WO1998002442A1 - Novel nitrogen monoxide synthetase inhibitors - Google Patents

Abstract

Drug compositions containing pyrido[2,3-c]furazan-1-oxide derivatives or pharmaceutically acceptable salts thereof, which show a potent inhibitory effect on nitrogen monoxide synthetases and are useful as nitrogen monoxide synthetase formation inhibitors.

Description

 Description New nitric oxide synthase inhibitor Technical field

 The present invention relates to a medicament, particularly to a nitric oxide synthase inhibitor, and more particularly to administration to a living body as an inhibitor of nitric oxide production.

 Background art

 For several decades, glycerin has been administered to humans as a vasodilator in the treatment of cardiovascular disease. Recently, it was found that such administered glycerin is converted in the body to nitric oxide, a pharmacologically active metabolite. Nitric oxide was also found to be an important component of vascular endothelium-derived relaxing factors (EDRFs) and to be enzymatically formed from arginine as a normal metabolite. . EDRFs have recently been actively studied as being involved in the regulation of blood flow and vascular resistance. In addition, it has been found that in vivo, nitric oxide is produced not only by vascular endothelium but also by macrophages and nerve cells. Nitric oxide produced by macrophage exhibits cytotoxic and cytostatic effects, and nitric oxide produced by neurons may be involved in memory as a signal transmitter. I understand.

More recently, the enzyme that forms nitric oxide from arginine is nitric oxide synthase, three different types, endothelial types, It was established that it consisted of neural type and induced type. Endothelial enzymes are constantly present in normal endothelial cells, and neural types are constantly present in neurons and the like. Nitric oxide formation by endothelial enzymes in endothelial cells is thought to play a role in normal blood pressure regulation.乂, the formation of nitric oxide by neuronal enzymes in neurons plays a role in synaptic transmission plasticity, plays a role in memory and learning, and in cerebral ischemia due to cerebrovascular disorders, etc. It may be involved in the development of the disease state. On the other hand, inducible enzymes are separated from activated macrophages, and endothelial cells or vascular smooth muscle cells can be used in various cytokins or combinations of cytokins. It became clear that it was more induced. In shocks induced by pulmonary blood or sitekines, the often life-threatening and potentially life-threatening hypotension is due to inducible enzymes. Excessive production of nitric oxide will be mainly or entirely assumed. Therefore, these inhibitors of nitric oxide synthase, when inhibiting inducible nitric oxide synthase, should be treated with septic shock (Lancet; 338: 1555 and 1555). 57, 1991), arthritis (Ann. Rheum. Dis .; 51, 1219S, 1992) and allergic rhinitis (Br) J. Pharmacol .; 116, pp. 1720, 1995), and its potential as a drug to improve diseases and symptoms, such as neuronal nitric oxide synthase. Inhibition of cerebrovascular disease (Eur. J. Pharmacol; 204, 339, 1991 and N euro sci. Lett .; 147, pp. 159, 1992 and Science; 265, 1883, 1994), no. -Kinson's disease (Proc. Natl. Acad. Sci. USA; 88, 6368, 1991), pain (Br. J. Pharmacol .; 1) 0, p. 198, p. 1991) and obesity (Eur. J. Pharmacol .; p. 23, p. 125, p. 1993). Potential as a drug to improve.

 As noted above, the physiological and pathophysiological importance of nitric oxide has led to studies of compounds that inhibit nitric oxide production in the body. The compound that has been found to have this effect is NG-methyl-L-arginine (hereinafter abbreviated as “Ν Μ Μ”. For example, Lancet; vol. 338, p. And pp.1577, 1991) and NG—Nitro-L-Arginine (abbreviated as NNA in the present specification; for example, Eur.J.Pharmacol .; Volume 204) Pp. 339, 1991 and Neurosci. Lett .; 147, 159, 1992).

E duardo Nava et al. Have reported an improvement effect of NMMA in a rat endotoxin model, a animal model of septic shock (Lancet; 33). (Vol. 8, p. 155, 1991). This effect is believed to be due to the fact that NMMA inhibits inducible nitric oxide synthase. However, it has been reported that high doses of NMMA can even worsen septic shock. The reason is said to be that high doses inhibit not only inducible nitric oxide synthase but also endothelial nitric oxide synthase. Therefore, in the case of septic shock, inhibition of endothelial nitric oxide synthase is weak, and it is considered that a selective inhibitor that strongly inhibits inducible nitric oxide synthase is desirable.

 On the other hand, J. P. Nowicki et al. Found that NNA, another nitric oxide synthase inhibitor, showed an improving effect on ischemic cerebral infarction (Eur. J. Pharmacol; 204, 339, 1991). This effect has been attributed to the fact that NNA inhibits neuronal nitric oxide synthase.

 However, the currently used nitric oxide synthase inhibitors NMMA and NNA are highly toxic, and other monoxide synthase inhibitors have been desired. Therefore, an investigation was carried out to find a nitric oxide synthase inhibitor belonging to a strain different from the conventional one in terms of chemical structure.

 In addition, the nitric oxide synthase inhibitor N

MMA and NNA were less potent than the inhibitory activity of inducible nitric oxide synthase than the inhibitory activity of endothelial nitric oxide synthase, and were not satisfactory in efficacy. Therefore, N M M A and

The power to which NNA derivatives and analogous compounds have been studied has never been found to be satisfactory. Thus, the inventors of the present invention strongly inhibited inducible nitric oxide synthase more than endothelial nitric oxide synthase, that is, inducible nitric oxide synthase. The study was conducted to find a nitric oxide synthase inhibitor that is selective for the synthase.

 Furthermore, NMMA and NNA were not yet fully satisfactory in their selectivity in inhibiting neuronal nitric oxide synthase and endothelial nitric oxide synthase. Therefore, various studies have been made on derivatives of NMMA and NNA and related compounds, but no satisfactory results have been found. Therefore, the present inventors have found that they inhibit neuronal nitric oxide synthase more strongly than endothelial nitric oxide synthase, that is, nitric oxide synthase selective for neuronal nitric oxide synthase. The study was conducted to find an enzyme inhibitor.

 Disclosure of the invention

 The present inventors have conducted intensive studies and have found that a new pyrido [2,3-c] flazan-1-oxoxide derivative or a pharmaceutically acceptable salt thereof has an inhibitory effect on nitric oxide synthase. Was found. In addition, the pyrid [2,3—c] flazan-11-year-old oxide derivative or a pharmaceutically acceptable salt thereof is more likely to be an inducible nitric oxide synthase than an endothelial nitric oxide synthase. Have a strong inhibitory effect on the Heretofore, there has been no report that a compound having pyrido [2,3-c] flazan-11-year-old oxide as a skeleton has the enzyme inhibitory activity. A new line of inhibitors has been pioneered.

 That is, the present invention

(1) 50% nitric oxide synthase inhibitory concentration (IC ₅₀ ) of 1 mM or less, having nitric oxide synthase inhibitory activity Nitrogen monoxide synthase inhibitor comprising a pyrid [2,3-c] furasan-11-year-old oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient;

 (2) — an active ingredient comprising a pyrido [2,3-c] flazan-11-oxide derivative having a nitric oxide synthase inhibitory activity and a molecular weight of 500 or less or a pharmaceutically acceptable salt thereof as an active ingredient; Nitric oxide synthase inhibitor,

 (3) General formula [1]

[1]

[Wherein, R ₁ , R ₂ , and R 3 are the same or independent substituents, and each represents a hydrogen atom, a halogen atom, a linear or branched C 1-6 Lower alkyl group (unsubstituted or halogen atom, cycloalkyl group having 3 to 8 carbon atoms, C〇R 4 group (where R ₄ is a hydrogen group, a linear or branched carbon atom) number

Represents 1 to 4 lower alkoxy groups), pyridyl group (unsubstituted or nitro group, linear or branched lower alkyl group having 1 to 4 carbon atoms, amino group) Or one or more hydrogen atoms may be substituted with), a oxypyridyl [2,3—c] phenyl group (unsubstituted, straight-chain or branched) One or more hydrogen atoms may be substituted with a chain lower alkyl group having 1 to 4 carbon atoms, 〇 R 5 group (where R ₅ is a hydrogen atom, straight chain or branched A chained lower alkyl group having 1 to 4 carbon atoms), NR 6 R 7 group (where R ₆ and R 7 are hydrogen atoms, linear or branched C ₁ to C 4 A lower alkyl group, a linear or branched lower alkoxycarbonyl group having 1 to 4 carbon atoms, and R 6 and R 7 are the same or each independently a substituent) May be substituted with one or more hydrogen atoms.}, 0 R 8 group (where R ₈ is a hydrogen atom, and straight chain A is a branched lower alkyl group having 1 to 4 carbon atoms) ) Or an NR 9 R 10 group (where R ₉ , R, are hydrogen atoms, linear or branched lower alkyl groups having 1 to 4 carbon atoms, linear or branched carbon atoms) And R ₉ , R and ϋ are the same or each independently a substituent), or R] and R ₂ or R ₂ and R _{3 are the same.} In the beginning A cycloalkane ring having 5 to 7 carbon atoms which may be unsubstituted or optionally substituted by one or more halogen atoms or lower alkyl groups, or 1 unsubstituted or substituted by halogen atoms or lower alkyl groups It can form a cycloargen ring having 5 to 7 carbon atoms which may be substituted. [2,3-c] flazan-11-oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient, a nitric oxide synthase inhibitor.

(4) Further, the present invention relates to the compound according to the above item 3, wherein R, is a hydrogen atom, a halogen atom, a linear or branched lower alkyl group having 1 to 6 carbon atoms (unsubstituted or unsubstituted). Alternatively, one or more hydrogen atoms may be substituted with a halogen atom.) Or a group R 0 (where R ₈ is a linear or branched C 1 -C 4 A lower alkyl group), R ₂ or a hydrogen atom, with C b gain down atoms, or a linear or branched having 1 to 6 carbon atoms lower alkyl group (unsubstituted or halogen atoms 1 4. The nitric oxide synthase inhibitor according to item 3, wherein the hydrogen atom may be replaced by at least two hydrogen atoms.

(5) Further, the present invention provides the compound according to the above item 3, wherein R, is a hydrogen atom, a chlorine atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a triflic group. Ruoro methylation group or main preparative key sheet group, R ₂ or a hydrogen atom, a chlorine atom, methylation Moto乂is Echiru group, R ₃ is a hydrogen atom, methylation group, Echiru group, n - propyl group, i Sopuro pill Item 3, the n-butyl group, the trifluoromethyl group, the 3-aminopropyl group or the 3- (t-butoxycarbonylaminoamino) propyl group It relates to a nitric oxide synthase inhibitor.

(6) Further, the present invention relates to a pyrido [2,3—c] furanzane 1—oxide, and a 7—black mouth pyrid [2,3—c] furansan. 1 — Oxide, 5 — Methyl pyrido [2, 3 — c] Frazan-1 1-Oxide, 6 — Methyl pyrido [2, 3-c] Frazan -1 oxide, 7-methyl pyrido [2, 3-c] Frazan 1 1 1 year old oxide, 7-ethinol pyrido [2, 3-c] Frasan 1 1- Kisid, 7 — n — Propyl pyrido [2,3-c] flazan 1-oxide, 7 — Isopropyl pyrido [2, 3 — c] flazan 1-oxide , 5,7-dimethylpyrid [2,3-c] frazan-1 1-oxide, 5—ethyl-1 7—methylpyrid [2,3—c] One 1 — Oxide, 7 — Methyl 5 — n — Propyl pyrido [2, 3 — c] Frazan 1 — Oxide, 5 — Isopropyl 1-7 — Methinole pyrido [2,3—c] phthalane 1 1-oxide, 5—n—butyl 7—methyl pyrido [2, 3—c] flazan 1 7-Methinole 5—Trifluoromethyl pyrido [2,3—c] Franz-1 1-oxide, 5, 7—Bis (tris) Fluoro-methyl) pyrido [2,3-c] Frazan 1-oxide, 6-Chlor 5, 5-Dimethyl pyrido [2, 3- c] Frazan-1 — oxide, 5, 6, 7 — Trimethyl pentyl [2, 3 — c] Frazan-1 oxide, 5, 7 — Dimethyl 6 — Etethyl pyrido [2, 3 — c] Frazan 1-oxide, 5 (3—aminopropyl) 1 7—methyl pyrido [2,3—c] flazan-11-oxide, 51-1 (3—t—butoxycarbonyl carbonyl) Propyl) 1 7-methylpyridone [2,3—c] flazan 1 1-year-old kid, 7-methylpyridinyl [2,3—c] flazan The present invention relates to a nitric oxide synthase inhibitor comprising, as an active ingredient, an oxide or a pharmaceutically acceptable salt thereof.

(7) Further, the present invention relates to 7-methylpyrid [2,3—c] frazan-111-year-old xylid, and 5,7-dimethylpyrid [2,3] -c] Pranzan 1-oxide, 5 — Etino 1 7-methyl pyrido [2, 3 — c] Pranzan 1-oxide, 5 — n — Propyl 1 7 — Methyl pyrido [2, 3 — c] Frazan 1-oxide, 5 — Isopropyl 1 7 — Methyl pyrido [2, 3 — c] Frazan-1-oxide or its pharmaceutical license The present invention relates to a nitric oxide synthase inhibitor containing a tolerable salt as an active ingredient.

 (8) The present invention relates to a derivative [1] comprising the pyrid [2,3—c] flazan-1-oxide derivative or the pharmaceutically acceptable salt thereof described in the above item 1, 2 or 3 as an active ingredient. It relates to a nitric oxide synthase inhibitor.

 (9) The present invention relates to 7-methyl pyrido [2, 3-c] furansan 1-oxid, 5, 7-dimethyl pyrido [2, 3-c] Frazan-1-oxide, 5—Ethyl 7—Methyl Bilide [2,3—c] Frazan—1—Oxide, 5—n—P Mouth pill 1 7 — methinolide pyrid [2,3 — c] flazan 1 1 — oxide, 5 — isopropyl — 7 — methyl pyrid [2, 3 — c] flazan The present invention relates to an inducible nitric oxide synthase inhibitor comprising a pharmaceutically acceptable salt thereof as an active ingredient.

 (10) The present invention relates to a pyridone [2,3-c] flazan-1-oxide derivative AMI according to the above 1, 2, or 3, wherein the pharmaceutically acceptable salt thereof is an active ingredient. It is a nitric oxide synthase inhibitor.

 (11) Further, the present invention relates to a pyrid described in the above item 2 or 3.

A selective inducible nitric oxide synthase inhibitor comprising [2,3-c] flazan-1-oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient, comprising: selectivity is IC _5. The ratio of the values (1 〇 _5. [Endothelial] / 1 _<5. [Inductive]) at 0. 5 above, selective inducible nitric oxide synthase good or to rather is 3 0 or more Related to inhibitors.

 (12) In addition, the present invention provides a septicemia containing the pyrid [2,3—c] flazan-1-oxide derivative or the pharmaceutically acceptable salt thereof described in the above item 1, 2 or 3 as an active ingredient. It relates to a drug for treating shock, a therapeutic agent for arthritis or a therapeutic agent for allergic rhinitis.

 (13) Further, the present invention provides a cerebrovascular disorder comprising, as an active ingredient, the pyrid [2,3-c] flazan-1-oxide derivative or the pharmaceutically acceptable salt thereof according to the above item 2 or 3. The present invention relates to a therapeutic agent, a therapeutic agent for Parkinson's disease, an analgesic agent or a therapeutic agent for obesity.

 (14) The present invention also relates to a medicament comprising, as an active ingredient, the pyrid [2,3-c] flazan-1-oxoxide derivative or the pharmaceutically acceptable salt thereof described in the above item 3.

