JPH10203970A - Anti-stenocardia containing optically active nitroxy derivative as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a preventive and therapeutic agent for stenocardia having excellent dilator activities of collateral vessel and antistenocaradic activities by including nitroxy derivative. SOLUTION: This preparation includes an optically active nitroxyl derivative of the formula [R<1> a is H or a 1-6C alkanoyl; R<3> is a 1-6C alkyl; (n) is 1 or 2] or a salt thereof as an active ingredient. The compound of the formula is exemplified by (1S)-1-methyl-2-nitroxyethylamine. This preparation has weak toxicity, hardly causes side effects such as headache, vertigo, tachycardia or a bad effect to digestive organs, liver, bone, etc., and hardly provides a fist-pass effect, and thereby is suitable for prevention and treatment of stenocardia. The preparation is excellent in preservation stability and easily treated. The divided dose is 1-1,000mg, preferably 5-300mg in a case of an oral administration, and 0.1-100mg, preferably 0.5-50mg in a case of an intravenous administration, and is administered 1-6 times per day for an adult.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a preventive or therapeutic agent for angina containing a nitroxy derivative or a pharmacologically acceptable salt thereof as an active ingredient, or an optical agent having an excellent collateral vasodilatory and antianginal effect. The present invention relates to an active nitroxy derivative or a pharmacologically acceptable salt thereof, or a prophylactic or therapeutic agent for angina pectoris containing them as an active ingredient.

[0002]

2. Description of the Related Art At present, nitroglycerin is most frequently used clinically as a remedy for cardiovascular diseases, particularly angina pectoris. However, this drug has the disadvantage that it is susceptible to the first-pass effect and its action duration is short. As side effects, headache, dizziness, and tachycardia due to a decrease in blood pressure appear. Under these circumstances, there has been a demand for a therapeutic agent for angina pectoris which is not clinically affected by the first-pass effect and has excellent durability. As a nitroxy derivative having an antianginal effect, for example, the following compound A and the like are known (JP-A-2-07072). Also, many nitroxy derivatives are known as synthetic intermediates of compounds having an antianginal effect [for example, Chemical Abstracts, vol. 41, p. 3868, 1947: Che.
m. Abst., 41 , 3868 (1947), JP-A-1-46873,
Chemical Abstracts, vol. 58, p. 12372, 1964
Year: Chem. Abst., 58 , 12372 (1964) etc.].

[0003]

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[0004]

SUMMARY OF THE INVENTION Over the years, the inventors have synthesized compounds having a series of nitroxy moieties,
Its pharmacological effects have been studied. As a result, they have found that a specific nitroxy derivative has an excellent collateral vasodilatory effect, that the effect is persistent, and that it has few side effects and is useful as a therapeutic agent for angina pectoris. Was completed. The present invention relates to a prophylactic or therapeutic agent for angina pectoris containing a nitroxy derivative or a pharmacologically acceptable salt thereof as an active ingredient, or an optically active nitroxy derivative having excellent collateral vasodilatory and antianginal effects, or a pharmacologically active agent thereof. The present invention provides a pharmaceutically acceptable salt or an agent for preventing or treating angina containing the same as an active ingredient.

[0005]

The nitroxy derivative which is the active ingredient of the present invention has the general formula BA-ONO ₂ (I) or ED-ONO ₂ (II).

[0006] In the above formula, A is, C ₂ -C substituted with ₅ alkylene the C ₂ -C ₆ alkylene group (provided that the alkylene substituents are attached to the same carbon atom of the C ₂ -C ₆ alkylene group to.) or nitroxy -C ₁ -C ₄ represents an alkyl which may be substituted, C ₂ -C ₈ alkylene group,
B is a group having the formula —NHR ¹ (wherein R ¹ is a hydrogen atom, a C ₁ -C ₆ alkanoyl group or a formula

[0007]

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Wherein R ² is a hydrogen atom, C
₁ -C ₄ alkyl group, C ₁ -C ₄ alkyl, C ₁ -C ₄
Alkoxy phenyl group, or be substituted or a halogen C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or halogen substituted phenyl -C be substituted with ₁ -
It represents a C ₂ alkyl group. ) Indicates, D is, C ₁ -C ₅ represents an alkylene group, E is a group (wherein the nitrogen atom has C ₁ -C ₆ alkanoyl or the above formula (Ia), R ²
Has the same meaning as described above. ) Represents a 5- or 6-membered cyclic amino group which may be substituted. However, A is C ₂
When it is a —C ₆ alkylene group, B has the formula —NHR
Group (wherein with ¹ a, R ¹ a is hydrogen atom or C ₁
—C _{6 represents an} alkanoyl group. ).

The optically active nitroxy derivative as the active ingredient of the present invention has the general formula

[0010]

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Has the following.

[0012] In the above formulas, R ¹ a have the same meanings as described above, R ³ represents a C ₁ -C ₆ alkyl group, n,
1 and 2 are shown.

Further, the nitroxy derivative which is the active ingredient of the present invention has the general formula B'-D-ONO ₂ (IIIa).

In the above formula, D has the same meaning as described above, and B ′ has the general formula

[0015]

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(Wherein, R ² has the same meaning as described above).

C substituted for C ₂ -C ₅ alkylene in A
₂ -C ₆ alkylene group (provided that the alkylene substituents are attached to the same carbon atom of the C ₂ -C ₆ alkylene group.), For example, 1,1-ethylene-ethylene group, 1,
1-ethylene trimethylene group, 1,1-ethylene tetramethylene group, 1,1-ethylene pentamethylene group, 1,
1-ethylenehexamethylene group, 1,1-trimethyleneethylene group, 1,1-tetramethyleneethylene group, 1,
May be a 1-pentamethyleneethylene group, preferably
1,1-C ₂ -C ₅ alkylene-ethylene group, 1,1-
A C ₂ -C ₅ alkylene-trimethylene group or 1,1-
C ₂ -C ₅ alkylene-tetramethylene group, more preferably 1,1-ethylene ethylene group, 1,1-tetramethylene ethylene group or 1,1-pentamethylene ethylene group, and particularly preferably , 1,1-ethylene is an ethylene group.

The C ₂ -C ₈ alkylene part of the C ₂ -C ₈ alkylene group which may be substituted by the nitroxy-C ₁ -C ₄ alkyl group of A is, for example, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene. , 1-
Methyl ethylene, 1-ethyl ethylene, 1-propyl ethylene, 1-isopropyl ethylene, 1-butyl ethylene, 1-isobutyl ethylene, 1-pentyl ethylene,
1-isopentylethylene, 1-hexylethylene, 1
-Isohexylethylene, which can be a 1,1-dimethylethylene group, preferably ethylene, trimethylene, tetramethylene, 1-methylethylene, 1-ethylethylene,
1-propyl ethylene, 1-isopropyl ethylene, 1
-Butylethylene, 1-isobutylethylene or 1,
1-dimethylethylene group, more preferably ethylene, 1-methylethylene, 1-ethylethylene, 1-
Propyl ethylene, 1-isopropyl ethylene, 1-butyl ethylene, 1-isobutyl ethylene or 1,1-
A dimethylethylene group, still more preferably 1-
A methylethylene, 1-ethylethylene, 1-propylethylene, 1-isopropylethylene, 1-butylethylene or 1-isobutylethylene group, and more preferably or more preferably 1-methylethylene, 1-propylethylene, A butylethylene or 1-isobutylethylene group, particularly preferably a 1-methylethylene group.

The C ₂ -C ₈ alkylene group substituted by the nitroxy-C ₁ -C ₄ alkyl of A is preferably a _1- nitroxymethylethylene group, a 1- (2-nitroxyethyl) ethylene group, 1- (3-nitroxypropyl) ethylene group, 1- (4-nitroxybutyl) ethylene group, 1
A nitroxymethyltrimethylene group or a 1-nitroxymethyltetramethylene group, more preferably a C ₂ -C ₄ alkylene group substituted with nitroxymethyl or 2-nitroxyethyl, and particularly preferably Is 1
-A nitroxymethylethylene group.

C ₁ -C ₆ alkanoyl groups such as R ¹ include, for example, formyl, acetyl, propionyl, butyryl,
Isobutyryl, valeryl, isovaleryl, pivaloyl,
It may be a hexanoyl group, preferably a C ₁ -C ₅ alkanoyl group, more preferably a C ₂ -C ₃ alkanoyl group, particularly preferably an acetyl group.

[0021] C ₁ of ² such as R -C ₄ alkyl group or R ²
The alkyl portion of the C ₁ -C ₄ alkoxy group contained in
For example, methyl, ethyl, propyl, isopropyl, butyl, s- butyl, t- butyl, be a isobutyl group, preferably a C ₁ -C ₃ alkyl group, more preferably, C ₁ -C ₂ An alkyl group, particularly preferably a methyl group.

The halogen atom contained in R ² is, for example,
It can be a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom.

The phenyl-C ₁ -C ₂ alkyl group for R ² is preferably a benzyl group or a phenethyl group,
More preferably, it is a benzyl group.

R ² is preferably a hydrogen atom, C ₁ -C ₄
An alkyl group, a phenyl group optionally substituted with methyl, methoxy, fluorine or chlorine or a benzyl group optionally substituted with methyl, methoxy, fluorine or chlorine;
More preferably, they are a hydrogen atom, a methyl group or a benzyl group, and particularly preferably a hydrogen atom.

The C ₁ -C ₅ alkylene group of D is, for example,
A methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, a pentamethylene group, preferably a C ₁ -C ₃ alkylene group, more preferably a methylene group or an ethylene group, Particularly preferably, it is a methylene group.

The 5- or 6-membered cyclic amino group of E is, for example,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl group,
It is preferably a 2-pyrrolidinyl or 2-piperidinyl group, particularly preferably a 2-piperidinyl group.

The C ₁ -C ₆ alkyl group for R ³ is, for example,
Methyl, ethyl, propyl, isopropyl, butyl, s
-Butyl, t-butyl, isobutyl, pentyl, hexyl, preferably C ₁ -C ₄ alkyl, more preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl. And even more preferably a methyl, propyl, butyl or isobutyl group, particularly preferably a methyl group.

N is preferably 1.

The above general formulas (I), (II), (III) and (IIIa)
Can be converted into a pharmacologically acceptable salt, if necessary. Such salts include, for example, salts with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, carbonic acid, acetic acid,
Salts with carboxylic acids such as fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, benzoic acid, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid It may be a salt with a sulfonic acid, a salt with an acidic amino acid such as glutamic acid or aspartic acid, and preferably a salt with hydrochloric acid or a carboxylic acid.

Further, the present invention provides a compound (I) or a salt thereof, a compound (II) or a salt thereof or a compound (II).
Also included are hydrates of Ia) or a salt thereof, wherein Compound (I),
When an asymmetric carbon atom is present in the molecule of the compound (II) or the compound (IIIa), the compound includes a racemic form and an optically active compound, and also includes a hydrate of the compound (III) or a salt thereof.
In the compound having the general formula (I), A is C _2-
A compound wherein A is a C ₂ -C ₆ alkylene group substituted by C ₅ alkylene, a compound wherein A is a C ₂ -C ₈ alkylene group substituted by nitroxy-C ₁ -C ₄ alkyl, and A
Is a C ₂ -C ₈ alkylene group, and B has the formula —NH
'Group (wherein, R having' indicates C ₁ -C ₆ alkanoyl group.) R, compound is a novel compound.

