JPH1171279A - Preventing or treating agent for angina pectoris containing thiazolidines as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a preventing or treating agent for angina pectoris, having excellent and continuous collateral vasodilation action and hardly causing adverse reaction by including thiazolidines having a substituent group specific to nitrogen atom on a ring as active ingredients. SOLUTION: This preventing agent or treating agent for angina pectoris comprises thiazolidines of the formula [X is methylene, O or S; R<1> is a 2-8C alkanoyl having a substituent group which consists essentially of a group of the formula, S-R<2> (R<2> is H or a 1-6C aliphatic acyl); A is a 1-8C alkylene or the like] [e.g. 1-(3-mercato-2-methylpropionyl)-L-proline-N-(1-methyl-2- nitroxyethyl)amide] as an active ingredient. The agent is administered at a daily dose of 1 mg/adult as lower limit and 1,000 mg/adult as upper limit in the case of oral administration and 0.1 mg/adult as lower limit and 1,000/adult mg as upper limit in the case of intravenous injection once to 6 times according to the symptom.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a preventive or therapeutic agent for angina pectoris containing a thiazolidine or a pharmacologically acceptable salt thereof as an active ingredient.

[0002]

2. Description of the Related Art At present, nitroglycerin is most frequently used clinically as a therapeutic agent 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, tachycardia due to a decrease in blood pressure, and the like appear. Under these circumstances, a therapeutic agent for angina pectoris that is not clinically affected by the first-pass effect and is persistent has been desired. Further, in the formula _{P-CONH-Q-ONO 2} ( wherein, P is a piperidine ring, pyrrolidinone ring, thiazolidine ring, indicates thiazolidinone ring and, Q is shown an ethylene group, 1-methylene-4-cyclohexylene group. ) Has the heart,
It is known that it is effective for the prevention and treatment of circulatory diseases such as angina pectoris (see, for example, JP-A-2-1695).
Japanese Patent Publication No. 70, Japanese Patent Publication No. 5-504353, Japanese Patent Publication No.
-500318, JP-A-5-213910, etc.).

[0003]

SUMMARY OF THE INVENTION The inventors of the present invention have conducted intensive studies on the synthesis of a series of thiazolidines and their pharmacological effects over many years, and have found that they have a specific substituent at the nitrogen atom on the ring. Thiazolidines such as pyrrolidine, oxazolidine and thiazolidine have excellent collateral vasodilatory effects, their effects are long-lasting and have few side effects, and they are used as therapeutic or preventive agents for angina pectoris (preferably as therapeutic agents). ) Was found to be useful, and the present invention was completed.

[0004]

The thiazolidine which is an active ingredient of the present invention has a general formula:

[0005]

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[0006]

In the above formula, X represents a methylene group, an oxygen atom or a sulfur atom, and R ¹ represents a substituted C ₂ -C _8.
Alkanoyl group [the substituent, the essential thing, in the formula -S-R ² (wherein, R ² is a hydrogen atom; C ₁ -C ₆ aliphatic acyl group; C ₂ -C ₇ alkoxycarbonyl group; C ₁ -C ₆
A C ₇ -C ₁₁ arylcarbonyl group which may be substituted by alkyl, C ₁ -C ₆ alkoxy or halogen;
₁ -C ₆ alkyl may be substituted by C ₁ -C ₆ alkoxy or halogen, nitrogen atom, 5 to contain 1 to 3 heteroatoms selected from the heteroatom group consisting of oxygen atom and sulfur atom It represents a 6-membered aromatic heterocyclic carbonyl group. ), And as desired, an amino group, a mono- or di-C ₁ -C ₆ alkylamino group, a protected amino group or a protected mono-C ₁ -C ₆ alkylamino group . Indicates], A is C ₁ -C ₈ in the alkylene radical or formula -B-D-E- (wherein, B and E are the same or different and each represents a single bond or a C ₁ -C ₆ alkylene group,
D represents a C ₃ -C ₆ cycloalkylene group which may be substituted with a C ₁ -C ₆ alkyl. ) Is shown.

In the above, the alkanoyl portion of the “C ₂ -C ₈ alkanoyl group having a substituent” in the definition of R ¹ is a C ₁ -C ₇ alkyl group (a linear C ₁ -C ₇ group). Or a branched alkyl group, for example, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl,
1-ethylpropyl, hexyl, 4-methylpentyl,
3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl or 4,4-dimethylpentyl group It is. ) Represents a group having a carbonyl group bonded thereto, for example, acetyl, propionyl, butyryl, isobutyryl, 2-methylbutyryl, 3-methylbutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, isohexanoyl, 3-methylvaleryl, 3,3-dimethyl Butyryl, 2-ethylbutyryl, heptanoyl, 5-methylhexanoyl, 4-
Methylhexanoyl, 3-methylhexanoyl, 2-methylhexanoyl, 4,4-dimethylvaleryl, 3,3
-Dimethylvaleryl, 2,2-dimethylvaleryl, 2,
3-dimethylvaleryl, 2,4-dimethylvaleryl,
3,4-dimethylvaleryl, 3-ethylvaleryl, octanoyl, 2-methylheptanoyl, 3-methylheptanoyl, 4-methylheptanoyl, 5-methylheptanoyl, 6-methylheptanoyl, 2-propylvaleryl, 5,5 can be a dimethyl-hexanoyl group, preferably a C ₂ -C ₆ alkanoyl groups, more preferably,
A C ₂ -C ₄ alkanoyl group, even more preferably,
A C ₃ -C ₄ alkanoyl group, particularly preferably a propionyl or isobutyryl group.

[0009] The above At a, in the definition of R ² 'C ₁ -
“C ₆ aliphatic acyl group” refers to a group in which a carbonyl group is bonded to a hydrogen atom or a saturated or unsaturated C ₁ -C ₅ chain hydrocarbon group, and includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl , Isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl, crotonoyl groups, preferably C _1-
C ₆ alkanoyl, more preferably C ₁ -C ₄
It is an alkanoyl group, even more preferably an acetyl or propionyl group, and particularly preferably an acetyl group.

[0010] The above-mentioned At a, in the definition of R ² "C ₂ -
The “C ₇ alkoxycarbonyl group” is a C ₁ -C ₆ alkoxy group (of the C ₁ -C ₇ alkyl groups, a linear or branched alkyl group having 1 to 6 carbon atoms is bonded to an oxygen atom. Represents a group having a carbonyl group bonded thereto, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s
-Butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl,
Hexyloxycarbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1
-Dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl group,
Preferably, it is a C ₂ -C ₅ alkoxycarbonyl group,
More preferably, C ₂ -C ₃ alkoxycarbonyl or t
-Butoxycarbonyl group, particularly preferably a methoxycarbonyl group.

In the above, the aryl group of the "optionally substituted C ₇ -C ₁₁ arylcarbonyl group" in the definition of R ²
The carbonyl portion is a C ₆ -C ₁₀ aryl group (having 6 carbon atoms).
It represents from 10 to 10 aromatic hydrocarbons, which may be, for example, phenyl, indenyl, naphthyl, preferably a phenyl group. ) Indicates a group having a carbonyl group bonded thereto, and may be, for example, benzoyl, indanecarbonyl, naphthoyl, and preferably a benzoyl group. The substituent (preferably 1 to 3, particularly preferably 1) is, for example, the above-mentioned C ₁ -C ₆ alkyl group, C ₁
It may be a —C ₆ alkoxy group (showing a group obtained by removing a carbonyl group from the C ₂ -C ₇ alkoxycarbonyl group) or a halogen atom (for example, fluorine, chlorine, bromine or iodine). , C ₁ -C ₂ alkyl, C ₁
-C ₂ alkoxy, fluorine or chlorine.

In the above description, the definition of R ² may be “substituted and containing 5 to 3 heteroatoms selected from the group consisting of heteroatoms consisting of nitrogen, oxygen and sulfur. "6-membered aromatic heterocyclic carbonyl group" refers to a group in which a carbonyl group is bonded to a 5- or 6-membered aromatic heterocyclic ring, for example, furylcarbonyl, thienylcarbonyl,
Pyrrolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl, pyridylcarbonyl, pyridazinylcarbonyl, pyrimidinylcarbonyl group, preferably , Furylcarbonyl, thienylcarbonyl or pyridylcarbonyl group. In addition, the substituent (preferably 1 to 3, particularly preferably 1) is, for example, the C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkoxy group, It may be a halogen atom, preferably methyl, methoxy, fluorine or chlorine, particularly preferably methyl or chlorine.

In the above, C ₂ -C in the definition of R ²
₈ mono or di-C ₁ -C ₆ alkylamino group as a desired substituent of the alkanoyl group refers to a group in which one or two C ₁ -C ₆ alkyl groups are bonded to an amino group, for example, A methylamino, ethylamino, propylamino, butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino group, It is preferably a mono- or di-C ₁ -C ₄ alkylamino group, more preferably a methylamino, ethylamino, dimethylamino or methylethylamino group, particularly preferably a methylamino group. . Where t−
The t-butyl group of the butylamino group is also used as a protecting group for the amino group.

In the above, "protected amino group" and "protected mono-C ₁ -C ₆ alkylamino group" in the definition of R ¹ are well known in the field of synthetic organic chemistry. It is not particularly limited as long as it is known, for example,
Wherein C ₁ -C ₆ aliphatic acyl group, the C ₂ -C ₇ alkoxycarbonyl group, wherein ^{_{-SiR 3 a R 3 b R 3}} c ( wherein, R ³ _a,
R ³ _b and R ³ _c are the same or different, wherein the C ₁ -C ₆ alkyl group or a C ₆ -C ₁₀ ants - shows Le group. ) Group having from 1 to 3 of the C ₆ -C ₁₀ ants - Le substituted methyl group by group, the C ₆ -C ₁₀ ants - be a Le substituted methoxycarbonyl group group, preferably Is C ₁ -C
₄ alkanoyl group, C ₁ -C ₄ alkoxycarbonyl group, tri-C ₁ -C ₂ alkylsilyl group, t-butyldimethylsilyl group, phenyldimethylsilyl group, benzyl group which may be substituted, Is the same or different and is a C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, fluorine or chlorine.) Or a benzyloxycarbonyl group which may be substituted (when the substituent is plural, Have the same or different meanings of C ₁ -C ₂ alkyl, C _1-
C ₂ alkoxy, fluorine or chlorine. And more preferably a C ₁ -C ₄ alkanoyl group, a C ₁ -C ₄ alkoxycarbonyl group, a t-butyldimethylsilyl group, a phenyldimethylsilyl group, a methoxybenzyl group or a methoxybenzyloxycarbonyl group; Even more preferably, a C ₁ -C ₄ alkanoyl group or a C ₁ -C ₄ alkoxycarbonyl group, still more preferably also, C ₁ -C
_{2 It is an} alkanoyl group or a t-butoxycarbonyl group, particularly preferably an acetyl or t-butoxycarbonyl group.

In the above, specific examples of the "C ₂ -C ₈ alkanoyl group having a substituent" in the definition of R ¹ include, for example, mercaptoacetyl, 2-mercapto-2-methylacetyl, 3-mercapto Propionyl, 3-mercapto-2-methylpropionyl, 3-mercapto-3-methylpropionyl, 3-mercapto-2-ethylpropionyl, 4-mercaptobutyryl, 4-mercapto-2
-Methylbutyryl, 4-mercapto-3-methylbutyryl, 4-mercapto-4-methylbutyryl, 5-mercaptovaleryl, 5-mercapto-2-methylvaleryl,
6-mercaptohexanoyl, 2-amino-3-mercaptopropionyl, 2-amino-4-mercaptobutyryl, 3-amino-4-mercaptobutyryl, 2-amino-5-mercaptovaleryl, 2-amino-6 -Mercaptohexanoyl, 2-acetylamino-3-mercaptopropionyl, 2-acetylamino-4-mercaptobutyryl, 3-acetylamino-4-mercaptobutyryl, 2-t-butoxycarbonylamino-3-mercaptopropionyl, 2-t-butoxycarbonylamino-
4-mercaptobutyryl, 3-t-butoxycarbonylamino-4-mercaptobutyryl, 2-methylamino-
3-mercaptopropionyl, 2-ethylamino-3-
Mercaptopropionyl, 2-ethylamino-4-mercaptobutyryl, 2-dimethylamino-3-mercaptopropionyl, acetylthioacetyl, 2-acetylthio-2-methylacetyl, 3-acetylthiopropionyl, 2-acetylthio-2-ethyl Acetyl, 3-acetylthio-2-methylpropionyl, 3-acetylthio-3-methylpropionyl, 4-acetylthiobutyryl, 4-acetylthio-2-methylbutyryl, 4-acetylthio-3-methylbutyryl, 4-acetylthio-4
-Methylbutyryl, 5-acetylthiovaleryl, 5-acetylthio-2-methylvaleryl, 6-acetylthiohexanoyl, 3-acetylthio-2-aminopropionyl, 4-acetylthio-2-aminobutyryl, 4-acetylthio-3-aminobutyryl, 5-acetylthio-2
-Aminovaleryl, 6-acetylthio-2-aminohexanoyl, 2-acetylamino-3-acetylthiopropionyl, 2-acetylamino-4-acetylthiobutyryl, 3-acetylamino-4-acetylthiobutyryl, 3- Acetylthio-2-t-butoxycarbonylaminopropionyl, 4-acetylthio-2-t-butoxycarbonylaminobutyryl, 4-acetylthio-3-
t-butoxycarbonylaminobutyryl, 3-acetylthio-2-methylaminopropionyl, 3-acetylthio-2-ethylaminopropionyl, 3-acetylthio-2-dimethylaminopropionyl, propionylthioacetyl, 2-methyl-2-propionylthio Acetyl, 3-propionylthiopropionyl, 2-methyl-
3-propionylthiopropionyl, 3-methyl-3-
Propionylthiopropionyl, 4-propionylthiobutyryl, 2-methyl-4-propionylthiobutyryl, 3-methyl-4-propionylthiobutyryl, 4-
Methyl-4-propionylthiobutyryl, 2-amino-
3-propionylthiopropionyl, 2-amino-4-
Propionylthiobutyryl, 3-amino-4-propionylthiobutyryl, 2-acetylamino-3-propionylthiopropionyl, 2-acetylamino-4-propionylthiobutyryl, 3-acetylamino-4-propionylthiobutyryl 2-t-butoxycarbonylamino-3-propionylthiopropionyl, 2-t-butoxycarbonylamino-4-propionylthiobutyryl, 3-t-butoxycarbonylamino-4-propionylthiobutyryl, 2-methylamino- 3-propionylthiopropionyl, 2-ethylamino-3-propionylthiopropionyl, 2-dimethylamino-3-propionylthiopropionyl, methoxycarbonylthioacetyl, 2-methoxycarbonylthio-2-methylacetyl, 3-methoxy Carbonyl thio propionyl, 2-
Methyl-3-methoxycarbonylthiopropionyl, 3
-Methyl-3-methoxycarbonylthiopropionyl,
4-methoxycarbonylthiobutyryl, 2-methyl-4
-Methoxycarbonylthiobutyryl, 3-methyl-4-
Methoxycarbonylthiobutyryl, 4-methyl-4-methoxycarbonylthiobutyryl, 2-amino-3-methoxycarbonylthiopropionyl, 2-amino-4-methoxycarbonylthiobutyryl, 3-amino-4-methoxycarbonylthio Butyryl, 2-acetylamino-3
-Methoxycarbonylthiopropionyl, 2-acetylamino-4-methoxycarbonylthiobutyryl, 2-t
-Butoxycarbonylamino-3-methoxycarbonylthiopropionyl, 2-t-butoxycarbonylamino-4-methoxycarbonylthiobutyryl, 2-methylamino-3-methoxycarbonylthiopropionyl, 2-
Ethylamino-3-methoxycarbonylthiopropionyl, 2-dimethylamino-3-methoxycarbonylthiopropionyl, ethoxycarbonylthioacetyl, 2-
Ethoxycarbonylthio-2-methylacetyl, 3-ethoxycarbonylthiopropionyl, 3-ethoxycarbonylthio-2-methylpropionyl, 3-ethoxycarbonylthio-3-methylpropionyl, 4-ethoxycarbonylthiobutyryl, 4-ethoxycarbonyl Thio-2-methylbutyryl, 4-ethoxycarbonylthio-
3-methylbutyryl, 4-ethoxycarbonylthio-4
-Methylbutyryl, 2-amino-3-ethoxycarbonylthiobutionyl, 2-amino-4-ethoxycarbonylthiobutyryl, 3-amino-4-ethoxycarbonylthiobutyryl, 2-acetylamino-3-ethoxycarbonylthiopropionyl, 2-acetylamino-4-
Ethoxycarbonylthiobutyryl, 2-tert-butoxycarbonylamino-3-ethoxycarbonylthiopropionyl, 2-tert-butoxycarbonylamino-4-ethoxycarbonylthiobutyryl, 3-ethoxycarbonylthio-2-methylaminopropionyl, 3 -Ethoxycarbonylthio-2-ethylaminopropionyl, 2-dimethylamino-3-ethoxycarbonylthiopropionyl, t-butoxycarbonylthioacetyl, 2-t-butoxycarbonylthio-2-methylacetyl, 3-t-
Butoxycarbonylthiopropionyl, 3-t-butoxycarbonylthio-2-methylpropionyl, 3-t-
Butoxycarbonylthio-3-methylpropionyl, 4
-Tert-butoxycarbonylthiobutyryl, 4-tert-butoxycarbonylthio-2-methylbutyryl, 4-tert-butoxycarbonylthio-3-methylbutyryl, 4-tert-
Butoxycarbonylthio-4-methylbutyryl, 2-amino-3-t-butoxycarbonylthiopropionyl,
2-amino-4-t-butoxycarbonylthiobutyryl, 3-amino-4-t-butoxycarbonylthiobutyryl, 2-acetylamino-3-t-butoxycarbonylthiopropionyl, 2-acetylamino-4-t -Butoxycarbonylthiobutyryl, 2-t-butoxycarbonylamino-3-t-butoxycarbonylthiopropionyl, 2-t-butoxycarbonylamino-4-t-
Butoxycarbonylthiobutyryl, 3-t-butoxycarbonylthio-2-methylaminopropionyl, 2-t
-Butoxycarbonylmethylamino-3-t-butoxycarbonylthiopropionyl, 3-t-butoxycarbonylthio-2-ethylaminopropionyl, 2-t-butoxycarbonylethylamino-3-t-butoxycarbonylthiopropionyl, 2-dimethyl Amino-3-t
-Butoxycarbonylthiopropionyl, benzoylthioacetyl, 3-benzoylthio-2-methylpropionyl, 3-benzoylthio-3-methylpropionyl,
4-benzoylthiobutyryl, 4-benzoylthio-2
-Methylbutyryl, 4-benzoylthio-3-methylbutyryl, 4-benzoylthio-4-methylbutyryl, 2
-Amino-3-benzoylthiopropionyl, 2-amino-4-benzoylthiobutyryl, 3-amino-4-benzoylthiobutyryl, 2-acetylamino-3-benzoylthiopropionyl, 3-benzoylthio-2-t
-Butoxycarbonylaminopropionyl, 3-benzoylthio-2-methylaminopropionyl, 3-benzoylthio-2-ethylaminopropionyl, 3-benzoylthio-2-dimethylaminopropionyl, 2- or 3-thienylcarbonylthioacetyl, − (2-
Or 3-thienylcarbonylthio) propionyl,
2-methyl-3- (2- or 3-thienylcarbonylthio) propionyl, 3-methyl-3- (2- or 3-thienylcarbonylthio) propionyl, 2-amino-3- (2- or 3-thienylcarbonyl Thio) propionyl, 2-acetylamino-3- (2- or 3-thienylcarbonylthio) propionyl, 2
-T-butoxycarbonylamino-3- (2- or 3-thienylcarbonylthio) propionyl, 2-methylamino-3- (2- or 3-thienylcarbonylthio) propionyl, 2-ethylamino-3- (2- Or 3-thienylcarbonylthio) propionyl, 2
-Dimethylamino-3- (2- or 3-thienylcarbonylthio) propionyl, 2- or 3-furylthioacetyl, 3- (2- or 3-furylcarbonylthio) propionyl, 3- (2- or 3-furyl Carbonylthio) -2-methylpropionyl, 3- (2
-Or 3-furylcarbonylthio) -3-methylpropionyl, 2-amino-3- (2- or 3-furylcarbonylthio) propionyl, 2-acetylamino-3- (2- or 3-furylcarbonylthio) propionyl , 2-t-butoxycarbonylamino-3-
(2- or 3-furylcarbonylthio) propionyl, 3- (2- or 3-furylcarbonylthio)-
2-methylaminopropionyl, 2-ethylamino-3
-(2- or 3-furylcarbonylthio) propionyl, 2-dimethylamino-3- (2- or 3-furylcarbonylthio) propionyl, 2-, 3- or 4-pyridylcarbonylthioacetyl, 3- (2- ,
3- or 4-pyridylcarbonylthio) propionyl, 2-methyl-3- (2-, 3- or 4-pyridylcarbonylthio) propionyl, 3-methyl-3-
(2-, 3- or 4-pyridylcarbonylthio) propionyl, 2-amino-3- (2-, 3- or 4
-Pyridylcarbonylthio) propionyl, 2-acetylamino-3- (2-, 3- or 4-pyridylcarbonylthio) propionyl, 2-t-butoxycarbonylamino-3- (2-, 3- or 4-pyridylcarbonyl Thio) propionyl, 3- (2-, 3- or 4-pyridylcarbonylthio) -2-methylaminopropionyl, 3- (2-, 3- or 4-pyridylcarbonylthio) -2-ethylaminopropionyl, 2- It may be a dimethylamino-3- (2-, 3- or 4-pyridylcarbonylthio) propionyl group, preferably
2-mercaptoacetyl, 2-mercapto-2-methylacetyl, 3-mercaptopropionyl, 3-mercapto-2-methylpropionyl, 3-mercapto-3-methylpropionyl, 2-mercapto-2-ethylacetyl, 4-mercaptobutyi Ryl, 4-mercapto-2-methylbutyryl, 4-mercapto-3-methylbutyryl,
4-mercapto-4-methylbutyryl, 2-ethyl-3
-Mercaptopropionyl, 2-amino-3-mercaptopropionyl, 2-amino-4-mercaptobutyryl, 3-amino-4-mercaptobutyryl, 2-acetylamino-3-mercaptopropionyl, 2-acetylamino-4- Mercaptobutyryl, 3-acetylamino-4-mercaptobutyryl, 2-t-butoxycarbonylamino-3-mercaptopropionyl, 2-t-butoxycarbonylamino-4-mercaptobutyryl, 3-
t-butoxycarbonylamino-4-mercaptobutyryl, 3-mercapto-2-methylaminopropionyl,
2-acetylthioacetyl, 3-acetylthiopropionyl, 3-acetylthio-2-methylpropionyl, 3
-Acetylthio-3-methylpropionyl, 4-acetylthiobutyryl, 4-acetylthio-2-methylbutyryl, 2-acetylamino-3-acetylthiopyropionyl, 3-propionylthiopropionyl, 2-methyl-
3-propionylthiopropionyl, 3-methyl-3-
A propionylthiopropionyl, 4-propionylthiobutyryl or 2-methyl-3-methoxycarbonylthiopropionyl group, more preferably 3-mercaptopropionyl, 3-mercapto-2-methylpropionyl, 3-mercapto-3- Methylpropionyl, 4-mercaptobutyryl, 3-mercapto-2-ethylpropionyl, 2-amino-3-mercaptopropionyl, 2
-Acetylamino-3-mercaptopropionyl, 3-
Acetylthiopropionyl, 3-acetylthio-2-methylpropionyl, 3-acetylthio-3-methylpropionyl, 4-acetylthiobutyryl or 2-acetylamino-3-acetylthiopropionyl; Mercapto-2-methylpropionyl,
2-amino-3-mercaptopropionyl, 2-acetylamino-3-mercaptopropionyl, 3-acetylthio-2-methylpropionyl or 2-acetylamino-3-acetylthiopropionyl group.

