JPH08152428A - Reagent for measuring no gas - Google Patents

Abstract

PURPOSE: To obtain a standard reagent which immediately releases NO gas after being dissolved in water or a proper solvent by using a compound expressed by a specific formula or its salt as a main constituent. CONSTITUTION: A standard reagent uses a compound expressed by a formula I (R<1> is hydrogen, a lower alkyl group etc., R<2> and R<6> are respectively hydrogen or lower alkyl groups, R<3> and R<5> are respectively hydrogen or form a single bond by mutual bounding, R<4> is hydrogen or a lower alkyl group etc., R<7> is hydrogen, hudroxyiminomethyl group, cyano group etc.) or its salt as main constituent. For example, a compound of formula II (R<1> is hydrogen, a lower alkyl group etc., R<2> , R<4> , and R<6> are respectively hydrogen or lower alkyl groups, and R<7> is hydrogen etc.) is especially preferable. For example, methyl, ethyl etc., or 1-6C alkane residue in straight or branched chain are preferable as a lower alkyl group. These compounds are dissolved in a proper solvent such as water or dimethylsulfoxide and then immediately releases NO gas, thus easily drawing a calibration curve by the normal method.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a standard reagent for measuring NO gas in a living body and N using the standard reagent for measuring NO gas.
The present invention relates to an O 2 gas measuring method.

[0002]

BACKGROUND OF THE INVENTION Since it was revealed that nitric oxide (NO) produced by vascular endothelial cells is the essential form of endothelium-derived vasorelaxant,
The research on the physiological action of NO and its involvement in pathological conditions has been actively conducted. On the other hand, however, NO is so unstable under physiological conditions that the concentration showing physiological activity has not been accurately determined at present. According to it
The development of measuring instruments that can selectively determine the concentration of NO at low concentrations has become popular in Japan and overseas. A chemiluminescence method, a polarography method, and the like have been developed as NO measurement methods.

As NO measuring instruments are developed, pure NO is required as a standard reagent. Currently, pure NO as a standard reagent is obtained mainly by dissolving commercially available NO gas in water, but it is difficult to know the exact concentration of NO at this time. Also, when using, change the NO concentration to NO.
I feel very inconvenient because I have to adjust from the cylinder. Therefore, if there is an NO-releasing agent capable of releasing the amount of NO just dissolved in water as the standard reagent, the above-mentioned problems can be solved. In consideration of such circumstances, for example, as a standard reagent for measuring NO gas in a living body, a standard reagent that releases NO immediately after being dissolved in water or an appropriate solvent was developed.

[0004]

The main component of the standard reagent for measuring NO gas of the present invention is represented by the following general formula (I) or a salt thereof.

The compounds represented by the following general formulas (II), (III) and (IV) or salts thereof can also be used as the main component of the standard reagent for measuring NO gas.

General formula (I) [Wherein R ¹ is hydrogen, a lower alkyl group, a lower alkoxy (lower) alkyl group or a lower alkoxyphenyl group, R ² is hydrogen or a lower alkyl group, R ³ and
R ⁵ is hydrogen, or is bonded to each other to form a single bond, R ⁴ is hydrogen or a lower alkyl group, a lower alkoxy (lower) alkyl group, or Is cyclized (In the formula, X ¹ _a represents an alkylene group, and may contain an oxygen atom, a sulfur atom, or a nitrogen atom which may have a substituent in the chain, Y ¹ _a is an alkyl group. Represents an alkylene group which may be substituted with, p is an integer of 0 to 3, R ⁶ is hydrogen or a lower alkyl group, R ⁷ is hydrogen, a hydroxyiminomethyl group, a cyano group, a formylpiperazinecarbonyl group, an alkanoyl group. An esterified carboxy group, hydroxy or a lower alkyl group optionally having a lower alkanoyloxy, or a formula: A lower alkyl group which may have one or more substituents selected from terified carboxy, hydroxy and phenyl, or lower alkyl, lower alkoxy, phenyl, carbamoyl, halogen, amino, lower alkylthio, hydroxy, lower A heterocyclic group which may be substituted with one or more substituents selected from alkylsulfonylamino and carbamoylmethyl; means a heterocyclic lower alkyl group, or R ⁸ and R ⁹ are bonded to each other to piperidine Forming a ring), R ¹⁰
Is hydrogen or a lower alkyl group optionally having carboxy or esterified carboxy, or R ⁷
Is the formula: (In the formula, X ¹ _b is —O—, —S— or —NH—, and m is 0.
Or an integer of 1, and R ¹¹ is a carbamoyl group, a lower alkylcarbamoyl group, a lower alkanoyl group, a di-lower alkylaminosulfonyl group, a lower alkylsulfonyl group, an oxamoyl group or a formula: (Y ¹ _b ) _n —R ¹² (wherein , Y ¹ _b is —CO—, —SO ₂ —, —COCH ₂ — or n is an integer of 0 or 1, and R ¹² is substituted with one or more substituents selected from lower alkyl, lower alkoxy, phenyl, carbamoyl, halogen, amino, lower alkylthio, hydroxy, lower alkylsulfonylamino and carbamoylmethyl. An optionally substituted heterocyclic group, or R ⁷ has the formula: [In the formula, a represents NH, O or S, and b, c
And d are the same or different and are CH or N
Wherein R ¹³ , R ¹⁴ and R ¹⁵ are the same or different and are hydrogen, lower alkyl, halogen, nitro, cyano,
Benzyl, (CH ₂ ) _M OR ¹⁶ (in the formula, R ¹⁶ represents hydrogen or lower alkyl, M is an integer of 0 to 3), lower alkanoyl, lower alkoxycarbonyl]
Respectively.].

General formula (II) [In the formula, R ¹⁷ is a hydroxyl group, a lower alkoxy group or a formula: —N (R ¹⁹ ) (R ²⁰ ) (In the formula, R ¹⁹ and R ²⁰ are the same or different and represent hydrogen, a lower alkyl group or an aralkyl group. , Or R ¹⁹
, R ²⁰ are bonded to each other to form a nitrogen-containing heterocycle with the adjacent nitrogen atom. R ¹⁸ is hydrogen, a lower alkyl group, an aralkyl group, an alkoxycarbonyl group, an aralkoxycarbonyl group, an alkoxyalkyl group, an aralkoxyalkyl group, an acyl group, an alkoxycarbonylalkyl group, an aryloxycarbonyl group. X ² alkyl or aralkyloxycarbonyl group is the formula: (In the formula, R ²¹ , R ²² , R ²³ and R ²⁴ are the same or different and each is hydrogen, a lower alkyl group, an aryl group or an aralkyl group, Y ² is an oxygen atom, a sulfur atom, a formula: N—R ²⁵ (formula: R ²⁵ represents hydrogen, an acyl group, an alkyl group, an aralkyl group or an alkoxycarbonyl group.) Or
formula: (In the formula, R ²⁶ and R ²⁷ are the same or different and each represents hydrogen, a lower alkyl group, an aryl group or an aralkyl group,
Indicates 0, 1 or 2. ), 1a and ma represent 0, 1 or 2, respectively. ) Represents a group represented by ].

General formula (III) [Wherein R ²⁸ represents an aryl group or a heteroaryl group,
R ²⁹ is hydrogen, an aryl group or a heteroaryl group,
³⁰ is hydrogen, lower alkyl group, aralkyl group, alkoxycarbonyl group, aralkoxycarbonyl group, alkoxyalkyl group, aralkoxyalkyl group, acyl group, alkoxycarbonylalkyl group, aryloxycarbonylalkyl group, aralkyloxycarbonylalkyl group A carbamoyl group or an N-substituted carbamoyl group,
R ³¹ and R ³² are the same or different and each represent hydrogen, a lower alkyl group or an aralkyl group, or they together represent a carbonyl group, and X ³ is a group represented by the formula: (In the formula, R ³³ , R ³⁴ , R ³⁵ and R ³⁷ are the same or different and each is hydrogen, a lower alkyl group, an aryl group or an aralkyl group, Y ³ is an oxygen atom, a sulfur atom, a formula: N—R ³⁷ (the formula: R ³⁷ represents hydrogen, an acyl group, an alkyl group, an aralkyl group or an alkoxycarbonyl group.) Or
formula: (In the formula, R ³⁸ and R ³⁹ are the same or different and each represents hydrogen, a lower alkyl group, an aryl group or an aralkyl group;
Indicates 0, 1 or 2. ), 1b and mb are 0, 1 or 2, respectively. ) Represents a group represented by Regarding the bond between 1'-2 'and 1'-3, one is a single bond and the other is a double bond. ].