In the compound having the general formula (I),
Preferably, 1) A is, 1,1-C ₂ -C ₅ alkylene - ethylene group, 1,1-C ₂ -C ₅ alkylene - trimethylene group,
1,1-C ₂ -C ₅ alkylene-tetramethylene group, ethylene group, trimethylene group, tetramethylene group, 1-methylethylene group, 1-ethylethylene group, 1-propylethylene group, 1-isopropylethylene group, 1 -Butylethylene group, 1-isobutylethylene group, 1,1-dimethylethylene group, nitroxymethyl or 2-nitroxyethyl-ethylene group, nitroxymethyl or 2
A compound which is -nitroxyethyl-trimethylene group or nitroxymethyl or 2-nitroxyethyl-tetramethylene group; 2) A represents 1,1-ethylene-ethylene group, 1,1-tetramethylene-ethylene group, , 1-pentamethylene-
Ethylene group, ethylene group, 1-methylethylene group, 1-
A compound which is an ethylethylene group, a 1-propylethylene group, a 1-isopropylethylene group, a 1-butylethylene group, a 1-isobutylethylene group, a 1,1-dimethylethylene group or a 1-nitroxymethylethylene group; 3) A Is 1,1-ethylene-ethylene group, 1-methylethylene group, 1-ethylethylene group, 1-propylethylene group, 1-isopropylethylene group, 1-butylethylene group, 1-isobutylethylene group or 1,1 4) A is a 1-methylethylene group, 1-propylethylene group, 1-butylethylene group or 1-isobutylethylene group, 5) A is a 1-methylethylene group 6) B is a group having the formula -NHR ¹ , wherein R ¹ is
A compound which is a hydrogen atom, a C ₁ -C ₃ alkanoyl group or a group having the formula (Ia), wherein R ² represents a hydrogen atom, a methyl group or a benzyl group; 7) B is an amino group, A compound in which R is an acetylamino group or a group having the formula (Ia) (wherein R ² represents a hydrogen atom); 8) a compound in which B is an amino group or an acetylamino group; And the compound which is a group.

Compounds obtained by selecting A from the group consisting of (1)-(5), selecting B from the group consisting of (6)-(9), and arbitrarily combining these are also suitable. Yes,
For example, the following can be mentioned. 10) A is, _1,1-C 2 -C ₅ alkylene - ethylene group, 1,1-C ₂ -C ₅ alkylene - trimethylene group, 1,1-C ₂ -C ₅ alkylene - tetramethylene group, an ethylene group , Trimethylene group, tetramethylene group,
1-methylethylene group, 1-ethylethylene group, 1-propylethylene group, 1-isopropylethylene group, 1-
Butylethylene group, 1-isobutylethylene group, 1,1
-Dimethylethylene group, nitroxymethyl or 2-
A nitroxyethyl-ethylene group, a nitroxymethyl or 2-nitroxyethyl-trimethylene group or a nitroxymethyl or 2-nitroxyethyl-tetramethylene group, wherein B is a group having the formula -NHR ¹ , wherein A compound wherein R ¹ is a hydrogen atom, a C ₁ -C ₃ alkanoyl group or a group having the formula (Ia) (wherein R ² represents a hydrogen atom, a methyl group or a benzyl group); , 1,1-ethylene-ethylene group, 1,1-
Tetramethylene-ethylene group, 1,1-pentamethylene-ethylene group, ethylene group, 1-methylethylene group, 1
-Ethylethylene group, 1-propylethylene group, 1-isopropylethylene group, 1-butylethylene group, 1-isobutylethylene group, 1,1-dimethylethylene group or 1-nitroxymethylethylene group, and B is A compound which is an amino group, an acetylamino group or a group having the formula (Ia) (wherein R ² represents a hydrogen atom); 12) A represents a 1,1-ethylene-ethylene group, 1-methylethylene A 1-ethylethylene group, a 1-propylethylene group, a 1-isopropylethylene group, a 1-butylethylene group, a 1-isobutylethylene group or a 1,1-dimethylethylene group, and B represents an amino group or an acetylamino group; A) a 1-methylethylene group, a 1-propylethylene group, a 1-butylethylene group or a 1-isobutylene group; An alkylene group, B is a compound or 14) A is an amino group or an acetylamino group, a 1-methylethylene group, B is a compound which is an amino group.

In the compound having the general formula (II),
Preferably, 15) a compound wherein D is a C ₁ -C ₃ alkylene group, 16) a compound wherein D is a methylene group or an ethylene group, 17) a compound wherein D is a methylene group, 18) E The nitrogen atom may be substituted by a C ₁ -C ₃ alkanoyl or a group having the formula (Ia), wherein R ² represents a hydrogen atom, a methyl group or a benzyl group.
A compound having from 6 to 6 membered cyclic amino groups, 19) E may be substituted by a group wherein the nitrogen atom is acetyl or a group having the formula (Ia), wherein R ² represents a hydrogen atom. Compounds in which 20) E is a 2-pyrrolidinyl group or 2-piperidinyl group or 21) Compounds in which E is a 2-piperidinyl group can be exemplified.

Compounds obtained by selecting D from the group consisting of (15)-(17), selecting E from the group consisting of (18)-(21), and arbitrarily combining these are also suitable. For example, the following can be mentioned. 22) D is a C ₁ -C ₃ alkylene group, E is a group having a nitrogen atom of a C ₁ -C ₃ alkanoyl or a formula (Ia) (wherein R ² is a hydrogen atom, a methyl group or a benzyl group) A) a 5- or 6-membered cyclic amino group which may be substituted with: 23) D is a methylene group or an ethylene group,
May be substituted with a group in which the nitrogen atom is acetyl or a group having the formula (Ia), wherein R ² represents a hydrogen atom.
A compound which is a 2-pyrrolidinyl group or a 2-piperidinyl group, 24) D is a methylene group or an ethylene group,
Is a 2-pyrrolidinyl group or a 2-piperidinyl group; or 25) a compound wherein D is a methylene group and E is a 2-piperidinyl group.

[0035] In the compounds having the general formula (III), preferably, 26) R ¹ a is hydrogen atom or a compound which is C ₁ -C ₅ alkanoyl group, 27) R ¹ a is hydrogen atom or C , compound ₂ -C ₃ alkanoyl group, 28) R ¹ a is hydrogen atom or compound is an acetyl group, 29) R ¹ a is a compound which is a hydrogen atom, 30) R ³ is C ₁ -C ₄ A compound wherein R ³ is a methyl, ethyl, propyl, isopropyl, butyl or isobutyl group; 32) a compound wherein R ³ is a methyl, propyl, butyl or isobutyl group; 33) R ³ Is a methyl group or 34) a compound wherein n is 1.

Further, the R ¹ a (26) - selected from the group consisting of (29), the R ³ (30) - selected from the group consisting of (33), and select n from (34), these Compounds obtained by arbitrarily combining are also suitable, and examples thereof include the following. 35) R ¹ a is hydrogen atom or a C ₁ -C ₅ alkanoyl group, R ³ is a compound which is C ₁ -C ₄ alkyl group, 36) R ¹ a is hydrogen atom or C ₂ -C ₃ alkanoyl group, R ³ is methyl, ethyl, propyl, isopropyl, butyl or isobutyl group, compounds wherein n is ^1, 37) R 1 a is hydrogen atom or an acetyl group, R ³
But methyl, propyl, butyl or isobutyl group, the compound or 38 n is 1) R ¹ a is hydrogen atom or an acetyl group, R ³
Is a methyl group.

Of the novel compounds of the formula (I), preferably 39) A is a C ₂ -C ₄ alkylene group substituted by ethylene, nitroxymethyl or 2-nitroxyethyl. 40) a compound wherein A is a 1,1-ethyleneethylene group or a 1-nitroxymethylethylene group; 41) a compound wherein A is a 1,1-ethyleneethylene group; 42) B is a compound of the formula -NHR A group having ¹ (wherein R ¹
Is a hydrogen atom, a C ₁ -C ₃ alkanoyl group or a compound of the formula (Ia)
Wherein R ² represents a hydrogen atom, a methyl group or a benzyl group; 43) B represents an amino group, an acetylamino group or a compound of the formula (Ia)
Group (wherein, R ² represents a hydrogen atom.) With compounds wherein, 44) B is a compound which is an amino group or an acetylamino group or 45) B is a compound which is an amino group or 46) A Is an ethylene group, 1-methylethylene group or 1,1-dimethylethylene group; 47) A is an ethylene group or 1-methylethylene group; 48) A is a 1-methylethylene group. Certain compounds, 49) wherein B is a group having the formula -NHR ¹ , wherein R ¹
Represents a C ₁ -C ₃ alkanoyl group. ) Or 50) B is an acetylamino group.

A is selected from the group consisting of (39)-(41), B is selected from the group consisting of (42)-(45), and a compound obtained by arbitrarily combining these compounds or A
Is selected from the group consisting of (46)-(48), and B is (4)
Compounds selected from the group consisting of 9) to (50) and obtained by arbitrarily combining these are also suitable, and examples thereof include the following. 51) A is ethylene, a C ₂ -C ₄ alkylene group substituted with a nitro carboxymethyl or 2-nitroxy-ethyl, B is a group (wherein having the formula -NHR ^1, R ¹
Is a hydrogen atom, a C ₁ -C ₃ alkanoyl group or a compound of the formula (Ia)
Wherein R ² represents a hydrogen atom, a methyl group or a benzyl group; 52) A is a 1,1-ethyleneethylene group or a 1-nitroxymethylethylene group; B is an amino group, an acetylamino group or a group having the formula (Ia) (wherein R ²
Represents a hydrogen atom. 53) a compound wherein A is a 1,1-ethyleneethylene group or a 1-nitroxymethylethylene group, and B is an amino group or an acetylamino group; Ethylene is an ethylene group;
Is an amino group; 55) A is an ethylene group, a propylene group or a 1,1-
A compound in which B is a dimethylethylene group and B is a group having the formula —NHR ¹ (wherein R ¹ represents a C ₁ -C ₃ alkanoyl group) or 56) A is an ethylene group or a propylene group Yes, B
Is a acetylamino group.

Among the compounds having the general formula (IIIa), 57) a compound wherein R ² is a hydrogen atom, a methyl group or a benzyl group; 58) a compound wherein R ² is a hydrogen atom; Compounds in which D is a C ₁ -C ₃ alkylene group; 60) compounds in which D is a methylene group or an ethylene group; and 61) compounds in which D is a methylene group.

