[go: up one dir, main page]

WO2002011725A1 - Inhibiteurs de production de cytokine inflammatoire - Google Patents

Inhibiteurs de production de cytokine inflammatoire Download PDF

Info

Publication number
WO2002011725A1
WO2002011725A1 PCT/JP2001/006814 JP0106814W WO0211725A1 WO 2002011725 A1 WO2002011725 A1 WO 2002011725A1 JP 0106814 W JP0106814 W JP 0106814W WO 0211725 A1 WO0211725 A1 WO 0211725A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyridone
nicotinic acid
production
methyl
nicotinamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2001/006814
Other languages
English (en)
Japanese (ja)
Inventor
Hisashi Oku
Ryuji Suzuki
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shionogi and Co Ltd
Original Assignee
Shionogi and Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shionogi and Co Ltd filed Critical Shionogi and Co Ltd
Priority to AU2001278699A priority Critical patent/AU2001278699A1/en
Publication of WO2002011725A1 publication Critical patent/WO2002011725A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an agent for suppressing the production of inflammatory site force-in, an agent for enhancing the production of interleukin 10, a poly-ADP-ribose-polymerase inhibitor, or an apoptotic inhibitor.
  • cytokine Inflammatory cytokines are a collective term for cytokines that have been shown to particularly cause inflammatory symptoms.
  • IFN interleukin
  • TNF tumor necrosis factor
  • IL-12 is mainly monocyte-macrophage
  • IL-18 is mainly macrophage cupper cells
  • IFN- ⁇ is an inflammatory cytokine produced mainly by T cells and NK cells. It is.
  • IFN-H, IFN- ⁇ TNF- ⁇ sIL- ⁇ , IL-1 ?, IL-5, IL-6, IL-10, and the like are known as inflammatory cytokines. Suppressing the production of these inflammatory cytokines is considered an important tool for achieving control of inflammatory conditions. For example, it has been reported that the use of compounds such as benzamide-nicotinic acid amide to suppress TNF-synthesis production can be used to treat inflammatory conditions (W097 / 32582).
  • apoptosis-inducing activity was confirmed for some of these compounds.
  • Apoptosis-inducing activity has also made it possible to control inflammatory conditions through induction of apoptosis.
  • SLE systemic lupus erythematosus
  • nicotinic acid amide can be applied to the treatment of diseases such as rheumatoid arthritis, asthma, sepsis, ulcerative colitis, psoriasis, and ischemic disorders.
  • SLE systemic lupus erythematosus
  • 3,4,2-phenylsulfonamide compounds W096 / 36595
  • N-substituted nicotinamides Japanese Unexamined Patent Publication No.
  • Fas-L Fas ligand
  • Fas-L Fas ligand
  • Fas-L Fas ligand
  • TNF-hi has been positioned as an apoptosis-inducing factor. Therefore, suppression of inflammatory cytokine production may lead to suppression of apoptosis.
  • suppression of the production of inflammatory cytokines is considered to be useful in controlling the pathology of many diseases related to inflammatory symptoms and apoptosis.
  • Apoptosis is cell death caused by activation of caspases. It is known that apoptosis is involved in many diseases, as well as in programmed cell death observed during development and homeostasis. For example, cancer can be described as a condition resulting from the breakdown of the apoptosis-inducing mechanism of abnormal cells. Conversely, a pathological increase in apoptosis leads to tissue atrophy. As the mechanisms by which apoptosis occurs become apparent, the association of apoptosis with various diseases has been suspected. It is speculated that the control and control of apoptosis will enable treatment and prevention of these diseases.
  • GVHD hepatitis symptoms and graft-versus-host disease
  • a compound capable of inhibiting the action of factors involved in apoptosis and controlling apoptosis it would be useful as a new therapeutic agent for diseases suspected of being involved in apoptosis.
  • various factors that induce apoptosis have been isolated, and their entire contents are being revealed gradually.
  • cytotoxic lymphocytes extracellularly induce apoptosis of target cells.
  • the site force acting at this time is Fas-L. If these factors can be effectively blocked, apoptotic control will be realized.
  • 5-methyl-tophenyl-2- (1H) -pyridone has a therapeutic effect on fibrosis in the lungs, arterial sclerosis and the like (Japanese Patent Publication 5-52814). From the structure shown below, this compound can also be said to be a nicotinic acid-related compound.
  • 5-Methyl-triphenyl-2- (1H) -pyridone was named generically as "pirfenidone”. A similar effect has been reported for its derivatives (Tokuheihei 8-510251).
  • Pirfenidone a compound represented by the following formula, has long been reported as a compound useful for treating inflammatory symptoms in the respiratory tract and skin (USP3974281, USP4042699 USP4052509). Since then, it has been focused on its antifibrotic effect, and is a compound under development as a drug for pulmonary fibrosis (Nicod, LP. Lancet, Vol. 354, July 24, 1999, p268-269).
  • TNF-hi tumor necrosis factor
  • TNF- ⁇ is positioned as an apoptosis inducer. It has also been suggested that the role of TNF-hi in hepatitis-induced liver tissue injury is important (Guidotti L., et a 1., Immunity, 4: 25-36, 1996, Kondo T., et al. , Nature Med., 3: 409-413, 1997, Seino K., et al., Gastroenterology, 113: 1315-1322, 1997) 0 Further, the present inventors have added to pirfenidone an inflammatory site. We found a use for inhibiting the production of force-in and as an inhibitor of apoptosis, and filed a patent application (Japanese Patent Application No. 2000-38048). However, in addition to these reports, no nicotinic acid-related compounds that can be used as inhibitors of inflammatory cytokine production or as inhibitors of apoptosis have not been reported. Disclosure of the invention
  • An object of the present invention is to provide a novel inflammatory cytokine production inhibitor, an interleukin 10 production enhancer, a poly-ADP-ribose-polymerase inhibitor, or an apoptosis inhibitor.
  • the present inventors administer a nicotinic acid-related compound to an artificially caused inflammatory condition, and analyze the effect in detail to obtain a mechanism of action of the nicotinic acid-related compound.
  • a model for artificial inflammation an acute hepatitis model of mouse liver induced by bacterial lipopolysaccharide (hereinafter abbreviated as LPS) was selected. This model is useful as a model for acute hepatitis because severe hepatic inflammation appears rapidly.
  • LPS bacterial lipopolysaccharide
  • the present inventors confirmed that the nicotinic acid-related compound has a therapeutic effect or a preventive effect on LPS-induced hepatitis. Furthermore, the present inventors have searched for the mechanism of action of a nicotinic acid-related compound having such an effect, and have studied its anti-inflammatory action, poly-ADP-ribose-polymerase inhibitory action, and anti-inflammatory action. The present inventors have found a cytokine production promoting action or an anti-apoptotic action, and completed the present invention. Furthermore, the present inventors have paid attention to the fact that all of the nicotinic acid-related compounds that have found these effects are present in vivo. Then, it was clarified that the anti-inflammatory effect can be evaluated using the activity of increasing the amount as an index, and a method for screening a compound useful as an anti-inflammatory agent was established.
  • the present invention provides the following inflammatory site force-in production inhibitor, interleukin-10 production enhancer, poly-ADP-ribose-polymerase inhibitor, or apoptosis inhibitor, and uses thereof. About.
  • a tumor necrosis factor production inhibitor comprising, as a main component, trimethyl-2-pyridone-5-carboxamide or a pharmaceutically acceptable salt thereof.
  • a tumor necrosis factor ⁇ production inhibitor comprising nicotinamide or a pharmaceutically acceptable salt thereof and tributophan or a pharmaceutically acceptable salt thereof as a main component.
  • nicotinic acid nicotinamide, 1-methyl-2-pyridone-5-carboxamide