General formula (IV) [In the formula, R ⁴⁰ , R ⁴¹ and R ⁴² are the same or different and each is hydrogen, lower alkyl, aralkyl or aryl. Indicates heteroaryl, or R ^41, R ⁴² is bonded to the formula ^{- (CR 46 R 47) mc} -X 4 - (CR 48 R 49) nc- (a) ( wherein R ^46, R ^48, R ⁴⁹ Are the same or different and represent hydrogen, lower alkyl, aralkyl or aryl, and X ⁴
Represents oxygen and sulfur, and = NR ⁵⁰ represents hydrogen, acyl, lower alkyl, aralkyl, alkoxycarbonyl and aralkoxycarbonyl. ),-(CR ⁵¹ R ⁵² ) q- (wherein R ⁵¹ and R ⁵² are the same or different and each represents hydrogen, lower alkyl, aralkyl or aryl, and q represents an integer of 0, 1, 2 or 3). And mc and nc represent 0, 1 or 2, respectively. And R ⁴³ and R ⁴⁴ are the same or different and each represent hydrogen, lower alkyl, aralkyl or aryl, or one of R ⁴³ and R ⁴⁴ is bonded to R ⁴² to form a single bond, or ⁴³ and R ⁴⁴ together form a carbonyl, = N-OR ⁵³ (where R ⁵³
Is hydrogen, lower alkyl, aralkyl, alkoxycarbonyl, aralkoxycarbonyl, alkoxyalkyl,
It represents aralkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, and acyl. ), A cycloalkyl having 3 to 7 carbon atoms, R ⁴⁵ is hydrogen, cyano, lower alkyl, -C
H = N-OR ⁵⁴ (wherein R ⁵⁴ hydrogen, lower alkyl,
Aralkyl, alkoxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aralkoxyalkyl,
Carboxyalkyl, alkoxycarbonylalkyl,
Indicates aralkoxycarbonylalkyl and acyl. ),
Formula —CR ⁵⁵ R ⁵⁶ —OR ⁵⁸ (b) (wherein R ⁵⁵ and R ⁵⁶ are the same or different and represent hydrogen, lower alkyl, aralkyl and aryl, and R ⁵⁸ is hydrogen, lower alkyl, aralkyl, alkoxyalkyl,
It represents aralkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, and acyl. ) Or the formula —COR ⁵⁸ (c) (wherein R ⁵⁸ is hydrogen, hydroxyl group, lower alkyl, lower alkoxy, aralkoxy, —NR ⁵⁹ R ⁶⁰ (where R
⁵⁹ and R ⁶⁰ are the same or different and each is hydrogen or lower alkyl.
Aralkyl, carboxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, hydroxyalkyl, aryl, heteroaryl, or R
⁵⁹ and R ⁶⁰ are combined to form a heterocycle with the adjacent nitrogen atom. ). )]].

Compounds (I), (II) and (II of the present invention
I) and (IV) are described in, for example, JP-A-59-152366.
Japanese Patent Laid-Open No. 4-364157 and Japanese Patent Laid-Open No. 5-2.
13909, JP-A-5-294917, JP-A-5-310695, and International Publication WO93 / 10.
Including the known compounds and novel compounds described in JP-A No. 097, the novel compounds can be produced according to the methods described in these publications or by the methods shown in the synthesis examples shown below.

In the above and subsequent descriptions of the present specification, preferred examples and explanations of various definitions included within the scope of the present invention will be explained in detail below.

The term "lower" means 1 to 6 carbon atoms unless otherwise specified. Preferable examples of "lower alkyl group" include linear or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl and the like. Examples thereof include alkane residues having 1 to 6 carbon atoms.

Preferable examples of "lower alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy and the like groups.
Preferable examples of “(lower) alkanoyl group” include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, 3,3-dimethylbutyryl, lauroyl, stearoyl and the like.

Preferable examples of "esterified carboxy group" include alkylesters, that is, lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl and the like. Alkoxycarbonyl groups such as Preferable examples of “halogen” include fluorine, chlorine, bromine, iodine and the like.

Preferable examples of "lower alkanoyloxy group" include acetoxy, propionyloxy, butyryloxy, tertiary butyryloxy and the like groups.
Preferable examples of "lower alkylcarbamoyl group" include:
Examples thereof include groups such as methylcarbamoyl, N, N dimethylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, and tert-butylcarbamoyl.

Preferable examples of "lower alkoxy (lower) alkyl group" include groups such as methoxymethyl, methoxyethyl, ethoxymethyl, propoxymethyl and the like.

Preferable examples of "di-lower alkylaminosulfonyl group" include dimethylaminosulfonyl,
Examples include groups such as diethylaminosulfonyl. Preferable examples of “lower alkylsulfonyl group” include, for example,
Examples include groups such as mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and butylsulfonyl.

Preferable examples of "lower alkylthio group" include, for example, methylthio, ethylthio, propylthio,
Examples include groups such as isopropylthio and butylthio. R
⁸ , 1 selected from lower alkyl, lower alkoxy, phenyl, carbamoyl, halogen, amino, lower alkylthio, hydroxy, lower alkylsulfonylamino and carbamoylmethyl represented by R ⁹ and R ^12.
“Heterocyclic group” of “heterocyclic group optionally substituted with one or more substituents” is preferably an unsaturated 3 to 8 membered containing 1 to 4 nitrogen atoms (more preferably 5 or 6).
Member) heteromonocyclic groups such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxides, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H-1,2,4-
Triazolyl, 1H-1,2,3-triazolyl, 2H
-1,2,3-triazolyl, etc.), tetrazolyl (for example, 1H-tetrazolyl, 2H-tetrazolyl,
Etc.), etc .; saturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc .; nitrogen atom 1 to 4 Unsaturated fused heterocyclic groups containing, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, pyrimidopyridine, etc .; 1-2 oxygen atoms and 1 nitrogen atom Three
Unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing, for example, thyminyl, cytosinyl,
Oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,
Etc.), etc .; saturated 3-8 member (more preferably 5 or 6) containing 1-2 oxygen atoms and 1-3 nitrogen atoms.
Member) heteromonocyclic group, for example, morpholinyl, sydnonyl,
Etc .; unsaturated fused heterocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, eg benzoxazolyl,
Benzoxadiazolyl, benzopiperidonyl, etc .; unsaturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, for example, Thiazolyl, isothiazolyl, thiadiazolyl (eg 1,2,3-thiadiazolyl, 1,2,
4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc .; saturated 3-8 member (more preferably 5 or 6 member) containing 1-2 sulfur atoms and 1-3 nitrogen atoms.
Heteromonocyclic groups such as thiazolidinyl, etc .; sulfur atom 1
Unsaturated containing 3 to 8 members (more preferably 5
Or 6-membered) heteromonocyclic group, for example, thienyl, dihydrodithiynyl, dihydrodithiolyl, etc .; sulfur atom 1-2
Fused heterocyclic group containing 1 to 3 nitrogen atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl, benzothiadiazolyl, etc .; Unsaturated 3 to 8 membered containing 1 oxygen atom (more preferably 5 or 6). Member) heteromonocyclic group such as furyl; etc .; unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 oxygen atom and 1-2 sulfur atoms, for example, dihydro. Oxathiynyl, etc .; unsaturated fused heterocyclic groups containing 1-2 sulfur atoms, eg,
Benzothienyl, benzothiynyl, etc .; unsaturated fused heterocyclic groups containing one oxygen atom and 1-2 sulfur atoms,
For example, a heterocyclic group such as benzoxathiynyl and the like;

Preferable examples of the "nitrogen-containing heterocyclic group" shown in R ¹⁹ and R ^{20 which} combine with each other to form a nitrogen-containing heterocyclic group together with the adjacent nitrogen atom include, for example, pyrrolidinyl, piperidino, 1- Piperazinyl, 4-methyl-1
-Piperazinyl, 4-benzyl-1-piperazinyl, morpholino and the like can be mentioned.

The pharmaceutically acceptable salts of compound (I) include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, ammonium salts; ethanolamine salts, triethylamine salts, dicyclohexyl. Examples thereof include salts with inorganic bases such as organic amine salts such as amine salts, and salts with organic bases.

Compounds (I), (II) and (II of the present invention
In I) and (IV), suitable examples and explanations of various definitions are described in detail below.

Aralkyl means that the alkyl part has 1 to 6 carbon atoms.
Aralkyl having 3 alkyl, benzyl, 2
-Phenylethyl, 3-phenylpropyl, 4-phenylputyl, 5-phenylpentyl, 6-phenylhexyl, naphthylmethyl, 2-naphthylethyl, 3-naphthylpropyl, 4-naphthylputyl, and halogens on these aromatic rings. An aralkyl having at least one substituent selected from (chlorine, bromine, iodine, fluorine), lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino and aralkyl is shown. The cycloalkyl having 3 to 7 carbon atoms is cyclopropyl, cycloputyl, cyclopentyl, cyclohexyl, cyclopentyl, etc., and the aralkoxy is aralkylaoxy having an alkoxy part having alkoxy having 1 to 6 carbon atoms and is benzyloxy, 2 -Phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy,
5-phenylpentyloxy, 6-phenylhexyloxy, and halogen (chlorine, bromine, iodine, fluorine), lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino and aralkyl on these aromatic rings. Aralkoxy or the like having at least one substituent selected from, hydroxyalkyl is a linear or branched hydroxylated alkyl having 1 to 6 carbon atoms, 2-hydroxyethyl,
3-hydroxypropyl, 1-hydroxymethylethyl, 4-hydroxybutyl, 5-hydroxypentyl,
6-Hydroxyhexyl and the like, carboxyalkyl is a linear or branched carboxylated alkyl having 1 to 6 carbon atoms, and is carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 1-carboxy. Methyl ethyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl and the like, aryl is phenyl, naphthyl or halogen on the aromatic ring, lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, It represents phenyl, naphthyl or the like having at least one substituent selected from amino and aralkyl.