Preferred examples of the compound having the general formula (I) are specifically shown in Table 1. _{B - A - ONO 2 (I} )

[0041]

[Table 1] ──────────────────────────────────── Compound BA No. No. ──── ──────────────────────────────── 1-1 NH ₂ CH ₂ CH ₂ 1-2 NH ₂ CH (Me) CH ₂ 1-3 NH ₂ C (Me) ₂ CH ₂ 1-4 NH ₂ CH ₂ CH ₂ CH ₂ 1-5 NH ₂ C (CH ₂ CH ₂ ) CH ₂ 1-6 NH ₂ C [(CH ₂ ) ₃ ] CH ₂ 1-7 NH ₂ C [(CH ₂ ) ₄ ] CH ₂ 1-8 NH ₂ C [(CH ₂ ) ₅ ] CH ₂ 1-9 NH ₂ CH (CH ₂ ONO ₂ ) CH ₂ 1- 10 NH ₂ CH (CH ₂ CH ₂ ONO ₂ ) CH ₂ 1-11 NHAc CH ₂ CH ₂ 1-12 NHAc CH (Me) CH ₂ 1-13 NHAc C (Me) ₂ CH ₂ 1-14 NHAc C (CH ₂ CH ₂ ) CH ₂ 1-15 NHAc C [(CH ₂ ) ₃ ] CH ₂ 1-16 NHAc C [(CH ₂ ) ₄ ] CH ₂ 1-17 NHAc C [(CH ₂ ) ₅ ] CH ₂ 1- 18 NHAc CH (CH ₂ ONO ₂ ) CH ₂ 1-19 NHPrn CH ₂ CH ₂ 1-20 NHPrn CH (Me) CH ₂ 1-21 NHPrn C (Me) ₂ CH ₂ 1-22 NHPrn C (CH ₂ CH ₂ ) CH ₂ 1-23 NHPrn C [(CH ₂ ) ₃ ] CH ₂ 1-24 NHPrn C [(CH ₂ ) ₄ ] CH ₂ 1-25 NHPrn C [(CH ₂ ) ₅ ] CH ₂ 1-26 NHPrn CH (CH ₂ ONO ₂ ) CH ₂ 1-27 NHBury CH ₂ CH ₂ 1-28 NHBury CH (Me) CH ₂ 1-29 NHBury C (Me) ₂ CH ₂ 1-30 NHBury C (CH ₂ CH ₂ ) CH ₂ 1-31 NHBury CH (CH ₂ ONO ₂ ) CH ₂ 1-32 NH-CO-4-Thiazd C (CH ₂ CH ₂ ) CH ₂ 1-33 NH-CO-4-Thiazd C [(CH ₂ ) ₃ ] CH ₂ 1-34 NH-CO-4-Thiazd C [(CH ₂ ) ₄ ] CH ₂ 1-35 NH-CO-4-Thiazd C [( CH ₂ ) ₅ ] CH ₂ 1-36 NH-CO-4-Thiazd CH (CH ₂ ONO ₂ ) CH ₂ 1-37 NH-CO-4-Thiazd CH (CH ₂ CH ₂ ONO ₂ ) CH ₂ 1-38 NH-CO- (5-Me-4-Thiazd) C (CH ₂ CH ₂ ) CH ₂ 1-39 NH-CO- (5-Me-4-Thiazd) C [(CH ₂ ) ₃ ] CH ₂ 1- 40 NH-CO- (5-Me-4-Thiazd) C [(CH ₂ ) ₄ ] CH ₂ 1-41 NH-CO- (5-Me-4-Thiazd) C [(CH ₂ ) ₅ ] CH ₂ 1-42 NH-CO- (5-Me-4-Thiazd) CH (CH ₂ ONO ₂ ) CH ₂ 1-43 NH-CO- (5-Ph-4-Thiazd) C (CH ₂ CH ₂ ) CH ₂ 1-44 NH-CO- (5-Ph-4-Thiazd) CH (CH ₂ ONO ₂ ) CH ₂ 1-45 NH-CO- [5- (4-MePh) -4-Thiazd] C (CH ₂ CH ₂ ) CH ₂ 1-46 NH-CO- [5- (4-MePh) -4-Thiazd] CH (CH ₂ ONO ₂ ) CH ₂ 1-47 NH-CO- [5- (4-MeOPh) -4 -Thiazd] C (CH ₂ CH ₂ ) CH ₂ 1-48 NH-CO- [5- (4-MeOPh) -4-Thiazd] CH (CH ₂ ONO ₂ ) CH ₂ 1-49 NH-CO- [5 -(4-FPh) -4-Thiazd] C (CH ₂ CH ₂ ) CH ₂ 1-50 NH-CO- [5- (4-FPh) -4-Thiazd] CH (CH ₂ ONO ₂ ) CH ₂ 1 -51 NH-CO- [5- (4-ClPh) -4-Thiazd] C (CH ₂ CH ₂ ) CH ₂ 1-52 NH-CO- [5 -(4-ClPh) -4-Thiazd] CH (CH ₂ ONO ₂ ) CH ₂ 1-53 NH-CO- (5-Bz-4-Thiazd) C (CH ₂ CH ₂ ) CH ₂ 1-54 NH- CO- (5-Bz-4-Thiazd) CH (CH ₂ ONO ₂ ) CH ₂ 1-55 NH-CO- [5- (4-MeBz) -4-Thiazd] C (CH ₂ CH ₂ ) CH ₂ 1 -56 NH-CO- [5- (4 -MeBz) -4-Thiazd] CH (CH 2 ONO 2) CH 2 1-57 NH-CO- [5- (4-MeOBz) -4-Thiazd] C ( CH ₂ CH ₂ ) CH ₂ 1-58 NH-CO- [5- (4-MeOBz) -4-Thiazd] CH (CH ₂ ONO ₂ ) CH ₂ 1-59 NH-CO- [5- (4-FBz ) -4-Thiazd] C (CH ₂ CH ₂ ) CH ₂ 1-60 NH-CO- [5- (4-FBz) -4-Thiazd] CH (CH ₂ ONO ₂ ) CH ₂ 1-61 NH-CO -[5- (4-ClBz) -4-Thiazd] C (CH ₂ CH ₂ ) CH ₂ 1-62 NH-CO- [5- (4-ClBz) -4-Thiazd] CH (CH ₂ ONO ₂ ) CH ₂ 1-63 NH ₂ (CH ₂ ) ₄ 1-64 NH ₂ CH (Et) CH ₂ 1-65 NH ₂ CH (Pr) CH ₂ 1-66 NH ₂ CH (i-Pr) CH ₂ 1-67 NH ₂ CH (Bu) CH ₂ 1-68 NH ₂ CH (i-Bu) CH ₂ 1-69 NHAc (CH ₂ ) ₃ 1-70 NHAc (CH ₂ ) ₄ 1-71 NHAc CH (Et) CH ₂ 1 _{-72 NHAc CH (Pr) CH 2} 1-73 NHAc CH (i-Pr) CH 2 1-74 NHAc CH (Bu) CH 2 1-75 NHAc CH (i-Bu) CH 2 1-76 NHPrn CH (Et _{) CH 2 1-77 NHPrn CH (Pr} ) CH 2 1-78 NHPrn CH (Bu) CH 2 1-79 NHPrn CH (i-Bu) CH 2 1-80 NHBury CH (Pr) CH 2 1-81 NHBury CH _{(Bu) CH 2 1-82 NHBury CH} (i-Bu) CH 2 1-83 NHi-Bury _{CH (Me) CH 2 1-84 NHi} -Bury CH (Pr) CH 2 1-85 NHi-Bury CH (Bu) CH 2 1-86 NHi-Bury CH (i-Bu) CH 2 1-87 NHValry CH ( _{Me) CH 2 1-88 NHValry CH (} Pr) CH 2 1-89 NHValry CH (Bu) CH 2 1-90 NHValry CH (i-Bu) CH 2 1-91 NHi-Valry CH (Me) CH 2 1- 92 NHi-Valry CH (Pr) CH ₂ 1-93 NHi-Valry CH (Bu) CH ₂ 1-94 NHi-Valry CH (i-Bu) CH ₂ ────────────── ────────────────────.

Preferred examples of the compound having the general formula (II) are specifically shown in Table 2. ED-ONO ₂ (II)

[0043]

[Table 2] ──────────────────────────────────── Compound ED No. ──── ──────────────────────────────── 2-1 2-Pyr CH ₂ 2-2 2-Pyr CH ₂ CH ₂ 2-3 2-Pyr (CH ₂ ) ₃ 2-4 2-Pyr CH ₂ C (Me) H 2-5 2-Pyr (CH ₂ ) ₄ 2-6 2-Pyr (CH ₂ ) ₅ 2-7 3 -Pyr CH ₂ 2-8 3-Pyr CH ₂ CH ₂ 2-9 3-Pyr (CH ₂ ) ₃ 2-10 1-Ac-2-Pyr CH ₂ 2-11 1-Ac-2-Pyr CH ₂ CH ₂ 2-12 1-Ac-2-Pyr (CH ₂ ) ₃ 2-13 1-Prn-2-Pyr CH ₂ 2-14 1-Prn-2-Pyr CH ₂ CH ₂ 2-15 1-Bury-2 -Pyr CH ₂ 2-16 1-Bury-2-Pyr CH ₂ CH ₂ 2-17 1- (CO-4-Thiazd) -2-Pyr CH ₂ 2-18 1- (CO-4-Thiazd) -2 -Pyr CH ₂ CH ₂ 2-19 1- (CO-4-Thiazd) -2-Pyr CH ₂ C (Me) H 2-20 1- (CO-4-Thiazd) -2-Pyr (CH ₂ ) ₃ 2-21 1- [CO- (5-Me-4-Thiazd)]-2-Pyr CH ₂ 2-22 1- [CO- (5-Me-4-Thiazd)]-2-Pyr CH ₂ CH ₂ 2-23 1- [CO- (5-Ph-4-Thiazd)]-2-Pyr CH ₂ 2-24 1- [CO- (5-Ph-4-Thiazd)]-2-Pyr CH ₂ CH ₂ 2-25 1- [CO- [5- (4-MePh) -4-Thiazd]]-2-Pyr CH ₂ 2-26 1- [CO- [5- (4-MePh) -4-Thiazd]] -2-Pyr CH ₂ CH ₂ 2-27 1- [CO- [5- (4-MeOPh) -4-Thiazd]]-2-Pyr CH ₂ 2-28 1- [CO- [5- (4-MeOPh) -4 -Thiazd]]-2-Pyr CH ₂ CH ₂ 2-29 1- [CO- [5- (4-FPh) -4-Thiazd]]-2-Pyr CH ₂ 2-30 1- [CO- [5 -(4-FPh) -4-Thiazd]]-2-Pyr CH ₂ CH ₂ 2-31 1- [CO- [5- (4-ClPh) -4-Thiazd]]-2-Pyr CH ₂ 2- 32 1- [CO- [5- (4-ClPh) -4-Thiazd]]-2-Pyr CH ₂ CH ₂ 2-33 1- [CO- (5-Bz-4-Thiazd)]-2-Pyr CH ₂ 2-34 1- [CO- (5-Bz-4-Thiazd)]-2-Pyr CH ₂ CH ₂ 2-35 1- [CO- [5- (4-MeBz) -4-Thiazd]] -2-Pyr CH ₂ 2-36 1- [CO- [5- (4-MeBz) -4-Thiazd]]-2-Pyr CH ₂ CH ₂ 2-37 1- [CO- [5- (4- MeOBz) -4-Thiazd]]-2-Pyr CH ₂ 2-38 1- [CO- [5- (4-MeOBz) -4-Thiazd]]-2-Pyr CH ₂ CH ₂ 2-39 1- [ CO- [5- (4-FBz) -4-Thiazd]]-2-Pyr CH ₂ 2-40 1- [CO- [5- (4-FBz) -4-Thiazd]]-2-Pyr CH ₂ CH ₂ 2-41 1- [CO- [5- (4-ClBz) -4-Thiazd]]-2-Pyr CH ₂ 2-42 1- [CO- [5- (4-ClBz) -4-Thiazd ]]-2-Pyr CH ₂ CH ₂ 2-43 2-Pip CH ₂ 2-44 2-Pip CH ₂ CH ₂ 2-45 2-Pip (CH ₂ ) ₃ 2-46 2-Pip CH ₂ C (Me ) H 2-47 2-Pip (CH ₂ ) ₄ 2-48 2-Pip (CH ₂ ) ₅ 2-49 3-Pip CH ₂ 2-50 3-Pip CH ₂ CH ₂ 2-51 3-Pip (CH ₂ ) ₃ 2-52 4-Pip CH ₂ 2-53 4-Pip CH ₂ CH ₂ 2-54 4-Pip (CH ₂ ) ₃ 2-5 5 1-Ac-2-Pip CH ₂ 2-56 1-Ac-2-Pip CH ₂ CH ₂ 2-57 1-Ac-2-Pip (CH ₂ ) ₃ 2-58 1-Prn-2-Pip CH ₂ 2-59 1-Prn-2-Pip CH ₂ CH ₂ 2-60 1-Bury-2-Pip CH ₂ 2-61 1-Bury-2-Pip CH ₂ CH ₂ 2-62 1- (CO-4 -Thiazd) -2-Pip CH ₂ 2-63 1- (CO-4-Thiazd) -2-Pip CH ₂ CH ₂ 2-64 1- (CO-4-Thiazd) -2-Pip (CH ₂ ) ₃ 2-65 1- (CO-4-Thiazd) -2-Pip CH ₂ C (Me) H 2-66 1- (CO-4-Thiazd) -2-Pip (CH ₂ ) ₄ 2-67 1- ( CO-4-Thiazd) -2-Pip (CH ₂ ) ₅ 2-68 1- [CO- (5-Me-4-Thiazd)]-2-Pip CH ₂ 2-69 1- [CO- (5- Me-4-Thiazd)]-2-Pip CH ₂ CH ₂ 2-70 1- [CO- (5-Ph-4-Thiazd)]-2-Pip CH ₂ 2-71 1- [CO- (5- Ph-4-Thiazd)]-2-Pip CH ₂ CH ₂ 2-72 1- [CO- [5- (4-MePh) -4-Thiazd]]-2-Pip CH ₂ 2-73 1- [CO -[5- (4-MePh) -4-Thiazd]]-2-Pip CH ₂ CH ₂ 2-74 1- [CO- [5- (4-MeOPh) -4-Thiazd]]-2-Pip CH ₂ 2-75 1- [CO- [5- (4-MeOPh) -4-Thiazd]]-2-Pip CH ₂ CH ₂ 2-76 1- [CO- [5- (4-FPh) -4- Thiazd]]-2-Pip CH ₂ 2-77 1- [CO- [5- (4-FPh) -4-Thiazd]]-2-Pip CH ₂ CH ₂ 2-78 1- [CO- [5- (4-ClPh) -4-Thiazd]]-2-Pip CH ₂ 2-79 1- [CO- [5- (4-ClPh) -4-Thiazd]]-2-Pip CH ₂ CH ₂ 2-80 1- [CO- (5-Bz-4-Thiazd)]-2-Pip CH ₂ 2-81 1- [CO- (5-Bz-4-Thiazd) ] -2-Pip CH ₂ CH ₂ 2-82 1- [CO- [5- (4-MeBz) -4-Thiazd]]-2-Pip CH ₂ 2-83 1- [CO- [5- (4 -MeBz) -4-Thiazd]]-2-Pip CH ₂ CH ₂ 2-84 1- [CO- [5- (4-MeOBz) -4-Thiazd]]-2-Pip CH ₂ 2-85 1- [CO- [5- (4-MeOBz) -4-Thiazd]]-2-Pip CH ₂ CH ₂ 2-86 1- [CO- [5- (4-FBz) -4-Thiazd]]-2- Pip CH ₂ 2-87 1- [CO- [5- (4-FBz) -4-Thiazd]]-2-Pip CH ₂ CH ₂ 2-88 1- [CO- [5- (4-ClBz)- 4-Thiazd]]-2-Pip CH ₂ 2-89 1- [CO- [5- (4-ClBz) -4-Thiazd]]-2-Pip CH ₂ CH ₂ ───────── ─────────────────────────.