  • An interleukin 10 production enhancer containing, as a main component, any compound selected from the group consisting of 1-methyl-2-pyridone and tributophan, or a pharmaceutically acceptable salt thereof.
  • a prophylactic or therapeutic agent for a disease caused by necrosis comprising as an active ingredient the inhibitor of poly-ADP-ribose-polymerase according to [7].
  • a method for screening a compound useful as an anti-inflammatory agent comprising the following steps. a) a step of administering a candidate compound to a test animal
  • An anti-inflammatory agent comprising, as a main component, a compound obtainable by the method according to [11].
  • the compounds utilized as active ingredients in the present invention are all known nicotinic acid Related compounds. The structures of these compounds are shown below.
  • An agent for inhibiting the production of cinnamon-leukin 12 and / or cinnamon-ferrona relates to nicotinic acid, nicotinamide, trimethyl-2-pyridone-5-carboxamide, and trimethyl-
  • the present invention relates to an interleukin 12 and / or interferona production inhibitor containing, as a main component, any compound selected from the group consisting of 2-pyridones, or a pharmaceutically acceptable salt thereof.
  • the term “pharmaceutically acceptable salt” includes hydrates thereof.
  • alkali metals lithium, sodium, potassium, etc.
  • alkaline earth metals magnesium, calcium, etc.
  • ammonium salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, hydrobromic acid, phosphorus) Acid, sulfuric acid, etc.) and organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, P-toluene) Sulfonic acid and the like).
  • These salts can be formed by a commonly used method. When forming a hydrate, any number of water molecules may be coordinated.
  • the present invention relates to a method for suppressing the production of interleukin 12 and / or insulin feron ", which comprises a step of administering an effective amount of the above compound.
  • the present invention relates to the use of 12 and / or interferona in the production of a production inhibitor.
  • TNF-spin When LPS is administered to a mammal's peritoneal cavity, first production of TNF-spin occurs. TNF- leads to the production of IL-12 and IL-18, and these two cytokines induce IFN- ⁇ production. IFN-a induces Fas and Fas-L, resulting in rapid induction of hepatocellular apoptosis in the liver and hepatic failure due to congestive necrosis with apoptosis (Tsutsui, H., et al. 1997).
  • IL-18 Accounts for Both TNF -hi-and Fas Ligand- mediated Hepatotoxic Pathways in Endotoxin- Induced Liver Injury in Mice. J.I thigh u nol. 159: 3961.) O It has been reported that it is more important than the elevation of IL-1, IL-6, IL-8, GM-CSF, etc., which are also known to be elevated in acute inflammation (Ozman, L., et al. al. 1994.Interleukin 12, interferon 7, and tumor necrosis factor are the key cyto ines of the generated Sh arzman reaction.J. Exp.Med. 180: 907, Wysocka, M. et al. 1995.Int erleukin 12 is required for interferon r production and lethality in lip opolysaccharide-induced shock in mice.Eur.J. Immunol. 25: 67) 0
  • nicotinic acid-related compounds have already been reported to suppress TNF-hi production. Further, it is also shown in Examples 1 and 7 described later that the production of TNF-hi increases by administration of the anti-niacin compound. This can be explained by the fact that endogenous niacin was competitively inhibited by the anti-niacin compound, and TNF-production was enhanced. In fact, anti-niacin compounds It has long been known that competitive inhibition of causative niacin causes symptoms similar to niacin deficiency. The present inventors have clarified that a specific nicotinic acid-related compound has an inhibitory effect not only on TNF-specific but also on IL-12 and IFN-y.
  • T- is located at the uppermost stream in the sequence of site force-in flow described here.
  • the inflammatory cytokine-suppressing effect of the nicotinic acid-related compound may appear as a result of suppressing the production of TNF-hi.
  • the action of inhibiting the production of inflammatory cytokines by nicotinic acid-related compounds is not indirect.
  • the peak of TNF-spike production by LPS administration was 1.25 hours after LPS administration, and nicotinic acid-related compounds were not detected in blood 3 hours after LPS administration.
  • Administration even after medium TNF-production has passed can protect against lethality.
  • the nicotinic acid-related compound also suppresses apoptosis even when administered 3 hours after LPS administration (Example 13).
  • the nicotinic acid-related compound has a characteristic that it can suppress acute inflammatory shock even after the release of TNF-fiber.
  • the nicotinic acid-related compound suppresses poly-ADP-ribosylation and a decrease in the amount of NAD even after 3 hours from LPS administration (Example 13).
  • These effects of nicotinic acid-related compounds are in contrast to the fact that protection, such as with anti-TNF-antibodies, fails to suppress the response of TNF-antibodies to automatically evolve after they are released into the blood in large quantities. . From the above, it is clear that these effects of nicotinic acid-related compounds are not merely manifested as a result of suppressing the effects of TNF-H.
  • T helper 1 type site potentin All of the cytokines whose production is suppressed by the inflammatory cytokine production inhibitor of the present invention are T helper 1 type site potentin. Therefore, the inflammatory cytokine inhibitory agent of the present invention is a disease caused by enhanced production of T helper 1 type cytokines, and particularly enhances the production of IL-12 and IFN- ⁇ . It is effective for the cause.
  • T helper 1 type site force in is a general term for a group of inflammatory cytokines involved in the induction of T helper 1 type immune response among inflammatory cytokines.
  • the T helper 1 type of site force-in includes a cytokine that induces the differentiation of T helper 1 cells and a cytokine that is produced by T helper 1 cells.
  • T helper 1 cells include IL-12 and the like. These site forces have been implicated in the induction of T helper 1 type immune responses (Xu, B. et al. J. Exp. Med., 188: 1485, 1998, and Takeda, K. et al. al. Immunity., 8: 383-390, 1998).
  • the site force produced by T helper-1 cells specifically includes IFN- ⁇ and the like.
  • T helper 1 / T helper 2 balance An imbalance in the T helper 1 / T helper 2 balance is thought to contribute to the development of immune disease.
  • T helper type 1 immunity When biased toward T helper type 1 immunity, cell-mediated immunity is enhanced and the immune response to cancer and infectious diseases is increased, but at the same time, self-injury is also increased, which is one of the causes of the onset of immune diseases. Therefore, the inhibitor of the production of inflammatory cytokines according to the present invention can be expected to be effective against all diseases which are said to be caused, for example, by an excessive T helper 1 type immune response.
  • organ-specific autoimmune diseases are thought to be caused by a bias toward T helper 1 type immune responses.
  • diabetes hepatic disorder, autoimmune myelitis, ulcerative colitis, graft-versus-host disease (GV HD), arthritis, thyroiditis, Hashimoto's disease, exocrine glanditis, intracellular infection (Leishmani A. Tuberculosis, mycobacterium tuberculosis, rye bacteria), delayed-type hypersensitivity, scleroderma, or Behcet's disease.
  • the inflammatory cytokine inhibitory agent of the present invention can be used for preventing or treating these diseases.
  • the etiology of the following diseases is not caused solely by TNF- ⁇ alone, and it is difficult to imagine the indication as an indication for a TNF-producing inhibitor. That is, diabetes, hepatic disorder, autoimmune myelitis, graft-versus-host disease (GVHD), arthritis, thyroiditis, Hashimoto's disease, exocrine glanditis, intracellular infection , Mycobacterium tuberculosis, Rye), delayed-type hypersensitivity, Behcet's disease, and the like can be said to be novel indications specific to the inflammatory cytokine inhibitory agent of the present invention.
