Conjugates of dithiocarbamates with pharmacologically active agents and uses therefor

专利摘要:
In accordance with the present invention, there are provided conjugates of nitric oxide scavengers (e.g., dithiocarbamates, or "DC") and pharmacologically active agents (e.g., NSAIDs). Invention conjugates provide a new class of pharmacologically active agents (e.g., anti- inflammatory agents) which cause a much lower incidence of side-effects due to the protective effects imparted by modifying the pharmacologically active agents as described herein. In addition, invention conjugates are more effective than unmodified pharmacologically active agents because cells and tissues contacted by the pharmacologically active agent(s) are protected from the potentially damaging effects of nitric oxide overproduction induced thereby as a result of the co-production of nitric oxide scavenger (e.g., dithiocarbamate), in addition to free pharmacologically active agent, when invention conjugate is cleaved.
公开号:KR20010013419A
申请号:KR19997011420
申请日:1998-05-19
公开日:2001-02-26
发明作者:칭-산 라이
申请人:메디녹스, 인크.；
IPC主号:

专利说明:

Conjugates of Dithiocarbamates with Pharmacologically Active Agents and Uses Therefor}
Despite the advent of modern pharmaceutical technology, many drugs still have undesirable toxicity that limits their therapeutic potential. For example, although nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of compounds widely used in the treatment of inflammation, pain and fever, NSAIDs (eg, aspirin, ibuprofen and ketoprofen) remain major limitations in their use. Cause side effect gastrointestinal ulceration (see, eg, JL Wallace, in Gastroenterol. 112: 1000-1016 (1997): AH Soll et al., In Ann Intern Med. 114: 307-319 (1991); Bjarnason et al., In Gastroenterol. 104: 1832-1847 (1993).
NSAIDs have two major ulcer-inducing effects: (1) local stimulatory effects on the epithelium of the gastrointestinal tract and (2) inhibition of prostaglandin synthesis in the gastrointestinal tract. Recently, numerous methods have been attempted for the manufacture and development of new NSAIDs that reduce damage to the gastrointestinal tract. However, this effort was not very successful. For example, enteric coatings or sustained release formulations to reduce local irritation of NSAIDs have been shown to be ineffective in reducing the scope of clinically significant side effects, including perforation and bleeding (see, for example, DY Graham et al., in Clin. Pharmacol. Ther. 38: 65-70 (1985); JL Carson, et al., in Arch.Intern. Med., 147: 1054-1059 (1987)).
Aspirin and other NSAIDs are well known to express their pharmacological effects by inhibiting cyclooxygenase (COX) enzymes, thereby inhibiting prostaglandin synthesis (see, eg, JR Van in Nature, 231: 232-235 ( 1971). There are two forms of COX enzymes: COX-1 and COX-2. COX-1 is constitutively expressed in many tissues, including the stomach, kidneys and platelets, and COX-2 is present only at the site of inflammation (see, eg, S. Kargan et al., In Gastroenterol., 111: 445- 454 (1996). Prostaglandins derived from COX-1 contribute to several physiological effects, including maintenance of gastric mucosal integrity.
Many efforts have been made to develop NSAIDs that inhibit only COX-2 without affecting the activity of COX-1 (see, eg, JA Michell et al., In Proc. Natl. Acad. Sci. USA 90 : 11693-11697 (1993); EA Meade et al., In J. Biol. Chem., 268: 6610-6614 (1993). Two or more NSAIDs (i.e. nabumetone and etodolac) that exhibit marked selectivity for COX-2 are currently commercially available (e.g., EA Meade, supra: K. Glaser et. al., in Eur. J. Pharmacol. 281: 107-111 (1995). These drugs appear to have reduced gastrointestinal toxicity compared to other NSAIDs on the market.
Based on clinical as well as experimental data, the development of highly selective COX-2 inhibitors seems to be a sufficient way to develop a new generation of anti-inflammatory drugs. However, the physiological function of COX-1 and COX-2 is not always well defined. Thus, prostaglandins produced as a result of expression of COX-1 also have the potential to cause inflammation, pain and fever. On the other hand, prostaglandins produced by COX-2 have been shown to play important roles in physiological functions such as initiation and maintenance of childbirth, and regulation of bone resorption (see, for example, DM Slater et al., In Am. J. Obstet.Gynecol., 172: 77-82 (1995); Y. Onoe et al., In J. Immunol. 156: 758-764 (1996)), inhibition of this pathway will not always be advantageous. . With this in mind, highly selective COX-2 inhibitors may cause additional side effects that are more or less than those observed with standard NSAIDs, so such inhibitors may not be highly desirable.
Since anthracycline, such as adriamycin, is a commonly used antitumor agent, considerable efforts are being made to develop methods to reduce the acute and delayed cardiomyopathy induced by anthracyclines while maintaining the therapeutic efficacy of these compounds. This has been. The molecular mechanism of cardiomyopathy contributes to the release of adriamycin-derived iron from intracellular iron proteins to form the adriamycin-iron complex. Adriamycin-iron complexes produce reactive oxygen species, causing cleavage and condensation of DNA, peroxidation of phospholipid membranes, loss of cellular reducing equivalents, interference with mitochondrial respiration, and disruption of cellular calcium homeostasis (eg, See, eg, Myers et al., In Science 197: 165-167 (1977); Gianni et al., In Rev. Biochem. Toxicol. 5: 1-82 (1983). In addition to cardiomyopathy, administration of adriamycin causes skin irritation and alopecia, mucositis (stomatitis and esophagitis), venous sclerosis and hematologic toxicity and numerous other local and systemic toxicity.
Recently, ICRF-187 (i.e., dextracarboxylic acid) removes iron from the anthracycline-iron complex and thus has been proven to be effective in preventing cardiotoxicity in cancer patients undergoing adriamycin chemotherapy (see, eg, Kolaric). et al., in Oncology 52: 251-5 (1995). However, when chelated with iron, the iron-ICRF-187 complex itself is also very effective in promoting hydroxyl group production via the Fenton reaction, resulting in oxidative damage of tissues (see, eg, Thomas et al., in Biochem.Pharmacol., 45: 1967-72 (1993). In addition, ICRF-187 is a strong chelating agent (having a structure similar to EDTA), which not only has low molecular weight iron, but also iron from transferrin and ferritin and copper from Ceruloplasmin. As it chelates, it potentially affects normal cellular iron metabolism.
Thus, there is still a need in the art for modified forms of NSAIDs and other pharmacologically active agents that reduce the range of adverse effects compared to the range of adverse effects caused by pharmacologically active agents such as aspirin, ibuprofen and the like.
<Summary of invention>
According to the present invention there is provided a combination of a physiologically suitable nitric oxide scavenger [eg dithiocarbamate (DC)] and a pharmacologically active agent (eg NSAID). The conjugates of the present invention provide novel pharmacologically active agents (eg anti-inflammatory agents) with a much lower range of adverse effects due to the protective effects imparted by the modification of the pharmacologically active agents described herein.
According to recent evidence, administration of NSAIDs upregulates the expression of inducible nitric oxide synthase (see, eg, BJR Whittle et al., In Br. J. Pharmacol., 116: 2286-2290 (1995). )] Reference). Excess nitric oxide produced from inducible nitric oxide synthase is known to cause mucosal damage (see, eg, SJ Middleton et al., In Lancet, 341: 456-466 (1993); MJS Miller et al. , in Scand. J. Gastroenterol., 264: 11-16 (1993). When chelated with iron (eg intracellular iron), the nitric oxide scavenger (eg dithiocarbamate-iron complex) binds tightly to nitric oxide, reducing the level of nitric oxide in vivo, It becomes an effective nitric oxide scavenger. Excess nitric oxide production decreases the expression of COX-2, suggesting that the multistage inflammatory response is enhanced. Thus, reducing the expression of COX-2 by scavenging NO with a nitric oxide scavenger (eg dithiocarbamate-iron complex) reduces the negative consequences caused by excess COX-2 levels. Can be.
In summary, the conjugates according to the invention (eg DC-NSAID) have a number of advantages including:
(i) reduce the local irritant effects of NSAIDs,
(ii), especially for acidic NSAIDs such as aspirin, diclofenac and ibuprofen, resulting in a reduction in molecular net charge resulting in improved tissue delivery of the two drugs, reducing the amount of substance that must be delivered to achieve an effective dosage,
(iii) chelate intracellular free iron ions to prevent iron-related oxidative damage,
(iv) inhibit VCAM-1 expression, blocking neutrophils attached to the vascular endothelium induced by administration of NSAIDs,
(v) Scavenging intracellular nitric oxide reduces the induction of expression of COX-2, which can induce an additional inflammatory response, and prevents the production of nitrite peroxide, i.e., a potent oxidant.
In another aspect of the invention, suitable nitric oxide scavenger (eg dithiocarbamate) and anti-neoplastic agents (eg, alleviate some of the toxicity associated with administration of anti-neoplastic agents such as adriamycin) The resulting conjugate discloses a biodegradable conjugate of adriamycin) called DC-Adriamycin. There are many advantages of using DC-Adriamycin over using Adriamycin alone, including:
(i) reduce skin irritation and alopecia and vascular damage (because the conjugate is inactive before reaching the site of intracellular action),
(ii) chelating intracellular iron to reduce free-radical-induced acute and delayed cardiomyopathy,
(iii) excess nitric oxide produced from malignant and cancerous tissues is removed.
The present invention relates to novel conjugated forms of pharmacologically active agents and methods and uses for their preparation. In certain aspects of the invention, the method treats pathological diseases with pharmacologically active agents while simultaneously lowering the level of nitric oxide.
According to the present invention there is provided a compound comprising a suitable nitric oxide scavenger (eg dithiocarbamate) covalently bound to a pharmacologically active agent.
As will be readily appreciated by those skilled in the art, scavenging nitric oxide may be used for various chemicals, such as dithiocarbamate, desperioxamine (DF), ethylenediaminetetraacetic acid (EDTA), Diethylenetriaminepentaacetic acid (DTPA), hydroxypyridinone, pyridoxalisonicotinoylhydrazone (PIH), quercetin, 1,2-dimethyl-3-hydroxypyrid-4-one (LI), phytic acid Iron-chelate compounds, such as dexlazoic acid (ICRF-187), N, N-dibenzylethylenediamine-N, N-diacetic acid (DBED) and the like can be used.
Other nitric oxide scavenging compounds that can be used in the present invention include 2-mercaptonicotinic acid, nitronylnitroxide, nitric oxide kilotrope (ie, 7,7,8,8-tetraalkyl-0-quinomimethane type). Residue-containing compounds), dimercaptosuccinic acid, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO), carboxy-PTIO, phenyl-n-tert-butyl Nitrons, other nitron derivatives, and the like.
Dithiocarbamates are sulfur-containing small molecules that are known heavy metal chelators (see, eg, FW Sunderman, in Ann. Clin. Lab. Sci., 8: 259-69 (1978); MM Jones and MG Cherian , in Toxicology, 62: 1-25 (1990)). Dithiocarbamates, such as diethyldithiocarbamate, have been used clinically for the treatment of nickel poisoning (see, for example, Sunderman, supra), and in clinical trials for the treatment of AIDS patients. (See, eg, E. Reisinger et al., In Lancet, 335: 679 (1990)).