(15) Further, the present invention provides the following general formula [2]

 [2]

[Wherein, RR 2 and R 3 are the same or each is an independent substituent, and are a hydrogen atom, a halogen atom, a linear or branched lower alkyl group having 1 to 6 carbon atoms (unsubstituted or halo gen atom, the number of 3-8 amino Sik □ alkyl group carbon, COR 4 group (R ₄ groups in here hydroxyl, straight-chain or branched carbon atoms 1-4 lower alkoxy group ), Pyridyl group (unsubstituted or nitro group, straight-chain or branched-chain A lower alkyl group, an amino group, which may be substituted with one or more hydrogen atoms), a 1-oxypyridyl [2,3—c] radical group (unsubstituted or A linear or branched lower alkyl group having 1 to 4 carbon atoms which may be substituted with one or more hydrogen atoms, a 0 R 5 group (where R ₅ is a hydrogen atom, a linear or A branched lower alkyl group having 1 to 4 carbon atoms; a NR 6 R 7 group (where R s and R 7 are a hydrogen atom, a linear or branched carbon number of 1 to 4); A lower alkyl group, a linear or branched lower alkoxycarbonyl group having 1 to 4 carbon atoms, and R ₆ and R 7 are the same or each is an independent substituent.) any in which one or more hydrogen atoms may be substituted> 〇 R 8 groups (R ₈ in here represents a hydrogen atom, Chokukusari乂is branched C 1-4 lower a carbon Indicating Kill group) or NR 9 R 1 0 group (R ₉ in here, R]. Is a hydrogen atom, Chokukusari乂is branched C 1-4 lower alkyl group having a carbon straight chain or branched A branched lower-chain acyl group having 1 to 4 carbon atoms, and R ₉ , R, is one or each independently a substituent), or R, R ₂ or R _{2 2} and R ₃ may be unsubstituted or a halogen atom, a cycloalkane ring having 5 to 7 carbon atoms which may be substituted with one or more lower alkyl groups having 1 to 4 carbon atoms, Alternatively, it may form a cycloalkene ring having 5 to 7 carbon atoms which may be unsubstituted or substituted by one or more halogen atoms or lower alkyl groups having 1 to 4 carbon atoms. it can. However, pyrido [2,3—c] frazan-1 1-oxide, 5—methyl pyrido [2,3—c] frazan-1 1-oxide, 6—methyl pyrid [ 2, 3 — c] frazan-1 1-year-old oxide, 7 — methyl pyrido [2,3-c] frazan-1 1-oxide, 5, 7 dimethyl pyrido [2, 3 3 — c] Frazan 1 — Oxide, 5 aminopyrido [2, 3 — c] Frazan 1 1 — Oxide, 5 — Acetyla minopyrido [2, 3 — c] Frazan Except for 1-oxod. [2,3-c] frazan-1 relates to a one-year-old oxide derivative.

 BEST MODE FOR CARRYING OUT THE INVENTION

 In the present invention, the pyrid [2,3-c] flazan-11-oxoside derivative may be unsubstituted or pyrid [1-3 having one to three substituents. 2,3-c] flazan-1 oxide derivatives, and when having two or three substituents, adjacent substituents may combine to form a ring It is. There are no particular restrictions on these substituents as long as they do not impair the inhibitory effect of nitric oxide synthase. A halogen atom, an alkyl group, a halogenoalkyl group, a cycloalkylalkyl group is not particularly limited. , Alkoxycarbonylalkyl group, aminoalkyl group, (alkoxyzolevonyl) aminoalkyl group, alkyl and nitro-substituted pyridylalkyl group, and alkyl-substituted 1-oxypyridide [2,3] — C] A radical alkyl group, an alkoxy group, an amino group, and a monoalkyl group include a dialkyl-substituted amino group and an acylamino group.

In addition, in the case where adjacent substituents are bonded to form a ring, one side is shared with the pyridin ring of pyrido [2,3—c] flazan 1-year-old oxide. May form a 5- to 7-membered ring These formed rings may be substituted with the aforementioned substituents and the like. As the alkyl group in the present invention, a lower alkyl group is preferable.

In the present invention, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom and a chlorine atom are preferred. Examples of the linear or branched lower alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an n-butyl group. Examples thereof include a pentyl group, an n-hexyl group and the like, and preferred are a methyl group, an ethyl group, an n-propyl group, an isopropyl group and an η-butyl group. Examples of the cycloalkyl group having 3 to 8 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexynole group, a cycloheptyl group, and a cycloalkyl group. And a cyclohexyl group, and is preferably a cyclohexyl group. Examples of the linear or branched lower alkoxy group having 1 to 4 carbon atoms include methoxy, ethoxy, η-propoxy, isopropoxy, η-butoxy and the like. An oxy group or the like is provided, and is preferably a methoxy group or an ethoxy group. Examples of the linear or branched lower alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an η-propyl group, an isopropyl group, and an η-butyl group. And preferably a methyl group or an ethyl group. Examples of the linear or branched lower alkoxycarbonyl group having 1 to 4 carbon atoms include a methoxycarbonyl group, an ethoxycarbonyl group and a t-butoxycarbonyl group. And preferably a t-butoxy group. is there. Examples of the linear or branched lower acyl group having 1 to 4 carbon atoms include an acetyl group, a propionyl group, an n-butylyl group, an isobutylyl group, and other alkyl carbonyl groups. And preferably an acetyl group and a propionyl group.

 As a cycloalkane ring or a cycloalkylene ring having 5 to 7 carbon atoms which may be unsubstituted or optionally substituted with one or more halogen atoms or lower alkyl groups having 1 to 4 carbon atoms, Examples include a cycloalkane ring and a cycloalkene ring which are unsubstituted or have at least one methyl, ethyl, propyl, chlorine or fluorine atom. It is preferably unsubstituted.

Preferred compounds in the present invention are the following compounds. In the compound of the above general formula [1], R 1, R 2, and R 3 are the same or independent substituents, and R is a hydrogen atom, a halogen atom, a straight chain or a branched chain. A lower alkyl group having 1 to 6 carbon atoms (which may be unsubstituted or one or more hydrogen atoms may be substituted with a halogen atom) or an OR 8 group (where _Ra is linear Represents a branched lower alkyl group having 1 to 4 carbon atoms), and R ₂ represents a hydrogen atom, a halogen atom, or a linear or branched carbon atom having 1 to 6 carbon atoms. A lower alkyl group (unsubstituted or one or more hydrogen atoms may be replaced with a halogen atom); R ₃ represents a hydrogen atom, a halogen atom, a straight-chain or branched carbon atom; Lower alkyl group of 1 to 6 [unsubstituted or halogen atom, cycloalkyl group of 3 to 8 carbon atoms, C 0 R 4 group (here) And R ₄ represents a hydroxyl group, a straight-chain or branched chain having a number of carbon atoms of 1 to 4 lower alkoxy groups. A jyl group (unsubstituted or substituted with a nitrogen group, a linear or branched lower alkyl group having 1 to 4 carbon atoms, or an amino group, in which one or more hydrogen atoms are substituted) Good), ォ -oxypyridyl [2,3—c] radical (unsubstituted or straight-chain or branched-chain lower alkyl having 1 to 4 carbon atoms) The above hydrogen atoms may be substituted), an OR 5 group (here, R ₅ represents a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms), NR 6 R 7 group (where R _e and R ₇ represent a hydrogen atom or a linear or branched lower alkoxycarbonyl group having 1 to 4 carbon atoms, and R _e and R are the same One or more hydrogen atoms may be substituted by any of the following: or R 8 is a hydrogen atom, a straight-chain or unsubstituted group. A branched chain lower alkyl group having 1 to 4 carbon atoms, or an NR 9 R 10 group (where R _s , R, and ₀ are hydrogen atoms, and a linear or branched carbon atom having 1 to 4 carbon atoms) Represents four lower alkyl groups, linear or branched lower acyl groups having 1 to 4 carbon atoms, and R ₉ , R, are the same or each independently a substituent ) Is preferable, and it is also preferable that R ₂ and R ₂ or R ₂ and R together form a cycloalkane ring or a cycloalkene ring.

 Further preferred compounds are the following compounds.

In the compound represented by the general formula [1], R 1, R 2, and R 3 are the same or different substituents, and R is a hydrogen atom, a chlorine atom, a methyl group, an ethyl group, n — propyl, isopropyl, trifluoromethyl or methoxy R ₂ represents a hydrogen atom, a chlorine atom, a methyl group or an ethyl group, and R ₃ represents a methyl group, an ethyl group, n — propyl group, isopropyl group, n — A butyl group, a trifluoromethyl group, a 3 -aminopropyl group or a 3-(t-butoxycarbonylamino) propyl group is preferred.

Specific examples of the pyrido [2,3—c] frazan-1 oxide of the present invention include, for example, pyrid [2,3—c] furazan—1— Oxide, 5 — Black mouth [2, 3 — c] Frazor 1-oxide, 7 — Black mouth [2, 3 — c] Frazer 1-oxo, 5—methyl pyrido [2,3-c] Frazan 1-oxo, 6—methyl pyrido [2,3-c ] Franzone 1 — oxide, 7 — methyl pyrido [2, 3 — c] Frazan 1 — oxide, 7 — ethynolepid [2, 3 3 — c] Frazan 1 — oxide, 7 — n — Propyl pyrido [2, 3-c] franzan 1 — oxide, 7 — Isopropyl Pyrid [2, 3 — c] Frazan 1 1 — oxide, 5 — Chlorine 7 — methyl pyrido [2, 3-c] Frazan 1-oxide, 5, 7-dimethyl pyrido [2, 3-c] Frazan ll-oxide, 5-ethyl-7-methyl pi Lido [2,3—c] frazan-1-oxide, 7—methinole-5—n—Propylpyrid [2,3—c] flazan-11 Peptide 7 — Methyl Pill 7 — Methyl Pyride [2,3-c] Frazzan 1 1 — Oxide, 5 — n — Petilur 7 — Methyl Pyr C [2, 3 — c] Frazan 1 1 — Oxide, 5 — Cyclohexyl methyl — 7 — Methyl pyrido [2, 3 — c] Frazanー 1 , 7 — Methyl 1 5 — Trifluoromethyl pyrido [2, 3 — c] Frazan 1-1-oxide, 5, 7 — Screw (Trifluoro (Methyl) pyrido [2,3—c] phrazane 1-oxydide, 5— {5- (6—amino 1—4—methyl 1—3—2 7-methylpyridone [2,3—c] flazan-1 1-oxide, 1,5—bis (7—methinolepi Lid [2,3—c] Frazan-1 1—Oxidone 5—Innole) Pentane, 6—Black mouth 1-5, 7—Dimethylpyrid [2, 3 — c] Frazan — 1-oxide, 5, 6, 7 — Trimethyl pyrido [2, 3 — c] Frazan 1-oxide, 5, 7 — Dimethyl 1 6 — Etinole pyrido [2, 3 — c] Frazan 1 1 — Oxid, 7 — Methynole 5, 6 — Cyclopentenolide [2, 3 — c] Frazan-11-oxide, 5 — Methylo 6, 7 — Cyclic Lopentenobilide [2,3—c] Frazan-1 1-oxodide, 7—Methylenolide 5, 6—Cyclohexenolide [2,3—c ] Frazan-1 1-oxide, 5 — Methyl 6, 7 — Cyclohexenopyrid [2, 3 — c] Frazan-1 1-oxide , 5 — Ethoxycarbonyl methyl 7 — Methyl pyrido [2, 3 — c] Franzone 1 — Oxide, 5 — Amino methyl 7 — Methyl pyrido [2, 3 — c] frazan-1-oxide, 5 — (t—butoxycarbonyl carbonyl) methyl 1-7 — methyl pyrido [2, 3—c] Franzine 1—oxide, 5— (3—amino 7-methyl pyrido [2, 3-c] flazan 1-oxide, 5-(3-t-butoxycarbonylamino propyl) 1 7 — Mechinore [2,3—c] frasan-1 1-oxide, 5—methoxypiride [2,3—c] frasan—1-oxo, 7— Methoxypyrid [2,3—c] Plasma 1-Oxid, 5—Metoxy 7—Methylpyrid [2,3—c] 1 — Oxide, 5 — Aminoviride [2, 3 — c] Frasan 1 1 — Oxide, 5 — Methylaminobilide [2, 3 — C] Frazan-1 1-oxide, 5 — Dimethylaminopropyl [2,3—c] Frazan-11-oxide, 5 — Acetylaminobi Lido [2,3—c] phrazin-1-oxide, 5—amino—7—methyl pyrid [2,3—c] phrazin-1—oxo Side, 5 — acetylamino 7 — Methyl pyrido [2,3-c] And the like.

Preferably, a pyrid [2, 3 — c] franz 1-oxide, 7 — a black mouth pyrid [2, 3 — c] phrazan 1 Side, 5 — methyl pyrido [2,3-c] frazan 1-1 oxy, 6-methyl pyrido [2, 3-c] frazan 1-1 Oxide, 7 — methinopyrid [2, 3 — c] phrazane 1 — Oxide, 7 — ethyl pyrid [2, 3 — c] phrazane — 1 7-n—Propyl pyrido [2, 3—c] Frazan 1-Oxide, 7—Isopropyl pyrido [2, 3—c] Frazan-1 1-oxide, 5, 7—dimethyl pyrido [2,3-c] Frazan-1 1-oxide, 5—ethyl — 7—methyl Tyrpyrid [2,3-c] Frazan-1-oxide, 7—methyl 5—n—propyl LID [2,3—c] Frazan 1—Oxide, 5—Pip 1 7—Methyl Pyr C [2,3,1c] Frazan-1 1—Oxide, 5—n—Butyl 7—Methylene pyridine [2,3, —c] Frazan-1 1 — Oxid, 7 — Methyl 5 — Trifluoromethyl pyrid [2, 3 — c] Franz 1 — Oxid, 5, 7 — Screws Fluoromethyl) pyrido [2, 3-c] phrazane 1-oxide, 6-chloro 5, 7-dimethylinolide [2, 3-1c ] Franzan-1-oxide, 5,6,7 — Trimethyl pyrido [2,3, —c] Frazan-11-oxide, 5,7— Dimethyltin 6—ethylphenol [2,3—c] Frazan 1—oxide, 5— (3—aminopropyl) 17—methylpyrid [2,3-c] Franzine 1-oxide, 5 — (3-t-butoxycarbonyl) 7-methylpyridone [2,3—c] frazan-1-oxide, 7—methoxypyridone [2,3-c] Zan 1-Oxides etc. are shown.

 More preferably, 7—methyl pyrido [2, 3—c] flazan 1—oxide, 5, 7—dimethyl, pyrido [2, 3— c] Frazan 1-oxide, 5—methyl-7—methyl butyl [2, 3—c] Frazan 1—oxide, 7—methyl—5—n—propyl Pyrid [2, 3 — c] phrazane — 1 — oxide, 5 — Isopropyl 1 — Methyl bilide [2, 3-c] phrazane 1 Year-old kid.

The pyrid [2,3-c] furan sulphate derivative used in the present invention includes, for example, pyrid [2,3—c] flasan— 3 — There are tautomers such as oxide derivatives. The compounds used in the present invention include each of the purely isolated isomers and their equilibrium mixtures.

 The nitric oxide synthase inhibitor of the present invention is used to suppress the synthesis of nitric oxide, and is used as a therapeutic agent for patients who need to inhibit nitric oxide synthesis.

 In the present invention, the pharmaceutically acceptable salt of the pyrid [2,3-c] flazan-1 oxoderivative includes, for example, hydrochloride, sulfate, nitrate, phosphate And methansulfonate, p-toluenesulfonate and the like. Preferably, they are hydrochloride and sulfate.