  • the present invention also relates to a TNF-hi production inhibitor comprising trimethyl-2-pyridone-5-carboxamide or a pharmaceutically acceptable salt thereof as a main component.
  • the present invention relates to an agent for inhibiting the production of TNF-hi, which comprises nicotinamide or a pharmaceutically acceptable salt thereof and tributophan or a pharmaceutically acceptable salt thereof as main components.
  • the present invention relates to a method for suppressing the production of TNF-hi, comprising the step of administering an effective amount of the compound.
  • the present invention relates to the use of the above compound in the production of a TNF- production inhibitor.
  • nicotinamide is said to show a protective effect in mice administered with SEB, a superantigen.
  • This report confirms the suppression of production of IL-1, TNF-, IL-2R, IL-2, and IFN-y (Toxicology, 1996, 107/1, 69-81).
  • TNF-hi is located upstream of the inflammatory cytokine signaling pathway. Therefore, Compounds that suppress its production are important in controlling inflammatory conditions.
  • the inhibitor of TNF-hi production is useful for treating the above-mentioned diseases caused by the action of inflammatory cytokines.
  • the interleukin-12, interferona, or TNF-hi production inhibitor may be simply referred to as an inflammatory site force-in production inhibitor.
  • the present invention relates to any compound selected from the group consisting of nicotinic acid, nicotinamide, trimethyl-2-pyridone-5-carboxamide, and 1-methyl-2-pyridone, Or an inhibitor of poly-ADP-ribose-polymerase (hereinafter abbreviated as PMP) containing a pharmaceutically acceptable salt thereof as a main component.
  • PMP poly-ADP-ribose-polymerase
  • the present invention relates to a method for inhibiting PARP, comprising a step of administering an effective amount of the compound.
  • the invention further relates to the use of said compounds in the manufacture of inhibitors of PMP.
  • PARP is an enzyme that catalyzes the reaction of poly-ADP-ribosylation of proteins near the damaged DNA strand (histone, PARP itself, etc.). This enzyme activity depends on the cleaved DNA, and is activated by caspase-3 cleavage (from 116KD to 85KD) during apoptosis.
  • PMP substrates are receptor-side proteins for NAD and poly-ADP-ribosylation.
  • Another important role of this enzyme is to consume large amounts of intracellular NAD by poly-ADP-ribosylation. That is, it is considered that apoptosis and necrosis of cells and tissues are promoted by rapidly decreasing NAD and ATP of cells and tissues (Ha, HC and Snyder, SH Proc. Natl. Acad. Sci. Vol. 96, No. 24, 13978-13982, 1999).
  • PMP enzyme inhibition is expected to have therapeutic effects on arthritis, type I diabetes, diseases derived from various types of neuronal cell death (cerebral ischemia, reperfusion, Alzheimer's disease, Parkinson's disease, etc.), retrovirus infection, and the like.
  • the PARP inhibitor of the present invention It is useful as a therapeutic or prophylactic agent for diseases associated with necrosis. It is particularly effective for diseases caused by necrosis caused by rapid apoptosis. Such diseases include acute hepatitis.
  • the present invention relates to any compound selected from the group consisting of nicotinic acid, nicotinamide, trimethyl-2-pyridone-5-potassium lipoxamide, and methyl-2-pyridone, or a pharmaceutically acceptable compound thereof.
  • the present invention relates to a prophylactic or therapeutic agent for hepatitis, comprising a salt as a main component.
  • the present invention relates to a method for treating or preventing hepatitis, comprising administering an effective amount of the compound.
  • the present invention also relates to the use of the compound in the manufacture of a prophylactic or therapeutic agent for hepatitis.
  • the compounds are particularly useful for the prevention and treatment of acute hepatitis and fulminant hepatitis.
  • the present invention provides a compound selected from the group consisting of nicotinic acid, nicotinamide, trimethyl-2-pyridone-5-carboxamide, and 1-methyl-2-pyridone, or
  • the present invention relates to an inhibitor of apoptosis, containing a pharmaceutically acceptable salt thereof as a main component.
  • the present invention relates to a method for inhibiting apoptosis, comprising a step of administering an effective amount of the compound.
  • the invention further relates to the use of said compounds in the manufacture of inhibitors of apoptosis.
  • a nicotinic acid-related compound has an apoptosis inhibitory action as shown in the Examples. It should be noted that administration of nicotinic acid-related compounds after LPS has a therapeutic effect, especially in acute hepatitis symptoms induced artificially by LPS peritoneal administration. Many known anti-apoptotic active compounds cannot be expected to have a sufficient apoptosis inhibitory effect unless administered prophylactically before apoptosis occurs. That is, although effective as a prophylactic agent, its effectiveness as a therapeutic agent could not be expected. In contrast, the apoptosis inhibitor according to the present invention can inhibit apoptosis that is in progress. That is, therapeutic The effect can be expected.
  • Nicotinic acid-related compounds that have this mechanism of action against apoptosis include, for example, prophylactic agents against internal hemorrhagic necrosis of the liver (with rapid pathological apoptosis) and chronic rejection after transplantation that occur in acute hepatitis. It is suitable for post-onset administration as a therapeutic agent. Accordingly, the apoptosis inhibitor of the present invention relates to a medicament used for treating ongoing apoptosis.
  • apoptosis include glomerulonephritis, acute lung injury, interstitial pneumonia, cardiac hypertrophy, cardiomyopathy, retinal detachment, autoimmune disease, myocardial infarction ischemia, diabetes, inflammatory bowel Disease, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, psoriasis, AIDS, pancytopenia, refractory anemia, aplastic anemia, viral hepatitis, fulminant hepatitis, cirrhosis, cerebral ischemia , Cerebral infarction, Cedaren syndrome, salivary glanditis, severe myeloma, arteriosclerosis, Peyette's disease, multiple sclerosis, glaucoma, cataract, Parkinson's disease, Alzheimer's, amyotrophic lateral sclerosis, radiation injury, sepsis And so on.
  • nicotinic acid-related compounds are effective in inhibiting the production of apoptosis-related factors, IL-12, IFN- ⁇ , PP, or TNF-hi. Since all of these apoptosis-related factors are closely related to apoptosis based on the mechanism described below, nicotinic acid-related compounds are useful as inhibitors of apoptosis.
  • Apoptosis is generally referred to as clean cell death without inflammation.
  • pathological apoptosis such as hepatitis due to intraperitoneal administration of LPS
  • necrosis occurs extensively in liver tissue with rapid apoptosis.
  • Pathological findings in cases have also been observed.
  • One of the causes is thought to be the rapid decrease in NAD in the organization.
  • ADP-ribosylation by PMP proceeds rapidly in apoptotic cells and consumes large amounts of NAD. Therefore, rapid apoptosis is accompanied by massive consumption of NAD in tissues.
  • Necrosis can be explained by a decrease in ATP in tissues and a decrease in tissue turnover associated with a decrease in NAD (Ha, HC and Snyder, SH Proc. Natl. Acad. Sci. Vol. 96, No. 24, 13978-13982, 1999).
  • Nicotinic acid-related compounds are thought to suppress the consumption of NAD, which causes necrosis through inhibition of PMP activity. Therefore, it can be said that nicotinic acid-related compounds can effectively contribute to the suppression of internal hemorrhagic necrosis of the liver (with rapid pathological apoptosis) caused by acute hepatitis through PMP inhibitory action. .