In Tables 1 and 2, abbreviations indicate the following groups. Ac ... acetyl Bu ... butyl i-Bu ... isobutyl Bury ... butyryl i-Bury ... isobutyryl Bz ... benzyl Et ... ethyl Me ...・ Methyl Ph ・ ・ ・ ・ Phenyl Pip ・ ・ ・ ・ Piperidyl Pr ・ ・ ・ ・ Propyl i-Pr ・ ・ ・ Isopropyl Prn ・ ・ ・ ・ Propionyl Pyr ・ ・ ・ ・ Pyrrolidinyl Thiazd ・ ・ ・ ・ 2-oxo-4- Thiazolidinyl.

Valry ··· Valeryl i-Valry ··· Isovaleryl.

In the above table, preferably, Compound No. 1-1, 1-2, 1-3, 1-5, 1-6, 1
-7, 1-8, 1-9, 1-12, 1-13, 1-2
0, 1-21, 1-28, 1-35, 1-36, 1-6
5, 1-67, 1-68, 1-72, 1-74, 1-7
5, 1-82, 2-1, 2-7, 2-43, 2-49 and 2-52, more preferably Compound No. 1-1, 1-2, 1-3, 1-5, 1-8,
1-9, 1-35, 1-36, 1-65, 1-67, 1
-68, 2-1, 2-7, 2-43, 2-49 and 2
-52, particularly preferably Compound No. 1-2: 1-methyl-2-nitroxyethylamine, Compound No. 1-3: 1,1-dimethyl-2-nitroxyethylamine, Compound No. 1-5: 1,1-ethylene-2-nitroxyethylamine, Compound No. 1-9: 1-nitroxymethyl-2-
Nitroxyethylamine Compound No. 1-65: 1-propyl-2-nitroxyethylamine, Compound No. 1-67: 1-butyl-2-nitroxyethylamine, Compound No. 1-68: 1-isobutyl-2-nitroxyethylamine and Compound No. 2-43: 2- (nitroxymethyl)
It is a compound of piperidine.

In the novel compounds in Tables 1 and 2, particularly preferably, Compound No. 1-5: 1,1-ethylene-2-nitroxyethylamine, Compound No. 1-9: 1-nitroxymethyl-2-
Nitroxyethylamine and Compound No. 2-43: 2- (nitroxymethyl)
It is a compound of piperidine.

Preferable examples of the compound having the general formula (III) are shown in Table 3.

[0049]

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[0050]

[Table 3] 化合物 Compound R ¹ a R ² n No. ──────────────────────────────────── 3-1 H Me 1 3-2 H Et 1 3- 3 H Pr 1 3-4 H i-Pr 1 3-5 H Bu 1 3-6 H i-Bu 1 3-7 H Pn 1 3-8 H i-Pn 13 9 H Hx 13 10 H i-Hx 1 3-11 Ac Me 1 3-12 Ac Et 1 3-13 Ac Pr 1 3-14 Ac i-Pr 1 3-15 Ac Bu 1 3-16 Ac i-Bu 1 3-17 Prn Me 1 3-18 Prn Et 1 3-19 Prn Pr 1 3-20 Prn Bu 1 3-21 Prn i-Bu 1 3-22 Bury Me 1 3-23 Bury Pr 1 3-24 Bury Bu 1 3-25 Bury i- Bu 1 3-26 i-Bury Me 1 3-27 i-Bury Pr 1 3-28 i-Bury Bu 1 3-29 i-Bury i-Bu 1 3-30 Valry Me 1 3-31 Valry Pr 13- 32 Valry Bu 1 3-33 Valry i-Bu 1 3-34 i-Valry Me 1 3-35 i-Valry Pr 13-36 i-Valry Bu 1 3-37 i-Valry i-Bu 1 3-38 H Me 2 3-39 H Et 2 3-40 H Pr 2 3-41 Hi i-Pr 2 3-42 H Bu 23 3-43 Hi i-Bu 23-44 Ac Me 23-45 Ac Et 23 46 Ac Pr 2 3-47 Ac i-Pr 2 3-48 Ac Bu 2 3-49 Ac i-Bu 2 3-50 Prn Me 2 3-51 Prn Pr 2 3-52 Prn Bu 2 3-53 Prn i-Bu 2 3-54 Bury Me 2 3-55 i-Bury Me 2 3-56 Valry Me 2 3-57 i-Valry Me 2 ──────── ──────────────────────────.

In Table 3 above, abbreviations indicate the following groups. Ac ... acetyl Bu ... butyl i-Bu ... isobutyl Bury ... butyryl i-Bury ... isobutyryl Et ... ethyl Hx ... hexyl i-Hx ...・ Isohexyl Me ・ ・ ・ ・ Methyl Pn ・ ・ ・ ・ Pentyl i-Pn ・ ・ ・ Isopentyl Pr ・ ・ ・ ・ Propyl i-Pr ・ ・ ・ Isopropyl Prn ・ ・ ・ ・ Propionyl Valry ..Isovaleryl.

In Table 3 above, preferably, Compound No. 3-1, 3-3, 3-5, 3-6, 3-7, 3-11, 3-1
3, 3-14, 3-15, 3-16, 3-17, 3-19, 3-20, 3-21
, 3-22, 3-26, 3-30 and 3-34, more preferably Compound No. 3-1, 3-3, 3-5, 3-
6, 3-7, 3-11, 3-13, 3-14, 3-15 and 3-16, particularly preferably Compound No. 3-1: (1S) -1-methyl-2-nitroxyethylamine, Compound No. 3-3: (1S) -1-propyl-2-
Nitroxyethylamine, Compound No. 3-5: (1S) -1-butyl-2-nitroxyethylamine and Compound No. 3-6: (1S) -1-isobutyl-2
-A compound of nitroxyethylamine.

[0053]

BEST MODE FOR CARRYING OUT THE INVENTION The general formula (I) or (II) of the present invention
Are known compounds [Chemical Abstracts, vol. 41, p. 3868, 1947: Chem. Abs
t., 41 , 3868 (1947), JP-A-1-46873, Chemical Abstracts, vol. 58, p. 12372, 1964: Chem.
Abst., 58 , 12372 (1964), etc.], or the following method.

[0054]

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[0055]

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[0056] In the above formula, A, B, D and E denote the same meanings as defined above, A 'is, C ₁ -C ₅ alkylene group or a hydroxy -C substituted by C ₂ -C ₅ alkylene
_A C ₁ -C ₇ alkylene group which may be substituted with _1- C ₄ alkyl, B ′ represents a protected amino group,
D ′ represents a single bond or a C ₁ -C ₄ alkylene group,
E ′ represents a 5- or 6-membered cyclic amino group, and E ″ represents a protected 5- or 6-membered cyclic amino group.

Protecting groups for amino groups include, for example, t-butoxycarbonyl group; methoxybenzyloxycarbonyl,
C ₁ -C such as ethoxybenzyloxycarbonyl group
₄ alkoxybenzyloxycarbonyl group; or a halogenoacetyl group such as chloroacetyl, bromoacetyl, or iodoacetyl group, preferably a t-butoxycarbonyl group or a p-methoxybenzyloxycarbonyl group, particularly preferably Is a t-butoxycarbonyl group.

Method A is a method for producing compound (I). Step A1 is a step for producing a compound having the general formula (V), which is achieved by protecting the amino group of the compound having the general formula (IV), if desired.

The reaction for protecting the amino group is carried out according to a method well-known in the field of synthetic organic chemistry. For example, compound (IV) can be prepared by reacting compound (IV) with di-t-butyl-di-carbonate; Do t- butyl halogenoalkyl carbonate; methoxybenzyl chlorocarbonate, methoxybenzyl bromo carbonate, C ₁ -C ₄ alkoxybenzyl halogenoalkyl carbonates such as ethoxy benzyl chlorocarbonate; or chloroacetyl chloride, bromoacetyl bromide, halogeno such as iodoacetyl chloride It is achieved by reacting acetyl halide with an inert solvent in the presence or absence of a base.

The base used is, for example, organic amines such as triethylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; sodium carbonate. , Potassium carbonate, preferably an alkali metal bicarbonate or an organic amine.