 Further, in the present invention, the compound represented by the general formula [2] is a novel substance, and is obtained by removing a known compound from the compound represented by the general formula [1]. That is, the compound of the formula [2] is obtained by converting the formula [1] from a pyrido [2,3—c] flazan—1—oxide, 5—methylpyrid [2,3—c] Razan-1 1-oxide, 6—methyl pyrido [2, 3—c] Frazan 1-oxo, 7—methyl pyrido [2, 3—c ] Franzan-1-oxide, 5, 7-dimethylpyridide [2,3-c] Frazan-1-oxide, 5—Aminobilide [2, 31-c] Frazan-1-oxide, 5-acetylaminopropyl [2,3-c] Frazan-11 The same as formula [1], except for the one-year-old oxide. These are useful as active ingredients of the nitric oxide synthase inhibitor as described above.

The above-mentioned known pyrid [2,3-c] flazan-1-oxo derivative (for example, J. Chem. Soc. (B); 6) (P. 36, 1970) and J. Org, Chem., Vol. 55, pp. 375-375 (p. 1991), are based on readily available raw materials. Oxidative cyclization reaction, addition reaction followed by denitrification cyclization reaction (for example, J. Am. Chem. S0c .; Vol. 75, p. Year, and pp. 78, 423, 1956, J. Chem. Soc. (C); 1874, 197.0). Can be manufactured.

 A typical method for producing the novel compound [2,3—c] furazane 11-year-old oxide derivative of the present invention is shown below. The method for synthesizing these pyrid [2,3-c] flazan-11-oxide derivatives is not limited to the following method.

 Manufacturing method A

(Here, R, R 2, and R 3 have the same meanings as described above.) The compound of the present invention represented by the general formula [2] is a 2-amino-3-dipyridine It is produced by oxidatively cyclizing a thiol derivative [3]. The 2-amino-3-dipyridine derivative [3] used here is commercially available, for example, from Aldrich Co., Ltd. It is obtained by The oxidative cyclization of the 2-amino-3 -nitropyridine derivative [3] is carried out using an oxidizing agent or the like. Examples of the oxidizing agent include, but are not limited to, sodium benzoate diacetate, sodium benzene benzoate (trifnorenoate acetate), and sodium benzene benzoate. Metal oxidizers, such as pseudosilicone oxidizers such as iron and potassium sorbents (chloroacetate), and second cerium nitrate ammonium nitrate, and lead tetraacetate Inorganic halogen-based oxidizing agents such as sodium hypochlorite and hypochlorous acid bean are used, but anodes such as positive sorbent diacetate are used. Compound-based oxidizing agents are preferred. These oxidizing agents are used in an amount of about 0.1 to 10 times the mol of the 2-amino-3-dipyridine derivative [3], and more preferably 0.5 to 10 times. Use about three times the molarity. The reaction is usually carried out in an organic solvent, in water or in a solvent-free solvent, but is preferably carried out in an organic solvent. Examples of the organic solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as methanol and ethanol; dioxane; Ethers such as hydridrofuran, halogenated hydrocarbons such as methylene chloride and black form, ketones such as acetate methyl ethyl ketone, methyl acetate, and ethyl acetate Esters such as butyl acetate, butyl acetate, methyl propionate, and propionic acid ester; and polar nonprotic solvents such as dimethyl sulfoxide and dimethylformamide. Aromatic hydrocarbons such as benzene, ketones such as acetone, and esters such as ethyl acetate are preferred. These reaction solvents can be used alone or as a mixture. The reaction temperature is There is no particular limitation, and cooling, room temperature, or heating may be used, but preferably −5 to 40 ° C. The reaction is carried out for 0.5 to 200 hours, more preferably for 1 to 100 hours.

 The compound of the present invention represented by the general formula [2] can be isolated by a conventional isolation method such as extraction, recrystallization, or chromatography. The reaction yield of this reaction varies depending on the starting material, reaction conditions, and the like, but is generally in the range of 10 to 100%. Examples of production by this method include Production Examples 1 to 9.

 Manufacturing method B

(Here, R, R2, and R3 have the same meanings as described above.) 2—Amino 3—nitropyridine derivative [3] is 2—amino pyridine Manufactured by nitrifying gin derivatives [4]. The 2—amino pyridine derivative [4] used here is commercially available from, for example, Aldrich Co., Ltd. or is easily available. 6 186 16, PCT publication W09709982, Chem. Abst .; Vol. 73, PI47OOx can be easily obtained.

The nitration reaction of 2-amino pyridine derivative [4] It is carried out with a trotting agent or the like. Examples of the nitrating agent include nitric acid, nitridium tetrafluoroporate, nitrating agent such as tetran nitrate-butylammonium, nitric acid monosulfuric acid, fuming nitric acid sulfuric acid A mixed acid such as nitric acid / monoacetic anhydride, nitric acid / trifluoroacetic acid, nitric acid / acetic acid, and potassium sulfate / sulfuric acid is used, but a mixed acid such as nitric acid / monosulfuric acid is preferred. These dithrolating agents are used in an amount of about 0.1 to 100 moles, preferably 0.5 to 100 times, based on the amount of the 2-aminobinidine derivative [4]. Use about twice the molar amount. The reaction is usually carried out in an organic solvent, water, an inorganic acid or without a solvent, but it is preferable to carry out the reaction in an inorganic acid. Sulfuric acid and the like are preferred as the inorganic acid. The reaction temperature is not particularly limited, and may be any of cooling, room temperature, and heating, but is preferably 15 to 120 ° C. The reaction is carried out for 0.5 to 100 hours, more preferably for 1 to 48 hours.

 2-Amino-3 -2-tropyridin derivative [3] produced by this method can be used for extraction, recrystallization, or conventional isolation methods such as chromatography. Thus, it is isolated. The reaction yield of this reaction varies depending on the starting material, reaction conditions, and the like, but is generally in the range of 10 to 100%. Examples of production via this method include Production Examples 2, 34, 6, and the like.

 Manufacturing method C

( こ こ で R , 、 R 2 、 R 3 は前記と同 じ意味を示す。 ） 2 — ァ ミ ノ 一 3 — ニ ト ロ ピ リ ジ ン誘導体 [ 3 ] は、 1 , 3 — ジカ ルボニル化合物 [ 5 ] と 1 , 1 ジァ ミ ノ ー 2 —二 ト ロェテ ン [ 6 ] を反応させる こ とによ つて も製造される。 こ こ で使用する 1 , 3 — ジカ ルボニル化合物 [ 5 ] は、 例 えばアル ド リ ッ チ （株） よ り市販されているか又は、 公知 の方法によ って容易に得られる。 1 ， 1 ー ジァ ミ ノ — 2 — ニ ト ロェテ ン [ 6 ] は例えば、 A r c h . P h a r m.

(Here, R, R 2, and R 3 have the same meanings as described above.) 2-Amino 13-nitropyridine derivative [3] is a 1,3-dicarbonyl compound It is also produced by reacting [5] with 1,1-diamino-2-ditrothene [6]. The 1,3-dicarbonyl compound [5] used here is commercially available, for example, from Aldrich Co., Ltd., or can be easily obtained by a known method. 1, 1-Giamino — 2 — Nitrothen [6] is, for example, Arch.

 (Weinheim); easily obtained by the method described in Vol. 324, p. 73, 1991, and the like.

The 1,1—diamino—2—nitrothene [6] is used in an amount of 0.1 to 10 times the molar amount of the 1,3—dicanibonyl compound [5], and is more preferable. Or about 0.2 to 3 moles. A catalyst can be used if necessary, and the use of a catalyst gives better results. The catalyst may be either an acid catalyst or a base catalyst, but it is preferable to use an acid catalyst. Examples of the acid catalyst include inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, and the like, acetic acid, propionic acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like. Organic acids and the like are used, but acetic acid is preferred. These acid catalysts are used in an amount of about 0.01 to 100 times, and more preferably about 0.1 to 10 times, the molar amount of the 1,3-dicalponyl compound [5]. Use. The reaction is usually carried out in an organic solvent, in water or without a solvent, but is preferably carried out in an organic solvent. Examples of the organic solvent include aromatic carbons such as benzene, toluene, and xylene. Alcohols such as hydrogen, methanol, and ethanol; ethers such as dioxane and tetrahydrofuran; and halogenated hydrocarbons such as methylene chloroform. Polar non-protonic catalysts such as dimethyl sulfoxide and dimethylformamide are used, and alcohols such as methanol and ethanol are preferred. The reaction temperature is not particularly limited, and may be any of cooling, normal temperature, and heating, but is preferably 15 to 100. The reaction takes place between 0.5 and 100 hours, more preferably between 1 and 500 hours.

 The 2-amino-3-nitropyridine derivative [3] produced by this method can be extracted, recrystallized, or used in a conventional isolation method such as chromatography. Thus, it is isolated. The reaction yield of this reaction varies depending on the starting material, reaction conditions, and the like, but is generally in the range of 1 to 100%. A production example via this method includes Production Example 8 and the like.

 Manufacturing method D

(Here, R, R2, and R3 have the same meanings as described above.) 2—Amino3—2-Tropyridin Derivative [3] Nitrogenation of the lysine derivative [7] yields a 2-chloro-3-ditropyridine derivative [8]. It is also manufactured by aminification. The 2-black pyridin derivative [7] used here is commercially available, for example, from Aldrich Co., Ltd., Or Chem. Ber.; It can be easily obtained by the method described on page 89, 1970. In addition, the 2—C—C—J—3—nitropyridine derivative [8] is commercially available from, for example, Aldrich Co., Ltd., or is known in the art. It can be easily obtained by the method described above.

 The nitration of the 2-pyropyridine derivative [7] is carried out with a dithrolating agent. Examples of the nitrifying agent include nitric acid, nitrous acid tetrafluoroborate, nitrating agent such as tetraethyl nitrate n-butylammonium, and nitric acid-sulfuric acid. Mixed acids such as fuming nitric acid-sulfuric acid, nitric acid-acetic anhydride, nitric acid-trifluoroacetic acid, nitric acid-acetic acid, potassium nitrate-sulfuric acid and the like are used, but mixed acids such as nitric acid-sulfuric acid are preferred. New These dithrolating agents are used in an amount of about 0.1 to 100-fold mol, more preferably about 0.5 to 100 times, as compared with the 2-cyclopentyl pyridine derivative [7].

Use about 100-fold molar. The reaction is usually carried out in an organic solvent, water, an inorganic acid or in the absence of a solvent, but it is preferable to carry out the reaction in an inorganic acid. Sulfuric acid and the like are preferred as the inorganic acid. The reaction temperature is not particularly limited, and may be any of cooling, room temperature, and heating, but is preferably −5 to 150 ° C. Reaction is 0.5 ~

It takes place in 100 hours, more preferably in 1 to 48 hours.

2 — Black mouth 3 — Amino of nitropyridine derivative [8] The oxidation reaction is carried out by using an aminating agent such as ammonia or sodium amide, but it is preferable to use ammonia or the like. Ammonia is a 2-chloro-3-nitropropylidine derivative

 It is used in an amount of about 0.1 to 50 times, more preferably about 0.5 to 10 times, as compared with [8]. The reaction is usually performed in an organic solvent or water. Examples of the organic solvent include alcohols such as methanol and ethanol, and ethers such as dioxane and tetrahydrofuran. Alcohols such as alcohol and ethanol are preferred. It is also preferable to do it in water. The reaction temperature is not particularly limited, and may be any of cooling, room temperature, and ripening, but is preferably −5 to 150 ° C. The reaction is carried out for 0.5 to 100 hours, more preferably for 1 to 48 hours.

 The amination of the 2—chloro-3—nitropyridine derivative [8] is carried out by an aminating agent such as ammonia or sodium amide. It is preferable to use ammonia, etc. Ammonia is a 2-black mouth 3-nitropyridine derivative

It is used in an amount of about 0.1 to 50 times, and more preferably about 0.5 to 10 times, the mole of [8]. The reaction is usually performed in an organic solvent or water. As the organic solvent, for example, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, and the like are used. Alcohols such as ethanol and ethanol are preferred. It is also preferable to do it in water. The reaction temperature is not particularly limited, and may be any of cooling, normal temperature, and heating, but is preferably —5 to 200 C is better. The reaction is carried out for 0.5 to 00 hours, more preferably for 1 to 48 hours.

 The 2-amino-3- (2-amino) pyridin derivative [3] produced by this method can be extracted, recrystallized, or chromatographed by a conventional isolation method. Thus, it is isolated. The reaction yield of this reaction varies depending on the starting material, reaction conditions, and the like, or is generally in the range of 10 to 100%. As a production example via this method, Production Example 9 and the like are given.

 When the pyrido [2,3-c] furazan-1-oxide derivative of the present invention or a pharmaceutically acceptable salt thereof is used as a nitric oxide synthase inhibitor, it may be used alone. Or injections, infusions, granules, tablets, fine granules, powders, capsules by mixing with pharmaceutically acceptable additives such as carriers, excipients, diluents, and dissolution aids. It can be safely orally or parenterally (systemically administered, topically administered, etc.) and administered to mammals in the form of preparations such as inhalants, suppositories, eye drops, patches, ointments and sprays.

 The content of the pyrido [2,3-c] furazan-1-oxide derivative or a pharmaceutically acceptable salt thereof in the preparation varies depending on the preparation, but is usually 0.1 to 0.1. It is preferably 100% by weight. The dose is determined according to the age, weight, symptoms, purpose of treatment, etc. of the patient, but the dose is generally about 0.01 to 30000 mg / kg / mouth.

In the present invention, a selective inducible nitric oxide synthase inhibitor containing a pyrido [2,3-c] furazan-1-oxide derivative or a salt thereof as an active ingredient has a selectivity of IC ₅ . Value ratio (IC _5. [Endothelial] / IC _5. [Induction]) ϋ. 5 or more to be Nodea Ri, 3 0 or more of what is good Ri favored arbitrariness.

 Example

 Next, the inhibitory action of the pyrido [2,3-c] flazan-]-oxide-derived nitric oxide synthase will be described based on the following experimental examples using the present compound. Further, Production Examples of the compound of the present invention are also shown.

 Compound of the present application

Compound Ν 0.1 pyrid [2, 3-c] Frazan 1 1 year old

Compound Ν. 2 2 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5...