  • Apoptosis is a complex system initiated by a variety of mechanisms, including physical effects. Therefore, it goes without saying that even the diseases caused by the same apoptosis have various causes. Therefore, an apoptosis inhibitor that is effective for a certain disease does not necessarily show the same effect for other apoptosis-causing diseases. In order to effectively utilize an apoptosis inhibitor for treatment or prevention, it is reasonable to clarify its action point and then select an apoptosis inhibitor having an action point at the cause of apoptosis. For these reasons, the utility of the present invention, which has found which apoptosis-related factor is affected by the inhibitory action of a nicotinic acid-related compound, is apparent.
  • Apoptosis inhibitors are caused by apoptosis containing the following diseases: It is effective for the treatment or prevention of diseases that occur. Therefore, it can be used as a therapeutic or prophylactic agent for these diseases.
  • Fulminant hepatitis Viral hepatitis C and B, Primary biliary cirrhosis, Secondary cirrhosis Glomerulonephritis, Tubular and interstitial nephritis, Focal glomerulosclerosis, Renal sclerosis, Peritoneal sclerosis, Nephrosis Syndrome, diabetic nephropathy
  • GVHD graft-versus-host disease
  • Hepatitis including fulminant, chronic, alcoholic, hepatitis C and B viral
  • toxic or metabolic liver damage include Behcet's disease, aplastic anemia, AIDS, pancytopenia, Refractory anemia, cerebral infarction, glaucoma, cataract, salivary glanditis, radioactive disorder, ultraviolet ray injury, sun dermatitis, erythema multiforme, fixed drug eruption, GVHD, TEN, flat warts, herpes simplex, lupus erythematosus, lichen group Tissue reactions, tubular injury, respiratory infections, diabetes, arteriosclerosis, cerebral ischemia, myocardial infarction, dilated and hypertrophic cardiomyopathy, alopecia areata, or drug-induced alopecia are evident in the present invention.
  • the present invention provides a compound selected from the group consisting of nicotinic acid, nicotinamide, trimethyl-2-pyridone-5-carboxamide, trimethyl-2-pyridone, and tributophan Or a pharmaceutically acceptable salt thereof as a main component.
  • the present invention also relates to a method for promoting the production of IL-10, comprising a step of administering an effective amount of the compound.
  • the present invention relates to the use of the compound in the production of an IL-10 production enhancer.
  • nicotinic acid nicotinamide, trimethyl-2-pyridone-5-carboxamide, tributofan, and methyl-2-pyridone further enhance IL-; 10 production in LPS-administered mice. It has an effect.
  • an anti-inflammatory drug In order for an anti-inflammatory drug to exert a strong anti-inflammatory effect, it must not only suppress the production of TNF-hi, which is an inflammatory cytokine, but also enhance the production of IL-10, which is an anti-inflammatory cytokine. Has been argued to be extremely effective.
  • the above-mentioned nicotinic acid-related compounds all have an anti-inflammatory drug, which has an action of promoting the production of an anti-inflammatory cytokine, IL-10, in addition to the action of producing inflammatory cytokines and the action of inhibiting PARP. It can be said that this is an ideal compound.
  • IL-10 production enhancer according to the present invention is useful for, for example, treating or preventing the following diseases.
  • TH1-dependent autoimmune disease multiple sclerosis (TH1-dependent autoimmune disease), scleroderma, insulin-dependent diabetes mellitus, inflammatory bowel disease, Crohn's disease, sepsis, septic shock, hepatitis C, severe perforated abdominal smog, deformity Arthritis, rheumatoid arthritis
  • Administer the inflammatory site production inhibitor, PMP inhibitor, apoptosis inhibitor or IL-1.0 production enhancer of the present invention to humans for the treatment or prevention of the above-mentioned diseases.
  • powders, granules, tablets, capsules, pills, liquids, etc. It can be administered orally or parenterally as injections, suppositories, transdermal absorbers, inhalants and the like. It can also be used externally as ointments and creams.
  • Pharmaceutical preparations can be made by mixing, as necessary, pharmaceutical additives such as excipients, binders, wetting agents, disintegrating agents, and lubricants with the effective amount of the compound. .
  • injections In the case of injections, they should be sterilized with a suitable carrier to produce the preparation. Dosage will also vary depending on disease state, route of administration, age or weight of patient, and will ultimately be at the discretion of a physician, but if administered orally to adults, usually 10 to 40 ⁇ ⁇ / 1 g / day Can be administered. It may be administered once or divided into several doses.
  • nicotinic acid-related compounds that have been shown to inhibit the production of inflammatory site power-in, inhibit apoptosis, or enhance the production of IL-10 are all compounds found in the living body.
  • the NAD cycle is known as a biosynthesis system for nicotinic acid-related compounds. That is, quinolinic acid obtained by synthesizing kynurenine from L-tributophan is converted to nicotinic acid mononucleotide.
  • the NAD cycle returns to nicotinic acid mononucleotide via nicotinic acid adenine nucleotide, NAD (nicotinamide adenine dinucleotide), nicotinamide and nicotinic acid.
  • NAD nicotinamide adenine dinucleotide
  • nicotinamide nicotinic acid
  • the following products are generated in the NAD cycle. These compounds are all metabolites of nicotinic acid found in urine and the like.
  • NADP NAD
  • Nicotinic acid produces trigonelline
  • Nicotinamide 1-methylnicotinamide ⁇ Generates 1-methyl-2-pyridone-5-carboxamide
  • the present inventors have clarified that a compound useful as an anti-inflammatory agent can be found in vivo by using the action of inducing the production of these nicotinic acid-related compounds as an index. did. That is, the present invention relates to a method for screening a compound useful as an anti-inflammatory agent, comprising the following steps.
  • the screening of the present invention has a metabolic pathway similar to that of humans, and in the If process for nicotinic acid-related compounds, nicotinic acid, nicotinamide, 1-methyl-2-pyridone-5-potency lipoxamide, or 1
  • Use animals that produce -methyl-2-pyridone, etc. as test animals For example, mice and rats are common experimental animals. You can also use egrets, dogs, dogs, bush, goats, goats, or sea lions. These test animals are given candidate compounds.
  • Candidate compounds can be taken orally or parenterally, based on their absorption characteristics and the like.
  • Parenteral administration includes intradermal injection and intraperitoneal administration.
  • a suspension (or aqueous solution) of a candidate compound is prepared using a 0.5% aqueous solution of methylcellulose as a carrier (vehicle), and the suspension is orally administered to animals at the same dose.
  • the dose of the candidate compound can be appropriately set, for example, in the range of generally 10 to 1000 mg, usually 50 to 500 mg per kg of body weight.
  • a control a group to which only the carrier is administered is provided.
  • the target tissue means a tissue expected to have an anti-inflammatory action by the candidate compound.
  • body fluids such as serum and urine also contain the nicotinic acid-related compound. It is important as an object to be measured.
  • Candidate compounds that effect changes in individual tissues are useful as compounds with specific anti-inflammatory activity in each tissue.
  • compounds that increase the content of nicotinic acid-related compounds in body fluids can be expected to have systemic anti-inflammatory effects.
  • the measurement interval of the nicotinic acid-related compound after administration of the candidate compound can be appropriately set. For example, if rapid effects are expected, measurements should be taken at short time intervals immediately after administration. Conversely, if you want to confirm long-term effects, you should continue to observe changes in the levels of nicotinic acid-related compounds over time.
  • Samples for which nicotinic acid-related compounds are to be measured can be stored frozen. Therefore, samples collected over time can be frozen and stored, and after the collection is completed, the measurement of the nicotinic acid-related conjugate can be performed simultaneously.
