JPH05213909A - Isoxazole derivative - Google Patents

Abstract

PURPOSE:To obtain a new isoxazole derivative useful as a therapeutic agent for ischemic heart disease and an antihypertensive agent, having strong vasodilating action, vasodilating action of crown blood and inhibitory action on blood platelet aggregation. CONSTITUTION:A compound of formula I {R<1> to R<3> are H, lower alkyl, aralkyl, aryl, heteroaryl or R<2> and R<3> are bonded to form group of formula II [R<7> to R<10> are H, lower alkyl, aralkyl or aryl; X is O, S or NR<11>) (R<11> is H, acyl, lower alkyl, etc.) or (CR<12>R<13>) p (R<12> and R<13> are H, lower alkyl, aryl, etc.; (p) is 0-3); (m) and (n) are 0-2]; R<4> and R<5> are H, lower alkyl, aralkyl, aryl or R<4> and R<5> are bonded to form CO, N-OR<14> (R<14> is H, alkyl, aralkyl, etc.), etc.; R<6> is H, CN, alkyl, CH=N-OR<15> (R<15> is H, alkyl, aralkyl, etc.), etc.} such as 6-nitro-9-phenyl-l-oxa-2-azaspiro[4,5]deca-2-ene-3-carboxylic acid amide. A compound of formula I wherein R<4> is H is obtained by subjecting a compound of formula III to ring closure.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel isoxazole derivative useful as a therapeutic agent for ischemic heart disease and an antihypertensive agent.

[0002]

2. Description of the Related Art Japanese Patent Publication No. 19822/1990 discloses a nitroaliphatic compound having a cardiovascular dilation effect and a blood pressure lowering effect. Moreover, Japanese Patent Application No. 2-271928 describes a novel oxime compound having a strong coronary vasodilatory action, a platelet aggregation inhibitory action and a blood pressure lowering action due to remarkable vasodilation.

[0003]

Nitroglycerin, amyl nitrite, and isosorbide nitrate have been used for a long time as therapeutic agents for angina, and are still widely used as the first-choice antianginal agents. However, these drugs have a short duration of action and are limited as preventive agents for angina attacks. The sustained action has been improved by the development of sustained-release tablets, ointments, and tape preparations, but recently, continuous administration of these has led to the problem of the development of resistance, which causes a decrease in the effect. Yes it has not been resolved yet. Also,
There are few cases where isoxazole derivatives have been developed as antihypertensive agents.

[0004]

In view of the above points, the present inventors have proposed a therapeutic agent for ischemic heart disease, which has a strong coronary vasodilatory effect and is less likely to cause resistance, and a novel effect. As a result of intensive studies aimed at the development of an antihypertensive agent, a new isoxazole derivative was discovered and the present invention was completed.

That is, the present invention has the general formula

[Chemical 2] [In the formula, R ¹ , R ² and R ³ are the same or different and are hydrogen;
Lower alkyl, aralkyl, aryl, heteroaryl, or R ² and R ³ are bonded to each other to form-(CR ⁷ R ⁸ ) m-X- (CR ⁹ R ¹⁰ ) n- (a) (wherein R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same or different and each represents hydrogen, lower alkyl, aralkyl or aryl, and X
Is oxygen, sulfur, ═N—R ¹¹ (wherein R ¹¹ represents hydrogen, acyl, lower alkyl, aralkyl, alkoxycarbonyl, aralkoxycarbonyl), — (CR ¹² R
¹³ ) p- (wherein R ¹² and R ¹³ are the same or different and each represents hydrogen, lower alkyl, aralkyl or aryl, p is an integer of 0, 1, 2 or 3), and m and n are each. Indicates 0, 1 or 2, respectively. ), And R ⁴ , R ⁵
Are the same or different and represent hydrogen, lower alkyl, aralkyl, aryl, or one of R ⁴ and R ⁵ is bonded to R ³ to form a single bond, or R ⁴ and R ⁵ are combined. Carbonyl, = N-OR ¹⁴ (wherein R ¹⁴ is hydrogen, lower alkyl, aralkyl, alkoxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aralkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, acyl Represents a cycloalkyl having 3 to 7 carbon atoms, R ⁶ represents hydrogen, cyano, lower alkyl, —CH
= N-OR ¹⁵ (wherein R ¹⁵ represents hydrogen, lower alkyl, aralkyl, alkoxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aralkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, acyl. ), The formula —CR ¹⁶ R ¹⁷ —OR ¹⁸ (b) (wherein R ¹⁶ and R ¹⁷ are the same or different and represent hydrogen, lower alkyl, aralkyl and aryl, and R ¹⁸ is hydrogen, lower alkyl, aralkyl and alkoxy. Alkyl, aralkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, acyl, or -COR ¹⁹ (c) (wherein R ¹⁹ is hydrogen, hydroxyl, lower alkyl, lower alkoxy, aralkoxy). , -NR ²⁰ R ²¹ (where R ²⁰ , R
²¹ is the same or different and represents hydrogen, lower alkyl, aralkyl, carboxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, hydroxyalkyl, aryl, heteroaryl, or R ²⁰ , R ²¹
Represents a group which is bonded to form a heterocycle with the adjacent nitrogen atom. ) Is shown. ) Is shown. ] It is related with the isoxazole derivative represented by.