The inert solvent used is not particularly limited as long as it does not participate in the reaction. Examples thereof include hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, dichloromethane, 1,2-dichloroethane, Halogenated hydrocarbons such as carbon chloride, ethers such as ether, tetrahydrofuran, dioxane, water,
It may be a mixed solvent of water and the above-mentioned organic solvent. In the reaction of compound (IV) with halogenocarbonate or acetyl halide, the compound is a hydrocarbon or ether. The reaction temperature varies depending on the type of the starting compound (IV) and the solvent, and is usually from -20 ° C to 100 ° C, preferably from 0 ° C to 50 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours.
Preferably, it is 30 minutes to 20 hours.

After the completion of the reaction, the target product of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering the precipitated crystals or adding water, extracting with a water-immiscible organic solvent such as ethyl acetate, drying, and distilling off the extraction solvent. Then, it can be further purified by a conventional method, for example, recrystallization, column chromatography and the like.

Step A2 is a step of preparing a compound having the general formula (VI), wherein the compound (V) or a reactive derivative thereof (for example, a C ₁ -C ₄ alkyl ester or acid chloride, acid bromide, acid iodidide) Acid halides, such as
Preferably, the reaction is carried out by reducing methyl ester, ethyl ester or acid chloride), and the reaction is carried out in an inert solvent in the presence of a reducing agent.

The reducing agent used can be, for example, an alkali metal borohydride such as sodium borohydride, potassium borohydride, lithium borohydride, calcium borohydride or an aluminum hydride compound such as lithium aluminum hydride. , Preferably lithium aluminum hydride.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, ethers such as ether, tetrahydrofuran and dioxane. And preferably ethers, especially tetrahydrofuran. The reaction temperature varies depending on the type of the starting compound (V), the reducing agent and the solvent, and the like.
Usually -20 ° C to 100 ° C, preferably -10 ° C
To 50 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours, preferably 3 minutes.
0 minutes to 16 hours. Also, compound (VI) can be produced by protecting the amino group of a known amino-alcohol compound in the same manner as in the step A1.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering the precipitated crystals or adding water, extracting with a water-immiscible organic solvent such as ethyl acetate, drying, and distilling off the extraction solvent. Then, it can be further purified by a conventional method, for example, recrystallization, column chromatography and the like.

Step A3 is a step of preparing a compound having the general formula (I) by nitrating compound (VI), removing an amino-protecting group if necessary, and further acylating if necessary. Achieved. The nitration reaction is achieved by reacting compound (VI) with a nitrating agent in an inert solvent, preferably in the presence of a base.

The nitrating agent used can be, for example, fuming nitric acid, nitrocorridium tetrafluoroboron, thionyl chloride nitric acid, thionyl nitric acid, nitronium tetrafluoroboron, preferably nitrocorridium.
Tetrafluoroboron or thionyl nitrate.

The inert solvent used is not particularly limited as long as it does not participate in the reaction. Examples thereof include hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene, dichloromethane, 1,2-dichloroethane, and tetrachloromethane. Halogen hydrocarbons such as carbon chloride, ethers such as ether, tetrahydrofuran and dioxane, ketones such as acetone, nitriles such as acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N -Methyl-2-pyrrolidone, amides such as hexamethylphosphoramide, sulfoxides such as dimethylsulfoxide, preferably halogenated hydrocarbons, ethers, nitriles, amides or sulfoxides It is.

The reaction temperature varies depending on the type of the starting compound (VI), the nitrating agent and the solvent, but is usually from -20 ° C to 80 ° C, preferably from 0 ° C to 50 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually 30 minutes to 2 minutes.
4 hours, preferably 1 hour to 10 hours.
In addition, when fuming nitric acid is used as the nitrating agent, a nitroxy compound can be suitably produced even if an amino-alcohol compound whose amino group is not protected is used.

After completion of the reaction, the target substance for the nitration reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the extraction solvent or adding water, extracting with a water-immiscible organic solvent such as ethyl acetate, drying, and then distilling off the extraction solvent. Law,
For example, it can be further purified by recrystallization, column chromatography or the like.

The reaction for removing the protecting group for the amino group depends on the type of the protecting group, but is carried out by a method usually used in the field of synthetic organic chemistry.

When the protecting group for the amino group is a t-butoxycarbonyl group or a C ₁ -C ₄ alkoxybenzyloxycarbonyl group, the corresponding compound is reacted with an inert solvent (for example, hexane, cyclohexane, benzene, toluene, xylene). Hydrocarbons, such as dichloromethane,
Halogen hydrocarbons such as 1,2-dichloroethane and carbon tetrachloride or ethers such as ether, tetrahydrofuran and dioxane, preferably ethers)
Medium acid (eg, hydrogen halide such as hydrogen chloride, hydrogen bromide, hydrogen iodide; mineral acid such as hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid; or acetic acid, formic acid, oxalic acid, methanesulfonic acid) Organic acids such as paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, preferably hydrogen halide, particularly preferably hydrogen chloride), and-
20 ° C to 80 ° C (preferably 0 ° C to 50 ° C)
The reaction is allowed to proceed for 0 minute to 10 hours (preferably 1 hour to 5 hours) to remove the protecting group.

When the protecting group for the amino group is a halogenoacetyl group, the corresponding compound is reacted with an inert solvent (for example,
Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoramide or sulfoxides such as dimethylsulfoxide, preferably amides)
Medium, thiourea and -20 ° C to 80 ° C (preferably
30 to 10 hours (preferably 1 to 50 ° C.).
The reaction is carried out for about 5 to 5 hours) to remove the protecting group.

After completion of the reaction, the target product of the reaction for removing the protecting group for the amino group is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering the precipitated crystals or adding water, extracting with a water-immiscible organic solvent such as ethyl acetate, drying, and distilling off the extraction solvent. Then, it can be further purified by a conventional method, for example, recrystallization, column chromatography and the like.

The acylation reaction is carried out by reacting a corresponding amine compound or an acid addition salt thereof (for example, a mineral acid salt such as hydrochloride, nitrate or sulfate) with a compound of the general formula R ¹ b-OH (VII) (wherein
R ¹ b is a group having C ₁ -C ₆ alkanoyl group or the formula (Ia). ) Or a reactive derivative thereof (acid halides, mixed acid anhydrides or active esters), for example, by the acid halide method, mixed acid anhydride method, active ester method or condensation method. Done.

The acid halide method is carried out using the compound (VII) (provided that
Except when R ¹ b is a formyl group. ) Is reacted with a halogenating agent (eg, thionyl chloride, oxalic acid chloride, phosphorus pentachloride, etc.), and the produced acid halide is reacted with a corresponding amine compound or an acid addition salt thereof in an inert solvent in the presence of a base or It is achieved by reacting in the absence. Bases used are, for example, organic amines such as triethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, sodium carbonate, potassium carbonate And preferably an organic amine.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, dichloromethane, 1,2-dichloroethane, Halogenated hydrocarbons such as carbon chloride, ethers such as ether, tetrahydrofuran, dioxane, ketones such as acetone, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl -2-
It may be an amide such as pyrrolidone or hexamethylphosphoramide, or a sulfoxide such as dimethyl sulfoxide, and is preferably a hydrocarbon, a halogenated hydrocarbon, an ether or an amide. The reaction temperature varies depending on the type of the starting compound and the solvent, but the reaction between the halogenating agent and the compound (VII) and the reaction between the acid halide and the corresponding amine compound or its acid addition salt are usually-
The reaction between the halogenating agent and the compound (VII) is from -10 ° C to 50 ° C, and the reaction between the acid halide and the corresponding amine compound or its acid addition salt is preferably 0 ° C to 150 ° C. C. to 100.degree. The reaction time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours, preferably 30 minutes to 16 hours.

The mixed acid anhydride method comprises reacting a C ₁ -C ₄ alkyl halide or di-C ₁ -C ₄ alkyl cyanophosphoric acid with a compound (VII) to produce an acid anhydride or formic acid and acetic acid. It is achieved by reacting an acid anhydride with a corresponding amine compound or an acid addition salt thereof.

The reaction for producing the mixed acid anhydride is carried out by a C ₁ -C carbonate such as ethyl chlorocarbonate or isobutyl chlorocarbonate.
₄ alkyl halide; di -C ₁ -C ₄ alkyl cyanophosphate, such as diethyl cyano phosphate; or diphenylphosphoryl azide, di (p- nitrophenyl) phosphoryl azide, diaryl azide with a compound such as dinaphthyl azide The reaction is carried out by reacting (VII), preferably in an inert solvent in the presence of a base.

The base and the inert solvent used are the same as those used in the above-mentioned acid halide method. The reaction temperature depends on the type of the starting compound and the solvent, etc.,
It is usually -20 ° C to 50 ° C, preferably 0 ° C to 3 ° C.
0 ° C., and the reaction time varies depending on the reaction temperature and the like.
It is usually 15 minutes to 24 hours, preferably 30 minutes to 16 hours.

The reaction of the mixed acid anhydride or formic acid with the acid anhydride of acetic acid and the corresponding amine compound or acid addition salt thereof is preferably carried out in an inert solvent in the presence or absence of a base. The base and inert solvent used are the same as those used in the above-mentioned acid halide method. The reaction temperature varies depending on the type of the starting compound and the solvent, but is usually from -20 ° C to 100 ° C, preferably from -10 ° C to 50 ° C. The reaction time varies depending on the reaction temperature and the like. 15 minutes to 24 hours,
Preferably, it is 30 minutes to 16 hours. When di-C ₁ -C ₄ alkylcyanophosphoric acid or diarylphosphoryl azide is used in the present method, compound (VII) is reacted directly with the corresponding amine compound or an acid addition salt thereof in the presence of a base. It can also be done.

In the active ester method, a condensing agent (for example, dicyclohexylcarbodiimide, carbonyldiimidazo-
Compound (VII) in the presence of an active esterifying agent (for example, N-hydroxy compounds such as N-hydroxysuccinimide, N-hydroxybenzotriazole)
And reacting the active ester produced with a corresponding amine compound or an acid addition salt thereof. The reaction for producing the active ester is preferably carried out in an inert solvent, and the inert solvent used is the same as that used in the above-mentioned acid halide method. The reaction temperature varies depending on the type of the starting compound and the solvent, but in the active esterification reaction, it is usually -20 ° C to 50 ° C, preferably -10 ° C to 30 ° C, and corresponds to the active ester compound. In the reaction with an amine compound or an acid addition salt thereof, the temperature is −20 ° C. to 50 ° C., and preferably −20 ° C.
The reaction temperature is 10 ° C. to 30 ° C., and the reaction time varies depending on the reaction temperature and the like, but both reactions are usually 15 minutes to 24 hours, preferably 30 minutes to 16 hours.

In the condensation method, a condensing agent (for example, dicyclohexylcarbodiimide, carbonyldiimidazole, 1-
In the presence of (N, N-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or the like), the reaction is carried out by directly reacting compound (VII) with the corresponding amine compound or acid addition salt thereof. This reaction is carried out in the same manner as the above-mentioned reaction for producing an active ester. After the completion of the reaction, the target substance of each reaction is collected from the reaction mixture according to a conventional method. For example, filtering out the precipitated crystals or adding water,
Extraction with a water-immiscible organic solvent such as ethyl acetate, drying, and extraction can be performed by distilling off the extraction solvent.If necessary, a conventional method, for example, recrystallization, column chromatography, etc., is used for further purification. can do.

The starting compound (IV) for the method A is known or is easily produced according to a known method or a method analogous thereto [for example, Beilstein, Vol. 14, No. 194].
Pp. 1951: Beil., 14 , 194 (1951), Beilstein, Vol. 14 , p. 299, 1951: Beil., 14 , 299 (195)
1), Beilstein, Vol. 14, p. 526, 1951: B
eil., 14 , 526 (1951) etc.]. Method B is a method for producing compound (II).