  • NAD content is determined by the method of Nisselbaum (Nisselbaum, JS., And S. Green.As imle ultramicro method for determination of pyridine nucleotide in tissues.Anal.Biochem. 27, 212-217, 1969). can do.
  • Measurement methods for other nicotinic acid-related compounds are also known (TA Tyler RR Shrago J. Liq.
  • Candidate compounds that have significantly increased nicotinic acid-related compound concentrations compared to the respective nicotinic acid-related compound concentrations in each organ of the control group of mice without drug administration have anti-inflammatory effects
  • Is selected as a compound having The selected candidate compounds are evaluated for their anti-inflammatory effect level and safety.
  • the level of the anti-inflammatory effect can be evaluated by comparing the anti-inflammatory effect in the acute inflammatory model of LPS-sensitized mice shown in the Examples.
  • the following compound groups are used as candidate compounds for the screening of the present invention.
  • compounds derived from the NAD cycle and compounds obtained by modifying a nicotinic acid-related compound by a synthetic method include many compounds capable of increasing the measured value of a nicotinic acid-related compound.
  • a compound showing the same anti-inflammatory effect as a large dose of nicotinic acid can be obtained by a small dose. If such a compound is used as an anti-inflammatory drug, it can be replaced with a large dose of a nicotinic acid-related compound. Some nicotinic acid-related compounds may cause minor side effects, such as flushing of the face and pruritus, with large doses.
  • the use of the compound of the present invention which can be obtained by screening makes it possible to avoid such side effects.
  • FIG. 1 is a graph showing the inhibitory effect of various nicotinic acid-related compounds on TNF- production in blood of mice administered with LPS in vivo. Significant differences were tested by Student's t-test. p * 0.05 *, p * 0.01 **, p * 0.005 ***.
  • FIG. 2 is a graph showing the inhibitory effect of nicotinic acid on the production of TNF-, Mr and IL-12 in blood of LPS-administered mice.
  • FIG. 3 shows the effect of nicotinic acid and its derivatives on serum TNF- ⁇ levels in LPS shock mice.
  • FIG. 4 is a graph showing the inhibitory effect of trimethyl-2-pyridone-5-carboxamide on the production of TNF-spi in blood of LPS-inoculated mice.
  • FIG. 5 is a graph showing the inhibitory effect of 1-methyl-2-pyridone-5-potorupoxamide on blood IL-12 production in LPS-inoculated mice.
  • the column labeled 1M2P5C shows the results for trimethyl-2-pyridone-5-carboxamide.
  • FIG. 6 is a graph showing the inhibitory effect of methyl-2-pyridone-5-potassium lipoxamide on the production of IFN ⁇ in blood of LPS-inoculated mice.
  • the column labeled 1M2P5C shows the results for 1-methyl-2-pyridone-5-carboxamide.
  • FIG. 7 is a graph showing the effect of 3-pyridinesulfonic acid on the production of TNF-spi in blood of LPS-inoculated mice.
  • FIG. 8 shows the effect of nicotinamide on the survival of LPS shock model mice.
  • FIG. 9 is a diagram showing the effects of nicotinamide and tritophan on survival of LPS shock model mice.
  • FIG. 10 is a graph showing the effect of post-treatment of nicotinamide on the survival of LPS shock model mice.
  • the plot labeled NM shows the results for nicotinamide.
  • FIG. 11 shows the effect of pretreatment with trimethyl-2-pyridone-5-carboxamide on the survival of LPS shock model mice.
  • the plot labeled 1M2P5C shows the results for 1-methyl-2-pyridone-5-carboxamide.
  • FIG. 12 is a diagram showing the therapeutic effect of trimethyl-2-pyridone-5-carboxamide on the survival of LPS shock model mice.
  • the plot described as 1M2P5C shows the results for trimethyl-2-pyridone-5-carboxamide.
  • FIG. 13 is a photograph showing a hematoxylin-eosin-stained image of a tissue section in which the effect of nicotinamide or 1-methyl-2-pyridone-5-carboxamide administration on the liver of an LPS shock model mouse was examined.
  • A control without LPS inoculation
  • B mouse administered with carrier only 3 hours after LPS inoculation
  • C nicotinamide administration 3 hours after LPS inoculation
  • D methyl-2-pyridone- 3 hours after LPS inoculation.
  • Administration of 5-carboxamide is administered to determine the effect of 5-carboxamide.
  • FIG. 14 is a photograph showing an ssDNA-stained image of a tissue section in which the effect of nicotinamide or methyl-2-bilidon-5-carboxamide administration on the S pancreas of an LPS shock model mouse was examined.
  • a ⁇ ! Is similar to Fig. 13.
  • Figure 15 shows the effects of nicotinamide and methyl-2-pyridone-5-carboxamide on DNA ladder formation, poly-ADP-ribosylation, and NAD levels in LPS shock model mice. It is.
  • NA indicates nicotinamide
  • MPC indicates trimethyl-2-pyridone-5-carboxamide.
  • FIG. 16 shows the effect of nicotinic acid and its derivatives on serum IL-10 levels in LPS-administered mice. It shows the action of nicotinic acid, nicotinamide, trimethyl-2-pyridone-5-carboxamide and tributofan to enhance IL-10 production.
  • FIG. 17 shows the effect of nicotinic acid and its derivatives on serum IL-10 levels in LPS-administered mice.
  • the results for trimethyl-2-pyridone, whose action was strong, are shown.
  • LPS (dO / g / g) + D-gal (250 mg / kg) was intraperitoneally administered, and after 75 minutes, the mice were sacrificed and the serum was collected. TNF-serum in serum was assayed by ELISA. As a result, it was found that nicotinic acid, nicotinamide, 1-methyl-2-pyridone, and trimethyl-2-pyridone-5-carboxamide suppressed the production of TNF-hi (FIG. 1). In mice that were orally administered pyridine-3-sulfonic acid, an anti-niacin active compound, LPS administration increased the production of TNF- spleen. This can be regarded as a pseudo niacin-deficient animal model.
  • THP-1 cells were washed twice in a medium (deficient medium) containing 10% of dialyzed FCS (Gibco BRL) in RPMI1640 (Niken) excluding both nicotinamide and tributophan, and cultured in the same medium as it was did. Comparison of the amount of TNF- production in the culture supernatant 3.5 hours after the addition of 10 g / mL LPS gave the following results. Conversely, TNF-spleen production showed significantly higher secretion when cultured in a deficient medium.
  • Defective medium (without LPS) 9 3 ⁇ 2.9 pg / mL.
  • Defective medium (with LPS) 7 2 7 ⁇ 31 pg / mL
  • nicotinamide and tributophan may have the effect of potentially suppressing cells from producing excessive TNF-spin in response to LPS stimulation.
  • nicotinic acid-related compounds control site force-in production in acute inflammation and exert an anti-inflammatory effect. It is suggested that there is a mechanism in vivo that regulates the cytokine production response in acute inflammation by nicotinic acid-related compounds.
  • nicotinic acid The inhibitory effect of nicotinic acid on the blood TF-, IFN-, and IL-12 production in LPS-shock mice in vivo was examined.
  • a carrier PBS
  • P-aggressive control P-aggressive control
  • nicotinic acid was orally administered 5 minutes before LPS inoculation.
  • LPS 50 g / kg + D-gal (250 mg / kg) was intraperitoneally administered, the mice were sacrificed 75 minutes after TNF, and 5 hours after IL-12 and INF, and serum was collected. TNF, IL-12, and IFN in serum were assayed by ELISA.
  • ELISA has the following The sales kit was used.
  • nicotinic acid was found to suppress the production of a series of inflammatory cytokines, TNF-, IL-12, and IFNa, which appear in serum during LPS shock in in vivo mice ( Figure 2 ) .
  • mice C57BL / 6, 9-week-old female
  • LPS (10 mg / kg) and D-gal (250 mg / kg) were intraperitoneally administered, and the mice were sacrificed 75 minutes later, and the serum was collected.
  • TNF-serum in serum was assayed by ELISA. Nicotinic acid, nicotine amide, and trimethyl-2-pyridone suppressed the production of TNF-hi ( Figure 3).
  • mice C57BL / 6, 9-week-old female
  • carrier 0.5% CMC
  • methyl-2-pyridone-5-carboxami was orally administered.
  • LPS 50 g / kg + D-gal (250 mg / kg) was intraperitoneally administered, and the mice were sacrificed 75 minutes later, and the serum was collected.