Dithiocarbamates, such as pyrrolidine dithiocarbamates, are potent inhibitors of nuclear factor kappa B in intact cells (see, eg, R. Schreck et al., In J. Exp. Med., 175: 1181-1194 (1992). Nuclear factor kappa B has also been shown to upregulate expression of cell adhesion molecules, including vascular cell adhesion molecule 1 (VCAM-1) (see, eg, MF Iademarco et al., In J. Biol. Chem ,. 267: 16323-16329 (1992). When VCAM-1 is expressed in the endothelium, the nucleophile adheres to the endothelium, which initially leads to inflammation and subsequent vascular damage and reduced blood flow (see, eg, MN Oppenheimer et al., In J. Immunol., 147: 42207-4210 (1991). It has been recognized that increasing the administration of NSAIDs increases the nucleophile that adheres to the vascular endothelium during gastrointestinal and mesenteric microcirculation (see, eg, JL Wallace et al., In Gastroenterol., 105: 1630-1636 (1993). H. Asako et al., In Am. J. Physiol., 262: G903-G908 (1992). Thus, the combination of NSAID and dithiocarbamate blocks VCAM-1 expression, thereby avoiding vascular problems associated with nucleophiles that adhere to the endothelium.
Suitable dithiocarbamate compounds that can be used in the present invention can be represented by the following formula (I).
_{[R 1 R 2 NC (S} ) -S -] x M +1, +2, +3
In the above formula,
Each of R ₁ and R ₂ is independently C ₁ -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, or
R ₁ and R ₂ together form a five, six or seven membered ring comprising N, R ₁ and R ₂ , or
R ₁ or R ₂ function as the same substituent for two dithiocarbamate structures, thereby combining the structures with one another to form bis (dithiocarbamate) species, alkylene, substituted alkylene, oxy A divalent moiety selected from the group consisting of alkylene, substituted oxyalkylene, alkenylene, substituted alkenylene, arylene, substituted arylene, alkylene, substituted alkylene, aralkylene and substituted aralkylene ,
x is 1 or 2,
M is a monovalent cation when x is 1 or a physiologically suitable divalent or trivalent transition metal cation when x is 2.
Preferred dithiocarbamate compounds of formula (I)
R ₁ and R ₂ are each C ₁ -C ₁₂ alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, wherein the substituents are carboxyl, —C (O) H, oxyacyl , Phenol, phenoxy, pyridinyl, pyrrolidinyl, amino, amido, hydroxy, nitro or sulfuryl, or
R ₁ and R ₂ together form a five, six or seven membered ring comprising N, R ₁ and R ₂ ,
M is Fe ⁺² or Fe ⁺³ .
Particularly preferred dithiocarbamate compounds of formula I are
R ₁ is selected from C ₂ -C ₈ alkyl or substituted alkyl, wherein the substituent is selected from carboxyl, acetyl, pyridinyl, pyrrolidinyl, amino, amido, hydroxy or nitro,
R ₂ is selected from C ₁ -C ₆ alkyl or substituted alkyl, or
And R ₂ form a 5-, 6- or 7-membered ring containing N, R ₁ and R ₂ together with R _1,
M is Fe ⁺² .
Most preferred dithiocarbamate compounds of formula I are
R ₁ is selected from C ₂ -C ₈ alkyl or substituted alkyl, wherein the substituent is selected from carboxyl, acetyl, amido or hydroxy,
R ₂ is selected from C ₁ -C ₄ alkyl or substituted alkyl, or
And R ₂ form a 5-, 6- or 7-membered ring containing N, R ₂ and R ₁ together with R _1,
M is Fe ⁺² .
When R ₁ and R ₂ together form a 5-, 6- or 7-membered ring, when R ₁ and R ₂ are combined, alkylene or —O—, —S—, —C (O) — and (or ) -N (R)-(where R is hydrogen or a lower alkyl group) can be saturated, unsaturated crosslinked species of 4, 5 or 6 atoms selected from alkylene moieties. Preferred dithiocarbamates wherein R ₁ and R ₂ together form a ring structure include pyrrolidine dithiocarbamates, proline dithiocarbamates, pyridine dithiocarbamates, pyrimidinium dithiocarbamates , Pyrimidine dithiocarbamate, pyrroline dithiocarbamate and the like.
Examples of preferred dithiocarbamates that can be used to prepare the conjugates of the present invention include sarcosine dithiocarbamates, iminodiacetic acid dithiocarbamates, diethyldithiocarbamate, diisopropyldithiocar Bamate, sugar-linked dithiocarbamate (eg, glucose-, lactose-, mannose-, fructose-linked dithiocarbamate, etc.), pyrrolidine dithiocarbamate, proline diti Orcarbamate and the like.
Monovalent cations that can be incorporated into the aforementioned dithiocarbamate compounds include H ⁺ , Na ⁺ , NH ₄ ⁺ , tetraalkyl ammonium and the like. Physiologically suitable divalent or trivalent transition metal cations that can be incorporated into the aforementioned dithiocarbamate compounds include iron, cobalt, copper, manganese, ruthenium, and the like (e.g., Fe ^{+ 2} , Fe ^{+ 3} , Co Charged forms of ⁺² , Co ⁺³ , Cu ⁺² , Mn ⁺² , Mn ^+3, or Ru ⁺³ , and the like. According to the invention, the ratio of dithiocarbamate-species to counter-ion M can be wide. Thus, the dithiocarbamate-containing nitric oxide scavenger is free of any additional metal counter ions (ie, M = H ⁺ , or a ratio of transition metal cation to dithiocarbamate-species zero), preferably The ratio of transition metal cation to dithiocarbamate-species may be administered at about 1: 2 or less (ie dithiocarbamate: transition metal cation = 2: 1 complex).
The term “substituted alkyl” as used herein refers to hydroxy, alkoxy (of lower alkyl groups), mercapto, of 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 And an alkyl group 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" refers to a cycloalkyl group having one or more substituents as described above.
"Alkenyl" as used herein refers to a straight or branched chain hydrocarbyl group having one or more carbon-carbon double bonds and having a carbon atom in the range of about 2 to 12, and "substituted alkenyl" An alkenyl group further having one or more substituents as described above is represented.
"Alkynyl" as used herein refers to a straight or branched chain hydrocarbyl group having one or more carbon-carbon triple bonds and having a carbon atom in the range of about 2 to 12, and "substituted alkynyl" An alkynyl group further having one or more substituents as described above.
"Aryl" as used herein refers to an aromatic group having from 6 to 14 carbon atoms, and "substituted aryl" refers to an aryl group further having one or more substituents as described above.
"Alkylaryl" as used herein refers to an alkyl-substituted aryl group and "substituted alkylaryl" refers to an alkylaryl group further having one or more substituents as described above.
"Arylalkyl" as used herein refers to an aryl-substituted alkyl group, and "substituted arylalkyl" refers to an arylalkyl group further having one or more substituents as described above.
As used herein, "arylalkenyl" refers to an aryl-substituted alkenyl group, and "substituted arylalkenyl" refers to an arylalkenyl group further having one or more substituents as described above.
As used herein, "arylalkynyl" refers to an aryl-substituted alkynyl group, and "substituted arylalkynyl" refers to an arylalkynyl group further having one or more substituents as described above.
"Aroyl" as used herein refers to an aryl-carbonyl species such as benzoyl, and "substituted aroyl" refers to an aroyl group further having one or more substituents as described above.
As used herein, “heterocyclic” is a cyclic containing at least one heteroatom (eg, N, O or S, etc.) as part of a ring structure and having a carbon atom ranging from 3 to 14 (Ie, ring-comprising) groups, and “substituted heterocyclic” refers to a heterocyclic group further having one or more substituents as described above.
"Acyl" as used herein refers to an alkyl-carbonyl species.
"Halogen" as used herein refers to a fluorine, chlorine, bromine or iodine atom.
Diseases and conditions contemplated for the treatment according to the invention include inflammatory and infectious diseases such as septic shock, hemorrhagic shock, anaphylactic shock, intoxication shock syndrome, ischemia, cerebral ischemia, administration of cytokines, overexpression of cytokines, Ulcers, inflammatory bowel disease (eg, 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 choroidal meningitis, glomerulonephritis, uveitis, ileitis, inflammation (e.g., liver inflammation and renal inflammation, etc.), burns, infections (including bacteria, viruses, fungal and parasitic infections), hemodialysis , Chronic fatigue syndrome, stroke, cancer (eg, breast cancer, melanoma and carcinoma, etc.), cardiopulmonary bypass, ischemia / reperfusion injury, gastritis, adult respiratory distress syndrome, cachexia, myocarditis, autologous Ailments, eczema, psoriasis, heart failure, heart disease, atherosclerosis, dermatitis, urticaria, systemic lupus erythematosus, AIDA, AIDS dementia, chronic neurodegenerative diseases, chronic pain, persistent erections, cystic fibrosis, muscular dystrophy Sclerosis, schizophrenia, depression, premenstrual syndrome, anxiety, addiction, migraine, Huntingtons' disease, epilepsy, neurodegenerative disorders, gastrointestinal dysfunction, obesity, bulimia, solid tumors (e.g. neuroblastoma), Malaria, blood cancer, myelofibrosis, lung damage, graft-versus-host disease, head injury, CNS trauma, hepatitis, renal failure, liver disease (e.g. chronic hepatitis C), drug-induced lung injury (e.g. paraquat )), Myasthenia gravis (MG), ophthalmic disease, angioplasty, restenosis, angina and coronary artery disease.
Pharmacologically active agents contemplated for modification according to the present invention include the following:
NSAIDs such as acetaminophen (Tylenol, Datril, etc.), aspirin, ibuprofen (Motrin, Advil, Rufen, etc.), magnesium salicylate (triacetate Triasate), choline salicylate (Anthropan), diclofenac (voltaren, cataflam), diflunisal (dolobid), etodollac (lodine) , Phenopropene calcium (nalfon), fluroprofen (ansaid), indomethacin (indocin, indometh, etc.), ketoprofen (orudis ( orudis, oruvail), ketorolac tromethamine (toradol), magnesium salicylate (Doan's, magan, mobidin, etc.), meclofenamide Sodium Acid (meclomen), Mefenamic Acid (relafan), Oxaprozin (daypro), Pyroxycam (feldene), Sodium Salicylate, Suldinak (Clinolyl) (clinoril)), Methine (Tall lectin (tolectin)), meloxicam, Nauvoo meton, naproxen, L'rust when Kam, you mesul lead, India propene, Remy penjon, gently rate, such as thiazol Pro pensan alcohol and workflow lead;
Analgesics / antipyretic agents (e.g., aspirin, acetaminophen, ibuprofen, naproxen sodium, buprenorphine hydrochloride, propoxyphene hydrochloride, naphsyl proppropene pene, meperidine hydrochloride, hydromorphone hydrochloride, morphine sulfate, oxycodone hydrochloride , Codeine phosphate, dihydrocodene of heavy tartaric acid, pentazosin hydrochloride, heavy tartaric acid hydrocodone, tartaric acid leborpanol, diflunisal, salicylic acid trolamine, nalbuphine hydrochloride, mephenamic acid, tartaric acid butyrolpanol, salicylic acid sheet, butalbital, citrate Phenyltoloxamine, diphenhydramine citrate, metotrimeprazine, cinnamicrine hydrochloride and meprobamate);
Sedatives / hypnotics (e.g. barbiturates (e.g. pentobarbital, pentobarbital sodium, secobarbital sodium), benzodiazepines (e.g. flulazepam hydrochloride, triazolam, tomazepam and midazolam hydrochloride, etc. );
Antianginal agents (e.g., beta-adrenergic nerve blockers, calcium channel blockers (e.g. nifedipine and diltiazem hydrochloride, etc.), nitrates (e.g. nitroglycerin, isosorbide dinitrate, pentaerythritol tetrasulfite and tetrasulfate Erythryl, etc.);
Anxiolytic agents (e.g., lazepam, hydrosulfone hydrochloride, prazepam, chlordiazepoxide, oxazepam, dipotassium chlorapyanate, diazepam, hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, dropperidol , Halazepam and chlormezzanone, etc.);
Antidepressants (e.g. doxepine hydrochloride, amoxapine, trazodone hydrochloride, amitriptyline hydrochloride, maprotiline hydrochloride, phenelzin sulfate, decipramine hydrochloride, nortriptyline hydrochloride, trinilcypromine sulfate, flu hydrochloride Oxepin, doxepin hydrochloride, imimipramine hydrochloride, imipramine pamoate, nortriptyline, amitriptyline hydrochloride, isocarboxide, decipramine hydrochloride, maleic acid trimipramine, and protriptyline hydrochloride;
Antipsychotics (e.g. haloperidol, roxapsin succinate, roxaphine hydrochloride, thiolidazine, thiolidazine hydrochloride, thiotixene, flufenazine, hydrofenazine decanoate, flufenazine deanthate, trifluchloride hydrochloride Operazine, chlorpromazine hydrochloride, perphenazine, lithium citrate and prochlorperazine;
Antihypertensives (eg lithium carbonate);
Antiarrhythmic medicines (e.g., brethlium tosylate, esmoldol hydrochloride, verapamil hydrochloride, amiodarone, encaine hydrochloride, digoxin, digitoxin, mesylenetin hydrochloride, disopyramid hydrochloride, procaineamide hydrochloride, quinidine sulfate, quiniconate gluconate) Dine, polygalacturonic acid quinidine, plecaine acetate, tocaine hydrochloride and lidocaine hydrochloride;