Heteroaryl means furyl (2-furyl,
3-furyl), pyridyl (2-pyridyl, 3-thienyl, 4-pyridyl), thienyl (2-thienyl, 3-thienyl), pyrrolyl (2-pyrrolyl, 3-pyrrolyl),
Imidazolyl (2-imidazolyl, etc.), pyrazolyl (3-pyrazolyl, 4-pyrazolyl), pyrazinyl, pyrimidinyl (2-pyrimidinyl, etc.), pyridazinyl (3-pyridazinyl, 4-pyridazinyl), triazinyl ([1,2,4] triazine) -3-yl), triazolyl ([1,2,4] triazol-3-yl, etc.), thiazolyl (2-thiazolyl, etc.), tetrazolyl (tetrazol-5-yl), quinolyl (2-quinolyl, 3-quinolyl). , 4-quinolyl), indolyl (2-
Indolyl, 5-indolyl, etc., isoquinolyl (1
-Isoquinolyl etc.), pyrrolopyridyl (1H-pyrrolo [2,3-b] pyridin-4-yl, 1H-pyrrolo [3,2-b] pyridin-7-yl, 1H-pyrrolo [3,4-b] pyridine -4-yl), pyrazolopyridyl (1h-pyrazolo [3,4-b] pyridin-4-
1H-pyrazolo [4,3-b] pyridin-7-yl), imidazopyridyl (1H-imidazo [4,5]
-B] pyridin-7-yl etc.), pyrrolopyrimidinyl (1H-pyrrolo [2,3-d] pyrimidin-4-yl,
1H-pyrrolo [3,2-d] pyrimidin-4-yl, 1
H-pyrrolo [3,4-d] pyrimidin-4-yl), pyrazolopyrimidinyl (1H-pyrazolo [3,4]
-D] pyrimidin-4-yl, pyrazolo [1,5-a]
Pyrimidin-7-yl, 1H-pyrazolo [4,3-d]
Pyrimidin-7-yl), imidazopyrimidinyl (imidazo [1,2-a] pyrimidin-5-yl, 1H
-Imidazo [4,5-d] pyrimidin-7-yl), pyrrolotriazinyl (pyrrolo [1,2-a]-
1,3,5-triazin-4-yl, pyrrolo [2,1-
f] -1,2,4-triazin-4-yl etc.), pyrazolotriazinyl (pyrazolo [1,5-a] -1,3,
5-triazin-7-yl), triazolopyridyl (1H-1,2,3-triazolo [4,5-b] pyridin-7-yl, etc.), triazolopyrimidinyl (1,3).
2,4-Triazolo [1,5-a] pyrimidin-7-yl, 1,2,4-triazolo [4,3-a] pyrimidin-5-yl, 1H-1,2,3-triazolo [4,4 5-
d] pyrimidin-7-yl), pyridopyridazinyl (pyrid [2,3-c] pyridazin-4-yl, pyrido [2,3-c] pyridazin-5-yl, etc.), pyridopyrazinyl (pyrid [2,3-b] pyrazin-5-yl, etc., pyridopyrimidinyl (pyrido [2,3-d] pyrimidin-4-yl, pyrido [2,3-d] pyrimidin-
5-yl, pyrido [3,2-d] pyrimidin-4-yl, pyrido [3,2-d] pyrimidin-8-yl, etc.), pyrimidopyrimidinyl (pyrimido [4,5-d])
Pyrimidin-4-yl, pyrimido [5,4-d] pyrimidin-4-yl, etc.), pyrazinopyrimidinyl (pyrazino [2,3-d] pyrimidin-4-yl, etc.), naphthyridinyl (1,8-naphthyridine-, etc.) 4-yl and the like), quinazolinyl (4-quinazolinyl and the like), tetrazolopyrimidinyl (tetrazolo [1,5-a] pyrimidine-7-
, Etc.), thienopyridyl (thieno [2,3-b] pyridin-4-yl, etc.), thienopyrimidinyl (thieno [2,3-d] pyrimidin-4-yl, etc.), thiazolopyridylwou (thiazolo [4, 5-b] pyridin-7-yl, thiazolo [5,4-b] pyridin-7-yl, etc.), thiazolopyrimidinyl (thiazolo [4,5-
d] pyrimidin-7-yl, thiazolo [5,4-d] pyrimidin-7-yl, etc.), oxazolopyridyl (oxazolo4,5-b] pyridin-7-yl, oxazolo [5,4-b] pyridine. -7-yl), oxazolopyrimidinyl (oxazolo [4,5-b] pyrimidine-
4-yl, oxazolo [5,4-d] pyrimidin-7-
, Etc.), furopyridyl (furo [2,3-b] pyridin-4-yl, furo [3,2-b] pyridin-7-yl, etc.), furopyrimidinyl (furo [2,3-d] pyrimidin-4) -Yl, furo [3,2-d] pyrimidin-4-
Etc.), 2,3-dihydropyrrolopyridiiyl (2,3-dihydro-7H-pyrrolo [2,3-b] pyridin-4-yl, 2,3-dihydro-5H-pyrrolo [3,2- b] pyridin-4-yl etc.), 2,3 dihydropyrrolopyrimidinyl (2,3-dihydro-7H-pyrrolo [2,3-d] pyrimidin-4-yl, 2,3-dihydro-5H-pyrrolo [3 , 2-d] pyrimidine-4-
And the like), 6,7-dihydropyridopyrimidinyl (6,7-dihydro-pyrido [2,3-d] pyrimidin-4-yl, 6,7-dihydro-pyrido [3,2-d]
Pyrimidin-4-yl etc.), 5,6,7,8-tetrahydropyridopyrimidinyl (5,6,7,8-tetrahydro-pyrido [2,3-d] pyrimidin-4-yl etc.), 6,7 , 8,9 Tetrahydropyridopyrimidinyl (6,7,8,9-tetrahydro-pyrido [1,2-
a] pyrimidin-4-yl, etc., 6,7-dihydronaphthyridinyl (6,7-dihydro-1,8-naphthyridin-4-yl, etc.)-5,6,7,8-tetrahydropyridopyrimidinyl (5 , 6,7,8-Tetrahydro-pyrido [2,3-d] pyrimidin-4-yl, etc.
7,8-Tetrahydronaphthyridinyl (5,6,7,8
-Tetrahydro-1,8-naphthyridin-4-yl etc.), 5,6,7,8-tetrahydroquinolyl (5,5)
6,7,8-tetrahydroquinolin-4-yl etc.),
Or a heteroaryl having at least one substituent selected from halogen, lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino and aralkyl on the ring.

Acyl means formyl, lower alkanoyl or aroyl and the like, lower alkanoyl is alkanoyl having 2 to 5 carbon atoms, which may be substituted by phenyl, and is acetyl, propionyl, butyryl, pareryl, Pivaloyl, phenylacetyl, phenylpropionyl, phenylbutyryl, and at least one substituent selected from halogen, lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino and aralkyl on these aromatic rings. Phenyl-substituted alkanoyl and the like, aroyl is selected from benzoyl, naphthoyl, halogen, lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino and aralkyl on these aromatic rings. Shows aroyl and having at least one substituent.

Alkoxycarbonyl means that the alkoxy part has an alkoxy having 1 to 6 carbon atoms, and is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, Pentyloxycarbonyl, hexyloxycarbonyl and the like, and aralkyloxycarbonyl is an aralkyl having an aralkyl having an alkyl group having 1 to 6 carbon atoms, such as benzyloxycarbonyl, 2-phenylethoxycarbonyl and 3-phenylpropoxycarbonyl. , 4-phenylbutoxycarbonyl, 5-phenylpentyloxycarbonyl, 6-phenylhexyloxycarbonyl, naphthylmethoxycarbonyl, 2-naphthylpropoxy Arbonyl, 4-naphthylbutoxycarbonyl, and aralkyl having at least one substituent selected from halogen, lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino and aralkyl on these aromatic rings. Indicates oxycarbonyl.

Alkoxyal means that the alkoxy part and the alkyl part have alkoxy and alkyl having 1 to 6 carbon atoms, and is methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5
-Methoxypentyl, 6-methoxyhexyl, ethoxymethyl, propoxymethyl, butoxymethyl, pentyloxymethyl, hexyloxymethyl, etc., and aralkoxy has an alkoxy part and an alkyl part having 1 carbon atom.
Aralkyloxyalkyl having ~ 6 alkoxy and alkyl, benzyloxymethyl, (2-
Phenylethoxy) methyl, (3-phenylpropoxy) methyl, (4-phenylbutoxy) methyl, (5-
Phenylpentyloxy) methyl, (6-phenylhexyloxy) methyl, 2-benzyloxyethyl, 3-
Benzyloxypropyl, 4-benzyloxybutyl,
5-benzyloxypentyl, 6-benzyloxyhexyl and the like are shown.

Alkoxycarbonylalkyl means that the alkoxy part and the alkyl part have alkoxy and alkyl having 1 to 6 carbon atoms, and is methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 4-methoxycarbonyl. Butyl, 5-methoxycarbonylpentyl, 6-methoxycarbonylhexyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, butoxycarbonylmethyl, pentyloxycarbonylmethyl, hexyloxycarbonylmethyl and the like, and the aralkoxycarbonylalkyl is an alkoxy part and an alkyl part. Are those having alkoxy and alkyl having 1 to 6 carbon atoms and are benzyloxycarbonylmethyl, (2-phenylethoxy) carbonylmethyl, ( -Phenylpropoxy) carbonylmethyl, (4-phenylbutoxy) carbonylmethyl, (5-phenylpentyloxy) carbonylmethyl, (6-phenylhexyloxy) carbonylmethyl, 2-benzyloxycarbonylethyl, 3-benzyloxycarbonylbutyl, 5-benzyloxycarbonylpentyl, 6-benzyloxycarbonylhexyl and the like are shown.

The heterocycle formed by R ⁵⁹ and R ⁶⁰ together with the adjacent nitrogen atom is pyrrolidinyl, piperidino,
1-piperazinyl, morpholino, thiomorpholino, and halogen, lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro on these rings.
A heterocycle having at least one substituent selected from amino, acyl and aralkyl is shown respectively.

The compound of the general formula (IV) having a carboxyl group can be an ester, and examples of the ester include an ester that can be hydrolyzed in vivo, and an ester that forms an ester that can be hydrolyzed in vivo. The residue is a compound that can be easily decomposed in vivo to give a free carboxylic acid or a salt thereof, and includes aminoalkyl esters such as dimethylaminoethyl, dimethylaminopropyl, benzylmethylaminoethyl, acetoxymethyl, and bivaloyl. Oxymethyl, 1-acetoxyethyl,
Alkanoyloxyalkyl esters such as 1-piparoyloxyethyl, ethoxycarbonyloxymethyl,
Alkoxycarbonyloxyalkyl esters such as 1-ethoxycarbonyloxyethyl, esters such as phthalidyl and dimethoxyphthalidyl, carbamoylmethyl, carbamoylethyl, N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, N, N-dimethylcarbamoylethyl , N, N-diethylcarbamoylmethyl, carbamoylalkyl ester such as N, N-diethylcarbamoylethyl, alkoxyalkyl ester such as methoxymethyl, methoxyethyl or 5-methyl-1,3-dioxolen-2-on-4-yl A methyl ester etc. can be mentioned. further,
The compound having a carboxyl group can be an amide, and as the amide-forming residue in the case of forming the amide in the case of forming the amide, amino or methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, Mention may be made of mono- or dialkylamino such as dipropylamino and dibutylamino.