  • TNF- ⁇ in serum was analyzed by ELISA (R & D, Quantikine). As a result, it was found that trimethyl-2-pyridone-5-carboxamide suppressed the production of sperm expressed in serum upon LPS shock in in vivo mice (FIG. 4).
  • mice C57BL / 6, 9-week-old female
  • vehicle 0.5% CMC
  • 1-methyl-2-pyridone-5-carboxamide was orally administered.
  • LPS 50 zg / kg + D-gal (250 mg / kg) was intraperitoneally administered, and 5 hours later, the mice were sacrificed and serum was collected. IFN in serum was analyzed by ELISA. As a result, it was found that methyl-2-pyridone-5-carboxamide suppressed the production of IFNy appearing in the serum upon LPS shock in in vivo mice (FIG. 6).
  • mice C57BL / 6, 7-week-old female
  • LPS 50 ⁇ g / kg + D-gal (250 mg / kg) was intraperitoneally administered, and after 75 minutes, the mice were sacrificed and serum was collected. Serum in serum was assayed by ELISA.
  • 3-pyridinesulfonic acid enhanced the production of TNF o: expressed in serum during LPS shock in in vivo mice (FIG. 7).
  • nicotinamide (NM) after LPS inoculation on the survival of LPS shock model mice was examined.
  • Example 13 Effect of nicotinic acid-related compound administration on congestive necrosis and apoptosis in liver of mice treated with LPS
  • mice C57BL / 6 about 10-week-old female
  • healthy mice control
  • LPS-administered mice E. coli ⁇ 0 ⁇ g / g + D-galactosamine 250 mg / kg, ip (volume 200 ⁇ 1)
  • nicotinamide and methyl-2-pyridone-5-carboxamide were selected as nicotinic acid-related compounds, and nicotinamide lg / kg and 1-methyl, respectively.
  • nicotinamide lg / kg 3 hours after LPS inoculation
  • the cells were fixed with a formalin buffer (for histopathological examination), a portion was immediately frozen on dry ice, and then stored frozen at -80 ° C (for biochemical examination). Liver was cut out for histopathological examination (outside After (left lobe), tissue sections were prepared, and then hematoxylin and eosin (HE) staining and ssDNA staining were performed.
  • HE hematoxylin and eosin
  • ssDNA anti-Single Stranded DNA
  • DAK0 product code A4506 egret polyclonal antibody
  • detection was performed using the DAK0 LSAB2 kit / HRP-Universal (catalog NO.K0677). used.
  • the protocol using the primary antibody was performed in the same manner as in the following literature.
  • nicotinamide-administered group M in the table
  • eosinophils and vitreous droplets were found in only a few places, and microvesicles and porosity were also found in some places, but almost all were “normal” (control) ) And the same.
  • ssDNA staining a very small number of positive cells were observed by ssDNA staining, they were significantly suppressed compared to the Vehicle group.
  • the trimethyl-2-pyridone-5-carboxamide-administered group MPC in the table
  • liver MA ladder formation was detected by preparing genomic DNA from the moon spleen of each mouse and following the Apoptosis Ladder Detection Kit Wako of the mouse.
  • Poly-ADP-ribosylation was detected by Western blot using an Anti-poly (ADP-Ribose) polyclonal antibody (rabMt, polyclonal).
  • the NAD amount was determined by the method of Nisselbaum. (Nisselbaum, J.S., and S. Green. A simple ultramicro method for determination of pyridine nucleotides in tissues. Anal. Biochem. 27, 212-217 (1969)).
  • Figure 15 summarizes the results of the biochemical studies.
  • nicotinamide is a precursor of NAD, This may be due to the large amount of NAD biosynthesized in the liver due to the administration of NAD ( considering that the drug was administered 3 hours after LPS inoculation, the above results indicate that nicotinamide and trimethyl-2 Nicotinic acid-related compounds, such as -pyridone-5-carboxamide, have an anti-apoptotic action in addition to an anti-inflammatory action, and are presumed to have a protective action against tissue damage by their combined actions.
  • Example 14 Enhancing effects of various nicotinic acid-related compounds on IL-10 production
  • the enhancing effects of various nicotinic acid-related compounds on blood IL-10 production were examined.
  • the inhibitory effect of a nicotinic acid-related compound on the production of inflammatory cytokines associated with apoptosis associated with IL-12, IFN- ⁇ , or TNF-like activity was revealed. Also, the inhibitory effect of nicotinic acid-related compounds on PARP was clarified. Furthermore, it has been found that a nicotinic acid-related compound has an activity of enhancing the production of an anti-inflammatory cytokine, IL-10.
  • apoptosis-related factors are closely related to each other and play important roles in the apoptotic execution cascade. Therefore, by inhibiting these factors, apoptosis can be effectively inhibited.
  • Apoptosis is presumed to be responsible for various disease states Have been. For example, fulminant hepatitis is caused by hepatocyte apoptosis. Therefore, inhibitors of apoptosis-related factors are useful for treating these conditions.
  • Apoptosis is a phenomenon that occurs as a result of the collective action of complex cellular regulatory mechanisms.
  • the causes of apoptosis that cause disease are diverse. Therefore, in the future, efforts will be required to determine what is causing apoptosis and to select drugs that act directly on the cause to increase the therapeutic effect. Since the target factor is clear, it is possible to carry out an effective treatment after identifying such a target factor.
  • the apoptosis-related factor inhibitor of the present invention is not only useful as an apoptosis inhibitor, but is also expected to have new utility by clarifying its mechanism of action. That is, for example, the inflammatory site force-in (IL-12, IFN- ⁇ , and TNF-H) in the present invention is an apoptosis-related factor and also plays an important role in various inflammatory conditions. I have. Therefore, the inflammatory site force production inhibitor of the present invention can also be used for alleviating inflammatory symptoms associated with these cytokines. In addition, since PMP has an action of inducing tissue necrosis, for example, by consuming NAD, an inhibitor of PMP may be used as a necrosis inhibitor.
  • nicotinic acid-related compounds have an activity of enhancing the production of an anti-inflammatory cytokine, IL-10. This further enhances the significance of controlling inflammatory symptoms using nicotinic acid-related compounds. Therefore, these drugs include anti-inflammatory drugs, therapeutic drugs for immunological disorders, Abdominal cavity inflammation (peritonitis etc.), rheumatoid arthritis, arthritis, Crohn's disease, cancer cachexia, diabetic retinopathy, psoriasis, ischemic disease, It is also useful as a drug for prevention and treatment of Alzheimer's and the like.
  • the target factor of the inhibitor of the production of inflammatory cytokines, the promoter of the production of anti-inflammatory cytokines, or the inhibitor of apoptosis according to the present invention is clear. Therefore, it provides a more rational and effective treatment or prevention for apoptosis-related diseases.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des inhibiteurs de production de cytokine inflammatoire, des promoteurs de production d'IL-10 ou des inhibiteurs d'apoptose contenant en tant qu'ingrédient actif des composés liés à l'acide nicotinique. Ces composés liés à l'acide nicotinique comprennent notamment acide nicotinique, nicotinamide, 1-méthyle-pyridone-5-carboxamide, 1-méthyle-2-pyridone et tryptophane. Ces médicaments servent à l'inhibition de la production de cytokines inflammatoires telles qu'IL-12, IFN-η ou TNF-α. Ces médicaments peuvent également être utilisés pour favoriser la production d'IL-10, une cytokine anti-inflammatoire. L'invention concerne également l'utilisation de ces médicaments dans le traitement de l'hépatite, etc.
PCT/JP2001/006814 2000-08-08 2001-08-08 Inhibiteurs de production de cytokine inflammatoire Ceased WO2002011725A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001278699A AU2001278699A1 (en) 2000-08-08 2001-08-08 Inflammatory cytokine production inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-239749 2000-08-08
JP2000239749 2000-08-08