In the above, “C ₁ -C” in the definition of A
" ₈ alkylene group" refers to a linear or branched alkylene group having 1 to 8 carbon atoms, for example, methylene, methylmethylene, ethylene, propylene, trimethylene, methylethylene, ethylethylene, tetramethylene, 1-methyltrimethylene group. Methylene, 2-methyltrimethylene, 3-methyltrimethylene, 1-methylpropylene, 1,1-dimethylethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4-methyl Tetramethylene, propylethylene,
1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene, 1-methylpentamethylene, 2-methylpentamethylene, 3-methylpentamethylene, 4-methylpentamethylene , 5-methylpentamethylene, 1,1-dimethyltetramethylene, 2,2-dimethyltetramethylene,
3,3-dimethyltetramethylene, 4,4-dimethyltetramethylene, butylethylene, isobutylethylene,
Heptamethylene, 1-methylhexamethylene, 2-methylhexamethylene, 5-methylhexamethylene, 3-ethylpentamethylene, octamethylene, 2-methylheptamethylene, 5-methylheptamethylene, 2-ethylhexamethylene, 2- Ethylmethylpentamethylene, 3-
Obtained is ethyl-2-methyl pentamethylene or tetra ethylene group, preferably a C ₂ -C ₆ alkylene group, more preferably, ethylene, methylethylene, trimethylene, ethylethylene, tetraethylene, propyl ethylene, Butylethylene or isobutylethylene group, even more preferably ethylene, methylethylene,
It is a propylethylene, butylethylene or isobutylethylene group, particularly preferably a methylethylene group.

In the above, “C” in the definitions of B and E
₁ -C ₆ alkylene group "is a said C ₁ -C ₈ In the alkylene group of 1 to 6 carbon atoms straight or branched chain alkylene group, in B, and preferably, C ₁ -C ₄ alkylene group, more preferably methylene or ethylene group, particularly preferably methylene group, and in E, preferably C ₁ -C ₄ alkylene group, more preferably , A methylene, ethylene, trimethylene or tetramethylene group, still more preferably a methylene or ethylene group, and particularly preferably a methylene group.

In the above definition, the cycloalkylene moiety of the “optionally substituted C ₃ -C ₆ cycloalkylene group” in the definition of D is a divalent group of a cyclic hydrocarbon having 3 to 6 carbon atoms. And may be, for example, a cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene group,
Preferably a C ₅ -C ₆ cycloalkylene group, more preferably a cyclohexylene group, particularly preferred,
1,4-cyclohexylene group. Further, the substituent (preferably 1 to 3, particularly preferably 1) is the C ₁ -C ₆ alkyl group, preferably
It is a C ₁ -C ₄ alkyl group, more preferably a C ₁ -C ₂ alkyl group, and particularly preferably a methyl group.

Among the compounds (I), which are the active ingredients of the present invention, compounds having a basic group such as an amino group can be converted into a pharmacologically acceptable salt by treating with an acid, if necessary. it can. Such salts include hydrofluorides, hydrochlorides, hydrobromides, hydrohalides such as hydroiodates, nitrates, perchlorates, sulfates, phosphates and the like. Inorganic acid salts; C ₁ -C ₆ alkane sulfonates which may be substituted with fluorine, such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate;
Benzenesulfonate, C ₆ -C ₁₀ ants such as p- toluenesulfonic acid salt - sulfonates such Rusuruhon acid salts;
Carboxylates such as fumarate, succinate, citrate, tartrate, oxalate and maleate; or amino acid salts such as glutamate and aspartate.

Compound (I) which is the active ingredient of the present invention
Alternatively, the salt may be left in the air or recrystallized to absorb water, to form adsorbed water or to form a hydrate, and a compound salt containing such water may be used in the present invention. Be included in. The compound (I) or a salt thereof, which is an active ingredient of the present invention, may have an asymmetric carbon atom in the molecule and may have a stereoisomer having an R configuration or an S configuration. Each of the compounds, or any proportion thereof, is encompassed by the present invention, and is preferably a compound in which, when X is a methylene group, the configuration at the 2-position on the pyrrolidine ring is the S-configuration. is there. Such stereoisomers can be obtained by synthesizing compound (I) using the optically resolved raw material compound or, if desired, optically resolving the synthesized compound (I) using ordinary optical resolution or separation. it can.

The compound (I) or a salt thereof, which is an active ingredient of the present invention, has a geometrical isomer when A is a group having the formula -BDE-. Such geometric isomers are included, and preferably, the trans isomer can be mentioned.

In the compound (I) which is an active ingredient of the present invention, preferred compounds include (1) a compound in which R ¹ is a C ₂ -C ₆ alkanoyl group having a substituent. Is a group represented by the formula -SR ² (wherein R ² is a hydrogen atom; a C ₁ -C ₆ alkanoyl group; a C ₂ -C ₅ alkoxycarbonyl group; a C ₁ -C ₂ alkyl, a C ₁ -C ₂ alkoxy, A benzoyl group which may be substituted by fluorine or chlorine; or a thienylcarbonyl, furylcarbonyl or pyridylcarbonyl group which may be substituted by methyl, methoxy, fluorine or chlorine). Is an amino group, mono-C ₁ -C ₄
An alkylamino group, a di-C ₁ -C ₄ alkylamino group or a protected amino or mono-C ₁ -C ₄ alkylamino group (the protecting group is a C ₁ -C ₄ alkanoyl group,
₁ -C ₄ alkoxycarbonyl group, tri -C ₁ -C ₂ alkyl silyl group, t- butyl dimethyl silyl group, a phenyl dimethylsilyl group, C ₁ -C ₂ alkyl, C ₁ -C ₂
A benzyl group which may be substituted with alkoxy, fluorine or chlorine, or a benzyloxycarbonyl group which may be substituted with C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, fluorine or chlorine. ). A compound which is
(2) R ¹ is a C ₂ -C ₆ alkanoyl group having a substituent [the substituent is essential as represented by the formula —SR ²
(Wherein R ² is a hydrogen atom; a C ₁ -C ₄ alkanoyl group; a C ₂ -C ₃ alkoxycarbonyl group; a t-butoxycarbonyl group; a benzoyl group; or a thienylcarbonyl which may be substituted with methyl or chlorine. , A furylcarbonyl or a pyridylcarbonyl group.), And is preferably an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a methylethylamino group or t-butyl, C _1-. C is a ₄ alkanoyl or C ₁ -C ₄ alkoxy protected amino or methylamino group with a carbonyl. A compound which is
(3) R ¹ is a C ₂ -C ₆ alkanoyl group having a substituent [wherein the substituent is essentially a compound of the formula —SR ²
(Wherein R ² is a hydrogen atom; a C ₁ -C ₄ alkanoyl group; a C ₂ -C ₃ alkoxycarbonyl group; a t-butoxycarbonyl group; a benzoyl group; or a thienylcarbonyl which may be substituted with methyl or chlorine. , A furylcarbonyl or a pyridylcarbonyl group.), And desired groups include amino, methylamino, dimethylamino, acetylamino, N-acetyl-
N-methylamino, t-butoxycarbonylamino or Nt-butoxycarbonyl-N-methylamino group. And (4) R ¹ is a group having a substituent
₂ -C ₄ alkanoyl group [the substituent, the essential thing, in the formula -S-R ² (wherein, R ² is a hydrogen atom or a C ₁
—C ₄ alkanoyl group. ), And the desired one is an amino, methylamino, dimethylamino, acetylamino or N-acetyl-N-methylamino group. And (5) R ¹ is a C ₃ -C ₄ alkanoyl group having a substituent. The substituent is essentially a compound of the formula —SR ² (wherein R ² is hydrogen Which is an atom or an acetyl group), and is preferably an amino or acetylamino group. ]
(6) R ¹ is 3-mercaptopropionyl, 3-mercapto-2-methylpropionyl, 3-
Mercapto-3-methylpropionyl, 4-mercaptobutyryl, 3-mercapto-2-ethylpropionyl,
2-amino-3-mercaptopropionyl, 2-acetylamino-3-mercaptopropionyl, 3-acetylthiopropionyl, 3-acetylthio-2-methylpropionyl, 3-acetylthio-3-methylpropionyl, 4-acetylthiobutyryl or A compound which is a 2-acetylamino-3-acetylthiopropionyl group,
(7) R ¹ is 3-mercapto-2-methylpropionyl, 2-amino-3-mercaptopropionyl, 2-acetylamino-3-mercaptopropionyl, 3-acetylthio-2-methylpropionyl or 2-acetylamino-3 -A compound which is an acetylthiopropionyl group,
(8) A is a C ₂ -C ₆ alkylene group or a formula -BD-
E- (wherein, B and E are the same or different and are a single bond or a C ₁ -C ₄ alkylene group, and D is a C ₅ -C ₆ cyclo which may be substituted by C ₁ -C ₂ alkyl; (9) A is a compound having an alkylene group).
₂ -C ₆ alkylene group or a formula -B-D-E-
There is a single bond or a C ₁ -C ₄ alkylene group, D is,
Substituted with methyl is also good C ₅ -C ₆ cycloalkylene group, E is a single bond, methylene, ethylene, trimethylene or tetramethylene group. And (10) A is ethylene, methylethylene,
Trimethylene, ethylethylene, tetramethylene, propylethylene, butylethylene or isobutylethylene group or a formula -BDE- (wherein B is a single bond, methylene or ethylene group, and D is C ₅ -C (11) A compound which is a group having ₆ cycloalkylene groups and E is a single bond, a methylene or ethylene group).
Is an ethylene, methylethylene, propylethylene, butylethylene or isobutylethylene group or a formula -B
-DE- (wherein B is a methylene group, D is a cyclohexylene group, and E is a methylene group.)
And (12) A is a methylethylene group. In the above description, in a group having the same variable, a group having a larger number is more preferable. The same applies hereinafter.

Also, R ¹ is selected from the group consisting of (1)-(7) and A is selected from the group consisting of (8)-(12), and any combination thereof is also a suitable compound. ,
For example, the following can be mentioned.

(13) R ¹ is a substituted C ₂ -C
₆ alkanoyl group [the substituent is essential
Formula -SR ² (wherein R ² is a hydrogen atom; C ₁ -C ₆ alkanoyl group; C ₂ -C ₅ alkoxycarbonyl group; C
₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, fluorine or optionally a benzoyl group optionally substituted by a chlorine; or methyl,
A thienylcarbonyl, furylcarbonyl or pyridylcarbonyl group which may be substituted by methoxy, fluorine or chlorine. ) Group having, as a desired one, amino group, mono--C ₁ -C ₄ alkylamino group, di -C ₁ -C ₄ alkylamino group or a protected amino or mono--C ₁ -C ₄ Alkylamino groups (the protecting groups are C ₁ -C ₄ alkanoyl, C ₁ -C ₄ alkoxycarbonyl, tri-C ₁ -C ₂ alkylsilyl, t-butyldimethylsilyl, phenyldimethylsilyl, ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy,
A benzyl group optionally substituted by fluorine or chlorine or C
₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, optionally benzyloxycarbonyl group optionally substituted with fluorine or chlorine. ). A], A is C ₂ -C ₆ alkylene radical or formula -B-D-E- (wherein, B and E are the same or different, is a single bond or a C ₁ -C ₄ alkylene group, D is optionally substituted with C ₁ -C ₂ alkyl C ₅
—C ₆ cycloalkylene group. And (14) R ¹ is a C ₂ -C ₆ alkanoyl group having a substituent [wherein the substituent is essentially a group represented by the formula-
S—R ² (wherein R ² is a hydrogen atom; a C ₁ -C ₄ alkanoyl group; a C ₂ -C ₃ alkoxycarbonyl group; a t-butoxycarbonyl group; a benzoyl group; A thienylcarbonyl, furylcarbonyl or pyridylcarbonyl group.)
And a desired group includes an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a methylethylamino group or t-butyl, C ₁ -C ₄ alkanoyl or C ₁ -C ₄ alkoxycarbonyl Is an amino or methylamino group protected by And A
There, C ₂ -C ₆ alkylene radical or formula -B-D-E- (wherein, B is a single bond or a C ₁ -C ₄ alkylene group,
D is a C ₅ -C ₆ cycloalkylene group optionally substituted with methyl, and E is a single bond, methylene, ethylene,
It is a trimethylene or tetramethylene group. ) Compound is a group having, (15) C ₂ having R ¹ is a substituent
-C ₆ alkanoyl group [the substituent is essentially required to be of the formula —SR ² (wherein R ² is a hydrogen atom; C ₁ -C
₄ alkanoyl group; C ₂ -C ₃ alkoxycarbonyl group; t-butoxycarbonyl group; benzoyl group; or thienylcarbonyl, furylcarbonyl or pyridylcarbonyl group which may be substituted by methyl or chlorine. And a group having amino, methylamino, dimethylamino, acetylamino, N-acetyl-N-methylamino, t-butoxycarbonylamino or Nt-butoxycarbonyl-N-
It is a methylamino group. A is an ethylene, methylethylene, trimethylene, ethylethylene, tetramethylene, propylethylene, butylethylene or isobutylethylene group or a formula -BDE-
Is a single bond, a methylene or ethylene group, and D is C
A ₅ -C ₆ cycloalkylene group, E is a single bond, methylene or ethylene group. (16) R ¹ is a C ₂ -C ₄ alkanoyl group having a substituent [the substituent is essentially a compound of the formula —S—
A group having R ² (wherein R ² is a hydrogen atom or a C ₁ -C ₄ alkanoyl group), and is preferably amino, methylamino, dimethylamino, acetylamino or N-acetyl. —N-methylamino group. A is ethylene, methylethylene, trimethylene, ethylethylene, tetramethylene, propylethylene, butylethylene or isobutylethylene group or a formula -BDE- (wherein B is a single bond, methylene or (17) R ¹ , a compound having an ethylene group, D being a C ₅ -C ₆ cycloalkylene group, and E being a single bond, a methylene or an ethylene group.
Is a C ₃ -C ₄ alkanoyl group having a substituent [The substituent is essentially a compound of the formula —SR ² (wherein R ²
Is a hydrogen atom or an acetyl group. ), And the desired one is an amino or acetylamino group. A is ethylene, methylethylene,
A propylethylene, butylethylene, or isobutylethylene group or a group having the formula -BDE- (where B is a methylene group, D is a cyclohexyl group, and E is a methylene group). (18) a compound which is
R ¹ is 3-mercaptopropionyl, 3-mercapto-2-methylpropionyl, 3-mercapto-3-methylpropionyl, 4-mercaptobutyryl, 3-mercapto-2-ethylpropionyl, 2-amino-3-mercaptopropionyl , 2-acetylamino-3-mercaptopropionyl, 3-acetylthiopropionyl, 3
-Acetylthio-2-methylpropionyl, 3-acetylthio-3-methylpropionyl, 4-acetylthiobutyryl or 2-acetylamino-3-acetylthiopropionyl, wherein A is ethylene, methylethylene,
A propylethylene, butylethylene, or isobutylethylene group or a group having the formula -BDE- (where B is a methylene group, D is a cyclohexyl group, and E is a methylene group). (19) a compound which is
R ¹ is 3-mercapto-2-methylpropionyl, 2
-Amino-3-mercaptopropionyl, 2-acetylamino-3-mercaptopropionyl, 3-acetylthio-2-methylpropionyl or 2-acetylamino-
A compound which is a 3-acetylthiopropionyl group and A is a methylethylene group.

The representative compounds of the present invention include, for example, the compounds described in Tables 1, 2 and 3, but the present invention is not limited to these compounds. Abbreviations in the table are as follows. Ac: acetyl group Boc: t-butoxycarbonyl group Bu: butyl group iBu: isobutyl group Btyl: butyryl group Et: ethyl group Fur: furyl group Hxn: hexanoyl group cHxln-2: 1,2-cyclohexylene group cHxln-3: 1,3-cyclohexylene group cHxln-4: 1,4-cyclohexylene group Me: methyl group cPnln-2: 1,2-cyclopentylene group cPnln-3: 1,3-cyclopentylene group Pr: propyl group Prn: propionyl group Pyr: pyridyl group Thi: thienyl group Val: valeryl group.