The aryloxycarbonylalkyl group is selected from phenoxycarbonylmethyl, phenoxycarbonylethyl, phenoxycarbonylpropyl or a halogen, a lower alkyl group, a lower alkoxy group, a hydroxyl group, trifluoromethyl, cyano, nitro or amino on an aromatic ring. Examples of the N-substituted carbamoyl group include phenoxycarbonylmethyl, phenoxycarbonylethyl, and phenoxycarbonylpropyl having at least one substituent. The N-substituted carbamoyl group is lower alkyl at the N-position or optionally substituted aryl. Represents a carbamoyl group substituted with, and includes methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, phenylcarbamoyl and the like.

Particularly preferred examples of the compound used in the present invention are as follows. General formula [Wherein R ¹ is hydrogen, a lower alkyl group or a lower alkoxy (lower) alkyl group, R ² is hydrogen or a lower alkyl group, R ⁴ is hydrogen or a lower alkyl group, R ⁶ is hydrogen or a lower alkyl group, R ⁷ Is hydrogen or the formula: (Wherein R ⁸ and R ⁹ are each hydrogen, a pyridyl group, a pyridyl lower alkyl group or a thyminyl group, or R ⁷ is a group represented by the formula: (In the formula, X ¹ _b is —O— or —NH—, and m is 0 or 1.
And R ¹¹ is a carbamoyl group, a lower alkanoyl group or the formula: (Y ¹ _b ) _n —R ¹² (wherein Y ¹ _b is —CO
-, - SO ₂ -, or -COCH ₂ -) n is an integer of 0 or 1, and R ¹² is a carbamoyl group;
Means a pyridyl group, a tetrazolyl group, a thiadiazolyl group, a pyrimidyl group or a benzothiazolyl group, which may be substituted with one or more substituents selected from lower alkyl, halogen, amino or lower alkylthio].

General formula[Where X is¹ _a'Is -0- or -CH ₂-, R¹ Is water
Elementary, lower alkyl group or lower alkoxy (lower) ar
Kill group, R² Is hydrogen or a lower alkyl group, R^FourIs hydrogen
Or a lower alkyl group, R⁶Is hydrogen or lower alkyl
Group, R⁷ Is hydrogen or the formula:(In the formula, R⁸ And R⁹ Are hydrogen and lower
Pyridyl group or thyminyl optionally substituted with kill
Group, or R⁷Is the formula:(In the formula, X¹ _bIs -O- or -NH-, m is 0 or 1
Integer and R¹¹Is a carbamoyl group, lower alkanoy
Group or formula: (Y¹ _b)_n-R¹²(In the formula, Y¹ _bIs -CO
-, -SO₂-Or-COCH₂-) N is an integer of 0 or 1, and R¹²Is a carbamoyl group;
Lower alkyl, halogen, amino or lower alkyl
Even if it is substituted with one or more substituents selected from thio
Good, pyridyl group, tetrazolyl group, thiadiazolyl
Group, pyrimidyl group or benzothiazolyl group
] The compound shown by these.

Among the compounds represented by the formulas (I ^a ) and (I ^b ) shown as the above preferable compounds, more preferable specific examples are shown by the structural formulas.

[0034]

[0035]

EFFECTS OF THE INVENTION General formulas (I), (I ^a ) (I ^b ), (II) and (II) which are the main components of the reagent for measuring NO gas of the present invention.
Since the compounds represented by I) and (IV) release NO gas immediately after they are dissolved in an appropriate solvent such as water or dimethylsulfoxide, a calibration curve can be easily prepared by a conventional method. That is, as described above, the chemiluminescence method, the polarography method, and the like are known as methods for directly measuring the generated NO.

Since the compounds used in the present invention have been confirmed to produce NO in solution by these methods, N in such a method can be used with these compounds.
An O calibration curve can be created.

On the other hand, NO is an extremely unstable compound.
Therefore, it is not easy to measure NO directly, so NO
Stable metabolite NO ₂ ^-And then quantify it
The method for estimating the amount of NO produced is a well-known technique that is often used.
Surgery (J, Pharmacol. Sci.5
2, 637 (1963)), so that
It is possible to measure the production amount and create a calibration curve for NO.
It

The prepared calibration curve can be used to measure, for example, the amount of NO in a living body whose NO gas content is unknown. Further, these compounds are also effective as NO gas generating reagents. In order to show the usefulness of the reagent for measuring NO gas of the present invention, a test was conducted on a representative compound of the compound (I) as the main component. Test compounds are, for example, known compounds and novel compounds shown in Table 1 below.

[0039]

[Table 1]

Test 1 Test Method NO reacts with dissolved oxygen in an aqueous solution and immediately reacts with NO.
₂ ^-And NO ₃ ^-Oxidation of NO
NO, one of the things ₂ ^-By the diazo coupling method
Quantified. Test compound at a concentration of 50 mM in dimethyl sulphate
Dissolve it in HOxide and add 0.2 ml of it to 0.1N phosphorus.
Add to 3.8 ml of sodium acid buffer (pH 8.0)
Was. The concentration of the compound at this time was 2.5 mM. this
Immediately afterwards, incubation was carried out at 30 ° C. Incu
Basation agent and various times after incubation
Then, 0.1 ml of the solution prepared above was added to 3.9 ml.
0.5 N. In addition to HCl, 0.5 ml of sulfanilic acid
(2 mg / ml) was reacted for 10 minutes at room temperature. That
Then 0.5 ml of N-1-naphthylethylenediamine
(1 mg / ml) was added and left at room temperature. 40 minutes later,
Absorbance was measured at a wavelength of 548 mm. At this time, the standard
As a reagent, NaNO₂NO in solution using ₂ ^-Concentration
Decided.

Test Results In the test compound, NO ₂ ^-Is produced in the first reaction
It was. By returning to the first-order reaction formula below, the compound
NO ₂ ^-The production rate constant k was determined.The structures and data of the test compounds are shown in Table 2 below.

[0042]

[Table 2] Since the compound used in the present invention decomposes to generate NO, it can be expected that the NO production rate obtained in Test 1 is proportional to the decomposition rate of the compound. Therefore, instead of the complicated test 1, the decomposition rate of the compound in an aqueous solution was measured as another method for simply estimating the NO production rate. That is, this test 2
Therefore, it can be estimated that the faster the decomposition of the compound, the higher the NO production rate.

Test 2 Test Method Compound 0.05 mmol was dissolved in 1 ml DMSO,
A pH 8.0 phosphate buffer solution kept at 30 ° C. is added thereto to adjust the volume to 20 ml. (Here, t = 0 minutes (mi
n)) Keep this solution warm at 30 ° C. t = 0, 20, 40, 60,
After 90 minutes, the 2 ml solution is removed, diluted with a solution having a pH of 1.0 to 20 ml, and the remaining amount is measured by HPLC. Three
The time taken for the 0% compound to decompose was defined as t _0.7 (minutes), and Table 3 shows the compounds having t _0.7 of 60 min or less.

[0044]

[Table 3]

Test 3 The NO generation amount spontaneously generated from the compound No. 1
The change over time (pH dependence) was measured. How to measure NO amount
As a method, (A) carboxy-PTIO
Trap (ESR method) (Biochemistry)
(1993) 32 827), (B) NO oxidation product
Is NO ₂ ^-The detected amount (Griess reaction) was used.

Test (A) Test Method Compound No. 1 (0.1 mM) and carboxy-P
A buffer solution containing TIO (spin trap agent) 0.1 mM at each pH was stored at 37 ° C., sampled with time,
The ESR spectrum was measured. The height of the signal in the lowest magnetic field of carboxy-PTIO was measured using the signal of Mn ²⁺ as an internal standard, and it is assumed that the amount of NO released from FK409 corresponds to the reduction amount from the initial value of this height. Calculations were performed (the values in the table represent the average value of three repeated measurements).

Test Results Change in NO Production over Time

Test (B) Test Method A buffer solution containing 1.5 mM of Compound No. 1 at each pH was used.
Store at 37 ℃, sample over time, grease
Reaction (NO under acidic conditions ₂ ^-And sulfanilic acid and N
By the reaction of -1-naphthylethylenediamine dihydrochloride
(Measure the absorbance at 548 nm of the produced compound)
Than NO ₂ ^-The amount of change with time was measured (3 in the table).
The average of repeated measurements is shown).

Test result NO ₂ ^-Change over time in production 43The present invention will be described below with reference to synthetic examples.