The step B1 is a step of preparing a compound having the general formula (IX), which is optionally achieved by protecting the amino group of the compound having the general formula (VIII). This is performed in the same manner as in the step A1.

Step B2 is a step of preparing a compound having the general formula (X), wherein the compound (IX) or a reactive derivative thereof (for example, C ₁ -C ₄ alkyl ester or acid chloride, acid bromide, acid iododide) Acid halides, such as
Preferably, it is achieved by reducing methyl ester, ethyl ester or acid chloride), and this step is carried out in the same manner as in the step A2.

Step B3 is a step of preparing a compound having the general formula (II) by nitrating compound (X), removing an amino-protecting group if desired, and further acylating if desired. This step is achieved, and the step A3
It is performed in the same manner as the process.

The starting compound (VIII) for Method B is known or is easily produced according to a known method or a method similar thereto [for example, Beilstein, Vol. 22, No. 4
P. 1953: Beil., 22 , 4 (1953), Beilstein, Vol. 22 , p. 7, 1953: Beil., 22 , 7 (1953)
etc].

The compound (III) of the present invention can be easily produced according to the following method.

[0091]

Embedded image

[0092] In the above ^{formulas, R 1 a, R 3,} B ' and n have the same meanings as those described above.

Method C is a method for producing compound (III). The step C1 is a step of producing a compound having the general formula (XII), which is optionally achieved by protecting the amino group of the compound having the general formula (XI). The same is done.

Step C2 is a step of preparing a compound having the general formula (XIII), wherein the compound (XII) or a reactive derivative thereof (for example, C ₁ -C ₄ alkyl ester or acid chloride, acid bromide, acid iododide) , Preferably a methyl ester, an ethyl ester or an acid chloride), and this step is carried out in the same manner as in the step A2.

Step C3 is a step of producing a compound having the general formula (III), wherein the compound (XIII) is nitrated, if necessary, the protecting group of the amino group is removed, and if necessary, the compound of the formula R ¹ c —OH (VII ′) wherein R ¹ c is
Represents a C ₁ -C ₆ alkanoyl group. This is achieved by acylation using a compound having the formula (I), and this step is performed in the same manner as in the above-mentioned step A3.

The starting compound (XI) for Method C is known or is easily produced according to a known method or a method analogous thereto [for example, Beilstein, Vol. 14, p. 194, 1951 : Beil., 14 , 194 (195
1), Beilstein, Vol. 14, p. 299, 1951: B
eil., 14 , 299 (1951), Beilstein, Vol. 14,
526, 1951: Beil., 14 , 526 (1951) etc.].

The compound having the general formula (IIIa) is represented by the formula B'-D'-COOH (wherein B 'has the same meaning as described above, and D' is a single bond or C _1- A compound having a C ₄ alkylene group) is reduced in the same manner as in the above-mentioned step A2, and the obtained hydroxy compound is converted into the above-mentioned compound A3.
It can be produced by nitration in the same manner as in the process. The starting compounds are known or are easily produced according to known methods or methods similar thereto [for example, Heterocycle, Vol. 18, No. 259].
1982, Heterocycle, 18 , 259 (1982), etc.].

Compounds (I) and (II) which are the active ingredients of the present invention
Or (IIIa) or a pharmaceutically acceptable salt thereof or compound (III) or a pharmaceutically acceptable salt thereof,
It has an excellent collateral vasodilator effect, is less toxic, has headaches,
Useful as a preventive or therapeutic agent for angina pectoris (preferably a therapeutic agent) because it has no side effects such as dizziness, tachycardia or adverse effects on the digestive organs, liver, bones, etc. and has no first-pass effect It is.

Compound (III) has excellent storage stability and is easy to handle.

Compounds (I) and (II) which are the active ingredients of the present invention
Or (IIIa) or a pharmacologically acceptable salt thereof or the compound (III) of the present invention or a pharmacologically acceptable salt thereof when used as a therapeutic or prophylactic agent for angina pectoris. Pharmacologically acceptable, mixed with excipients, diluents, etc., tablets, capsules, granules,
It can be administered orally by powder or syrup or parenterally by injection or the like.

These preparations contain excipients (eg, lactose,
Sugar derivatives such as sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxy Cellulose derivatives such as methylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate; Salt derivatives; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.), binders (for example, the above-mentioned excipients). Gelatin; polyvinylpyrrolidone;
Disintegrants (eg, the above-mentioned excipients; croscarmellose sodium, sodium carboxymethyl starch, chemically modified starch such as cross-linked polyvinyl pyrrolidone, starch, cellulose derivatives, etc.), lubricants (eg, Talc; stearic acid; metal stearates such as calcium stearate and magnesium stearate; colloidal silica; luxes such as veegum, gay wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium benzoate; Carboxylic acid sodium salt; sulfuric acid salt such as sodium sulfate; leucine; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid such as silicic anhydride and silicic acid hydrate; Starch derivatives etc.), stable (For example, paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; Sorbic acid, etc.), flavoring agents (eg, commonly used sweeteners, sour agents, flavors, etc.), diluents, solvents for injections (eg, water, ethanol, glycerin, etc.). It is manufactured by a well-known method. The amount used depends on symptoms, age, etc.,
In the case of oral administration, the lower limit is 1 mg per dose (preferably,
5mg), upper limit 1000mg (preferably 300mg)
In the case of intravenous administration, the lower limit is 0.1 mg (preferably 0.5 mg) and the upper limit is 100 mg (preferably 50 mg) per dose.
mg) is desirably administered to an adult 1 to 6 times a day depending on the symptoms. Below, production examples, reference examples,
The present invention will be described in more detail with reference to Test Examples and Formulation Examples, but the scope of the present invention is not limited thereto.

[0102]

EXAMPLES Preparation Example 1 N- (1,1-ethylene-2-nitroxyethyl) amine hydrochloride (Exemplary Compound No. 1-5)
(A) 1-t-butoxycarbonylamino-1-cyclopropanecarboxylic acid 2.42 g of 1-amino-1-cyclopropanecarboxylic acid was dissolved in 25 ml of water, and 5.0
0 ml of triethylamine and 8.4 ml of di-t-butyl-di-carbonate in dioxane (10 ml) were added and the reaction was stirred at room temperature overnight. Dioxane was distilled off under reduced pressure, and citric acid was added to the resulting aqueous solution.
It was set to 4, and the precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, isopropyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration to obtain the desired compound 4.0.
4 g were obtained as colorless crystals. Melting point: 175-176C.
NMR spectrum (CDCl ₃ ) δppm: 1.22 (2H, s), 1.45 (9
H, s), 1.58 (2H, s), 5.17 (1H, bs). (B) 1-t-butoxycarbonylamino-1-hydroxymethylcyclopropane 4.04 g of the compound of Preparation Example 1 (a) was dissolved in 40 ml of anhydrous tetrahydrofuran, and stirred under ice-cooling for 22.0 g.
ml of a 1M lithium aluminum hydride-tetrahydrofuran solution was added dropwise at 3-8 ° C. 2 under ice cooling
The mixture was further stirred overnight at room temperature. Under ice-cooling, excess sodium sulfate decahydrate was added, and the mixture was stirred at the same temperature for 30 minutes.
The reaction solution was filtered and the solvent was distilled off under reduced pressure. The residue was dissolved in dichloromethane and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1 to 1/2), crystallized by adding cold hexane, and crystallized. The target compound 1.40 was collected by filtration.
g were obtained as colorless crystals. Melting point: 82-84 [deg.] C. NMR spectrum (CDCl ₃ ) δppm: 0.83 (4H, s), 1.45 (9H, s),
3.52 (1H, bs), 3.59 (2H, d, J = 4.6Hz), 5.12 (1H, bs).
(C) 1-t-butoxycarbonylamino-1-nitroxymethylcyclopropane 1.80 g of 2,4,6-collidine was dissolved in 30 ml of anhydrous acetonitrile, and stirred under ice-cooling and stirring in a nitrogen stream. 00 g of nitronium tetrafluoroboron was added, and the mixture was stirred at the same temperature for 30 minutes.
1.40 g of the compound of Production Example 1 (b) was added to the above solution, and the mixture was stirred at room temperature for 6 hours and 30 minutes. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, the insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 19/1), and cold hexane was added.
The crystals were crystallized, and the crystals were collected by filtration to obtain 0.39 g of the desired compound as colorless crystals. Melting point: 63-65 [deg.] C. NMR spectrum (CDCl ₃ ) δppm: 0.85-1.00 (4H, m), 1.45 (9H, s),
4.51 (2H, s), 4.98 (1H, bs). (D) N- (1,1-ethylene-2-nitroxyethyl) amine hydrochloride (Exemplified Compound No. 1-5)
dissolved in 4N-hydrogen chloride-dioxane at room temperature.
Stirred for hours. 20 ml of ether was added, and the precipitated crystals were collected by filtration to obtain 260 mg of the desired compound as colorless crystals. Melting point: 158-159 [deg.] C (decomposition). NMR spectrum (CDCl ₃ + d ₆ -DMSO) δ ppm: 0.95 (2H, t, J = 7 Hz), 1.43 (2
H, t, J = 7Hz), 4.71 (2H, s).

Preparation Example 22 2- (Nitroxymethyl) piperidine hydrochloride (Exemplified Compound No. 2-43) (a) Nt-
Butoxycarbonyl-2-hydroxymethylpiperidine 5.00 g of 2-hydroxymethylpiperidine is dissolved in a solution of 25 ml of dichloromethane and 25 ml of methanol, and 11.2 ml of di-t-butyl-di-carbonate is added, followed by stirring at room temperature for 2 hours. did. The solvent was distilled off under reduced pressure, the precipitated crystals were added with hexane, and the precipitated crystals were collected by filtration to obtain 7.21 g of the desired compound as colorless crystals.
Melting point: 71-72 ° C. NMR spectrum (CDCl ₃ ) δppm:
1.47 (9H, s), 1.35-1.75 (6H, m), 1.85-2.20 (1H, bs), 2.8
7 (1H, t, J = 11Hz), 3.53-3.65 (1H, m), 3.75-3.87 (1H, m),
3.94 (1H, d, J = 13Hz), 4.20-4.35 (1H, m). (B) Nt-
6.90 g of nitronium in a butoxycarbonyl-2-nitroxymethylpiperidine nitrogen stream under ice-cooling and stirring
Tetrafluoroboron was suspended in 70 ml of anhydrous acetonitrile, 6.74 ml of 2,4,6-collidine was added, and the mixture was stirred at the same temperature for 30 minutes. 5.00 g of the compound of Production Example 2 (a) was added to the above solution, and the mixture was stirred at room temperature for 1 hour and 50 minutes. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 19/1) to obtain the target compound 3.3.
6 g were obtained as a pale yellow oil. NMR spectrum (CDC
l ₃ ) δppm: 1.457 (9H, s), 1.38-1.78 (6H, m), 2.76 (1H,
t, J = 11Hz), 4.08 (1H, d, J = 13Hz), 4.48-4.70 (3H, m).
(C) Production Example 2 of 2-nitroxymethylpiperidine hydrochloride
3.36 g of the compound (b) was dissolved in 35 ml of a 4N-hydrogen chloride-dioxane solution and stirred at room temperature for 15 minutes.
120 ml of ether was added to the reaction solution, the precipitated crystals were collected by filtration, and the crystals were washed with ether to give the target compound 2.1
8 g were obtained as colorless crystals. Melting point: 155-156C.
NMR spectrum (d ₆ -DMSO) δppm: 1.40-1.85 (6H, m),
2.86 (1H, t, J = 12Hz), 3.23 (1H, d, J = 12Hz), 3.45-3.55 (1H,
m), 4.78 (2H, m).