[0026]

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[0027]

[Table 1] {Compound No. R ¹ A} ─────────────────────────────── 1-1 2-SH-Ac - (CH 2) 2 - 1-2 2 _{-SH-Ac - (CH 2)} 3 - 1-3 2-SH-Ac -CH (Me) CH 2 - 1-4 2-SH-Ac - (cHxln-4) -CH 2 - 1-5 2- _{SH-Ac -CH 2 - (cHxln} -4) - 1-6 2-SH-Ac -CH 2 - (cHxln-2) -CH 2 - 1-7 2-SH-Ac -CH 2 - (cHxln-3 _{) -CH 2 - 1-8 2-SH} -Ac -CH 2 - (cHxln-4) -CH 2 - 1-9 2-SH-Ac -CH 2 - (cHxln-4) - (CH 2) 2 - 1-10 2-SH-Ac - ( cPnln-3) -CH 2 - 1-11 2-SH-Ac -CH 2 - (cPnln-3) - 1-12 2-SH-Ac -CH 2 - (cPnln _{-2) -CH 2 - 1-13 2-} SH-Ac -CH 2 - (cPnln-3) -CH 2 - 1-14 2-Me-2-SH-Ac - (CH 2) 2 - 1-15 2-Me-2-SH- Ac - (CH 2) 3 - 1-16 2-Me-2-SH-Ac -CH (Me) CH 2 - 1-17 2-Me-2-SH-Ac - ( _{cHxln-4) -CH 2 - 1-18} 2-Me-2-SH-Ac -CH 2 - (cHxln-4) - 1-19 2-Me-2-SH-Ac -CH 2 - (cHxln-2 _{) -CH 2 - 1-20 2-Me} -2-SH-Ac -CH 2 - (cHxln-3) -CH 2 - 1-21 2-Me-2-SH-Ac -CH 2 - (cHxln-4 _{) -CH 2 - 1-22 2-Me} -2-SH-Ac -CH 2 - (cHxl _{n-4) - (CH 2} ) 2 - 1-23 2-Me-2-SH-Ac - (cPnln-3) -CH 2 - 1-24 2-Me-2-SH-Ac -CH 2 - ( cPnln-3) - 1-25 2- Me-2-SH-Ac -CH 2 - (cPnln-2) -CH 2 - 1-26 2-Me-2-SH-Ac -CH 2 - (cPnln-3 _{) -CH 2 - 1-27 3-SH} -Prn - (CH 2) 2 - 1-28 3-SH-Prn - (CH 2) 3 - 1-29 3-SH-Prn -CH (Me) CH 2 - 1-30 3-SH-Prn -CH 2 CH (Me) - 1-31 3-SH-Prn -CH (Et) CH 2 - 1-32 3-SH-Prn -CH (Pr) CH 2 - 1 -33 3-SH-Prn - ( CH 2) 4 - 1-34 3-SH-Prn - (CH 2) 5 - 1-35 3-SH-Prn - (CH 2) 6 - 1-36 3-SH -Prn - (cHxln-4) - 1-37 3-SH-Prn - (cHxln-4) -CH 2 - 1-38 3-SH-Prn - (cHxln-4) - (CH 2) 2 - 1- 39 3-SH-Prn -CH _2- (cHxln-4)-1-40 3-SH-Prn-(CH ₂ ) _2- (cHxln-4)-1-41 3-SH-Prn -CH _2- ( _{cHxln-2) -CH 2 - 1-42} 3-SH-Prn -CH 2 - (cHxln-3) -CH 2 - 1-43 3-SH-Prn -CH 2 - (cHxln-4) -CH 2 - _{1-44 3-SH-Prn -CH 2} -2-Me- (cHxln-4) -CH 2 - 1-45 3-SH-Prn -CH 2 -3-Me- (cHxln-4) -CH 2 - _{1-46 3-SH-Prn -CH 2} - (cHxln-4) - (CH 2) 2 - 1-47 3-SH-Prn - (CH 2) 2 - (cHxln-4) -CH 2 - 1- 48 3-SH-Prn - ( CH 2) 2 - (cHxln-4) - (CH 2) 2 - 1-49 3-SH-Prn - (cPnln-3) - 1-50 3-SH-Prn - ( _{cPnln-3) -CH 2 - 1-51} 3-SH-Prn -CH 2 - (cP nln-3) - 1-52 3- SH-Prn -CH 2 - (cPnln-2) -CH 2 - 1-53 3-SH-Prn -CH 2 - (cPnln-3) -CH 2 - 1-54 _{3-SH-Prn -CH 2 -} (cPnln-3) - (CH 2) 2 - 1-55 2-Me-3-SH-Prn - (CH 2) 2 - 1-56 2-Me-3-SH _{-Prn - (CH 2) 3 -} 1-57 2-Me-3-SH-Prn -CH (Me) CH 2 - 1-58 2-Me-3-SH-Prn -CH 2 CH (Me) - 1 -59 2-Me-3-SH -Prn -CH (Et) CH 2 - 1-60 2-Me-3-SH-Prn -CH (Pr) CH 2 - 1-61 2-Me-3-SH- _{prn - (CH 2) 4 -} 1-62 2-Me-3-SH-prn - (CH 2) 5 - 1-63 2-Me-3-SH-prn - (CH 2) 6 - 1-64 2 -Me-3-SH-Prn - (cHxln-4) - 1-65 2-Me-3-SH-Prn - (cHxln-4) -CH 2 - 1-66 2-Me-3-SH-Prn - (cHxln-4) - (CH 2) 2 - 1-67 2-Me-3-SH-Prn -CH 2 - (cHxln-4) - 1-68 2-Me-3-SH-Prn - (CH 2 _{) 2 - (cHxln-4)} - 1-69 2-Me-3-SH-Prn -CH 2 - (cHxln-2) -CH 2 - 1-70 2-Me-3-SH-Prn -CH 2 - _{(cHxln-3) -CH 2 -} 1-71 2-Me-3-SH-Prn -CH 2 - (cHxln-4) -CH 2 - 1-72 2-Me-3-SH-Prn -CH 2 - 2-Me- (cHxln-4) -CH 2 - 1-73 2-Me-3-SH-Prn -CH 2 -3-Me- (cHxln-4) -CH 2 - 1-74 2-Me-3 _{-SH-Prn -CH 2 - (cHxln} -4) - (CH 2) 2 - 1-75 2-Me-3-SH-Prn - (CH 2) 2 - (cHxln-4) -CH 2 - 1- 76 2-Me-3-SH -Prn - (CH 2) 2 - (cHxln-4) - (CH 2) 2 - 1-77 2-Me-3-SH-Prn - (cPnln-3) - 1-78 2-Me-3-SH-Prn - (cPnln-3) -CH 2 - 1-79 2-Me-3-SH-Prn -CH 2 - (cPnln-3) - 1-80 2-Me-3- SH-Prn -CH 2 - (cPnln-2) -CH 2 - 1-81 2-Me-3-SH-Prn -CH 2 - (cPnln-3) -CH 2 - 1-82 2-Me-3- SH-Prn -CH 2 - (cPnln-3) - (CH 2) 2 - 1-83 3-Me-3-SH-Prn - (CH 2) 2 - 1- 84 3-Me-3-SH -Prn - (CH 2) 3 - 1-85 3-Me-3-SH-Prn -CH (Me) CH 2 - 1-86 3-Me-3-SH-Prn - _{(cHxln-4) -CH 2 -} 1-87 3-Me-3-SH-Prn -CH 2 - (cHxln-4) - 1-88 3-Me-3-SH-Prn -CH 2 - (cHxln- _{2) -CH 2 - 1-89 3-} Me-3-SH-Prn -CH 2 - (cHxln-3) -CH 2 - 1-90 3-Me-3-SH-Prn -CH 2 - (cHxln- _{4) -CH 2 - 1-91 3-} Me-3-SH-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 1-92 3-Me-3-SH-Prn - (cPnln- _{3) -CH 2 - 1-93 3-} Me-3-SH-Prn -CH 2 - (cPnln-3) - 1-94 3-Me-3-SH-Prn -CH 2 - (cPnln-2) - _{CH 2 - 1-95 3-Me-} 3-SH-Prn -CH 2 - (cPnln-3) -CH 2 - 1-96 2-Et-3-SH-Prn - (CH 2) 2 - 1-97 2-Et-3-SH- Prn - (CH 2) 3 - 1-98 2-Et-3-SH-Prn -CH (Me) CH 2 - 1-99 2-Et-3-SH-Prn - ( _{cHxln-4) -CH 2 - 1-100} 2-Et-3-SH-Prn -CH 2 - (cHxln-4) - 1-101 2-Et-3-SH-Prn -CH 2 - (cHxln-2 ) -CH ₂ -1-102 2-Et-3-SH-Prn -CH _2- (cHxln-3) -CH ₂ -1-103 2-Et- _{3-SH-Prn -CH 2 -} (cHxln-4) -CH 2 - 1-104 2-Et-3-SH-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 1-105 2 -Et-3-SH-Prn - (cPnln-3) -CH 2 - 1-106 2-Et-3-SH-Prn -CH 2 - (cPnln-3) - 1-107 2-Et-3-SH -Prn -CH _2- (cPnln-2) -CH ₂ -1-108 2-Et-3-SH-Prn -CH _2- (cPnln-3) -CH ₂ -1-109 4-SH-Btyl-( _{CH 2) 2 - 1-110 4-} SH-Btyl - (CH 2) 3 - 1-111 4-SH-Btyl -CH (Me) CH 2 - 1-112 4-SH-Btyl - (cHxln-4) _{-CH 2 - 1-113 4-SH-} Btyl -CH 2 - (cHxln-4) - 1-114 4-SH-Btyl -CH 2 - (cHxln-2) -CH 2 - 1-115 4-SH- Btyl -CH _2- (cHxln-3) -CH ₂ -1-116 4-SH-Btyl -CH _2- (cHxln-4) -CH ₂ -1-117 4-SH-Btyl -CH _2- (cHxln- _{4) - (CH 2) 2} - 1-118 4-SH-Btyl - (cPnln-3) -CH 2 - 1-119 4-SH-Btyl -CH 2 - (cPnln-3) - 1-120 4- _{SH-Btyl -CH 2 - (cPnln} -2) -CH 2 - 1-121 4-SH-Btyl -CH 2 - (cPnln-3) -CH 2 - 1-122 2-Me-4-SH-Btyl - _{(CH 2) 2 - 1-123 2} -Me-4-SH-Btyl - (CH 2) 3 - 1-124 2-Me-4-SH-Btyl -CH (Me) CH 2 - 1-125 2- Me-4-SH-Btyl - (cHxln-4) -CH 2 - 1-126 2-Me-4-SH-Btyl -CH 2 - (cHxln-4) - 1-127 2-Me-4-SH- _{Btyl -CH 2 - (cHxln-2} ) -CH 2 - 1-128 2-Me-4-SH-Btyl -CH 2 - (cHxln-3) -CH 2 - 1-129 2-Me-4-S _{H-Btyl -CH 2 - (cHxln} -4) -CH 2 - 1-130 2-Me-4-SH-Btyl -CH 2 - (cHxln-4) - (CH 2) 2 - 1-131 2-Me -4-SH-Btyl - (cPnln -3) -CH 2 - 1-132 2-Me-4-SH-Btyl -CH 2 - (cPnln-3) - 1-133 2-Me-4-SH-Btyl _{-CH 2 - (cPnln-2)} -CH 2 - 1-134 2-Me-4-SH-Btyl -CH 2 - (cPnln-3) -CH 2 - 1-135 3-Me-4-SH-Btyl _{- (CH 2) 2 - 1-136} 3-Me-4-SH-Btyl - (CH 2) 3 - 1-137 3-Me-4-SH-Btyl -CH (Me) CH 2 - 1-138 3 -Me-4-SH-Btyl - (cHxln-4) -CH 2 - 1-139 3-Me-4-SH-Btyl -CH 2 - (cHxln-4) - 1-140 3-Me-4-SH _{-Btyl -CH 2 - (cHxln-2} ) -CH 2 - 1-141 3-Me-4-SH-Btyl -CH 2 - (cHxln-3) -CH 2 - 1-142 3-Me-4-SH _{-Btyl -CH 2 - (cHxln-4} ) -CH 2 - 1-143 3-Me-4-SH-Btyl -CH 2 - (cHxln-4) - (CH 2) 2 - 1-144 3-Me- 4-SH-Btyl - (cPnln -3) -CH 2 - 1-145 3-Me-4-SH-Btyl -CH 2 - (cPnln-3) - 1-146 3-Me-4-SH-Btyl - _{CH 2 - (cPnln-2)} -CH 2 - 1-147 3-Me-4-SH-Btyl -CH 2 - (cPnln-3) -CH 2 - 1-148 4-Me-4-SH-Btyl - _{(CH 2) 2 - 1-149 4} -Me-4-SH-Btyl - (CH 2) 3 - 1-150 4-Me-4-SH-Btyl -CH (Me) CH 2 - 1-151 4- Me-4-SH-Btyl - (cHxln-4) -CH 2 - 1-152 4-Me-4-SH-Btyl -CH 2 - (cHxln-4) - 1-153 4-Me-4-SH- Btyl -CH _2- (cHxln-2 _{) -CH 2 - 1-154 4-Me} -4-SH-Btyl -CH 2 - (cHxln-3) -CH 2 - 1-155 4-Me-4-SH-Btyl -CH 2 - (cHxln-4 _{) -CH 2 - 1-156 4-Me} -4-SH-Btyl -CH 2 - (cHxln-4) - (CH 2) 2 - 1-157 4-Me-4-SH-Btyl - (cPnln-3 _{) -CH 2 - 1-158 4-Me} -4-SH-Btyl -CH 2 - (cPnln-3) - 1-159 4-Me-4-SH-Btyl -CH 2 - (cPnln-2) -CH _{2 - 1-160 4-Me-4} -SH-Btyl -CH 2 - (cPnln-3) -CH 2 - 1-161 5-SH-Val - (CH 2) 2 - 1-162 5-SH-Val _{-CH (Me) CH 2 - 1-163} 5-SH-Val - (cHxln-4) -CH 2 - 1-164 5-SH-Val -CH 2 - (cHxln-4) - 1-165 5-SH _{-Val -CH 2 - (cHxln-4} ) -CH 2 - 1-166 2-Me-5-SH-Val - (CH 2) 2 - 1-167 2-Me-5-SH-Val -CH (Me _{) CH 2 - 1-168 2-Me} -5-SH-Val - (cHxln-4) - 1-169 2-Me-5-SH-Val - (cHxln-4) -CH 2 - 1-170 2- Me-5-SH-Val -CH 2 - (cHxln-4) - 1-171 2-Me-5-SH-Val -CH 2 - (cHxln-4) -CH 2 - 1-172 5-Me-5 _{-SH-Val - (CH 2)} 2 - 1-173 5-Me-5-SH-Val -CH (Me) CH 2 - 1-174 5-Me-5-SH-Val - (cHxln-4) - _{CH 2 - 1-175 5-Me-} 5-SH-Val -CH 2 - (cHxln-4) - 1-176 5-Me-5-SH-Val -CH 2 - (cHxln-4) -CH 2 - 1-177 6-SH-Hxn - ( CH 2) 2 - 1-178 6-SH-Hxn -CH (Me) CH 2 - 1-179 6-SH-Hxn - (cHxln-4) -CH 2 - 1 -180 6-SH-Hxn -CH _2- (cH xln-4) - 1-181 6- SH-Hxn -CH 2 - (cHxln-4) -CH 2 - 1-182 2-NH 2 -3-SH-Prn - (CH 2) 2 - 1-183 2 _{-NH 2 -3-SH-Prn -} (CH 2) 3 - 1-184 2-NH 2 -3-SH-Prn -CH (Me) CH 2 - 1-185 2-NH 2 -3-SH-Prn _{-CH 2 CH (Me) - 1-186} 2-NH 2 -3-SH-Prn -CH (Et) CH 2 - 1-187 2-NH 2 -3-SH-Prn -CH (Pr) CH 2 - _{1-188 2-NH 2 -3-SH} -Prn - (CH 2) 4 - 1-189 2-NH 2 -3-SH-Prn - (CH 2) 5 - 1-190 2-NH 2 -3- _{SH-Prn - (CH 2)} 6 - 1-191 2-NH 2 -3-SH-Prn - (cHxln-4) - 1-192 2-NH 2 -3-SH-Prn - (cHxln-4) - CH ₂ -1-193 2-NH ₂ -3-SH-Prn-(cHxln-4)-(CH ₂ ) ₂ -1-194 2-NH ₂ -3-SH-Prn -CH _2- (cHxln-4 )-1-195 2-NH ₂ -3-SH-Prn-(CH ₂ ) _2- (cHxln-4)-1-196 2-NH ₂ -3-SH-Prn -CH _2- (cHxln-2) -CH ₂ -1-197 2-NH ₂ -3-SH-Prn -CH _2- (cHxln-3) -CH ₂ -1-198 2-NH ₂ -3-SH-Prn -CH _2- (cHxln- _{4) -CH 2 - 1-199 2-} NH 2 -3-SH-Prn -CH 2 -2-Me- (cHxln-4) -CH 2 - 1-200 2-NH 2 -3-SH-Prn - CH ₂ -3-Me- (cHxln-4) -CH ₂ -1-201 2-NH ₂ -3-SH-Prn -CH _2- (cHxln-4)-(CH ₂ ) ₂ -1-202 2- _{NH 2 -3-SH-Prn -} (CH 2) 2 - (cHxln-4) -CH 2 - 1-203 2-NH 2 -3-SH-Prn - (CH 2) 2 - (cHxln-4) - _{(CH 2) 2 - 1-204 2} -NH _{2 -3-SH-Prn - (} cPnln-3) - 1-205 2-NH 2 -3-SH-Prn - (cPnln-3) -CH 2 - 1-206 2-NH 2 -3-SH-Prn _{-CH 2 - (cPnln-3)} - 1-207 2-NH 2 -3-SH-Prn -CH 2 - (cPnln-2) -CH 2 - 1-208 2-NH 2 -3-SH-Prn - _{CH 2 - (cPnln-3)} -CH 2 - 1-209 2-NH 2 -3-SH-Prn -CH 2 - (cPnln-3) - (CH 2) 2 - 1-210 2-NH 2 -4 _{-SH-Btyl - (CH 2)} 2 - 1-211 2-NH 2 -4-SH-Btyl - (CH 2) 3 - 1-212 2-NH 2 -4-SH-Btyl -CH (Me) CH _{2 - 1-213 2-NH 2 -4} -SH-Btyl - (cHxln-4) -CH 2 - 1-214 2-NH 2 -4-SH-Btyl -CH 2 - (cHxln-4) - 1- _{215 2-NH 2 -4-SH} -Btyl -CH 2 - (cHxln-2) -CH 2 - 1-216 2-NH 2 -4-SH-Btyl -CH 2 - (cHxln-3) -CH 2 - _{1-217 2-NH 2 -4-SH} -Btyl -CH 2 - (cHxln-4) -CH 2 - 1-218 2-NH 2 -4-SH-Btyl -CH 2 - (cHxln-4) - ( _{CH 2) 2 - 1-219 2-} NH 2 -4-SH-Btyl - (cPnln-3) -CH 2 - 1-220 2-NH 2 -4-SH-Btyl -CH 2 - (cPnln-3) _{- 1-221 2-NH 2 -4-} SH-Btyl -CH 2 - (cPnln-2) -CH 2 - 1-222 2-NH 2 -4-SH-Btyl -CH 2 - (cPnln-3) - _{CH 2 - 1-223 3-NH 2} -4-SH-Btyl - (CH 2) 2 - 1-224 3-NH 2 -4-SH-Btyl -CH (Me) CH 2 - 1-225 3-NH _{2 -4-SH-Btyl - (} cHxln-4) -CH 2 - 1-226 3-NH 2 -4-SH-Btyl -CH 2 - (cHxln-4) - 1-227 3-NH 2 -4 _{-SH-Btyl -CH 2 - (cHxln} -2) -CH 2 - 1-228 3-NH 2 -4-SH-Btyl -CH 2 - (cHxln-3) -CH 2 - 1-229 3-NH 2 _{-4-SH-Btyl -CH 2 -} (cHxln-4) -CH 2 - 1-230 2-NH 2 -5-SH-Val - (CH 2) 2 - 1-231 2-NH 2 -5-SH _{-Val -CH (Me) CH 2 -} 1-232 2-NH 2 -5-SH-Val - (cHxln-4) -CH 2 - 1-233 2-NH 2 -5-SH-Val -CH 2 - (cHxln-4) - 1-234 2 -NH 2 -5-SH-Val -CH 2 - (cHxln-4) -CH 2 - 1-235 2-NH 2 -6-SH-Hxn - (CH 2) _{2 - 1-236 2-NH 2 -6} -SH-Hxn -CH (Me) CH 2 - 1-237 2-NH 2 -6-SH-Hxn - (cHxln-4) -CH 2 - 1-238 2 _{-NH 2 -6-SH-Hxn -CH} 2 - (cHxln-4) - 1-239 2-NH 2 -6-SH-Hxn -CH 2 - (cHxln-4) -CH 2 - 1-240 2- NHAc-3-SH-Prn - (CH 2) 2 - 1-241 2-NHAc-3-SH-Prn - (CH 2) 3 - 1-242 2-NHAc-3-SH-Prn -CH (Me) CH ₂ -1-243 2-NHAc-3-SH-Prn-(cHxln-4) -CH ₂ -1-244 2-NHAc-3-SH-Prn -CH _2- (cHxln-4)-1-245 2-NHAc-3-SH- Prn -CH 2 - (cHxln-2) -CH 2 - 1-246 2-NHAc-3-SH-Prn -CH 2 - (cHxln-3) -CH 2 - 1-247 2-NHAc-3-SH- Prn -CH 2 - (cHxln-4) -CH 2 - 1-248 2-NHAc-3-SH-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 1-249 2-NHAc-3-SH -Prn - (cPnln-3) -CH 2 - 1-250 2-NHAc-3-SH-Prn -CH 2 - (cPnln-3) - 1-251 2-NHAc _{-3-SH-Prn -CH 2 -} (cPnln-2) -CH 2 - 1-252 2-NHAc-3-SH-Prn -CH 2 - (cPnln-3) -CH 2 - 1-253 2-NHAc -4-SH-Btyl - (CH 2) 2 - 1-254 2-NHAc-4-SH-Btyl - (CH 2) 3 - 1-255 