Antihypertensive drugs such as diuretics (hydrochlorothiazide, chlortalidone, metolazone, indamide, furosemide, bumetanide, torcemide, triamterene, amylolide, spironolactone), Beta-adrenergic nerve blockers (acebutolol, atenolol, betaxolol, cartelol, labetalol, metoprolol, nadolol, fenbutolol, pindolol, propranolol, timolol), angiotensin converting enzyme inhibitors (benazepril , Captopril, enalapril, posinopril, quinoapril, ramimpril, losartan), calcium channel blockers (diltiazem, verapamil, amlodipine, felodipine, isradipine, nicadipine, nifedipine), alpha Adrenaline receptor blockers, sympathetic blockers and vasodilators (e.g., prazosin, terrazosin, doxazosin, clonidine, guanabenz, guanpacin, methyllodopa, guanetidine, guanetidine, reserpin, hydride Lalazine and Minoxidil Etc.), as well as trematapancamylate, phenoxybenzamine hydrochloride, pargiline hydrochloride, deserpidine, diazoxide, recinnamin, sodium nitroprusside, saponosa, alseroxylon and pentolamin mesylate drugs;
Antihistamines / antipruritic agents, for example ethanolamine (e.g. diphenhydramine, diphenhydramine hydrochloride, clemastine and clemastine fumarate), ethylenediamine (e.g. brompheniramine, brompheniramine maleate, chlor) Pheniramine, maleic chlorpheniramine, maleic acid chlorphenylamine, triprodine and triprolidine hydrochloride, etc., phenothiazine (e.g. promethazine), piperidine (e.g. hydroxyzine, hydrochloride hydrochloride Oxyzin, terpenadine, astemizol, azatadine and azatadine maleate), ciproheptadine, ciproheptadine hydrochloride, loratidine, carbinoxamine maleic acid, diphenylpyralline hydrochloride, phenyltamine hydrochloride, phenyltamine tartaric acid, hydrochloric acid Tripelennamin, metdilazine hydrochloride and tartaric acid trimprazine;
Immunosuppressive agents such as glucocorticoids (methylprednisolone), myelin based proteins (eg 7-capacone), anti-Fc receptor monoclonal antibodies, hydroorotate dehydrogenase inhibitors, anti-IL2 monoclones Antibodies (e.g., CHI-621 and multicyclic simab), buspyron, castanospermine, CD-59 (complement factor inhibitor), 5-lipoxygenase inhibitors (e.g. CMI-392), phosphatidic acid synthetic antagonists , Eepselen, edelfosine, enlimab, galactin, platelet activator antagonist, selectin antagonist (e.g. ICAM-4), interleukin-10 agonist, macrocyclic lactone, methoxatone, mizoribin, OX-19, Peptigen preparations, PG-27, protein kinase C inhibitors, phosphodiesterase IV inhibitors, short chain antigen binding proteins, complement factor inhibitors, sialoporins, sirolimus, spirocyclic lactams, 5-hydroxytrytamine antagonists, Anti-TCR monoclonal antibodies, CD5 gelonin and TOK-8801 and the like;
Anti-metabolic cytotoxic agents (azatioprine, cyclophosphamide), C5a release inhibitors, benzidamine, feldscein, pentostatin, SDZ-ASM-981, thalidomide, benzoporphyrin derivatives, arachidonic acid antagonists (e.g., halomethasone , Halobetasol propionate), corticosteroids (clobetasol propionate), growth hormone antagonists (octapeptide somatostatin analogs, lanreotide, angiopeptin and dermopeptin), and thymopentin;
Neuroprotective agents such as α-adrenergic receptor antagonists (ie, α-dihydroergocriptine), NMDA antagonists (eg 5,6,7-trichloro-THQTQ), remasemide, 2-piperazincar Acids, N-indologlycinamide derivatives, spiro [benzo (b) thiophene-4 (5H) derivatives, CP-101606, elliprodil, dexanabinol, GV-150526, L-695902, L-701324, Amantadine derivatives, dizocilpin, benzomorphan derivatives, aptiganels, (S) -α-phenyl-2-pyridine ethaneamide dihydrochloride and 1-aminocyclopentanecarboxylic acid), sodium channel antagonists (e.g. 619C89), Glycine antagonists (e.g., glycascin), calcium channel antagonists (e.g., 3,5-pyridinedicarboxylic acid derivatives, coopeptides, 1-piperazineethanol, thieno [2,3-b] pyridine-5-carr Acid derivatives, NS-3034, nilvadipine, nizoldipine, tyrilazad mesylate, 2H-1-enzopyran-6-ol, nitron spin trap, isididipine, iomeric erazine hydrochloride, remildipine, Lipari , CPC-304, eponidipine, F-0401, piperazine derivatives), calpine inhibitors, fibrinogen antagonists (e.g. ancrorods), integrin antagonists (e.g. antrene), thromboxane A 2 antagonists (e.g., 9H-carboxes) Bazol-9-propanoic acid derivatives, 5-heptenic acid derivatives and 1-azulenesulfonic acid derivatives), brain-derived neuronal factors, adrenal neurotransmitter uptake inhibitors (eg 1-butanamine), endothelin A receptors Antagonists (e.g. benzenesulfonamide derivatives, GABA A receptor antagonists (e.g. triazolopyrimidine derivatives and cyclohexaneacetic acid derivatives), GPIIb IIIa receptor antagonists (e.g. C68-22), platelet aggregation antagonists (e.g. 2 (1H)) -Quinolinone derivatives, 1H-pyrrole-1-acetic acid derivatives and coumadines), factor Xa inhibitors, CPC-211, corticotropin releasing factor agonists, thrombin inhibitors (e.g., citrombinx, proxiparin, dermatan and Heparinoids), dotarizine, intracellular calcium chelators (e.g. BAP TA derivatives), radical blood antagonists (EPC-K1, 3-pyridinecarboxamide derivatives, superoxide dismutase, lacsopelast, ruberazole, 3H-pyrazol-3-one derivatives, kynurenic acid derivatives, Homopiperazine derivatives and polyniloxyl albumin), protein kinase inhibitors (e.g. 1H-1,4-diazepine), nerve growth agonists (e.g. floor plate factor-5), glutamate antagonists (e.g., Cyclohexanepropanoic acid, rirusol, NS-409 and acetamide derivatives), lipid peroxidase inhibitors (eg 2,5-cyclohexanediene-1,4-dione derivatives), sigma receptor agonists (eg cyclopropane Methanamine derivatives and SA-4503), tyrotropin releasing hormone agonists (eg JTP-2942, L-prolineamide and posatyrrelin), prolyl endopeptidase inhibitors, monosialogganglioside GM1, Protease inhibitors (eg, napamosat), neutrophil inhibitors, platelet activation Factor antagonists (e.g., nupapant), monoamine oxidase B inhibitors (e.g., parafluoroselegiline and benzonitrile derivatives), PARS inhibitors, angiotensin I converting enzyme inhibitors (e.g., perindopril and ramipril), acetylcholine Agonists (e.g. pramiracetam), protein synthesis antagonists (e.g. prostain), phosphodiesterase inhibitors (e.g. propentophylline), opioid kappa receptor agonists (e.g. 10H-phenothiazine-2 Carboxamine derivatives), complement factor inhibitors (sCRI fragments), somatomedin-1 and carnitine acetyltransferase stimulants (eg, acetylcarnitine) and the like;
T cell inhibitors such as synthetic leucosite antigen derived peptides, interleukin-1 receptor antagonists, MG / AnergiX, anti-CD3 monoclonal antibodies, anti-CD23 monoclonal antibodies, anti-CD28 antibodies, anti-CD2 monoclonal antibodies CD4 antagonists, anti-E selectin antibodies, MHC inhibitors, monogens, mycophenolate mefetils, LRA-1 inhibitors and selectin inhibitors, and the like;
Migraine treatments such as MK-462, 324C91, Phytomedicine, (S) -fluoxetine, calcium channel antagonists (e.g. nimodipine / Nimotop, flunarizine, dotarizine / FI-6026) , Iomerazine HCL / KB-2796, CPC-304 and CPC-317), α-dihydroergocliptin, 5-HT1 agonists (e.g., Sumatriptan / Imitrex, Imigrand ( Imigran), GR-85548, 311C and GR-127607), 5-HT1D agonists, 5-HT1A antagonists, 5-HT1B antagonists (eg CP-93129), 5-HT1D antagonists (eg, 1H-indole-5- Ethanesulfonamide derivatives and 1H-indole-5-methanesulfonamide), 5-HT1D receptor (cloned) (eg from 5-HT1D), 2-thiophenecarboxamide, 3-piperidinamine, diclofenac potassium, Dehydroergotamine (e.g. DHE 45 ), Ergotamine tartarate, dolacetron mesylate, dotarizine, flupyritin, histamine-H3 receptor agonist, indobufen, 1-azulenesulfonic acid derivatives, cholinesterase inhibitors (e.g. S-9977), brady Kinin antagonists, nitric oxide reductase inhibitors (e.g. BN-52296), nitric oxide receptor antagonists, substance P antagonists (e.g. Capsaicin / Nasocap), endopeptidase inhibitors (e.g. neutral endo Peptidase, cloned), piperazine derivatives, neurokinin 1 antagonists, metgoline, dopamine D2 antagonists (e.g. metoclopramide + lysine acetyl), enkephalinase inhibitors (e.g., neutral endopeptidase), 5-HT2 antagonist (e.g. LY-053857), 5-HT3 antagonist (e.g. dolacetron mesylate / MDL-73147 and 4H-carbazol-4-one derivatives), tenosal, tolpenamic acid, cyclooxygena Inhibitors (eg, carbasalate / carbaspirin calcium and tenosal / MR-Y134), alpha adrenaline water Solution antagonists (e.g., arotinol and dihydroergocriptine), opioid agonists (e.g. flupyretin / D-9998), beta adrenergic nerve antagonists (e.g. propranolol), valproate semi-sodium, proparate hydrochloride Norol, imethetene mutate and dichloralfenazone;
Arthritis therapies such as anti-CD4 monoclonal antibodies, phospholipase A1 inhibitors, loteprednol, tobramycin, combinations of loteprednol and tobramycin, salasedine, amiprirose, anakinra, anergiX , Anti-B7 antibody, anti-CD3H, anti-gp39, anti-MHC MAb, anti-rheumatic peptide, anti-Tac (Fv) -PE40, AP-1 inhibitor, AR-324, purine nucleotide phosphorylase inhibitor (eg , BCX-5), vindarit, CD2 antagonist (eg, BTI-322), camppart-1H, CD4-antagonist (eg, CE9.1 and SB-210396), tumor necrosis factor antagonist (eg, p80 TNFR, rhTNFbp , Peptide T, CenTNF, thalidomide, CDP-571, and TBP-1), cobra venom factor, interleukin 1a agonists (e.g., cytogenin), interleukin 2 receptor antagonists (e.g., multiclicksimab), ICAM 1 antagonist (e.g., , Enlimab), interleukin 1 beta converting enzyme inhibitor (eg ICE-inhibitor), interferon (eg timothytin), interleukin-10, interleukin-13, interleukin 1 antagonist (eg SR-31 747 and TJ-114), interleukin-2 antagonists (eg, sirolimus), phospholipase C inhibitors, neurokinin 1 antagonists (eg, L-733060), lapunimus, leflunomide, leukotriene antagonists, leva Misole, LFA3TIP, Macrocyclic Lactone, MHC Class II Inhibitors, Missouribin, Mycophenolate Mefetyl, NfkB Inhibitors, Oncolysine CD6, Peldesine, Pidotimod, PKC-RACK Inhibitors, PNP Inhibitors, Rheumacon, CD28 Antagonist, Loquinimex, RWJ-50271, Subbreum, T7 Vector, Tacrolimus, VLA Antagonist (e.g. TBC-772), Converting Growth Factor Beta Agonist, Methionine Synthase Inhibitor (e.g. Vitamin B12 Antagonist), Adenosine A2 Receptor agonists (e.g., YT-146), CD5 antagonists (e.g. zolimob), 5-lipoxygenase inhibitors (e.g., zileuton, tenidab and ABT-761), cyclooxygenase inhibitors (e.g., tenox Cycam, talmethacin, pyroxycam, pyroxycam cinnamate, oxaprozin, NXTHIO, ML-3000, mefezolac, nabumethone, Rubiprofen, aceclofetax, diclofetax and dexibuprofen), metalloproteinase inhibitors (eg XR-168, TNF convertase inhibitors, GI-155704A, AG-3340 and BB-2983), Nitric oxide synthase inhibitors (ie ARL-16556), phospholipase A2 inhibitors (eg ARL-67974), selectin antagonists (eg CAM inhibitors), leukotriene B4 antagonists (eg CGS-25019C), collagenase inhibitors (Eg GR-129574A), cyclooxygenase 2 inhibitors (eg methoxylocamp), thromboxane synthase inhibitors (eg curcumin), cysteine protease inhibitors (eg GR-373), metalloproteinase inhibitors (D-5410), lipocortin synthesis agonists (e.g., lymexone, predonzolone, 21-farnesylate, HYC-141 and deplazacort), chelating agents (diacerane), elastase Inhibitors, DNA directed RNA polymerase inhibitors (e.g. estrogens), oxygen radical forming antagonists (e.g. glucosamine sulfate), thrombin inhibitors (e.g. G S-522), collagen inhibitors (e.g. halofuginone), hyaluronic acid agonists (e.g. NRD-101, Hailan, Dispasan and Hyalart), nitric oxide antagonists (e.g. Loxocobalamin), stromelysin inhibitors (e.g. L-758354), prostaglandin E1 agonists (e.g. microprostol and microprostol + diclofenac), dihydrofolate reductase inhibitors (e.g. trimetrexate and MX -68), opioid antagonists (e.g. nalmefene), corticotropin releasing factor antagonists (e.g. NBI-103 and NBI-104), protease inhibitors (e.g., protease nexin-1 and NCY-2010), bradykinin Antagonists (eg, tachykinin antagonists and NPC-17731), growth hormone antagonists (eg, octreotide), phosphodiesterase IV inhibitors (eg, PDEIV inhibitors), gelatinase inhibitors (eg, REGA-3G12) , Free radical scavengers (eg SIDR-1026), prostaglandin synthase inhibitors (eg sulfasalazine), ph Nilbutazone, penicillamine, salsalate, azathioprine, indomethacin, meclofenamate sodium, gold sodium thiomalate, ketoprofen, oranopine, orothioglucose and tolmetin sodium;