In the above definition of each symbol, the lower alkyl is a linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl. , Pentyl, isopentyl, hexyl and the like, lower alkoxy has 1 to 6 carbon atoms.
Straight chain or branched chain alkoxy including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy,
Hexyloxy and the like, aralkyl is an aralkyl having an alkyl portion having 1 to 6 carbon atoms, such as benzyl, 2-phenylethyl, 3-phenylpropyl,
4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, naphthylmethyl, 2-naphthylethyl,
3-naphthylpropyl, 4-naphthylbutyl, and halogen (chlorine, bromine, iodine, fluorine), lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino and aralkyl on these aromatic rings. Is an aralkyl having at least one substituent.

Cycloalkyl having 3 to 7 carbon atoms is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and the like, and aralkoxy is aralkyloxy 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 on these aromatic rings, Aralkoxy and the like having at least one substituent selected from lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino and aralkyl, and hydroxyalkyl is a straight or branched chain having 1 to 6 carbon atoms. Hydroxylated alky And 2-hydroxyethyl, 3-hydroxypropyl, 1-hydroxymethylethyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl and the like, and carboxyalkyl is a straight chain having 1 to 6 carbon atoms. Or branched chain carboxylated alkyl such as carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 1-carboxymethylethyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, Aryl is phenyl, naphthyl or phenyl or naphthyl having at least one substituent selected from halogen, lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino and aralkyl on the aromatic ring. Indicates.

Heteroaryl means furyl (2-furyl,
3-furyl), pyridyl (2-pyridyl, 3-pyridyl, 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 etc.), 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), 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 etc.), pyrazolopyrimidinyl (1H-pyrazolo [3,4
-D] pyrimidin-4-yl, pyrazolo [1,5-a]
Pyrimidin-7-yl, 1H-pyrazolo [4,3-d]
Pyrimidin-7-yl, etc., imidazopyrimidinyl (imidazo [1,2-a] pyrimidin-5-yl, 1H
-Imidazo [4,5-d] pyrimidin-7-yl, etc.), 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-
And the like), thienopyridyl (thieno [2,3-b] pyridin-4-yl and the like), thienopyrimidinyl (thieno [2,3-d] pyrimidin-4-yl and the like), thiazolopyridyl (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 (oxazolo [4,5-b] pyridin-7-yl, oxazolo [5,4-b] pyridin- 7-yl), oxazolopyrimidinyl (oxazolo [4,5-d] pyrimidin-
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] pyrimidine-4-
, Etc.), 2,3-dihydropyrrolopyridyl (2,3
-Dihydro-7H-pyrrolo [2,3-b] pyridine-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] pyrimidin-4-yl), 6,7-dihydropyridopyrimidinyl (6,7
-Dihydro-pyrido [2,3-d] pyrimidin-4-yl, 6,7-dihydro-pyrido [3,2-d] pyrimidin-4-yl), 5,6,7,8-tetrahydropyrido Pyrimidinyl (such as 5,6,7,8-tetrahydro-pyrido [2,3-d] pyrimidin-4-yl), 6,
7,8,9-Tetrahydropyridopyrimidinyl (6,6
7,8,9-Tetrahydro-pyrido [1,2-a] pyrimidin-4-yl), 6,7-dihydronaphthyridinyl (6,7-dihydro-1,8-naphthyridine-4-, etc.)
And the like), 5,6,7,8-tetrahydropyridopyrimidinyl (5,6,7,8-tetrahydro-pyrido [2,3-d] pyrimidin-4-yl and the like), 5,6,
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.),
Alternatively, it represents a heteroaryl having on the ring at least one substituent selected from halogen, lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino and aralkyl.