Compound Ν 0.37 — black mouth pyrido [2,3 — c] flazan 1-oxide

Compound Ν ο. 4 5 — methyl pyrido [2,3 — c] flazan 1 — oxide

Compound Ν 0.56 — methyl pyrido [2,3 — c] flazan-1-oxide

6 7 — methyl pyrido [2, 3 — c] flazan-1 monooxide

7 —. 7-ethyl chloride [2, 3-c] Frazan-1-oxide

Compound Ν 0.87 — η — Propyl pyrido [2,3 — c]

Compound N 0.97 — isopropyl pyridine [2,3 — c] Franz 1 1 year old

Compound No. 105-Chloro 7 — styrene pyrido [2,3-c] flazan-1 1-oxide

Compound No. 1 15, 7 — dimethyl pyrido [2,3-c] flazan 1

Compound N 0.125-ethyl 7-methyl pyrido [2,3-c]

Compound N 0.13 7-Methyl-5-n-pipylpyr [2,3—c] Frazan-1—oxide

Compound N 0.15-Isopropyl 1 7 — Methylbili [2,3-c] Frazan 1 1-Oxide

Compound N 0.15 5-n-butyl-7-methylpyri

 [2, 3-c] Franz ann

Compound N 0.16 5-Cyclohexylmethyl 7-Methylbilide [2,3-c] Frazan-1-1-oxide

Compound N 0.17 7-methyl-5-trifluoromethyl pyrido [2,3-c] Frazan-111-oxydide

Compound N 0.185, 7 — bis (1, fluoromethyl) pyrido [2, 3 — c] flazan-111

Compound N 0.195- {5- (6-amino-4-methyl-1-3-yl-2-pyridyl-12-yl)) dimethyl} -7-methylpyri [2, 3-c] Franz ann

Compound N 0.21,1,5 —bis (71-methylbilide [2,3-c] flamsan-1oxoh "-5-yl) pentane Compound N 0. 2 1 6-black o-5, 7 1 dimethyl pyrid [2, 3—c] Frassin

Compound N 0.25, 6, 7 — Trimethyl pyrido [2, 3-c] Frazan-1 1-oxide

Compound N 0.25,7—Dimethyl — 6—Ethyl pyrido [2,3—c] Frazan 1 —Oxide

Compound No. 2 4 7 — Methyl-5, 6 — Cyclopentenopylide [2, 3 — c] Frazan-1-oxide and 5 — Methyl 6, 7 — cyclopentenoviride [2, 3 — c] flazan — 1 mixture with 1-year-old xide

Compound No. 2 5 7 — Methyl-5, 6 — Cyclohexenopyrido [2,3-c] Frazan-1-oxide and 5 — Methyl-6, 7 — cyclohexenopyridide [2, 3 — c] frazan — a mixture with 1-oxodide

Compound No. 2 6 5 — Ethoxycarbonyl methyl 7 — Methyl pyrido [2, 3 — c] flazan 1 — Oxide Compound N 0.27 5—Amino methyl 7—Methyl pyrido [2,3—c] Frasan 1 1 year old

Compound N 0.28 5 — (t—butoxycarbonylamino) methyl 7 — methyl pyrido [2,3-c] flazan 1 — oxide

Compound No. 29 5 — (3-aminopropyl) 17-methyl pyrido [2,3-c] flazan-1-year-old compound Compound N 0.3. (3—t—butoxycarbonyl aminopropyl) 1 7—methyl pyrido [2,3-c] Compound No. 3 15-methoxypyrid [2, 3-c] Frazan-1 1-oxide

Compound No.3 2 7 — methoxypyrid [2,3—c]

Compound N 0.33 5 — Methoxy 7 — Methyl pyrido [2,3-c] Frazan 11

Compound N 0.34 5 — Aminoviride [2, 3 — c] Frazan-1 1 year old

Compound N 0.35 5 — Methylaminobilide [2,3 — c]

Compound N 0.36 5 — dimethylaminopropyl [2,3-c]

Compound N 0.37 5 — acetylaminopropyl [2, 3 — c]

Compound N 0.385-Amino 7-Methyl pyrido [2,3-c] Frazan 1-Oxid

Compound N 0.39 5 — acetylamino 7 — methyl pyrido [2,3-c] flazan-1-oxide

Compound N 0.45-(3-carboxypropyl) 1-7-methylbilide [2, 3-c] Frazan-1 1-year-old compound Compound No. 15-( 3 — t — Butoxycarbonylamino 3 — Powerbox 7) Propyl 1 7 — Methyl Bilide [2, 3c] Frazan 1 1-Oxid

Compound N 0.42 5-(3-Carboxy 1 3-amino) propyl-7 1 Methyl pyrido [2,3-c] Frazan 1 1 One-sided

 Example 1

 The inhibitory activity of the compound of the present invention on inducible nitric oxide synthase was compared with that of an existing nitric oxide synthase inhibitor.

 experimental method

Inducible nitric oxide synthase was prepared by the following method. The method of Richard G. K nowles et al. (Biochem. J .; 270, 833, pp. 1900) was partially modified with the liver of an endotoxin-administered rat. I got The obtained liver was derived by a partial modification of the method of Dennis J. Stuhr et al. (Proc. Atl. Acad Sci. USA; 88, 7773, 1991). The type enzyme was purified. The enzyme solution thus obtained was used as a crude enzyme solution of inducible nitric oxide synthase, and the production amount of nitric oxide was measured. In this case, the reaction solution was ImML-arginine, iNOSl enzyme solution, 3 mMDTT, 0.3 mMNADPH, 4 ug / mIFAD, AM tetrahydrobi〇pterine, 5 g Zm laprotinin 5 g Zm lchymostatin, A μg / m 11 e e peptin 5 g / m 1 epstatin A, 0.1 m MPMSF, 20 m MT ris — H (:) (pH 7.5) compound or control compound were added. 3 7 ° C Day Nkyube tion after was measured nitric oxide produced. measurement of nitric oxide is its metabolite N 0 ₂ to Laura C. Green Biochem .; Vol. 126, pp. 131, 1982; The results, IC _5. Values (concentrations required for 50% activity inhibition) are shown. IC _5. When the value could not be calculated, it was expressed as the inhibition rate (%) at each concentration.

 Result

 Table 1 shows the results. The compound of the present invention showed strong inhibitory activity on inducible nitric oxide synthase.

 table 1

Compound of the present invention I C 50 (M)

Compound N 0.13

 Three

Compound No. 2 25% (30 ο 0 〃 M) ο Compound N 0.3

 Μ

Compound N 0.4 1 3 0

Compound N 0.50 4 0 0

Compound N 0.60 0.37

Compound N 0.73 0

Compound No. 8 2 2 0

Compound N 0.92 5 0

Compound No. 10 25%

Compound No. 1 10.8.

Compound N 0.12 1.7

Compound N 0.13 ϋ. 80 One

Compound 0.1 4 7 u

Compound

Chemical compound M willow m l r

 o. 1 b 0% 0 c 1 n u u u M)

/

Compound N 0.17 6 7 u

 4 1

Compound Ν 0. L 8 6 0

Chemical compound ΛΛ "NT 1

 Object N 0 .1 π> 1 U U u

 o

A product An N Ts.7

 0 .Δon (JLu% (όu / M

J IN 0. Δ 1 y 4

Rum fim s.1

 0 .I 6 4 b

 / Les A ΛΛιι NT Λ

 0 .D U 0 (\ U U 1V1

0. Δ 0 m U 0 U n U β M) room iWn Mo 1

 0 L 0 z n U 0 1 U n U fl M J I TsNJ

 n 0 .o 7

 i¾ Δ 0 o U 0 (

 1 u U U jl 1V1

Λ! Hn TS.1 0. Δ O U 0 (o 〃 λ / ί

 0 U π U

 Les y

Compound

 / Rehachi 4½ o

Compound N M

 0. Ό u o n

 D I U

Compound Ν 0.3 0.32 ft C 3 0 0 μ.Μ)

Compound Ν o

 0. 6 2 7 0

 o

Compound n (

 J 0 .0 0 0 o u 1 0 0 U P. Μ.)

1 L L eight

U U

UU

Compound N 0.35> 100

Compound N 0.36 20% (30 μ.Μ) Compound N 0.37 30% (300 Μ) Compound N 0.38 10% (100 U Μ) Compound 90% (30} iM) Compound No.

Compound No. 4 15% (\ ΰ ΰ 0 (ΐ Μ ') Compound No. 4 2 3 5% (100 0 i i) NMM A (positive control) 25

 Example 2.

 An experimental method in which the inhibitory activities of some of the compounds of the present application on neuronal nitric oxide synthase, endothelial nitric oxide synthase and inducible nitric oxide synthase were compared with existing nitric oxide synthase inhibitors.

Neuronal nitric oxide synthase was prepared according to the method of David S. Bredt et al. (Proc. Natl. Acad. Sci. USA; 87, 682, 1990). It was prepared by changing the parts. The cerebellum obtained from the slaughterhouse was centrifuged at 1.0 x X g after homogenizing, adding 5 volumes of 50 mM MTris-HCIm MEDTA (pH 7.4) buffer. . The obtained supernatant was centrifuged at 100,000 X g for 6 minutes, and the obtained supernatant was used as a crude enzyme solution of neuronal nitric oxide synthase. The activity of neuronal nitric oxide synthase was determined by the method of DaVid S. Bredt et al. (Proc. Natl. Acad. Sci. USA; 86, 9030, 19). 1989) with some modifications, and was determined by quantifying the amount of L- [3H] arginine converted to — [3H] citrul1ine. The reaction solution at that time, 3 2 n ML one ^[3 H] arginine neuronal nitric oxide synthase Crude enzyme solution, 0. 8 m MDTT, 1 m MC a C l 2, 0. 8 m MEDTA, 8 μ. G / m 1 calmodulin, 0. 8 NADPH, 8 MFAD, 8 0 M tetrahydrobiopterine. 2 0 m MH epes (pH 7.4) to which the compound of the present invention or a control compound was added. L one ^[3 H] was added to arginine to initiate the reaction, after 3 7 ° C Day emissions Kyube shea Yo emissions, 5 0 m MT ris - HC 1 (. H 5 5), the reaction stop solution 1 m mM EDTA in after it was stopped Les reaction, and through the the cation on-exchange resins mosquito ram (Dowex AG 50W X8, Na + fo rm), to remove the L one ^[3 H] arginine unreacted is generated product L was recovered an ^[3 H] citrul 1 ine. The recovered L-[H] citrul 1 ine was quantified by measuring the radioactivity. The results, IC _5. The value (concentration required for 50% activity inhibition) was shown.

Endothelial nitric oxide synthase is obtained by the method of Jennifer S.? 011: 1: et al. (? 1 "0. Natl. Acad. Sci. USA; P. 1991) Endothelial cells were isolated from the slaughterhouse by using a standard method from a slaughterhouse aorta. m MT ris — HC1, 0.1 mM MEDTA, 0.1 m MEGTA, 0.1% 2-Mercaptoethano 1 buffer, homogenize, 100,000 X g for 60 min After centrifugation, the obtained precipitate was washed with a buffer containing 1 MKC1, and then 20 mM MCHA Endothelial nitric oxide synthase was extracted in a buffer containing Ps. The extract was centrifuged at 100,000 xg for 30 minutes, and the obtained supernatant was used as a crude enzyme solution of endothelial nitric oxide synthase. The measurement of the activity of endothelial nitric oxide synthase and the evaluation of the results were performed in the same manner as in the case of neuronal nitric oxide synthase.

 ロ

Table 2 shows the results. Results were shown in IC ₅ 0 values (concentration required to 50% activity inhibition), IC _5. If the value cannot be calculated, the inhibition rate at each concentration ()

 The compound of the present invention showed a strong inducible and neuronal nitric oxide synthase inhibitory action. Furthermore, a selective inducible nitric oxide synthase inhibitory effect was also observed.

 Table 2

C _5. M) Compound of the present application Neural type endothelial type inducing compound N 0.13 9 15 0 9 3

Compound N 0.32 0 1 2 1 7

Compound N 0.43 4 0 3 6 0 1 3 0

Compound N 0.5 1 1 0 3 2 0 4 0 0

Compound N 0.6 1.1.7 8 0

Compound N 0.74 3 0 3 8 0 3 0

Compound N 0.81 0 0 0 6 6 0 2 2 0 Compound No. 9 6 6 3 9 2 5 0

Compound No. 1 1 2 1 3 5% (1 mM) 0 8 4 Compound No. 1 2 2 3 1 6 0 1

Compound No. 13 0 6 0 0 0 8 0 Compound No. 14-25% (1 mM) 70 Compound No. 2 9 4 .3 3 0 0 1 0 0

Compound No. 3 2 4 5% (1 mM) 1 0 0 7 6

N MM A (positive control) 0.491 225 The production method of the pyrido [2,3—c] prazane-1-oxide derivative of the present invention will be specifically described below with reference to production examples. However, the present invention is not limited to these production examples. Production Example 1

 Preparation of 7-ethylpyrido [2,3-c] flazan-1-oxide (Compound N 0.7)

 2—Amino 4—Easily obtained from picolin 2—Amino 4—Ethyru 3—Ditropyridine 33 Dissolve 43.4 mg in 10 ml of benzene. Then, add 0.99 mg of podosorbenzene diacetate and react at room temperature for 44 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography, and 7-ethylpropyl [2,3—c] flazan was purified. To obtain 328 mg.

 1 H-N M R (200 MHz, CDC ") δ

1.33 (t, 3rd), 3.02 (q, 2nd), 6.93 (br, lH), 8.65 (br, lH) FA Β-ΜS (m / ζ): 16 6 [Μ + Η] + The following compound can also be produced by the same method as above.

 7 — η — Propyl pyrido [2,3-c] flazan-1 oxide (compound of the present invention Ν 0.8)

 1 Η-NMR (200 MHz, CDC1) δ:

 1.04 (t, 3rd), 1.63-183 (m, 2nd) 2.94 (t, 2nd), 6.92 (br1st), 8.64 (br, 1 H)

FAB-MS (m / z): 180 [M + H] ⁺ , 359 [2M + H] ⁺

 7 — Isopropyl propyl [2, 3-c] flazan-11-oxide (Compound No. 9 of the present application)

1 H - NMR (2 0 0 MH z, CDC 1 3) δ:

 1.34 (d, 6H), 3.45-3.65 (m, 1H) 6.97 (d, lH), 8.66 (d, lH)

 F A B — M S (mZ z): 180 [M + H] +, 359 [2 + H] +

 Production Example 2

 5—Ethyru 7—Methyl pyrido [2,3-c] Frazan Production of 11-year-old xide (Compound No. 12)

(1) 6-Amino 2, 4—Easily obtained from lutidine 2—Amino 1-6—ethyl-41-methylpyridin Dissolve in 2.5 ml of sulfuric acid, add 0.158 ml of concentrated nitric acid dropwise, and stir at the same temperature for 1 hour. In addition, react for 1 hour at room temperature and 1 hour at 60 ° C. Drop the reaction solution into ice water Then, a 40% aqueous sodium hydroxide solution 1 (J ml was added to neutralize (pH> 9)), the crude product was extracted with methylene chloride, and the organic layer was washed with saturated saline. After drying over anhydrous magnesium sulfate, the inorganic substance was filtered, concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography chromatography. Amino 6 —ethyl 4 —methyl 3 —nitropyridine 2 12 mg.

^{1 H - NMR (2 0 0} MH z, CDC 1 3) δ:

 1.25 (t, 3H), 2.54 (s, 3H), 2.62 (q, 2H), 6.34 (br, 2H), 6.44 (d , 1 H)

FAB-MS (m / z): 18 2 [M + H] ⁺

 (2) 2—Amino 6—Ethyl-4—Methyl-3—Nitro-mouth Pyridin 108 mg was dissolved in benzene 5 ml, and sodium orthobenzene diacetate 2 1 3 Add mg and react at room temperature for 40 hours. The reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel chromatography, and purified by 5-ethylethyl 7-methylpyridine [2,3-c ] To obtain 100 mg of flazan-1 oxide.