Publications (1)

Publication Number Publication Date
WO2002011725A1 true WO2002011725A1 (fr) 2002-02-14

Family

ID=18731237

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2001/006814 Ceased WO2002011725A1 (fr) 2000-08-08 2001-08-08 Inhibiteurs de production de cytokine inflammatoire

Country Status (2)

Country Link
AU (1) AU2001278699A1 (fr)
WO (1) WO2002011725A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007004613A1 (fr) * 2005-07-01 2007-01-11 Ajinomoto Co., Inc. Agent thérapeutique contre l'affection abdominale inflammatoire et inhibiteur de la production de tnf-α
WO2007033112A1 (fr) * 2005-09-12 2007-03-22 Celgene Corporation Methodes et compositions utilisant des composes immunomodulateurs pour le traitement des troubles associes a de faibles taux de leptine du plasma
JP2015519388A (ja) * 2012-06-15 2015-07-09 コナリス リサーチ インスティチュート アーゲー ニコチン酸および／もしくはニコチンアミドならびに／またはトリプトファンを含有する、腸内微生物叢によい影響を及ぼすための医薬組成物
US10758552B2 (en) 2013-12-13 2020-09-01 Conaris Research Institute Ag Pharmaceutical composition containing combinations of nicotinamide and 5-aminosalicylic acid for beneficially influencing the intestinal microbiota and/or treating gastrointestinal inflammation
US10888555B2 (en) 2013-12-13 2021-01-12 Conaris Research Institute Ag Pharmaceutical composition containing nicotinic acid and/or nicotinamide for beneficially influencing blood lipid levels by modifying the intestinal microbiota
WO2022047182A1 (fr) * 2020-08-28 2022-03-03 University Of Washington Schémas posologiques de précurseurs de nicotinamide adénine dinucléotide (nad) à haute dose pour la réduction de l'inflammation chez des patients humains présentant une inflammation préexistante

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997010712A1 (fr) * 1995-09-19 1997-03-27 Margolin Solomon B INHIBITION DU FACTEUR α DE NECROSE TUMORALE

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997010712A1 (fr) * 1995-09-19 1997-03-27 Margolin Solomon B INHIBITION DU FACTEUR α DE NECROSE TUMORALE