2-NHAc-4-SH-Btyl -CH (Me) CH _{2 - 1-256 2-NHAc-4} -SH-Btyl - (cHxln-4) -CH 2 - 1-257 2-NHAc-4-SH-Btyl -CH 2 - (cHxln-4) - 1-258 2 -NHAc-4-SH-Btyl -CH 2 - (cHxln-2) -CH 2 - 1-259 2-NHAc-4-SH-Btyl -CH 2 - (cHxln-3) -CH 2 - 1-260 2 -NHAc-4-SH-Btyl -CH 2 - (cHxln-4) -CH 2 - 1-261 3-NHAc-4-SH-Btyl - (CH 2) 2 - 1-262 3-NHAc-4-SH _{-Btyl -CH (Me) CH 2 -} 1-263 3-NHAc-4-SH-Btyl - (cHxln-4) -CH 2 - 1-264 3-NHAc-4-SH-Btyl -CH 2 - (cHxln -4) - 1-265 3-NHAc- 4-SH-Btyl -CH 2 - (cHxln-4) -CH 2 - 1-266 2-NHAc-5-SH-Val - (CH 2) 2 - 1- 267 2-NHAc-5-SH -Val -CH (Me) CH 2 - 1-268 2-NHAc-5-SH-Val -CH 2 - (cHxln-4) -CH 2 - 1-269 2-NHAc- 6-SH-Hxn - (CH 2) 2 - 1-270 2-NHAc-6-SH-Hxn -CH (Me) CH 2 - 1-271 2-NHAc-6-SH-Hxn -CH 2 - (cHxln _{-4) -CH 2 - 1-272 2-} NHBoc-3-SH-Prn - (CH 2) 2 - 1-273 2-NHBoc-3-SH-Prn - (CH 2) 3 - 1-274 2- NHBoc-3-SH-Prn -CH (Me) CH 2 - 1-275 2-NHBoc-3-SH-Prn - (cHxln-4) -CH 2 - 1- 276 2-NHBoc-3-SH -Prn -CH 2 - (cHxln-4) - 1-277 2-NHBoc-3-SH-Prn -CH 2 - (cHxln-2) -CH 2 - 1-278 2- NHBoc-3-SH-Prn -CH 2 - (cHxln-3) -CH 2 - 1-279 2-NHBoc-3-SH-Prn -CH 2 - (cHxln-4) -CH 2 - 1-280 2- NHBoc-3-SH-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 1-281 2-NHBoc-3-SH-Prn - (cPnln-3) -CH 2 - 1-282 2- NHBoc-3-SH-Prn -CH 2 - (cPnln-3) - 1-283 2-NHBoc-3-SH-Prn -CH 2 - (cPnln-2) -CH 2 - 1-284 2-NHBoc-3 _{-SH-Prn -CH 2 - (cPnln} -3) -CH 2 - 1-285 2-NHBoc-3-SH-Prn -CH 2 - (cPnln-3) - (CH 2) 2 - 1-286 2- NHBoc-4-SH-Btyl - (CH 2) 2 - 1-287 2-NHBoc-4-SH-Btyl -CH (Me) CH 2 - 1-288 2-NHBoc-4-SH-Btyl - (cHxln- _{4) -CH 2 - 1-289 2-} NHBoc-4-SH-Btyl -CH 2 - (cHxln-4) - 1-290 2-NHBoc-4-SH-Btyl -CH 2 - (cHxln-2) - _{CH 2 - 1-291 2-NHBoc-} 4-SH-Btyl -CH 2 - (cHxln-3) -CH 2 - 1-292 2-NHBoc-4-SH-Btyl -CH 2 - (cHxln-4) - _{CH 2 - 1-293 3-NHBoc-} 4-SH-Btyl - (CH 2) 2 - 1-294 3-NHBoc-4-SH-Btyl -CH (Me) CH 2 - 1-295 3-NHBoc-4 -SH-Btyl - (cHxln-4 ) -CH 2 - 1-296 3-NHBoc-4-SH-Btyl -CH 2 - (cHxln-4) - 1-297 3-NHBoc-4-SH-Btyl -CH _{2 - (cHxln-4) -CH} 2 - 1-298 2-NHBoc-5-SH-Val - (CH 2 _{) 2 - 1-299 2-NHBoc-} 5-SH-Val -CH (Me) CH 2 - 1-300 2-NHBoc-5-SH-Val -CH 2 - (cHxln-4) -CH 2 - 1- 301 2-NHBoc-6-SH -Hxn - (CH 2) 2 - 1-302 2-NHBoc-6-SH-Hxn -CH (Me) CH 2 - 1-303 2-NHBoc-6-SH-Hxn - _{CH 2 - (cHxln-4)} -CH 2 - 1-304 2-NHMe-3-SH-Prn - (CH 2) 2 - 1-305 2-NHMe-3-SH-Prn -CH (Me) CH 2 - 1-306 2-NHMe-3- SH-Prn - (cHxln-4) -CH 2 - 1-307 2-NHMe-3-SH-Prn -CH 2 - (cHxln-4) - 1-308 2- NHMe-3-SH-Prn -CH 2 - (cHxln-2) -CH 2 - 1-309 2-NHMe-3-SH-Prn -CH 2 - (cHxln-3) -CH 2 - 1-310 2- NHMe-3-SH-Prn -CH 2 - (cHxln-4) -CH 2 - 1-311 2-NHMe-4-SH-Btyl - (CH 2) 2 - 1-312 2-NHMe-4-SH- _{Btyl -CH (Me) CH 2 -} 1-313 2-NHMe-4-SH-Btyl -CH 2 - (cHxln-2) -CH 2 - 1-314 2-NHMe-4-SH-Btyl -CH 2 - _{(cHxln-3) -CH 2 -} 1-315 2-NHMe-4-SH-Btyl -CH 2 - (cHxln-4) -CH 2 - 1-316 3-NHMe-4-SH-Btyl - (CH 2 _{) 2 - 1-317 3-NHMe-} 4-SH-Btyl -CH (Me) CH 2 - 1-318 3-NHMe-4-SH-Btyl -CH 2 - (cHxln-4) -CH 2 - 1- 319 2-NHMe-5-SH -Val -CH (Me) CH 2 - 1-320 2-NHMe-6-SH-Hxn -CH (Me) CH 2 - 1-321 2-NHEt-3-SH-Prn _{- (CH 2) 2 - 1-322} 2-NHEt-3-SH-Prn -CH (Me) CH 2 - 1-323 2-NHEt-3-SH-Prn - ( _{cHxln-4) -CH 2 - 1-324} 2-NHEt-3-SH-Prn -CH 2 - (cHxln-4) - 1-325 2-NHEt-3-SH-Prn -CH 2 - (cHxln-2 _{) -CH 2 - 1-326 2-NHEt} -3-SH-Prn -CH 2 - (cHxln-3) -CH 2 - 1-327 2-NHEt-3-SH-Prn -CH 2 - (cHxln-4 _{) -CH 2 - 1-328 2-NHEt} -4-SH-Btyl - (CH 2) 2 - 1-329 2-NHEt-4-SH-Btyl -CH (Me) CH 2 - 1-330 2-NHEt _{-4-SH-Btyl -CH 2 -} (cHxln-4) -CH 2 - 1-331 3-NHEt-4-SH-Btyl - (CH 2) 2 - 1-332 3-NHEt-4-SH-Btyl _{-CH (Me) CH 2 - 1-333} 3-NHEt-4-SH-Btyl -CH 2 - (cHxln-4) -CH 2 - 1-334 2-NHEt-5-SH-Val -CH (Me) _{CH 2 - 1-335 2-NHEt-} 6-SH-Hxn -CH (Me) CH 2 - 1-336 2-NMe 2 -3-SH-Prn - (CH 2) 2 - 1-337 2-NMe 2 -3-SH-Prn -CH (Me ) CH 2 - 1-338 2-NMe 2 -3-SH-Prn - (cHxln-4) -CH 2 - 1-339 2-NMe 2 -3-SH-Prn _{-CH 2 - (cHxln-4)} - 1-340 2-NMe 2 -3-SH-Prn -CH 2 - (cHxln-2) -CH 2 - 1-341 2-NMe 2 -3-SH-Prn - _{CH 2 - (cHxln-3)} -CH 2 - 1-342 2-NMe 2 -3-SH-Prn -CH 2 - (cHxln-4) -CH 2 - 1-343 2-NMe 2 -4-SH- _{Btyl - (CH 2) 2 -} 1-344 2-NMe 2 -4-SH-Btyl -CH (Me) CH 2 - 1-345 2-NMe 2 -4-SH-Btyl -CH 2 - (cHxln-4 _{) -CH 2 - 1-346 3-NMe} 2 -4-SH-Btyl - (CH 2) 2 - 1-347 3-NMe 2 -4-SH-Btyl -C _{H (Me) CH 2 - 1-348} 3-NMe 2 -4-SH-Btyl -CH 2 - (cHxln-4) -CH 2 - 1-349 2-NMe 2 -5-SH-Val -CH (Me _{) CH 2 - 1-350 2-NMe} 2 -6-SH-Hxn -CH (Me) CH 2 - 1-351 2-NMeAc-3-SH-Prn - (CH 2) 2 - 1-352 2-NMeAc -3-SH-Prn -CH (Me ) CH 2 - 1-353 2-NMeAc-3-SH-Prn -CH 2 - (cHxln-4) -CH 2 - 1-354 2-NMeAc-4-SH- _{Btyl -CH (Me) CH 2 -} 1-355 2-NMeBoc-3-SH-Prn - (CH 2) 2 - 1-356 2-NMeBoc-3-SH-Prn -CH (Me) CH 2 - 1- 357 2-NMeBoc-3-SH -Prn -CH 2 - (cHxln-4) -CH 2 - 1-358 2-SAc-Ac - (CH 2) 2 - 1-359 2-SAc-Ac -CH (Me _{) CH 2 - 1-360 2-SAc} -Ac - (cHxln-4) -CH 2 - 1-361 2-SAc-Ac -CH 2 - (cHxln-4) - 1-362 2-SAc-Ac -CH _{2 - (cHxln-2) -CH} 2 - 1-363 2-SAc-Ac -CH 2 - (cHxln-3) -CH 2 - 1-364 2-SAc-Ac -CH 2 - (cHxln-4) - _{CH 2 - 1-365 2-Me-} 2-SAc-Ac - (CH 2) 2 - 1-366 2-Me-2-SAc-Ac - (CH 2) 3 - 1-367 2-Me-2- SAc-Ac -CH (Me) CH 2 - 1-368 2-Me-2-SAc-Ac - (cHxln-4) -CH 2 - 1-369 2-Me-2-SAc-Ac -CH 2 - ( cHxln-4) - 1-370 2- Me-2-SAc-Ac -CH 2 - (cHxln-2) -CH 2 - 1-371 2-Me-2-SAc-Ac -CH 2 - (cHxln-3 _{) -CH 2 - 1-372 2-Me} -2-SAc-Ac -CH 2 - (cHxln-4) -CH 2 - 1-373 3-SAc-Prn - (CH 2) 2 - 1-374 3-SAc-Prn - (CH 2) 3 - 1-375 3-SAc-Prn -CH (Me) CH 2 - 1-376 3-SAc-Prn -CH 2 CH (Me) - 1-377 3-SAc _{-Prn -CH (Et) CH 2 -} 1-378 3-SAc-Prn -CH (Pr) CH 2 - 1-379 3-SAc-Prn - (CH 2) 4 - 1-380 3-SAc-Prn - _{(CH 2) 5 - 1-381 3} -SAc-Prn - (CH 2) 6 - 1-382 3-SAc-Prn - (cHxln-4) - 1-383 3-SAc-Prn - (cHxln-4) _{-CH 2 - 1-384 3-SAc-} Prn - (cHxln-4) - (CH 2) 2 - 1-385 3-SAc-Prn -CH 2 - (cHxln-4) - 1-386 3-SAc- _{prn - (CH 2) 2 -} (cHxln-4) - 1-387 3-SAc-prn -CH 2 - (cHxln-2) -CH 2 - 1-388 3-SAc-prn -CH 2 - (cHxln- _{3) -CH 2 - 1-389 3-} SAc-Prn -CH 2 - (cHxln-4) -CH 2 - 1-390 3-SAc-Prn -CH 2 -2-Me- (cHxln-4) -CH _{2 - 1-391 3-SAc-Prn} -CH 2 -3-Me- (cHxln-4) -CH 2 - 1-392 3-SAc-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 1-393 3-SAc-Prn - (CH 2) 2 - (cHxln-4) -CH 2 - 1-394 3-SAc-Prn - (CH 2) 2 - (cHxln-4) - (CH 2) _{2 - 1-395 3-SAc-Prn} - (cPnln-3) - 1-396 3-SAc-Prn - (cPnln-3) -CH 2 - 1-397 3-SAc-Prn -CH 2 - (cPnln- 3) - 1-398 3-SAc- Prn -CH 2 - (cPnln-2) -CH 2 - 1-399 3-SAc-Prn -CH 2 - (cPnln-3) -CH 2 - 1-400 3- _{SAc-Prn -CH 2 - (cPnln} -3) - (CH 2) 2 - 1-401 2-Me-3-SAc-Prn - (C _{H 2) 2 - 1-402 2-} Me-3-SAc-Prn - (CH 2) 3 - 1-403 2-Me-3-SAc-Prn -CH (Me) CH 2 - 1-404 2-Me _{-3-SAc-Prn -CH 2 CH} (Me) - 1-405 2-Me-3-SAc-Prn -CH (Et) CH 2 - 1-406 2-Me-3-SAc-Prn -CH (Pr _{) CH 2 - 1-407 2-Me} -3-SAc-Prn - (CH 2) 4 - 1-408 2-Me-3-SAc-Prn - (CH 2) 5 - 1-409 2-Me-3 _{-SAc-Prn - (CH 2)} 6 - 1-410 2-Me-3-SAc-Prn - (cHxln-4) - 1-411 2-Me-3-SAc-Prn - (cHxln-4) -CH _{2 - 1-412 2-Me-3} -SAc-Prn - (cHxln-4) - (CH 2) 2 - 1-413 2-Me-3-SAc-Prn -CH 2 - (cHxln-4) - 1 -414 2-Me-3-SAc -Prn - (CH 2) 2 - (cHxln-4) - 1-415 2-Me-3-SAc-Prn -CH 2 - (cHxln-2) -CH 2 - 1 -416 2-Me-3-SAc -Prn -CH 2 - (cHxln-3) -CH 2 - 1-417 2-Me-3-SAc-Prn -CH 2 - (cHxln-4) -CH 2 - 1 -418 2-Me-3-SAc -Prn -CH 2 -2-Me- (cHxln-4) -CH 2 - 1-419 2-Me-3-SAc-Prn -CH 2 -3-Me- (cHxln _{-4) -CH 2 - 1-420 2-} Me-3-SAc-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 1-421 2-Me-3-SAc-Prn - (CH _{2) 2 - (cHxln-4} ) -CH 2 - 1-422 2-Me-3-SAc-Prn - (CH 2) 2 - (cHxln-4) - (CH 2) 2 - 1-423 2-Me -3-SAc-Prn - (cPnln -3) - 1-424 2-Me-3-SAc-Prn - (cPnln-3) -CH 2 - 1-425 2-Me-3-SAc-Prn -CH 2 -(cPnln-3)-1-426 2-Me-3-S _{Ac-Prn -CH 2 - (cPnln} -2) -CH 2 - 1-427 2-Me-3-SAc-Prn -CH 2 - (cPnln-3) -CH 2 - 1-428 2-Me-3- _{SAc-Prn -CH 2 - (cPnln} -3) - (CH 2) 2 - 1-429 3-Me-3-SAc-Prn - (CH 2) 2 - 1-430 3-Me-3-SAc-Prn _{-CH (Me) CH 2 - 1-431} 3-Me-3-SAc-Prn - (cHxln-4) -CH 2 - 1-432 3-Me-3-SAc-Prn -CH 2 - (cHxln-4 ) - 1-433 3-Me-3 -SAc-Prn -CH 2 - (cHxln-4) -CH 2 - 1-434 2-Et-3-SAc-Prn - (CH 2) 2 - 1-435 2 -Et-3-SAc-Prn -CH (Me) CH 2 - 1-436 2-Et-3-SAc-Prn - (cHxln-4) -CH 2 - 1-437 2-Et-3-SAc-Prn _{-CH 2 - (cHxln-4)} - 1-438 2-Et-3-SAc-Prn -CH 2 - (cHxln-4) -CH 2 - 1-439 4-SAc-Btyl - (CH 2) 2 - 1-440 4-SAc-Btyl -CH ( Me) CH 2 - 1-441 4-SAc-Btyl - (cHxln-4) -CH 2 - 1-442 4-SAc-Btyl -CH 2 - (cHxln-4 ) - 1-443 4-SAc-Btyl -CH 2 - (cHxln-4) -CH 2 - 1-444 2-Me-4-SAc-Btyl - (CH 2) 2 - 1-445 2-Me-4 -SAc-Btyl -CH (Me) CH 2 - 1-446 2-Me-4-SAc-Btyl - (cHxln-4) -CH 2 - 1-447 2-Me-4-SAc-Btyl -CH 2 - (cHxln-4) - 1-448 2 -Me-4-SAc-Btyl -CH 2 - (cHxln-4) -CH 2 - 1-449 3-Me-4-SAc-Btyl - (CH 2) 2 - 1-450 3-Me-4-SAc -Btyl -CH (Me) CH 2 - 1-451 3-Me-4-SAc-Btyl -CH 2 - (cHxln-4) -CH 2 - 1-45 2 4-Me-4-SAc -Btyl - (CH 2) 2 - 1-453 4-Me-4-SAc-Btyl -CH (Me) CH 2 - 1-454 4-Me-4-SAc-Btyl - _{CH 2 - (cHxln-4)} -CH 2 - 1-455 5-SAc-Val - (CH 2) 2 - 1-456 5-SAc-Val -CH (Me) CH 2 - 1-457 2-Me- 5-SAc-Val - (CH 2) 2 - 1-458 2-Me-5-SAc-Val -CH (Me) CH 2 - 1-459 2-Me-5-SAc-Val -CH 2 - (cHxln _{-4) -CH 2 - 1-460 5-} Me-5-SAc-Val - (CH 2) 2 - 1-461 5-Me-5-SAc-Val -CH (Me) CH 2 - 1-462 5 -Me-5-SAc-Val -CH 2 - (cHxln-4) -CH 2 - 1-463 6-SAc-Hxn - (CH 2) 2 - 1-464 6-SAc-Hxn -CH (Me) CH _{2 - 1-465 6-SAc-Hxn} -CH 2 - (cHxln-4) -CH 2 - 1-466 2-NH 2 -3-SAc-Prn - (CH 2) 2 - 1-467 2-NH 2 -3-SAc-Prn - (CH 2) 3 - 1-468 2-NH 2 -3-SAc-Prn -CH (Me) CH 2 - 1-469 2-NH 2 -3-SAc-Prn - (cHxln _{-4) -CH 2 - 1-470 2-} NH 2 -3-SAc-Prn - (cHxln-4) - (CH 2) 2 - 1-471 2-NH 2 -3-SAc-Prn -CH 2 - (cHxln-4) - 1-472 2 -NH 2 -3-SAc-Prn -CH 2 - (cHxln-2) -CH 2 - 1-473 2-NH 2 -3-SAc-Prn -CH 2 - ( _{cHxln-3) -CH 2 - 1-474} 2-NH 2 -3-SAc-Prn -CH 2 - (cHxln-4) -CH 2 - 1-475 2-NH 2 -3-SAc-Prn -CH 2 - (cHxln-4) - ( CH 2) 2 - 1-476 2-NH 2 -3-SAc-Prn - (cPnln-3) -CH 2 - 1-477 2-NH 2 -3-SAc _{-Prn -CH 2 - (cPnln-3} ) - 1-478 2-NH 2 -3-SAc-Prn -CH 2 - (cPnln-2) -CH 2 - 1-479 2-NH 2 -3-SAc- _{prn -CH 2 - (cPnln-3} ) -CH 2 - 1-480 2-NH 2 -4-SAc-Btyl - (CH 2) 2 - 1-481 2-NH 2 -4-SAc-Btyl -CH ( _{Me) CH 2 - 1-482 2-} NH 2 -4-SAc-Btyl - (cHxln-4) -CH 2 - 1-483 2-NH 2 -4-SAc-Btyl -CH 2 - (cHxln-4) _{- 1-484 2-NH 2 -4-} SAc-Btyl -CH 2 - (cHxln-4) -CH 2 - 1-485 3-NH 2 -4-SAc-Btyl - (CH 2) 2 - 1-486 _{3-NH 2 -4-SAc-} Btyl -CH (Me) CH 2 - 1-487 3-NH 2 -4-SAc-Btyl -CH 2 - (cHxln-4) -CH 2 - 1-488 2-NH _{2 -5-SAc-Val - (} CH 2) 2 - 1-489 2-NH 2 -5-SAc-Val -CH (Me) CH 2 - 1-490 2-NH 2 -5-SAc-Val -CH _{2 - (cHxln-4) -CH} 2 - 1-491 2-NHAc-3-SAc-Prn - (CH 2) 2 - 1-492 2-NHAc-3-SAc-Prn - (CH 2) 3 - 1 -493 2-NHAc-3-SAc -Prn -CH (Me) CH 2 - 1-494 2-NHAc-3-SAc-Prn - (cHxln-4) -CH 2 - 1-495 2-NHAc-3- _{SAc-Prn -CH 2 - (cHxln} -4) - 1-496 2-NHAc-3-SAc-Prn -CH 2 - (cHxln-2) -CH 2 - 1-497 2-NHAc-3-SAc-Prn _{-CH 2 - (cHxln-3)} -CH 2 - 1-498 2-NHAc-3-SAc-Prn -CH 2 - (cHxln-4) -CH 2 - 1-499 2-NHAc-3-SAc-Prn _{- (cPnln-3) -CH 2} - 1-500 2-NHAc-3-SAc-Prn -CH 2 - (cPnln-3) - 1-501 2-NHAc-3-SAc- Prn -CH 2 - (cPnln-2) -CH 2 - 1-502 2-NHAc-3-SAc-Prn -CH 2 - (cPnln-3) -CH 2 - 1-503 2-NHAc-4-SAc- Btyl - (CH 2) 2 - 1-504 2-NHAc-4-SAc-Btyl -CH (Me) CH 2 - 1-505 2-NHAc-4-SAc-Btyl -CH _{2 - (cHxln-4) -CH} 2 - 1-506 3-NHAc-4-SAc-Btyl - (CH 2) 2 - 1-507 3-NHAc-4-SAc-Btyl -CH (Me) CH 2 - 1-508 3-NHAc-4-SAc -Btyl -CH 2 - (cHxln-4) -CH 2 - 1-509 2-NHAc-5-SAc-Val -CH (Me) CH 2 - 1-510 2- NHBoc-3-SAc-Prn - (CH 2) 2 - 1-511 2-NHBoc-3-SAc-Prn - (CH 2) 3 - 1-512 2-NHBoc-3-SAc-Prn -CH (Me) _{CH 2 - 1-513 2-NHBoc-} 3-SAc-Prn - (cHxln-4) -CH 2 - 1-514 2-NHBoc-3-SAc-Prn - (cHxln-4) - (CH 2) 2 - 1-515 2-NHBoc-3-SAc -Prn -CH 2 - (cHxln-4) - 1-516 2-NHBoc-3-SAc-Prn -CH 2 - (cHxln-2) -CH 2 - 1-517 2-NHBoc-3-SAc- Prn -CH 2 - (cHxln-3) -CH 2 - 1-518 2-NHBoc-3-SAc-Prn -CH 2 - (cHxln-4) -CH 2 - 1-519 2-NHBoc-3-SAc- Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 1-520 2-NHBoc-3-SAc-Prn - (cPnln-3) -CH 2 - 1-521 2-NHBoc-3-SAc- Prn -CH 2 - (cPnln-3) - 1-522 2-NHBoc-3-SAc-Prn -CH 2 - (cPnln-2) -CH 2 - 1-523 2-NHBoc _{-3-SAc-Prn -CH 2 -} (cPnln-3) -CH 2 - 1-524 2-N HBoc-4-SAc-Btyl - (CH 2) 2 - 1-525 2-NHBoc-4-SAc-Btyl -CH (Me) CH 2 - 1-526 2-NHBoc-4-SAc-Btyl -CH 2 - _{(cHxln-4) -CH 2 -} 1-527 3-NHBoc-4-SAc-Btyl - (CH 2) 2 - 1-528 3-NHBoc-4-SAc-Btyl -CH (Me) CH 2 - 1- 529 3-NHBoc-4-SAc -Btyl -CH 2 - (cHxln-4) -CH 2 - 1-530 2-NHBoc-5-SAc-Val -CH (Me) CH 2 - 1-531 2-NHMe- 3-SAc-Prn - (CH 2) 2 - 1-532 2-NHMe-3-SAc-Prn -CH (Me) CH 2 - 1-533 2-NHMe-3-SAc-Prn -CH 2 - (cHxln _{-4) -CH 2 - 1-534 2-} NHMe-4-SAc-Btyl -CH (Me) CH 2 - 1-535 3-NHMe-4-SAc-Btyl -CH (Me) CH 2 - 1-536 2-NHEt-3-SAc- Prn - (CH 2) 2 - 1-537 2-NHEt-3-SAc-Prn -CH (Me) CH 2 - 1-538 2-NHEt-3-SAc-Prn -CH _{2 - (cHxln-4) -CH} 2 - 1-539 2-NHEt-4-SAc-Btyl -CH (Me) CH 2 - 1-540 3-NHEt-4-SAc-Btyl -CH (Me) CH 2 _{- 1-541 2-NMe 2 -3-} SAc-Prn - (CH 2) 2 - 1-542 2-NMe 2 -3-SAc-Prn -CH (Me) CH 2 - 1-543 2-NMe 2 - _{3-SAc-Prn -CH 2 -} (cHxln-4) -CH 2 - 1-544 2-NMe 2 -4-SAc-Btyl -CH (Me) CH 2 - 1-545 3-NMe 2 -4-SAc _{-Btyl -CH (Me) CH 2 -} 1-546 2-NMeAc-3-SAc-Prn -CH (Me) CH 2 - 1-547 2-NMeBoc-3-SAc-Prn -CH (Me) CH 2 - 1-548 2-SPrn-Ac - ( CH 2) 2 - 1-549 2-SPrn-Ac _{-CH (Me) CH 2 - 1-550} 2-SPrn-Ac -CH 2 - (cHxln-4) -CH 2 - 1-551 2-Me-2-SPrn-Ac - (CH 2) 2 - 1- 552 2-Me-2-SPrn -Ac -CH (Me) CH 2 - 1-553 2-Me-2-SPrn-Ac -CH 2 - (cHxln-4) -CH 2 - 1-554 3-SPrn- _{prn - (CH 2) 2 -} 1-555 3-SPrn-prn -CH (Me) CH 2 - 1-556 3-SPrn-prn - (cHxln-4) -CH 2 - 1-557 3-SPrn-prn _{-CH 2 - (cHxln-4)} - 1-558 3-SPrn-Prn -CH 2 - (cHxln-2) -CH 2 - 1-559 3-SPrn-Prn -CH 2 - (cHxln-3) -CH _{2 - 1-560 3-SPrn-Prn} -CH 2 - (cHxln-4) -CH 2 - 1-561 2-Me-3-SPrn-Prn - (CH 2) 2 - 1-562 2-Me-3 -SPrn-Prn -CH (Me) CH 2 - 1-563 2-Me-3-SPrn-Prn - (cHxln-4) -CH 2 - 1-564 2-Me-3-SPrn-Prn -CH 2 - (cHxln-4) - 1-565 2 -Me-3-SPrn-Prn -CH 2 - (cHxln-2) -CH 2 - 1-566 2-Me-3-SPrn-Prn -CH 2 - (cHxln- _{3) -CH 2 - 1-567 2-} Me-3-SPrn-Prn -CH 2 - (cHxln-4) -CH 2 - 1-568 3-Me-3-SPrn-Prn - (CH 2) 2 - 1-569 3-Me-3-SPrn -Prn -CH (Me) CH 2 - 1-570 3-Me-3-SPrn-Prn -CH 2 - (cHxln-4) -CH 2 - 1-571 2- Et-3-SPrn-Prn - (CH 2) 2 - 1-572 2-Et-3-SPrn-Prn -CH (Me) CH 2 - 1-573 2-Et-3-SPrn-Prn -CH 2 - _{(cHxln-4) -CH 2 -} 1-574 4-SPrn-Btyl - (CH 2) 2 - 1-575 4-SPrn-Btyl -CH (M _{e) CH 2 - 1-576 4-} SPrn-Btyl -CH 2 - (cHxln-4) -CH 2 - 1-577 2-Me-4-SPrn-Btyl - (CH 2) 2 - 1-578 2- Me-4-SPrn-Btyl -CH (Me) CH 2 - 1-579 2-Me-4-SPrn-Btyl -CH 2 - (cHxln-4) -CH 2 - 1-580 3-Me-4-SPrn _{-Btyl -CH (Me) CH 2 -} 1-581 4-Me-4-SPrn-Btyl -CH (Me) CH 2 - 1-582 5-SPrn-Val -CH (Me) CH 2 - 1-583 2 _{-NH 2 -3-SPrn-Prn -} (CH 2) 2 - 1-584 2-NH 2 -3-SPrn-Prn -CH (Me) CH 2 - 1-585 2-NH 2 -3-SPrn-Prn _{- (cHxln-4) -CH 2} - 1-586 2-NH 2 -3-SPrn-Prn -CH 2 - (cHxln-4) - 1-587 2-NH 2 -3-SPrn-Prn -CH 2 - _{(cHxln-4) -CH 2 -} 1-588 2-NH 2 -4-SPrn-Btyl -CH (Me) CH 2 - 1-589 3-NH 2 -4-SPrn-Btyl -CH (Me) CH 2 - 1-590 2-NHAc-3- SPrn-Prn - (CH 2) 2 - 1-591 2-NHAc-3-SPrn-Prn -CH (Me) CH 2 - 1-592 2-NHAc-3-SPrn _{-Prn -CH 2 - (cHxln-4} ) -CH 2 - 1-593 2-NHAc-4-SPrn-Btyl -CH (Me) CH 2 - 1-594 3-NHAc-4-SPrn-Btyl -CH ( _{Me) CH 2 - 1-595 2-} NHBoc-3-SPrn-Prn - (CH 2) 2 - 1-596 2-NHBoc-3-SPrn-Prn -CH (Me) CH 2 - 1-597 2-NHBoc _{-3-SPrn-Prn -CH 2 -} (cHxln-4) -CH 2 - 1-598 2-NHBoc-4-SPrn-Btyl -CH (Me) CH 2 - 1-599 3-NHBoc-4-SPrn- _{Btyl -CH (Me) CH 2 -} 1-600 2-NHMe-3-SPrn-Prn - _{CH (Me) CH 2 - 1-601} 2-NHEt-3-SPrn-Prn -CH (Me) CH 2 - 1-602 2-NMe 2 -3-SPrn-Prn -CH (Me) CH 2 - 1- 603 3-SBrn-Prn - ( CH 2) 2 - 1-604 3-SBrn-Prn -CH (Me) CH 2 - 1-605 3-SBrn-Prn -CH 2 - (cHxln-4) -CH 2 - 1-606 2-Me-3-SBrn -Prn - (CH 2) 2 - 1-607 2-Me-3-SBrn-Prn -CH (Me) CH 2 - 1-608 2-Me-3-SBrn- _{prn -CH 2 - (cHxln-4} ) -CH 2 - 1-609 2-NH 2 -3-SBrn-prn -CH (Me) CH 2 - 1-610 2-SBoz-Ac -CH (Me) CH 2 - 1-611 2-Me-2- SBoz-Ac -CH (Me) CH 2 - 1-612 3-SBoz-Prn - (CH 2) 2 - 1-613 3-SBoz-Prn -CH (Me) CH _{2 - 1-614 3-SBoz-Prn} -CH 2 - (cHxln-4) -CH 2 - 1-615 2-Me-3-SBoz-Prn - (CH 2) 2 - 1-616 2-Me-3 -SBoz-Prn -CH (Me) CH 2 - 1-617 2-Me-3-SBoz-Prn -CH 2 - (cHxln-4) -CH 2 - 1-618 3-Me-3-SBoz-Prn - _{CH (Me) CH 2 - 1-619} 2-Et-3-SBoz-Prn -CH (Me) CH 2 - 1-620 4-SBoz-Btyl -CH (Me) CH 2 - 1-621 2-NH 2 -3-SBoz-Prn - (CH 2) 2 - 1-622 2-NH 2 -3-SBoz-Prn -CH (Me) CH 2 - 1-623 2-NH 2 -3-SBoz-Prn -CH 2 _{- (cHxln-4) -CH 2} - 1-624 2-NH 2 -4-SBoz-Btyl -CH (Me) CH 2 - 1-625 3-NH 2 -4-SBoz-Btyl -CH (Me) CH _{2 - 1-626 2-NHAc-3} -SBoz-Prn - (CH 2) 2 - 1-627 2-NHAc-3-SBoz- _{Prn -CH (Me) CH 2 -} 1-628 2-NHAc-3-SBoz-Prn -CH 2 - (cHxln-4) -CH 2 - 1-629 2-NHBoc-3-SBoz-Prn - (CH 2 _{) 2 - 1-630 2-NHBoc-} 3-SBoz-Prn -CH (Me) CH 2 - 1-631 2-NHBoc-3-SBoz-Prn -CH 2 - (cHxln-4) -CH 2 - 1- 632 2-NHMe-3-SBoz -Prn -CH (Me) CH 2 - 1-633 2-NHEt-3-SBoz-Prn -CH (Me) CH 2 - 1-634 2-NMe 2 -3-SBoz- _{prn -CH (Me) CH 2 -} 1-635 2- (2-ThiCOS) -Ac -CH (Me) CH 2 - 1-636 2-Me-2- (2-ThiCOS) -Ac -CH (Me) _{CH 2 - 1-637 3- (2-} ThiCOS) -Prn - (CH 2) 2 - 1-638 3- (2-ThiCOS) -Prn -CH (Me) CH 2 - 1-639 3- (3- ThiCOS) -Prn -CH (Me) CH 2 - 1-640 3- (2-ThiCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 1-641 2-Me-3- (2-ThiCOS _{) -Prn - (CH 2) 2} - 1-642 2-Me-3- (2-ThiCOS) -Prn -CH (Me) CH 2 - 1-643 2-Me-3- (3-ThiCOS) -Prn _{-CH (Me) CH 2 - 1-644} 2-Me-3- (2-ThiCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 1-645 3-Me-3- (2-ThiCOS _{) -Prn -CH (Me) CH 2} - 1-646 2-Et-3- (2-ThiCOS) -Prn -CH (Me) CH 2 - 1-647 4- (2-ThiCOS) -Btyl -CH ( _{Me) CH 2 - 1-648 2-} NH 2 -3- (2-ThiCOS) -Prn - (CH 2) 2 - 1-649 2-NH 2 -3- (2-ThiCOS) -Prn -CH (Me _{) CH 2 - 1-650 2-NH} 2 -3- (2-ThiCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 1-651 2-NHAc-3- (2-ThiCOS) -Prn -CH ( Me) CH 2 - 1-652 2-NHBoc-3- (2-ThiCOS) -Prn -CH (Me) CH 2 - 1-653 2-NHMe-3- (2 -ThiCOS) -Prn -CH (Me) CH 2 - 1-654 2-NHEt-3- (2-ThiCOS) -Prn -CH (Me) CH 2 - 1-655 2-NMe 2 -3- (2- ThiCOS) -Prn -CH (Me) CH 2 - 1-656 2- (2-FurCOS) -Ac -CH (Me) CH 2 - 1-657 2-Me-2- (2-FurCOS) -Ac -CH _{(Me) CH 2 - 1-658 3-} (2-FurCOS) -Prn - (CH 2) 2 - 1-659 3- (2-FurCOS) -Prn -CH (Me) CH 2 - 1-660 3- (3-FurCOS) -Prn -CH ( Me) CH 2 - 1-661 3- (2-FurCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 1-662 2-Me-3- ( 2-FurCOS) -Prn - (CH 2) 2 - 1-663 2-Me-3- (2-FurCOS) -Prn -CH (Me) CH 2 - 1-664 2-Me-3- (3-FurCOS _{) -Prn -CH (Me) CH 2} - 1-665 2-Me-3- (2-FurCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 1-666 3-Me-3- ( 2-FurCOS) -Prn -CH (Me ) CH 2 - 1-667 2-Et-3- (2-FurCOS) -Prn -CH (Me) CH 2 - 1-668 4- (2-FurCOS) -Btyl _{-CH (Me) CH 2 - 1-669} 2-NH 2 -3- (2-FurCOS) -Prn - (CH 2) 2 - 1-670 2-NH 2 -3- (2-FurCOS) -Prn - _{CH (Me) CH 2 - 1-671} 2-NH 2 -3- (2-FurCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 1-672 2-NHAc-3- (2-FurCOS _{) -Prn -CH (Me) CH 2} - 1-673 2-NHBoc-3- (2-FurCOS) -Prn -CH (Me) CH 2 - 1-674 2-NHMe-3- (2-FurCOS) - _{Prn -CH (Me) CH 2 -} 1-675 2-NHEt-3- (2-FurCOS) -Prn -CH (Me) CH 2 - 1-676 2-NMe 2 -3- (2-FurCOS) -Prn _{-CH (Me) CH 2 - 1-677} 2- (4-PyrCOS) -Ac -CH (Me) CH 2 - 1-678 2-Me-2- (4-PyrCOS) -Ac -CH (Me) CH _{2 - 1-679 3- (4-PyrCOS} ) -Prn - (CH 2) 2 - 1-680 3- (2-PyrCOS) -Prn -CH (Me) CH 2 - 1-681 3- (3-PyrCOS _{) -Prn -CH (Me) CH 2} - 1-682 3- (4-PyrCOS) -Prn -CH (Me) CH 2 - 1-683 3- (4-PyrCOS) -Prn -CH 2 - (cHxln- _{4) -CH 2 - 1-684 2-} Me-3- (4-PyrCOS) -Prn - (CH 2) 2 - 1-685 2-Me-3- (2-PyrCOS) -Prn -CH (Me) _{CH 2 - 1-686 2-Me-} 3- (3-PyrCOS) -Prn -CH (Me) CH 2 - 1-687 2-Me-3- (4-PyrCOS) -Prn -CH (Me) CH 2 - 1-688 2-Me-3- ( 4-PyrCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 1-689 3-Me-3- (4-PyrCOS) -Prn -CH (Me _{) CH 2 - 1-690 2-Et} -3- (4-PyrCOS) -Prn -CH (Me) CH 2 - 1-691 4- (4-PyrCOS) -Btyl -CH (Me) CH 2 - 1- _{692 2-NH 2 -3- (4} -PyrCOS) -Prn - (CH 2) 2 - 1-693 2-NH 2 -3- (4-PyrCOS) -Prn -CH (Me) CH 2 - 1-694 _{2-NH 2 -3- (4-} PyrCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 1-695 2-NHAc-3- (4-PyrCOS) -Prn -CH (Me) CH 2 - 1-696 2-NHBoc-3- ( 4-PyrCOS) -Prn -CH (Me) CH 2 - 1-697 2-NHMe-3- (4-PyrCOS) -Prn -CH (Me) CH 2 - 1 -6 98 2-NHEt-3- (4 -PyrCOS) -Prn -CH (Me) CH 2 - 1-699 2-NMe 2 -3- (4-PyrCOS) -Prn -CH (Me) CH 2 - 1-700 2-SH-Ac -CH (Et ) CH 2 - 1-701 2-SH-Ac -CH (Pr) CH 2 - 1-702 2-SH-Ac -CH (Bu) CH 2 - 1-703 2- SH-Ac -CH (iBu) CH 2 - 1-704 2-SAc-Ac -CH (Et) CH 2 - 1-705 2-SAc-Ac -CH (Pr) CH 2 - 1-706 2-SAc- _{Ac -CH (Bu) CH 2 -} 1-707 2-SAc-Ac -CH (iBu) CH 2 - 1-708 2-NH 2 -2-SH-Ac -CH (Me) CH 2 - 1-709 2 _{-NH 2 -2-SH-Ac -CH} (Et) CH 2 - 1-710 2-NH 2 -2-SH-Ac -CH (Pr) CH 2 - 1-711 2-NH 2 -2-SH- _{Ac -CH (Bu) CH 2 -} 1-712 2-NH 2 -2-SH-Ac -CH (iBu) CH 2 - 1-713 2-NHAc-2-SH-Ac -CH (Me) CH 2 - 1-714 2-NHAc-2-SH -Ac -CH (Et) CH 2 - 1-715 2-NHAc-2-SH-Ac -CH (Pr) CH 2 - 1-716 2-NHAc-2-SH _{-Ac -CH (Bu) CH 2 -} 1-717 2-NHAc-2-SH-Ac -CH (iBu) CH 2 - 1-718 2-NH 2 -2-SAc-Ac -CH (Me) CH 2 _{- 1-719 2-NH 2 -2-} SAc-Ac -CH (Et) CH 2 - 1-720 2-NH 2 -2-SAc-Ac -CH (Pr) CH 2 - 1-721 2-NH 2 -2-SAc-Ac -CH (Bu ) CH 2 - 1-722 2-NH 2 -2-SAc-Ac -CH (iBu) CH 2 - 1-723 2-NHAc-2-SAc-Ac -CH ( _{Me) CH 2 - 1-724 2-} NHAc-2-SAc-Ac -CH (Et) CH 2 - 1-725 2-NHAc-2-SAc-Ac -CH (Pr) CH 2 - 1-726 2- NHAc-2-SAc-Ac -CH (Bu) CH _{2 - 1-727 2-NHAc-2} -SAc-Ac -CH (iBu) CH 2 - 1-728 3-SH-Prn -CH (Et) CH 2 - 1-729 3-SH-Prn -CH (Pr _{) CH 2 - 1-730 3-SH} -Prn -CH (Bu) CH 2 - 1-731 3-SH-Prn -CH (iBu) CH 2 - 1-732 3-SAc-Prn -CH (Bu) CH _{2 - 1-733 3-SAc-Prn} -CH (iBu) CH 2 - 1-734 2-Me-3-SH-Prn -CH (Et) CH 2 - 1-735 2-Me-3-SH-Prn _{-CH (Pr) CH 2 - 1-736} 2-Me-3-SH-Prn -CH (Bu) CH 2 - 1-737 2-Me-3-SH-Prn -CH (iBu) CH 2 - 1- 738 2-Me-3-SAc -Prn -CH (Bu) CH 2 - 1-739 2-Me-3-SAc-Prn -CH (iBu) CH 2 - 1-740 2-NH 2 -3-SH- _{prn -CH (Bu) CH 2 -} 1-741 2-NH 2 -3-SH-prn -CH (iBu) CH 2 - 1-742 2-NHAc-3-SH-prn -CH (Et) CH 2 - 1-743 2-NHAc-3-SH -Prn -CH (Pr) CH 2 - 1-744 2-NHAc-3-SH-Prn -CH (Bu) CH 2 - 1-745 2-NHAc-3-SH _{-Prn -CH (iBu) CH 2 -} 1-746 2-NH 2 -3-SAc-Prn -CH (Et) CH 2 - 1-747 2-NH 2 -3-SAc-Prn -CH (Pr) CH _{2 - 1-748 2-NH 2 -3} -SAc-Prn -CH (Bu) CH 2 - 1-749 2-NH 2 -3-SAc-Prn -CH (iBu) CH 2 - 1-750 2-NHAc -3-SAc-Prn -CH (Et ) CH 2 - 1-751 2-NHAc-3-SAc-Prn -CH (Pr) CH 2 - 1-752 2-NHAc-3-SAc-Prn -CH (Bu _{) CH 2 - 1-753 2-NHAc} -3-SAc-Prn -CH (iBu) CH 2 - ───────────────── ─────────────────.

