement inhibitors, coronary vasodilators (e.g., nicolandil, Adancor, etc.), cytidyl diphosphocholine / cyticholine, cytokine, dexanabiol, dopamine agonists, endothelin antagonists, endothelin receptor antagonists, excitatory amino acid agonists (e.g. acylated polyamine analogues, N- (4-hydroxyphenylpropanoyl) -spermine analogs, etc.), excitatory amino acid antagonists (e.g. tryptophan, 4,6-disubstituted seizures & kynurenine derivatives), glutamate antagonists (e.g. For example, kainate, quizet Eluate), glutamate receptor antagonists (e.g., aracin compounds, quinoxaline derivatives, etc.), glycine antagonists, glycine NMDA agonists (e.g., 3-hydroxy-2,5-dioxo-1H- Benz [b] azepine), glycine NMDA related antagonists (eg, strychnine-nonsensitized glycine binding sites of NMDA receptors, glycistacin, eliprodil, etc.), growth factor antagonists (eg, nonpeptides) Indolocarbazole neutrophil molecules, etc.), GPIIb / IIIa antagonists, heparin, hydroxyl radical formation inhibitors (eg, homopiperazin derivatives), hypocalcemia agents (eg, calcitonin peptides related to hCGRP peptides) , ICAM-1 compounds (e.g., Enlimomab), interleukin-1 antagonists (e.g., cyclic nitrones), iron-dependent lipid peroxidation inhibitors (e.g., 2- (aminomethyl) Manth), lactic acid accumulation / inhibitors, lipid peroxidase inhibitors (e.g., Benon, Avan, etc.), methyltransferase stimulant (e.g. 4-methyl benzenesulfonate, ademethionine sulfate tosylate, cetane, etc.), monoamine oxidase B inhibitor (e.g. razabamide), nad Roparin (eg, proxiparin), napronyl / naphthydrofuryl (eg, xyxylene), nerve growth factor agonists (eg, small molecule compounds, monosialoganglioside GM1, etc.), Neuronal calcium channel blockers, NMDA antagonists (e.g., spiroisoindole / dizosilpin derivatives, auxindol compounds, sialic acid derivatives, N-palmitoyl-betaethylglycoside neuramic acid, dextropane, ifenprodil analogs Elliprodil, lipophilic molecules, remasemide, etc.), NMDA antagonist partial agonists (e.g. Conantokin G peptide), NMDA channel blockers (e.g. Aptiganel, Cerestat, etc.) , NMDA receptor antagonist, nootropic / acetylcholine action Vagina (e.g., oxracetam, neuratic, etc.), norepinephrine inhibitors (e.g., midicipran), N-type calcium channel antagonists, opioid antagonists (e.g. nalmefene, nal) Methylene, cerbene, incisten, etc.), opioid kappa receptor agonists (e.g. acrylacetamide enadoline), organoselenim (e.g. eselene), oxygen scavenger (e.g. Tyrilazad mesylate, lazaroid, predox and the like), PAF antagonist (e.g. nupapant), partially glycine NMDA agonist (e.g. ACPC), peptide / GPIIb / IIIa antagonist (e.g. For example, integral), peptidic neuron specific calcium channel antagonists, phosphodiesterase inhibitors (e.g., xanthine derivatives, propentophylline, Hoe-285, hextol, etc.), plasminogen activators (e.g. For example, r-ProUK (recombinant prourokinase), platelet activator antagonists, platelet aggregation antagonists (eg For example, cilostazol, peptide preparations, GPIIb-IIIA inhibitors, etc.), platelet aggregation inhibitors (eg, diaminoalkanoic acid derivatives), potassium channel agonists (eg, nicolandil, adancor, etc.) Prolyl endopeptidase (PEP) inhibitors, protein kinase C inhibitors (e.g., monosialoganglioside derivatives), proteolytic enzyme inhibitors (e.g., protease nexin-1, insights, napamosat, dutan, Futanes, etc.), pyrimidine derivatives, quinolizine derivatives, recombinant tissue plasminogen activators (e.g., Alteplas, activiva, etc.), Schwann cell-derived molecules / promoters, sigma receptor antagonists (e.g. For example, tetrahydropyridinyl-isoxazoline), sodium / calcium channel modulators (e.g. Liparizine), sodium channel antagonists, streptokinase (e.g. streptase), peroxide dismutase stimulant ( For example, PEG-conjugated enzyme peroxide dismutase / dismutec, PEG-SOD, etc., thrombin inhibitors (eg, nonpeptides), thromboxane synthase inhibitors (eg, linotroban), tyrotropin releasing hormone action Vaginal (e.g. TRH agonist, protyreline analog thymolyberine, etc.), ticlopidine (e.g. ticlide), TRH agonist (e.g. tyrotropin releasing hormone), trilazad, urokinase (Eg, avokinase), warfarin (eg, coumadine), and the like.
Thus, preferred indications for treatment according to the combination therapies of the present invention include septic shock, ischemia, ulcers, ulcerative colitis, diabetes, arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, cirrhosis or allograft rejection, etc. do.
According to a particular aspect of the present invention, dithiocarbamate-containing nitric oxide scavengers optionally contain antibiotics (e.g., gentamicin, tobramycin, amikacin, piperacillin, clindamycin, sepoxithin or vancomycin or Mixtures), and vascular agonists (e.g., catecholamines, noradrenaline, dopamine or dobutamine) or mixtures thereof. In this way, the deleterious side effects and / or focus of many of the above pharmaceutical formulations (eg, systemic hypotension) are prevented by the administration of a combination formulation comprising dithiocarbamate-containing nitric oxide scavenger or Or may be reduced.