Ή - NMR (. 2 0 0 MH z CDC 1 3) δ:

 1.36 (t, 3rd), 2.60 (s, 3rd), 2.87 (q, 2nd), 6.81 (d, lH)

FAB-MS (m / z): 180 [Μ + Η] +, 359 [2Μ + Η] ⁺

The following compounds can also be produced by the same method as described above. 2 — Amino 6 — n — Propyl 1-4-methyl 3-Nit

^{1 H - NMR (2 0 0} MH z, CDC 1 3) δ:

0.97 (t, 3H), 1.6 1-1.80 (m, 2H), 2.54 (s, 3H), 2.56 (dd, 2H), 6 36 (br, 2 H), 6.4 3 (s, 1 H)

FAB-MS (m / z): 19 6 [M + H] ⁺ , 39 1 C 2 M + H] ⁺

 7 — Methyl 1 5 — n — Propyl pyrido [2, 3 — c] lazan 11-oxoside (Compound N 0.13)

1 H - NMR (2 0 0 MH z, CDC 1 3) δ:

 1.02 (t, 3H), 1.73-1.92 (m, 2H), 2.60 (s, 3H), 2.82 (t, 2H), 6 . 8 1 (s, 1 H)

ESI — MS (m / z): 1 94 [M + H] ⁺

 2 — Amino 6 — Isopropyl 1-4 — Methyl 3 — Nito

^{1 H - NMR (2 ϋ Ο} Μ Η ζ, CDC 1 3) δ:

 1.23 (d, 6H), 2.55 (s, 3H), 2.73-2.94 (m, 1H), 6.33 (br, 2H), 6 . 4 4 (s, 1 H)

 F A B-M S (m / z: 19 6 [M + H] +

 5 — ISOPROPYL-1 7 — METHINOLEPYRID [2,3—c] Frazan — 1 — oxide (Compound No. 14)

1 H - NR (2 0 0 MH z, CDC 1 3) δ: 1.3.4 (d, 6H), 2.60 (s, 3H), 3.02-3.19 (m, 1H), 6.8.4 (s, 1H)

ESI-MS (mZz): 19 4 [M + H] ⁺

 2 1 Amino 6 1 n-Butyl_ 4 -Methyl-3 -2

¹ H-NMR (200 MHz, CDC) ₃ ) ：:

0.94 (t, 3H), 1.28-1.47 (in, 2H) 1.57-73 (m, 2H), 2.54 (s, 3H) ) 2.58 (t, 2 H), 6.36 (br, 2 H), 6.42 (s, 1 H)

FAB-MS (mZz): 210 [M + H] ⁺

 5 1 n 1 butyl — 7 — methyl pyrido [2, 3 — c] flazan-1 oxyside (Compound No, 15)

'H one NR (2 0 0 MH z, CDC 1 3) δ:

0.96 (t, 3rd), 1.26-1.52 (m, 2nd) 1.69-1.85 (m, 2nd), 2.60 (s, 3rd) Η)

2.8 3 (t, 2 Η), 6.8 1 (s, 1 Η)

FAB-MS (m Ζ ζ): 208 [Μ + Η] ⁺ , 4 1 5

[2 M + H] ⁺

 2 1 Amino 6 — Cyclohexinol methyl 1 4-Methyl 1

3 — Two propylene

'H one NMR (2 0 0 MH z, CDC 1 3) δ:

0.88-1.34 (m, 5H), 1.60-1.84 (m, 6H), 2.45 (d, 2H), 2.54 (s, 3H), 6.35 (br, 2H), 6.39 (s, 1H) FAB-MS (m / z): 250 [M + H] ⁺ , 49 9

[2 M + H] +

 5 1-Mouth hexinolemethyl 1-methyl benzoyl [2,3-c] flazan 111-year-old xydide (Compound N 0.16)

¹ H-NMR (2 OOMH z. CDC ls) δ:

0.95-1.37 (m, 5 layers), 1.60-2.00

(m, 6H), 2.60 (s, 3rd), 2.71 (d, 2H), 6.79 (s, 1H)

F A B-M S (m / z): 2 48 [M + H] +, 49 5

[2 M + H] +

 2-Amino — 6 1 {5- (6—Amino 4 — Methyl 3 port pyridyl 1 2 — Dinole) Pentyl} 14 4-Methyl 1

3-Two-way mouth pyridine

'H NR (200 MHz, CDC l ₃ ) δ

 9 (m, 2H) for 1.32-, 1.62-1.82

(m, 4H), 2.26 (s, 3H) .2.54 (s, 3H), 2.54-2.69 (, 4H), 4.7] (br , 2H), 6.18 (s, 1H), 6.34 (br, 1H) 6.42 (s, 1H)

 5 1 {5-(6 — Amino 4 — Methyl 1 3 — Nitro pyridine 2-yl) pentyl} — 7 — Methyl pyrido [2, 3-c] flazan-1 1-oxide (Compound N 0.19)

¹ H one NR (2 0 0 MH z, CDC l 3) δ:

 1.3 7-1.5 4 (m, 2H), 1.6 7-1.90

(m, 4H), 2.27 (s, 3H), 2.54-2.7 2 (m, 5H), 2.83 (t, 2H), 4.73 (br

2H), 6.28 (s, 1H), 6.77-7.05 (m1H)

FAB - MS (m / z) : 3 7 3 [M + H] +, 7 4 5 [2 M + H] +, 3 5 7 [M + H - 0] +

 1, 5 — screw (61 amino 4 — methyl 1 5 — 2 tropidine 1 2 — yl)

1 H-NMR (200 MHz, CDCl ₃ ) δ: 32-1.8 (m, 2H), 1.62-1.7.9 (m, 4H), 2.5 1-2.65 (m, 10H), 6.

3 2 (br, 4H), 6.4 1 (s, 2H)

FAB-MS (m / z): 375 [M + H] ⁺

 1, 5-bis (71-methyl pyrido [2, 3-c] flazan-1-oxy-5-yl) pentane (Compound No. 20 of the present application)

'H - NR (2 0 0 MH z, CDC l 3) δ:

 1.39-1.62 (m, 2H), 1.77-1.97 (m, 4H), 2.59 (s, 6H). 2.85 (t, 4 H), 6.75-7.08 (m, 2H)

FAB-S (m / z): 37 1 [M + H] ⁺ , 74 1 [2M + H] +, 35 3 [M + H-H 20] ⁺

 Production Example 3

7—Cross-mouth pyrido [2,3—c] flazan-1 1-oxide (compound N 0.3) and 7—Methoxypropyl [2,3—c] flaza 1-year-old oxide (compound of the present application Ν 0.32 Manufacturing of

 (1) Dissolve 4.85 g of 2-amino-4-pyridin hydrochloride, which is easily obtained from picolinic acid, in 30 ml of concentrated sulfuric acid under ice-cooling. 1,87 ml of concentrated nitric acid is added dropwise and stirred at the same temperature for 2 hours. In addition, react for 2 hours at room temperature and 1 hour at 60 ° C. The reaction solution is added dropwise to ice water, 100 ml of a 40% aqueous sodium hydroxide solution is added to neutralize (pH> 9), and the precipitated crystals are collected by filtration. The obtained crude product was purified by silica gel chromatography chromatography, and 2-amino-4,1-, 3-, 3-, 2-, and 2-pyrimidine 0.99 Get g.

^{1 H - NMR (2 0 0} MH z, CDC 1 3) δ:

 6.01 (br, 2H), 6.81 (d, 1H), 8.09 (d, 1H)

 E S 1-S (m / z): 17 2, 1 7 4 [-H]-(2) 2 —Amino 4-41 chloro 3 —Nitropyridine 3

Dissolve 47 mg in 10 ml of benzene, add 70 mg of pseudosobenzen diacetate, and react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography, and 7-chloropyridone [2,3—c] flazan-1 1 — Obtain the oxide 3 4 2 mg ο

^{1 H - NMR (2 0 0} MH z, CDC 1 3) δ:

 7.35 (br, 1H), 8.55 (br, 1H)

FAB-MS (m / z): 17 2, 17 4 [M + H] ⁺ (3) 2 — Amino 4 — Chlor 3 — 2-Tropyridin 8 Dissolve 68 mg in 15 ml of methanol, add 1 N-Natrium methoxide / methanol to 10 ml, and react for 4 hours while heating under reflux. Let it. The reaction mixture was quenched by adding 1N-hydrochloric acid, concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography to obtain 2-amino. 1 4 1 1 1 2 3 2 N 2 mouth mouth Obtain 0.22 mg of pyridine.

1 H - NMR (2 0 0 MH z, CDC l 3) δ:

 3.96 (s, 3H), 6.16 (br, 2H), 6.3

4 (d, 1H), 8.08 (d, 1H)

FAB-MS (m / z): 170 [M + H] ⁺

 (4) 2-Amino-4—Methoxy 3—Ditropyridin 338 mg was dissolved in benzene 10 ml, and the anode was dissolved. Add 70 mg of acetate and react at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography, and 7-methoxypyridine [2,3-c] Razan-1 1-year-old cyside 32 9 mg was obtained.

 1 H-N M R (200 MHz, CDC 1) δ:

4.11 (s, 3H) .6.40 (br, 1H), 8.58 (br, 1H)

FAB-MS (m / z): 16 8 [M + H] ⁺

 Production Example 4

5- (t-butoxycarbonylamino) methyl —7—methylpyrid [2,31c] flazan-1 1-year-old compound (Compound N 0.28) And 5—Amino methyl 7—Methyl ruby Production of Lido [2,3-c] flazan-1-oxide (Compound No. 27)

 (1) Under argon atmosphere, 6—Amino 2,4—Easily obtained from lutidine 2— (2,5—Dimethylpyrroyl—1—yl) _4—6— Dimethyl pyridine (24.g) was added to a solution of anhydrous ether (250 ml) at room temperature, and n-butyllithium hexane solution (1.58 M) 75.9 m 1 And stirred at the same temperature for 1 hour. Further, the reaction solution is cooled to -78 ° C, a dry ice is added, and the temperature is gradually raised to room temperature. The reaction is stopped by adding 2N-hydrochloric acid to the reaction solution, the crude product is extracted with ethyl acetate, and the organic layer is dried over anhydrous sodium sulfate. After filtering the inorganic substances, the mixture is concentrated under reduced pressure, and the obtained crude product is crystallized from hexane, and 6-carboxymethyl-2- (2,5-dimethylpyrroyl-11-yl) 2) Obtain 13.3 g of 1-methylpyridin.

^{1 H - NMR (2 0 0} MH z, CDC 1 3) o:

2.11 (s, 6H), 2.46 (s, 3H), 3.90 (s, 2H), 5.91 (s, 2H), 7.01 (s) , 1 H), 7 1 0 (s, 1 H), 9 1 0 (br, 1 H) FAB - MS (m / z):.. 2 4 4 M +, 2 4 5 [M + H] + (2) 6-carboxymethyl 2-(2,5-dimethylpyro 1-1-yl) 1-4-methylpyridine 19.5 g t- To the solution (120 ml), add 8.90 g of triethylamine and 24.2 g of azidodiphenylphosphoric acid at room temperature, and add 10 g at 80 ° C for 1 hour. Incubate at 0 ° C for 5 hours. Anti Water is added to the reaction solution to stop the reaction, the crude product is extracted with ether, and the organic layer is washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. After filtering the inorganic substance, the mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography to obtain 6-azidocanolevonylaminomethyl 2- (2, (2, 5-methyl pyrene 1-yl) 1-4-methyl pyridin 8.8 1 g is obtained.

^{1 H - NMR (2 0 0} MH z, CDC 1 3) δ:

2.1 1 (s, 6H), 2.43 (s, 3rd), 4.53 (d, 2H), 5.91 (s, 2H), 6.32 (br , 1Η), 6.95 (s, 1Η), 7.08 (s, 1Η) FAB-MS (m / z): 284 8 ⁺ ■, 285 [[+ Η] ⁺ (3) 6 — Azidocarbonylaminomethyl 2 — (2, 5 — Dimethyl pyrrole 1 — yl) 1 41 1 methyl pyridin 8 Dissolve 15 g in 100 ml of ethanol, add 10 ml of 8 N sodium hydroxide, and allow to react under heating and reflux for 6 hours. Water (100 ml) is added to the reaction solution, the crude product is extracted with ether, and the organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. After the inorganic substance was filtered, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography, and 6-aminomethyl-2- (2,5-dimethyl) was purified. Chilled mouth 1 1) 1 4 _ methyl pyridine 5.60 g

'H - NMR (2 0 0 MH z, CDC 1 3) δ:

1.69 (s, 2H), 2.13 (s, 6H), 2.41 (s, 3H), 3.95 (s, 2H), 5.89 (s, 2H), 6.90 (s, 1H), 7.09 (s, 1H)

FAB-MS (m / z): 2 15 M ⁺ ■, 2 16 [M + H] + 4 3 1 [2 M + H] ⁺

 (4) 6—Aminomethyl 2— (2,5—Dimethylpyrro- 1-yl) 1 4—Methynolepyridine 5.57 g in ethanol 80 m 1 and 30 m 1 of water are dissolved in a mixed solvent, 9.03 g of hydroxylamin hydrochloride is added, and the reaction mixture is reacted under heating and reflux for 10 hours. The reaction is quenched by adding aqueous sodium hydrogen carbonate to the reaction mixture, and concentrated under reduced pressure. The crude product is extracted from the residue with ethanol, and the obtained organic layer is concentrated under reduced pressure. The obtained crude product is purified by silica gel chromatography chromatography to obtain 2-amino-6-aminomethyl-14-methylpyridin. 2—Amino 6—Amino methine 1 4—Methyl pyridine is dissolved in 30 mL of methanol, and 3 N of 4N—Dioxane hydrochloride is added. The reaction mixture is concentrated under reduced pressure, crystallized from ethanol, and 4.95 g of 2-amino-6-aminomethyl-4-methylpyridin dihydrochloride is obtained. obtain.

1 H-NMR (200 MHz, CD ₃₀ D) δ:

 2.42 (s, 3H). 4.26 (s, 2H) .6.85 (s, 2H)

FAB-MS (m / z): 13 8 [M + H] ⁺ , 2775 [2M + H] +

(5) 2—Amino 6—Aminomethyl-4—Methylpyridin dihydrochloride 4.20 g is dissolved in concentrated sulfuric acid 20 ml under ice-cooling. Then, add 1.27 ml of concentrated nitric acid, and stir at the same temperature for 1 hour. In addition, react for 1 hour at room temperature and 1 hour at 60 ° C. The reaction solution was added dropwise to ice water, added with 10 ml of a 40% aqueous sodium hydroxide solution and neutralized (pH> 9) .The crude product was extracted with methylene chloride, and the organic layer was extracted. Is washed with a saturated saline solution and dried over anhydrous sodium sulfate. After filtering the inorganic substance, the mixture is concentrated under reduced pressure to obtain 0.615 g of a crude product. The resulting crude product was dissolved in a mixed solvent of 8 x 1 dioxane and 4 ml of water, and a solution of 0.864 g of dioxane (8 ml) in di-t-butyl dicarbonate at room temperature was added. Add 3.63 ml of IN-sodium hydroxide aqueous solution and stir at the same temperature for 4 minutes. After concentrating the reaction solution under reduced pressure, 30 ml of water is added, the crude product is extracted with ethyl acetate, and the organic layer is washed with saturated saline and dried over anhydrous magnesium sulfate. After the inorganic substance was filtered, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography, and further crystallized with hexane to give 2-amino-6-t. There is obtained 0.647 g of 1-butoxycarbonylaminomethyl 4-141-methyl-3-nitropyridine.

1 H - NMR (2 0 0 MH z, CDC 1 3) δ:

 1.47 (s, 9 H). 2.55 (s, 3 H), 4.26 (d, 2), 5.40 (br, 1), 6.32 (br) , 2 H), 6.5 1 (s, 1 H)

FAB-MS (m / z): 28 3 [M + H] ⁺ , 5 65 [2M + H] +

(6) 2-amino-6-t Dissolve 56.5 mg of methyl-14-methyl-3-nitropyridin in 20 ml of benzene, and add 709 mg of pure sodium benzene acetate. In addition, react at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography and purified by 5-(t-butoxycarbonylamino) methyl 7 — Methyl pyrido [2,3-c] flazan-1 1-year-old xydide Get 4 85 mg.

'H - NMR (2 0 0 MH z, CDC 1 3) δ:

 1.8 (s, 9H), 2.62 (s, 3H), 4.49 (d, 2H), 5.70 (br, lH), 6.86 (s, 3H) 1H)

FAB-MS (m / z): 28 1 [M + H] ⁺ , 56 1 [2M + H] ⁺ , 2 25 [M + H-t-butyl] ⁺ , 18 1 [M + H—B oc] ⁺

 (7) 5-(t-butoxyl rubonylamino) methyl-

7 — Methyl pyrido [2,3-c] flazan-1 Dissolve 20 mg of 1-year-old xydide in 0.5 ml of methanol and 2 ml of trifluoroacetic acid And react for 1.5 hours at room temperature. The reaction mixture is concentrated under reduced pressure, and the resulting crude product is purified by silica gel chromatography with a mouth chromatography to obtain 5—aminomethyl—7—methylpyrid [ [2,3-c] Frazan 1 — Get ozone. 5-Aminomethyl-7-Methyl pyrido [2,3-c] flazan-1-oxide 0.04 N-Add 2 ml of ether ether hydrochloride. The reaction mixture is concentrated under reduced pressure, and 5 — aminomethyl 7 — methyl pyrido [2, 3 — c] flazan 1 — oxide salt This gives 8.9 mg of the acid salt.