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[Table 2] {Compound No. R ¹ A} ─────────────────────────────── 2-1 2-SH-Ac - (CH 2) 2 - 2-2 2 -SH-Ac -CH (Me) CH 2 - 2-3 2-SH-Ac - (cHxln-4) -CH 2 - 2-4 2-SH-Ac -CH 2 - (cHxln-4) - 2- _{5 2-SH-Ac -CH 2} - (cHxln-4) -CH 2 - 2-6 2-Me-2-SH-Ac - (CH 2) 2 - 2-7 2-Me-2-SH-Ac _{-CH (Me) CH 2 - 2-8} 2-Me-2-SH-Ac - (cHxln-4) -CH 2 - 2-9 2-Me-2-SH-Ac -CH 2 - (cHxln-4 ) - 2-10 2-Me-2 -SH-Ac -CH 2 - (cHxln-4) -CH 2 - 2-11 3-SH-Prn - (CH 2) 2 - 2-12 3-SH-Prn _{- (CH 2) 3 - 2-13} 3-SH-Prn -CH (Me) CH 2 - 2-14 3-SH-Prn - (cHxln-4) -CH 2 - 2-15 3-SH-Prn - _{CH 2 - (cHxln-4)} - 2-16 3-SH-Prn -CH 2 - (cHxln-2) -CH 2 - 2-17 3-SH-Prn -CH 2 - (cHxln-3) -CH 2 - 2-18 3-SH-Prn -CH 2 - (cHxln-4) -CH 2 - 2-19 3-SH-Prn -CH 2 -2-Me- (cHxln-4) -CH 2 - 2-20 _{3-SH-Prn -CH 2 -3} -Me- (cHxln-4) -CH 2 - 2-21 3-SH-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 2-22 3 -SH-Prn - (cPnln-3 ) -CH 2 - 2- _{23 3-SH-Prn -CH 2} - (cPnln-3) - 2-24 3-SH-Prn -CH 2 - (cPnln-2) -CH 2 - 2-25 3-SH-Prn -CH 2 - ( _{cPnln-3) -CH 2 - 2-26} 2-Me-3-SH-Prn - (CH 2) 2 - 2-27 2-Me-3-SH-Prn - (CH 2) 3 - 2-28 2 -Me-3-SH-Prn -CH (Me) CH 2 - 2-29 2-Me-3-SH-Prn - (cHxln-4) -CH 2 - 2-30 2-Me-3-SH-Prn _{-CH 2 - (cHxln-4)} - 2-31 2-Me-3-SH-Prn -CH 2 - (cHxln-2) -CH 2 - 2-32 2-Me-3-SH-Prn -CH 2 _{- (cHxln-3) -CH 2} - 2-33 2-Me-3-SH-Prn -CH 2 - (cHxln-4) -CH 2 - 2-34 2-Me-3-SH-Prn -CH 2 -2-Me- (cHxln-4) -CH 2 - 2-35 2-Me-3-SH-Prn -CH 2 -3-Me- (cHxln-4) -CH 2 - 2-36 2-Me- _{3-SH-Prn -CH 2 -} (cHxln-4) - (CH 2) 2 - 2-37 2-Me-3-SH-Prn - (cPnln-3) -CH 2 - 2-38 2-Me- _{3-SH-Prn -CH 2 -} (cPnln-3) - 2-39 2-Me-3-SH-Prn -CH 2 - (cPnln-2) -CH 2 - 2-40 2-Me-3-SH _{-Prn -CH 2 - (cPnln-3} ) -CH 2 - 2-41 3-Me-3-SH-Prn - (CH 2) 2 - 2-42 3-Me-3-SH-Prn -CH (Me _{) CH 2 - 2-43 3-Me} -3-SH-Prn - (cHxln-4) -CH 2 - 2-44 3-Me-3-SH-Prn -CH 2 - (cHxln-4) - 2- 45 3-Me-3-SH -Prn -CH 2 - (cHxln-4) -CH 2 - 2-46 2-Et-3-SH-Prn - (CH 2) 2 - 2-47 2-Et-3 -SH-Prn -CH (Me) CH 2 - 2-48 2-Et-3-SH-Prn - (cHxln-4) -CH 2 - 2-49 2 -Et-3-SH-Prn -CH 2 - (cHxln-4) - 2-50 2-Et-3-SH-Prn -CH 2 - (cHxln-4) -CH 2 - 2-51 4-SH- _{Btyl - (CH 2) 2 -} 2-52 4-SH-Btyl -CH (Me) CH 2 - 2-53 4-SH-Btyl - (cHxln-4) -CH 2 - 2-54 4-SH-Btyl _{-CH 2 - (cHxln-4)} - 2-55 4-SH-Btyl -CH 2 - (cHxln-4) -CH 2 - 2-56 2-Me-4-SH-Btyl - (CH 2) 2 - 2-57 2-Me-4-SH -Btyl -CH (Me) CH 2 - 2-58 2-Me-4-SH-Btyl - (cHxln-4) -CH 2 - 2-59 2-Me-4 _{-SH-Btyl -CH 2 - (cHxln} -4) - 2-60 2-Me-4-SH-Btyl -CH 2 - (cHxln-4) -CH 2 - 2-61 3-Me-4-SH- _{Btyl - (CH 2) 2 -} 2-62 3-Me-4-SH-Btyl -CH (Me) CH 2 - 2-63 3-Me-4-SH-Btyl -CH 2 - (cHxln-4) - _{CH 2 - 2-64 4-Me-} 4-SH-Btyl - (CH 2) 2 - 2-65 4-Me-4-SH-Btyl -CH (Me) CH 2 - 2-66 4-Me-4 _{-SH-Btyl -CH 2 - (cHxln} -4) -CH 2 - 2-67 5-SH-Val - (CH 2) 2 - 2-68 5-SH-Val -CH (Me) CH 2 - 2- _{69 5-SH-Val -CH 2} - (cHxln-4) -CH 2 - 2-70 2-Me-5-SH-Val - (CH 2) 2 - 2-71 2-Me-5-SH-Val _{-CH (Me) CH 2 - 2-72} 2-Me-5-SH-Val -CH 2 - (cHxln-4) -CH 2 - 2-73 5-Me-5-SH-Val - (CH 2) _{2 - 2-74 5-Me-5} -SH-Val -CH (Me) CH 2 - 2-75 5-Me-5-SH-Val -CH 2 - (cHxln-4) -CH 2 - 2-76 6-SH-Hxn - (CH 2) 2 - 2-77 6-SH-Hxn -CH (M _{e) CH 2 - 2-78 6-} SH-Hxn -CH 2 - (cHxln-4) -CH 2 - 2-79 2-NH 2 -3-SH-Prn - (CH 2) 2 - 2-80 2 _{-NH 2 -3-SH-Prn -} (CH 2) 3 - 2-81 2-NH 2 -3-SH-Prn -CH (Me) CH 2 - 2-82 2-NH 2 -3-SH-Prn _{-CH 2 CH (Me) - 2-83} 2-NH 2 -3-SH-Prn -CH (Et) CH 2 - 2-84 2-NH 2 -3-SH-Prn -CH (Pr) CH 2 - _{2-85 2-NH 2 -3-SH} -Prn - (CH 2) 4 - 2-86 2-NH 2 -3-SH-Prn - (CH 2) 5 - 2-87 2-NH 2 -3- _{SH-Prn - (CH 2)} 6 - 2-88 2-NH 2 -3-SH-Prn - (cHxln-4) - 2-89 2-NH 2 -3-SH-Prn - (cHxln-4) - _{CH 2 - 2-90 2-NH 2} -3-SH-Prn - (cHxln-4) - (CH 2) 2 - 2-91 2-NH 2 -3-SH-Prn -CH 2 - (cHxln-4 )-2-92 2-NH ₂ -3-SH-Prn-(CH ₂ ) _2- (cHxln-4)-2-93 2-NH ₂ -3-SH-Prn -CH _2- (cHxln-2) _{-CH 2 - 2-94 2-NH 2} -3-SH-Prn -CH 2 - (cHxln-3) -CH 2 - 2-95 2-NH 2 -3-SH-Prn -CH 2 - (cHxln- _{4) -CH 2 - 2-96 2-} NH 2 -3-SH-Prn -CH 2 -2-Me- (cHxln-4) -CH 2 - 2-97 2-NH 2 -3-SH-Prn - _{CH 2 -3-Me- (cHxln-} 4) -CH 2 - 2-98 2-NH 2 -3-SH-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 2-99 2- _{NH 2 -3-SH-Prn -} (CH 2) 2 - (cHxln-4) -CH 2 - 2-100 2-NH 2 -3-SH-Prn - (CH 2) 2 - (cHxln-4) - _{(CH 2) 2 - 2-101 2} -NH 2 -3-SH-Prn - (cPnln- _{3) - 2-102 2-NH 2} -3-SH-Prn - (cPnln-3) -CH 2 - 2-103 2-NH 2 -3-SH-Prn -CH 2 - (cPnln-3) - 2 _{-104 2-NH 2 -3-SH} -Prn -CH 2 - (cPnln-2) -CH 2 - 2-105 2-NH 2 -3-SH-Prn -CH 2 - (cPnln-3) -CH 2 _{- 2-106 2-NH 2 -3-} SH-Prn -CH 2 - (cPnln-3) - (CH 2) 2 - 2-107 2-NH 2 -4-SH-Btyl - (CH 2) 2 - _{2-108 2-NH 2 -4-SH} -Btyl - (CH 2) 3 - 2-109 2-NH 2 -4-SH-Btyl -CH (Me) CH 2 - 2-110 2-NH 2 -4 -SH-Btyl - (cHxln-4 ) -CH 2 - 2-111 2-NH 2 -4-SH-Btyl -CH 2 - (cHxln-4) - 2-112 2-NH 2 -4-SH-Btyl _{-CH 2 - (cHxln-2)} -CH 2 - 2-113 2-NH 2 -4-SH-Btyl -CH 2 - (cHxln-3) -CH 2 - 2-114 2-NH 2 -4-SH _{-Btyl -CH 2 - (cHxln-4} ) -CH 2 - 2-115 2-NH 2 -4-SH-Btyl -CH 2 - (cHxln-4) - (CH 2) 2 - 2-116 2-NH _{2 -4-SH-Btyl - (} cPnln-3) -CH 2 - 2-117 2-NH 2 -4-SH-Btyl -CH 2 - (cPnln-3) - 2-118 2-NH 2 -4- _{SH-Btyl -CH 2 - (cPnln} -2) -CH 2 - 2-119 2-NH 2 -4-SH-Btyl -CH 2 - (cPnln-3) -CH 2 - 2-120 3-NH 2 - 4-SH-Btyl - (CH 2) 2 - 2-121 3-NH 2 -4-SH-Btyl -CH (Me) CH 2 - 2-122 3-NH 2 -4-SH-Btyl - (cHxln- _{4) -CH 2 - 2-123 3-} NH 2 -4-SH-Btyl -CH 2 - (cHxln-4) - 2-124 3-NH 2 -4-SH-Btyl -CH 2 - (cHxl _{n-2) -CH 2 - 2-125} 3-NH 2 -4-SH-Btyl -CH 2 - (cHxln-3) -CH 2 - 2-126 3-NH 2 -4-SH-Btyl -CH 2 _{- (cHxln-4) -CH 2} - 2-127 2-NH 2 -5-SH-Val - (CH 2) 2 - 2-128 2-NH 2 -5-SH-Val -CH (Me) CH 2 _{- 2-129 2-NH 2 -5-} SH-Val - (cHxln-4) -CH 2 - 2-130 2-NH 2 -5-SH-Val -CH 2 - (cHxln-4) - 2-131 _{2-NH 2 -5-SH-} Val -CH 2 - (cHxln-4) -CH 2 - 2-132 2-NH 2 -6-SH-Hxn - (CH 2) 2 - 2-133 2-NH 2 -6-SH-Hxn -CH (Me ) CH 2 - 2-134 2-NH 2 -6-SH-Hxn - (cHxln-4) -CH 2 - 2-135 2-NH 2 -6-SH-Hxn _{-CH 2 - (cHxln-4)} - 2-136 2-NH 2 -6-SH-Hxn -CH 2 - (cHxln-4) -CH 2 - 2-137 2-NHAc-3-SH-Prn - ( _{CH 2) 2 - 2-138 2-} NHAc-3-SH-Prn - (CH 2) 3 - 2-139 2-NHAc-3-SH-Prn -CH (Me) CH 2 - 2-140 2-NHAc -3-SH-Prn - (cHxln -4) -CH 2 - 2-141 2-NHAc-3-SH-Prn -CH 2 - (cHxln-4) - 2-142 2-NHAc-3-SH-Prn _{-CH 2 - (cHxln-2)} -CH 2 - 2-143 2-NHAc-3-SH-Prn -CH 2 - (cHxln-3) -CH 2 - 2-144 2-NHAc-3-SH-Prn _{-CH 2 - (cHxln-4)} -CH 2 - 2-145 2-NHAc-3-SH-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 2-146 2-NHAc-3- SH-Prn - (cPnln-3 ) -CH 2 - 2-147 2-NHAc-3-SH-Prn -CH 2 - (cPnln-3) - 2-148 2-NHAc-3-SH-Prn -CH 2 -(cPn _{ln-2) -CH 2 - 2-149} 2-NHAc-3-SH-Prn -CH 2 - (cPnln-3) -CH 2 - 2-150 2-NHAc-4-SH-Btyl - (CH 2) _{2 - 2-151 2-NHAc-4} -SH-Btyl - (CH 2) 3 - 2-152 2-NHAc-4-SH-Btyl -CH (Me) CH 2 - 2-153 2-NHAc-4- SH-Btyl - (cHxln-4 ) -CH 2 - 2-154 2-NHAc-4-SH-Btyl -CH 2 - (cHxln-4) - 2-155 2-NHAc-4-SH-Btyl -CH 2 _{- (cHxln-2) -CH 2} - 2-156 2-NHAc-4-SH-Btyl -CH 2 - (cHxln-3) -CH 2 - 2-157 2-NHAc-4-SH-Btyl -CH 2 _{- (cHxln-4) -CH 2} - 2-158 3-NHAc-4-SH-Btyl - (CH 2) 2 - 2-159 3-NHAc-4-SH-Btyl -CH (Me) CH 2 - 2 -160 3-NHAc-4-SH -Btyl - (cHxln-4) -CH 2 - 2-161 3-NHAc-4-SH-Btyl -CH 2 - (cHxln-4) - 2-162 3-NHAc- _{4-SH-Btyl -CH 2 -} (cHxln-4) -CH 2 - 2-163 2-NHAc-5-SH-Val - (CH 2) 2 - 2-164 2-NHAc-5-SH-Val - _{CH (Me) CH 2 - 2-165} 2-NHAc-5-SH-Val -CH 2 - (cHxln-4) -CH 2 - 2-166 2-NHAc-6-SH-Hxn - (CH 2) 2 - 2-167 2-NHAc-6- SH-Hxn -CH (Me) CH 2 - 2-168 2-NHAc-6-SH-Hxn -CH 2 - (cHxln-4) -CH 2 - 2-169 2 -NHBoc-3-SH-Prn - (CH 2) 2 - 2-170 2-NHBoc-3-SH-Prn - (CH 2) 3 - 2-171 2-NHBoc-3-SH-Prn -CH (Me _{) CH 2 - 2-172 2-NHBoc} -3-SH-Prn - (cHxln-4) -CH 2 - 2-173 2-NHBoc-3-SH-Prn _{-CH 2 - (cHxln-4)} - 2-174 2-NHBoc-3-SH-Prn -CH 2 - (cHxln-2) -CH 2 - 2-175 2-NHBoc-3-SH-Prn -CH 2 _{- (cHxln-3) -CH 2} - 2-176 2-NHBoc-3-SH-Prn -CH 2 - (cHxln-4) -CH 2 - 2-177 2-NHBoc-3-SH-Prn -CH 2 - (cHxln-4) - ( CH 2) 2 - 2-178 2-NHBoc-3-SH-Prn - (cPnln-3) -CH 2 - 2-179 2-NHBoc-3-SH-Prn -CH 2 - (cPnln-3) - 2-180 2-NHBoc-3-SH-Prn -CH 2 - (cPnln-2) -CH 2 - 2-181 2-NHBoc-3-SH-Prn -CH 2 - (cPnln _{-3) -CH 2 - 2-182 2-} NHBoc-3-SH-Prn -CH 2 - (cPnln-3) - (CH 2) 2 - 2-183 2-NHBoc-4-SH-Btyl - (CH _{2) 2 - 2-184 2-NHBoc} -4-SH-Btyl -CH (Me) CH 2 - 2-185 2-NHBoc-4-SH-Btyl - (cHxln-4) -CH 2 - 2-186 2 -NHBoc-4-SH-Btyl -CH 2 - (cHxln-4) - 2-187 2-NHBoc-4-SH-Btyl -CH 2 - (cHxln-2) -CH 2 - 2-188 2-NHBoc- _{4-SH-Btyl -CH 2 -} (cHxln-3) -CH 2 - 2-189 2-NHBoc-4-SH-Btyl -CH 2 - (cHxln-4) -CH 2 - 2-190 3-NHBoc- 4-SH-Btyl - (CH 2) 2 - 2-191 3-NHBoc-4-SH-Btyl -CH (Me) CH 2 - 2-192 3-NHBoc-4-SH-Btyl - (cHxln-4) _{-CH 2 - 2-193 3-NHBoc-} 4-SH-Btyl -CH 2 - (cHxln-4) - 2-194 3-NHBoc-4-SH-Btyl -CH 2 - (cHxln-4) -CH 2 - 2-195 2-NHBoc-5- SH-Val - (CH 2) 2 - 2-196 2-NHBoc-5 -SH-Val -CH (Me) CH 2 - 2-197 2-NHBoc-5-SH-Val -CH 2 - (cHxln-4) -CH 2 - 2-198 2-NHBoc-6-SH-Hxn - _{(CH 2) 2 - 2-199 2} -NHBoc-6-SH-Hxn -CH (Me) CH 2 - 2-200 2-NHBoc-6-SH-Hxn -CH 2 - (cHxln-4) -CH 2 - 2-201 2-NHMe-3- SH-Prn - (CH 2) 2 - 2-202 2-NHMe-3-SH-Prn -CH (Me) CH 2 - 2-203 2-NHMe-3-SH _{-Prn -CH 2 - (cHxln-4} ) -CH 2 - 2-204 2-NHMe-4-SH-Btyl -CH (Me) CH 2 - 2-205 3-NHMe-4-SH-Btyl -CH ( _{Me) CH 2 - 2-206 2-} NHEt-3-SH-Prn - (CH 2) 2 - 2-207 2-NHEt-3-SH-Prn -CH (Me) CH 2 - 2-208 2-NHEt _{-3-SH-Prn -CH 2 -} (cHxln-4) -CH 2 - 2-209 2-NHEt-4-SH-Btyl -CH (Me) CH 2 - 2-210 3-NHEt-4-SH- _{Btyl -CH (Me) CH 2 -} 2-211 2-NMe 2 -3-SH-Prn - (CH 2) 2 - 2-212 2-NMe 2 -3-SH-Prn -CH (Me) CH 2 - _{2-213 2-NMe 2 -3-SH} -Prn -CH 2 - (cHxln-4) -CH 2 - 2-214 2-NMe 2 -4-SH-Btyl -CH (Me) CH 2 - 2-215 _{3-NMe 2 -4-SH-} Btyl -CH (Me) CH 2 - 2-216 2-NMeAc-3-SH-Prn -CH (Me) CH 2 - 2-217 2-NMeAc-4-SH-Btyl _{-CH (Me) CH 2 - 2-218} 2-NMeBoc-3-SH-Prn -CH (Me) CH 2 - 2-219 2-SAc-Ac - (CH 2) 2 - 2-220 2-SAc- _{Ac -CH (Me) CH 2 -} 2-221 2-SAc-Ac -CH 2 - (cHxln-4) -CH 2 - 2-222 