Those skilled in the art will appreciate that agents capable of inactivating species that induce expression of inducible nitric oxide (or agents that can inhibit the production of such species) and the dithiocarbamate-containing oxidations described herein. Formulations of nitrogen scavengers can be delivered by various means, for example, oral, topical, intravenous, subcutaneous, parenteral, rectal, inhalation and the like.
Because individual subjects may exhibit varying degrees of symptoms and each drug has its own unique therapeutic properties, the exact mode of administration, dosage used and treatment protocol for each subject is determined by the practitioner.
According to another embodiment of the invention, in a suitable vehicle that enables oral delivery, transdermal delivery, intravenous delivery, intramuscular delivery, topical delivery, intranasal delivery, the "therapeutic agent" (as described herein) and the present invention There is provided a physiologically active composition (s) comprising a dithiocarbamate-containing nitric oxide removal compound described herein.
The composition can be delivered in various pharmaceutically suitable forms, depending on the mode of delivery employed. For example, the composition can be delivered in the form of a solid, solution, emulsion, dispersion, micelle, liposomes and the like.
The invention will now be described in more detail with reference to the following non-limiting examples.
Example 1
Preparation of Poly MGD-BSA by Crosslinking
Crosslinking experiments were conducted as follows: 1 ml of bovine serum albumin (BSA; 0.1-2.0 mM in water) was added 20-400 mM N-hydroxysulfosuccinimidyl-4-azido salicylic acid (Sulfo-NHS in DMSO). -10 ml beaker containing aliquots of ASA; Piece Chemical Co.). The reaction mixture was incubated for 10-60 minutes at room temperature with gentle stirring in the dark. Upon addition of N-methyl-D-glucamine dithiocarbamate (MGD; 5-100 mg), the solution was irradiated for 1-5 minutes at 365 nm using a UV lamp. After irradiation, the solution was placed in a G-25 prefilled column. Fractions containing MGD-BSA were pooled and immediately re chromatographed. The stoichiometry of MGD bound to BSA molecules can be assessed by measuring absorbance at 215 nm (for MGD) and 280 nm (for BSA).
Example 2
Preparation of Poly MGD-BSA by Nonspecific Binding
Serum albumin is known as a carrier for fatty acids, amino acids and drugs (Halliwell, supra). The procedure for the preparation of nonspecific binding of MGD to BSA is as follows: 1 ml of bovine serum albumin (BSA; 0.1-2.0 mM in water) is added to a 10 ml beaker and the solution is gently stirred until complete dissolution. MGD (5-100 mg) was added to the solution and incubated for 5 to 60 minutes at room temperature. The solution was placed in a G-25 prefilled column. The stoichiometry of MGD bound to the BSA molecule can be assessed by spectroscopy as described above.
Example 3
Preparation of Poly [(MGD) _2- Fe] -BSA
The procedure for preparing the MGD-bridged BSA complex and the nonspecific binding of MGD to BSA are the same as described in Examples 1 and 2, respectively. Ferrous sulfate (2-20 mg) was added to the purified MGD-BSA complex prior to column separation. The protein fractions turned dark brown, suggesting the presence of [(MGD) ₂ -Fe] complexes.
Example 4
Local Cerebral Anemia-reperfusion Model in Rats
Long Evans rats (325 ± 25 g) were anesthetized with isoflurane and the rat right middle cerebral artery (MCA) was exposed and occluded as described in the literature (eg, He et al., In Am. J. Physiol. 265: H252-256 (1993). Both carotid arteries were occluded with non-traumatic aneurysm clips. After 45 minutes of ischemia, reperfusion started in all occluded vessels. Center temperature (identified by rectal probe) and temporal muscle temperature were maintained at 37 ± 0.5 ° C. using a heat lamp. Arterial blood vessel samples were collected at various time intervals to determine blood gas and plasma glucose content before, during and after ischemia.
Example 5
Neuroprotective Effects of N-methyl-D-Glucamine Dithiocarbamate (MGD) in a Rat Ischemic Attack Model
After 1 to 4 hours of reperfusion, the rats were treated per hour with 2 ml MGD / BSA solution (containing 24 mg MGD and 50 mg bovine serum albumin (BSA)) or 2 ml BSA solution (containing 50 mg BSA in saline) per hour. Intravenously injected at an infusion rate of 2 ml / hour. Animals were sacrificed 24 hours after initiation of ischemia and brain edema was quantified as already disclosed (see, eg, Lin et al., In Stroke 24: 117-121 (1993)). The remaining animals were also sacrificed 24 hours after initiation of ischemia, dissected, stained with 2,3,5-triphenyltetrazolium chloride (TTC) in saline and described by Lin et al., Supra. Infarct volume was visualized using an image analysis system to quantify cerebral infarct volume (see above).
The results shown in FIG. 1 show an infarct volume reduction of about 40% (p <0.0215) as compared to treatment with MGD + BSA compared to treatment with vehicle alone (BSA).
While the invention will be described in detail with reference to certain preferred embodiments thereof, it will be understood by those skilled in the art that modifications and variations can be made within the spirit and scope of the invention as described and claimed.