Synthesis Example Synthesis Example 1 To a solution of diethylphosphonoacetamide (2.92 g) in methylene chloride (10 ml) was added potassium t-butoxide (1.68 g) at 0 ° C., and the mixture was stirred at the same temperature in a nitrogen atmosphere. To do. After 10 minutes, (E) -4-methoxy-2-methyl-2-butenal (1.71 g) was added dropwise at 0 ° C. over 5 minutes, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with cold water and brine, dried over anhydrous magnesium sulfate,
The solvent is distilled off under reduced pressure. The residue is crystallized from methylene chloride-diethyl ether to give (E), (E) -6-methoxy-4-methyl-2,4-hexadienamide. mp: 91-93 ° C IR (nujol): 3300, 3150, 1665
cm ^-1 NMR (DMSO-d ₆ , δ): 1.74 (3H,
s), 3.24 (3H, s), 4.07 (2H, d, J
= 6.19 Hz) 5.92 (1 H, t, J = 6.19 H
z), 6.00 (1H, d, J = 15.54Hz),
7.05 (1H, d, J = 15.54Hz), 7.0
(1H, bs), 7.4 (1H, bs)

Synthesis Example 2 A mixture of 6-methoxy-4-methyl-2,4-hexadienamide (1.1 g), sodium nitrite (2.93 g), water (7 ml) and methylene chloride (7 ml) was added.
6N hydrochloric acid (4.3 ml) is added dropwise at 10 to 15 ° C over 15 minutes. After stirring for 30 minutes, the formed precipitate was collected, washed with water and methylene chloride, and then treated with 2-hydroxyimino-6-
Methoxy-4-methyl-5-nitro-3-hexenecarboxamide is obtained. mp: 113-114 ° C IR (nujol): 3300, 1640, 1550,
1535, 1375 cm ^-1 NMR (DMSO-d ₆ , δ): 1.61 (3H,
s), 3.31 (3H, s), 3.6-4.2 (2H,
m), 5.57 (1H, d, d, J = 3.27Hz),
6.27 (1H, s), 7.32 (1H, s), 7.4
5 (1H, s), 12.0 (1H, s)

Synthetic Example 3 In the same manner as in Synthetic Example 1, the following compound was obtained. 3- (6,6-dimethylbicyclo [3.1.1] hept-2-en-2-yl) propenamide IR (nujol): 3350, 3170, 1655,
1600 cm ^-1 NMR (DMSO-d ₆ , δ): 0.75 (3H,
s), 1.32 (3H, s), 1.90-2.20 (2
H, m), 2.30-2.50 (4H, m), 5.90.
(1H, d, J = 15.6 Hz), 5.97 (1H, b
rs), 6.92 (1H, brs), 7.02 (1H,
d, J = 15.6 Hz), 7.32 (1H, brs)

Synthesis Example 4 In the same manner as in Synthesis Example 2, the following compound was obtained. 2-hydroxyimino-3- (6,6-dimethyl-2-
Nitrobicyclo [3.1.1. ] Hept-2-Iride
N) Propanamide. mp: 136-138 ° C (dec) (CH₂Cl₂) IR (Nujol): 3460, 3350, 3150,
1690, 1585, 1550 cm^-1 Elemental analysis C ₁₂H₁₇N₃O_FourCalculated as: C, 53.92; H, 6, 41; N, 15.72 Measured value: C, 54.24: H, 6.54; N, 15.72

Synthesis Example 5 Same as Example 1 of JP-A-59-152366g
Then, the following compound is obtained. N- (pyridin-3-yl) methyl-4-ethyl-2-
Hydroxyimino-5-nitro-3-hexenamide mp: 110-112 (H₂O) IR (Nujol): 3300, 1655, 1
600, 1580, 1540 cm^-1  NMR (DMSO-d₆, Δ): 0.83 (3H,
t, J = 7 Hz), 1.59 (3H, d, J = 7H)
z), 1.96 (2H, q, J = 7Hz), 4.40.
(2H, d, J = 6Hz), 15.42 (1H, q, J
= 7 Hz), 6.22 (1H, s), 7.50 (1H,
m), 7.85 (1H, m), 8.55 (2H, m),
8.86 (1H, t, J = 6Hz), 12.04 (1
H, s), MS m / Z = 306 (M⁺)

Synthesis Example 6 In the same manner as in Synthesis Example 2, the following compound was obtained. N- [2.4-dioxo (1H, 3H) -pyrimidine-
5-yl) -4-methyl-2-hydroxy-imino-5
-Nitro-3-heptenamide mp: 239-241 ° C (dioxane-H₂O) IR (Nujol): 3115, 1725,
 1640, 1550cm^-1  NMR (DMSO-d₆, Δ): 0.89 (3H,
 t, J = 7.4H z), 1.56 (3H,
s), 1.82-2.22 (2H, m), 5.3.
1 (1H, t, J = 7.4H z), 6.22 (1
H, s), 8.06 (1H, d, J = 6.0H
z), 8.90 (1H, s), 10.76 (1
H, d, J = 6.0H z), 11.63 (1H,
 s), 12.54 (1H, s)

Synthesis Example 7 3- (1-Cyclohexen-1-yl) -2-propen-1-amine (4.8 g) and triethylamine (3.3)
To a solution of g) in methylene chloride (50 ml) at 0 ° C. is added acetic anhydride (6.1 g) dropwise. After 1 hour, the reaction mixture is washed with water (30 ml twice), dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is subjected to silica gel chromatography (eluent: 10% methanol / chloroform) to give 1-acetylamino-3- (1-cyclohexen-1-yl) -2-propene (3.5 g). Melting point 63-65 ° C IR (nujol): 3300, 1640, 1530
cm ^-1 NMR (DMSO-d ₆ , δ): 1.4-1.8 (4
H, m), 1.81 (3H, s), 1.9-2.2 (4
H, m), 3.68, 3.70 (2H, dd, J = 5.
7, 5.7 Hz), 5.3-5.6 (1 H, m), 5.
70 (1H, brs), 6.08 (1H, d, J = 1
5.7 Hz), 7.96 (1H, brs)

Synthesis Example 8 1-Acetylamino-3- (1-cyclohexene-1-
Yl) -2-propene (3.2 g), sodium nitrite (7.4 g), water (18 ml) and methanol (54
ml) mixture at 15 ° C. with 6N aqueous hydrochloric acid solution (14 ml).
Is added dropwise over 20 minutes. After stirring for 1 hour, the reaction mixture is diluted with water and extracted with chloroform (50 ml 3 times). The extracts are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel (eluent: 50% ethyl acetate /
Chloroform). The first eluting compound is isomer A and the second eluting compound is isomer B. High Rf on thin layer chromatography (8% methanol / chloroform)
Isomer A having a value and Isomer B having a low Rf value are the desired 1-acetylamino-2-hydroxyimino-3-
(2-nitrocyclohexylidene) It is a configurational isomer in the hydroxyimino group of propane. Isomer A is crystallized from ethyl acetate / diethyl ether to give the 1 isomer of 1-acetylamino-2-hydroxyimino-3- (2-nitrocyclohexylidene) propane (372 mg). Melting point 115-117 ° C IR (nujol): 3270, 1620, 1545,
1375 cm ^-1 NMR (DMSO-d ₆ , δ): 1.2-2.5 (7
H, m), 2.8-3.0 (1H, m), 3.97 (2
H, d, J = 6.0 Hz), 5.29 (1H, t, J =
4.1 Hz), 5.77 (1 H, s), 8.07 (1
H, t, J = 5.9 Hz), 11.26 (1H, s)

From the second eluting compound, the other isomer B (1.0 g) of 1-acetylamino-2-hydroxyimino-3- (2-nitrocyclohexylidene) propane is obtained as an oil. IR (neat): 3250, 1650, 1540, 13
70 cm ^-1 NMR (DMSO-d ₆ , δ): 1.3-2.5 (8
H, m), 1.80 (3H, S), 3.86 (2H, d
d, J = 1.6, 5.8 Hz), 5.34 (1H, t,
J = 4.3 Hz), 5.86 (1H, s), 8.04
(1H, t, J = 5.8Hz), 10.91 (1H,
s)

Synthesis Example 9 4-Ethyl-2,4-heptadienamide (3.1
g), sodium nitrite (8.3 g), water (15 ml)
And a mixture of methanol (45 ml) at 20 ° C.
Aqueous hydrochloric acid solution (16 ml) is added dropwise over 15 minutes. After stirring for 1 hour, sodium nitrite (8.3 g) is added to the solution, and then 6N hydrochloric acid aqueous solution (16 ml) is added dropwise over 15 minutes. The mixture is stirred at the same temperature for 1 hour. The reaction mixture is diluted with water and extracted with chloroform (30 ml twice). The extract is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was subjected to silica gel chromatography (eluent: 8% methanol / chloroform) to give 4-ethyl-2-hydroxyimino-5-.
Nitro-3-heptenamide (1.90 g) is obtained. Melting point 132-134 ° C IR (nujol): 3420, 3200, 1660,
1550,1375 cm ^-1 NMR (DMSO-d ₆ , δ): 0.8-1.1 (6
H, m), 1.8-2.3 (4H, m), 5.21 (1
H, t, J = 7.6 Hz), 6.19 (1H, s),
7.31 (1H, s), 7.47 (1H, s), 11.
90 (1H, s)

Synthesis Example 10 In the same manner as in Synthesis Example 9, the following compound was obtained. 6,6-Dimethyl-4-ethyl-2-hydroxyimino-5-nitro-3-heptenamide Melting point 157-158 ° C IR (nujol): 3470, 3270, 1670,
1640, 1570, 1550, 1370 cm ^-1 NMR (DMSO-d ₆ , δ): 0.92 (3H,
t, J = 7.5 Hz), 1.06 (9H, s), 1.8
-2.3 (2H, m), 5.18 (1H, s), 6.2
7 (1H, s), 7.29 (1H, s), 7.47 (1
H, s), 11.88 (1H, s)

Synthesis Example 11 In the same manner as in Synthesis Example 9, the following compound was obtained. 4-ethyl-2-hydroxyimino-6-methyl-5-
Nitro-3-heptenamide Melting point 146-148 ° C IR (nujol): 3460, 3230, 1665,
1640, 1555, 1375 cm ^-1 NMR (DMSO-d ₆ , δ): 0.8-1.1 (9
H, m), 2.06 (2H, q, J = 7.0Hz),
2.3-2.5 (1H, m), 4.94 (1H, d, J
= 10.7 Hz), 6.29 (1H, s), 7.31
(1H, s), 7.47 (1H, s), 11.90 (1
H, s)

Synthesis Example 12 In the same manner as in Synthesis Example 9, the following compound was obtained. 2-Hydroxyimino-4-isopropyl-5-nitro-3-hexenamide melting point 181-182 ° C IR (nujol): 3460, 3200, 1665,
1655, 1590, 1550 cm ^-1 NMR (DMSO-d ₆ , δ): 0.9-1.1 (6
H, m), 1.62 (3H, d, J = 6.7 Hz),
2.5-2.7 (1H, m), 5.42 (1H, q, J
= 6.7 Hz), 6.10 (1 H, s), 7.28 (1
H, s), 7.43 (1H, s), 11.84 (1H,
s)