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

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 having 1 to 6 carbon atoms, such as benzyloxycarbonyl, 2-phenylethoxycarbonyl and 3-phenylpropoxycarbonyl. , 4-phenylbutoxycarbonyl, 5-phenylpentyloxycarbonyl, 6-phenylhexyloxycarbonyl, naphthylmethoxycarbonyl, 2-naphthylethoxycarbonyl Bonyl, 3-naphthylpropoxycarbonyl, 4-naphthylbutoxycarbonyl, and at least a substituent selected from halogen, lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino and aralkyl on the aromatic ring. The aralkyloxycarbonyl having one is shown.

Alkoxyalkyl means that the alkoxy part and the alkyl part have alkoxy having 1 to 6 carbon atoms and alkyl, and is methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxy. Pentyl, 6-methoxyhexyl, ethoxymethyl, propoxymethyl, butoxymethyl, pentyloxymethyl, hexyloxymethyl and the like, and aralkoxyalkyl has an alkoxy part and an alkyl part having 1 to 6 carbon atoms of alkoxy and alkyl. Aralkyloxyalkyl which is benzyloxymethyl, (2-phenylethoxy) methyl, (3-phenylpropoxy) methyl, (4-phenylbutoxy) methyl, (5-phenylpentyloxy) methyl, (6-phenylhexyloxy) ) Indicates methyl, 2-benzyloxy-ethyl, 3-benzyloxy-propyl, 4-benzyloxy-butyl, 5-benzyloxy-pentyl, and the like 6-benzyloxy-hexyl.

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-benzyloxycarbonylpropyl, 4-benzyloxycarbonylbutyl, 5-benzyloxycarbonylpentyl, 6-benzyloxycarbonylhexyl and the like are shown.

The heterocyclic ring formed by combining R ²⁰ and R ²¹ 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 pharmaceutically acceptable salt of the compound of the general formula (I) is a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid or maleic acid, fumaric acid, succinic acid, tartaric acid. , Salts with organic acids such as citric acid, acetic acid, and methanesulfonic acid.

When the compound of the general formula (I) has a carboxyl group, its salt is a metal salt such as lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt or aluminum salt, triethylamine,
It may be a salt with an organic base such as dicyclohexylamine, N-methylmorpholine or pyridine, a salt with an amino acid such as lysine, histidine, ornithine or arginine, or an ammonium salt.

The compound having a carboxyl group may be an ester, and examples of the ester include an ester hydrolyzable in vivo, and an ester residue forming an ester hydrolyzable in vivo. 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, pivaloyloxymethyl. , 1-acetoxyethyl, 1-pivaloyloxyethyl and other alkanoyloxyalkyl esters, ethoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and other alkoxycarbonyloxyalkyl esters, phthalidyl, dimethoxyphthalidyl, etc. Le, carbamoylmethyl, carbamoylethyl, N- methylcarbamoylmethyl, N, N
Carbamoylalkyl ester such as dimethylcarbamoylmethyl, N, N-dimethylcarbamoylethyl, N, N-diethylcarbamoylmethyl, N, N-diethylcarbamoylethyl, alkoxyalkyl ester such as methoxymethyl or methoxyethyl or 5-methyl-1 , 3-dioxolen-2-on-4-ylmethyl ester and the like. Further, the compound having a carboxyl group can be an amide,
Examples of the amide-forming residue when forming the amide include amino or methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino,
Mention may be made of mono- or dialkylamino such as dipropylamino and dibutylamino.

Since the compound of the present invention represented by the general formula (I) has one or more asymmetric carbon atoms, racemic compounds, diastereoisomers and individual optical isomers may exist, but the present invention is Include them all. Also included in the invention are stereoisomers and geometric isomers.

The compound of the present invention can be synthesized by the method shown below. Method 1 Among the compounds of general formula (I), those in which R ⁴ is hydrogen are

[Chemical 3] (In the formula, each symbol has the same meaning as described above.) The compound can be obtained by ring closure. The reaction is carried out in the presence of a base in a suitable solvent at −78 to 50 ° C. for 5 minutes to 10 hours. As the solvent, for example, tetrahydrofuran, dioxane, acetone, N, N-dimethylformamide and the like which do not inhibit the reaction can be used singly or in combination, and as the base, sodium hydroxide, potassium carbonate, sodium hydride, triethylamine and the like are used at appropriate times. You can choose.