权利要求:
Claims (28)
[1" claim-type="Currently amended] Therapeutic derivatives comprising dithiocarbamates associated non-covalently with macromolecules.
[2" claim-type="Currently amended] The therapeutic derivative of claim 1, wherein the derivative is complexed with iron.
[3" claim-type="Currently amended] The therapeutic derivative of claim 1, wherein the macromolecule is a polypeptide, polysaccharide or polynucleic acid.
[4" claim-type="Currently amended] The therapeutic derivative of claim 3, wherein the polypeptide is a synthetic protein, a natural protein or a modified natural protein.
[5" claim-type="Currently amended] The therapeutic derivative of claim 4, wherein the protein is selected from serum albumin, hemocyanin or ovalbumin.
[6" claim-type="Currently amended] The method according to claim 3, wherein the macromolecule is dextran, chitosan, alginate, polymannuronic acid, polymannuronate, hyaluronic acid, chitin, cellulose, starch, glycogen, guar gum, locust bean rubber, levan, inulin, A therapeutic derivative that is a polysaccharide selected from cyclodextran, agarose, xanthan gum, carrageenan, heparin, pectin, gellan gum or scleroglucan.
[7" claim-type="Currently amended] The therapeutic derivative of claim 1, wherein the dithiocarbamate is selected from compounds of formula (I)
<Formula I>
(R) ₂ NC (S) -SH
Where
Each R is independently C ₁ to C ₁₈ alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, Aroyl, substituted aroyl, acyl or substituted acyl, or
The two R groups together may form a 5-, 6- or 7-membered ring comprising N and two R groups, or
One of the R groups is alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, substituted alkenylene, arylene, substituted arylene, alkylene, substituted alkalylene, aralkylene , Substituted aralkylene, aralkenylene, substituted aralkenylene, aralkynylene, substituted aralkynylene, cycloalkylene, substituted cycloalkylene, heterocycloalkylene and substituted heterocycloalkylene A divalent moiety selected from the group, wherein the divalent moiety acts as the same substituent on the two dithiocarbamate structures to bind the structures together to form a bis (dithiocarbamate) species.
[8" claim-type="Currently amended] A therapeutic derivative of dithiocarbamate comprising at least one dithiocarbamate covalently crosslinked with a macromolecule.
[9" claim-type="Currently amended] The therapeutic derivative of claim 8, wherein the derivative is complexed with iron.
[10" claim-type="Currently amended] The therapeutic derivative of claim 1, wherein the macromolecule is a polypeptide, polysaccharide or polynucleic acid.
[11" claim-type="Currently amended] The therapeutic derivative of claim 3, wherein the polypeptide is a synthetic protein, a natural protein or a modified natural protein.
[12" claim-type="Currently amended] The therapeutic derivative of claim 4, wherein the protein is selected from serum albumin, hemocyanin or ovalbumin.
[13" claim-type="Currently amended] The method according to claim 3, wherein the macromolecule is dextran, chitosan, alginate, polymannuronic acid, polymannuronate, hyaluronic acid, chitin, cellulose, starch, glycogen, guar gum, locust bean rubber, levan, inulin, A therapeutic derivative that is a polysaccharide selected from cyclodextran, agarose, xanthan gum, carrageenan, heparin, pectin, gellan gum or scleroglucan.
[14" claim-type="Currently amended] The therapeutic derivative of claim 1, wherein the dithiocarbamate is selected from compounds of formula (I)
<Formula I>
(R) ₂ NC (S) -SH
Where
Each R is independently C ₁ to C ₁₈ alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, Aroyl, substituted aroyl, acyl or substituted acyl, or
The two R groups together may form a 5-, 6- or 7-membered ring comprising N and two R groups, or
One of the R groups is alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, substituted alkenylene, arylene, substituted arylene, alkylene, substituted alkalylene, aralkylene , Substituted aralkylene, aralkenylene, substituted aralkenylene, aralkynylene, substituted aralkynylene, cycloalkylene, substituted cycloalkylene, heterocycloalkylene and substituted heterocycloalkylene A divalent moiety selected from the group, wherein the divalent moiety acts as the same substituent on the two dithiocarbamate structures to bind the structures together to form a bis (dithiocarbamate) species.