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
CAIN W.C. ET AL.: "Inhibition of tumor necrosis factor and subsequent endotoxin shock by pirfenidone", INT. J. IMMUNOPHARMACOL., vol. 20, no. 12, 1998, pages 685 - 695, XP002949717 *
FANTUZZI G., REED D.A., DINARELLO C.A.: "IL-12-induced IFN-gamma is dependent on caspase-1 processing of the IL-18 precursor", J. CLIN. INVEST., vol. 104, no. 6, 1999, pages 761 - 767, XP002949719 *
HA H.C., SNYDER S.H.: "Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion", PROC. NATL. ACAD. SCI. USA, vol. 96, no. 24, pages 13978 - 13982, XP002949720 *
KRETOWSKI A. ET AL.: "Nicotinamide inhibits enhanced in vitro production of interleukin-12 and tumour necrosis factor-alpha in peripheral whole blood of people at high risk of developing type 1 diabetes and people with newly diagnosed type 1 diabetes", DIABETES RES. CLIN. PRACT., vol. 47, no. 2, February 2000 (2000-02-01), pages 81 - 86, XP002949712 *
KROGER H. ET AL.: "Exacerbation of acetaminophen hepatotoxicity by thalidomide and protection by nicotinic acid amide", GEN. PHARMACOL., vol. 26, no. 6, 1995, pages 1243 - 1247, XP002949716 *
KROGER H. ET AL.: "The influence of nicotinamide, tryptophan and methionine upon galactosamine-induced effects in the liver", ARZNEIMITTELFORSCHUNG, vol. 31, no. 6, 1981, pages 987 - 993, XP002949715 *
LECLAIRE R.D. ET AL.: "Protective effects of niacinamide in staphylococcal enterotoxin-B-induced toxicity", TOXICOLOGY, vol. 107, no. 1, 1996, pages 69 - 81, XP002949714 *
O'BRIEN B.A. ET AL.: "Nicotinamide prevents the development of diabetes in the cyclophosphamide-induced NOD mouse model by reducing beta-cell apoptosis", J. PATHOL., vol. 191, no. 1, May 2000 (2000-05-01), pages 86 - 92, XP002949713 *
TSUJI H. ET AL.: "Alleviation of lipopolysaccharide-induced acute liver injury in propionibacterium acnes-primed IFN-gamma-deficient mice by a concomitant reduction of TNF-alpha, IL-12 and IL-18 production", J. IMMUNOL., vol. 162, no. 2, 1999, pages 1049 - 1055, XP002949718 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007004613A1 (fr) * 2005-07-01 2007-01-11 Ajinomoto Co., Inc. Agent thérapeutique contre l'affection abdominale inflammatoire et inhibiteur de la production de tnf-α
JPWO2007004613A1 (ja) * 2005-07-01 2009-01-29 味の素株式会社 炎症性腸疾患治療薬及びＴＮＦ−α産生抑制剤
EP1920770A4 (fr) * 2005-07-01 2010-09-29 Ajinomoto Kk Agent thérapeutique contre l'affection abdominale inflammatoire et inhibiteur de la production de tnf- alpha
US8168669B2 (en) 2005-07-01 2012-05-01 Ajinomoto Co., Inc. Therapeutic agent for inflammatory bowel disease and TNF-α production inhibitor
WO2007033112A1 (fr) * 2005-09-12 2007-03-22 Celgene Corporation Methodes et compositions utilisant des composes immunomodulateurs pour le traitement des troubles associes a de faibles taux de leptine du plasma
JP2019069972A (ja) * 2012-06-15 2019-05-09 コナリス リサーチ インスティチュート アーゲー ニコチン酸および／もしくはニコチンアミドならびに／またはトリプトファンを含有する、腸内微生物叢によい影響を及ぼすための医薬組成物
JP2015519388A (ja) * 2012-06-15 2015-07-09 コナリス リサーチ インスティチュート アーゲー ニコチン酸および／もしくはニコチンアミドならびに／またはトリプトファンを含有する、腸内微生物叢によい影響を及ぼすための医薬組成物
US10426765B2 (en) 2012-06-15 2019-10-01 Conaris Research Institute Ag Pharmaceutical composition containing nicotinic acid and/or nicotinamide and/or tryptophan for positively influencing the intestinal microbiota
KR20200011619A (ko) * 2012-06-15 2020-02-03 코나리스 리써치 인스티튜트 아게 니코틴산 및/또는 니코틴아미드 및/또는 트립토판을 포함하는 장내 세균총에 유익한 효능을 가진 약학 조성물
KR102211832B1 (ko) 2012-06-15 2021-02-02 코나리스 리써치 인스티튜트 아게 니코틴산 및/또는 니코틴아미드 및/또는 트립토판을 포함하는 장내 세균총에 유익한 효능을 가진 조성물
JP2022017332A (ja) * 2012-06-15 2022-01-25 コナリス リサーチ インスティチュート アーゲー ニコチン酸および／もしくはニコチンアミドならびに／またはトリプトファンを含有する、腸内微生物叢によい影響を及ぼすための医薬組成物
US10758552B2 (en) 2013-12-13 2020-09-01 Conaris Research Institute Ag Pharmaceutical composition containing combinations of nicotinamide and 5-aminosalicylic acid for beneficially influencing the intestinal microbiota and/or treating gastrointestinal inflammation
US10888555B2 (en) 2013-12-13 2021-01-12 Conaris Research Institute Ag Pharmaceutical composition containing nicotinic acid and/or nicotinamide for beneficially influencing blood lipid levels by modifying the intestinal microbiota
WO2022047182A1 (fr) * 2020-08-28 2022-03-03 University Of Washington Schémas posologiques de précurseurs de nicotinamide adénine dinucléotide (nad) à haute dose pour la réduction de l'inflammation chez des patients humains présentant une inflammation préexistante

Also Published As

Publication number Publication date
AU2001278699A1 (en) 2002-02-18

Similar Documents

Publication Publication Date Title
JP5869469B2 (ja) 鉄が病因に関与する肝臓疾患の処置
US10806735B2 (en) Use of neutrophil elastase inhibitors in liver disease
AU2012224499B2 (en) New pyridazinone and pyridone compounds
EP3536320A1 (fr) Application d'un inhibiteur de la voie hedgehog servant au traitement de maladies fibrotiques
JP6490097B2 (ja) 脂肪肝疾患の予防又は治療用組成物
EP4494701A2 (fr) Nouvelles combinaisons thérapeutiques pour le traitement de maladies pulmonaires interstitielles fibrosantes progressives
TW201815420A (zh) 使用fxr促效劑之方法
Fraser et al. Dasatinib inhibits the secretion of TNF-α following TLR stimulation in vitro and in vivo
US20250025466A1 (en) New oral pharmaceutical composition and dose regimen for the therapy of progressive fibrosing interstitial lung diseases
KR102714537B1 (ko) 신규한 글루타미닐 고리화효소 억제제 및 다양한 질환의 치료에서의 이의 용도
KR20190044666A (ko) Fxr 작용제들의 조합물
WO2002011725A1 (fr) Inhibiteurs de production de cytokine inflammatoire
WO2024221990A1 (fr) Utilisation d'un inhibiteur ciblant spécifiquement l'inflammasome nlrp3
Zeng et al. A novel gut-restricted RIPK1 inhibitor, SZ-15, ameliorates DSS-induced ulcerative colitis
JP4139453B2 (ja) 細胞接着阻害剤
WO2017089555A1 (fr) Oligonucléotides antisens il-34 et leurs procédés d'utilisation
CN113262218B (zh) 异硫氰酸酯类化合物的用途
JPWO2002011725A1 (ja) 炎症性サイトカインの産生抑制剤
JP2007055900A (ja) 炎症性疾患の治療及び予防用医薬組成物
US20100099719A1 (en) Composition and method for treating proteinuria
JP2021513548A (ja) アセトアミノフェン（ａｐａｐ）によって引き起こされる毒性を予防、低減または根絶するための方法および組成物
JPWO2001058448A1 (ja) アポトーシス阻害剤
JP2024509183A (ja) Ｓｇｌｔ－１阻害剤およびその使用
HK40113149A (en) New oral pharmaceutical composition and dose regimen for the therapy of progressive fibrosing interstitial lung diseases
HK40113149B (en) New oral pharmaceutical composition and dose regimen for the therapy of progressive fibrosing interstitial lung diseases

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase