JPH1081622A - New inhibitor for nitrogen monooxide synthetic enzyme - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject inhibitor useful as a treating agent for coreborovascular disorder, a treating agent for Parkinson's disease, an analgesic and a treating agent for obesity by using a specific new compound except some compounds as an active ingredient. SOLUTION: This inhibitor contains pyrido[2,3-c]furazan-1-oxide derivative or its pharmaceutically permissible salt (the molecular weight of 500 or less is suitable) which shows inhibitor concentration 50% (IC50 ) of 1mM or less for nitrogen monooxide synthetic enzyme and process inhibitory activity for nitrogen monooxide synthetic enzyme as an active ingredient. As this active ingredient, particularly a compound of the formula (R<1> -R<3> are each H, a hologen, an alkyl, and a cycloalkane and a cycloalkene combinating R<1> with R<2> and R<12> with R<13> ) is preferable. For example, 7-methylpyrido[2,3-c]furazan-1-oxide and 5,7-dimethylpyrido[2,3-c]furazan-1-oxide can be illustrated. This drug is also useful for septic shock and as a treating agent for arthritis and a treating agent for allergic rhinitis.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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.

[0002]

BACKGROUND OF THE INVENTION For decades, nitroglycerin has been administered to humans as a vasodilator in the treatment of cardiovascular disease. Recently, nitroglycerin administered in this way
It has been found in the body to convert it to nitric oxide, a pharmacologically active metabolite. Also, nitric oxide is an important component of vascular endothelium-derived relaxing factors (EDRFs),
It was found to be enzymatically formed from arginine as a normal metabolite. EDRFs have been actively studied recently as being involved in the regulation of blood flow and vascular resistance. It has been found that in vivo, macrophages and nerve cells also produce nitric oxide in addition to vascular endothelium. It was found that nitric oxide produced by macrophages exhibited cytotoxic and cytostatic effects, and that nitric oxide produced by nerve cells was involved in memory and the like as a signal transmitter.

[0003] More recently, it has been established that the enzyme that forms nitric oxide from arginine is nitric oxide synthase, consisting of three different types, endothelial, neuronal and inducible. Endothelial enzymes are constantly present in normal endothelial cells, and neural types are constantly present in nerve cells and the like. The formation of nitric oxide by endothelial enzymes in endothelial cells
It is thought to play a role in normal blood pressure regulation. or,
The formation of nitric oxide by neuronal enzymes in neurons plays a role in synaptic transmission plasticity and plays a role in memory and learning. It is thought that there is. On the other hand, the inducible enzyme was separated from activated macrophages, and it was revealed that endothelial cells or vascular smooth muscle cells were induced by various cytokines or combinations of cytokines. Severe and life-threatening severe hypotension, often observed in sepsis or cytokine-induced shock, is thought to be due primarily or entirely to overproduction of nitric oxide by inducible enzymes.

[0004] Therefore, these inhibitors of nitric oxide synthase, when inhibiting inducible nitric oxide synthase, produce septic shock (Lancet; 338, 15).
55 and 1557, 1991), arthritis (An
n. Rheum. Dis. ; 51, 1219, 19
92) and allergic rhinitis (Br. J. Pharm)
acol. 116, 1720, 1995), and the like, as a drug for improving diseases and symptoms.
When inhibiting neuronal nitric oxide synthase, cerebrovascular disorders (Eur. J. Pharmacol; 204, 33)
9, 1991 and Neurosci. Lett. ;
147, 159, 1992 and Science;
265, 1883, 1994), Parkinson's disease (Proc. Natl. Acad. Sci. USA; 8).
8, 6368, 1991), pain (Br. JP)
Pharmacol. 102, 198, 1991
Years) and obesity (Eur. J. Pharmacol .;
230, p. 125, 1993), and the like, as a drug for improving diseases and symptoms.

[0005] As noted above, the physiological and pathophysiological importance of nitric oxide has led to research into compounds that inhibit nitric oxide production in the body. The compound found to have this effect is NG-methyl-L-arginine (hereinafter abbreviated as NMMA in the present specification; for example, L
ancet; 338, 1555 and 1557, 1
991) and NG-nitro-L-arginine (hereinafter abbreviated as NNA in the present specification. For example, Eur. J. Pha
rmacol. 204, 339, 1991 and Neurosci. Lett. 147, 159,
1992).

Have reported an improving effect of NMMA in a rat endotoxin model which is an animal model of septic shock (L.
ancet; 338, 1555, 1991). This effect is attributed to the fact that NMMA inhibits inducible nitric oxide synthase. However, NMMA
It has also been reported that high doses can exacerbate 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. A. P. Have found that NNA, another nitric oxide synthase inhibitor, has an ameliorating effect on ischemic cerebral infarction (Eu).
r. J. Pharmacol; 204, 339, 1
991). This effect has been attributed to NNA's inhibition of neuronal nitric oxide synthase.

[0008]

However, the currently used nitric oxide synthase inhibitors NMMA and N
NA is highly toxic and other nitric oxide synthase inhibitors have been desired. Therefore, an investigation was made to find a nitric oxide synthase inhibitor belonging to a strain different from the conventional one in chemical structure.

In addition, the currently used nitric oxide synthase inhibitors NMMA and NNA have an inhibitory activity of inducible nitric oxide synthase weaker than that of endothelial nitric oxide synthase. Was not satisfactory.
For this reason, 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 find a nitric oxide synthase inhibitor that inhibits inducible nitric oxide synthase more strongly than endothelial nitric oxide synthase, that is, is selective for inducible nitric oxide synthase. We considered it.

[0010] Furthermore, NMMA and NNA have not been sufficiently satisfactory in their selectivity in the inhibitory action of neuronal nitric oxide synthase and endothelial nitric oxide synthase. For this reason, various studies have been made on derivatives of NMMA and NNA and related compounds, but no satisfactory results have been found. Thus, the present inventors find a nitric oxide synthase inhibitor that inhibits neuronal nitric oxide synthase more strongly than endothelial nitric oxide synthase, that is, is selective for neuronal nitric oxide synthase. We considered it.

[0011]

Means for Solving the Problems As a result of diligent studies, the present inventors have newly found that pyrido [2,3-c] furazan-1-oxide derivatives or pharmaceutically acceptable salts thereof inhibit nitric oxide synthase. It has been found to have an effect. Also, the pyrido [2,3-c] furazan-1-oxide derivative or a pharmaceutically acceptable salt thereof has a stronger inhibitory effect on inducible nitric oxide synthase than endothelial nitric oxide synthase. Was found to have. Conventionally, pyrido [2,3-c]
There is no report that a compound having a furazan-1-oxide skeleton has the enzyme inhibitory activity, and a new class of the inhibitors has been developed by the present invention.

That is, the present invention provides (1) a 50% nitric oxide synthase inhibitory concentration (IC ₅₀ ) of 1 mM or less;
Pyrido [2,3- having nitric oxide synthase inhibitory activity
c] a nitric oxide synthase inhibitor comprising a furan-1-oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient;
(2) Nitric oxide synthase inhibitory activity, molecular weight 5
A pyrido [2,3-c] furazan-1-oxide derivative or a pharmaceutically acceptable salt thereof having an active ingredient of not more than 00; (3) a general formula [1]

[0013]

Embedded image

[Wherein R ¹ , R ² and R ³ are the same or each independently a substituent, and are a hydrogen atom, a halogen atom, a straight-chain or branched lower-chain having 1 to 6 carbon atoms. Alkyl group 置換 unsubstituted or halogen atom, cycloalkyl group having 3 to 8 carbon atoms, COR ⁴ group (where R ⁴ group is a hydroxyl group, linear or branched lower alkoxy having 1 to 4 carbon atoms) Group), 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 may be substituted with an amino group) A 1-oxy-pyrido [2,3-c] furazyl group (unsubstituted or substituted by one or more hydrogen atoms by a linear or branched lower alkyl group having 1 to 4 carbon atoms) An OR ⁵ group (where R ⁵ is a hydrogen atom, a linear or branched C 1 group)
４4 lower alkyl groups), NR ⁶ R ⁷ group (where R ⁶ and R ⁷ are a hydrogen atom, a linear or branched C 1 group)
~ 4 lower alkyl groups, straight or branched C1
It indicates to four lower alkoxycarbonyl group, R ^6, R
⁷ is the same or each is an independent substituent), and one or more hydrogen atoms may be substituted.
An R ⁸ group (where R ⁸ represents a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms) or NR ⁹ R ¹⁰
A group (where R ⁹ and R ¹⁰ are a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or branched lower acyl group having 1 to 4 carbon atoms) And R ⁹ and R ¹⁰ are the same or each independently a substituent), or further, R ¹ and R ² or R ² and R ³ together are unsubstituted or halogen atom, lower A cycloalkane ring having 5 to 7 carbon atoms which may be substituted with one or more alkyl groups, or a cycloalkane ring having 5 to 7 carbon atoms which may be unsubstituted or substituted with one or more halogen atoms or lower alkyl groups; An alkene ring can be formed. [2,3]
-C] A nitric oxide synthase inhibitor comprising a furan-1-oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

(4) Further, the present invention provides a compound as described in the above item 3, wherein R ¹ is a hydrogen atom, a halogen atom, a straight-chain or branched lower alkyl group having 1 to 6 carbon atoms. One or more hydrogen atoms may be substituted or substituted with a halogen atom) or an OR ⁸ group (where R ⁸ is a linear or branched lower alkyl group having 1 to 4 carbon atoms) , R ² is a hydrogen atom, a halogen atom, or a linear or branched lower alkyl group having 1 to 6 carbon atoms (unsubstituted or one or more hydrogen atoms may be substituted with a halogen atom) 4. The nitric oxide synthase inhibitor according to item 3, wherein

(5) The present invention further provides the compound according to the above item 3, wherein R ¹ is hydrogen, chlorine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy. R ² represents a hydrogen atom, a chlorine atom, a methyl group or an ethyl group, R ³ represents a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n
4. The nitric oxide synthase inhibitor according to item 3, which represents -butyl, trifluoromethyl, 3-aminopropyl or 3- (t-butoxycarbonylamino) propyl.

(6) Further, the present invention provides a pyrido [2,3-
c] Furazan-1-oxide, 7-chloropyrido [2,
3-c] furazan-1-oxide, 5-methylpyrido [2,3-c] furazan-1-oxide, 6-methylpyrido [2,3-c] furazan-1-oxide, 7-methylpyrido [2,3- c] Furazan-1-oxide, 7-
Ethylpyrido [2,3-c] furazan-1-oxide,
7-n-propylpyrido [2,3-c] furazan-1-
Oxide, 7-isopropylpyrido [2,3-c] furazan-1-oxide, 5,7-dimethylpyrido [2,3
-C] furazan-1-oxide, 5-ethyl-7-methylpyrido [2,3-c] furazan-1-oxide, 7-
Methyl-5-n-propylpyrido [2,3-c] furazan-1-oxide, 5-isopropyl-7-methylpyrido [2,3-c] furazan-1-oxide, 5-n-butyl-7-methylpyrido [ 2,3-c] furazan-1-
Oxide, 7-methyl-5-trifluoromethylpyrido [2,3-c] furazan-1-oxide, 5,7-bis (trifluoromethyl) pyrido [2,3-c] furazan-1-oxide, 6-chloro-5,7-dimethylpyrido [2,3-c] furazan-1-oxide, 5,6,7-
Trimethylpyrido [2,3-c] furazan-1-oxide, 5,7-dimethyl-6-ethylpyrido [2,3-
c] Furazan-1-oxide, 5- (3-aminopropyl) -7-methylpyrido [2,3-c] furazan-1-
Oxide, 5- (3-t-butoxycarbonylaminopropyl) -7-methylpyrido [2,3-c] furazan-
The present invention relates to a nitric oxide synthase inhibitor comprising 1-oxide, 7-methoxypyrido [2,3-c] furazan-1-oxide or a pharmaceutically acceptable salt thereof as an active ingredient.

(7) Further, the present invention relates to 7-methylpyrido [2,3-c] furazan-1-oxide, 5,7-dimethylpyrido [2,3-c] furazan-1-oxide,
-Ethyl-7-methylpyrido [2,3-c] furazan-
1-oxide, 5-n-propyl-7-methylpyrido [2,3-c] furazan-1-oxide, 5-isopropyl-7-methylpyrido [2,3-c] furazan-1-
The present invention relates to a nitric oxide synthase inhibitor comprising, as an active ingredient, an oxide or a pharmaceutically acceptable salt thereof.

(8) The present invention relates to an inducible monoxide comprising the pyrido [2,3-c] furazan-1-oxide derivative or the pharmaceutically acceptable salt thereof according to the above item 1, 2 or 3 as an active ingredient. It relates to a nitrogen synthase inhibitor.

(9) The present invention relates to 7-methylpyrido [2,3
-C] furazan-1-oxide, 5,7-dimethylpyrido [2,3-c] furazan-1-oxide, 5-ethyl-7-methylpyrido [2,3-c] furazan-1-oxide, 5-n -Propyl-7-methylpyrido [2,3-
c] Furazan-1-oxide, 5-isopropyl-7-
The present invention relates to an inducible nitric oxide synthase inhibitor comprising methylpyrido [2,3-c] furazan-1-oxide or a pharmaceutically acceptable salt thereof as an active ingredient.

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

(11) Further, the present invention provides a method for selectively deriving a pyrido [2,3-c] furazan-1-oxide derivative or a pharmaceutically acceptable salt thereof as described in the above item 1, 2 or 3 as an active ingredient. A nitric oxide synthase inhibitor, wherein the selectivity is the ratio of IC50 values (IC50 [endothelial type] / IC50
[Inducible type]) and a selective inducible nitric oxide synthase inhibitor of 0.5 or more, preferably 30 or more.

(12) The present invention also provides a septic shock comprising the pyrido [2,3-c] furazan-1-oxide derivative or the pharmaceutically acceptable salt thereof as described in the above item 1, 2 or 3 as an active ingredient. And a therapeutic agent for treating arthritis or a therapeutic agent for allergic rhinitis.

(13) The present invention also provides a cerebrovascular disorder comprising the pyrido [2,3-c] furazan-1-oxide derivative or the pharmaceutically acceptable salt thereof as described in the above item 1, 2 or 3 as an active ingredient. 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 the pyrido [2,3-c] furazan-1-oxide derivative or the pharmaceutically acceptable salt thereof described in the above item 3 as an active ingredient.

(15) Further, the present invention provides a compound represented by the following general formula [2]:

[0027]

Embedded image [Wherein, R ¹ , R ² , and R ³ are the same or each independently a substituent, and are a hydrogen atom, a halogen atom, a linear or branched lower alkyl group having 1 to 6 carbon atoms.] Unsubstituted or halogen atom, cycloalkyl group having 3 to 8 carbon atoms, COR ⁴ group (here, R ⁴ group is 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, and one or more hydrogen atoms may be substituted with an amino group), 1- Oxy-pyrido [2,3-c] furazyl group (unsubstituted or one or more hydrogen atoms may be substituted by a linear or branched lower alkyl group having 1 to 4 carbon atoms) , OR ⁵ groups (where R
⁵ represents a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms), an NR ⁶ R ⁷ group (here, R ⁶ and R
⁷ represents a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or branched lower alkoxycarbonyl group having 1 to 4 carbon atoms, R ⁶ , R ^{6 7} are the same or, alternatively each independent is a substituent) of which may be substituted one or more hydrogen atoms on either}, oR ⁸ group (wherein R ⁸ is a hydrogen atom, a linear or branched Carbon number 1
Or 4 to 4 lower alkyl groups) or NR ⁹ R ¹⁰ group (where R ⁹ and R ¹⁰ are a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or Represents a branched lower acyl group having 1 to 4 carbon atoms, wherein R ⁹ and R ¹⁰ are the same,
Or R ¹ and R ² or R ² and R ³ together are unsubstituted or at least one of a halogen atom and a lower alkyl group having 1 to 4 carbon atoms. A cycloalkane ring having 5 to 7 carbon atoms which may be substituted, or 5 to 5 carbon atoms which may be unsubstituted or substituted by one or more halogen atoms or lower alkyl groups having 1 to 4 carbon atoms;
Seven cycloalkene rings can be formed. However, pyrido [2,3-c] furazan-1-oxide, 5
-Methylpyrido [2,3-c] furazan-1-oxide, 6-methylpyrido [2,3-c] furazan-1-oxide, 7-methylpyrido [2,3-c] furazan-1
-Oxide, 5,7-dimethylpyrido [2,3-c] furazan-1-oxide, 5-aminopyrido [2,3-
c] Furazan-1-oxide, excluding 5-acetylaminopyrido [2,3-c] furazan-1-oxide. And a pyrido [2,3-c] furazan-1-oxide derivative represented by the formula:

[0028]

DETAILED DESCRIPTION OF THE INVENTION In the present invention, pyrido [2,3
-C] furazane-1-oxide derivatives include pyrido [2,3-
c] furazane-1-oxide derivatives,
When it has two substituents, adjacent substituents may be bonded to form a ring. There are no particular restrictions on these substituents as long as they do not impair the nitric oxide synthase inhibitory action, and halogen atoms, alkyl groups, halogenoalkyl groups, cycloalkylalkyl groups, alkoxycarbonylalkyl groups, aminoalkyl Group, (alkoxycarbonyl) aminoalkyl group, alkyl and nitro-substituted pyridylalkyl group, alkyl-substituted 1-oxy-pyrido [2,3-c] furazylalkyl group, alkoxy group, amino group, mono- or dialkyl-substituted amino group, acylamino And the like.

In the case where adjacent substituents are bonded to form a ring, pyrido [2,3-c] furazan-
There is a case where a 5- to 7-membered ring is formed by sharing one side with the pyridine ring of 1-oxide, and these formed rings may be substituted with the substituents described above. As the alkyl group in the present invention, a lower alkyl group is preferable.

In the present invention, the halogen atom includes
Examples 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, an n-pentyl group, and an n-hexyl group. And preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group and an n-butyl group. Examples of the cycloalkyl group having 3 to 8 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group, and a cyclohexyl group is preferable. Examples of the linear or branched lower alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, and an n-butoxy group.
Preferred are a methoxy group and an ethoxy group. Examples of the straight-chain or branched lower alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group and an n-butyl group.
It is 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, a t-butoxycarbonyl group and the like, and a t-butoxycarbonyl group is preferable. Examples of the linear or branched lower acyl group having 1 to 4 carbon atoms include an alkylcarbonyl group such as an acetyl group, a propionyl group, an n-butyryl group and an isobutyryl group, and preferably an acetyl group and a propionyl group. Group.

Unsubstituted or halogen atom, having 1 to 4 carbon atoms
5 carbon atoms which may be substituted by one or more lower alkyl groups
As the cycloalkane ring or cycloalkene ring of up to 7, unsubstituted or methyl, ethyl, propyl, chlorine atom,
Cycloalkane rings and cycloalkene rings into which one or more fluorine atoms have been introduced are exemplified. Preferably it is 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 each independently a substituent, and R ¹ is a hydrogen atom, a halogen atom, a linear or branched lower alkyl group having 1 to 6 carbon atoms ( An unsubstituted or halogen atom may be substituted with one or more hydrogen atoms, or an OR ⁸ group (where R ⁸ represents a linear or branched lower alkyl group having 1 to 4 carbon atoms) ) And R ² are a hydrogen atom, a halogen atom, or a linear or branched lower alkyl group having 1 to 6 carbon atoms (unsubstituted or substituted with one or more hydrogen atoms by a halogen atom. R ³ is a hydrogen atom, a halogen atom, a linear or branched lower alkyl group having 1 to 6 carbon atoms [unsubstituted or a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, COR ⁴ group (where R ⁴ group is a hydroxyl group, a linear or branched lower alkyl group having 1 to 4 carbon atoms) A alkoxy group), 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) A 1-oxy-pyrido [2,3-c] furazyl group (unsubstituted or a linear or branched lower alkyl group having 1 to 4 carbon atoms and one or more hydrogen atoms ^May be substituted), an OR ⁵ group (where R ⁵ is a hydrogen atom, a linear or branched C 1 group)
４4 lower alkyl groups), NR ⁶ R ⁷ groups (where R ⁶ and R ⁷ represent a hydrogen atom or a linear or branched lower alkoxycarbonyl group having 1 to 4 carbon atoms) , R
⁶ , R ⁷ may be the same or each independently a substituent), and one or more hydrogen atoms may be substituted], or an OR ⁸ group (where R ⁸ is a hydrogen atom, a linear or Represents a branched lower alkyl group having 1 to 4 carbon atoms) or N
R ⁹ R ¹⁰ groups (where R ⁹ and R ¹⁰ are a hydrogen atom, a straight-chain or branched lower alkyl group having 1 to 4 carbon atoms, a straight-chain or branched-chain lower alkyl group having 1 to 4 carbon atoms) Represents a lower acyl group of R ⁹ ,
R ¹⁰ is the same or each independently a substituent). R ¹ and R ² or R ² and R ³ may together form a cycloalkane ring or a cycloalkene ring. preferable.

Further preferred compounds are the following compounds. In the compound of the general formula [1], R ¹ , R ² , R ³
Are the same or independent substituents, and R ¹ is a hydrogen atom, a chlorine atom, a methyl group, an ethyl group, an n-
Propyl group, isopropyl group, trifluoromethyl group or methoxy group, R ² is a hydrogen atom, a chlorine atom, a methyl group or an ethyl group, R ³ is a methyl group, an ethyl group,
n-propyl group, isopropyl group, n-butyl group, trifluoromethyl group, 3-aminopropyl group or 3- (t
A -butoxycarbonylamino) propyl group is preferred.

The specific pyrido [2,3-c] furazan-1-oxide of the present invention includes, for example, pyrido [2,3
-C] furazan-1-oxide, 5-chloropyrido [2,3-c] furazan-1-oxide, 7-chloropyrido [2,3-c] furazan-1-oxide, 5-methylpyrido [2,3-c ] Furazan-1-oxide, 6-
Methylpyrido [2,3-c] furazan-1-oxide,
7-methylpyrido [2,3-c] furazan-1-oxide, 7-ethylpyrido [2,3-c] furazan-1-oxide, 7-n-propylpyrido [2,3-c] furazan-1-oxide, 7-isopropylpyrido [2,3-
c] furazan-1-oxide, 5-chloro-7-methylpyrido [2,3-c] furazan-1-oxide, 5,7
-Dimethylpyrido [2,3-c] furazan-1-oxide, 5-ethyl-7-methylpyrido [2,3-c] furazan-1-oxide, 7-methyl-5-n-propylpyrido [2,3-c ] Furazan-1-oxide, 5-isopropyl-7-methylpyrido [2,3-c] furazan-
1-oxide, 5-n-butyl-7-methylpyrido [2,3-c] furazan-1-oxide, 5-cyclohexylmethyl-7-methylpyrido [2,3-c] furazan-1-oxide, 7-methyl -5-trifluoromethylpyrido [2,3-c] furazan-1-oxide, 5,
7-bis (trifluoromethyl) pyrido [2,3-c]
Furazan-1-oxide, 5- {5- (6-amino-4)
-Methyl-3-nitropyridyl-2-yl) pentyl
-7-methylpyrido [2,3-c] furazan-1-oxide, 1,5-bis (7-methylpyrido [2,3-c]
Furazan-1-oxide-5-yl) pentane, 6-chloro-5,7-dimethylpyrido [2,3-c] furazan-1-oxide, 5,6,7-trimethylpyrido [2
3-c] Furazan-1-oxide, 5,7-dimethyl-
6-ethylpyrido [2,3-c] furazan-1-oxide, 7-methyl-5,6-cyclopentenopyrido [2
3-c] furazan-1-oxide, 5-methyl-6,7
-Cyclopentenopyrido [2,3-c] furazan-1-
Oxide, 7-methyl-5,6-cyclohexenopyrido [2,3-c] furazan-1-oxide, 5-methyl-
6,7-cyclohexenopyrido [2,3-c] furazan-1-oxide, 5-ethoxycarbonylmethyl-7-
Methylpyrido [2,3-c] furazan-1-oxide,
5-aminomethyl-7-methylpyrido [2,3-c] furazan-1-oxide, 5- (t-butoxycarbonylamino) methyl-7-methylpyrido [2,3-c] furazan-1-oxide, 5- (3-aminopropyl) -7
-Methylpyrido [2,3-c] furazan-1-oxide, 5- (3-t-butoxycarbonylaminopropyl) -7-methylpyrido [2,3-c] furazan-1-
Oxide, 5-methoxypyrido [2,3-c] furazan-1-oxide, 7-methoxypyrido [2,3-c] furazan-1-oxide, 5-methoxy-7-methylpyrido [2,3-c] furazan- 1-oxide, 5-aminopyrido [2,3-c] furazan-1-oxide, 5-methylaminopyrido [2,3-c] furazan-1-oxide, 5-dimethylaminopyrido [2,3- c] Furazan-1-oxide, 5-acetylaminopyrido [2,3-
c] furazan-1-oxide, 5-amino-7-methylpyrido [2,3-c] furazan-1-oxide, 5-acetylamino-7-methylpyrido [2,3-c] furazan-1-oxide and the like No.

Preferably, pyrido [2,3-c] furazan-1-oxide, 7-chloropyrido [2,3-c] furazan-1-oxide, 5-methylpyrido [2,3-
c] Furazan-1-oxide, 6-methylpyrido [2,
3-c] furazan-1-oxide, 7-methylpyrido [2,3-c] furazan-1-oxide, 7-ethylpyrido [2,3-c] furazan-1-oxide, 7-n-
Propylpyrido [2,3-c] furazan-1-oxide, 7-isopropylpyrido [2,3-c] furazan-
1-oxide, 5,7-dimethylpyrido [2,3-c]
Furazan-1-oxide, 5-ethyl-7-methylpyrido [2,3-c] furazan-1-oxide, 7-methyl-5-n-propylpyrido [2,3-c] furazan-1
-Oxide, 5-isopropyl-7-methylpyrido [2,3-c] furazan-1-oxide, 5-n-butyl-7-methylpyrido [2,3-c] furazan-1-oxide, 7-methyl-5 -Trifluoromethylpyrido [2,3-c] furazan-1-oxide, 5,7-bis (trifluoromethyl) pyrido [2,3-c] furazan-1-oxide, 6-chloro-5,7 -Dimethylpyrido [2,3-c] furazan-1-oxide, 5,6,7-
Trimethylpyrido [2,3-c] furazan-1-oxide, 5,7-dimethyl-6-ethylpyrido [2,3-
c] Furazan-1-oxide, 5- (3-aminopropyl) -7-methylpyrido [2,3-c] furazan-1-
Oxide, 5- (3-t-butoxycarbonylaminopropyl) -7-methylpyrido [2,3-c] furazan-
1-oxide, 7-methoxypyrido [2,3-c] furazan-1-oxide and the like.

More preferably, 7-methylpyrido [2,
3-c] furazan-1-oxide, 5,7-dimethylpyrido [2,3-c] furazan-1-oxide, 5-ethyl-7-methylpyrido [2,3-c] furazan-1-oxide, 7- Methyl-5-n-propylpyrido [2,3
-C] furazan-1-oxide, 5-isopropyl-7
-Methylpyrido [2,3-c] furazan-1-oxide and the like.

The pyrido [2,3-
The c] furazan-1-oxide derivatives include, for example, tautomers such as pyrido [2,3-c] furazan-3-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 for inhibiting 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, pharmaceutically acceptable salts of the pyrido [2,3-c] furazan-1-oxide derivative include, for example, hydrochloride, sulfate, nitrate, phosphate, methanesulfonate, Toluenesulfonate and the like can be mentioned. Preferred 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 converted from the formula [1] by a pyrido [2,
3-c] furazan-1-oxide, 5-methylpyrido [2,3-c] furazan-1-oxide, 6-methylpyrido [2,3-c] furazan-1-oxide, 7-methylpyrido [2,3- c] furazan-1-oxide, 5,
7-dimethylpyrido [2,3-c] furazan-1-oxide, 5-aminopyrido [2,3-c] furazan-1-oxide
It is the same as the formula [1] except that the oxide and 5-acetylaminopyrido [2,3-c] furazan-1-oxide are excluded. These are useful as an active ingredient of the nitric oxide synthase inhibitor as described above.

The above-mentioned known pyrido [2,3-c] furazan-1-oxide derivatives (for example, J. Chem. So
c. (B); p. 636, 1970; Org, C
hem. 55, 3755-3761, 1990.
) Is based on oxidative cyclization reactions described in the literature from readily available raw materials, addition reactions and subsequent denitrification cyclization reactions (for example, J. Am. Chem. Soc .; 75, 5298).
Pp. 1953 and 78, 423, 1956,
J. Chem. Soc. (C); p. 1874, 1970
) Can be easily manufactured by using a known technique.

A typical process for producing the pyrido [2,3-c] furazan-1-oxide derivative of the present invention, which is a novel compound, is shown below. Note that these pyridos [2,
The method for synthesizing 3-c] furazan-1-oxide derivative is not limited to the following method.

Manufacturing method A

[0044]

Embedded image

(Wherein R ¹ , 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 2-amino-
It is produced by oxidatively cyclizing a 3-nitropyridine derivative [3]. 2-amino-3 used here
-Nitropyridine derivative [3] is commercially available from, for example, Aldrich Co., Ltd., or can be obtained by production methods BD.

The oxidative cyclization of the 2-amino-3-nitropyridine derivative [3] is carried out with an oxidizing agent or the like. Examples of the oxidizing agent include iodosyl compound-based oxidizing agents such as iodosobenzene diacetate, iodosobenzenebis (trifluoroacetate), iodosobenzenediformate, iodosobenzenedi (chloroacetate), and ceric nitrate Metal oxidizing agents such as ammonium and lead tetraacetate, and inorganic halogen oxidizing agents such as sodium hypochlorite and potassium hypochlorite are used, and iodosyl compound oxidizing agents such as iodosobenzene diacetate are used. Is preferred. These oxidizing agents are used in an amount of about 0.1 to 10 moles, more preferably about 0.5 to 3 moles, per mol of the 2-amino-3-nitropyridine derivative [3]. The reaction is usually performed in an organic solvent, in water or without a solvent, but is preferably performed in an organic solvent. As the organic solvent, for example, benzene, toluene, aromatic hydrocarbons such as xylene, methanol, alcohols such as ethanol, dioxane, ethers such as tetrahydrofuran,
Halogen-based hydrocarbons such as methylene chloride and chloroform;
Ketones such as acetone and methyl ethyl ketone, esters such as methyl acetate, ethyl acetate, butyl acetate, methyl propionate and ethyl propionate, and polar aprotic solvents such as dimethyl sulfoxide and dimethylformamide are used. And aromatic ketones such as acetone, and esters such as ethyl acetate. These reaction solvents can be used alone or as a mixture. The reaction temperature is not particularly limited, cooling, room temperature,
Any heating may be used, but preferably -5 to 40 ° C. The reaction is performed 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]
It is 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 10 to 10
The range is 0%. Examples of production by this method include Production Examples 1 to 9.

Manufacturing method B

[0049]

Embedded image

(Here, R ¹ , R ² and R ³ have the same meanings as described above.) The 2-amino-3-nitropyridine derivative [3] is
It is produced by nitrating an aminopyridine derivative [4]. The 2-aminopyridine derivative [4] used here is commercially available, for example, from Aldrich Co., Ltd., or obtained from easily available raw materials, for example, PCT Publication WO9618616, PCT Publication WO9709982,
Chem. Abst. 73, p. 14700x.

The nitration reaction of the 2-aminopyridine derivative [4] is performed with a nitrating agent or the like. Examples of the nitrating agent include nitrating agents such as nitric acid, nitronium tetrafluoroborate, tetra-n-butylammonium nitrate, nitric acid-sulfuric acid, fuming nitric acid-sulfuric acid, nitric acid-acetic anhydride, nitric acid-trifluoroacetic anhydride, and nitric acid A mixed acid such as acetic acid, potassium nitrate-sulfuric acid and the like are used, but a mixed acid such as nitric acid-sulfuric acid and the like are preferable. These nitrating agents are used in an amount of about 0.1 to 100 moles, more preferably about 0.5 to 100 moles, per mole of the 2-aminopyridine derivative [4]. The reaction is usually carried out in an organic solvent, water, an inorganic acid or in the absence of a solvent, but is preferably carried out in an inorganic acid. Sulfuric acid and the like are preferable as the inorganic acid. The reaction temperature is not particularly limited, and may be any of cooling, normal temperature, and heating, but preferably -5 to 120 ° C. The reaction is carried out for 0.5 to 100 hours, more preferably for 1 to 48 hours.

The 2-amino-3-nitropyridine derivative [3] produced by this method is 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%. Manufacturing examples via this method include Manufacturing Examples 2, 3, 4, and 6
And the like.

Manufacturing method C

[0054]

Embedded image

(Here, R ¹ , R ² and R ³ have the same meanings as described above.) The 2-amino-3-nitropyridine derivative [3]
3-dicarbonyl compound [5] and 1,1-diamino-2
Also produced by reacting -nitroethene [6]. The 1,3-dicarbonyl compound [5] used here is, for example, commercially available from Aldrich Co., Ltd., or easily obtained by a known method. 1,1
-Diamino-2-nitroethene [6] is, for example, Arc
h. Pharm. (Weinheim); 324, 7
It can be easily obtained by the method described on page 3, 1991, or the like.

1,1-Diamino-2-nitroethene [6] is added to the 1,3-dicarbonyl compound [5] in an amount of 0.1 to 0.1.
It is used in an amount of about 10 to 10 moles, more preferably about 0.2 to 3 moles. A catalyst can be used if necessary, and the use of a catalyst gives good results. The catalyst may be either an acid catalyst or a base catalyst, but it is preferable to use an acid catalyst. As the acid catalyst, for example, sulfuric acid,
Inorganic acids such as hydrochloric acid, hydrobromic acid and hydrofluoric acid, and organic acids such as acetic acid, propionic acid, p-toluenesulfonic acid and camphorsulfonic acid are used, but acetic acid is preferred.
These acid catalysts include 1,3-dicarbonyl compounds [5]
It is used in an amount of about 0.01 to 100 moles, more preferably about 0.1 to 10 moles. The reaction is usually performed in an organic solvent, in water or without a solvent, but is preferably performed in an organic solvent. As the organic solvent, for example, benzene, toluene, aromatic hydrocarbons such as xylene, methanol, alcohols such as ethanol, dioxane,
Ethers such as tetrahydrofuran and the like, halogenated hydrocarbons such as methylene chloride and chloroform, polar aprotic solvents such as dimethyl sulfoxide and dimethylformamide and the like are used, and alcohols such as methanol and ethanol are preferable. The reaction temperature is not particularly limited, cooling,
Any of normal temperature and heating may be used, but preferably -5 to 10
0 ° C is good. The reaction is performed for 0.5 to 100 hours, more preferably for 1 to 50 hours.

The 2-amino-3-nitropyridine derivative [3] produced by this method is isolated by a usual isolation method such as extraction, recrystallization or chromatography. The reaction yield of this reaction varies depending on the starting materials, reaction conditions and the like, but is generally in the range of 1 to 100%. As a production example via this method, Production Example 8 and the like are given.

Manufacturing method D

[0059]

Embedded image

(Here, R ¹ , R ² and R ³ have the same meanings as described above.) The 2-amino-3-nitropyridine derivative [3]
It is also produced by aminating a 2-chloro-3-nitropyridine derivative [8] obtained by nitrating a chloropyridine derivative [7]. The 2-chloropyridine derivative [7] used here is commercially available, for example, from Aldrich Co., Ltd.
m. Ber. 103, p. 389, 1970. Also, 2-chloro-3
-Nitropyridine derivative [8] is commercially available from Aldrich Co., Ltd., or can be easily obtained by a known method or the like.

The nitration reaction of the 2-chloropyridine derivative [7] is performed with a nitrating agent or the like. Examples of the nitrating agent include nitrating agents such as nitric acid, nitronium tetrafluoroborate, tetra-n-butylammonium nitrate, nitric acid-sulfuric acid, fuming nitric acid-sulfuric acid, nitric acid-acetic anhydride, nitric acid-trifluoroacetic anhydride, and nitric acid A mixed acid such as acetic acid, potassium nitrate-sulfuric acid and the like are used, but a mixed acid such as nitric acid-sulfuric acid and the like are preferable. These nitrating agents are used in an amount of about 0.1 to 100 moles, more preferably about 0.5 to 100 moles, based on the 2-chloropyridine derivative [7]. The reaction is usually carried out in an organic solvent, water, an inorganic acid or in the absence of a solvent, but is preferably carried out in an inorganic acid. Sulfuric acid and the like are preferable as the inorganic acid. The reaction temperature is not particularly limited, and may be any of cooling, normal temperature, and heating, but 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 reaction of the 2-chloro-3-nitropyridine derivative [8] is carried out with an aminating agent such as ammonia or sodium amide, but it is preferable to use ammonia or the like. Ammonia is 2-chloro-3-
It is used in an amount of about 0.1 to 50 times, more preferably about 0.5 to 10 times, the mole of the nitropyridine derivative [8]. The reaction is usually performed in an organic solvent or water. As the organic solvent, for example, alcohols such as methanol and ethanol, and ethers such as dioxane and tetrahydrofuran are used, and alcohols such as methanol and ethanol are preferable. It is also preferable to carry out in water. The reaction temperature is not particularly limited, cooling, room temperature,
Any heating may be used, but preferably -5 to 200 ° C
Is good. The reaction is carried out for 0.5 to 100 hours, more preferably for 1 to 48 hours.

The 2-amino-3-nitropyridine derivative [3] produced by this method is 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%. A production example via this method includes Production Example 9 and the like.

The pyrido [2,3-c] furazan- of the present invention
When the 1-oxide derivative or a pharmaceutically acceptable salt thereof is used as a nitric oxide synthase inhibitor, it may be used alone or with a pharmaceutically acceptable additive such as a carrier, an excipient, a diluent, and a solubilizing agent. Mixed orally or non-injectively, in the form of injections, drops, granules, tablets, fine granules, powders, capsules, inhalants, suppositories, eye drops, patches, ointments, sprays, etc. It can be safely administered orally (systemic administration, local administration, etc.) to mammals.

Pyrido [2,3-c] furazan in the formulation
The content of the 1-oxide derivative or a pharmaceutically acceptable salt thereof varies depending on the preparation, but is usually preferably 0.1 to 100% by weight. The dosage depends on the patient's age, weight,
The dose is generally about 0.001 to 3000 mg / kg / day, depending on the condition, the purpose of treatment and the like.

In the present invention, pyrido [2,3-c]
The selective inducible nitric oxide synthase inhibitor containing a furan-1-oxide derivative or a salt thereof as an active ingredient has a selectivity of a ratio of IC50 value (IC50 [endothelial type] / IC50
[Induction type]) It is 0.5 or more, more preferably 30 or more.

[0067]

EXAMPLES Next, pyrido [2,3-c] furazan-1-
The inhibitory effect of the oxide derivative on nitric oxide synthase will be described based on the following experimental examples using the present compound. Furthermore,
Production examples of the compound of the present invention are also shown.

Compound of the present application Compound No. 1 pyrido [2,3-c] furazan-1-
Oxide Compound No. 25-chloropyrido [2,3-c] furazan-1-oxide Compound No. 37-Chloropyrido [2,3-c] furazan-1-oxide Compound No. 4 5-Methylpyrido [2,3-c] furazan-1-oxide Compound No. 4 5 6-Methylpyrido [2,3-c] furazan-1-oxide Compound No. 5 67-Methylpyrido [2,3-c] furazan-1-oxide Compound no. 77-ethylpyrido [2,3-c] furazan-1-oxide Compound No. 87-n-propylpyrido [2,3-
c] Furazan-1-oxide Compound No. 97-isopropylpyrido [2,3-
c] Furazan-1-oxide Compound No. Compound No. 10 5-Chloro-7-methylpyrido [2,3-c] furazan-1-oxide 11 5,7-dimethylpyrido [2,3-
c] Furazan-1-oxide Compound No. 12 5-Ethyl-7-methylpyrido [2,3-c] furazan-1-oxide Compound no. 13 7-Methyl-5-n-propylpyrido [2,3-c] furazan-1-oxide Compound no. 14 5-Isopropyl-7-methylpyrido [2,3-c] furazan-1-oxide Compound No. 15 5-n-butyl-7-methylpyrido [2,3-c] furazan-1-oxide Compound No. 15 16 5-cyclohexylmethyl-7-methylpyrido [2,3-c] furazan-1-oxide Compound no. 177-Methyl-5-trifluoromethylpyrido [2,3-c] furazan-1-oxide 18 5,7-bis (trifluoromethyl) pyrido [2,3-c] furazan-1-oxide Compound No. 19 5- {5- (6-amino-4-methyl-3-nitropyridyl-2-yl) pentyl} -7-
Methylpyrido [2,3-c] furazan-1-oxide Compound No. 20 1,5-bis (7-methylpyrido [2,3-c] furazan-1-oxide-5-yl) pentane Compound No. 20 21 6-chloro-5,7-dimethylpyrido [2,3-c] furazan-1-oxide Compound No. 21 22 5,6,7-trimethylpyrido [2,3-c] furazan-1-oxide Compound no. 23 5,7-dimethyl-6-ethylpyrido [2,3-c] furazan-1-oxide Compound no. 24 7-Methyl-5,6-cyclopentenopyrido [2,3-c] furazan-1-oxide and 5-
Methyl-6,7-cyclopentenopyrido [2,3-c]
Mixture with furan-1-oxide 25 7-Methyl-5,6-cyclohexenopyrido [2,3-c] furazan-1-oxide and 5-
Methyl-6,7-cyclohexenopyrido [2,3-c]
Mixture with furan-1-oxide 26 5-ethoxycarbonylmethyl-7
-Methylpyrido [2,3-c] furazan-1-oxide Compound No. 27 5-Aminomethyl-7-methylpyrido [2,3-c] furazan-1-oxide Compound No. 27 28 5- (t-butoxycarbonylamino) methyl-7-methylpyrido [2,3-c] furazan-1-oxide Compound no. 29 5- (3-aminopropyl) -7-
Methylpyrido [2,3-c] furazan-1-oxide Compound No. 30 5- (3-t-butoxycarbonylaminopropyl) -7-methylpyrido [2,3-c] furazan-1-oxide Compound no. 31 5-methoxypyrido [2,3-c]
Furazan-1-oxide Compound No. 327-Methoxypyrido [2,3-c]
Furazan-1-oxide Compound No. 33 5-Methoxy-7-methylpyrido [2,3-c] furazan-1-oxide Compound No. 33 34 5-aminopyrido [2,3-c] furazan-1-oxide Compound no. 35 5-methylaminopyrido [2,3-
c] Furazan-1-oxide Compound No. 36 5-dimethylaminopyrido [2,3
-C] furazan-1-oxide Compound No. 37 5-acetylaminopyrido [2,3
-C] furazan-1-oxide Compound No. 38 5-Amino-7-methylpyrido [2,3-c] furazan-1-oxide Compound no. 39 5-acetylamino-7-methylpyrido [2,3-c] furazan-1-oxide Compound No. 39 40 5- (3-carboxypropyl)-
7-methylpyrido [2,3-c] furazan-1-oxide Compound No. 41 5- (3-t-butoxycarbonylamino-3-carboxy) propyl-7-methylpyrido [2,3-c] furazan-1-oxide Compound no. 42 5- (3-Carboxy-3-amino) propyl-7-methylpyrido [2,3-c] furazan-1-oxide

Embodiment 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.
Richard G. The method of Knowles et al. (Bio
chem. J. 270, 833, 1990
Year) was partially changed to obtain livers of rats administered with endotoxin. The resulting liver was Dennis J. et al. Stuhr
(Proc. Natl. Acad. Sc.)
i. USA; 88, 7773, 1991) was partially modified to purify the inducible enzyme. 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. The reaction solution at that time was 1 mM L-argine, iNOS crude enzyme solution, 3 mM DTT, 0.3 mM NADPH, 4 μg
/ Ml FAD, 4 μM tetrahydrobio
pterine, 5 μg / ml aprotinin,
5 μg / ml chymostatin, 4 μg / ml
leupeptin, 5 μg / ml pepstat
in A, 0.1 mM PMSF, 20 mM Tris
-HCl (pH 7.5) to which the compound of the present invention or a control compound was added. After incubation at 37 ° C., the nitric oxide produced was measured. Nitric oxide was measured by the metabolite NO ₂
C. Green et al. (Anal. Bioche).
m. 126, 131, 1982). The results were expressed as IC50 values (concentration required for 50% activity inhibition). When the IC ₅₀ value could not be calculated, it was shown as the inhibition rate (%) at each concentration. Results The results are shown in Table 1. The compound of the present invention showed strong inhibitory activity on inducible nitric oxide synthase.

[0070]

[Table 1] {Compound compound IC50 (μM)} ──────────────────────────────── Compound No. Compound No. 193 Compound No. 2 25% (300 μM) Compound No. 317 4 130 Compound no. Compound No. 5400 6 0.37 Compound No. Compound No. 730 Compound No. 8220 9250 Compound no. Compound No. 10 25% (300 μM) 11 0.84 Compound No. 12 1.7 Compound No. 13 0.80 Compound No. 14 7.0 Compound No. 15 1000 Compound No. 165% (1000 μM) Compound No. 17 670 Compound No. 18 670 Compound No. 19> 1000

Compound No. 20 20% (30 μM) Compound No. Compound No. 2194 22 46 Compound no. 23 100 Compound no. 24 50% (100 μM) Compound No. 25 20% (300 μM) Compound No. 26 20% (100 μM) Compound No. 27 30% (1000 μM) Compound No. Compound No. 28 20% (300 μM) Compound No. 29100 30 670 Compound No. 31 20% (300 μM) Compound No. 32 76 Compound No. 33 30% (1000 μM) Compound No. 34> 1000 Compound no. 35> 1000 Compound no. 36 20% (30 μM) Compound No. 37 30% (300 μM) Compound No. 38 10% (100 μM) Compound No. 39 10% (30 μM) Compound No. 40 550 Compound No. 415% (1000 μM) Compound No. 42 35% (1000 μM) NMMA (positive control) 25%

Embodiment 2 FIG. The inhibitory activities of some of the compounds of the present invention on neuronal nitric oxide synthase, endothelial nitric oxide synthase and inducible nitric oxide synthase were compared with existing nitric oxide synthase inhibitors.

Experimental Method Neural nitric oxide synthase was obtained from David S. Br
Edt et al. (Proc. Natl. Acad.
Sci. USA; 87, 682, 1990
Year). The bovine cerebellum obtained from the slaughterhouse was diluted with 5 times the volume of 50 mM Tris-HCl, 1 mM
An EDTA (pH 7.4) buffer was added, homogenized, and centrifuged at 1,000 × g. The obtained supernatant is
The mixture was centrifuged at 100,000 × g for 60 minutes, and the obtained supernatant was used as a crude enzyme solution of nerve-type nitric oxide synthase. Measurement of the activity of neuronal nitric oxide synthase is described in David S. et al.
Bredt et al. (Proc. Natl. Ac
ad. Sci. USA; 86, 9030, 1
989) with some modifications to L- [3H] argi
It was determined by quantifying the amount of Nine converted to L- [3H] citrulline. The reaction solution at that time is
32 nM L- [ ³ H] arginine, a crude enzyme solution of neuronal nitric oxide synthase, 0.8 mM DTT, 1 m
M CaCl ₂ , 0.8 mM EDTA, 8 μg / ml
calmodulin, 0.8 μM NADPH, 8
μ MFAD, 80 μM tetrahydrobio
pterine, 20 mM Hepes (pH 7.4)
To which the compound of the present invention or a control compound was added. The reaction was started by adding L- [ ³ H] arginine, and after incubation at 37 ° C., 50 m
M Tris-HCl (pH 5.5), 1 mM EDT
After terminating the reaction with the reaction terminating solution of A, the reaction product was passed through a cation exchange resin column (Dowex AG 50W X8, Na ⁺ form) to remove unreacted L- [ ³ H] arginine, and the product L -[ ³ H] citrulline was recovered. It was quantified by measuring the collected L- ^[3 H] citrulline radioactivity. The result is the IC ₅₀ value (5
Concentration required for 0% activity inhibition).

The endothelial nitric oxide synthase was obtained from Jenni.
fer S. Pollock et al. (Proc.
Natl. Acad. Sci. USA; 88
Volume, p. 10480, 1991). Endothelial cells were isolated from bovine aorta obtained from the slaughterhouse according to a conventional method. Isolate the endothelial cells by 5x 50m
M Tris-HCl, 0.1 mM EDTA, 0.1
mM EGTA, 0.1% 2-Mercaptoet
hanol buffer was added and homogenized.
After centrifugation at 00 xg for 60 minutes, the resulting precipitate was
After washing with a buffer containing KCl, 20 mM CHAP was used.
Endothelial nitric oxide synthase was extracted in a buffer containing S. The extract was centrifuged at 100,000 × g 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 according to the case of neuronal nitric oxide synthase.

Results The results are shown in Table 2. The results were shown as IC ₅₀ values (concentration required for 50% activity inhibition). When the IC ₅₀ value could not be calculated, the results were shown as 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 action was observed.

[0076]

[Table 2] ──────────────────────────────────── IC50 (μM) ────── ──────────────────── Compound of the present invention Neural type Endothelial type Inducible type ──────────────────────化合物 Compound No. 139 150 93 Compound no. 3 20 12 17 Compound No. 4 340 360 130 Compound No. 5 110 320 400 Compound no. 6 1.1 78 0.37 Compound No. 7 430 380 30 Compound No. 8 1000 660 220 Compound No. 966 39 250 Compound No. 11 21 35% (1 mM) 0.84 Compound No. 12 23 160 1.7 Compound No. 13-600 0.80 Compound No. 14-25% (1 mM) 7.0 Compound No. 29 4.3 300 100 Compound No. 32 45% (1 mM) 1000 76 NMMA (positive control) 0.49 4.1 25 ─────

Hereinafter, the method for producing the pyrido [2,3-c] furazan-1-oxide derivative of the present invention will be described specifically with reference to production examples. However, the present invention is not limited to these production examples. is not.

Production Example 1 Production of 7-ethylpyrido [2,3-c] furazan-1-oxide (Compound No. 7 of the present application)

2-amino-4-ethyl-3-nitropyridine 33 easily obtainable from 2-amino-4-picoline
4 mg is dissolved in 10 ml of benzene, 709 mg of iodosobenzene diacetate is added, and the mixture is reacted at room temperature for 44 hours. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to give 7-ethylpyrido [2,3-c] furazan-1-oxide 328m
g.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.33 (t, 3H), 3.02 (q, 2
H), 6.93 (br, 1H), 8.65 (br, 1
H) FAB-MS (m / z): 166 [M + H] +

The following compounds can also be prepared in the same manner as described above. 7-n-propylpyrido [2,3-c] furazan-1-
Oxide (Compound No. 8) ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
1.04 (t, 3H), 1.63-1.83 (m, 2
H), 2.94 (t, 2H), 6.92 (br, 1
H), 8.64 (br, 1H) FAB-MS (m / z): 180 [M + H] +, 359
[2M + H] +

7-Isopropylpyrido [2,3-c] furazan-1-oxide (Compound No. 9) ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
1.34 (d, 6H), 3.45-3.65 (m, 1
H), 6.97 (d, 1H), 8.66 (d, 1H) FAB-MS (m / z): 180 [M + H] +, 359
[2M + H] +

Production Example 2 Production of 5-ethyl-7-methylpyrido [2,3-c] furazan-1-oxide (Compound No. 12 of the present application)

(1) 340 mg of 2-amino-6-ethyl-4-methylpyridine, which is easily obtained from 6-amino-2,4-lutidine, is dissolved in 2.5 ml of concentrated sulfuric acid under ice-cooling. .158 ml was added dropwise and stirred at the same temperature for 1 hour. Further, the reaction is performed at room temperature for 1 hour and at 60 ° C. for 1 hour. The reaction solution was added dropwise to ice water, neutralized (pH> 9) by adding 10 ml of a 40% aqueous sodium hydroxide solution, the crude product was extracted with methylene chloride, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. I do. After filtering inorganics,
The mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to give 2-amino-6-ethyl-
212 mg of 4-methyl-3-nitropyridine are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.25 (t, 3H), 2.54 (s, 3
H), 2.62 (q, 2H), 6.34 (br, 2
H), 6.44 (d, 1H) FAB-MS (m / z): 182 [M + H] +

(2) 108 mg of 2-amino-6-ethyl-4-methyl-3-nitropyridine are dissolved in 5 ml of benzene, 213 mg of iodosobenzene diacetate is added, and the mixture is reacted at room temperature for 40 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to give 5-ethyl-7-methylpyrido [2,
3-c] Furazan-1-oxide 100 mg is obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.36 (t, 3H), 2.60 (s, 3)
H), 2.87 (q, 2H), 6.81 (d, 1H) FAB-MS (m / z): 180 [M + H] +, 359
[2M + H] +

The following compounds can also be prepared in the same manner as described above. 2-amino-6-n-propyl-4-methyl-3-nitropyridine ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
0.97 (t, 3H), 1.61-1.80 (m, 2
H), 2.54 (s, 3H), 2.56 (dd, 2
H), 6.36 (br, 2H), 6.43 (s, 1H) FAB-MS (m / z): 196 [M + H] +, 391
[2M + H] +

7-methyl-5-n-propylpyrido [2,3-c] furazan-1-oxide (Compound N
o. 13) ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
1.02 (t, 3H), 1.73-1.92 (m, 2
H), 2.60 (s, 3H), 2.82 (t, 2H),
6.81 (s, 1H) ESI-MS (m / z): 194 [M + H] +

2-amino-6-isopropyl-4-methyl-3-nitropyridine ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
1.23 (d, 6H), 2.55 (s, 3H), 2.7
3-2.94 (m, 1H), 6.33 (br, 2H),
6.44 (s, 1H) FAB-MS (m / z): 196 [M + H] +

5-isopropyl-7-methylpyrido [2,3-c] furazan-1-oxide (Compound N
o. 14) ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
1.34 (d, 6H), 2.60 (s, 3H), 3.0
2-3.19 (m, 1H), 6.84 (s, 1H) ESI-MS (m / z): 194 [M + H] +

2-amino-6-n-butyl-4-methyl-3-nitropyridine ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
0.94 (t, 3H), 1.28-1.47 (m, 2
H), 1.57-1.73 (m, 2H), 2.54
(S, 3H), 2.58 (t, 2H), 6.36 (b
r, 2H), 6.42 (s, 1H) FAB-MS (m / z): 210 [M + H] +

5-n-butyl-7-methylpyrido [2,
3-c] furazan-1-oxide (Compound No. 1 of the present application)
5) ¹ H-NMR (200 MHz, CDCl3) δ:
0.96 (t, 3H), 1.26 to 1.52 (m, 2
H), 1.69-1.85 (m, 2H), 2.60.
(S, 3H), 2.83 (t, 2H), 6.81 (s,
1H) FAB-MS (m / z): 208 [M + H] +, 415
[2M + H] +

2-amino-6-cyclohexylmethyl-
4-methyl-3-nitropyridine ¹ H-NMR (200 MHz, CDCl 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, 1
H) FAB-MS (m / z): 250 [M + H] +, 499.
[2M + H] +

5-cyclohexylmethyl-7-methylpyrido [2,3-c] furazan-1-oxide (Compound No. 16) ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
0.95-1.37 (m, 5H), 1.60-2.00
(M, 6H), 2.60 (s, 3H), 2.71 (d,
2H), 6.79 (s, 1H) FAB-MS (m / z): 248 [M + H] +, 495
[2M + H] +

2-amino-6- {5- (6-amino-4)
-Methyl-3-nitropyridyl-2-yl) pentyl
-4-methyl-3-nitropyridine ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
1.32-1.49 (m, 2H), 1.62-1.82
(M, 4H), 2.26 (s, 3H), 2.54 (s,
3H), 2.54-2.69 (m, 4H), 4.71.
(Br, 2H), 6.18 (s, 1H), 6.34 (b
r, 1H), 6.42 (s, 1H)

5- {5- (6-amino-4-methyl-3)
-Nitropyridyl-2-yl) pentyl {-7-methylpyrido [2,3-c] furazan-1-oxide (Compound No. 19) ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
1.37-1.54 (m, 2H), 1.67-1.90
(M, 4H), 2.27 (s, 3H), 2.54-2.
72 (m, 5H), 2.83 (t, 2H), 4.73
(Br, 2H), 6.28 (s, 1H), 6.77-
7.05 (m, 1H) FAB-MS (m / z): 373 [M + H] +, 745
[2M + H] +, 357 [M + HO] +

1,5-bis (6-amino-4-methyl-
5-nitropyridin-2-yl) pentane ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
1.32-1.48 (m, 2H), 1.62-1.79
(M, 4H), 2.51-2.65 (m, 10H),
6.32 (br, 4H), 6.41 (s, 2H) FAB-MS (m / z): 375 [M + H] +

1,5-bis (7-methylpyrido [2,3
-C] Furazan-1-oxide-5-yl) pentane (Compound No. 20 of the present application) ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
1.39-1.62 (m, 2H), 1.77-1.97
(M, 4H), 2.59 (s, 6H), 2.85 (t,
4H), 6.75-7.08 (m, 2H) FAB-MS (m / z): 371 [M + H] +, 741
[2M + H] +, 353 [M + H-H2O] +

Production Example 3 7-chloropyrido [2,3-c] furazan-1-oxide (Compound No. 3) and 7-methoxypyrido [2,3-c] furazan-1-oxide (Compound N)
o. 32) Manufacturing

(1) 2-Easily obtained from picolinic acid
Under ice-cooling, 4.85 g of amino-4-chloropyridine hydrochloride was dissolved in 30 ml of concentrated sulfuric acid, and 1.87 ml of concentrated nitric acid was added dropwise, followed by stirring at the same temperature for 2 hours. In addition, at room temperature for 2 hours,
Incubate at 60 ° C for 1 hour. The reaction solution was added dropwise to ice water,
Neutralize by adding 100 ml of 0% aqueous sodium hydroxide solution (p
H> 9), and the precipitated crystals are collected by filtration. The obtained crude product is purified by silica gel column chromatography,
-Amino-4-chloro-3-nitropyridine 0.979
g.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 6.01 (br, 2H), 6.81 (d, 1
H), 8.09 (d, 1H) ESI-MS (m / z): 172, 174 [MH]-

(2) Dissolve 347 mg of 2-amino-4-chloro-3-nitropyridine in 10 ml of benzene, add 709 mg of iodosobenzene diacetate and react at room temperature for 18 hours. The reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography to obtain 342 mg of 7-chloropyrido [2,3-c] furazan-1-oxide.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 7.35 (br, 1H), 8.55 (br, 1H)
1H) FAB-MS (m / z): 172,174 [M + H] +

(3) 868 mg of 2-amino-4-chloro-3-nitropyridine was dissolved in 15 ml of methanol,
10 ml of 1N-sodium methoxide / methanol is added, and the mixture is reacted under heating and reflux for 4 hours. The reaction solution was quenched by adding 1N-hydrochloric acid and concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography.
2-amino-4-methoxy-3-nitropyridine 802
mg.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 3.96 (s, 3H), 6.16 (br, 2
H), 6.34 (d, 1H), 8.08 (d, 1H) FAB-MS (m / z): 170 [M + H] +

(4) 338 mg of 2-amino-4-methoxy-3-nitropyridine was dissolved in 10 ml of benzene.
709 mg of iodosobenzene diacetate is added and reacted at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to give 7-methoxypyrido [2,3-c] furazan-1.
329 mg of oxide are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 4.11 (s, 3H), 6.40 (br, 1
H), 8.58 (br, 1H) FAB-MS (m / z): 168 [M + H] +

Production Example 4 5- (t-butoxycarbonylamino) methyl-7-methylpyrido [2,3-c] furazan-1-oxide (Compound No. 28 of the present application) and 5-aminomethyl-7-methylpyrido [2 , 3-c] Furazan-1-oxide (Compound No. 27 of the present application)

(1) 6-amino-
N-Butyllithium hexane was added at room temperature to a solution of 24.0 g of 2- (2,5-dimethylpyrrol-1-yl) -4-6-dimethylpyridine easily obtained from 2,4-lutidine in 250 ml of anhydrous ether. Solution (1.58M) 7
5.9 ml is added dropwise and stirred at the same temperature for 1 hour. Furthermore,
The reaction solution is cooled to -78 ° C, and after adding dry ice, the temperature is gradually raised to room temperature. The reaction was stopped by adding 2N-hydrochloric acid to the reaction solution, and the crude product was extracted with ethyl acetate.
The organic layer is dried with anhydrous sodium sulfate. After filtering the inorganic substance, the mixture was concentrated under reduced pressure, and the obtained crude product was crystallized from hexane to give 6-carboxymethyl-2- (2,5-dimethylpyrrol-1-yl) -4-methylpyridine.
3 g are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 2.11 (s, 6H), 2.46 (s, 3
H), 3.90 (s, 2H), 5.91 (s, 2H),
7.01 (s, 1H), 7.10 (s, 1H), 9.1
0 (br, 1H) FAB-MS (m / z): 244M +., 245 [M +
H] +

(2) 6-carboxymethyl-2- (2,
5-dimethylpyrrol-1-yl) -4-methylpyridine in a solution of 19.5 g of t-butanol (120 ml),
At room temperature, 8.90 g of triethylamine and 24.2 g of diphenyl azide are added and reacted at 80 ° C. for 1 hour and at 100 ° C. for 5 hours. Water was added to the reaction solution to stop the reaction, the crude product was extracted with ether, and the organic layer was washed successively with water and 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 column chromatography to give 6-azidocarbonylaminomethyl-2- (2,5-dimethylpyrrol-1-yl) -4-. 8.81 g of methylpyridine
Get.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 2.11 (s, 6H), 2.43 (s, 3)
H), 4.53 (d, 2H), 5.91 (s, 2H),
6.32 (br, 1H), 6.95 (s, 1H), 7.
08 (s, 1H) FAB-MS (m / z): 284M +., 285 [M +
H] +

(3) 6-azidocarbonylaminomethyl-2- (2,5-dimethylpyrrol-1-yl) -4-
8.15 g of methylpyridine is dissolved in 100 ml of ethanol, 100 ml of 8N-sodium hydroxide is added, and the mixture is reacted under heating and reflux for 6 hours. 100 ml of water was added to the reaction solution, the crude product was extracted with ether, and the organic layer was 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 column chromatography to give 6-aminomethyl-2- (2,5-dimethylpyrrol-1-yl) -4.
5.60 g of methylpyridine are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.69 (s, 2H), 2.13 (s, 6)
H), 2.41 (s, 3H), 3.95 (s, 2H),
5.89 (s, 2H), 6.90 (s, 1H), 7.0
9 (s, 1H) FAB-MS (m / z): 215 M +., 216 [M +
H] +, 431 [2M + H] +

(4) 6-aminomethyl-2- (2,5-
5.57 g of dimethylpyrrole-1-yl) -4-methylpyridine is dissolved in a mixed solvent of 80 ml of ethanol and 30 ml of water, 9.03 g of hydroxylamine hydrochloride is added, and the reaction solution is reacted under heating and reflux for 10 hours. The reaction was stopped by adding an aqueous solution of sodium hydrogen carbonate to the reaction solution,
Concentrate 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 column chromatography,
-Amino-6-aminomethyl-4-methylpyridine is obtained. 2-Amino-6-aminomethyl-4-methylpyridine is dissolved in 30 ml of methanol, and 13 ml of 4N hydrochloric acid / dioxane is added. The reaction solution is concentrated under reduced pressure and crystallized from ethanol-ether to obtain 4.95 g of 2-amino-6-aminomethyl-4-methylpyridine dihydrochloride.

¹ H-NMR (200 MHz, CD3O
D) δ: 2.42 (s, 3H), 4.26 (s, 2
H), 6.85 (s, 2H) FAB-MS (m / z): 138 [M + H] +, 275
[2M + H] +

(5) 2-amino-6-aminomethyl-4
-Methylpyridine dihydrochloride (4.20 g) is dissolved in concentrated sulfuric acid (20 ml) under ice cooling, concentrated nitric acid (1.27 ml) is added dropwise, and the mixture is stirred at the same temperature for 1 hour. Further, the reaction is performed at room temperature for 1 hour and at 60 ° C. for 1 hour. The reaction solution was dropped into ice water, and 100 ml of a 40% aqueous sodium hydroxide solution was added for neutralization (pH> 9).
Then, the crude product is extracted with methylene chloride, and the organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. After filtering the inorganic substance, it is concentrated under reduced pressure to obtain 0.615 g of a crude product. 8 ml of dioxane and 4 ml of water were obtained.
And a solution of 0.864 g of di-t-butyl dicarbonate (8 ml) in dioxane (8 ml) at room temperature.
Add 3.63 ml of aqueous sodium hydroxide solution and stir at the same temperature for 40 minutes. After the reaction solution was concentrated under reduced pressure, water 30
Then, the crude product was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtering the inorganic substance, the mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography.
Further crystallization from hexane gives 0.647 g of 2-amino-6-t-butoxycarbonylaminomethyl-4-methyl-3-nitropyridine.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.47 (s, 9H), 2.55 (s, 3
H), 4.26 (d, 2H), 5.40 (br, 1
H), 6.32 (br, 2H), 6,51 (s, 1H) FAB-MS (m / z): 283 [M + H] +, 565.
[2M + H] +

(6) 565 mg of 2-amino-6-t-butoxycarbonylaminomethyl-4-methyl-3-nitropyridine is dissolved in 20 ml of benzene, 709 mg of iodosobenzene diacetate is added, and the mixture is reacted at room temperature for 20 hours. . The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to give 5-
(T-butoxycarbonylamino) methyl-7-methylpyrido [2,3-c] furazan-1-oxide 485m
g.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.48 (s, 9H), 2.62 (s, 3)
H), 4.49 (d, 2H), 5.70 (br, 1
H), 6,86 (s, 1H) FAB-MS (m / z): 281 [M + H] +, 561
[2M + H] +, 225 [M + Ht-butyl]
+, 181 [M + H-Boc] +

(7) 20 mg of 5- (t-butoxycarbonylamino) methyl-7-methylpyrido [2,3-c] furazan-1-oxide was dissolved in 0.5 ml of methanol, and 2 ml of trifluoroacetic acid was added. For 1.5 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography.
-Aminomethyl-7-methylpyrido [2,3-c] furazan-1-oxide is obtained. To 4-aminomethyl-7-methylpyrido [2,3-c] furazan-1-oxide, 2 ml of 0.04 N hydrochloric acid / ether is added. The reaction solution was concentrated under reduced pressure to give 5-aminomethyl-7-methylpyrido [2,3-c] furazan-1-oxide hydrochloride 8.9 m.
g.

¹ H-NMR (200 MHz, CD3O
D) δ: 2.64 (s, 3H), 4.42 (s, 2)
H), 7.10 (s, 1H) FAB-MS (m / z): 181 [M + H] +, 361
[2M + H] +

Production Example 5 5- (3-t-butoxycarbonylaminopropyl)-
7-methylpyrido [2,3-c] furazan-1-oxide (Compound No. 30 of the present application) and 5- (3-aminopropyl) -7-methylpyrido [2,3-c] furazan-1
Production of Oxide (Compound No. 29)

(1) 336 mg of 2-amino-6- (3-aminopropyl) -4-methyl-3-nitropyridine easily obtained from 6-amino-2,4-lutidine is mixed with 4 ml of dioxane and 2 ml of water. It was dissolved in a solvent, and a solution of di-t-butyl dicarbonate (419 mg) in dioxane (4 ml) and a 1N aqueous solution of sodium hydroxide (1.7) were added at room temperature.
6 ml is added and stirred 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 filtering the inorganic substance, the mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to give 2-amino-6- (3-t-butoxycarbonylaminopropyl) -4-methyl-3-nitro 444 mg of pyridine are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.44 (s, 9H), 1.76-1.94
(M, 2H), 2.53 (s, 3H), 2, 63 (t,
2H), 3.17 (q, 2H), 4.83 (br, 1
H), 6.32 (br, 2H), 6.43 (s, 1H) FAB-MS (m / z): 311 [M + H] +, 255
[M + Ht-butyl] +, 211 [M + H-Bo
c] +

(2) 438 mg of 2-amino-6- (3-t-butoxycarbonylaminopropyl) -4-methyl-3-nitropyridine was dissolved in 10 ml of benzene, and 499 mg of iodosobenzene diacetate was added. Incubate for 22 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to give 5- (3-t-butoxycarbonylaminopropyl) -7-methylpyrido [2,3-c] furazan-1-.
392 mg of oxide are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.44 (s, 9H), 1.94-2.08
(M, 2H), 2.59 (s, 3H), 2,88 (t,
2H), 3.23 (q, 2H), 4.70 (br, 1
H), 6.81 (s, 1H) FAB-MS (m / z): 309 [M + H] +, 617
[2M + H] +, 253 [M + Ht-butyl]
+, 209 [M + H-Boc] +

(3) 10 mg of 5- (3-t-butoxycarbonylaminopropyl) -7-methylpyrido [2,3-c] furazan-1-oxide was added at 0 ° C. to 4N-hydrochloric acid /
Dissolve in 1 ml of dioxane and react at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 5- (3-aminopropyl) -7-methylpyrido [2,3-c] furazan-1-.
9.2 mg of oxide hydrochloride are obtained. FAB-MS (m / z): 209 [M + H] +

Production Example 6 5-ethoxycarbonylmethyl-7-methylpyrido [2,3-c] furazan-1-oxide (Compound N of the present application)
o. 26) Manufacturing

(1) 6-carboxymethyl-2- (2,5-dimethylpyrrole-1 obtained in Production Example 4- (1)
15.7 g of -yl) -4-methylpyridine is dissolved in a mixed solvent of 170 ml of ethanol and 60 ml of water, 25.7 g of hydroxylamine hydrochloride is added, and the reaction solution is reacted under heating and refluxing for 7.5 hours. The reaction is stopped by adding a 2N aqueous solution of sodium hydroxide to the reaction solution, and concentrated under reduced pressure.
The crude product was extracted from the residue with methanol, and the obtained organic layer was concentrated under reduced pressure. The obtained crude product and ethanol 20
A mixture of 0 ml and 5 ml of concentrated sulfuric acid is reacted under heat and reflux 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 column chromatography to give 2-amino-6-ethoxycarbonylmethyl-4-.
5.71 g of methylpyridine are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.26 (t, 3H), 2.21 (s, 3
H), 3.60 (s, 2H), 4.17 (q, 2H),
5. 42 (br, 2H), 6.21 (s, 1H),
47 (s, 1H) FAB-MS (m / z): 195 [M + H] +, 389
[2M + H] +

(2) Under ice-cooling, 2.91 g of 2-amino-6-ethoxycarbonylmethyl-4-methylpyridine was dissolved in 22.5 ml of concentrated sulfuric acid, and 0.951 ml of concentrated nitric acid was added dropwise. Stir for hours. In addition, at room temperature for 2 hours,
Incubate at 60 ° C for 1 hour. The reaction solution was added dropwise to ice water,
Add 50 ml of 0% sodium hydroxide aqueous solution to neutralize (pH
7-8), 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 further crystallized from ethyl acetate to give 2-amino-6-ethoxycarbonylmethyl-4-methyl-3.
0.699 g of nitropyridine are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.28 (t, 3H), 2.55 (s, 3
H), 3.63 (s, 2H), 4.20 (q, 2H),
6.33 (br, 2H), 6.56 (s, 1H) FAB-MS (m / z): 240 [M + H] +, 479
[2M + H] +

(3) 2-amino-6-ethoxycarbonylmethyl-4-methyl-3-nitropyridine 359 mg
Is dissolved in 10 ml of benzene, 531 mg of iodosobenzene diacetate is added, and the mixture is reacted at room temperature for 28 hours.
The reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography to obtain 137 mg of 5-ethoxycarbonylmethyl-7-methylpyrido [2,3-c] furazan-1-oxide.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.31 (t, 3H), 2.35 (s, 3
H), 4.21 (q, 2H), 5.04 (s, 1H),
6.13 (s, 1H) 11.26 (br, 1H) FAB-MS (m / z): 238 [M + H] +

Production Example 7 5-chloropyrido [2,3-c] furazan-1-oxide (Compound No. 2 of the present application), 5-methoxypyrido [2
3-c] furazan-1-oxide (Compound No. 3 of the present application)
1), 5-methylaminopyrido [2,3-c] furazan-1-oxide (Compound No. 35) and 5-dimethylaminopyrido [2,3-c] furazan-1-oxide (Compound of the present application) Production of No. 36)

(1) 434 mg of 2-amino-6-chloro-3-nitropyridine easily obtained from 2,6-dichloropyridine was dissolved in 20 ml of ethyl acetate, and 1208 mg of iodosobenzene diacetate was added.
Let react for hours. The reaction solution is purified by silica gel column chromatography to obtain 345 mg of 5-chloropyrido [2,3-c] furazan-1-oxide.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 7.50 (d, 1H), 8.25 (d, 1)
H) FAB-MS (m / z): 172,174 [M + H] +

(2) 173 mg of 2-amino-6-chloro-3-nitropyridine, 6 ml of methanol and 129 mg of sodium methoxide were mixed.
And react for hours. 30 ml of water was added to the reaction solution to stop the reaction, and the precipitated crystals were collected by filtration to obtain 151 mg of 2-amino-6-methoxy-3-nitropyridine.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 3.90 (s, 3H), 6.15 (d, 1
H), 8.14 (br, 2H), 8.26 (d, 1H)

(3) 423 mg of 2-amino-6-methoxy-3-nitropyridine was dissolved in 20 ml of ethyl acetate, and 966 mg of iodosobenzene diacetate was added.
Incubate at room temperature for 64 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography, and further crystallized from ether-hexane to give 5-
329 mg of methoxypyrido [2,3-c] furazan-1-oxide are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 4.02 (s, 3H), 7.00 (d, 1)
H), 8.03 (d, 1H) FAB-MS (m / z): 168 [M + H] +

(4) 868 mg of 2-amino-6-chloro-3-nitropyridine was dissolved in 10 ml of ethanol.
2.0 ml of a 40% aqueous solution of methylamine was added, and 1 ml was sealed in a sealed tube.
The reaction is performed at 00 ° C (external temperature) for 1 hour. Water 10
0 ml was added, and the precipitated crystals were collected by filtration, and 2-amino-6 was added.
772 mg of -methylamino-3-nitropyridine are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 2.86 (d, 3H), 5.94 (d, 1)
H), 7.90 (d, 1H), 7.60-8.20 (b
r, 3H)

(5) 2-amino-6-methylamino-3
Dissolve 464 mg of -nitropyridine in a mixed solvent of 5 ml of ethyl acetate and 15 ml of acetone, add 1067 mg of iodosobenzene diacetate, and react at room temperature for 24 hours. The crystals precipitated in the reaction solution are collected by filtration, and 5-methylaminopyrido [2,3-c] furazan-1-oxide 39
8 mg are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 2.92 (d, 3H), 6.79 (d, 1)
H), 7.62 (d, 1H), 8.49 (br, 1H) FAB-MS (m / z): 167 [M + H] +

(6) 868 mg of 2-amino-6-chloro-3-nitropyridine was dissolved in 10 ml of ethanol.
2.2 ml of a 50% aqueous dimethylamine solution is added, and the mixture is reacted at 100 ° C. (external temperature) in a sealed tube for 2.5 hours. 200 ml of water was added to the reaction solution, the precipitated crystals were collected by filtration, and 750 m of 2-amino-6-dimethylamino-3-nitropyridine was collected.
g.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 3.13 (s, 6H), 6.19 (d, 1
H), 8.04 (d, 1H), 7.60-8.00 (b
r, 2H)

(7) 2-amino-6-dimethylamino-
451 mg of 3-nitropyridine is dissolved in 15 ml of acetone, 960 mg of iodosobenzene diacetate is added, and the mixture is reacted at room temperature for 24 hours. Hexane 60 in the reaction solution
The precipitated crystals were collected by filtration, and 5-dimethylaminopyrido [2,3-c] furazan-1-oxide 411 was added.
mg.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 3.23 (s, 6H), 7.28 (d, 1)
H), 7.77 (d, 1H) FAB-MS (m / z): 181 [M + H] +, 361
[2M + H] +

Production Example 8 Production of 5,6,7-trimethylpyrido [2,3-c] furazan-1-oxide (Compound No. 22 of the present application)

(1) 1.74 ml of 3-methyl-2,4-pentanedione, 1.03 g of 1,1-diamino-2-nitroethene, 15 ml of ethanol and 3 ml of acetic acid were mixed, and the reaction solution was heated to reflux for 16 hours. Let react for hours. The reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography to obtain 0.30 g of 2-amino-3-nitro-4,5,6-trimethylpyridine.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 2.15 (s, 3H), 2.36 (s, 3
H), 2.41 (s, 3H), 5.68 (br, 2H) FAB-MS (m / z): 182 [M + H] +

(2) 2-amino-3-nitro-4,5
274 mg of 6-trimethylpyridine in 15 ml of benzene
And add 536 mg of iodosobenzene 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 column chromatography to give 5,6,7-trimethylpyrido [2,
244 mg of 3-c] furazan-1-oxide are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.58 (s, 3H), 2.56 (s, 3H)
H), 2.63 (s, 3H) FAB-MS (m / z): 180 [M + H] +, 359
[2M + H] +

The following compounds can also be prepared in the same manner as described above. 2-amino-4-methyl-3-nitro-6-trifluoromethylpyridine ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
2.51 (s, 3H), 6.15 (br, 2H), 6.
87 (s, 1H) FAB-MS (m / z): 222 [M + H] +

7-methyl-5-trifluoromethylpyrido [2,3-c] furazan-1-oxide (Compound No. 17 of the present application) ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
2.74 (s, 3H), 7.24-7.53 (m, 1
H) FAB-MS (m / z): 220 [M + H] +

2-Amino-4,6-bis (trifluoromethyl) -3-nitropyridine ESI-MS (m / z): 274 [MH]-, 549
[2M-H]-

5,7-bis (trifluoromethyl) pyrido [2,3-c] furazan-1-oxide (Compound No. 18) ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
7.58-7.89 (m, 1H)

2-amino-5-chloro-4,6-dimethyl-3-nitropyridine ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
2.52 (s, 3H), 2.54 (s, 3H), 5.9
0 (br, 2H) FAB-MS (m / z): 202, 204 [M + H] +

6-chloro-5,7-dimethylpyrido [2,3-c] furazan-1-oxide (Compound N
o. 21) ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
2.66 (s, 3H), 2.75 (s, 3H) FAB-MS (m / z): 200, 202 [M + H]
+, 399,401 [2M + H] +

2-amino-4,6-dimethyl-5-ethyl-3-nitropyridine ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
1.11 (t, 3H), 2.39 (s, 3H), 2.4
3 (s, 3H), 2.60 (q, 2H), 5.69 (b
r, 2H) FAB-MS (m / z): 196 [M + H] +

5,7-dimethyl-6-ethylpyrido [2,3-c] furazan-1-oxide (Compound N
o. 23) ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
1.19 (t, 3H), 2.57 (s, 3H), 2.6
7 (s, 3H), 2.74 (q, 2H) FAB-MS (m / z): 194 [M + H] +, 387
[2M + H] +

2-amino-4-methyl-3-nitro-
Mixture of 5,6-cyclopentenopyridine and 2-amino-6-methyl-3-nitro-4,5-cyclopentenopyridine FAB-MS (m / z): 194 [M + H] +

7-methyl-5,6-cyclopentenopyrido [2,3-c] furazan-1-oxide and 5-methyl-6,7-cyclopentenopyrido [2,3-c] furazan -1-Oxide mixture (Compound No. 24) FAB-MS (m / z): 192 [M + H] +, 383
[2M + H] +

2-amino-4-methyl-3-nitro-
Mixture of 5,6-cyclohexenopyridine and 2-amino-6-methyl-3-nitro-4,5-cyclohexenopyridine FAB-MS (m / z): 208 [M + H] +

7-methyl-5,6-cyclohexenopyrido [2,3-c] furazan-1-oxide and 5-methyl-6,7-cyclohexenopyrido [2,3-c] furazan-1 -Oxide mixture (Compound No. 25) FAB-MS (m / z): 206 [M + H] +, 411
[2M + H] +

Production Example 9 5-Amino-7-methylpyrido [2,3-c] furazan-1-oxide (Compound No. 38 of the present application), 5-acetylamino-7-methylpyrido [2,3-c] furazan-
1-oxide (Compound No. 39 of the present application), 5-chloro-
Of 7-methylpyrido [2,3-c] furazan-1-oxide (Compound No. 10 of the present application) and 5-methoxy-7-methylpyrido [2,3-c] furazan-1-oxide (Compound No.33 of the present application) Manufacture

(1) Chem. Ber. ; 103, 3
89, easily obtained by the method described in 1970.
29.5 g of 2,6-dichloro-4-methylpyridine, 130 ml of concentrated sulfuric acid and 75 ml of concentrated nitric acid are mixed, and the reaction solution is stirred for 6 hours while heating under reflux. The reaction solution was ice-water 2000
The reaction was stopped by adding dropwise to the resulting solution, and the precipitated crystals were collected by filtration.
2,6-dichloro-4-methyl-3-nitropyridine 2
0.1 g is obtained. ESI-MS (m / z): 206, 208, 210M +
・

(2) 2,6-dichloro-4-methyl-3
-Nitropyridine, 5 ml of ethanol and 10 ml of 28% aqueous ammonia were mixed, and the reaction solution was placed in a sealed tube at 100 ° C.
(Outside temperature) for 6 hours. The reaction solution was concentrated under reduced pressure,
100 ml of water was added to the residue, and the precipitated crystals were collected by filtration and further crystallized with ether to obtain 0.67 g of 2,6-diamino-4-methyl-3-nitropyridine.

¹ H-NMR (200 MHz, DMSO
−d6)) δ: 2.40 (s, 3H), 5.74
(S, 1H), 6.94 (br, 2H), 7.64 (b
r, 2H) FAB-MS (m / z): 169 [M + H] +, 337
[2M + H] +

(3) 2,6-diamino-4-methyl-3
-1.10 g of nitropyridine, 40 ml of acetone and 2.53 g of iodosobenzene diacetate are mixed, and this reaction solution is reacted at room temperature for 23 hours. The reaction solution was concentrated under reduced pressure and crystallized from methanol-ether to give 5-amino-7.
1.02 g of -methylpyrido [2,3-c] furazan-1-oxide are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 2.38 (d, 3H), 6.51 (d, 1)
H), 7.69 (br, 2H) FAB-MS (m / z): 167 [M + H] +

(4) 5-Amino-7-methylpyrido [2,3-c] furazan-1-oxide (371 mg), acetic acid (9 ml) and acetic anhydride (9 ml) are mixed, and the reaction mixture is stirred for 10 hours while heating under reflux. The reaction solution is dropped into 100 ml of ice water to stop the reaction, and extracted with ethyl acetate. The organic layer is washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and dried over anhydrous sodium sulfate. After filtering the inorganic substance, the mixture was concentrated under reduced pressure, crystallized from ethyl acetate-hexane, and 5-acetylamino-7-methylpyrido [2,3-
c] 397 mg of furazan-1-oxide are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 2.19 (s, 3H), 2.52 (s, 3
H), 7.91 (d, 1H), 11.22 (s, 1H) FAB-MS (m / z): 209 [M + H] +

(5) 2,6-dichloro-4-methyl-3
Dissolve 8.30 g of nitropyridine in 30 ml of ethanol, add 30 ml of 28% aqueous ammonia, and react at 50 ° C. for 20 hours. After concentrating the reaction solution 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 is purified by silica gel column chromatography to obtain 5.08 g of 2-amino-6-chloro-4-methyl-3-nitropyridine.

¹ H-NMR (200 MHz, DMSO
−d6) δ: 2.37 (s, 3H), 6.70 (s,
1H), 7.58 (br, 2H), FAB-MS (m / z): 188,190 [M + H] +

(6) 563 mg of 2-amino-6-chloro-4-methyl-3-nitropyridine was added to 20 ml of acetone.
1160mg of iodosobenzene diacetate
And react at room temperature for 18 hours. The reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography to obtain 5-chloro-7-methylpyrido [2,3-c] furazan-1-oxide.

¹ H-NMR (200 MHz, DMSO
−d6) δ: 2.53 (s, 3H), 7.34 (s,
1H) FAB-MS (m / z): 186,188 [M + H] +

(7) 1.31 g of 2-amino-6-chloro-4-methyl-3-nitropyridine, 30 m of methanol
and 1.13 g of sodium methoxide, and the reaction solution was allowed to stand at room temperature for 16 hours, at 40 ° C. for 8 hours, and at
Let react for hours. 30 ml of water was added to the reaction solution to stop the reaction, and the precipitated crystals were collected by filtration to obtain 1.26 g of 2-amino-6-methoxy-4-methyl-3-nitropyridine.

¹ H-NMR (200 MHz, DMSO
−d6) δ: 2.44 (s, 3H), 3.83 (s,
3H), 6.05 (s, 1H), 7.79 (br, 2
H) FAB-MS (m / z): 184 [M + H] +

(8) 733 mg of 2-amino-6-methoxy-4-methyl-3-nitropyridine was added to 25 ml of acetone.
1546m, and iodosobenzene diacetate 1546m
g and react at room temperature for 18 hours. The reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography to obtain 686 mg of 5-methoxy-7-methylpyrido [2,3-c] furazan-1-oxide.

¹ H-NMR (200 MHz, DMSO
−d6) δ: 2.47 (d, 3H), 4.00 (s,
3H), 6.81 (q, 1H) FAB-MS (m / z): 182 [M + H] +

Production Example 10 5- (3-Alkoxypropyl) -7-methylpyrido [2,3-c] furazan-1-oxide (Compound N
o. Preparation of 40) (1) Diethyl [2- {6- (2,5-dimethylpyrrole) easily obtained from 6-amino-2,4-lutidine
5.32 g of 1-yl) -4-methyl-2-pyridinyl {ethyl] malonate in 60 ml of ethanol and 20 ml of water
In a mixed solvent of hydroxylamine hydrochloride 3.47
g is added, and the reaction solution is reacted for 8 hours under reflux.
The reaction solution 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 reacted under heating and reflux for 3 hours. 20 g of sodium bicarbonate and 200 ml of water
To stop the reaction. The reaction solution is concentrated under reduced pressure to remove ethanol, and extracted with ethyl acetate. 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 column chromatography, and diethyl [2- (6-amino-4-methyl-2-pyridinyl)) was obtained.
2.62 g of [ethyl] malonate are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.27 (t, 6H), 2.19 (s, 3
H), 2.21-2.33 (m, 2H), 2.60 (d
d, 2H), 3.39 (t, 1H), 4.19 (q, 4
H), 4.34 (br, 2H), 6.17 (s, 1
H), 6.35 (s, 1H) FAB-MS (m / z): 295 [M + H] +

(2) Diethyl [2- (6-amino-4-)
Methyl-2-pyridinyl) ethyl] malonate 2.60
g was dissolved in 12 ml of concentrated sulfuric acid, and concentrated
Then, the mixture was added dropwise and stirred at the same temperature for 1 hour. Further, the reaction is carried out at room temperature for 1 hour and at 60 ° C. for 1 hour. The reaction solution is dropped into ice water, neutralized (pH 5 to 6) by adding 25 ml of a 40% aqueous sodium hydroxide solution, 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. Sodium bicarbonate 3
The reaction is stopped by adding 5 g and 200 ml of water. The insoluble material is filtered, 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 the inorganic substance was filtered, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography, and diethyl [2- (6-amino-4) was obtained.
-Methyl-5-nitro-2-pyridinyl) ethyl] malonate 1.59 g are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.28 (t, 6H), 2.23-2.34
(M, 2H), 2.53 (s, 3H), 2.65 (d
d, 2H), 3.40 (t, 1H), 4.21 (q, 4
H), 6.33 (br, 2H), 6.43 (s, 1H) FAB-MS (m / z): 340 [M + H] +

(3) Diethyl [2- (6-amino-4-)
Methyl-5-nitro-2-pyridinyl) ethyl] malonate (679 mg) is dissolved in 2N-hydrochloric acid (10 ml), and the mixture is heated and refluxed for 8 hours. 90 ml of water is added to the reaction solution, which is washed with 30 ml of methylene chloride. The aqueous layer is concentrated under reduced pressure,
549 mg of 2-amino-6- (3-carboxypropyl) -4-methyl-3-nitropyridine hydrochloride are obtained.

¹ H-NMR (200 MHz, DMSO
−d6) δ: 1.83-1.98 (m, 2H), 2.
28 (t, 2H), 2.46 (s, 3H), 2.69
(T, 2H), 6.73 (s, 1H) FAB-MS (m / z): 240 [M + H] +

(4) 2-amino-6- (3-carboxypropyl) -4-methyl-3-nitropyridine hydrochloride 1
38 mg is dissolved in 5 ml of methanol, and 42 mg of sodium hydrogen carbonate is added. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to give 2-amino-6- (3-carboxypropyl)-
4-Methyl-3-nitropyridine is obtained. Obtained 2
-Amino-6- (3-carboxypropyl) -4-methyl-3-nitropyridine is dissolved in 10 ml of acetone,
177 mg of iodobenzene diacetate is added and reacted at room temperature for 20 hours. The reaction solution is concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography to obtain 102 mg of 5- (3-carboxypropyl) -7-methylpyrido [2,3-c] furazan.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 2.08-2.23 (m, 2H), 2.52
(T, 2H), 2.60 (s, 3H), 2.93 (t,
2H), 6.83 (s, 1H) FAB-MS (m / z): 238 [M + H] +, 475
[2M + H] +

Production Example 11 5- (3-t-butoxycarbonylamino-3-carboxy) propyl-7-methylpyrido [2,3-c] furazan-1-oxide (Compound No. 41 of the present application)
Preparation of (3-carboxy-3-amino) propyl-7-methylpyrido [2,3-c] furazan-1-oxide (Compound No. 42) (1) Easier than 6-amino-2,4-lutidine The resulting diethyl [2-acetamido-2- {6- (2,5-
8.59 g of dimethylpyrrole-1-yl) -4-methyl-2-pyridinyl {ethyl] malonate in ethanol 8
It is dissolved in a mixed solvent of 0 ml and 30 ml of water, 6.95 g of hydroxylamine hydrochloride is added, and the reaction solution is reacted for 9 hours while heating under reflux. The reaction solution was concentrated under reduced pressure, and the obtained crude product and 100 ml of ethanol. A mixture of 3 ml of concentrated sulfuric acid is reacted under heating to reflux for 3 hours. Sodium bicarbonate 1
The reaction is stopped by adding 5 g and 100 ml of water. The reaction solution is concentrated under reduced pressure to remove ethanol, and extracted with ethyl acetate. The organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. After filtering the inorganic substance, it was concentrated under reduced pressure,
The obtained crude product was purified by silica gel column chromatography, and diethyl [2-acetamido-2- (6-
5.49 g of [amino-4-methyl-2-pyridinyl) ethyl] malonate are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.25 (t, 6H), 2.00 (s, 3
H), 2.18 (s, 3H), 2.42-2.50.
(M, 2H), 2.67-2.76 (m, 2H), 4.
16-4.28 (mp4H), 4.35 (br, 2
H), 6.14 (s, 1H), 6.33 (s, 1H),
6.93 (s, 1H) FAB-MS (m / z): 352 [M + H] +

(2) Diethyl [2-acetamido-2-
(6-amino-4-methyl-2-pyridinyl) ethyl]
2.81 g of malonate was dissolved in 14 ml of concentrated sulfuric acid, and 0.507 ml of concentrated nitric acid was added dropwise under ice cooling, followed by stirring at the same temperature for 1 hour. Further, the reaction is carried out at room temperature for 1 hour and at 60 ° C. for 1 hour. The reaction solution is added dropwise to ice water, neutralized (pH 5-6) by adding 30 ml of a 40% aqueous sodium hydroxide solution, and concentrated under reduced pressure. 100 ml of ethanol was added to the obtained crude product,
The insolubles are filtered and concentrated under reduced pressure. 75 ml of ethyl acetate and 25 ml of ethanol were further added to the obtained crude product,
The insolubles are filtered and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography to obtain 1.96 g of diethyl [2-acetamido-2- (6-amino-4-methyl-5-nitro-2-pyridinyl) ethyl] malonate.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.26 (t, 6H), 2.02 (s, 3
H), 2.46-2.49 (m, 2H), 2.52
(S, 3H), 2.69-2.79 (m, 2H), 4.
18-4.32 (m, 4H), 6.32 (br, 2
H), 6.41 (s, 1H), 6.81 (s, 1H) FAB-MS (m / z): 397 [M + H] +

(3) Diethyl [2-acetamino-2-
(6-amino-4-methyl-5-nitro-2-pyridinyl) ethyl] malonate (1.90 g) was added to 2N hydrochloric acid (20 m).
and heated under reflux for 10 hours. 180 ml of water is added to the reaction solution, and the mixture is washed with 50 ml of methylene chloride. The aqueous layer is concentrated under reduced pressure to obtain 1.56 g of 2-amino-6- (3-amino-3-carboxy) propyl-4-methyl-3-nitropyridine dibasic salt.

¹ H-NMR (200 MHz, DMSO
−d6) δ: 2.08-2.27 (m, 2H), 2.
41 (s, 3H), 2.64-2.92 (m, 2H),
3.97 (br, 1H), 6.62 (br, 1H),
8.57 (br, 2H) FAB-MS (m / z): 255 [M + H] +

(4) 2-amino-6- (3-amino-3
779 mg of -carboxy) propyl-4-methyl-3-nitropyridine dihydrochloride in 8 ml of dioxane and 4 ml of water
And a dioxane (8 ml) solution of 624 mg of di-t-butyl dicarbonate and 3.69 ml of a 2N aqueous solution of sodium hydroxide were added at room temperature.
Stir for hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography.
-Amino-6- (3-t-butoxycarbonylamino-
836 mg of 3-carboxy) propyl-4-methyl-3-nitropyridine are obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
1.44 (s, 9H), 1.98-2.32 (m, 2
H), 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) FAB-MS (m / z): 353 [MH]-, 707
[2M-H]-(5) 2-amino-6- (3-t-butoxycarbonylamino-3-carboxy) propyl-4-methyl-3-
Dissolve 709 mg of nitropyridine in 30 ml of benzene, add 709 mg of iodobenzene diacetate, 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 column chromatography to give 5- (3-t-butoxycarbonylamino-3
-Carboxy) propyl-7-methylpyrido [2,3-
c] 413 mg of furazan-1-oxide are obtained.

¹ H-NMR (200 MHz, CDCl
₃ ) δ: 1.44 (s, 9H), 2.10-2.50
(M, 2H), 2.59 (s, 3H), 2.91-3.
00 (m, 2H), 4.35 (br, 1H), 5.52
(D, 1H), 6.85 (s, 1H) FAB-MS (m / z): 353 [M + H] +, 705
[2M + H] +, 297 [M + Ht-butyl] +

(6) 216 mg of 5- (3-t-butoxycarbonylamino-3-carboxy) propyl-7-methylpyrido [2,3-c] furazan-1-oxide was dissolved in 2.5 ml of methanol, and Acetic acid 7.5
Then, the mixture is reacted at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography and Diaion HP-20 to obtain 5- (3-amino-3-carboxy) propyl-7.
80.6 mg of -methylpyrido [2,3-c] furazan-1-oxide are obtained.

¹ H-NMR (200 MHz, D 2 O)
δ: 2.27 (q, 2H), 2.52 (s, 3H),
2.92-3.05 (m, 2H), 3.80 (t, 1
H), 7.08 (s, 1H) FAB-MS (m / z): 253 [M + H] +

[0204]

According to the present invention, it has been found that pyrido [2,3-c] furazan-1-oxide derivatives and pharmaceutically acceptable salts thereof have a potent nitric oxide synthase inhibitory action. . That is, it has been found that a pharmaceutical composition containing a pyrido [2,3-c] furazan-1-oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient is useful as a nitric oxide production inhibitor. Was.

Claims (15)

[Claims] (1) a nitric oxide synthase inhibitory concentration (I)
A pyrido [2,3-c] furazan-1-oxide derivative or a pharmaceutically acceptable salt thereof having an inhibitory activity on nitric oxide synthase having a C ₅₀ ) of 1 mM or less; Inhibitors. 2. A pyrido [2,3-c] furazan-1- having a molecular weight of 500 or less and having an activity of inhibiting nitric oxide synthase.
A nitric oxide synthase inhibitor comprising an oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 3. A compound of the general formula [1] [Wherein, R ¹ , R ² , and R ³ are the same or each independently a substituent, and are a hydrogen atom, a halogen atom, a linear or branched lower alkyl group having 1 to 6 carbon atoms.] Unsubstituted or halogen atom, cycloalkyl group having 3 to 8 carbon atoms, COR ⁴ group (here, R ⁴ group is 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, and one or more hydrogen atoms may be substituted with an amino group), 1- Oxy-pyrido [2,3-c] furazyl group (unsubstituted or one or more hydrogen atoms may be substituted by a linear or branched lower alkyl group having 1 to 4 carbon atoms) , OR ⁵ groups (where R
⁵ represents a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms), an NR ⁶ R ⁷ group (here, R ⁶ and R
⁷ represents a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or branched lower alkoxycarbonyl group having 1 to 4 carbon atoms, R ⁶ , R ^{6 7} are the same or, alternatively each independent is a substituent) of which may be substituted one or more hydrogen atoms on either}, oR ⁸ group (wherein R ⁸ is a hydrogen atom, a linear or branched Carbon number 1
Or 4 to 4 lower alkyl groups) or NR ⁹ R ¹⁰ group (where R ⁹ and R ¹⁰ are a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or Represents a branched lower acyl group having 1 to 4 carbon atoms, wherein R ⁹ and R ¹⁰ are the same,
Or R ¹ and R ² or R ² and R ³ together are unsubstituted or at least one of a halogen atom and a lower alkyl group having 1 to 4 carbon atoms. A cycloalkane ring having 5 to 7 carbon atoms which may be substituted, or 5 to 5 carbon atoms which may be unsubstituted or substituted by one or more halogen atoms or lower alkyl groups having 1 to 4 carbon atoms;
Seven cycloalkene rings can be formed. A nitric oxide synthase inhibitor comprising, as an active ingredient, a pyrido [2,3-c] furazan-1-oxide derivative represented by the formula: or a pharmaceutically acceptable salt thereof. 4. The compound of the formula [1] according to claim 3, wherein R ¹ is a hydrogen atom, a halogen atom, a linear or branched lower alkyl group having 1 to 6 carbon atoms (unsubstituted or substituted). A halogen atom may be substituted with one or more hydrogen atoms, or an OR ⁸ group (where R ⁸ is a linear or branched C 1 group)
R ⁴ represents a hydrogen atom, a halogen atom, or a linear or branched lower alkyl group having 1 to 6 carbon atoms (unsubstituted or one or more halogen atoms) Wherein the hydrogen atom may be substituted). 5. The compound according to claim 3, wherein R ¹ is a hydrogen atom, a chlorine atom, a methyl group, an ethyl group,
n-propyl, isopropyl, trifluoromethyl or methoxy, R ² is hydrogen, chlorine, methyl or ethyl, R ³ is hydrogen, methyl, ethyl, n-propyl, isopropyl , N-butyl group,
Trifluoromethyl group, 3-aminopropyl group or 3-
The nitric oxide synthase inhibitor according to claim 3, which is represented by (t-butoxycarbonylamino) propyl. 6. Pyrid [2,3-c] furazan-1-oxide, 7-chloropyrido [2,3-c] furazan-1-oxide
Oxide, 5-methylpyrido [2,3-c] furazan-
1-oxide, 6-methylpyrido [2,3-c] furazan-1-oxide, 7-methylpyrido [2,3-c] furazan-1-oxide, 7-ethylpyrido [2,3-
c] furazan-1-oxide, 7-n-propylpyrido [2,3-c] furazan-1-oxide, 7-isopropylpyrido [2,3-c] furazan-1-oxide,
5,7-dimethylpyrido [2,3-c] furazan-1-
Oxide, 5-ethyl-7-methylpyrido [2,3-
c] furazan-1-oxide, 7-methyl-5-n-propylpyrido [2,3-c] furazan-1-oxide,
5-isopropyl-7-methylpyrido [2,3-c] furazan-1-oxide, 5-n-butyl-7-methylpyrido [2,3-c] furazan-1-oxide, 7-methyl-5-trifluoro Methylpyrido [2,3-c] furazan-1-oxide, 5,7-bis (trifluoromethyl) pyrido [2,3-c] furazan-1-oxide, 6
-Chloro-5,7-dimethylpyrido [2,3-c] furazan-1-oxide, 5,6,7-trimethylpyrido [2,3-c] furazan-1-oxide, 5,7-dimethyl-6 -Ethylpyrido [2,3-c] furazan-1-
Oxide, 5- (3-aminopropyl) -7-methylpyrido [2,3-c] furazan-1-oxide, 5- (3
-T-butoxycarbonylaminopropyl) -7-methylpyrido [2,3-c] furazan-1-oxide, 7-
A nitric oxide synthase inhibitor comprising methoxypyrido [2,3-c] furazan-1-oxide or a pharmaceutically acceptable salt thereof as an active ingredient. 7. A 7-methylpyrido [2,3-c] furazan-1-oxide, 5,7-dimethylpyrido [2,3-
c] furazan-1-oxide, 5-ethyl-7-methylpyrido [2,3-c] furazan-1-oxide, 5-n
-Propyl-7-methylpyrido [2,3-c] furazan-1-oxide, 5-isopropyl-7-methylpyrido [2,3-c] furazan-1-oxide or a pharmaceutically acceptable salt thereof as an active ingredient Nitric oxide synthase inhibitor. 8. The pyrido [2,3] according to claim 1, 2 or 3
-C] An inducible nitric oxide synthase inhibitor comprising as an active ingredient a furan-1-oxide derivative or a pharmaceutically acceptable salt thereof. 9. A compound comprising 7-methylpyrido [2,3-c] furazan-1-oxide and 5,7-dimethylpyrido [2,3-
c] furazan-1-oxide, 5-ethyl-7-methylpyrido [2,3-c] furazan-1-oxide, 5-n
-Propyl-7-methylpyrido [2,3-c] furazan-1-oxide, 5-isopropyl-7-methylpyrido [2,3-c] furazan-1-oxide or a pharmaceutically acceptable salt thereof as an active ingredient Inducible nitric oxide synthase inhibitor. 10. The pyrido [2, according to claim 1, 2 or 3,
3-c] A neuronal nitric oxide synthase inhibitor comprising a furan-1-oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 11. The pyrido [2, according to claim 1, 2 or 3,
3-c] a selective inducible nitric oxide synthase inhibitor comprising a furan-1-oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the selectivity is a ratio of IC50 value (IC50 [endothelium Type] / IC50 [inductive type])
The selective inducible nitric oxide synthase inhibitor as described above. 12. The pyrido [2, according to claim 1, 2 or 3,
3-c] An agent for treating septic shock, an agent for treating arthritis or an agent for treating allergic rhinitis, which comprises a furazan-1-oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 13. The pyrido [2, according to claim 1, 2 or 3,
3-c] A therapeutic agent for cerebrovascular disorders, a therapeutic agent for Parkinson's disease, an analgesic agent or a therapeutic agent for obesity, comprising a furan-1-oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 14. A medicament comprising the pyrido [2,3-c] furazan-1-oxide derivative according to claim 3 or a pharmaceutically acceptable salt thereof as an active ingredient. 15. A compound of the general formula [2] [Wherein, R ¹ , R ² , and R ³ are the same or each independently a substituent, and are a hydrogen atom, a halogen atom, a linear or branched lower alkyl group having 1 to 6 carbon atoms.] Unsubstituted or halogen atom, cycloalkyl group having 3 to 8 carbon atoms, COR ⁴ group (here, R ⁴ group is 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, and one or more hydrogen atoms may be substituted with an amino group), 1- Oxy-pyrido [2,3-c] furazyl group (unsubstituted or one or more hydrogen atoms may be substituted by a linear or branched lower alkyl group having 1 to 4 carbon atoms) , OR ⁵ groups (where R
⁵ represents a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms), an NR ⁶ R ⁷ group (here, R ⁶ and R
⁷ represents a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or branched lower alkoxycarbonyl group having 1 to 4 carbon atoms, R ⁶ , R ^{6 7} are the same or, alternatively each independent is a substituent) of which may be substituted one or more hydrogen atoms on either}, oR ⁸ group (wherein R ⁸ is a hydrogen atom, a linear or branched Carbon number 1
Or 4 to 4 lower alkyl groups) or NR ⁹ R ¹⁰ group (where R ⁹ and R ¹⁰ are a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or Represents a branched lower acyl group having 1 to 4 carbon atoms, wherein R ⁹ and R ¹⁰ are the same,
Or R ¹ and R ² or R ² and R ³ together are unsubstituted or at least one of a halogen atom and a lower alkyl group having 1 to 4 carbon atoms. A cycloalkane ring having 5 to 7 carbon atoms which may be substituted, or 5 to 5 carbon atoms which may be unsubstituted or substituted by one or more halogen atoms or lower alkyl groups having 1 to 4 carbon atoms;
Seven cycloalkene rings can be formed. However, pyrido [2,3-c] furazan-1-oxide, 5
-Methylpyrido [2,3-c] furazan-1-oxide, 6-methylpyrido [2,3-c] furazan-1-oxide, 7-methylpyrido [2,3-c] furazan-1
-Oxide, 5,7-dimethylpyrido [2,3-c] furazan-1-oxide, 5-aminopyrido [2,3-
c] Furazan-1-oxide, excluding 5-acetylaminopyrido [2,3-c] furazan-1-oxide. [2] a pyrido [2,3-c] furazan-1-oxide derivative or a pharmaceutically acceptable salt thereof.