Synthesis Example 13 To a solution of diethylphosphonoacetamide (8.6 g) in methylene chloride (25 ml) was added potassium t-butoxide (5 g) at -10 ° C under a nitrogen atmosphere. 1 mixture at the same temperature
After stirring for 0 minutes, 4,4-dimethyl-2-ethyl-
2-Pentenal (6.2 g) is added. The mixture at 15 ° C
Stir for 2 hours. The reaction mixture is poured into cold water and extracted with methylene chloride (2 x 50 ml). The extract is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was subjected to silica gel chromatography (eluent: 10% ethyl acetate / chloroform),
(E, E) -6,6-Dimethyl-4-ethyl-2,4-
Heptadiene amide (6.4 g) is obtained as an oil. IR (neat): 3320, 3170, 1670, 16
10 cm ^-1 NMR (CDCl ₃ , δ): 0.8-1.1 (3H,
m), 1.17 (9H, S), 2.1-2.5 (2H,
m), 5.82 (1H, d, J = 15.2Hz), 5.
84 (1H, s), 7.08 (1H, d, J = 15.2)
Hz)

Synthesis Example 14 In the same manner as in Synthesis Example 13, the following compound was obtained. (E, E) -4-Ethyl-2,4-heptadienamide IR (Neat): 3320, 3180, 1660, 16
00 cm ^-1 NMR (DMSO-d ₆ , δ): 0.8-1.1 (6
H, m), 2.0-2.4 (4H, m), 5.75 (1
H, t, J = 7.5 Hz), 5.95 (1H, d, J =
15.6 Hz), 6.92 (1H, d, J = 15.6H)
z), 6.91 (1H, s), 7.38 (1H, s)

Synthesis Example 15 In the same manner as in Synthesis Example 13, the following compound was obtained. (E, E) -4-Ethyl-6-methyl-2,4-heptadienamide Melting point 34-35 ° C IR (nujol): 3350, 3180, 1665,
1600 cm ^-1 NMR (DMSO-d ₆ , δ): 0.8-1.1 (9
H, m), 2.22 (2H, q, J = 7.5 Hz),
2.5-2.7 (1H, m), 5.56 (1H, d, J
= 9.8 Hz), 5.96 (1H, d, J = 15.7H)
z), 6.89 (15.7 Hz), 6.93 (1H,
s), 7.39 (1H, s)

Synthesis Example 16 In the same manner as in Synthesis Example 13, the following compound was obtained. (E, E) -4-Isopropyl-2,4-hexadienamide (oil) IR (neat): 3350,3180,1650,16
00 cm ^-1 NMR (CDCl ₃ , δ): 1.0-1.2 (6H,
m), 1.79 (3 / 2H, d, J = 7.2Hz),
1.87 (3 / 2H, d, J = 7.2Hz), 2.5-
2.7 (1 / 2H, m), 2.8-3.0 (1 / 2H,
m), 5.7-6.3 (4H, m), 7.22 (1/2)
H, d, J = 15.6 Hz), 7.64 (1 / 2H,
d, J = 15.6 Hz)

Synthesis Example 17 To a solution of diisopropylamine (21.4g) in tetrahydrofuran (100ml) was added a hexane solution of n-butyllithium (1.66M, 132ml) at -10 ° C under a nitrogen atmosphere. After stirring the mixture for 20 minutes, 1-
(N-tert-butyl) butylimine (26.9 g)
Is added at the same temperature. The solution is stirred at -10 ° C for 20 minutes, then cooled to -65 ° C and a solution of trimethylacetaldehyde (18.2g) in tetrahydrofuran (40ml) is added. The reaction mixture is kept at -65 ° C for 2 hours, then slowly warmed to room temperature and stirred at room temperature overnight. The resulting mixture was poured into saturated aqueous oxalic acid solution (300 ml),
The mixture is stirred for 2 hours. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (100 ml x 2). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 4,4-dimethyl-2-ethyl-2-pentenal (6.3 g) as an oil. . IR (Neat): 2970, 1690, 1635, 12
30 cm ^-1 NMR (CDCl ₃ , δ): 0.8-1.1 (3H,
m), 1.35 (9H, S), 2.2-2.5 (2H,
m), 6.34 (3 / 4H, s), 6.43 (1/4)
H, s), 9.27 (3/4 H, s), 9.37 (1 /
4H, s)

Synthesis Example 18 4-oxo- (4H) -pyrimido [1,2-a] pyridine-3-carboxylic acid (3.8 g), 1-ethyl-3-
Dimethylformamide (90 ml) of (3-dimethylaminopropyl) carbodiimide hydrochloride (4.22 g) and N-hydroxybenzotriazole (3.1 g)
The solution is stirred at 5 ° C for 15 minutes. 4-methyl-2,4-
A solution of heptadien-1-ylamine (2.84 g) in methylene chloride (10 ml) is added and the solution is stirred at room temperature for 2 hours. The reaction mixture is evaporated under reduced pressure, and the residue is diluted with aqueous sodium hydrogen carbonate solution (100 ml) and ethyl acetate (100 ml). The separated organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was crystallized from ethyl acetate to give N
-[(2E, 4E)-and (2Z, 4E) -4-methyl-2,4-heptadien-1-yl] -4-oxo-
(4H) -pyrimido [1,2-a] pyridine-3-carboxamide (2.99 g) is obtained. Melting point 173-177 ° C IR (nujol): 3300, 1730, 1630,
1570, 1550 cm ^-1 NMR (DMSO-d ₆ , δ): 0.94 (3H,
t, J = 7.5 Hz), 1.69 (3H, s), 2.0
-2.2 (2H, m), 4.05 (2H, t, J = 5.
8Hz), 5.45 (1H, t, J = 7.3Hz),
5.51-5.73 (1H, m), 6.21 (1H,
d, J = 15.6 Hz), 7.5-7.7 (1H,
m), 7.90 (1H, d, J = 8.3 Hz), 8.1
2-8.33 (1H, m), 9.0-9.1 (2H,
m), 9.19 (1H, d, J = 6.3Hz)

Synthesis Example 19 The following compound was obtained in the same manner as in Synthesis Example 8. N- (2-hydroxyimino-4-methyl-5-nitro-3-hepten-1-yl) -4-oxo- (4H)-
Pyrimido [1,2-a] pyridine-3-carboxamide Isomer A: Melting point 166-173 ° C. (dec.) IR (nujol): 3290, 1670, 1630,
1570, 1530, 1520, 1490, 1450,
1370 cm ^-1 NMR (DMSO-d ₆ , δ): 0.75 (3H,
t, J = 7.4 Hz), 1.69-2.13 (2H,
m), 1.84 (3H, s), 4.32 (2H, d, J
= 6.1 Hz), 5.09 (1H, t, J = 7.5H
z), 6.13 (1H, s), 7.59-7.66 (1
H, m), 7.90 (1H, d, J = 8.7 Hz),
8.18-8.26 (1H, m), 9.01 (1H,
s), 9.20 (1H, d, J = 6.8 Hz), 9.2.
8 (1H, t, J = 7.5 Hz), 11.51 (1H,
s)

Isomer B: melting point 158-161 ° C. IR (nujol): 1670, 1630, 1540,
1520 cm ^-1 NMR (DMSO-d ₆ , δ): 0.83 (3H,
t, J = 7.3 Hz), 1.67 (3H, d, J = 0.
93 Hz), 1.82-2.84 (2H, m), 4.2
4 (2H, d, J = 5.4Hz), 5.19 (1H,
t, J = 7.5 Hz), 6.19 (1H, s), 7.5
8-7.66 (1H, m), 7.91 (1H, d, J =
8.4 Hz), 8.17-8.26 (1 H, m), 9.
04 (1H, s), 9.19 (1H, d, J = 6.3H)
z), 9.27 (1H, t, J = 5.4Hz), 11.
18 (1H, s)

Synthesis Example 20 The following compound was obtained in the same manner as in Synthesis Example 18. N-[(2E, 4E) -4-methyl-2,4-heptadien-1-yl] -2-amino-3-pyridinecarboxamide Melting point 153-156 ° C IR (nujol): 3300, 3200, 1630
cm ^-1 NMR (DMSO-d ₆ , δ): 0.94 (3H,
t, J = 7.5 Hz), 1.68 (3H, s), 2.0
-2.2 (2H, m), 3.84-4.00 (2H,
m), 5.4-5.7 (2H, m), 6.15 (1H,
d, J = 15.6 Hz), 6.57 (1H, dd, J =
4.8, 7.7 Hz), 7.07 (2H, s), 7.9
2 (1H, dd, J = 1.6, 7.7Hz), 8.07
(1H, dd, J = 1.6, 4.8Hz), 8.59
(1H, t, J = 5.5Hz)

Synthesis Example 21 The following compound was obtained in the same manner as in Synthesis Example 8. N- (2-hydroxyimino-4-methyl-5-nitro-3-hepten-1-yl) -2-amino-3-pyridinecarboxamide Isomer A: melting point 181-185 ° C IR (nujol): 3300 , 1620, 1550,
1370, 1350 cm ^-1 NMR (DMSO-d ₆ , δ): 0.73 (3H,
t, J = 7.3 Hz), 1.73-2.11 (2H,
m), 1.84 (3H, s), 4.08-4.31 (2
H, m), 5.08 (1H, t, J = 7.4Hz),
6.04 (1H, s), 6.59 (1H, dd, J =
4.8, 7.7 Hz), 7.04 (2H, brs),
7.88 (1H, dd, J = 1.8, 7.7Hz),
8.07 (1H, dd, J = 1.8, 4.8Hz),
8.70 (1H, t, J = 5.8Hz), 11.33
(1H, s)