Production Example 3 N- (1-Methyl-2-nitroxyethyl) acetamide (Exemplary Compound No. 1-12)
1.00 g of 1-methyl-2-nitroxyethylamine hydrochloride was suspended in 50 ml of anhydrous dichloromethane, 1.55 ml of pyridine and 0.73 ml of acetic anhydride were added under ice-cooling and stirring, and the mixture was stirred at room temperature for 1 hour and 10 minutes. After stirring,
0.73 ml of acetic anhydride and a catalytic amount of 4-N, N-dimethylaminopyridine were added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 1).
And 950 mg of the target compound were obtained as a pale yellow oil. NMR spectrum (CDCl ₃ ) δppm: 1.26
(3H, d, J = 7Hz), 2.00 (3H, s), 4.30-4.60 (3H, m), 5.60
(1H, bs).

Production Example 4 2-Amino-1,3-dinitroxypropane hydrochloride (Exemplary Compound No. 1-9) (a) 2-
t-Butoxycarbonylamino-1,3-propanediol 3.0 g of 2-amino-1,3-propanediol are dissolved in a solution of 20 ml of dichloromethane and 10 ml of methanol, and 9.3 ml of di-tert- Butyl-
Di-carbonate was added and stirred at room temperature for 3 hours. After leaving overnight, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain a colorless oil. This was crystallized from hexane, and the crystals were collected by filtration to obtain 5.99 g of the desired compound as colorless crystals. Melting point: 81-83 [deg.] C. NMR spectrum (CDCl ₃ ) δppm: 1.45 (9H, s), 3.05 (2H, t, J = 5Hz), 3.
60-3.88 (5H, m), 5.30 (1H, d, J = 7Hz). (B) 2-t-butoxycarbonylamino-1,3-propanediol 1.27 g of 2,4,6-collidine was dissolved in 20 ml of anhydrous acetonitrile, and the mixture was stirred under ice-cooling and stirring in a nitrogen stream.
1.40 g of nitronium tetrafluoroboron was added and stirred at the same temperature for 30 minutes. 1.00 g of the compound of Production Example 4 (a) was added to the above solution, and the mixture was stirred at room temperature for 3 hours.
The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 4/1) to obtain 0.90 g of the desired compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.
46 (9H, s), 4.25-4.40 (1H, m), 4.57 (4H, d, J = 5.3Hz), 4.8
8 (1H, bs). (C) 2-amino-1,3-dinitroxypropane hydrochloride (Exemplary Compound No. 1-9) Production Example 4
0.90 g of the compound (b) was added to 9 ml of 4N-hydrogen chloride-
It was dissolved in a dioxane solution and stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and washed with ether to give 0.53 g of the desired compound as colorless plate crystals. Melting point: 136-
137 ° C (decomposition). NMR spectrum (d ₆ -DMSO) δppm:
3.90-4.05 (1H, m), 4.77 (2H, dd, J = 6Hz, J = 12Hz), 4.87 (2H
H, dd, J = 4Hz, J = 12Hz), 8.84 (3H, bs).

Production Example 5 (4R) -N- (1,1-ethylene-2-nitroxyethyl) -2-oxothiazolidine-4-yl-carboxamide (Exemplified Compound No. 1-3)
2) 260 mg of (4R) -2-oxothiazolidine-
4-Carboxylic acid was suspended in 5 ml of anhydrous benzene,
3 ml of oxalic acid chloride and 2-3 drops of dimethylformamide were added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, benzene was further added, and the mixture was azeotropically dried to obtain a light yellow oily acid chloride. On the other hand, 250 mg of N-
(1,1-Cyclopropylidene-2-nitroxyethyl) amine hydrochloride was suspended in anhydrous dichloromethane (10 ml), and under ice-cooling and stirring, 0.62 ml of triethylamine and a solution of the above acid chloride in dichloromethane (5 ml) were added.
The mixture was stirred for 3 hours under ice cooling. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain pale yellow crystals. This was washed with ethyl acetate to obtain 88.4 mg of the desired compound as colorless crystals. Melting point: 140-141 [deg.] C (decomposition). NMR
Spectrum (CDCl ₃ ) δppm: 1.02 (4H, s), 3.59 (1H, dd,
J = 5Hz, J = 11Hz), 3.78 (1H, dd, J = 9Hz, J = 11Hz), 4.30-4.42
(1H, m), 4.59 (2H, s), 7.20 (1H, s), 7.57 (1H, s).

Production Example 6 (4R) -N- (1,3-dinitroxy-2-propyl) -2-oxothiazolidine-4
-Yl-carboxamide (Exemplified Compound No. 1-36) 3
20 mg of (4R) -2-oxothiazolidine-4-carboxylic acid was suspended in 7 ml of anhydrous benzene, and 0.40 ml
Of oxalic acid chloride and 2-3 drops of dimethylformamide were added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and benzene was added to the residue to obtain an acid chloride as a pale yellow oil. On the other hand, 400 mg of 2-amino-
1,3-Dinitroxypropane hydrochloride was suspended in 10 ml of anhydrous dichloromethane, and 0.80 ml of triethylamine and a solution of the above acid chloride in 5 ml of dichloromethane were added under ice-cooling and stirring, followed by stirring for 1 hour under ice-cooling. Under reduced pressure,
The solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 3 /
Separation and purification in 1) gave pale yellow crystals. This was recrystallized from dichloromethane to obtain 140 mg of the desired compound as colorless crystals. Melting point: 111-113 ° C (decomposition). NMR spectrum (d ₆ -DMSO) δppm: 3.25-3.35 (1H, m), 3.70 (1H, d
d, J = 9Hz, J = 11Hz), 4.27-4.33 (1H, m), 4.45-4.75 (5H, m),
8.31 (1H, s), 8.50 (1H, d, J = 8Hz).

Production Example 7 (1S) -1-methyl-2-nitroxyethylamine hydrochloride (Exemplified Compound Nos. 1-2, 3
-1) (a) (1S) -N- (t-butoxycarbonyl) -1-methyl-2-nitroxyethylamine
200 ml of 9 g of nitronium tetrafluoroboron
And suspended in anhydrous acetonitrile in a nitrogen stream at 17.5.
ml of 2,4,6-collidine at -5 ° C to 0 ° C,
Stir for 30 minutes. 10.70 g of Nt-butoxycarbonyl-L-alaninol was added to the above solution, and
Stirred for 20 minutes. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the insoluble material was filtered off, and the solvent was distilled off. The obtained residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 9/1) to obtain 7.12 g of the desired compound as a colorless oil. NM
R spectrum (CDCl ₃ ) δppm: 1.23 (3H, d, J = 7.3Hz),
1.45 (9H, s), 3.90-4.15 (1H, m), 4.27-4.75 (3H, m).
(B) (1S) -1-methyl-2-nitroxyethylamine hydrochloride (Exemplified Compound No. 1-2, 3-1) 4.52
g of (1S) -N- (t-butoxycarbonyl) -1-
80 ml of 4N methyl-2-nitroxyethylamine
Dissolved in hydrogen chloride-dioxane solution, and
Stirred for 0 minutes. 160 ml of ether was added, and the precipitated crystals were collected by filtration and washed with ether to give 3.02 g of the desired compound as colorless crystals. Melting point: 134-135 [deg.] C. NMR spectrum (CDCl ₃ + d ₆ -DMSO) δ ppm: 1.47 (3H, d, J = 6.6H
z), 3.55-3.70 (1H, m), 4.65-4.80 (2H, m).

Production Example 8 (1R) -1-Methyl-2-nitroxyethylamine hydrochloride (Exemplary Compound No. 1-2)
(A) (1R) -N- (t-butoxycarbonyl) -1
-Methyl-2-nitroxyethylamine 13.09 g of nitronium tetrafluoroboron and 7.72 g of N
Using -t-butoxycarbonyl-D-alaninol,
8.55 g of the target compound was obtained as a colorless oil in the same manner as in Production Example 7 (a). NMR spectrum (CDCl ₃ ) δppm
: 1.23 (3H, d, J = 7.3Hz), 1.45 (9H, s), 3.95-4.15 (1H,
m), 4.28-4.75 (3H, m). (B) (1R) -1-methyl-
2-nitroxyethylamine hydrochloride (Exemplary Compound No. 1
-2) As in Production Example 7 (b), using 8.55 g of (1R) -N- (t-butoxycarbonyl) -1-methyl-2-nitroxyethylamine and 90 ml of a 4N hydrogen chloride-dioxane solution. As a result, 1.60 g of the target compound was obtained as colorless crystals. Melting point: 133-135 [deg.] C. NMR spectrum (CDCl ₃ + d ₆ -DMSO) δppm: 1.47 (3H, d, J = 6.9Hz),
3.55-3.70 (1H, m), 4.65-4.78 (2H, m).

Production Example 9 (1S) -1-ethyl-2-nitroxyethylamine hydrochloride (Exemplified Compound No. 1-64,
3-2) (a) (1S) -N- (t-butoxycarbonyl) -1-ethyl-2-nitroxyethylamine 4.0
0 g of nitronium tetrafluoroboron and 4.03 g
Production Example 7 using (1S) -N- (t-butoxycarbonyl) -1-ethyl-2-hydroxyethylamine
In the same manner as in (a), 3.19 g of the target compound was obtained as a pale yellow oil. NMR spectrum (CDCl ₃ ) δppm:
0.98 (3H, t, J = 7.3Hz), 1.40-1.70 (2H, m), 1.45 (9H, s),
3.70-3.95 (1H, m), 4.20-4.70 (3H, m). (B) (1S)-
3.19 g of 1-ethyl-2-nitroxyethylamine hydrochloride (Exemplified Compound No. 1-64, 3-2) (1S)-
Using N- (t-butoxycarbonyl) -1-ethyl-2-nitroxyethylamine and 50 ml of 4N hydrochloric acid-dioxane, 2.10 g of the desired compound were obtained as colorless crystals in the same manner as in Production Example 7 (b). Was. Melting point: 121-1
23 ° C (decomposition). NMR spectrum (d ₆ -DMSO) δppm
: 0.96 (3H, t, J = 7.2Hz), 1.50-1.80 (2H, m), 3.35-3.50
(1H, m), 4.66 (1H, dd, J = 6.6Hz, J = 11.9Hz), 4.81 (1H, dd, J
= 4.0Hz, J = 11.9Hz), 8.49 (3H, bs).

Production Example 10 (1S) -1-propyl-2-
Nitroxyethylamine hydrochloride (Exemplary Compound No. 1-6
5,3-3) (a) (1S) -N- (t-butoxycarbonyl) -1-propyl-2-nitroxyethylamine 8.60 g of nitronium tetrafluoroboron and 7.
49 g of (1S) -N- (t-butoxycarbonyl)-
Using 1-propyl-2-hydroxyethylamine,
In the same manner as in Production Example 7 (a), 3.03 g of the target compound was obtained as colorless crystals. Melting point: 57-58 [deg.] C. NMR spectrum (CDCl ₃ ) δppm: 0.95 (3H, t, J = 7.0Hz), 1.25-
1.70 (4H, m), 1.45 (9H, s), 3.80-4.05 (1H, m), 4.20-4.70
(3H, m). (B) (1S) -1-propyl-2-nitroxyethylamine hydrochloride (Exemplary Compound No. 1-65, 3-
3) Production Example 7 using 4.00 g of (1S) -N- (t-butoxycarbonyl) -1-propyl-2-nitroxyethylamine and 40 ml of 4N hydrochloric acid-dioxane.
In the same manner as in (b), 2.77 g of the target compound was obtained as colorless crystals. Melting point: 157-158 [deg.] C (decomposition). NMR
Spectrum (d ₆ -DMSO) δppm: 0.89 (3H, t, J = 7.2Hz),
1.30-1.70 (4H, m), 3.40-3.55 (1H, m), 4.65 (1H, dd, J = 6.
8Hz, J = 11.9Hz), 4.81 (1H, dd, J = 3.4Hz, J = 11.9Hz), 8.51
(3H, bs).