[15" claim-type="Currently amended] A method for preparing a therapeutic derivative of dithiocarbamate, comprising contacting dithiocarbamate with macromolecules in the presence of a crosslinking agent under crosslinking conditions.
[16" claim-type="Currently amended] A product made by the method of claim 15.
[17" claim-type="Currently amended] A method of obtaining a magnetic resonance image in vivo by administering a derivative according to claim 2 to a subject.
[18" claim-type="Currently amended] A method of obtaining a magnetic resonance image in vivo by administering a derivative according to claim 9 to a subject.
[19" claim-type="Currently amended] Septic shock, ischemia, administration of cytokines, overexpression of cytokines, ulcers, inflammatory bowel disease, diabetes, arthritis, asthma, Alzheimer's disease, Parkinson's disease, comprising administering to a subject an effective amount of the derivative according to claim 1 Multiple sclerosis, cirrhosis, allograft rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choroiditis, glomerulonephritis, eye disease, ileitis, inflammation caused by overproduction of inflammatory cytokines, hemorrhagic shock, anaphylaxis Ischemic / reperfusion associated with sexual shock, burns, infections that cause overproduction of inflammatory cytokines, hemodialysis, chronic fatigue syndrome, seizures, cancer, cardiovascular diseases associated with overproduction of inflammatory cytokines, and overproduction of inflammatory cytokines , Toxic shock syndrome, adult respiratory distress syndrome, cachexia, myocarditis, autoimmune disease, eczema, psoriasis, heart failure, dermatitis, gallbladder, cerebral anemia, systemic lupus erythematosus, AIDS, AIDS Falcon, neurodegenerative disorders, chronic pain, erection, cystic fibrosis, muscular dystrophy, schizophrenia, depression, premenstrual syndrome, anxiety, intoxication, migraine, Huntington's disease, epilepsy, gastrointestinal motility, obesity, polyphagia, Solid tumor, malaria, blood cancer, myelofibrosis, lung injury, graft-versus-host disease, head injury, CNS injury, hepatitis, renal failure, liver disease, drug-induced lung injury, graft rejection and preservation, increased fertilization rate, bacterial translocation A method of treating a subject suffering from cyclic shock, traumatic shock, photoaging or photodamage.
[20" claim-type="Currently amended] Septic shock, ischemia, administration of cytokines, overexpression of cytokines, ulcers, inflammatory bowel disease, diabetes, arthritis, asthma, Alzheimer's disease, Parkinson's disease, comprising administering to the subject an effective amount of the derivative according to claim 8 Multiple sclerosis, cirrhosis, allograft rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choroiditis, glomerulonephritis, eye disease, ileitis, inflammation caused by overproduction of inflammatory cytokines, hemorrhagic shock, anaphylaxis Ischemic / reperfusion associated with sexual shock, burns, infections that cause overproduction of inflammatory cytokines, hemodialysis, chronic fatigue syndrome, seizures, cancer, cardiovascular diseases associated with overproduction of inflammatory cytokines, and overproduction of inflammatory cytokines , Toxic shock syndrome, adult respiratory distress syndrome, cachexia, myocarditis, autoimmune disease, eczema, psoriasis, heart failure, dermatitis, gallbladder, cerebral anemia, systemic lupus erythematosus, AIDS, AIDS Falcon, neurodegenerative disorders, chronic pain, erection, cystic fibrosis, muscular dystrophy, schizophrenia, depression, premenstrual syndrome, anxiety, intoxication, migraine, Huntington's disease, epilepsy, gastrointestinal motility, obesity, polyphagia, Solid tumor, malaria, blood cancer, myelofibrosis, lung injury, graft-versus-host disease, head injury, CNS injury, hepatitis, renal failure, liver disease, drug-induced lung injury, graft rejection and preservation, increased fertilization rate, bacterial translocation A method of treating a subject suffering from cyclic shock, traumatic shock, photoaging or photodamage.