Antigout drugs (eg, colchicine and allopurinol, etc.);
Anticoagulants (eg, heparin, heparin sodium and warfarin sodium, etc.);
Thrombolytics (eg, urokinase, streptokinase and altoplase, etc.);
Antifibrinolytic agents (eg aminocaproic acid);
Blood flow drugs (eg, pentoxifylline);
Antiplatelet drugs (eg, aspirin, emphyrin and ascriptin, etc.);
Anticonvulsants (e.g., valproic acid, divalproate sodium, phenytoin, phenytoin sodium, clonazepam, primidone, phenobarbitol, phenobarbitol sodium, carbamazepine, amobarbital sodium, metsuccimid, Metharbital, mepobarbital, mefenitoin, pensuccimid, paramethadione, etotoin, phenacemid, secobarbitol sodium, chlorazate dipotassium and trimetadione and the like);
Agents useful for the regulation of calcium (eg, calcitonin and parathyroid hormone, etc.);
Antibacterial agents (e.g. amikacin sulfate, aztreonam, chloramphenicol, chloramphenicol, palmitic acid chloramphenicol, chloramphenicol sodium succinate, ciprofloxacin hydrochloride, klindamycin hydrochloride, palmitic acid klindamycin, phosphalicinmycin, metronidazole, metronidazole hydrochloride, gentamicin hydrochloride, gentamicin hydrochloride Mycin, tobramycin sulfate, vancomycin hydrochloride, polymyxin sulfate B, colistetate sodium and colistin sulfate);
Antifungal agents (eg, griseofulvin and ketoconazole, etc.);
Antiviral agents (eg, interferon gamma, zidobudine, amantadine hydrochloride, ribavirin and acyclovir, etc.);
Antimicrobial agents (e.g., cephalosporins (e.g., cefazoline sodium, cepradine, cefacller, cefapirine sodium, ceftioxime sodium, cephaperazole sodium, cetethetan disodium, ceputoxime azotyl, cefotaxime sodium, Sepaderoxyl monohydrate, ceftazidime, cephalexin, cephalotin sodium, cephalexin monohydrate, cefamandol naphate, cefacithin sodium, cenisidide sodium, celaridide, ceftriaxone sodium, ceftazidim , Cephadoxyl, cepradine and cefuroxime sodium, etc., penicillin (e.g., ampicillin, amoxicillin, penicillin G benzatin, cyclacillin, ampicillin sodium, penicillin G potassium, penicillin V potassium, piperacillin sodium, oxacillin Sodium, Bacampicillin, Kreaxacillin Sodium, Ticarcillin Disodium, Azolocillin Sodium, Carbenicillin Indanyl Sodium, Penicillin G Potassium, Penicillin G Procaine, Methicillin Sodium and naphcillin sodium, etc.), erythromycin (e.g., erythromycin ethyl succinate, erythromycin, erythromycin estoleate, erythromycin lactobionate, erythromycin sierate and erythromycin ethyl succinate, etc.) and tetra Cyclins (eg, tetracycline hydrochloride, doxycycline cyclate and minocycline hydrochloride, etc.);
Antioxidants (eg, N-acetylcysteine, vitamin A, vitamin C, vitamin E, β-carotene, EUK-8, flavonoids, glutathione, α-lipoic acid, melatonin and retinol, etc.);
Anti-infective agents (eg, myconazole, vidarabine, inosine, pranovex, vidarabine, inosine prabonex, cepipisol sodium and pradiomycin, etc.);
Bronchodilators (e.g., sympathetic stimulants (e.g. epinephrine hydrochloride, methaproterenol sulfate, terbutalene sulfate, isotarin, isotarin mesylate, isoetherin hydrochloride, albuterol sulfate, albuterol, bitol) Terrol mesylate, isoproterenol hydrochloride, terbutaline sulfate, epinephrine bitartarate, methaproterenol sulfate, epinephrine, epinephrine bitartarate), anticholinergic agents (e.g., ipratropium bromide), xanthine (e.g., aminophylline, Diphylline, metaproterenol sulfate, aminophylline), mast cell stabilizer (e.g. chromoline sodium), inhaled corticosteroids (e.g. fluolisolid, beclomethasone dipropionate, beclomethasone dipropio Nate monohydrate), salbutamol, beclomethasone dipropionate (BDP), ipratropium bromide, budesonide, ketotifen, salmeterol, xinapoate, terbuta sulfate , Triamcinolone, theophylline, nedo croissant wheat sodium sulfate meth Pro terephthalate play, albuterol and flu you solid and the like);
Hormones (e.g. androgens (e.g., danazole, testosterone cypionate, fluoxymesterone, ethyl testosterone, testosterone enaniate, methyltestosterone, fluoxymesterone, testosterone cypionate), estrogen (e.g. estradiol) , Estrophytate, complex estrogens), progestins (e.g. methoxyprogesterone acetate, noethynedrone acetate), corticosteroids (e.g. triamcinolone, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium, dexamethasone acetate, prednisone, methyl Prednisolone Acetate Suspension, Triamcinolone Acetonide, Methylprednisolone, Prednisolone Sodium Phosphate, Methylprednisolone Sodium Succinate, Hydrocortisone Sodium Succinate, Methylprednisolone Sodium Succinate, Triamcinolone Hexacato Hydrocortisone, hydrocortisone cypionate, prednisolone, fluorocortizone acetate, paramethasone acetate, prednisolone tebulate, prednisolone acetate, prednisolone sodium phosphate and succinic acid hydrocortisone sodium ) And thyroid hormones (eg, levothyroxine sodium) and the like;
Hypoglycemic agents (eg, human insulin, purified bovine insulin, purified porcine insulin, glyburide, chlorpropamide, glypide, tolbutamide and tolazamide, etc.);
Hypolipidemic agents (eg, clofibrate, dextrothyroxine sodium, probucol, lovastatin and niacin, etc.);
Proteins (eg, DNases, alginases, superoxide dismutases and lipases, etc.);
Nucleic acids (eg, sense or antisense nucleic acids encoding any therapeutically active protein, including proteins described herein);
Erythropoietic stimulants (eg, erythropoietin);
Ulcer therapy / antireflective agents (eg, famotidine, cimetidine and ranitidine hydrochloride, etc.);
Anti-nausea medications (eg, mecrizine hydrochloride, nabilone, prochlorperazine, dimenhydrinate, promethazine hydrochloride, thiethylperazine and scopolamine, etc.);
Septic shock therapeutic agents, such as angiogenesis inhibitors (OLX-514), bradykinin antagonists (eg CP-0502 and NPC-17731), complement factor inhibitors (eg C3 convertase inhibitors), C5a release inhibitors (eg , CAB-2.1), dopamine agonists (eg dopexamine), elastase inhibitors (eg ONO-5046), E selectin antagonists (eg CY-1787), farnesyltransferase inhibitors (RBE limonene), immune Stimulants (e.g. CGP-19835A, lipid A vaccine, Edobakomab, Nevakumab, StaphGAM and Diache), immunosuppressants (e.g. CytoTAB and transcyclopentanyl purine analogs), interleukin 1 antagonists (e.g. interleukin 1 receptor) , Interleukin 1 receptor antagonist (e.g. Anakinra), interleukin 1b antagonist (e.g. interleukin-1β), interleukin 1beta converting enzyme inhibitor (e.g. ICE-inhibitor), interleukin 8 antagonist (e.g. IL-8 receptor), interleukin 13 agonists (eg interleukin-13), ITF-1697, lipase scavenging factor inhibitors (eg SC-59735), membrane permeability Hyperstimulants (e.g. bactericidal permeation enhancing protein / BPI), nitric oxide antagonists (e.g. hydroxylcobalamin), nitric oxide synthase inhibitors (e.g. L-NMMA and α-methyl-N-delta-iminoethyl-ornithine ), P2 receptor stimulants (e.g., ATP analogs), phosphatidic acid synthetic antagonists (e.g. lysophylline), phospholipase A2 inhibitors (e.g., S-448), acylpyrrole-alkanoic acid derivatives and indoleacetic acid derivatives), platelets Activator factor antagonists (eg, ABT-299, TCV-309, SM-12502, (2RS, 4R) -3- (2- (3-pyridinyl) -thiazolidine-4-yl) indole, UR-12670 and E-5880), prostacyclin agonists (eg taprosten), prostaglandin E1 agonists (eg TLC C-53), protein kinase inhibitors (eg SB-203580), protein kinase C inhibitors, protein synthesis Antagonists (e.g. prostains), protease inhibitors (e.g. napamostat), SDZ-PMX-622, selectin antagonists (e.g. sulfated glycolipid cell adhesion inhibitors), thrombin inhibitors (e.g. GS-522), TNF receptor-Ig, tumor necrosis factor antagonists (eg anti-TNF MAb, MAK-195F, TBP-I, Yeda, rhTNFbp and CDP-571) and tumor necrosis factor alpha antagonists (eg E-5531 ) Etc;
Multiple sclerosis therapeutics such as 4-aminopyridine, 15 ± deoxyspergualin, ACTH, amantadine, antibody excipients (eg poly-ICLC and poly-IC + poly-L-lysine + carboxymethylcellulose), anti Cytokine MAb (CDP-835), anti-inflammatory agents (eg CY-1787 and CY-1503), anti-selectin MAb (eg CY-1787), anti-TCR MAb (eg NBI-114, NBI-115 and NBI-116), baclothene, betanechol chloride, carbamazepine, carbohydrate agents (eg CY-1503), clonazepam, CNS and immune system modulators (eg NBI-106 and NBI-107), cyclo Phosphamide, cyclosporin A, cytokines (e.g. IFN-α, alphaferon, IFN-β 1b, betaceron, TGF-β2, PEG-TGF-β2, betacaine, IFN-β / Redif) , Pron, interferon-β and IFN-β), CD4 + T cell inhibitors (eg, AnergiX), CD28 antagonists (eg, B7-1, B7-2 and CD28), direct cytotoxic therapeutics (eg, benzoporphyrin derivatives (BPD)), FK-506, growth factor (eg, glia cell growth factor, GGF, neuronal growth Factor, TGF-β2, PEG-TGF-β2 and betacaine), humanized MAb (eg, anti-IFN-γMAb, smart anti-IFN-γMAb, anti-Tac antibody and smart anti-Tac antibody), humanized Anti-CD4 MAb (eg anti-CD4 MAb, Centara), hydrolase stimulant (eg castanospermine), IFN-α, IFN-γ antagonist (eg anti-IFN-γ MAb and smart anti- IFN-γ MAb), IL-2 antagonist (e.g. tacrolimus, FK-506, FR-900506, fuzimycin, Prograf, IL-2 fusion toxin and DAB ₃₈₉ IL-2), IL-4 antagonist ( Eg, IL-4 fusion toxin and DAB ₃₈₉ IL-4), immune mediated neuronal damage inhibitors (eg, NBI-114, NBI-115, and NBI-116), immunoglobins, immunostimulants (eg, poly-ICLC, edelfossin , ALP, ET-18-OCH3, ET-18-OME, NSC-24 and poly-IC + poly-L-lysine + carboxymethylcellulose, immunosuppressive agents (eg azathioprine, AI-100 animal protein, rDNA human Protein AI-101, Peptide, AI-102, Castanospermine, Tacrolimus, FK-506, FR-900506, Fuzimycin, Frog , Anti-leucointegrin MAb, Hu23F2G, primatized anti-CD4 antibody, CE9.1, gallaptin 14-1, GL14-1, lectin-1, recombinant IML-1, linomide, loquinimex, LS-2616, transcyclo-pentanyl purine analog, MS-6044, spanidine, 15-deoxyspergualin, deoxyspurgiline, gusperimus HCL, NSC-356894, NKT-01, TCR, CD3 / Ti, cyclosporin, OL-27-400, SandImmune, human IL-10, monogen, anti-TCR MAb, TCAR MAb, Monogen TM19, Monogen TM27, Monogen TM29, Monogen TM31, Peptide TP12, anti-CD4 MAb, cantara, immunophilins, VX-10367, VX-10393, VX-10428, amino acid synthetic base copolymer, copolymer-1, COP-1, T lymphocyte immunofusion (TIF) protein And cyclophosphamide), integrin antagonists (eg anti-integrin (cell adhesion molecule α4β1 integrin) MAb, AN-100225 and AN-100226), interferon agonists (eg poly-ICLC and poly-IC + poly-L- Lysine + Carboxymethylcellulose), Interferon- β-1b, isopranosine, IV methylprednisolone, macrolides (e.g. tacrolimus, FK-506, FR-900506, fuzimycin and prograpes), MAO B inhibitors (e.g. selegiline and parquinyl), Methotrexate, mitoxantrone, muscle relaxant (eg RGH-5002), muscarinic antagonist (eg RGH-5002), neurosteroids (eg NBI-106 and NBI-107), octapeptides (eg peptide T), oxy Butynin chloride, oxygen free radical antagonist (e.g., tetrarandrin, biobenzylisoquinoline alkaloid), peptide agonist (e.g. peptide T), phenoxybenzamine, phospholipase C inhibitor (e.g., edelposin, ALP, ET -18-OCH3, ET-18-OME, NSC-24), photodynamic therapeutics (e.g. benzoporphyrin derivatives (BPD)), plasma separation, platelet activating factor antagonists (e.g. ginkgolide B and BN-52021), potassium Channel antagonists (eg aminodiaquine and EL-970), propranolol, prostaglandin synthase inhibitors (eg sulfasalazine, sala) Sulfa-pyridine, PJ-306, SI-88, azulpidine, salaziprine), protease antagonists (e.g. ginkride B and BN-52021), recombinant soluble IL-1 receptors, sperguline analogs (e.g. spani Dean, 15-deoxyspergualin, deoxyspurgiline, gusperimus HCl, NSC-356894, NKT-01), TCR peptide disruptors (e.g., NBI-114, NBI-115 and NBI) -116), TCR peptidomimetic disruptors (eg NBI-114, NBI-115 and NBI-116), TCR peptide vaccines (eg AI-208 (Vβ6.2 / 6.5 phenotypes)), selectin antagonists (eg , Lectin-1 and recombinant IML-1), soluble TNF receptor I, TCAR (eg, TCR, CD3 / Ti and peptogen TP12), TNF antagonists (eg, thalidomide and TNF inhibitors) and tricyclic antidepressants, and the like;
Organ transplant therapeutics such as anti-CD25 MAb, anti-Tac antibody, anti-TNF MAb (eg CDP571), apoptocin, azathioprine (eg immunoran), BCX-34, CA3, CD28, complement Inhibitory factor (e.g. CD59), CTLA4Ig, cyclosporin (e.g. CsA), FK-506 / rapamicin binding protein (FKBP), glucocorticoid, humanized class of OKT3 (e.g. huOKT3-185), mycophenolate mofetil Hydroorotate dehydrogenase inhibitors (e.g., Brequinar), orthoclonal OKT3 (e.g., IgG2a anti-T cell rat monoclonal antibodies and muromonab-CD3), rapamycin (e.g., , AY-22989) and Streptomyces isolates (eg FR-900520 and FR-900523) and the like;