Production Example 11 (1S) -1-butyl-2-nitroxyethylamine hydrochloride (Exemplified Compound No. 1-6)
7,3-5) (a) (1S) -N- (t-butoxycarbonyl) -1-butyl-2-nitroxyethylamine 1.87 g of nitronium tetrafluoroboron and
09 g of (1S) -N- (t-butoxycarbonyl)-
Using 1-butyl-2-hydroxyethylamine, 1.56 g of the desired compound was obtained as a yellow oil in the same manner as in Production Example 7 (a). NMR spectrum (CDCl ₃ ) δpp
m: 0.91 (3H, t, J = 7.3Hz), 1.25-1.65 (6H, m), 1.45 (9H,
s), 3.83-3.98 (1H, m), 4.30-4.60 (3H, m). (B) (1
1.56 g of (S) -1-butyl-2-nitroxyethylamine hydrochloride (Exemplified Compound No. 1-67, 3-5)
S) -N- (t-butoxycarbonyl) -1-butyl-
Using 2-nitroxyethylamine and 15 ml of 4N hydrochloric acid-dioxane, 702 mg of the desired compound were obtained as colorless crystals in the same manner as in Production Example 7 (b). Melting point: 13
3-135 ° C (decomposition). NMR spectrum (CDCl ₃ ) δ
ppm ： 0.94 (3H, t, J = 7.3Hz), 1.20-2.00 (6H, m), 3.55-
3.70 (1H, m), 4.65-4.85 (2H, m).

Production Example 12 (1S) -1-isopropyl-
2-nitroxyethylamine hydrochloride (Exemplary Compound No. 1
-66, 3-4) (a) (1S) -N- (t-butoxycarbonyl) -1-isopropyl-2-nitroxyethylamine 3.19 g of nitronium tetrafluoroboron and 3.31 g of (1S)- Using N- (t-butoxycarbonyl) -1-isopropyl-2-hydroxyethylamine, and in the same manner as in Production Example 7 (a), 3.07 g of the desired compound was obtained as a yellow oil. NMR spectrum
(CDCl ₃ ) δppm: 0.97 (3H, d, J = 5.9Hz), 0.99 (3H, d, J
= 6.6Hz), 1.45 (9H, s), 3.65-3.80 (1H, m), 4.35-4.63 (3
H, m). (B) (1S) -1-isopropyl-2-nitroxyethylamine hydrochloride (Exemplary Compound No. 1-66,
3-4) Using 3.07 g of (1S) -N- (t-butoxycarbonyl) -1-isopropyl-2-nitroxyethylamine and 30 ml of 4N hydrochloric acid-dioxane,
In the same manner as in Production Example 7 (b), 1.97 g of the target compound was obtained as colorless crystals.

Melting point: 174-175 ° C. (decomposition). NMR
Spectrum (CDCl ₃ ) δppm: 1.14 (3H, d, J = 7.3Hz),
1.17 (3H, d, J = 6.6Hz), 2.10-2.30 (1H, m), 3.40-3.52 (1H,
m), 4.70-4.90 (2H, m).

Production Example 13 (1S) -1-isobutyl-2
-Nitroxyethylamine hydrochloride (Exemplary Compound No. 1-
68, 3-6) (a) (1S) -N- (t-butoxycarbonyl) -1-isobutyl-2-nitroxyethylamine 3.91 g of nitronium tetrafluoroboron and 4.35 g of (1S) -N Using-(t-butoxycarbonyl) -1-isobutyl-2-hydroxyethylamine in the same manner as in Production Example 7 (a), the target compound 3.
84 g were obtained as a yellow oil. NMR spectrum (CD
Cl ₃ ) δppm: 0.93 (3H, d, J = 4.6Hz), 0.95 (3H, d, J = 4.6Hz)
Hz), 1.20-1.50 (2H, m), 1.45 (9H, s), 1.60-1.80 (1H, m),
3.90-4.10 (1H, m), 4.25-4.65 (3H, m). (B) (1S)
3.84 g of -1-isobutyl-2-nitroxyethylamine hydrochloride (Exemplary Compound No. 1-66, 3-6) (1
S) -N- (t-butoxycarbonyl) -1-isobutyl-2-nitroxyethylamine and 40 ml of 4N hydrochloric acid-dioxane were used to give 2.32 g of the target compound in the same manner as in Production Example 7 (b). Obtained as crystals. Melting point: 174-175 [deg.] C (decomposition). NMR spectrum (CD
Cl ₃ ) δppm: 0.93-1.10 (6H, m), 1.50-1.70 (1H, m), 1.
72-2.00 (2H, m), 3.65-3.82 (1H, m), 4.63-4.85 (2H, m).

Reference Example 1 (4R) -4-nitroxymethyl-2-oxothiazolidine 1.17 g of nitronium
Using tetrafluoroboron and 1.0 g of (4R) -2-oxo-4-hydroxymethylthiazolidine, 0.11 g of the target compound was obtained as a colorless oil in the same manner as in Production Example 7 (a). NMR spectrum (CDCl ₃ ) δppm: 3.2
2 (1H, dd, J = 4.6Hz, 11.6Hz), 3.64 (1H, dd, J = 7.7Hz, 11.7
Hz), 4.10-4.28 (1H, m), 4.45-4.65 (2H, m), 6.21 (1H, b
s).

Test Example 1 Collateral Vasodilator Action by Intravenous Administration A beagle dog (male) weighing 9-13 kg was anesthetized by intravenous injection of pentobarbital 30 mg / Kg, and the experiment was performed under artificial respiration. To measure the left carotid artery pressure, a polyethylene cannula (atom vein catheter) was placed on one branch of the left thyroid artery.
Tell 2F) was inserted retrograde. The left carotid artery upstream of the pressure measurement site was occluded with arterial clement for one minute, and the pressure immediately before occlusion (P) and the decrease in peripheral pressure (ΔP) were measured. Next, the test drug was administered from a polyethylene cannula inserted into the crotch vein, and after 5, 15, 30, 45 and 60 minutes, the left carotid artery was again occluded for 1 minute, and the pressure (P,) immediately before the occlusion at this time.
And the decrease in peripheral pressure (ΔP,) were measured. The collateral vasodilator effect (CollateralIndex = CI) of the test drug was determined by the following equation. CI = 100− (ΔP, / P,) × 100 /
(ΔP / P) collateral vasodilatory action for 60 minutes (Collatera
l Index = CI ₆₀ ) is shown in Table 4 below.

[0118]

[Table 4] 例 示 Exemplified compound dose (mg / kg iv) CI ₆₀ (Area value) No. ──────────────────────────────────── 1-1 0.1 29 1 -2 (racemic) 0.1 10 1-2 (R-isomer) 0.1 5.3 1-2 (S-isomer) = 3-1 0.114 1-3 0.116 1-5 0. 1 14 1-9 0.1 14 --------------------------------------------------- Compound A 0.1 0.3 ──────────────────────────────────.

Formulation Example 1 Tablet Compounds having the following formulation were mixed, and one tablet was obtained by direct tableting.
A tablet of 100 mg, tablet diameter 6.5 mm is obtained. ───────────────────────────── Compound parts by weight ──────────────────化合物 Compound of Exemplified Compound No. 3-1 5 Lactose 68.5 Crystalline cellulose 20 Sodium carboxymethyl starch 5 Light silicic anhydride 0.5 Magnesium stearate 1 ─────────── ──────────────────.

[0120]

The compounds (I) and (I) which are the active ingredients of the present invention
I) or (IIIa) or a pharmaceutically acceptable salt thereof or compound (II) or a pharmaceutically acceptable salt thereof,
According to tests using the collateral vasculature of the carotid artery in anesthetized dogs, it has strong collateral vasodilatory effects, is not affected by the first pass, has low toxicity, and has headaches, dizziness, tachycardia or digestive organs, liver, bones, etc. Since it has few side effects such as adverse effects of the compound, it is useful as a medicine, particularly as an agent for preventing or treating angina pectoris (preferably, a therapeutic agent).

 ──────────────────────────────────────────────────の Continued on the front page (72) Inventor Shigeki Miyake 1-258 Hiromachi, Shinagawa-ku, Tokyo Inside Sankyo Co., Ltd.

Claims (11)

[Claims] 1. A compound of the general formula (Wherein, R ¹ a represents a hydrogen atom or a C ₁ -C ₆ alkanoyl group, R ³ represents a C ₁ -C ₆ alkyl radical, n denotes 1 to 2) optically active with An agent for preventing or treating angina pectoris comprising a nitroxy derivative or a pharmacologically acceptable salt thereof as an active ingredient. Wherein the active ingredient is, R ¹ a is hydrogen atom or C ₁ -C ₅ angina prophylactic agent of claim 1 which is an optically active nitroxy derivative or a pharmacologically acceptable salt thereof alkanoyl group Or a therapeutic agent. Wherein the active ingredient is, R ¹ a is hydrogen atom or C ₂ -C ₃ angina prophylactic agent of claim 1 which is an optically active nitroxy derivative or a pharmacologically acceptable salt thereof alkanoyl group Or a therapeutic agent. Wherein the active ingredient is, R ¹ a is, angina prophylactic or therapeutic agent according to claim 1 which is an optically active nitroxy derivative or a pharmacologically acceptable salt thereof is a hydrogen atom or an acetyl group. Wherein the active ingredient is, R ¹ a is, angina prophylactic or therapeutic agent according to claim 1 which is an optically active nitroxy derivative or a pharmacologically acceptable salt thereof is a hydrogen atom. 6. The preventive or therapeutic agent for angina pectoris according to claim 1, wherein the active ingredient is an optically active nitroxy derivative wherein R ³ is a C ₁ -C ₄ alkyl group or a pharmacologically acceptable salt thereof. Agent. 7. The method according to claim 1, wherein the active ingredient is an optically active nitroxy derivative wherein R ³ is a methyl, ethyl, propyl, isopropyl, butyl or isobutyl group, or a pharmaceutically acceptable salt thereof. Preventive or therapeutic agent for the disease. 8. An agent for preventing angina according to claim 1, wherein the active ingredient is an optically active nitroxy derivative wherein R ³ is a methyl, propyl, butyl or isobutyl group or a pharmacologically acceptable salt thereof. Therapeutic agent. 9. The agent for preventing or treating angina according to claim 1, wherein the active ingredient is an optically active nitroxy derivative wherein R ³ is a methyl group or a pharmacologically acceptable salt thereof. 10. The prophylactic or therapeutic agent for angina according to claim 1, wherein the active ingredient is an optically active nitroxy derivative wherein n is 1 or a pharmacologically acceptable salt thereof. (11) (1S) -1-methyl-2-nitroxyethylamine or a pharmaceutically acceptable salt thereof, (1S) -1-propyl-2-nitroxyethylamine or a pharmaceutically acceptable salt thereof, Angina pectoris containing 1S) -1-butyl-2-nitroxyethylamine or a pharmaceutically acceptable salt thereof or (1S) -1-isobutyl-2-nitroxyethylamine or a pharmaceutically acceptable salt thereof as an active ingredient Prophylactic or therapeutic agent.