2-Me-2-SAc-Ac _{- (CH 2) 2 - 2-223} 2-Me-2-SAc-Ac -CH (Me) CH 2 - 2-224 2-Me-2-SAc-Ac -CH 2 - (cHxln-4) -CH _{2 - 2-225 3-SAc-Prn} - (CH 2) 2 - 2-226 3-SAc-Prn - (CH 2) 3 - 2-227 3-SAc-Prn -CH (Me) CH 2 - 2- 228 3-SAc-Prn - ( cHxln-4) - 2-229 3-SAc-Prn - (cHxln-4) -CH 2 - 2-230 3-SAc-Prn -CH 2 - (cHxln-4) - 2 _{-231 3-SAc-Prn -CH 2} - (cHxln-2) -CH 2 - 2-232 3-SAc-Prn -CH 2 - (cHxln-3) -CH 2 - 2-233 3-SAc-Prn - _{CH 2 - (cHxln-4)} -CH 2 - 2-234 3-SAc-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 2-235 3-SAc-Prn - (cPnln-3) _{-CH 2 - 2-236 3-SAc-} Prn -CH 2 - (cPnln-3) - 2-237 3-SAc-Prn -CH 2 - (cPnln-2) -CH 2 - 2-238 3-SAc- _{prn -CH 2 - (cPnln-3} ) -CH 2 - 2-239 2-Me-3-SAc-prn - (CH 2) 2 - 2-240 2-Me-3-SAc-prn - (CH 2) _{3 - 2-241 2-Me-3} -SAc-Prn -CH (Me) CH 2 - 2-242 2-Me-3-SAc-Prn - (cHxln-4) - 2-243 2-Me-3- SAc-Prn - (cHxln-4 ) -CH 2 - 2-244 2-Me-3-SAc-Prn -CH 2 - (cHxln-4) - 2-245 2-Me-3-SAc-Prn -CH 2 _{- (cHxln-2) -CH 2} - 2-246 2-Me-3-SAc-Prn -CH 2 - (cHxln-3) -CH 2 - 2-247 2-Me-3-SAc-Prn -CH 2 _{- (cHxln-4) -CH 2} - 2-248 2-Me-3-SAc-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 2-249 2-Me-3 -SAc-Prn - (cPnln-3 ) -CH 2 - 2-250 2-Me-3-SAc-Prn -CH 2 - (cPnln-3) - 2-251 2-Me-3-SAc-Prn -CH _{2 - (cPnln-2) -CH} 2 - 2-252 2-Me-3-SAc-Prn -CH 2 - (cPnln-3) -CH 2 - 2-253 3-Me-3-SAc-Prn - ( _{CH 2) 2 - 2-254 3-} Me-3-SAc-Prn -CH (Me) CH 2 - 2-255 3-Me-3-SAc-Prn -CH 2 - (cHxln-4) -CH 2 - 2-256 2-Et-3-SAc -Prn - (CH 2) 2 - 2-257 2-Et-3-SAc-Prn -CH (Me) CH 2 - 2-258 2-Et-3-SAc- _{prn -CH 2 - (cHxln-4} ) -CH 2 - 2-259 4-SAc-Btyl - (CH 2) 2 - 2-260 4-SAc-Btyl -CH (Me) CH 2 - 2-261 4- _{SAc-Btyl -CH 2 - (cHxln} -4) -CH 2 - 2-262 2-Me-4-SAc-Btyl - (CH 2) 2 - 2-263 2-Me-4-SAc-Btyl -CH ( _{Me) CH 2 - 2-264 2-} Me-4-SAc-Btyl -CH 2 - (cHxln-4) -CH 2 - 2-265 3-Me-4-SAc-Btyl -CH (Me) CH 2 - 2-266 4-Me-4-SAc -Btyl -CH (Me) CH 2 - 2-267 5-SAc-Val -CH (Me) CH 2 - 2-268 2-Me-5-SAc-Val -CH _{(Me) CH 2 - 2-269 5} -Me-5-SAc-Val -CH (Me) CH 2 - 2-270 6-SAc-Hxn -CH (Me) CH 2 - 2-271 2-NH 2 - 3-SAc-Prn - (CH 2) 2 - 2-272 2-NH 2 -3-SAc-Prn -CH (Me) CH 2 - 2-273 2-NH 2 -3-SAc-Prn - (cHxln- _{4) -CH 2 - 2-274 2-} NH 2 -3-SAc-Prn -CH 2 - (cHxln-4) - 2-275 2-NH 2 -3-SAc-Prn -CH 2 - (cHxl _{n-2) -CH 2 - 2-276} 2-NH 2 -3-SAc-Prn -CH 2 - (cHxln-3) -CH 2 - 2-277 2-NH 2 -3-SAc-Prn -CH 2 _{- (cHxln-4) -CH 2} - 2-278 2-NH 2 -4-SAc-Btyl - (CH 2) 2 - 2-279 2-NH 2 -4-SAc-Btyl -CH (Me) CH 2 _{- 2-280 2-NH 2 -4-} SAc-Btyl -CH 2 - (cHxln-4) -CH 2 - 2-281 3-NH 2 -4-SAc-Btyl -CH (Me) CH 2 - 2- _{282 2-NH 2 -5-SAc} -Val -CH (Me) CH 2 - 2-283 2-NHAc-3-SAc-Prn - (CH 2) 2 - 2-284 2-NHAc-3-SAc-Prn _{-CH (Me) CH 2 - 2-285} 2-NHAc-3-SAc-Prn - (cHxln-4) -CH 2 - 2-286 2-NHAc-3-SAc-Prn -CH 2 - (cHxln-4 ) - 2-287 2-NHAc-3 -SAc-Prn -CH 2 - (cHxln-4) -CH 2 - 2-288 2-NHAc-4-SAc-Btyl -CH (Me) CH 2 - 2-289 3-NHAc-4-SAc- Btyl -CH (Me) CH 2 - 2-290 2-NHBoc-3-SAc-Prn - (CH 2) 2 - 2-291 2-NHBoc-3-SAc-Prn -CH _{(Me) CH 2 - 2-292 2} -NHBoc-3-SAc-Prn - (cHxln-4) -CH 2 - 2-293 2-NHBoc-3-SAc-Prn -CH 2 - (cHxln-4) - 2-294 2-NHBoc-3-SAc -Prn -CH 2 - (cHxln-4) -CH 2 - 2-295 2-NHBoc-4-SAc-Btyl -CH (Me) CH 2 - 2-296 3- NHBoc-4-SAc-Btyl -CH (Me) CH 2 - 2-297 2-NHMe-3-SAc-Prn -CH (Me) CH 2 - 2-298 2-NHEt-3-SAc-Prn -CH ( _{Me) CH 2 - 2-299 2-} NMe 2 -3-SAc-Prn -CH (Me) CH 2 - 2-300 2-NMeAc -3-SAc-Prn -CH (Me ) CH 2 - 2-301 2-NMeBoc-3-SAc-Prn -CH (Me) CH 2 - 2-302 2-SPrn-Ac -CH (Me) CH 2 - 2-303 2-Me-2-SPrn -Ac -CH (Me) CH 2 - 2-304 3-SPrn-Prn - (CH 2) 2 - 2-305 3-SPrn-Prn -CH (Me) CH 2 - 2-306 3-SPrn-Prn -CH 2 - (cHxln-4) -CH 2 - 2-307 2-Me-3-SPrn-Prn - (CH 2) 2 - 2-308 2-Me-3- SPrn-Prn -CH (Me) CH 2 - 2-309 2-Me-3-SPrn-Prn -CH 2 - (cHxln-4) -CH 2 - 2-310 3-Me-3-SPrn-Prn -CH _{(Me) CH 2 - 2-311 2} -Et-3-SPrn-Prn -CH (Me) CH 2 - 2-312 4-SPrn-Btyl -CH (Me) CH 2 - 2-313 2-Me-4 -SPrn-Btyl -CH (Me) CH 2 - 2-314 3-Me-4-SPrn-Btyl -CH (Me) CH 2 - 2-315 4-Me-4-SPrn-Btyl -CH (Me) CH _{2 - 2-316 2-NH 2 -3} -SPrn-Prn - (CH 2) 2 - 2-317 2-NH 2 -3-SPrn-Prn -CH (Me) CH 2 - 2-318 2-NH 2 _{-3-SPrn-Prn -CH 2 -} (cHxln-4) -CH 2 - 2-319 2-NHAc-3-SPrn-Prn -CH (Me) CH 2 - 2-320 2-NHBoc-3-SPrn- _{prn -CH (Me) CH 2 -} 2-321 2-NHMe-3-SPrn-prn -CH (Me) CH 2 - 2-322 2-NHEt-3-SPrn-prn -CH (Me) CH 2 - 2 _{-323 2-NMe 2 -3-SPrn} -Prn -CH (Me) CH 2 - 2-324 3-SBrn-Prn -CH (Me) CH 2 - 2-325 2-Me-3-SBrn-Prn -CH _{(Me) CH 2 - 2-326 2} -NH 2 -3-SBrn-Prn -CH (Me) CH 2 - 2-327 2-SBoz _{-Ac -CH (Me) CH 2 -} 2-328 2-Me-2-SBoz-Ac -CH (Me) CH 2 - 2-329 3-SBoz-Prn - (CH 2) 2 - 2-330 3- SBoz-Prn -CH (Me) CH 2 - 2-331 3-SBoz-Prn -CH 2 - (cHxln-4) -CH 2 - 2-332 2-Me-3-SBoz-Prn - (CH 2) 2 - 2-333 2-Me-3- SBoz-Prn -CH (Me) CH 2 - 2-334 2-Me-3-SBoz-Prn -CH 2 - (cHxln-4) -CH 2 - 2-335 4 -SBoz-Btyl -CH (Me) CH 2 - 2-336 2-NH 2 -3-SBoz-Prn - (CH 2) 2 - 2-337 2-NH 2 -3-SBoz-Prn -CH (Me) _{CH 2 - 2-338 2-NH 2} -3-SBoz-Prn -CH 2 - (cHxln-4) -CH 2 - 2-339 2-NH 2 -4-SBoz-Btyl -CH (Me) CH 2 - 2-340 2-NHAc-3-SBoz -Prn - (CH 2) 2 - 2-341 2-NHAc-3-SBoz-Prn -CH (Me) CH 2 - 2-342 2-NHAc-3-SBoz- _{prn -CH 2 - (cHxln-4} ) -CH 2 - 2-343 2-NHBoc-3-SBoz-prn - (CH 2) 2 - 2-344 2-NHBoc-3-SBoz-prn -CH (Me) _{CH 2 - 2-345 2-NHBoc-} 3-SBoz-Prn -CH 2 - (cHxln-4) -CH 2 - 2-346 2- (2-ThiCOS) -Ac -CH (Me) CH 2 - 2- 347 2-Me-2- (2 -ThiCOS) -Ac -CH (Me) CH 2 - 2-348 3- (2-ThiCOS) -Prn - (CH 2) 2 - 2-349 3- (2-ThiCOS _{) -Prn -CH (Me) CH 2} - 2-350 3- (2-ThiCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 2-351 2-Me-3- (2-ThiCOS) _{-Prn - (CH 2) 2 -} 2-352 2-Me-3- (2-ThiCOS) -Prn -CH (Me) CH 2 - 2 -353 2-Me-3- (2 -ThiCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 2-354 4- (2-ThiCOS) -Btyl -CH (Me) CH 2 - 2- _{355 2-NH 2 -3- (2} -ThiCOS) -Prn - (CH 2) 2 - 2-356 2-NH 2 -3- (2-ThiCOS) -Prn -CH (Me) CH 2 - 2-357 _{2-NH 2 -3- (2-} ThiCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 2-358 2-NHAc-3- (2-ThiCOS) -Prn -CH (Me) CH 2 - 2-359 2-NHBoc-3- ( 2-ThiCOS) -Prn -CH (Me) CH 2 - 2-360 2- (2-FurCOS) -Ac -CH (Me) CH 2 - 2-361 2- Me-2- (2-FurCOS) -Ac -CH (Me) CH 2 - 2-362 3- (2-FurCOS) -Prn - (CH 2) 2 - 2-363 3- (2-FurCOS) -Prn _{-CH (Me) CH 2 - 2-364} 3- (2-FurCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 2-365 2-Me-3- (2-FurCOS) -Prn - _{(CH 2) 2 - 2-366 2} -Me-3- (2-FurCOS) -Prn -CH (Me) CH 2 - 2-367 2-Me-3- (2-FurCOS) -Prn -CH 2 - _{(cHxln-4) -CH 2 -} 2-368 4- (2-FurCOS) -Btyl -CH (Me) CH 2 - 2-369 2-NH 2 -3- (2-FurCOS) -Prn - (CH 2 _{) 2 - 2-370 2-NH 2} -3- (2-FurCOS) -Prn -CH (Me) CH 2 - 2-371 2-NH 2 -3- (2-FurCOS) -Prn -CH 2 - ( _{cHxln-4) -CH 2 - 2-372} 2-NHAc-3- (2-FurCOS) -Prn -CH (Me) CH 2 - 2-373 2-NHBoc-3- (2-FurCOS) -Prn -CH _{(Me) CH 2 - 2-374 2-} (4-PyrCOS) -Ac -CH (Me) CH 2 - 2-375 2-Me-2- (4-PyrCOS) -Ac -CH (Me) CH 2 - 2-376 3- (4-PyrCOS) -Prn - (CH 2) 2 - 2-377 3- (4-PyrCOS) -Prn -CH (Me) CH 2 - 2-378 3- (4-PyrCOS) _{-Prn -CH 2 - (cHxln-4} ) -CH 2 - 2-379 2-Me-3- (4-PyrCOS) -Prn - (CH 2) 2 - 2-380 2-Me-3- (4- PyrCOS) -Prn -CH (Me) CH 2 - 2-381 2-Me-3- (4-PyrCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 2-382 3-Me-3- (4-PyrCOS) -Prn -CH ( Me) CH 2 - 2-383 4- (4-PyrCOS) -Btyl -CH (Me) CH 2 - 2-384 2-NH 2 -3- (4-PyrCOS) _{-Prn - (CH 2) 2 -} 2-385 2-NH 2 -3- (4-PyrCOS) -Prn -CH (Me) CH 2 - 2-386 2-NH 2 -3- (4-PyrCOS) - _{prn -CH 2 - (cHxln-4} ) -CH 2 - 2-387 2-NHAc-3- (4-PyrCOS) -Prn -CH (Me) CH 2 - 2-388 2-NHBoc-3- (4- PyrCOS) -Prn -CH (Me) CH 2 - 2-389 2-SH-Ac -CH (Et) CH 2 - 2-390 2-SH-Ac -CH (Pr) CH 2 - 2-391 2-SH _{-Ac -CH (Bu) CH 2 -} 2-392 2-SH-Ac -CH (iBu) CH 2 - 2-393 2-SAc-Ac -CH (Et) CH 2 - 2-394 2-SAc-Ac _{-CH (Pr) CH 2 - 2-395} 2-SAc-Ac -CH (Bu) CH 2 - 2-396 2-SAc-Ac -CH (iBu) CH 2 - 2-397 2-NH 2 -2- SH-Ac -CH (Me) CH 2 - 2-398 2-NH 2 -2-SH-Ac -CH (Et) CH 2 - 2-399 2-NH 2 -2-SH-Ac -CH (Pr) _{CH 2 - 2-400 2-NH 2} -2-SH-Ac -CH (Bu) CH 2 - 2-401 2-NH 2 -2-SH-Ac -CH (iBu) CH 2 - 2-402 2- NHAc-2-SH-A _{c -CH (Me) CH 2 -} 2-403 2-NHAc-2-SH-Ac -CH (Et) CH 2 - 2-404 2-NHAc-2-SH-Ac -CH (Pr) CH 2 - 2 -405 2-NHAc-2-SH -Ac -CH (Bu) CH 2 - 2-406 2-NHAc-2-SH-Ac -CH (iBu) CH 2 - 2-407 2-NH 2 -2-SAc _{-Ac -CH (Me) CH 2 -} 2-408 2-NH 2 -2-SAc-Ac -CH (Et) CH 2 - 2-409 2-NH 2 -2-SAc-Ac -CH (Pr) CH _{2 - 2-410 2-NH 2 -2} -SAc-Ac -CH (Bu) CH 2 - 2-411 2-NH 2 -2-SAc-Ac -CH (iBu) CH 2 - 2-412 2-NHAc -2-SAc-Ac -CH (Me ) CH 2 - 2-413 2-NHAc-2-SAc-Ac -CH (Et) CH 2 - 2-414 2-NHAc-2-SAc-Ac -CH (Pr _{) CH 2 - 2-415 2-NHAc} -2-SAc-Ac -CH (Bu) CH 2 - 2-416 2-NHAc-2-SAc-Ac -CH (iBu) CH 2 - 2-417 3-SH _{-Prn -CH (Et) CH 2 -} 2-418 3-SH-Prn -CH (Pr) CH 2 - 2-419 3-SH-Prn -CH (Bu) CH 2 - 2-420 3-SH-Prn _{-CH (iBu) CH 2 - 2-421} 3-SAc-Prn -CH (Et) CH 2 - 2-422 3-SAc-Prn -CH (Pr) CH 2 - 2-423 3-SAc-Prn -CH _{(Bu) CH 2 - 2-424 3} -SAc-Prn -CH (iBu) CH 2 - 2-425 2-Me-3-SH-Prn -CH (Et) CH 2 - 2-426 2-Me-3 -SH-Prn -CH (Pr) CH 2 - 2-427 2-Me-3-SH-Prn -CH (Bu) CH 2 - 2-428 2-Me-3-SH-Prn -CH (iBu) CH _{2 - 2-429 2-Me-3} -SAc-Prn -CH (Me) CH 2 - 2-430 2-Me-3-SAc-Prn -CH (Et) CH 2 - 2-431 2-Me-3 -SAc-Prn -CH (Pr) CH _{2 - 2-432 2-Me-3} -SAc-Prn -CH (Bu) CH 2 - 2-433 2-Me-3-SAc-Prn -CH (iBu) CH 2 - 2-434 2-NH 2 - 3-SH-Prn -CH (Bu ) CH 2 - 2-435 2-NH 2 -3-SH-Prn -CH (iBu) CH 2 - 2-436 2-NHAc-3-SH-Prn -CH (Et ) CH ₂ -2-437 2-NHAc-3-SH-Prn -CH (Pr) CH ₂ -2 -438 2-NHAc-3-SH-Prn -CH (Bu) CH ₂ -2 -439 2-NHAc -3-SH-Prn -CH (iBu ) CH 2 - 2-440 2-NH 2 -3-SAc-Prn -CH (Et) CH 2 - 2-441 2-NH 2 -3-SAc-Prn -CH _{(Pr) CH 2 - 2-442 2} -NH 2 -3-SAc-Prn -CH (Bu) CH 2 - 2-443 2-NH 2 -3-SAc-Prn -CH (iBu) CH 2 - 2- 444 2-NHAc-3-SAc -Prn -CH (Me) CH 2 - 2-445 2-NHAc-3-SAc-Prn -CH (Et) CH 2 - 2-446 2-NHAc-3-SAc-Prn _{-CH (Pr) CH 2 - 2-447} 2-NHAc-3-SAc-Prn -CH (Bu) CH 2 - 2-448 2-NHAc-3-SAc-Prn -CH (iBu) CH 2 - ── ────────────────────────────────.