For systemic lupus erythematosus (SLE) therapeutics, such as androgen derived steroids (eg Org-4094), anti-CD4 humanized antibodies, anti-DNA / V-88, anti-genic rat MAb (eg, 3E10) Anti-genic antibody / MAb1C7), CD2 antagonist (eg CD2), complement inhibitor (eg, recombinant MCP based complement inhibitor), cyclosporin (eg Sandimmune, cyclosporin analogue, OG-37325, cyclosporin-G and NVal- CyA), cytokines (eg, IL-4 fusion toxins), cytokine receptor antagonists (eg, immunoregulatory cytokines), E-selectin antagonists (eg, anti-ELAM and CY-1787), FK506 / tacrolimus (eg, Prographs), hypercalcemia treatments (eg KH-1060), IFN-γ antagonists (eg anti-IFN-γ MAb and smart anti-IFN-γMAb), IL-1β converting enzyme inhibitors (ICE), e. IL-2 produced by E. coli (eg, Selmoleukin, IL-2, TGP-3, and Celuk), immunoglobulins (eg, anti-ELAM, CY-1788, and humanized CY-1787 ), Immunostimulatory agents (e.g., thymotrinan, RGH-0205 and TP3), immunosuppressive agents (e.g., rapamycin, AY-22989, NSC-226080, NSC-606698, anti-CD4, T-cell inhibitors, anti- tac MAb, smart anti-tac MAb, Migis (membrane immunoglobulin-isotope specificity) antibodies, SM-8849, immunophilin, VX-10367, VX-10393, VX-10428, mycofetolate mofetil, ME-MPA, RS-61444, cyclosporin, OL-27-400, Sandimmune, IL-4 fusion toxin, tripanosomal inhibitor (TIF), T-cell receptor, CD3 / Ti, Org-4094, anti-TBM, CP 17193, Leflunomide / A-77-1726, ELAM-1, AnergiX, Spanidin, 15-deoxysperguline, deoxyspurgiline, gusperimus hydrochloride, NSC-356894, NKT-01 , Roquinimex, LS-2616, linomide, LJP-394 and CD-59 antigens, immunotoxins (e.g. Zolimomab aritox), zmmly-h65-rta, Xomazyme-lym / CD5-plus, OrthoZyme-CD5 +, Somazyme-H65-rta, Simazyme-CD5-plus), intravenous Immunoglobulins (eg IVIG), integrin antagonists (eg integrin blockers), Migis ™ antibodies, monoclonal antibody therapeutics, murine MAb (eg anti-SLE vaccines and MAb 3E10), primatized anti-CD4 antibodies (eg CE9) .1), protease inhibitors (eg, matrix metalloprotease (MMP) inhibitors and stromelysin), protein synthesis antagonists (eg, anti-CD6-bR, anti-T12-bR and oncolysine CD6), purine nucleo Seed phosphorylase inhibitors (e.g. BCX-25 and CBCX-14), selectin antagonists (e.g. CY1503 and Cylexin), spheruline analogs (e.g. Spanidin, 15-de Oxiferguarine, deoxyspurgiline, gusperimus hydrochloride, NSC-356894 and NKT-01), T-cell inhibitors (eg, AnergiX) and tumor necrosis factor (TNF) antagonists, and the like;
Alzheimer's disease therapies, such as ACh release enhancers (e.g., T-588 (benzothiophene derivatives)), acetylcholine release stimulants (e.g., DUP-996 and analogs), AMPA agonists (e.g., AMAlex and isoxazole compounds Family), AMPA GluR agonists (eg, IDRA-21 [7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazinine]), AMPA GluR antagonists (eg, S-18986 and related quinolone derivatives), anticholinesterases (e.g. E-2020), Ca-antagonists (e.g. NS-649, spider venom derived ICM peptides and analogues and substituted 2-aminoindane compounds), bound anticholine Esterase and muscarinic AChR antagonists (eg PD142676), K-channel blockers (eg, Trans-R-4- (4-methoxyphenyl-methyl) cyclohexalanine and analogs, and margatoxin based functionalities And / or functional analogues), MI muscarinic receptor agonists (eg Xanomeline), NMDA antagonists (eg some indole derivatives and (R- (R¹, S¹) -α- (4-hydroxyphenyl) ) -Beta-meth -4- (phenylmethyl) -1-piperidinepropanol and analogs) and nicotinic AchR agonists (eg, ABT-418 [isoxazole, 3-meth-5- (1-meth-2-pyrrolidinyl) ]) Etc;
Anti-Parkinson's drugs (eg, ethosucciamide, etc.);
Psoriasis drugs, such as 5-LO inhibitors (e.g., Wy-50295, Wy-49232, Ronapalene, RS-43179, MK-886, L-663536, ETH-615, DUP-654, Gilluton, Epocarbazoline- A, and A-64077), 5-LO / CO inhibitors (e.g. BF-397, Teniadp, CP-309, and CP-66248), angiogenesis inhibitors (e.g. platelet factor 4), anticancer antibiotics (e.g. , AGM-1470, and TNP-470), anti-inflammatory cytochrome P450 oxidoreductase inhibitors (eg DuP-630, and DuP-983), antiproliferative compounds (eg Zyn-linkers), arachidonic acid analogs (eg, CD581 and CD554), arachidonic acid antagonists (e.g., lonophalene, RS-43179, triamcinolone acetonide, including beta enhancer azone, betamethasone dipropionate steroid wipes), G-202, halobetasol propionate, ultrabate , Halomethasone, C-48401-Ba and cycorten), beta-glucan receptor antagonists, betamethasone steroid wipes, calcium metabolism modulators (e.g. tacalcitol, bonalpha, TV-02 ointment, Ro-23-6474 , KH-1060, calcipotriol, BMS-181161, BMY-30434, Gulnex and Dibonex), CD4 binding inhibitors (eg PIC 060), cell adhesion compounds (eg CY-726, VCAM-1, ELAM- 1, and ICAM), cell adhesion inhibitors (eg, selectin inhibitors, GM-1930), cell aging inhibitors (eg, factor X), corticosteroids (eg, halobetasol propionate, ultrabate, halomethasone, C -48401-Ba and cycortene), cyclosporin analogues (e.g. IMM-125), dihydrofolate reductase inhibitors (e.g. G-301, dichlorobenzoprim, methotrexate and methotrexate in microspongy derived systems), E- Selectin inhibitors (e.g. ISIS 4730), angiogenic active forms of vitamin D ₃ (e.g. calcitriol and Du-026325), fibroblast growth factor antagonists (e.g. saporin mitotoxin and steno-start), fumaginine analogs (Eg AGM-1470 and TNP-470), G-proteins and signal transducing compounds (eg CPC-A), gel preparations for acne ( , Nicotinamide, N-547 and papulex), growth hormone antagonists (e.g. octreotide, acidstatin, lanreotide, angiopeptin, BIM-23014 and somatulin), humanized antibodies (e.g., anti-CD4 antibodies ), Hydroorotate dehydrogenase inhibitors (e.g. Brequinar sodium, bifenquinate and DuP-785), ICAM-1 inhibitors (e.g. ISIS 939), IL-1 and other cytokine inhibitors (e.g. septanyl) , IL-1 converting enzyme inhibitor, IL-1 receptor inhibitor (eg, anthryl), IL-2 antagonist (eg, tacrolimus, prograph and FK-506), IL-2 receptor target binding toxin (DAB389IL-2 ), IL-8 receptors, immune stimulants (e.g. thymopentin and thymunox), immunosuppressive agents (e.g., somazyme-CD5 plus, cyclosporin, sandib, SR-31747, anti-CD11, 18 MAb, tacrolimus , Prograph, FK-506 and FK-507), FK-506 target immunosuppressive agents (eg, immunophilin, VX-10367 and VX-10428), immunotoxin MAb induced against CD antigen ( , Somazyme-CD5 plus), leukotriene antagonists (e.g. Sch-40120, Wy-50295, and Wy-49232), leukotriene B4 antagonists (e.g. SC-41930, SC-50605, SC-48928, ONO-4057, LB -457, LY-255283, LY-177455, LY-223982, LY-223980 and LY-255253), leukotriene synthesis inhibitors (e.g. MK-886 and L-663536), lipase scavenging factor inhibitors (e.g. 1-docosanol And lidacol), lipid encapsulating reducing agents (e.g., ditranol), liposome gels (e.g., ditranol), LO inhibitors (e.g., CD581, CD554, Masoprocol and Actinix), lithium succinate ointment (e.g., Lithium salts and epalite), LO / CO inhibitors (e.g. P-8892, P-8977, CHX-108 and FPL-62064), membrane preservative agents (e.g. lithium salts and epalite), microtubule inhibitors ( E.g., posophiliotoxin containing compounds and psorex), octapeptide somatostatin analogs (e.g. lanreotide, angiopeptin, BIM-23014 and somatulin), oligonucleotides (e.g., ISIS 4730, ISIS 3801, ISIS 1939 and IL) -1 inhibitor), peptide Agents (eg octapeptide and peptide T), PKC inhibitors, phospholipase A2 compounds, phospholipase D compounds, photodynamic anticancer agents (eg 5-aminolevulinic acid and 5-ALA), photodynamic therapeutic agents (eg, Benzoporphyrin derivatives, synthetic chlorine, synthetic porphyrins and EF-9), photosensitizers (e.g. porpermer sodium), PKC inhibitors (e.g. sapingol and kinac), platelet activator factor antagonists (e.g. TCV-309), platelet aggregation inhibitors (E.g. CPC-A), prodrug NSAIDs (e.g. G-201), prostaglandin agonists (e.g. eicosapentaenoic acid + gamma-linolenic acid combination and efamolmarine), protein inhibitors (e.g. SPC-103600 and SPC -101210), protein kinase C (PKC) inhibitors (eg Ro-31-7549, Ro-31-8161 and Ro-31-8220), protein synthesis antagonists (eg calcitriol, Du-026325, LG-1069, LG -1064, AGN-190168, namirotene and CBS-211A), purine nucleoside phosphorylase inhibitors (eg BCX-34), radical forming agents (eg ben Porphyrin derivatives), recombinant anti-leukocyte proteinases (eg ALP-242), retinoids (eg BMY-30123, LG-1069 and LG-1064), retinoid derivatives (eg AGN-190168), rapamycin binding protein (FKBP ) (Eg, immunophilin, VX-10367 and VX-10428), secondary generating monoaromatic retinoids (eg, acitretin and neotigasone), soluble IL-1, IL-4 and IL-7 receptors, somatostatin and somatostatin Analogues (eg octreotide and acidstatin), steroids (eg AGN-191743), Streptomyces isolates (eg epocarbazoline-A), superoxide dismutase (eg EC-SOD -B), thymidylate synthase inhibitors (e.g. AG-85, MPI-5002, 5-FU in biodegradable gelled matrices, epinephrine in biodegradable gelled matrices, and accusite), topical preparations (e.g., , P-0751 and P-0802), glutamine transferase inhibitors, tyrphostin EGF receptor kinase inhibitory antibodies (eg AG-18 AG-555), VCAM-1 inhibitors (e.g. ISIS 3801), vitamin D analogues (e.g. Ro-23-6474, KH-1060, calcipotriol, BMS-181161, BMY-30434, Galinex and Divonex) , Vitamin D ₃ analogues (eg tacalitol, bone alpha, TV-02 ointment) and vitamin D ₃ derivatives (eg 1,2-diOH-vitamin D ₃ );
Diabetic drugs such as ACE inhibitors (e.g. captopril), amylin, amylin agonists and antagonists (e.g., normylin®, AC137, GC747, AC253 and AC625), autoimmune compounds (e.g. AI -401), capsaicin (e.g., Jostrix-HP), cell modulators (e.g., protein kinase C inhibitors and ballanols), domperidone (e.g., Motilium®), fluvastatin (e.g. , Rescol), FOX 988, binding toxins (eg DAB ₃₈₉ IL-2 and DAB ₄₈₆ IL-2), gene therapy (eg transcarotitic therapy), glucagon (eg recombinant yeast glucagon), IL-10 compounds , Iloprost, immunosuppressive agents (e.g. tacrolimus, prograph and FK-506), proinsulin, insulin and insulin analogues (e.g. AI-401, Nu-insulin compound, humulin, eletin, humalog , LYs-Pro and Amaryl), insulin-like growth factors (e.g., Chiron / Shiba-Geigy compound, Fujisawa compound, and Genentech compound), Insulinnotropin (e.g., Pfizer / Schks Nova compound), nerve growth factor (e.g. Genentech compound), oral hypoglycemia (e.g. AS-6, glymepiride, amiryl, CL 316,243, acarbose, miglitol , Recombinant yeast glucagon, glucagen® (GlucaGen®), novonom® (NovoNorm®), glipizide, insulinotropin, and CI-991 / CS-045), platelet induced growth factor (eg, Zimogenetics / Novo Nordisk Compound), Sulfonylurea (e.g., tolbutamide, acetohexamide, tolazamide, and chlorpropramide), T cell accessor (Anergaize, Anergix, Trader) ), Procept compounds and T cell science compounds), and tolesat (eg, Aledase® and ARI-509), actibin, somatostatin, and the like;