Method 2 Among the compounds of the general formula (I), R ⁶ is —CONR ²⁰ R ²¹ are the compounds of the general formula (I) in which R ⁶ is a carboxyl or a reactive derivative thereof. It can be synthesized by reacting with a compound represented by HNR ²⁰ R ²¹ (III) (wherein each symbol has the same meaning as defined above). Examples of the reactive derivative of the carboxylic acid compound include acid halides (carboxylic acid chloride, carboxylic acid bromide, etc.), active esters (p-nitrophenyl ester, N-hydroxysuccinimide ester, etc.), acid anhydrides or mixed acid anhydrides. Can be given. The reaction is carried out in the presence of a base in a suitable solvent at -78 to 50 ° C for 30 minutes to 24 minutes.
It is performed by reacting for a time. Examples of the solvent include benzene, toluene, chloroform, acetone, N, N
Solvents that do not inhibit the reaction such as dimethylformamide can be used alone or in combination, and the base can be appropriately selected from sodium hydroxide, potassium carbonate, pyridine, triethylamine and the like.

Method 3 Of the compounds of the general formula (I), R ⁶ is —CR ¹⁶ R ¹⁷ —OR.
The compound of ¹⁸ (provided that R ¹⁸ is other than hydrogen) is a compound of the formula (I) in which R ⁶ is —CR ¹⁶ R ¹⁷ —OH and a compound of the formula R ¹⁸ ′ —Y (IV) , R ¹⁸ ′ represents a group other than hydrogen in R ¹⁸ , Y represents halogen or —OR ²² (wherein R ²² represents toluenesulfonyl, methanesulfonyl, etc.). ] It can synthesize | combine by making it react with the compound represented by this. The reaction is carried out in the presence of a base in a suitable solvent at -7
It is carried out by reacting at 8 to 50 ° C. for 5 minutes to 24 hours.
As the solvent, for example, solvents which do not inhibit the reaction such as benzene, toluene, tetrahydrofuran, acetone, N, N-dimethylformamide and the like can be used alone or in combination, and as the base, sodium hydroxide, potassium carbonate, pyridine, triethylamine, hydrogen can be used. It can be selected from sodium chloride, etc. The starting compound (II) is described in JP-B-2-19822 and JP-A-2-27192.
It can be obtained by the method described in No. 8.

The compound of general formula (I) thus obtained can be separated and purified from the reaction mixture by a method known per se such as recrystallization or chromatography. Further, since the compound of the general formula (I) has an asymmetric carbon, optical isomers based on it exist. Therefore, when the compound of the general formula (I) is a racemate, an acidic optical resolving agent such as tartaric acid, malic acid, N-acetyltryptophan, 10-camphorsulfonic acid, mandelic acid, dibenzoyltartaric acid or α-methylbenzyl. The corresponding optical isomer can be resolved by using a basic optical resolution agent such as amine and 1-phenyl-2-p-tolylethylamine. Furthermore, these optical isomers can also be produced by using the corresponding optically active raw material compounds, and the individual optical isomers can be recrystallized, or optically active column chromatography, other various chromatography, etc. It can be purified by a known method. The compound of the general formula (I) thus obtained is, if necessary, hydrochloric acid,
Salts with inorganic acids such as hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid,
A salt with an organic acid such as methanesulfonic acid, paratoluenesulfonic acid, lactic acid, acetic acid, maleic acid, fumaric acid, succinic acid, citric acid and tartaric acid can be used.

When the compound of the general formula (I) has a carboxyl group, its salt is a metal salt such as lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt and aluminum salt, triethylamine,
It may be a salt with an organic base such as dicyclohexylamine, N-methylmorpholine or pyridine, a salt with an amino acid such as lysine, histidine, ornithine or arginine, or an ammonium salt.

The compound having a carboxyl group may be an ester, and examples of the ester include an ester that can be hydrolyzed in vivo, and an ester residue that forms an ester that can be hydrolyzed in vivo. 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, pivaloyloxymethyl. , 1-acetoxyethyl, 1-pivaloyloxyethyl and other alkanoyloxyalkyl esters, ethoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and other alkoxycarbonyloxyalkyl esters, phthalidyl, dimethoxyphthalidyl, etc. Le, carbamoylmethyl, carbamoylethyl, N- methylcarbamoylmethyl, N, N
Carbamoylalkyl ester such as dimethylcarbamoylmethyl, N, N-dimethylcarbamoylethyl, N, N-diethylcarbamoylmethyl, N, N-diethylcarbamoylethyl, alkoxyalkyl ester such as methoxymethyl or methoxyethyl or 5-methyl-1 , 3-dioxolen-2-on-4-ylmethyl ester and the like. Further, the compound having a carboxyl group can be an amide,
Examples of the amide-forming residue when forming the amide include amino or methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino,
Mention may be made of mono- or dialkylamino such as dipropylamino and dibutylamino.