Isomer B: melting point 140-142 ° C IR (nujol): 3250, 1625, 1540,
1370 cm ^-1 NMR (DMSO-d ₆ , δ): 0.80 (3H,
t, J = 7.3 Hz), 1.64 (3H, d, J = 0.
7 Hz), 1.71-2.15 (2H, m), 4.08
(2H, d, J = 5.7 Hz), 5.16 (1H, t,
J = 7.5 Hz), 6.08 (1H, s), 6.55
(1H, dd, J = 4.8, 7.7 Hz), 7.01
(2H, brs), 7.85 (1H, dd, J = 1.
3, 7.7 Hz), 8.06 (1H, dd, J = 1.
7, 4.7 Hz), 8.63 (1H, t, J = 5.7H
z), 11.00 (1H, s)

Synthesis Example 22 The following compound was obtained in the same manner as in Synthesis Example 18. 6- [4- (4-methyl-2,4-heptadienoyl)
-1-Piperazinyl] -3,4-dihydrocarbostyril (amorphous powder) IR (nujol): 3175, 1720, 1640,
1590,1510 cm ^-1 NMR (DMSO-d ₆ , δ): 0.98 (3H,
t, J = 7.6 Hz), 1.79 (3H, s), 2.1
0-2.25 (2H, m), 2.35-2.43 (2
H, m), 2.78-2.86 (2H, m), 3.02
-3.07 (4H, m), 3.65-3.82 (4H,
m), 5.87 (1H, t, J = 7.3Hz), 6.4
4 (1H, d, J = 15.1Hz), 6.71-6.7.
5 (2H, m), 6.82 (1H, s), 7.13 (1
H, d, J = 15.1Hz), 9.87 (1H, s)

Synthesis Example 23 The following compound was obtained in the same manner as in Synthesis Example 8. 6- [4- (2-hydroxyimino-4-methyl-5-
Nitro-3-heptenoyl) -1-piperazinyl]-
3,4-dihydrocarbostyril Melting point 191-192 ° C (methylene chloride) IR (nujol): 3200, 1660, 1550,
1520 cm ^-1 NMR (DMSO-d ₆ , δ): 0.86 (3H,
t, J = 7.3 Hz), 1.77 (3H, s), 1.8
2-2.23 (2H, m), 2.44-2.51 (2
H, m), 2.89-2.99 (6H, m), 3.52
-3.63 (4H, m), 5.26 (1H, t, J =
7.5 Hz), 6.24 (1 H, s), 7.30 (1
H, s), 7.36 (2H, s), 10.27 (1H,
s), 11.89 (1H, s)

Synthesis Example 24 The following compound was obtained in the same manner as in Synthesis Example 18. N- [2,4 (1H, 3H) -dioxopyrimidine-5
-Yl]-(2E, 4E) -4-methyl-2,4-heptadienamide (amorphous powder) IR (nujol): 3450, 1725, 1690,
1645, 1600, 1560 cm ^-1 NMR (DMSO-d ₆ , δ): 0.98 (3H,
t, J = 7.4 Hz), 1.74 (3H, s), 2.1
0-2.34 (2H, m), 5.89 (1H, t, J =
7.3 Hz), 6.49 (1H, d, J = 15.2H)
z), 7.09 (1H, d, J = 15.2 Hz), 8.
23 (1H, d, J = 5.9 Hz), 9.23 (1H,
s), 10.65 (1H, d, J = 5.9Hz), 1
1.47 (1H, brs)

Synthesis Example 25 The following compound was obtained in the same manner as in Synthesis Example 8. N- [2,4 (1H, 3H) -dioxopyrimidine-5
-Yl] -4-methyl-2-hydroxyimino-5-nitro-3-heptenamide Melting point 239-241 ° C (dioxane-water) IR (nujol): 3115, 1725, 1640,
1550 cm ^-1 NMR (DMSO-d ₆ , δ): 0.89 (3H,
t, J = 7.3 Hz), 1.56 (3H, s), 1.8
2-2.22 (2H, m), 5.31 (1H, t, J =
7.5 Hz), 6.22 (1 H, s), 8.06 (1
H, d, J = 6.0 Hz), 8.90 (1H, br
s), 10.76 (1H, d, J = 6.0 Hz), 1
1.63 (1H, brs), 12.54 (1H, s)

Synthesis Example 26 The following compound was obtained in the same manner as in Synthesis Example 18. N- (2-hydroxypyridin-5-yl)-(2E,
4E) -4-Methyl-2,4-heptadienamide (amorphous powder) IR (nujol): 3400, 1670, 1610,
1570 cm ^-1 NMR (DMSO-d ₆ , δ): 0.99 (3H,
t, J = 7.5 Hz), 1.76 (3H, s), 2.1
2-2.23 (2H, m), 5.92 (1H, t, J =
7.5 Hz), 6.02 (1H, d, J = 15.3H)
z), 6.36 (1H, d, J = 9.6 Hz), 7.1
3 (1H, d, J = 15.3 Hz), 7.43, 7.4
8 (1H, dd, J = 2.9, 9.6 Hz), 7.99
(1H, d, J = 2.9 Hz), 9.82 (1H, br
s), 11.33 (1H, brs)

Synthesis Example 27 The following compound was obtained in the same manner as in Synthesis Example 8. N-(5-2-hydroxy-yl) -4-methyl-2-hydroxyimino-5-nitro-3-Heputen'amido mp 198-199 (methylene _{chloride) NMR (DMSO-d 6,} δ): 0.88 (3H,
t, J = 7.3 Hz), 1.58 (3H, s), 1.8
2-2.22 (2H, m), 5.31 (1H, t, J =
7.5 Hz), 6.35 (1H, d, J = 9.7H)
z), 6.36 (1H, s), 7.58, 7.63 (1
H, dd, J = 2.9, 9.7 Hz), 7.88 (1
H, d, J = 2.9 Hz), 9.99 (1H, br
s), 11.40 (1H, brs), 12.17 (1
H, brs)

Synthesis Example 28 The following compound was obtained in the same manner as in Synthesis Example 18. N- (1H-tetrazol-2-yl)-(2E, 4
E) -4-Methyl-2,4-heptadienamide (amorphous powder) IR (nujol): 3150, 1680, 1610,
1330 cm ^-1 NMR (DMSO-d ₆ , δ): 1.00 (3H,
t, J = 7.4 Hz), 1.77 (3H, s), 2.1
5-2.30 (2H, m), 6.07 (1H, t, J =
7.4 Hz), 6.24 (1H, d, J = 15.4H)
z), 7.37 (1H, d, J = 15.4Hz), 1
2.02 (1H, S), 15.86 (1H, brs)

Synthesis Example 29 The following compound was obtained in the same manner as in Synthesis Example 8. N- (1H-tetrazol-2-yl) -4-methyl-
2-Hydroxyimino-5-nitro-3-heptenamide Melting point 151-153 (dioxane-water) IR (nujol): 3650, 3400, 3200,
1700,1595 cm ^-1 NMR (DMSO-d ₆ , δ): 0.90 (3H,
t, J = 7.3 Hz), 1.59 (3H, s), 1.8
3-2.24 (2H, m), 5.34 (1H, t, J =
7.5 Hz), 6.37 (1 H, s), 12.07 (1
H, brs), 12.70 (1H, brs), 16.0
9 (1H, brs)

Synthesis Example 30 The following compound was obtained in the same manner as in Synthesis Example 18. N-[(2E, 4E) -4-Methyl-2,4-heptadien-1-yl] -2-hydroxy-6-methylpyridine-3-carboxamide (amorphous powder) IR (nujol): 3100 , 1670, 1610,
1550, 1320 cm ^-1 NMR (DMSO-d ₆ , δ): 0.94 (3H,
t, J = 7.5 Hz), 1.68 (3H, s), 2.0
2-2.17 (2H, m), 2.29 (3H, s),
3.97 (2H, t, J = 5.7Hz), 5.44 (1
H, t, J = 7.3 Hz), 5.52-5.66 (1
H, m), 6.17 (1H, d, J = 15.6 Hz),
6.31 (1H, d, J = 7.4Hz), 8.22 (1
H, d, J = 7.4 Hz), 9.78 (1H, t, J =
5.7 Hz), 12.47 (1H, brs)

Synthesis Example 31 The following compound was obtained in the same manner as in Synthesis Example 8. N- (2-hydroxyimino-4-methyl-5-nitro-3-hepten-1-yl) -2-hydroxy-6-methyl-3-pyridinecarboxamide Isomer A: Melting point 161-163 ° C (methanol) -Water) IR (nujol): 3150, 1655, 1630,
1540 cm ^-1 NMR (DMSO-d ₆ , δ): 0.75 (3H,
t, J = 7.3 Hz), 1.82 (3H, s), 2.0
0-2.13 (2H, m), 2.28 (3H, s),
4.26 (2H, d, J = 6.0Hz), 5.08 (1
H, t, J = 7.4 Hz), 6.06 (1H, s),
6.29 (1H, d, J = 7.4Hz), 8.19 (1
H, d, J = 7.4 Hz), 9.92 (1H, t, J =
6.0 Hz), 11.41 (1H, brs), 12.4
6 (1H, brs)

Isomer B: Melting point 182-184 ° C. (methanol-water) IR (nujol): 3150, 1650, 1625,
1540 cm ^-1 NMR (DMSO-d ₆ , δ): 0.81 (3H,
t, J = 7.4 Hz), 1.65 (3H, s), 1.8
3-2.24 (2H, m), 2.28 (3H, s),
4.15 (2H, d, J = 6.0Hz), 5.18 (1
H, t, J = 7.4 Hz), 6.14 (1H, s),
6.29 (1H, d, J = 7.4Hz), 8.20 (1
H, d, J = 7.4 Hz), 9.92 (1H, t, J =
6.0 Hz), 11.08 (1H, s), 12.44
(1H, brs)