Stroke drugs such as 5-HT antagonists (e.g. piperazine derivatives), 5-HT reuptake inhibitors (e.g. milnacipran and dalcifran), 5-HT 1A agonists (e.g. SR-57746A and SR-57746) , 5-HT 3 agonists (eg SR-57227), 5-HT 4 antagonists, 5-lipoxygenase inhibitors (eg low MW double 5-lipoxygenase and PAF inhibitor CMI-392), ACh agents (eg Pramiracetam, choline-L-alphaphosphate L-alpha-glycerylphosphoryl-choline and derexit), adenosine agonists (e.g. GP-1-4683, ARA-100, and arasine analogs), adenosine A1 receptors Agents (eg, azaisotere, 2-chloro-N- [4 (phenylthio) -1-piperidinyl] adenosine, and 2120136), adenosine reuptake inhibitors (eg, diphenyloxazole derivatives), adrenergic delivery agents Absorption inhibitors (e.g., bifemelan, E-0687, MCI-2016, alnut, and selport), aldose reductase inhibitors (e.g. spiro-3'pyrroline derivatives), alpha antagonists (e.g., drotavirin ace Flynney And dopagen), alpha 2 agonists (eg, SNAP-5083, SNAP-5608, and SNAP-5682), AMPA receptor agonists (eg, heterocyclic compound SYM-1207, and heterocyclic compound SYM-1252), AMPA Receptor antagonists (e.g., LY-293558, and LY-215490), ankrod / arbin, aspirin, benzothiazole (e.g., ruvelazole, and R87926), benzodiazepine receptor antagonists (e.g., 3-oxazozolyl-1, 6-naphthyridine derivatives, tetracyclicimidazodiazepines series imidazenyl, FID-02-023, and Ro-23-1412), blood substitutes, bradykinin antagonists (e.g. CP-0127, brady Kor, and septicor), C5a release inhibitors (e.g. protein derivative CMI-46000), calcium antagonists (e.g. remildipine, NB-818, NPK-1886, trimetazidine derivatives, iomerizin KP-2796, diltia Gem homologs Clentiazem maleate, and TA-3090), calcium channel antagonists (e.g., nitrendipine type compound diferdipine, YS-201, U-92032, diltiazem derivatives, 1058, SM-6586, KP-840, F-0401, D-31-D, tetrahydronaphthalene derivative, fasudil, AT-877, H-7, HA-1044, HA-1077, aryl, darodipine, dazodipine, PY- 108-068, plymo, dihydropyridine, AE 0047, GJ-0956, laccidipine, GR-43659, GR-43659X, GX-1048, S-312-d, S-312, S-830312, nilbody Pin, and FK-235), calpine inhibitors (eg, AK-275, and CX-275), carnitine palmitoyl transferase inhibitors, carvedilol, cerebral calcium antagonist vasodilators (eg, nimodipine, and nimtop) , Cholinesterase inhibitors (eg, indole and indazole derivatives, and tacrine homologues), complement factor inhibitors (eg, TK9C, protein derivative TP16, Compinact A, Compinact C, Factor D inhibitors, and soluble, recombination MCP- Base complement inhibitors, complement inhibitors (eg sCRI / BRL-55730, and YM-203), coronary vasodilators (eg nicolandil, RP-46417, SG-75, and Adancor), CPC-111, CIT Dill diphosphoclean / citiline, cell division (e.g. NBI-117), dexanabiol, dopamine Solvents, EAA receptors, endothelin antagonists (eg SB209670), endothelin receptor antagonists, excitatory amino acid agonists (eg acylated polyamine homologues, and N- (4-hydroxyphenylpropanoyl) -spermine homologues), Excitatory amino acid antagonists (e.g. tryptophan, 4,6-disubstituted stroke and kynurenine derivatives, NPC-17742, CPC-701, and CPC-702), glutamate antagonists (e.g. cyanate squilate NNC-07-9202 , NPC-17742, small molecules CNS-1237, NS-257, NS-072, BW-S19C, CGS 19755, rilusol, PK-26124, and RP 54274), glutamate receptor antagonists (e.g., aracin compounds, quinoxaline Derivatives, YM-90K, and YM-900), glycine antagonists, glycine NMDA agonists (eg, 3-hydroxy-2,5-dioxo-1H-benz [b] azepine), glycine NMDA related antagonists (eg, 5,6-dihydro-1H-pyrrolo [1,2,3-de] quinoxaline-2,3-dione, strikinin-insensitive glycine binding site of NMDA receptor L-687414, glycistacin, ACEA -2011, A CEA-3031, AC-1021, ACPC, and elliprodil), growth factor antagonists (eg, non-peptide indolocarbazole neurotropic molecules, and CEP-075), GPIIb / IIIa antagonists (eg, peptide C68-22) Blood flow aids (e.g., drotaberin acepilinate, and dopagen), heparin, hydroxyl radical formation inhibitors (e.g., homopiperazin derivative K-7259), serum lime reducing agents (e.g., calcitonin related to hCGRP peptides) Peptides), hypothermia / BMY-20862, ICAM-1 compounds (eg enrimab), immunosuppressive agents (eg small molecule compounds and NBI-117), integrin general antagonists (eg single cell antibody AN-100225) And single cell antibody AN-100226), interleukin-1 antagonists (eg cyclic nitrones), iron-dependent lipid peroxidation inhibitors (eg 2- (amino-methyl) chromans), lactic acid accumulation / inhibitors (eg bovine Molecule CPC-211), leukotriene B4 antagonist (e.g. ebselen, DR-3305, PZ-25, PZ-51, RP 60931, and RP61605), lipid peroxidase inhibition Agents (e.g., idebenone, and avan), low molecular weight small molecules, methyltransferase stimulants (e.g. 4-methyl benzenesulfonate, ademethionine sulfate tosylate, FO-156, and cetane), monoamine oxidase B inhibitors (E.g., MD-280040, MD-200243, MD-280080, razabemid, and Ro-19-6327), MS-153, MS-424, Na ⁺ / H ⁺ Na ⁺ / Li ⁺ exchange inhibitor (e.g., Pyrazine derivatives), nadroparin (e.g., proxiparin), napronyl / naphthydrofuryl (e.g., xyxylene), nerve growth factor agonists (e.g. small molecule compounds, CNTF, BDNF, 2.5S NGF, monosialogan Glioside GM1, and cygen / cygen), neuronal calcium channel blocker antibodies (eg CPC-304, and CPC-317), neuron derivative compounds (eg F-spondin), neuropeptide agonists (eg neuropro) Pick peptides tropexin), Neutrophil Inhibitors (e.g. small molecule compounds), Nitric Oxide Agents (e.g. hydroxy derivatives N-3393, hydroxy derivatives N-3398, Nicorandil and Therapy) Bovine antagonists, NMDA antagonists (e.g. spiroisoindole / dizocilpin derivatives, auxindol compounds, CP-112116, LY-104658, LY-235959, FR-115427, sialic acid derivatives, N-palmitoyl-betaethylglycoside nu Laminic acid, ND-37, Ro-01-6794, 706, dextropan, ifenprodil-like elliprodil, SL-82.0715, lipophilic molecule, HU-211, remamide, 934-423, 12495, 12859 , 12942AA, Cellpotel, CGS-19755, SDZ-EAA-494, CGP-40116, CGP-37849, CGP-39511 and CGP-43487), NMDA antagonist-partial agonists (eg, Conantokin G peptide SYM-1010), NMDA channel inhibitors (e.g. Aptiganel, cerestat, and CNS 1102), NMDA receptor antagonists, NMDA receptor subtypes (e.g. kinate quescu-rate NNC-07-9202), noncompetitive NMDA antagonists (e.g. , FPL-15896), nonionic copolymers Leotrox (RheothRx), nootropic / acetylcholine agonists (e.g. oxyracetan, CT-848, and neurolactic), norepinephrine inhibitors (e.g., mida-fran ), N- Calcium channel antagonists (e.g. NS-626, and NS-638), opioid antagonists (e.g. nalmefene, nalmetrene, JF-1, ORF-11676, cerbene, and incisten), opioid kappa receptor agonists (e.g. , Acrylacetamide endolaline, and CI-997), organoselenims (e.g. eoselen, DR-3305, PZ-25, PZ-51, RP 60913, RP 61605), oxygen scavenger (e.g. Tyrilazad mesylate, lazaroid, and predox), PA2 inhibitors (eg, phospholipase A2 inhibitors), PAF antagonists (eg, nufapant, and BB-2113), partial glycine NMDA antagonists (eg, ACPC) , Peptide / GPIIb / IIIa antagonists (e.g. integral), peptide neuron specific calcium channel antagonists (e.g. SNX-111), phosphodiesterase inhibitors (e.g. xanthine derivatives, propentophylline, Hoe-285, and hex Toll), phospholipase A2 inhibitor (eg small organic molecule CEP-217), plasminogen activator (eg r-ProUK (recombinant pro-urokinase), platelet-activation Ruler antagonists (e.g. UK-74505), platelet adhesion inhibitors (e.g. peptides), platelet aggregation antagonists (e.g. cilostazol, peptide drugs, GPHb-IIIA inhibitors, and TP-9201), platelet aggregation inhibitors (e.g. dia Minoalkanoic acid derivatives), potassium channel agonists (e.g. nicorandil, RP-46417, SG-75, and adancor), prolyl endopeptidase (PEP) inhibitors (e.g. JTP-4819), protein kinase C inhibitors ( E.g., monosialogologlioside derivatives Riga-20), protease inhibitors (e.g., protease nexin-1, insight, PN-1, PN-2, napamosat, FUT-175, dutan, and futan) , Pyrimidine derivatives, quinolizine derivatives (eg KF-17329, and KF-19863), radical forming antagonists (eg EPC-K1), recombinant tissue plasminogen activators (eg alteplase, and activase) , Schwann cell inducing molecule / promoter, sigma antagonist (eg sigma ligand), sigma receptor antagonist (eg tetrahydropyridinyl Soxazoline and isoxazole PD-144418), sodium / calcium channel modulators (e.g. Liparizin, and RS-87476), sodium channel antagonists, streptokinase (e.g. streptase), substituted guanadines (e.g. small molecules CNS-1237), superoxide dismutase stimulant (eg PEG bound enzyme superoxide dismutase / dismutec, and PEG-SOD), thrombin inhibitor (eg non-peptide), thromboxane synthase inhibitor (eg, Linotrovan and HN-11500), tyrotropin-releasing hormone agonists (e.g. TRH agonists, protyreline analogs thymoberine and RX-77368), ticlopidine (e.g. ticlides), TJ-8007, TRH agonists ( Eg, tyropropine releasing hormone and JTP-2942), trilazad, urokinase (e.g., abbokinase), w-conopeptide (e.g., SNX-111), and warfarin (e.g., coumadine);
Drugs useful for the treatment of carcinomas (e.g., adriamycin, taxol, interleukin-1, interleukin-2 (especially useful for the treatment of renal carcinoma)) and especially leuprolide acetate, LHRH analogues (e.g. naparel, useful for the treatment of prostate carcinoma) Lean acetate), etc.),
Agents useful for the treatment of endometriosis (eg, LHRH analogues),
Agents useful for the treatment of uterine contractions (eg oxytocin),
Drugs useful for the treatment of diuretics (for example, vasopressin),
Agents useful for the treatment of cystic fibrosis (eg, deoxyribonucleases (ie, deoxyribonucleases, SLPI, etc.),
Agents useful for the treatment of neutropenia (eg, GCSF),
Agents useful for the treatment of lung cancer (eg beta 1-interferon),
Agents useful for the treatment of respiratory diseases (eg superoxide bismuthase),
Agents useful for the treatment of ischemia / reperfusion injury (eg, selectin inhibitors, Irfl, etc.),
Nitric oxide synthase inhibitors (eg, N ⁴ -methyl-L-arginine, aminoguanidine, N ^4- (iminoethyl) -L-ornithine, thiocitrulline and other citrulline derivatives, N ⁴ -nitro-L-arginine, N ⁴ -nitro-L-arginine methyl ester, N ⁴ -amino-L-arginine and other arginine derivatives, isothiourea and derivatives thereof, etc.)
As well as acyclovir, alendronate sodium, amlodipine, ampicillin, azelaic acid, azithromycin, beclomethasone, betamethasone, bicalutamide, buspyrone, carisoprodol, carvedilol, cefachlor, cephadroxyl, Sepiksim, ceftirozil, ceftutibutene, cefuroxime axetyl, cephalexin, cetirizine hydrochloride, cimetidine, ciprofloxacin, cysaprid, clarithromycin, clavulanate, clonazepam, clotrimazole, codeine, conjugate estrogen , Cyclobenzaprine, desogestrel, dexrazoic acid, diazepam, dicyclomin HCl, digoxin, diltiazem, dirithromycin, doxazosin, doxycycline, enalapril, erythromycin, erythromycin base, erythromycin stearate Latex, estradiol, ethynyl estradiol, ethinodiol, diacetate, etodolak, famotidine, fluconazole, fluoxe , Fluvastatin, furosemide, gelfibrozil, glipizide, glyburide, guapenesine, hydrochlorothiazide, hydrocodone, hydrocortisone, ibuprofen, ibutylide fumarate, indamide, insulin , Ipratropium bromide, ketoconazole, ketoprofen, ketorolactromethamine, lamivudine, lansoprazole, levonorgestrel, levothyroxine, ricinopril, loracarbef, loratinidine, lorazepam, losartan potassium Lovastatin, methoxyprogesterone, methylphenidate, methylprednisolone, metoprolol, metoprolol tartrate, moexipril hydrochloride, mometasone furoate, mupyrosine, mycophenolate mofetil, nabumethone, nalmefene hydrochloride, Naproxen, neomycin, nifedipine, nisoldipine, nitrofurantoin, nizatidine, noethine drone, norgestrel, nortriptyline, oproxacin, omepr , Oxaprozin, oxycodone, paroxetine, penicillin, pentoxifylline, phenylpropanolamine, phenytoin, polymyxin, sodium perfermer, potassium chloride, pravastatin, prednisone, promethazine, propoxyphene, pseudoephedrine, quinapril, ramipril, ranitidine , Rilusol, salmeterol, saquinavir mesylate, sertraline, sevoflurane, simvastatin, sucralate, sulfametoxazole, sumatriptan, temazepam, terazosine, terconazole, terpenadine, tetracycline, Theophylline, timolol, tramadol, tramadol hydrochloride, tretinoin, triamcinolone acetonide, triamterene, trimethoprim, valproic acid, venlafaxine, verapamil, warfarin, zolpidem and the like.
Nitric oxide scavenging components (e.g., dithiocarbamate components) and pharmaceutically active agents of the conjugates of the present invention are ester bonds, disulfide bonds, amide bonds, ether bonds, thioether bonds, imide bonds, sulfate ester bonds It can be covalently bonded using various bonds such as sulfonic acid ester bonds, phosphate ester bonds, carbonate bonds, O-glycoside bonds, and S-glycoside bonds. Such linkages can be made using standard synthetic techniques known to those skilled in the art to directly react the starting materials or to incorporate suitable functional groups in the starting materials, followed by coupling the reactants.
According to another embodiment of the present invention, there is provided a process for the preparation of a protected form of a pharmacologically active agent comprising covalently binding a nitric oxide scavenger (eg, dithiocarbamate) to the pharmacologically active agent. The resulting binder is biologically active only when the covalent bond that binds the nitric oxide scavenger (e.g. dithiocarbamate) to the pharmacologically active agent is degraded (e.g. by esterase, amidase or other suitable enzyme). It provides a latent form of the pharmacologically active agent. Degradation of the covalent bond that binds dithiocarbamate to the pharmacologically active agent releases free dithiocarbamate, which typically results in nitric oxide production as a result of the disease state to be treated and / or as a result of its treatment. Provide effective nitric oxide scavenging activity directly at the site of induction.