When the compound of the present invention is used as a medicine,
Orally in the form of powder, granules, tablets, capsules, syrups, suppositories, external preparations, injections, infusions, etc., preferably by mixing with a pharmaceutically acceptable carrier, excipient, diluent, etc. It can be safely administered parenterally or parenterally. The dose may vary depending on the sex, age, weight or symptom of the patient, but is usually about 1 to 500 mg orally per day for an adult, and these are administered once or divided into several times.

[0025]

[Examples] The present invention will now be specifically described with reference to Examples, but the present invention is not limited thereto.

Example 1 0.26 g of (E) -3- (2-nitro-5-phenylcyclohexylidene) -2-hydroxyiminopropionamide was dissolved in 10 ml of dimethylformamide,
0.12 g of potassium carbonate is added, and the mixture is stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution is poured into water and extracted with ethyl acetate. After washing with saturated saline, it is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is separated and purified by thin layer chromatography and recrystallized from isopropyl alcohol-diethyl ether to give a melting point of 167-
6-nitro-9-phenyl-1-oxa-2 at 169 ° C
-Azaspiro [4.5] dec-2-ene-3-carboxylic acid amide is obtained.

Example 2 (E) -4-Ethyl-2-hydroxyimino-5-nitro-3-hexenamide 2 g was added to dimethylformamide 2
It is dissolved in 0 ml, 1.3 g of potassium carbonate is added, and the mixture is stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution is poured into water and extracted with ethyl acetate. After washing with saturated saline, it is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. Two kinds of compounds are obtained by separating and purifying the obtained residue by thin layer chromatography. Each was recrystallized from isopropyl alcohol-n-hexane to give 5-ethyl-5- (1-nitroethyl) -4,5-dihydroisoxazole-3 having a melting point of 111 to 112 ° C. from the low polar fraction.
-82 mg of carboxylic acid amide are obtained. In addition, 5-ethyl-5- (1-
Nitroethyl) -4,5-dihydroisoxazole-
150 mg of 3-carboxylic acid amide are obtained.

Example 3 (E) -3- (2-nitrocyclohexylidene) -2-
Dissolve 0.5 g of hydroxyiminopropionic acid amide in 10 ml of dimethylformamide, and add potassium carbonate 0.3
g, and stirred at room temperature for 2.5 hours. After the reaction,
The reaction solution is poured into water and extracted with ethyl acetate. After washing with saturated saline, it is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from isopropyl ether to give 6-nitro-mp having a melting point of 184-186 ° C.
1-Oxa-2-azaspiro [4.5] dec-2-ene-3-carboxylic acid amide is obtained.

Example 4 (E) -3- (2-Nitro-5-ethylcyclohexylidene) -2-hydroxyiminopropionic acid amide
5 g is dissolved in 10 ml of tetrahydrofuran, 0.6 ml of triethylamine is added, and the mixture is stirred at room temperature for 4.5 hours. After completion of the reaction, the reaction solution is poured into water and extracted with ethyl acetate. After washing with saturated saline, it is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is recrystallized from isopropyl alcohol to give a melting point of 176-17.
6-Nitro-9-ethyl-1-oxa-2-azaspiro [4.5] dec-2-ene-3-carboxylic acid amide at 9 ° C. is obtained.

Example 5 3 g of N- (4-pyridyl)-(E) -3- (2-nitrocyclohexylidene) -2-hydroxyiminopropionic acid amide was dissolved in 100 ml of ethyl acetate to obtain 0.7 g of sodium carbonate. And stir at room temperature for 1 hour. After completion of the reaction, the extract is washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is converted into hydrochloride with hydrochloric acid-ethanol and recrystallized from ethanol to give N- (4-pyridyl) -having a melting point of 154-157 ° C.
6-Nitro-1-oxa-2-azaspiro [4.5] dec-2-ene-3-carboxylic acid amide hydrochloride is obtained.