Synthesis Example 32 The following compound was obtained in the same manner as in Synthesis Example 18. N-[(2E, 4E) -4-ethyl-6-methyl-2,
4-heptadien-1-yl] -5-methyl-4-imidazolecarboxamide (oil) IR (neat): 3100, 1620, 1515 cm
_{^{-1 NMR (DMSO-d 6,}} δ): 0.92-1.00
(9H, m), 2.17 (2H, q, J = 7.5H
z), 2.44 (3H, s), 2.49-2.67 (1
H, m), 3.87 (2H, t, J = 5.8Hz),
5.14 (1H, d, J = 9.6Hz), 5.54-
5.68 (1H, m), 5.96 (1H, d, J = 1
5.8 Hz), 7.54 (1 H, s), 7.84 (1
H, t, J = 5.8 Hz), 12.24 (1H, br
s)

Synthesis Example 33 The following compound was obtained in the same manner as in Synthesis Example 8. N- (4-Ethyl-2-hydroxyimino-6-methyl-5-nitro-3-hepten-1-yl) -5-methyl-4-imidazolecarboxamide Isomer A: melting point 148-149 ° C (acetic acid Ethyl) IR (nujol): 3150, 1740, 1630,
1590, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 0.65 (3H,
d, J = 6.7 Hz), 0.84 (3H, d, J = 6.
3Hz), 0.96 (3H, t, J = 7.4Hz),
2.22-2.33 (3H, m), 2.40 (3H,
s), 4.08-4.19 (2H, m), 4.73 (1)
H, d, J = 10.7 Hz), 6.16 (1 H, s),
7.53 (1H, s), 8.06 (1H, t, J = 6.
4 Hz), 11.27 (1 H, s), 12.21 (1
H, brs)

Isomer B: melting point 188-189 ° C. (ethyl acetate) NMR (DMSO-d ₆ , δ): 0.83 (3H,
d, J = 6.7 Hz), 0.91 (3H, d, J = 6.
3Hz), 0.94 (3H, t, J = 7.4Hz),
2.12 (2H, q, J = 7.4Hz), 2.34-
2.46 (1H, m), 2.41 (3H, s), 4.0
4 (2H, d, J = 5.5Hz), 4.86 (1H,
d, J = 10.7 Hz), 6.16 (1H, s), 7.
51 (1H, s), 7.84 (1H, t, J = 5.5H
z), 10.97 (1H, s), 12.23 (1H, b
rs)

Synthesis Example 34 The following compound was obtained in the same manner as in Synthesis Example 18. N-[(2E, 4E) -4-ethyl-6-methyl-2,
4-heptadien-1-yl]-(1H) -1,2,4
- triazol --3-carboxamide (amorphous _{powder) NMR (DMSO-d 6,} δ): 0.92-0.99
(9H, m), 2.18 (2H, q, J = 7.5H
z), 2.56-2.68 (1H, m), 3.91 (2
H, t, J = 5.7 Hz), 5.18 (1H, d, J =
9.6 Hz), 5.54-5.68 (1 H, m), 5.
98 (1H, d, J = 15.8Hz), 8.46 (1
H, brs), 8.76 (1H, brs), 14.64.
(1H, brs)

Synthesis Example 35 The following compound was obtained in the same manner as in Synthesis Example 8. N- (4-Ethyl-2-hydroxyimino-6-methyl-5-nitro-3-hepten-1-yl)-(1H)-
1,2,4-Triazol-3-carboxamide Isomer A: Melting point 174-176 ° C. (methylene chloride) NMR (DMSO-d ₆ , δ): 0.60 (3H,
d, J = 6.7 Hz), 0.75-0.84 (3H,
m), 0.89-1.00 (3H, m), 2.09-
2.33 (3H, m), 4.17-4.26 (2H,
m), 4.75 (1H, d, J = 10.7 Hz), 6.
16 (1H, s), 8.68 (1H, brs), 11.
37 (1H, s), 14.65 (1H, brs)

Isomer B: Melting point 180-183 ° C. (methylene chloride) NMR (DMSO-d ₆ , δ): 0.80 (3H,
d, J = 6.7 Hz), 0.89-0.98 (6H,
m), 2.06-2.18 (2H, m), 2.32-
2.44 (1H, m), 4.08 (2H, d, J = 6.
1Hz), 4.85 (1H, d, J = 10.7Hz),
6.13 (1H, s), 8.43 (1H, brs),
8.70 (1H, brs), 10.99 (1H, s)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location C07D 213/53 213/56 213/70 213/81 213/82 215/38 233/90 A 239 / 26 239/28 239/54 249/10 257/04 NM 257/06 A 277/74 285/04 285/125 309/28 471/04 117 A (72) Inventor Hisashi Takasugi 3-116 Momokita, Sakai City -10 (72) Inventor Yoshimi Hirasawa 4-9-12 Minami Katsuyama, Ikuno-ku, Osaka

Claims (5)

[Claims] 1. A general formula [Wherein R ¹ is hydrogen, a lower alkyl group, a lower alkoxy (lower) alkyl group or a lower alkoxyphenyl group, R ² is hydrogen or a lower alkyl group, R ³ and
R ⁵ is hydrogen, or is bonded to each other to form a single bond, R ⁴ is hydrogen or a lower alkyl group, a lower alkoxy (lower) alkyl group, or Is cyclized (In the formula, X ¹ _a represents an alkylene group, and may contain an oxygen atom, a sulfur atom, or a nitrogen atom which may have a substituent in the chain, Y ¹ _a is an alkyl group. Represents an alkylene group which may be substituted with, p is an integer of 0 to 3, R ⁶ is hydrogen or a lower alkyl group, R ⁷ is hydrogen, a hydroxyiminomethyl group, a cyano group, a formylpiperazinecarbonyl group, an alkanoyl group. An esterified carboxy group, hydroxy or a lower alkyl group optionally having a lower alkanoyloxy, or a formula: A lower alkyl group which may have one or more substituents selected from terified carboxy, hydroxy and phenyl; or lower alkyl, lower alkoxy, phenyl, carbamoyl, halogen, amino, lower alkylthio, hydroxy, A heterocyclic group optionally substituted with one or more substituents selected from lower alkylsulfonylamino and carbamoylmethyl; means a heterocyclic lower alkyl group, or R ⁸ and R ⁹ are bonded to each other. Forming a piperidine ring), R ¹⁰
Is hydrogen or a lower alkyl group optionally having carboxy or esterified carboxy, or R
⁷ is the formula: (In the formula, X ¹ _b is —O—, —S— or —NH—, and m is 0.
Or an integer of 1, and R ¹¹ is a carbamoyl group, a lower alkylcarbamoyl group, a lower alkanoyl group, a di-lower alkylaminosulfonyl group, a lower alkylsulfonyl group, an oxamoyl group or a formula: (Y ¹ _b ) _n —R ¹² (wherein , Y ¹ _b is —CO—, —SO ₂ —, —COCH ₂ — or n is an integer of 0 or 1, and R ¹² is substituted with one or more substituents selected from lower alkyl, lower alkoxy, phenyl, carbamoyl, halogen, amino, lower alkylthio, hydroxy, lower alkylsulfonylamino and carbamoylmethyl. An optionally substituted heterocyclic group, or R ⁷ has the formula: [In the formula, a represents NH, O or S, and b, c
And d are the same or different and are CH or N
Wherein R ¹³ , R ¹⁴ and R ¹⁵ are the same or different and are hydrogen, lower alkyl, halogen, nitro, cyano,
Benzyl, (CH ₂ ) _M OR ¹⁶ (in the formula, R ¹⁶ represents hydrogen or lower alkyl, M is an integer of 0 to 3), lower alkanoyl, lower alkoxycarbonyl]
A standard reagent for measuring NO gas containing a compound or a salt thereof. 2. The general formula[Wherein, R¹ Is hydrogen, a lower alkyl group or a lower alkyl
Coxy (lower) alkyl group, R² Is hydrogen or lower
Rukiru group, R^Four Is hydrogen or a lower alkyl group, R ⁶Is water
Elementary or lower alkyl group, R⁷ Is hydrogen or the formula:(In the formula, R⁸ And R⁹ Are hydrogen and pyridyl, respectively
Group, pyridyl lower alkyl group or thyminyl group, or
R⁷Is the formula:(In the formula, X¹ _bIs -O- or -NH-, m is 0 or 1
Integer and R¹¹Is a carbamoyl group, lower alkanoy
Group or formula: (Y¹ _b)_n-R¹²(In the formula, Y¹ _bIs -CO
-, -SO₂-Or-COCH₂-) N is an integer of 0 or 1, and R¹²Is a carbamoyl group;
Lower alkyl, halogen, amino, hydroxy or
Substituted with one or more substituents selected from lower alkylthio
Optionally, pyridyl group, tetrazolyl group, thia
Diazolyl group, pyrimidyl group, benzothiazolyl group, a
Means imidazole group or triazole group]
For measuring NO gas containing a compound to be treated or its salt
Semi-reagent. 3. General formula[Where X is¹ _a'Is -0- or -CH ₂-, R⁶Is hydrogen
Or lower alkyl group, R⁷ Is hydrogen or the formula:(In the formula, R⁸ And R⁹ Are hydrogen and lower
Pyridyl group or thyminyl optionally substituted with kill
Group, or R⁷Is the formula:(In the formula, X¹ _bIs -O- or -NH-, m is 0 or 1
Integer and R¹¹Is a carbamoyl group, lower alkanoy
Group or formula: (Y¹ _b)_n-R¹²(In the formula, Y¹ _bIs -CO
-, -SO₂-Or-COCH₂-) N is an integer of 0 or 1, and R¹²Is a carbamoyl group;
Lower alkyl, halogen, amino or lower alkyl
Even if it is substituted with one or more substituents selected from thio
Good, pyridyl group, tetrazolyl group, thiadiazolyl
Group, pyrimidyl group or benzothiazolyl group
NO gas containing a compound represented by
Standard reagent for measurement. 4. 2-Hydroxyimino-6-methoxy-
4-Methyl-5-nitro-3-hexenecarboxamide or a salt thereof. 5. 2-Hydroxyimino-6-methoxy-
A standard reagent for NO gas measurement containing 4-methyl-5-nitro-3-hexenecarboxamide or a salt thereof.