'H - NMR (2 0 0 MH z, CD 3 0 D) δ:

 2.64 (s, 3H), 4.42 (s, 2H), 7.10 (s, 1H)

FAB-MS (m / z): 18 1 [+ H] ⁺ , 36 1 [2 M + H] ⁺

 Production Example 5

 5-(3-t-butoxycarbonylaminopropyl) 7-methylpyrid [2,3-c] flazan-11-oxide (compound N 0.30) and 5-(3 -Aminopropyl) 17-Methyl pyrido [2,3-c] Preparation of flazan-11-oxide (Compound N 0.29)

(1) 6—Amino—2, 4—Easier to obtain than lutidine 2—Amino 6— (3—Aminopropyl) 1-41 methyl—3—2 A mixture of 3336 mg of pyridin and 4 ml of dioxane and 2 ml of water was dissolved in a solvent mixture of dioxane (4 ml) and 1 N-solution at room temperature. Add 1.76 ml of an aqueous sodium hydroxide solution and stir at the same temperature for 1 hour. After concentrating the reaction solution under reduced pressure, 20 ml of water is added, the crude product is extracted with ethyl acetate, and the organic layer is washed with saturated saline and dried over anhydrous magnesium sulfate. After the inorganic substance was filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography and purified by 2-amino 16-(3-t-butoxycarbonyl). Aminopropyl) 1-4-methyl-3-nitropropylidine 44.4 mg is obtained. ^{1 H - NMR (2 0 0} H z, CDC 1 3) δ:

 1.4 (s, 9H), 1.76-1.94 (m, 2H), 2.53 (s, 3H), 2.63 (t, 2H), 3. 17 (q, 2H), 4.83 (br, 1H), 6.32 (br, 2H), 6.43 (s, 1H)

FAB-MS (m / z): 3 1 1 [M + H] ⁺ , 255 5 [M + H-t-butyl] ⁺ , 2 1 1 [M + H-Boc] + (2) 2 — Amino 6 — (3 — t — butoxycarbonyl aminopropyl) 1 4 — Methyl 3 — 2 tropolidin 4 3 8 mg benzene 10 m 1 And add 499.9 mg of sodium benzene acetate and react at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography, and the 5– (3–t-butoxycarbonylaminopropyl) was purified. 1) 7-Methyl pyrido [2,3-c] flazan-1 1-year-old thiside 39 9 mg was obtained.

1 H - NMR (2 0 0 MH z, CDC 1 3) δ:

 1.44 (s, 9 9), 1.94 — 2.08 (m, 2Η), 2.59 (s, 3Η), 2.88 (t, 2Η), 3 2 3 (q, 1 word), 4.70 (br, 1 word), 6.8 1 (s, 1 word)

FAB-MS (m / z): 309 [Μ + Η] +, 6 17 [2 Μ + Η] ⁺ , 25 3 [M + H-t-butyl] ⁺ , 20 9 [Μ + Η-B oc] ⁺

(3) 5-(3-t-butoxycarbonyl carbonyl mine propyl) 1 7-methyl pyrido [2,3-c] Frazan 1 11 years old Dissolve 10 mg of xide in 1 ml of 4N hydrochloric acid / dioxane at 0 ° C and react at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 9.2 mg of 5- (3-aminopropyl) 17-methylpyrid [2,3—c] flazan-1 1-year-old hydrate. You.

FAB-MS (mZz): 209 [M + H] ⁺

 Production Example 6

 5 — Ethoxycarbonyl — 7 — Preparation of methyl pyrido [2,3 — c] flazan — 1-oxide (Compound No. 26)

(1) Preparation example 4 6-Carboxymethyl 2 obtained in 1 (1) 2-(2, 5-dimethylinopyrro 1-1 yl) 14-methylpyridin 15 Was dissolved in a mixed solvent of 170 ml of ethanol and 60 ml of water, 25.7 g of hydroxylamine hydrochloride was added, and the reaction mixture was heated under reflux for 7.5 hours. Let it react. The reaction solution is quenched with 2N-sodium hydroxide aqueous solution, and concentrated under reduced pressure. The crude product is extracted from the residue with methanol, and the obtained organic layer is concentrated under reduced pressure. A mixture of the obtained crude product, 200 ml of ethanol and 5 ml of concentrated sulfuric acid is reacted under heating and refluxing for an hour. The reaction is stopped by adding 60 g of sodium hydrogen carbonate and 300 ml of water. The crude product is extracted with ethyl acetate, and the organic layer is washed with brine and dried over anhydrous sodium sulfate. After filtering the inorganic substance, the mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography, and 2 -amino 6 -ethoxyquinone was obtained. Le Mechi Roux 4 — 5.7 g of methyl pyridine.

1 H - NR (2 0 0 MH z, CDC 1 3) δ:

1.26 (t, 3H), 2.21 (s, 3H), 3.60 (s, 2H), 4.17 (q, 2H), 4.42 (br , 2H), 6.21 (s, lH), 6.47 (s, lH) FAB-MS (m / z): 1995 [M + H] ⁺ , 389 [2 M + H] ⁺

 (2) 2—Amino 6—Ethoxycarbonyl methyl 4-41 methyl pyridine 2,91 g was dissolved in 22.5 ml of concentrated sulfuric acid under ice-cooling, and concentrated nitric acid was added. 0.95 ml was added dropwise and stirred at the same temperature for 2 hours. In addition, react for 2 hours at room temperature and 1 hour at 60 ° C. The reaction solution is dropped into ice water, neutralized (ρΗ7-8) by adding 5% of a 4% aqueous sodium hydroxide solution, and the precipitated crystals are collected by filtration and extracted with ethyl acetate. The obtained crude product was purified by silica gel column chromatography and crystallized with ethyl acetate to give 2-amino-6-ethoxycarbonyl methyl 4-methyl Chill 3—get 0.69 g of nitropyridine

^{1 H - NMR (2 0 0} MH z, CDC 1 3) δ:

 1.28 (t, 3H), 2.55 (s, 3H), 3.63 (s, 2H), 4.20 (q, 2H) .6.33 (br , 2H), 6.56 (s, 1H)

FAB-MS (m / z): 2400 [M + H] ⁺ , 479 [2M + H] ⁺

(3) 2—Amino 6—Ethoxycarbonyl carbonyl-1 -Dissolve 59 mg of 3-methyl-2-pyrrolidine in 10 ml of benzene, add 53 mg of iodosobenzene diacetate and react at room temperature for 28 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography chromatography to obtain 5-ethoxycarbonylmethyl 7-methylpyrid [2,3 — C] Get 1 37 mg of Frazan 1 1 year old oxide.

^] H-NMR (200 MHz, CDC ") δ:

 1.31 (t, 3H), 2.35 (s, 3H), 4.21 (q, 2H), 5.04 (s, lH), 6.13 (s , l H), 11.26 (br, 1 H)

F A B-M S (m / z): 2 3 8 [M + H] +

 Production Example 7

 5—Cross-mouth pyrido [2,3-c] furazan-1 1-oxide (compound No. 2 of the present application), 5—methoxypropyl [2,3-c] flazan-11 Thioxide (Compound No. 31) of the present application, 5—methylamino borohydride [2,3—c] flazan-1—oxide (Compound No. 35 of the present application) and 5—dimethyla Production of Minopyrido [2,3-c] Frazan-1 One-year-old oxide (Compound N 0.36)

(1) 2, 6—Diaminopyridine—Easier to obtain than 21-amino 6—Cro- mouth 13—Nitropyridin 43 to 4 mg of ethyl acetate 20 m 1), add 122 mg of pseudosobenzene diacetate, and react at room temperature for 18 hours. The reaction solution was purified by silica gel column chromatography, and 5 — Black mouth pyrid [2,3-c] phthalone 1 —Oxide 3 4 5 ΙΏ g is obtained.

^{1 H - NMR (2 0 0} MH z, CDC 1 3) δ

7.50 (d, 1H), 8.25 (d, 1H)

F A B-M S (m / z): 17 2, 1 7 4 [M + H] +

 (2) 2 — Amino 6 — Chloro 3 — Ditropyridine 173 mg, methanol 6 m 1, sodium methoxide 1 2 Mix 9 mg, and react this reaction solution at 50 ° C for an hour. The reaction was stopped by adding 30 ml of water to the reaction mixture, and the precipitated crystals were collected by filtration, and 2-amino 6-methoxy 13-nitropyridine 15 1 mg Get.

1 H - NMR (2 0 0 MH z, CDC 1 3) δ:

 3.90 (s, 3H), 6.15 (d, 1H), 8.14 (br, 2H), 8.26 (d, 1H)

 (3) 2 — Amino 6 — Metoshi I 3 — 2-Tropyridin

Dissolve 42,3 mg in 20 ml of ethyl acetate, add 96,6 mg of sodium benzene acetate, and react at room temperature for 64 hours. The reaction solution was concentrated under reduced pressure, and the obtained product was purified by silica gel chromatography and further crystallized by ether-hexane to give 5 — methoxy. Obtain 329 mg of pyrido [2,3-c] flazan-1-oxide.

1 H - NMR (2 ϋ ( ) Μ Η ζ, CDC 1 3) δ:

 4.02 (s, 3H), 7.00 (d, 1H), 8.03 (d, 1H)

FAB — MS (m / z): 16 8 [M + H] + () 2 — Amino 6 — Chloro 3 — Nitropyridin 868 mg was dissolved in 1 O ml of ethanol, and 40% aqueous methylamine solution 2.0 was dissolved. Add m 1 and react at 100 ° C (external temperature) in a sealed tube for 1 hour. 100 ml of water is added to the reaction solution, and the precipitated crystals are collected by filtration to obtain 772 mg of 2-amino-6-methylamino-3-nitropyridine.

1 H - NR (2 0 0 MH z, CDC 1 3) δ:

2.86 (d, 3H), 5.94 (d, 1H), 7.90 (d, 1Η), 7.60-8.2 2 (br, 3Η)

 (5) 2-Amino 6-methylamino 3-Nitropyridin 4 64 mg was dissolved in a mixed solvent of 5 ml of ethyl acetate and 15 ml of acetonitrile. Add 1067 mg of sodium sorbensen diacetate and react at room temperature for 24 hours. The crystals precipitated in the reaction solution are collected by filtration to obtain 39.8 mg of 5-methylamino borohydride [2, 3 — c] flazan-1 1-year-old xide.

'H - NMR (2 0 0 MH z, CDC 1 3) δ:

2.92 (d, 3H), 6.79 (d, 1H), 7.62 (d, 1H), 8.49 (br, 1H)

FAB-MS (m / z): 16 7 [M + H] ⁺

 (6) 2 — Amino 6-Black mouth 3 — Nitropyridine 8

Dissolve 68 mg in 10 ml of ethanol, add 2.2 ml of 50% aqueous dimethylamine solution, and place in a sealed tube at 100 ° C (external temperature) for 2.5 ml. Let react for hours. Water (200 ml) is added to the reaction mixture, and the precipitated crystals are collected by filtration to obtain 2- (amino-6-dimethylamino-3- (2-trifluoropyridine) (750 mg). ¹ H-NMR (200 MHz, CDC 1) δ:

3.13 (s, 6H), 6.19 (d, 1H), 8.4 (d, 1H), 7.60-8.00 (br, 2H)

 (7) 2—Amino 6—Dimethylamino 3—Nitropyridin 45 1 mg was dissolved in Acetone 15 ml to obtain a sodium benzene. Add 960 mg of the acetate and react at room temperature for 24 hours. Hexane (60 ml) was added to the reaction solution, and the precipitated crystals were collected by filtration. 5 -dimethylaminopyridine [2,3-c] flazan-1 1-year-old kiss 4 1 Take 1 mg.

 'Η-NMR (200 MHz, CDC1) 0:

3.23 (s, 6 Η). 7.28 (d, 1 H), 7.77 (d, 1 Η)

FAB-MS (m / z): 18 1 [M + H] ⁺ , 36 1 [2Μ + Η] +

 Production Example 8

 5, 6, 7-Trimethylpyridide [2, 3-c] flazan-1 Manufacture of one-year-old oxide (compound of the present application Ν o.22)

 (1) 3 — Methyl-2,4-pentanthion 1.74 m 1, 1,1-diamino 1-2 —2 Trotten 1.03 g, And 15 ml of acetic acid, and the reaction mixture is reacted under heating and reflux for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel gel chromatography, and the resulting 2 -amino 3 -2-port 1,4,5, 6—Get 0.30 g of trimethyl pyridine.

Ή-NMR (200 MHz, CDC δ 2.15 (s, 3H), 2.36 (s, 3H), 2.1 (s, 3H), 5.68 (br, 2H)

FAB-MS (m / z): 1 8 2 [M + H] ⁺

 (2) 2-Amino 3 —2,4,5,6—Dissolve 27.4 mg of trimethyl viridine in 15 ml of benzene, and add Add 536 mg of benzene diacetate and react at room temperature for 95 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography to obtain a crude product.

6,7-Trimethinolepyrid [2,3—c] Frazan-1-oxide 24 4 mg is obtained.

¹ H-NMR (200 MHz, CDC ls) (5:

 1.58 (s, 3H), 2.56 (s, 3H), 2.63 (s, 3H)

F A B-M S (m z) 180 [M + H] +, 359 [2M + H] +

The following compounds can also be produced by the same method as described above.