According to another embodiment of the invention, a pharmacologically active agent to a patient, comprising covalently binding a nitric oxide scavenger (eg, dithiocarbamate) to the pharmacologically active agent (s) prior to administration to the patient. A method of reducing side effects induced by administering (s) is provided.
According to another embodiment of the present invention, there is provided a method for enhancing the efficacy of a pharmacologically active agent (s) comprising covalently binding a nitric oxide scavenger (eg, dithiocarbamate) to a pharmacologically active agent. .
According to another embodiment of the present invention, a pharmacologically active agent (s) for a patient for the treatment of a pathological condition comprising covalently binding dithiocarbamate to the pharmacologically active agent prior to administering the pharmacologically active agent to the patient. An improved method of administering is provided.
Those skilled in the art understand that the nitric oxide scavenger containing scavenger disclosed herein can be delivered in a variety of ways, including, for example, oral, intravenous, subcutaneous, parenteral, rectal, inhalation, and the like.
Depending on the mode of delivery used, the nitric oxide scavenger contemplated for use herein may be delivered in a variety of pharmaceutically acceptable forms. For example, the scavenger can be delivered in the form of solids, solutions, emulsions, dispersions, micelles, liposomes and the like.
Therefore, according to another embodiment of the invention, a compound comprising Formula I in a suitable vehicle such that the compound (s) is suitable for oral delivery, transdermal delivery, intravenous delivery, intramuscular delivery, local delivery, intranasal delivery, etc. Physiologically active composition (s) comprising the same).
The pharmaceutical compositions of the present invention may be used in the form of solids, solutions, emulsions, dispersions, micelles, liposomes, and the like, wherein the resulting composition is an active ingredient comprising one or more of the compounds of the present invention in an organic or inorganic carrier or enteric or parenteral. With carriers or excipients suitable for sphere application. The active ingredient may be mixed with conventional nontoxic pharmaceutically acceptable carriers, for example for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and other forms suitable for use. Carriers that can be used include glucose, lactose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextran, and solids, There are other carriers suitable for use in the manufacture of pharmaceuticals in semisolid or liquid form. In addition to the auxiliaries, stabilizers, thickeners and coloring agents and flavorings may also be used. The active compound (s) (eg, one or more pharmacologically active agents covalently bound to the dithiocarbamate of Formula I) are included in the pharmaceutical composition in an amount sufficient to have the desired effect on progression or disease state.
Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use such as, for example, tablets, pills, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs have. Compositions intended for oral use may be prepared according to methods known in the art for the preparation of pharmaceutical compositions, such compositions may include sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint, roebal or cherry oil, And one or more agents selected from the group consisting of colorants, preservatives, and the like, to provide pharmaceutical formulations with a good appearance and taste. Tablets containing the active ingredient with non-toxic pharmaceutically acceptable excipients may be prepared by known methods. Excipients used include, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate, (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid, (3) tragacanth Binders such as gum, corn starch, gelatin or acacia, and (4) lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques to provide sustained activity over a long period of time by retarding degradation and absorption in the stomach. For example, a time delay substance such as glyceryl monostearate or glyceryl distearate may be used. These are coated by techniques disclosed in US Pat. Nos. 4,256,108, 4,160,452, and 4,265,874 and the like to form osmotic therapeutic tablets for controlled release.
In some cases, preparations for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as, for example, calcium carbonate, calcium phosphate or kaolin. They may be in the form of soft gelatin capsules in which the active ingredient is mixed with oil or water such as, for example, peanut oil, liquid paraffin, or olive oil.
Pharmaceutical compositions may be in the form of sterile injectable suspensions. Suspensions can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may be sterile injectable solutions or suspensions in a nontoxic parenterally acceptable diluent or solution as a solution in 1,3-butanediol. Sterile nonvolatile oils are conventionally employed as a solvent or suspending medium. To this end, non-irritating nonvolatile oils including synthetic mono- or diglycerides, fatty acids (including oleic acid), sesame oil, coconut oil, peanut oil, cottonseed oil, naturally occurring vegetable oils, or synthetic fatty vehicles such as ethyl oleate, and the like. Can be used. Buffers, preservatives, antioxidants and the like may be incorporated as needed.
Compounds deemed to be used in the methods of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions are usually solid at temperature, but can be prepared by mixing the drug with synthetic glyceride esters of polyethylene glycol, a suitable non-stimulatory excipient such as cocoa butter that liquefies and / or dissolves in the rectum to release the drug.
Since the individual patients are present in varying degrees of symptom and each drug has its specific therapeutic characteristics, the mode and dosage of administration used for each patient is at the discretion of the physician.
In general, the dosage of the nitric oxide scavenger containing binder of the present invention used as disclosed herein is from about 0.01 mmole / kg of body weight per hour to about 0.5 mmole / kg / hr. Typical daily dosages generally range from about 10 μg to about 100 mg / kg body weight, preferably 50 μg to 10 mg / kg body weight, and may be administered up to four times a day.
According to another embodiment of the invention, amelioration of a patient suffering from a pathological condition by the administration of the pharmacologically active agent (s), comprising covalently binding dithiocarbamate to the pharmacologically active agent prior to administration to the patient. Provides a method of treatment.
Therefore, the method of the present invention for the treatment of a patient suffering from a pathological disease is effective in treating the disease, and administering to the patient an effective amount of a pharmacologically active agent, modified by covalent linkages of dithiocarbamate. Include.
The invention will be explained in more detail by the following non-limiting examples.
<Example 1>
Preparation of Ester Conjugates of Pyrrolidinol and Ibuprofen
200 ml of methylene chloride in a 500 ml reaction vessel suitable binders such as 24 g of ibuprofen (α-methyl-4- (2-methylpropyl) benzene-acetic acid), 10 g of 2-pyrrolidinol and dicyclohexylcarbodiimide g was added. The reaction was allowed to proceed at room temperature for 1 to 3 hours while heating. Ester conjugates were isolated and purified and yields were 60-70%.
<Example 2>
Conversion of ester conjugates of pyrrolidinol and ibuprofen to ester conjugates of pyrrolidinol dithiocarbamate and ibuprofen
To 100 ml of methanol in a 500 ml reaction vessel was added 10 g of the ester conjugate obtained in Example 1. Aqueous NaOH solution (6.9 g in 10 ml of water) was added dropwise at 4 ° C. The reaction was run at 4 ° C. for an additional hour. A solution mixture of carbon disulfide (5 ml) and ethanol (15 ml) was added dropwise to the reaction mixture with gentle stirring at 4 ° C. The final product was isolated and purified and the yield was about 70%.
<Example 3>
Preparation of Ester Conjugates of L-Proline and Adriamycin
To 200 ml of methylene chloride in a 500 ml reaction vessel was added 47.2 g of adriamycin, 10 g of L-proline and 0.5 g of a suitable binder such as dicyclohexylcarbodiimide. The reaction was allowed to proceed at room temperature for 1-3 hours with stirring. Ester binder was isolated and purified, yield 70%.
<Example 4>
Conversion of ester conjugates of L-proline and adriamycin to ester conjugates of L-proline dithiocarbamate and adriamycin
To 100 ml of methanol in a 500 ml reaction vessel was added 10 g of the ester binder obtained in Example 3. Aqueous NaOH solution (6.9 g in 10 ml of water) was added dropwise at 4 ° C. The reaction was run at 4 ° C. for an additional hour. A solution mixture of carbon disulfide (5 ml) and ethanol (15 ml) was added dropwise to the reaction mixture with gentle stirring at 4 ° C. The final product was isolated and purified and the yield was about 70%.
<Example 5>
Evaluation of the Effect of Combination of Pyrrolidinol Dithiocarbamate and Ibuprofen (PDI) on Acute Gastric Mucosal Injury
Wistar rats (200-250 g, male) were fasted except water overnight. Ten rats in each group were orally administered ibuprofen or PDI at a dose of 10, 20 or 50 mg / kg. Mice were killed after 5 hours, and visually visible gastric injury was measured by microscopic and histological evaluation.
<Example 6>
Evaluation of the Effect of Combination of Pyrrolidinol Dithiocarbamate and Ibuprofen (PDI) on Acute Gastric Ulcer
White New Zealand rabbits (male, about 1 kg) were injected subcutaneously with ibuprofen or PDI at a dose of 30 mg / kg for every 12 hours. Animals were killed on day 4 (after the seventh dose), and gastric ulcers of the stomach were examined and measured with calipers. Tissue samples were placed in neutral buffered formalin and histologically evaluated.
<Example 7>
Evaluation of the Anti-inflammatory Effects of the Combination of Pyrrolidinol Dithiocarbamate and Ibuprofen (PDI)
Wistar rats (200-250 g, male) were fasted except water overnight. Six rats in each group were orally administered ibuprofen or PDI at a dose of 1, 10 or 30 mg / kg. After 1 hour the rats were anesthetized and 0.1 ml (0.1% solution) of lambda carrageenan was injected into the right rear foot. The volume of the plantar was measured by hydroplethysmometry every hour for the subsequent 5 hours.
<Example 8>
Evaluation of the Effect of the Combination of Pyrrolidinol Dithiocarbamate and Ibuprofen (PDI) on Prostaglandin Synthesis
Wistar rats (200-250 g, male) were fasted except water overnight. Rats were anesthetized and their backs shaved. After the incision was made, a sponge soaked with 2 ml of 0.5% carrageenan was implanted. After 5 hours, rats (6 animals in each group) were dosed orally with ibuprofen or PDI at a dose of 30 mg / kg, or with an excipient orally in the control group. After 1 hour the mice were killed and the sponges were carefully removed. The exudate was recovered from the sponge and the prostaglandin E2 concentration in the exudate was measured by enzyme-linked immunosorbent assay.
<Example 9>
Evaluation of the Protective Effect of L-Proline Dithiocarbamate and Adriamycin (PDA) on Adriamycin-induced Cardiotoxicity
Balb / c mice (male, 20-25 g) were fed a standard diet and water was allowed freely. Mice were anesthetized and a telemetry system consisting of a buried transmitter, telemetry receiver, and similar ECG adapter was implanted into the peritoneum of each mouse. After surgery, mice were recovered for two weeks. Mice were injected intravenously with adriamycin or PDA at a dose of 4 mg / kg through the tail vein. Treated mice were observed for 2 weeks. Body weight, ECG and heart rate were recorded daily. At the end of the study, animals were killed and the heart processed for histological evaluation.
While the invention has been described in detail with certain preferred embodiments, it will be understood that modifications and variations are possible within the spirit and scope of the invention as disclosed and claimed.