[21" claim-type="Currently amended] A method of treating iron overload, comprising administering to a subject an effective amount of the derivative of claim 1.
[22" claim-type="Currently amended] A method for treating iron overload, comprising administering to a subject an effective amount of the derivative according to claim 8.
[23" claim-type="Currently amended] A method of treating a non-ferrous overload disease and condition comprising administering an effective amount of the derivative according to claim 1 to a subject.
[24" claim-type="Currently amended] A method of treating a non-ferrous overload disease and condition comprising administering to a subject an effective amount of the derivative according to claim 8.
[25" claim-type="Currently amended] The subject may be treated with at least one drug and at least one of the two or more drugs capable of directly or indirectly inactivating a species inducing expression of inducible nitric oxide synthase or inhibiting the production of said species. A method of directly or indirectly treating production of a species that induces expression of inducible nitric oxide synthase in a subject, comprising coadministering the subject with an effective amount of a combination of an orcarbamate-containing nitric oxide scavenger.
[26" claim-type="Currently amended] The subject may be treated with at least one drug and at least one of the at least one drug according to claim 9, which may directly or indirectly inactivate the species inducing expression of the inducible nitric oxide synthase or inhibit the production of said species. A method of directly or indirectly treating production of a species that induces expression of inducible nitric oxide synthase in a subject, comprising coadministering the subject with an effective amount of a combination of an orcarbamate-containing nitric oxide scavenger.
[27" claim-type="Currently amended] A combination of a drug capable of inactivating a substance which directly or indirectly induces the expression of an inducible nitric oxide synthase and a dithiocarbamate-containing nitric oxide scavenger according to claim 2 in its pharmaceutically acceptable carrier A composition comprising.
[28" claim-type="Currently amended] A combination of a drug capable of inactivating a substance that directly or indirectly induces the expression of an inducible nitric oxide synthase and a dithiocarbamate-containing nitric oxide scavenger according to claim 9 is incorporated into a pharmaceutically acceptable carrier. A composition comprising.

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同族专利:

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公开号 | 公开日

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US6649591B2|2003-11-18|

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WO1998011066A1|1998-03-19|

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AU4172597A|1998-04-02|

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AU746790B2|2002-05-02|

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JP2002511837A|2002-04-16|

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EP0927159A1|1999-07-07|

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US20020045573A1|2002-04-18|

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CN1230178A|1999-09-29|

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CA2265877A1|1998-03-19|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1996-09-10|Priority to US2586796P

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1996-09-10|Priority to US60/025,867

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1997-07-23|Priority to US89908797A

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1997-07-23|Priority to US8/899,087

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1997-08-28|Application filed by 메디녹스, 인크.

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2000-06-26|Publication of KR20000035992A

优先权:

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申请号 | 申请日 | 专利标题

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US2586796P| true| 1996-09-10|1996-09-10|

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US60/025,867|1996-09-10|

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US89908797A| true| 1997-07-23|1997-07-23|

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US8/899,087|1997-07-23|