 2-Amino 4-Methyl 3-2-Tro 6-Trifluoromethyl pyridine

 'H-N M R (200 MHz, CDCls) δ:

2.5 1 (s, 3rd), 6.15 (br, 2H), 6.8

7 (s, 1 H)

FABMS (mXz): 2 2 2 [M + H] ⁺

7 — Methyl 5 — Trifluoromethyl pyrido [2,3 — c] flazan-11-oxide (Compound N 0.17) 'H-NMR (20 0 MHz, CDC] ₃ ) δ: 2.74 (s, 3H), 7.24-0.753 (m, 1H) FAB-MS (m / z): 220 [M + H] ⁺

 2 1, 4, 6-Screw (trifluoromethyl) 1 3 □ Pyridin

 E S I-M S (m / z): 2 7 4 [M-H]-, 5 4 9

[2 M-H]

 5,7-bis (tris-norelomethyl) pyrid [2,3-c] flazan-11-oxide (Compound No. 18)

¹ H-one NR (200 MHz, CDC ls) δ:

7.5 8 1 7.8.9 (m, 1H)

 2 — Amino — 5 — Black 4, 6 — Dimethylene 3 — 2 □ Pyridine

¹ H one NR (2 0 0 MH z, CDC 1 3) δ:

2.52 (s, 3rds), 2.54 (s, 3rds), 5.90

(br, 2H)

FAB-MS (m / z): 202, 204 [+ H] ⁺ 6 a D 15, 7-Dimethyl phenol [2, 3-c] Frazan 1 1 Oxide (Compound N 0.21

'H - NMR (. 2 0 0 MH z CDC 1 3) δ:

 2.66 (s, 3), 2.75 (s, 3)

FAB-S (m / z): 200, 202 [Μ + Η] ⁺ ,

3 9 9, 4 0 1 [2 Μ + +] ⁺

 2 Amino — 4, 6 — Dimethyl 1 5 — Ethylene 3 — Nito π pyridine

¹ H NMR (200 MHz, CDC ls) δ: 1.11 (t, 3H), 2.39 (s, 3rd) .2.43

(s, 3 H), 2.60 (q, 2 Η), 5.69 (br, 2 H)

F A B-M S (m / z): 19 6 [Μ + Η] +

 5, 7 — Dimethylene 6 — Ethyl pyrido [2, 3 — c] Frazan 11-year-old compound (Compound No.23)

 1 H-N M R (200 M Hz. CDC 1) δ:

 1.19 (t, 3H), 2.57 (s, 3H), 2.67 (s, 3H), 2.74 (q, 2H)

FAB-MS (m / z): 19 4 [M + H] ⁺ , 387 [2M ten H] ⁺

 2-AMINO 4-MECHINOLE 3-2-TRO5, 6-Cyclopentenopyridine and 2-AMINO 6-METHYL 3-2 4,5-Cyclopentenopyridine mixture

FAB — MS (m / z): 1 4 [M + H] ⁺

 7-methyl-5,6-cyclopentenoviride [2,3-c] flazan — 1-oxodide and 5—methyl-6,7—six mouth A mixture of pentenopyryl [2,3 — c] flazan 1]-oxide (Compound No. 24 of the present application)

FAB-MS (m / z): 19 2 [M + H] ⁺ , 38 3 [2M + H] ⁺

 2-Amino 4-Methyl 3-2-to-5, 6-cyclohexenopyridin and 2-Amino 6-Methyl 13-2 □-4 , Mixture of 5-cyclohexenopyridine

FAB-MS (m / z): 208 [M + H] ⁺ 7 — methylone 5, 6 — cyclohexenolide [2,3-c] flazan 1-oxide and 5 — methyl 1, 6 — 7 Mixture of lid [2,3—c] flazan-1 oxyside (Compound N 0.25)

F A B-S (m / z): 206 [M + H] 4 1 1 [2M + H] +

 Production Example 9

 5—Amino 7—Methinolepyrid [2,3—c] Frazan 11-year-old compound (Compound N 0.38), 5-acetylamino 7 — Methyl pyrido [2,3 — c] flazan-111-oxide (Compound No. 39), 5 — Chloro 7 — methyl pyrido [ [2,3—c] furazan-1—oxide (compound N 0.10) and 5—methokine—7—methylpyrid [2,3-c] furan Xan 1-oxide (Production of the compound of the present application No. 33)

 (1) Chem. Ber .; 2, 3, 6-dichloro mouth, 4 — methyl pyr, easily obtained by the method described in Vol. 103, p. 389, 197 9. A mixture of 29.5 g of pyridine, 130 ml of concentrated sulfuric acid and 75 ml of concentrated nitric acid is stirred, and the reaction mixture is stirred for 6 hours while heating under reflux. The reaction mixture was added dropwise to 200 ml of ice water to stop the reaction. The precipitated crystals were collected by filtration, and 2,6-dichloro-4-4-methyl-13-nitropropyl This gives 20.1 g of gin.

ESI-MS (m / z): 206, 208, 210 M ⁺

(2) 2, 6-Dichloro 4-Methinole 3-Ditropyridine, 5 ml of ethanol, 10 ml of 28% ammonia water Mix and react the reaction mixture in a sealed tube at 100 (external temperature) for 6 hours. The reaction station was concentrated under reduced pressure, water (100 ml) was added to the residue, and the precipitated crystals were collected by filtration and further crystallized with ether to give 2,6-diamino-4-methyl-3. — Obtain 0.67 g of nitropyridine.

¹ H-NMR (200 MHz, DMS 0-d 6) δ:

2.40 (s, 3H), 5.74 (s, 1H), 6.94 (br, 2H), 7.64 (br, 2H)

FAB-MS (m / z): 16 9 [M + H] ⁺ , 3 3 7 [2 M + H] ⁺

 (3) 2, 6 — diamino 4 — methyl 3 — nitropyridine 1.10 g, acetate 40 m 1, pseudosodium benzene acetate Mix 2.53 g, and allow this reaction mixture to react at room temperature for 23 hours. The reaction mixture was concentrated under reduced pressure, crystallized from methanol and ether, and 5 -amino-7-methyl pyrido [2,

3-c] Frazan 1 1 year old kid Get 1.02 g.

1 H - NMR (2 0 0 MH z, CDC 1 3) δ:

 2.38 (d, 3H), 6.51 (d, 1H), 7.69 (br, 2H)

F A B — M S (m / z): 1 6 7 [M + H] +

(4) 5-Amino 7-Methyl pyrido [2,3-c] Frazan-11-oxide 37 1 mg, 9 ml of acetic acid, 9 ml of acetic anhydride Then, the reaction solution is stirred for 10 hours under heating and reflux. The reaction solution is dropped into 100 ml of ice water to stop the reaction, and extracted with ethyl acetate. Organic layer is saturated sodium bicarbonate Wash sequentially with an aqueous solution and saturated saline, and dry with anhydrous sodium sulfate. After filtering the inorganic substances, the filtrate is concentrated under reduced pressure, crystallized with ethyl persulfate-hexane, and 5-acetylamino-7-methyl pyrido [2,3-c] flazan 1) Obtain 397 mg of 1-year-old kiss.

^{1 H - NMR (2 0 0} MH z, CDC 1 3) δ:

2.19 (s, 3H), 2.52 (s, 3rd), 7.91 (d, lH), 11.22 (s, 1st)

F A B — M S (m / z): 209 [M + H] +

 (5) 2,6-Dichloro-4 1-methyl 13-3-Nitropyridin 8.30 g is dissolved in ethanol 30 ml, and 28% ammonia water 3 Add 0 ml and incubate at 50 ° C for 20 hours. After concentrating the reaction mixture under reduced pressure, 900 ml of hexane is added, and the precipitated crystals are collected by filtration and extracted with a mixed solvent of ethyl acetate and hexane (1: 2). The obtained crude product was purified by silica gel chromatography with chromatography, and 2—amino 6—chloro 4—methyl 3—nitropropyl 5.08 g are obtained.

 'H-NMR (200 MHz, DMS 0-d 6) δ: 2.37 (s, 3H), 6.70 (s, 1H), 7.58 (br, 2H) )

FAB-MS (m / z): 18 8, 19 0 [M + H] ⁺

(6) Dissolve 2 mg of 3-6 mg of pyrimidine in 20 ml of acetone by dissolving 2 mg Add diacetate (111 mg) and react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure with The product is purified by silica gel chromatography chromatography to give 51-clo 17-methylpyrid [2,3-c] flazan 11-oxide.

 1 H-N M R (200 M Hz, D M S 0-d 6) δ: 2.53 (s, 3H), 7.34 (s, lH)

FAB-MS (m / z): 18 6, 18 8 [M + H] ⁺

(7) 2 — Amino 6 — Chlorine 4 — Methinole 3 — Two-way pyridin 1.3 1 g, methanol 30 m 1, sodium Mix 1.13 g of methoxide, and react this reaction solution for 16 hours at room temperature, 8 hours at 40 ° C, and 4 hours at 60 ° C. The reaction was stopped by adding 30 ml of water to the reaction solution, and the precipitated crystals were collected by filtration, and 2-amino-1-6-methoxy-14-methynoley 3-nitropyridine 1. 26 g are obtained.

¹ H-NMR (200 MHz, DMSO-d 6) δ: 2.44 (s, 3 H), 3.83 (s, 3 H), 6.05 (s, 1 H) , 7.79 (br, 2H)

F A B-M S (m / z): 18 4 [M + H] +

 (8) 2-Amino 6-Methoxy 4-Methinol 3-Ditropyridine 73 3 mg is dissolved in 25 ml of acetone, and Add 1546 mg of benzene diacetate and react at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography to give 5-methoxy 17-methyl pyrido [2,3-c]. Get 1 86-mg of flazan-1-oxoxide.

Ή-NMR (200 MHz, DMSO ~ d 6) d: 2.47 (d, 3H), 4.00 (s, 3H), 6.8 1 (q, 1H)

FAB-MS (m / z): 18 2 [M + H] ⁺

 Production Example 10

 5 — (3 — Karboki cypro pill) 1 7 —

[2,3—c] Frazan-1 Manufacture of a one-year-old xide (the compound of the present application No. 4)

 (1) 6 — Amino 2, 4 — Getyl easily obtained from lutidine [2 — {6 — (2,5 — dimethylpyrro 1-yl) 1 4 -Methyl-2 -pyridinyl} ethyl] malonethate Dissolve 5.32 g in a mixed solvent of 60 ml of carinol and 20 ml of water, and add hydroxyamine hydrochloride. . 47 g was added and the reaction mixture was reacted for 8 hours while heating under reflux. The reaction mixture is concentrated under reduced pressure, and a mixture of the obtained crude product, 100 ml of ethanol and 4 ml of concentrated sulfuric acid is heated under reflux for 3 hours. The reaction is stopped by adding 20 g of sodium hydrogen carbonate and 20 μm of water. The reaction mixture is concentrated under reduced pressure to remove ethanol, extracted with ethyl acetate, and the organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. After filtering the inorganic substance, the mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography and purified by getyl [2— (6—amino-4—methyl). 2-pyridinyl) ethyl] malonate 2.62 g is obtained.

^{1 H - NMR (2 0 0} MH z, CDC 1 3) δ

1.27 (t, 6H), 2.19 (s, 3H), 2.21 I 2.33 (m, 2H), 2.60 (dd, 2H), 3.39 (t, 1H), 4.19 (q, 4H), 4.34 ( br, 2 H), 6.17 (s, 1 H), 6.35 (s, 1 H)

F A B — M S (m / z): 2 95 [M + H] +

 (2) Dissolve 2.60 g of getyl [2— (6-amino-4-methyl-1-2—pyridinyl) methyl] malonate in concentrated sulfuric acid ί2 ml, and cool under ice-cooling with concentrated nitric acid 0.56 μm 1 is added dropwise and stirred at the same temperature for 1 hour. In addition, react for 1 hour at room temperature and 1 hour at 60 ° C. The reaction solution is added dropwise to ice water, 25 ml of a 40% aqueous sodium hydroxide solution is added to neutralize the solution (pH 5 to 6), and concentrated under reduced pressure. A mixture of the obtained crude product, 200 ml of ethanol and 8 ml of concentrated sulfuric acid is reacted under heating and refluxing for 2.5 hours. The reaction is stopped by adding 35 g of sodium hydrogen carbonate and 200 ml of water. After filtering the insoluble matter and concentrating under reduced pressure to remove ethanol, the residue is extracted with ethyl acetate, and the organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. After the inorganic substance was filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography and purified with getyl [2— (6—amino 4-methyl). Chill 1-5—2 tro-2-pyridinyl) ethyl] malonate 1.59 g.

1 H - NMR (2 0 0 MH z, CDC 1 3) δ

1.28 (t, 6H), 2.23-2.34 (m, 2H), 2.53 (s, 3H), 2.65 (dd, 2H), 3 . 40 (t, lH): 4.21 (q, 4H), 6.33 (br , 2H), 6.43 (s, 1H)

 F A B-M S (m / z): 340 [M + H] +

 (3) Jetyl [2 — (6 — Amino 4-methyl-5-Nitrate — 2 — pyridinyl) ethyl] malonate 67 9 mg in 2 N — hydrochloric acid 10 m Dissolve in 1 and react with heating under reflux for 8 hours. Add 90 ml of water to the reaction mixture, and wash with 30 ml of methylene chloride. The aqueous layer is concentrated under reduced pressure to give 2-amino-6- (3-carboxypropyl) -14-methyl-3-nitropropylidine hydrochloride 549 mg.

 'H-NMR (200 MHz, DMS 0-d 6) δ: 1.83-1.98 (m, 2H), 2.28 (t, 2H), 2.46 (s, 3H), 2.69 (t, 2H), 6.73

(s, 1 H)

 F A B-M S (mZ z): 240 [M + H] +

() 2-Amino 6-(3-Carboxypropyl)-4-Methyl 3-Nitropyridine hydrochloride 13 8 mg in 5 ml of methanol Dissolve and add 42 mg of sodium bicarbonate. The reaction mixture is concentrated under reduced pressure, and the resulting crude product is purified by silica gel chromatography, and is purified by 2-amino-6-1 (3-carboxypropyl)- 4 — Methyl — 3 — Get the nitropyridine. The resulting 2—amino 6— (3—carboxypropyl) —4—methyl-1-3—2-methyl pyridine was dissolved in 1 μm of acetone and dissolved in 1 μm of acetone. Add 177 mg of dobenzen diacetate and react at room temperature for 20 hours. The reaction mixture is concentrated under reduced pressure, and the resulting crude product is purified by silica gel chromatography. Purification by chromatography yields 102 mg of 5- (3-carboxypropyl) -17-methylpyri [2,3, c] flazan-11-oxide.

^{1 H - NR (2 0 0} MH z, CDC 1 3) δ:

2.08 — 2.23 (m, 2H), 2.52 (t, 2Η), 2.60 (s, 3Η), 2.93 (t, 2Η), 6 . 8 3 (s, 1 Η)

FAB-MS (m / z): 2 3 8 [Μ + Η] ⁺ , 4 7 5 [2Μ + Η] +

 Production example 1 1

 5-(3-t-Butoxycarbonylamino 3-carboxy) propyl-1 7-methyl pyrido [2,3-c] flazan-1-oxide (Compound N 0. 4 1) and 5-(3-carboxyl-3-amino) propyl-1 7-methyl pyrido [2,3-c] flazan-1-oxide (Compound No.42 of the present application) Manufacturing of

(1) 6-Amino-2,4-Jetyl [2] -Acetatoamido 2— {6— (2,5—Dimethylpyruroyl) — Yl) 1-methyl 2- 1-pyridinyl] malonate 8.59 g is dissolved in a mixed catalyst of 80 ml of water and 30 ml of water, and hydrochloric acid is added. 6.95 g of hydroquineamine is added, and the reaction mixture is reacted for 9 hours while heating under reflux. The reaction mixture is concentrated under reduced pressure, and a mixture of the obtained crude product, 100 ml of ethanol and 3 ml of concentrated sulfuric acid is reacted with heating under reflux for 3 hours. 150 g of sodium bicarbonate in 100 m of water Stop the reaction by adding 1. The reaction mixture is concentrated under reduced pressure to remove ethanol, extracted with ethyl citrate, and the organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. After the inorganic substance was filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography chromatography, and getyl [2—acetamido 2— (6— Amino 1 4 -methyl 2 -pyridinyl) ethyl] 5.49 g of maloneate is obtained.

1 H - NMR (2 0 0 MH z, CDC 1 3) δ

 1.25 (t, 6H), 2.00 (s, 3rd), 2.18 (s, 3rd), 2.42-2.50 (m, 2nd), 2 6 7 — 2.76 (m, 2Η), 4.16 — 4.28 (m, 4 4), 4.35 (br, 2Η), 6.14 (s, 1) Η), 6.3 3 (s, 1 Η), 6.9 3 (s, 1 Η)

FAB-MS (m / ζ): 3 5 2 [Μ + Η] ⁺

(2) Jetil [2-Acetate Amido 2-(6-Amino 14-1-methyl 1-2-Pyridinyl) ethyl] Malonate 2.8 1 g of concentrated sulfuric acid 14 m 1 Then, add 0.507 ml of concentrated nitric acid dropwise under ice-cooling, and stir at the same temperature for 1 hour. In addition, react for 1 hour at room temperature and 1 hour at 60 ° C. The reaction solution is added dropwise to ice water, 30 ml of a 40% aqueous sodium hydroxide solution is added to neutralize (pH 5 to 6), and concentrated under reduced pressure. 100 ml of ethanol is added to the obtained crude product, and the insoluble matter is filtered and concentrated under reduced pressure. To the obtained crude product are further added 75 ml of ethyl acetate and 25 ml of ethanol, and the insolubles are filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography chromatography. [2—Acetate Amido 2-(6-Amino 4 -methyl 5 -Nitro 2 -Pyridinyl) ethyl] Malonate i.96 get g.