权利要求:
Claims (29)
[1" claim-type="Currently amended] A compound comprising a nitric oxide scavenger covalently bound to a pharmacologically active agent.
[2" claim-type="Currently amended] The compound of claim 1, wherein said nitric oxide scavenger is dithiocarbamate.
[3" claim-type="Currently amended] The compound according to claim 1, wherein the dithiocarbamate component of the compound is represented by the following formula (I).
<Formula I>
_{[R 1 R 2 NC (S} ) -S -] x M +1, +2, +3
In the above formula,
Each of R ₁ and R ₂ is independently C ₁ -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, or
R ₁ and R ₂ together form a five, six or seven membered ring comprising N, R ₁ and R ₂ , or
R ₁ or R ₂ function as the same substituent for two dithiocarbamate structures, thereby combining the structures with one another to form bis (dithiocarbamate) species, alkylene, substituted alkylene, oxy Divalent moiety selected from the group consisting of alkylene, substituted oxyalkylene, alkenylene and substituted alkenylene, wherein R ₁ and / or R ₂ further contain a site for said covalent bond,
x is 1 or 2,
M is a monovalent cation when x is 1 or a physiologically suitable divalent or trivalent transition metal cation when x is 2.
[4" claim-type="Currently amended] The compound of claim 3, wherein each of R ₁ and R ₂ is C ₁ -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, or
R ₁ and R ₂ together form a five, six or seven membered ring comprising N, R ₁ and R ₂ ,
M is Fe ⁺² or Fe ⁺³ .
[5" claim-type="Currently amended] The compound of claim 3, wherein R ₁ is selected from C ₂ -C ₈ alkyl or substituted alkyl, wherein the substituent is selected from carboxyl, acetyl, pyridinyl, pyrrolidinyl, amino, amido, hydroxy or nitro ,
R ₂ is selected from C ₁ -C ₆ alkyl or substituted alkyl, or
And R ₂ form a 5-, 6- or 7-membered ring containing N, R ₁ and R ₂ together with R _1,
M is Fe ⁺² .
[6" claim-type="Currently amended] The compound of claim 3, wherein R ₁ is selected from C ₂ -C ₈ alkyl or substituted alkyl, wherein the substituent is selected from carboxyl, acetyl, amido or hydroxy,
R ₂ is selected from C ₁ -C ₄ alkyl or substituted alkyl, or
And R ₂ form a 5-or 6-membered ring containing N, R ₁ and R ₂ together with R _1,
M is Fe ⁺² .
[7" claim-type="Currently amended] The dithiocarbamate residue according to claim 2, wherein the dithiocarbamate residue is sarcosine dithiocarbamate, iminodiacetic acid dithiocarbamate, diethyldithiocarbamate, diisopropyldithiocarbamate, sugar- Compounds that are bound dithiocarbamates, pyrrolidine dithiocarbamates or proline dithiocarbamates.
[8" claim-type="Currently amended] 4. A compound according to claim 3, wherein R ₁ and R ₂ of said dithiocarbamate residues together form a five or six membered ring comprising N, R ₁ and R ₂ .
[9" claim-type="Currently amended] The compound of claim 8, wherein the dithiocarbamate residue is pyrrolidine dithiocarbamate or proline dithiocarbamate.
[10" claim-type="Currently amended] The compound of claim 8, wherein the dithiocarbamate component of the compound is L-proline dithiocarbamate.
[11" claim-type="Currently amended] The covalent bond according to claim 1, wherein the covalent bond is an ester bond, a disulfide bond, an amide bond, an ether bond, a thioether bond, an imide bond, a sulfate ester bond, a sulfonic acid ester bond, a phosphate ester bond, a carbonate bond, O-glycoside A compound selected from the group consisting of bonds and S-glycoside bonds.
[12" claim-type="Currently amended] The compound of claim 1, wherein the covalent bond is an ester bond.
[13" claim-type="Currently amended] The compound of claim 1, wherein the covalent bond is a disulfide bond.
[14" claim-type="Currently amended] The compound of claim 1, wherein the covalent bond is an amide bond.
[15" claim-type="Currently amended] The compound of claim 1, wherein the covalent bond is a sulfonic acid ester bond.
[16" claim-type="Currently amended] The compound of claim 1, wherein the covalent bond is a sulfuric acid ester bond.
[17" claim-type="Currently amended] The compound of claim 1, wherein the covalent bond is a phosphate ester bond.
[18" claim-type="Currently amended] The method of claim 1, wherein the pharmacologically active agent is NSAID, analgesic / antipyretic, sedative / hypnotic, antianginal, antianxiety, antidepressant, antipsychotic, antihypertensive, antiarrhythmic, antihypertensive, antihistamine / anti Antipruritic drugs, immunosuppressants, anti-metabolic cytotoxic agents, neuroprotective agents, T cell inhibitors, migraine drugs, arthritis drugs, antigout drugs, anticoagulants, thrombolytic drugs, antifibrolytic agents, blood flow drugs, antiplatelet drugs, anticonvulsants , Antibacterial, antifungal, antiviral, antimicrobial, anti-infective, bronchodilator, hormone, hypoglycemic, hypolipidemic, protein, nucleic acid, erythropoietic, anti-reflective, anti-nausea / Jinto medicine, septic shock treatment, multiple sclerosis treatment, organ transplant treatment, systemic lupus erythematosus (SLE) treatment, Alzheimer's disease treatment, antiparkinsonism, psoriasis, diabetes, stroke, carcinoma Medicaments useful for the treatment of endometriosis, medicaments for the treatment of uterine contractions, medicaments for the treatment of diuretics, medicaments for the treatment of cystic fibrosis, medicaments for the treatment of neutropenia, medicaments for the treatment of lung cancer, A compound useful for the treatment of respiratory diseases, a drug useful for the treatment of ischemia / reperfusion injury, a drug useful for the treatment of eye diseases, a drug useful for cardiovascular diseases, an anti-inflammatory drug or an antioxidant.
[19" claim-type="Currently amended] The compound of claim 1, wherein the pharmacologically active agent is a nonsteroidal anti-inflammatory drug, a hypertensive drug, an anti-neoplastic drug, an anti-allograft, neuroprotective, immunosuppressant or antioxidant.
[20" claim-type="Currently amended] The compound of claim 1, wherein the pharmacologically active agent is aspirin, ibuprofen, ketoprofen, diclofenac, adriamycin, cyclosporin, FK506, LFA-1, selectin inhibitor, tissue plasminogen activator or ruvelazole.
[21" claim-type="Currently amended] A composition comprising the compound of claim 1 in a pharmaceutically acceptable carrier.
[22" claim-type="Currently amended] The composition of claim 21, wherein the pharmaceutically acceptable carrier is selected from solids, solutions, emulsions, dispersions, micelles or liposomes.
[23" claim-type="Currently amended] The composition of claim 21 further comprising an enteric coating.
[24" claim-type="Currently amended] A method of administering a pharmacologically active agent to a patient in need thereof, the method comprising covalently binding a nitric oxide scavenger suitable for the pharmacologically active agent before administering the pharmacologically active agent to the patient. .
[25" claim-type="Currently amended] A method of treating a patient suffering from a pathological disease by administering a pharmacologically active agent, the method comprising covalently binding a nitric oxide scavenger suitable for the pharmacologically active agent before administering the pharmacologically active agent to the patient. .
[26" claim-type="Currently amended] Administering an effective amount of a modified pharmacologically active agent to a patient suffering from a pathological disease, wherein the pharmacologically active agent is effective in the treatment of the disease and is modified by covalent bonding with a suitable nitric oxide scavenger. Method of treatment of patients suffering from enemy diseases.
[27" claim-type="Currently amended] A process for preparing a protected form of a pharmacologically active agent, comprising covalently binding a suitable nitric oxide scavenger to the pharmacologically active agent.
[28" claim-type="Currently amended] A method of reducing side effects induced by administering said pharmacologically active agent to said patient comprising covalently binding a suitable nitric oxide scavenger prior to administering said pharmacologically active agent to said patient.
[29" claim-type="Currently amended] A method of enhancing the efficacy of a pharmacologically active agent comprising covalently binding a nitric oxide scavenger suitable for the pharmacologically active agent.

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同族专利:

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公开号 | 公开日

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EP1001932A1|2000-05-24|

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WO1998055453A1|1998-12-10|

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JP2002511858A|2002-04-16|

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AU7582898A|1998-12-21|

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US5916910A|1999-06-29|

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AU743205B2|2002-01-24|

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US6407135B1|2002-06-18|

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CA2292478A1|1998-12-10|

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CN1265648A|2000-09-06|

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:
1997-06-04|Priority to US08/869,158

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1997-06-04|Priority to US08/869,158

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1998-05-19|Application filed by 메디녹스, 인크.

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1998-05-19|Priority to PCT/US1998/010295

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2001-02-26|Publication of KR20010013419A

优先权:

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申请号 | 申请日 | 专利标题

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US08/869,158|1997-06-04|

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US08/869,158|US5916910A|1997-06-04|1997-06-04|Conjugates of dithiocarbamates with pharmacologically active agents and uses therefore|

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PCT/US1998/010295|WO1998055453A1|1997-06-04|1998-05-19|Conjugates of dithiocarbamates with pharmacologically active agents and uses therefor|