The following compounds can be synthesized according to the above method. (6) 6-nitro-1-oxa-2-azaspiro [4.
5] Deca-2-ene-3-carboxylic acid amide (7) 6-nitro-1-oxa-2-azaspiro [4.
5] Deca-2-ene-3-carboxylic acid ethyl ester (8) 3-hydroxymethyl-6-nitro-1-oxa-2-azaspiro [4.5] dec-2-ene (9) 3-acetoxymethyl -6-Nitro-1-oxa-2-azaspiro [4.5] dec-2-ene (10) 3-ethoxycarbonyloxymethyl-6-nitro-1-oxa-2-azaspiro [4.5] deca 2-
Ene (11) 4-hydroxyimino-6-nitro-1-oxa-2-azaspiro [4.5] dec-2-ene-3-carboxylic acid amide (12) 3-ethoxycarbonylmethoxymethyl-6-nitro- 1-oxa-2-azaspiro [4.5] deca-2
-Ene (13) 4-ethoxycarbonyloxyimino-6-nitro-1-oxa-2-azaspiro [4.5] dec-2-
En-3-carboxylic acid amide

[0032]

INDUSTRIAL APPLICABILITY The compound of the general formula (I) of the present invention has strong coronary vasodilatory action and platelet aggregation inhibitory action, and is useful as a therapeutic agent for ischemic heart disease such as angina that can be administered for a long period of time. is there. In addition, a remarkable blood pressure-lowering effect due to vasodilation is observed, and it is also useful as an antihypertensive agent.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication C07D 471/04 Z 8829-4C 106 Z 8829-4C 107 Z 8829-4C 498/10 A 8415-4C // A61K 31/42 ABR 7252-4C ABS 7252-4C ABU 7252-4C 31/44 ACB 7252-4C (72) Inventor Masayoshi Uehata 3-725 Oyata, Iruma City, Saitama Yoshitomi Pharmaceutical Co., Ltd. Tokyo Research (72) Inventor Kimihara Kawanori 3-7-25 Oyata, Iruma City, Saitama Yoshitomi Pharmaceutical Co., Ltd. Tokyo Research Laboratory

Claims (1)

[Claims] 1. A general formula: [In the formula, R ¹ , R ² and R ³ are the same or different and are hydrogen;
Lower alkyl, aralkyl, aryl, heteroaryl, or R ² and R ³ are bonded to each other to form-(CR ⁷ R ⁸ ) m-X- (CR ⁹ R ¹⁰ ) n- (a) (wherein R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same or different and each represents hydrogen, lower alkyl, aralkyl or aryl, and X
Is oxygen, sulfur, ═N—R ¹¹ (wherein R ¹¹ represents hydrogen, acyl, lower alkyl, aralkyl, alkoxycarbonyl, aralkoxycarbonyl), — (CR ¹² R
¹³ ) p- (wherein R ¹² and R ¹³ are the same or different and each represents hydrogen, lower alkyl, aralkyl or aryl, p is an integer of 0, 1, 2 or 3), and m and n are each. Indicates 0, 1 or 2, respectively. ), And R ⁴ , R ⁵
Are the same or different and represent hydrogen, lower alkyl, aralkyl, aryl, or one of R ⁴ and R ⁵ is bonded to R ³ to form a single bond, or R ⁴ and R ⁵ are combined. Carbonyl, = N-OR ¹⁴ (wherein R ¹⁴ is hydrogen, lower alkyl, aralkyl, alkoxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aralkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, acyl Represents a cycloalkyl having 3 to 7 carbon atoms, R ⁶ represents hydrogen, cyano, lower alkyl, —CH
= N-OR ¹⁵ (wherein R ¹⁵ represents hydrogen, lower alkyl, aralkyl, alkoxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aralkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, acyl. ), The formula —CR ¹⁶ R ¹⁷ —OR ¹⁸ (b) (wherein R ¹⁶ and R ¹⁷ are the same or different and represent hydrogen, lower alkyl, aralkyl and aryl, and R ¹⁸ is hydrogen, lower alkyl, aralkyl and alkoxy. Alkyl, aralkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, acyl, or the formula -COR ¹⁹ (c) (wherein R ¹⁹ is hydrogen, hydroxyl group, lower alkyl, lower alkoxy, Aralkoxy, -NR ²⁰ R ²¹ (where R ²⁰ , R
²¹ is the same or different and represents hydrogen, lower alkyl, aralkyl, carboxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, hydroxyalkyl, aryl, heteroaryl, or R ²⁰ , R ²¹
Represents a group which is bonded to form a heterocycle with the adjacent nitrogen atom. ) Is shown. ) Is shown. ] The isoxazole derivative represented by these.