'H - NMR (2 0 0 MH z, CDC l 3) δ:

 1.26 (t, 6H), 2.02 (s, 3Η), 2.46-2.49 (m, 2H), 2.52 (s, 3Η), 2 . 69-2.79 (m, 2Η), 4.18-4.32 (m, 4H), 6.32 (br, 2Η), 6.41 (s, 1) Η), 6.8 1 (s, 1H)

FAB-MS (m / z): 397 [Μ + Η] ⁺

 (3) Jethyl [21-Acetamide 1-2-(6-Amino-1-methyl-5-2-2-pyridinyl) ethyl] Malonate 1.9 Dissolve 0 g in 20 ml hydrochloric acid and react with heating under reflux for 10 hours. Add 180 ml of water to the reaction mixture, and wash with 50 ml of methylene chloride. The aqueous layer is concentrated under reduced pressure to give 2-amino-6- (3-amino-3-carboxy) propyl 4-monomethyl-3-nitropyridine dibasic salt To obtain 56 g.

¹ H-NMR (200 MHz, DMS 0-d 6)) o: 2.08-2.27 (m, 2H), 2.41 (s, 3H), 2.6 4-2.92 (m, 2H), 3.97 (br, 1H) 6.62 (br, 1H), 8.57 (br, 2H)

FAB-MS (m / z): 2 5 5 [M + H] ⁺

() 2-Amino 6-1 (3-Amino 1-3-Carboxy) Pout pill-4-Methinole 13-Nitropyridin dihydrochloride 7 7 9 mg was dissolved in a mixed solvent of 8 ml of dioxane and 4 ml of water, and di-t-butyl dicarbonate (64 ml) in dioxane (8 ml) solution at room temperature and 2N-hydroxylated Add 3.69 ml of an aqueous sodium solution and stir at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography and purified by 2-amino-6-(3-t-butoxyca Noreponylamino 3 — Power Noreboquine) Propyl 4 —Methyl — 3 —2 Tropyridine 836 mg is obtained.

'H - NMR (2 0 0 MH z, CDC 1 3) δ:

 1.4 (s, 9H), 1.98-2.32 (m, 2H) 2.52 (s, 3H), 2.64-2.76 (m, 2H) ) 4.32 (br, 1H), 5.66 (d, 1H), 6.43 (s, 1H), 6.73 (s, 2H)

F A B-M S (m / z): 3 5 3 [M-H]-, 7 07 [2 M-H]-

(5) 2—Amino 6— (3—t—butoxy carbyl amino 1—3—carboxy) Propyl 1—4—Methyl-3—2-Tropyridin 7 Dissolve 9 mg in 3 O ml of benzene, add 0.9 mg of benzyl acetate, and react at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography and purified by 5-3-X-butoxycarbonylamino-3- 7- Methyl pyrido [2, 3-c] flazan-1-oxide 4 13 mg is obtained.

] H - NR (2 0 0 MH z, CDC 1 3) δ: 1.44 (s, 9H), 2.10-2.5ϋ (m, 2H) 2.59 (s, 3H), 2.91-3.00 (m, 2H) H)

4.35 (br, 1H), 5.52 (d, 1H), 6.8

5 (s, 1H)

FAB-MS (m / z): 35 3 [M + H] +, 705 [2M + H] ^+, 297 [M + H-t ~ butyl] ⁺

(6) 5-(3-t-butyncarbonylamino 3-carboxy) propyl 7-methyl pyrido [2,3-c] flazan-1-oxide 21 mg Dissolve in 2.5 ml of ethanol, add 7.5 ml of trifluoroacetic acid, and react at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified with silica gel chromatography chromatography and Dyion HP-20 to obtain 5— (3—a Mino 3-carboxy) Propyl 7-methyl pyrido [2,3-c] flazan-1 1-year-old kiss 80.6 mg is obtained.

 Ή-N M R (200 MHz, D20) δ:

2.27 (q, 2H), 2.52 (s, 3H), 2.92-3.05 (m, 2H), 3.80 (t, 1H), 7 0 8 (s, 1 H)

F A B-M S (m / z): 25 3 [M + H] +

 Industrial applicability

According to the present invention, it has been found that pyrido [2,3-c] furazan-1-oxide derivatives and pharmaceutically acceptable salts thereof have strong nitric oxide synthase inhibitory activity. Was issued. That is, pyrido [2,3-c] flazan-1 one-year-old xide derivative Alternatively, a pharmaceutical composition containing a pharmaceutically acceptable salt thereof as an active ingredient was found to be useful as a nitric oxide production inhibitor.

Claims

The scope of the claims Nitric oxide synthase inhibitory pyrido [2,3—c] furazan-1 with a 1.5% nitric oxide synthase inhibitory concentration (IC ₅₀ ) of less than ImM —A nitric oxide synthase inhibitor containing an oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.  2. —Pyrido [2,3—c] flazan-1 having a nitric oxide synthase inhibitory activity and a molecular weight of 500 or less 1 containing a one-year-old oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient Nitric oxide synthase inhibitor. 3. General formula [1]

 Π3 [Wherein, R 1, R 2, and R 3 are the same or independent substituents, and each represents a hydrogen atom, a halogen atom, a linear or branched lower alkyl group having 1 to 6 carbon atoms substituted or halogen atom, the number of 3-8 pieces of a cycloalkyl group having a carbon, C 〇 R 4 group (this Kodewa R ₄ groups hydroxyl, straight-chain or branched technique chain having 1 to 4 carbon atoms or lower alkoxy groups ), A pyridyl group (unsubstituted or a nitro group, a linear or branched lower alkyl group having 1 to 4 carbon atoms, and one or more hydrogen atoms substituted with an amino group) ), 1-oxygen-pyrid [2,3-c] Frazyl group (unsubstituted or linear or branched lower alkyl group having 1 to 4 carbon atoms which may be substituted with one or more hydrogen atoms), OR 5 group ( R ₅ represents a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms, NR 6 R 7 groups (where R 6 and v are hydrogen atoms, Represents a chain or branched lower alkyl group having 1 to 4 carbon atoms, a linear or branched lower alkoxycarbonyl group having 1 to 4 carbon atoms, and R ₆ and R 7 are the same. Or one or more hydrogen atoms may be substituted independently) or 0 R 8 groups (where R ₈ is a hydrogen atom, straight-chain or branched) A chain lower alkyl group having 1 to 4 carbon atoms) or an NR 9 R 10 group (where R ₉ , R, are hydrogen atoms, linear or branched carbon atoms having 1 to 4 carbon atoms) Lower alkyl groups Represents a straight-chain or branched-chain C 1-4 lower § sill group carbon, R _9, R, 0 denotes the same or, alternatively each independent substituents), or even R, and R ₂ or R ₂ and R ₃ together such connexion unsubstituted or or halogen atom, one or more on an optionally substituted carbon atoms 5 even seven sheets click a lower alkyl group having 1 to 4 carbon atoms To form a cycloalkane ring having 5 to 7 carbon atoms which may be unsubstituted or substituted by one or more halogen atoms or lower alkyl groups having 1 to 4 carbon atoms. Can be done. ] A nitric oxide synthase inhibitor comprising, as an active ingredient, a pyrido [2,3-c] flazan-1-oxide derivative or a pharmaceutically acceptable salt thereof represented by the formula: 4. In the compound of the general formula [1] of claim 3, R, is a hydrogen atom, a halogen atom, a linear or branched lower alkyl group having 1 to 6 carbon atoms (even if one or more hydrogen atoms are substituted with a halogen atom, A good or zero R 8 group (where R 8 represents a linear or branched lower alkyl group having 1 to 4 carbon atoms); R 2 represents a hydrogen atom, a halogen atom, or 4. The method according to claim 3, wherein is a linear or branched lower alkyl group having 1 to 6 carbon atoms (which may be unsubstituted or one or more hydrogen atoms may be substituted with a halogen atom). Nitric oxide synthase inhibitor. 5. The compound of the general formula [1] according to claim 3, wherein R, is a hydrogen atom, a chlorine atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a trifluorene group. R ₂ is a hydrogen atom, a methyl atom or an ethyl group, R 3 is a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n — Butyl, trifluoromethyl, 4. The nitric oxide synthase inhibitor according to claim 3, which is represented by 3 -aminopropyl group or 3-(t-butoxycarbonylamino) propyl group.  6. Pyrid [2,3—c] Franzine 1-oxide, 7 — Black mouth pill [2, 3c] 5 — methyl pyrido [2,3C] 6 — Methyl pyrido [2, 3C] 7 — Methyl bilide [2, 3C] flazan — Oxide 7 — Etezole pyrido [2, 3C] frazan — 1 year old n — Propir pyrido [2, 3 — c] Kisid, 7—isopropyl pyridone [2, 3 — c] Franzone 1-oxodid, 5, 7—dimethyl pyridone [2, 3-c] fura Zan-1-oxide, 5—ethyl-1 7—methinolide [2,3—c] Frazan-1-1-oxide, 7—methyl-5-η—propyl pyrid [2,3—c] phrazane-1 1-oxide, 5—isopropyl-1 7—methyl pyrido [2,3—c] phrazane-1 oxide, 5 — Η — Butyl — 7 — Methyl Bilide [2, 3 — c] Frazan-1 1-oxide, 7 — Methyl 1 5 — Trifluoromethyl pyrido [2, 3,- c] Frazan 1-11 years old, 5,7-bis (trifluoromethyl) pyrido [2,3—c] Frazan 11-year-old, 6 — Black mouth 5, 7 — Dimethyl pyrido [2 , 3 — c] Frazan-1 11-oxide, 5, 6, 6 — Trimethylpyridide [2, 3 — c] Frazan-11-oxide, 5, 7 —Dimethyl-6—ethylpyrid [2,3-c] frazan 1 1-oxide, 5— (3-aminopropyl) 1 7—methylpyrid 2 , 3-c] Frazan-1-oxide, 5-(3-t-butoxylrubonyl-amino-propyl)-1 7-Methynorpyrid [2,3-c ] Frazan-1-oxide, 7-methoxypyrid [2,3-c] Frazan-1-oxide, or a pharmaceutically acceptable salt thereof Nitric oxide synthase as an active ingredient. 7.7 — Methyl pyrido [2,3 — c] frazan 1 1 — oxide, 5, 7 — dimethyl pyrido [2, 3 — c] frazan -1-oxide, 5-ethyl 1 7-methyl pyrido [2,3-c] Franz-1 -oxide, 5-n-propyl 1 7 1-methylpyridone [2,3—c] flazan-1-oxide, 5—isopropyl-17-methylpyridone [2,3—c] flazan— 1-A nitric oxide synthase inhibitor comprising, as an active ingredient, acetic oxide or a pharmaceutically acceptable salt thereof.  8. An inducible nitric oxide synthase comprising the pyrid [2,3-c] flazan-1 one-year-old oxide derivative or a pharmaceutically acceptable salt thereof according to claim 1, 2 or 3 as an active ingredient. Inhibitors.  9.7 — Methinolepid [2, 3 — c] Frazan 1-Oxide, 5, 7 — Dimethyl pyrido [2, 3 — c] Frazan 1-1 oxide , 5 — ethyl 7 — methyl pyrido [2,3-c] frazan 1-oxide, 5 — η — propyl — 7-methyl pyrido [2, 3 — c] 1 — Oxide, 5 — Isopropyl 1 7 — Methyl pyrido [2,3-c] flazan 1 — Oxide or a pharmaceutically acceptable salt thereof as an active ingredient Inducible nitric oxide synthase inhibitor.  10. Inhibition of neuronal nitric oxide synthase comprising the pyrid [2,3-c] flazan-1-oxide derivative or the pharmaceutically acceptable salt thereof according to claim 1, 2 or 3 as an active ingredient. Agent. 11. A selectively derivatized nitric oxide comprising, as an active ingredient, a pyrid [2,3—c] flazan-1-oxoxide derivative or a pharmaceutically acceptable salt thereof according to claim 1, 2 or 3. What synthase inhibitors der, its selectivity is 1 C _5. . The ratio of the values (IC ₅ [endothelial] / 1 (:.. ₅ 0 5 or more in which selectively induced monoacid nitric synthase inhibitors [induced]. 1 2. The pyrid according to claim 1, 2 or 3 [2, 3 — c] Frazan-1 1 A drug for treating septic shock, an agent for treating arthritis or a therapeutic agent for allergic rhinitis, comprising a one-year-old xid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.  13. A therapeutic agent for cerebrovascular disorders comprising as an active ingredient a pyrido [2,3—c] flazan-1 monooxide derivative or a pharmaceutically acceptable salt thereof according to claim 1, 2 or 3. An agent for treating Parkinson's disease, an analgesic or an agent for treating obesity.  14. A medicament comprising the pyrid [2,3-c] flazan-1-year-old oxide derivative or a pharmaceutically acceptable salt thereof according to claim 3 as an active ingredient.  1 5. —General formula [2]

 [2] [Wherein, R 2 and R 3 are the same or independent substituents, and each represents a hydrogen atom, a halogen atom, a linear or branched lower alkyl group having 1 to 6 carbon atoms A substituted or halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, a COR 4 group (where R ₄ represents a hydroxyl group, a linear or branched lower alkoxy group having 1 to 4 carbon atoms) ), A pyridyl group (unsubstituted or a nitro group, a linear or branched lower alkyl group having 1 to 4 carbon atoms, or an amino group in which one or more hydrogen atoms are substituted) 1-oxypropyl [2,3—c] A jyl group (which may be unsubstituted, or a linear or branched lower alkyl group having 1 to 4 carbon atoms, in which one or more hydrogen atoms may be substituted), a 0R5 group (here, R ₅ represents a hydrogen atom, a straight-chain or branched lower alkyl group having 1 to 4 carbon atoms, an NR 6 R 7 group (where R _s and R 7 are a hydrogen atom, a straight-chain or branched A lower alkyl group having 1 to 4 carbon atoms in a technical chain, and a lower alkoxycarbonyl group having 1 to 4 linear or branched carbon atoms, R ₆ and R 7 may be the same or each are independent substituents, and one or more hydrogen atoms may be substituted}), OR 8 group (where R ₈ is a hydrogen atom, A chain or branched lower alkyl group having 1 to 4 carbon atoms; or an NR 9 R 10 group (where R ₉ , R, are hydrogen atoms, straight-chain or branched-chain carbon groups). Represents a lower alkyl group having 1 to 4 primes or a linear or branched lower acyl group having 1 to 4 carbons, and R ₃ , R, are the same or independent substituents Or R or R ₂ or R ₂ and R ₃ may be unsubstituted or substituted by a halogen atom or a lower alkyl group having 1 to 4 carbon atoms. 5 to 7 cycloalkane rings, or unsubstituted or 1 or more halogen atoms or lower alkyl groups having 1 to 4 carbon atoms Ru can and child to form a prime number five to seven of the city click lower Luque down ring. However, pyrido [2,3-1c] fluazane 1-oxide, 5-methyl pyrido [2,3-c] fluazane 1-oxide, 6- Methyl pyrido [2,3—c] frazan-1-oxide, 7—methyl pyrido [2,3-C] frazan-1-oxide, 5, 7 — Dimethyl Pyrid [2,3—c] flazan-1 1- flazan-1—oxide, 5—acetylaminopyrido [2,3—c] flazan-1—oxide Exclude. ] Or a pharmaceutically acceptable salt thereof.