[0030]

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[0031]

[Table 3] {Compound No. R ¹ A} ─────────────────────────────── 3-1 2-SH-Ac - (CH 2) 2 - 3-2 2 -SH-Ac -CH (Me) CH 2 - 3-3 2-SH-Ac - (cHxln-4) -CH 2 - 3-4 2-SH-Ac -CH 2 - (cHxln-4) - 3- _{5 2-SH-Ac -CH 2} - (cHxln-4) -CH 2 - 3-6 2-Me-2-SH-Ac - (CH 2) 2 - 3-7 2-Me-2-SH-Ac _{-CH (Me) CH 2 - 3-8} 2-Me-2-SH-Ac - (cHxln-4) -CH 2 - 3-9 2-Me-2-SH-Ac -CH 2 - (cHxln-4 ) - 3-10 2-Me-2 -SH-Ac -CH 2 - (cHxln-4) -CH 2 - 3-11 3-SH-Prn - (CH 2) 2 - 3-12 3-SH-Prn _{- (CH 2) 3 - 3-13} 3-SH-Prn -CH (Me) CH 2 - 3-14 3-SH-Prn - (cHxln-4) -CH 2 - 3-15 3-SH-Prn - _{CH 2 - (cHxln-4)} - 3-16 3-SH-Prn -CH 2 - (cHxln-2) -CH 2 - 3-17 3-SH-Prn -CH 2 - (cHxln-3) -CH 2 - 3-18 3-SH-Prn -CH 2 - (cHxln-4) -CH 2 - 3-19 3-SH-Prn -CH 2 -2-Me- (cHxln-4) -CH 2 - 3-20 _{3-SH-Prn -CH 2 -3} -Me- (cHxln-4) -CH 2 - 3-21 3-SH-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 3-22 3 -SH-Prn - (cPnln-3 ) -CH 2 - 3- _{23 3-SH-Prn -CH 2} - (cPnln-3) - 3-24 3-SH-Prn -CH 2 - (cPnln-2) -CH 2 - 3-25 3-SH-Prn -CH 2 - ( cPnln-3) -CH ₂ -3-26 2-Me-3-SH-Prn-(CH ₂ ) ₂ -3-27 2-Me-3-SH-Prn-(CH ₂ ) ₃ -3-28 2 -Me-3-SH-Prn -CH (Me) CH 2 - 3-29 2-Me-3-SH-Prn - (cHxln-4) -CH 2 - 3-30 2-Me-3-SH-Prn _{-CH 2 - (cHxln-4)} - 3-31 2-Me-3-SH-Prn -CH 2 - (cHxln-2) -CH 2 - 3-32 2-Me-3-SH-Prn -CH 2 _{- (cHxln-3) -CH 2} - 3-33 2-Me-3-SH-Prn -CH 2 - (cHxln-4) -CH 2 - 3-34 2-Me-3-SH-Prn -CH 2 -2-Me- (cHxln-4) -CH 2 - 3-35 2-Me-3-SH-Prn -CH 2 -3-Me- (cHxln-4) -CH 2 - 3-36 2-Me- _{3-SH-Prn -CH 2 -} (cHxln-4) - (CH 2) 2 - 3-37 2-Me-3-SH-Prn - (cPnln-3) -CH 2 - 3-38 2-Me- _{3-SH-Prn -CH 2 -} (cPnln-3) - 3-39 2-Me-3-SH-Prn -CH 2 - (cPnln-2) -CH 2 - 3-40 2-Me-3-SH _{-Prn -CH 2 - (cPnln-3} ) -CH 2 - 3-41 3-Me-3-SH-Prn - (CH 2) 2 - 3-42 3-Me-3-SH-Prn -CH (Me ) CH ₂ -3-43 3-Me-3-SH-Prn-(cHxln-4) -CH ₂ -3-44 3-Me-3-SH-Prn -CH _2- (cHxln-4)-3- 45 3-Me-3-SH -Prn -CH 2 - (cHxln-4) -CH 2 - 3-46 2-Et-3-SH-Prn - (CH 2) 2 - 3-47 2-Et-3 -SH-Prn -CH (Me) CH 2 - 3-48 2-Et-3-SH-Prn - (cHxln-4) -CH 2 - 3-49 2 -Et-3-SH-Prn -CH 2 - (cHxln-4) - 3-50 2-Et-3-SH-Prn -CH 2 - (cHxln-4) -CH 2 - 3-51 4-SH- _{Btyl - (CH 2) 2 -} 3-52 4-SH-Btyl -CH (Me) CH 2 - 3-53 4-SH-Btyl - (cHxln-4) -CH 2 - 3-54 4-SH-Btyl _{-CH 2 - (cHxln-4)} - 3-55 4-SH-Btyl -CH 2 - (cHxln-4) -CH 2 - 3-56 2-Me-4-SH-Btyl - (CH 2) 2 - 3-57 2-Me-4-SH -Btyl -CH (Me) CH 2 - 3-58 2-Me-4-SH-Btyl - (cHxln-4) -CH 2 - 3-59 2-Me-4 _{-SH-Btyl -CH 2 - (cHxln} -4) - 3-60 2-Me-4-SH-Btyl -CH 2 - (cHxln-4) -CH 2 - 3-61 3-Me-4-SH- _{Btyl - (CH 2) 2 -} 3-62 3-Me-4-SH-Btyl -CH (Me) CH 2 - 3-63 3-Me-4-SH-Btyl -CH 2 - (cHxln-4) - _{CH 2 - 3-64 4-Me-} 4-SH-Btyl - (CH 2) 2 - 3-65 4-Me-4-SH-Btyl -CH (Me) CH 2 - 3-66 4-Me-4 _{-SH-Btyl -CH 2 - (cHxln} -4) -CH 2 - 3-67 5-SH-Val - (CH 2) 2 - 3-68 5-SH-Val -CH (Me) CH 2 - 3- _{69 5-SH-Val -CH 2} - (cHxln-4) -CH 2 - 3-70 2-Me-5-SH-Val - (CH 2) 2 - 3-71 2-Me-5-SH-Val _{-CH (Me) CH 2 - 3-72} 2-Me-5-SH-Val -CH 2 - (cHxln-4) -CH 2 - 3-73 5-Me-5-SH-Val - (CH 2) _{2 - 3-74 5-Me-5} -SH-Val -CH (Me) CH 2 - 3-75 5-Me-5-SH-Val -CH 2 - (cHxln-4) -CH 2 - 3-76 6-SH-Hxn - (CH 2) 2 - 3-77 6-SH-Hxn -CH (M _{e) CH 2 - 3-78 6-} SH-Hxn -CH 2 - (cHxln-4) -CH 2 - 3-79 2-NH 2 -3-SH-Prn - (CH 2) 2 - 3-80 2 _{-NH 2 -3-SH-Prn -} (CH 2) 3 - 3-81 2-NH 2 -3-SH-Prn -CH (Me) CH 2 - 3-82 2-NH 2 -3-SH-Prn _{-CH 2 CH (Me) - 3-83} 2-NH 2 -3-SH-Prn -CH (Et) CH 2 - 3-84 2-NH 2 -3-SH-Prn -CH (Pr) CH 2 - _{3-85 2-NH 2 -3-SH} -Prn - (CH 2) 4 - 3-86 2-NH 2 -3-SH-Prn - (CH 2) 5 - 3-87 2-NH 2 -3- _{SH-Prn - (CH 2)} 6 - 3-88 2-NH 2 -3-SH-Prn - (cHxln-4) - 3-89 2-NH 2 -3-SH-Prn - (cHxln-4) - CH ₂ -3-90 2-NH ₂ -3-SH-Prn-(cHxln-4)-(CH ₂ ) ₂ -3-91 2-NH ₂ -3-SH-Prn -CH _2- (cHxln-4 )-3-92 2-NH ₂ -3-SH-Prn-(CH ₂ ) _2- (cHxln-4)-3-93 2-NH ₂ -3-SH-Prn -CH _2- (cHxln-2) _{-CH 2 - 3-94 2-NH 2} -3-SH-Prn -CH 2 - (cHxln-3) -CH 2 - 3-95 2-NH 2 -3-SH-Prn -CH 2 - (cHxln- 4) -CH ₂ -3-96 2-NH ₂ -3-SH-Prn -CH ₂ -2-Me- (cHxln-4) -CH ₂ -3-97 2-NH ₂ -3-SH-Prn- _{CH 2 -3-Me- (cHxln-} 4) -CH 2 - 3-98 2-NH 2 -3-SH-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 3-99 2- _{NH 2 -3-SH-Prn -} (CH 2) 2 - (cHxln-4) -CH 2 - 3-100 2-NH 2 -3-SH-Prn - (CH 2) 2 - (cHxln-4) - _{(CH 2) 2 - 3-101 2} -NH 2 -3-SH-Prn - (cPnln- _{3) - 3-102 2-NH 2} -3-SH-Prn - (cPnln-3) -CH 2 - 3-103 2-NH 2 -3-SH-Prn -CH 2 - (cPnln-3) - 3 _{-104 2-NH 2 -3-SH} -Prn -CH 2 - (cPnln-2) -CH 2 - 3-105 2-NH 2 -3-SH-Prn -CH 2 - (cPnln-3) -CH 2 _{- 3-106 2-NH 2 -3-} SH-Prn -CH 2 - (cPnln-3) - (CH 2) 2 - 3-107 2-NH 2 -4-SH-Btyl - (CH 2) 2 - _{3-108 2-NH 2 -4-SH} -Btyl - (CH 2) 3 - 3-109 2-NH 2 -4-SH-Btyl -CH (Me) CH 2 - 3-110 2-NH 2 -4 -SH-Btyl - (cHxln-4 ) -CH 2 - 3-111 2-NH 2 -4-SH-Btyl -CH 2 - (cHxln-4) - 3-112 2-NH 2 -4-SH-Btyl _{-CH 2 - (cHxln-2)} -CH 2 - 3-113 2-NH 2 -4-SH-Btyl -CH 2 - (cHxln-3) -CH 2 - 3-114 2-NH 2 -4-SH _{-Btyl -CH 2 - (cHxln-4} ) -CH 2 - 3-115 2-NH 2 -4-SH-Btyl -CH 2 - (cHxln-4) - (CH 2) 2 - 3-116 2-NH _{2 -4-SH-Btyl - (} cPnln-3) -CH 2 - 3-117 2-NH 2 -4-SH-Btyl -CH 2 - (cPnln-3) - 3-118 2-NH 2 -4- _{SH-Btyl -CH 2 - (cPnln} -2) -CH 2 - 3-119 2-NH 2 -4-SH-Btyl -CH 2 - (cPnln-3) -CH 2 - 3-120 3-NH 2 - 4-SH-Btyl - (CH 2) 2 - 3-121 3-NH 2 -4-SH-Btyl -CH (Me) CH 2 - 3-122 3-NH 2 -4-SH-Btyl - (cHxln- _{4) -CH 2 - 3-123 3-} NH 2 -4-SH-Btyl -CH 2 - (cHxln-4) - 3-124 3-NH 2 -4-SH-Btyl -CH 2 - (cHxl _{n-2) -CH 2 - 3-125} 3-NH 2 -4-SH-Btyl -CH 2 - (cHxln-3) -CH 2 - 3-126 3-NH 2 -4-SH-Btyl -CH 2 _{- (cHxln-4) -CH 2} - 3-127 2-NH 2 -5-SH-Val - (CH 2) 2 - 3-128 2-NH 2 -5-SH-Val -CH (Me) CH 2 _{- 3-129 2-NH 2 -5-} SH-Val - (cHxln-4) -CH 2 - 3-130 2-NH 2 -5-SH-Val -CH 2 - (cHxln-4) - 3-131 _{2-NH 2 -5-SH-} Val -CH 2 - (cHxln-4) -CH 2 - 3-132 2-NH 2 -6-SH-Hxn - (CH 2) 2 - 3-133 2-NH 2 -6-SH-Hxn -CH (Me ) CH 2 - 3-134 2-NH 2 -6-SH-Hxn - (cHxln-4) -CH 2 - 3-135 2-NH 2 -6-SH-Hxn _{-CH 2 - (cHxln-4)} - 3-136 2-NH 2 -6-SH-Hxn -CH 2 - (cHxln-4) -CH 2 - 3-137 2-NHAc-3-SH-Prn - ( _{CH 2) 2 - 3-138 2-} NHAc-3-SH-Prn - (CH 2) 3 - 3-139 2-NHAc-3-SH-Prn -CH (Me) CH 2 - 3-140 2-NHAc -3-SH-Prn - (cHxln -4) -CH 2 - 3-141 2-NHAc-3-SH-Prn -CH 2 - (cHxln-4) - 3-142 2-NHAc-3-SH-Prn _{-CH 2 - (cHxln-2)} -CH 2 - 3-143 2-NHAc-3-SH-Prn -CH 2 - (cHxln-3) -CH 2 - 3-144 2-NHAc-3-SH-Prn _{-CH 2 - (cHxln-4)} -CH 2 - 3-145 2-NHAc-3-SH-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 3-146 2-NHAc-3- SH-Prn - (cPnln-3 ) -CH 2 - 3-147 2-NHAc-3-SH-Prn -CH 2 - (cPnln-3) - 3-148 2-NHAc-3-SH-Prn -CH 2 -(cPn _{ln-2) -CH 2 - 3-149} 2-NHAc-3-SH-Prn -CH 2 - (cPnln-3) -CH 2 - 3-150 2-NHAc-4-SH-Btyl - (CH 2) _{2 - 3-151 2-NHAc-4} -SH-Btyl - (CH 2) 3 - 3-152 2-NHAc-4-SH-Btyl -CH (Me) CH 2 - 3-153 2-NHAc-4- SH-Btyl - (cHxln-4 ) -CH 2 - 3-154 2-NHAc-4-SH-Btyl -CH 2 - (cHxln-4) - 3-155 2-NHAc-4-SH-Btyl -CH 2 _{- (cHxln-2) -CH 2} - 3-156 2-NHAc-4-SH-Btyl -CH 2 - (cHxln-3) -CH 2 - 3-157 2-NHAc-4-SH-Btyl -CH 2 _{- (cHxln-4) -CH 2} - 3-158 3-NHAc-4-SH-Btyl - (CH 2) 2 - 3-159 3-NHAc-4-SH-Btyl -CH (Me) CH 2 - 3 -160 3-NHAc-4-SH -Btyl - (cHxln-4) -CH 2 - 3-161 3-NHAc-4-SH-Btyl -CH 2 - (cHxln-4) - 3-162 3-NHAc- _{4-SH-Btyl -CH 2 -} (cHxln-4) -CH 2 - 3-163 2-NHAc-5-SH-Val - (CH 2) 2 - 3-164 2-NHAc-5-SH-Val - _{CH (Me) CH 2 - 3-165} 2-NHAc-5-SH-Val -CH 2 - (cHxln-4) -CH 2 - 3-166 2-NHAc-6-SH-Hxn - (CH 2) 2 - 3-167 2-NHAc-6- SH-Hxn -CH (Me) CH 2 - 3-168 2-NHAc-6-SH-Hxn -CH 2 - (cHxln-4) -CH 2 - 3-169 2 -NHBoc-3-SH-Prn - (CH 2) 2 - 3-170 2-NHBoc-3-SH-Prn - (CH 2) 3 - 3-171 2-NHBoc-3-SH-Prn -CH (Me _{) CH 2 - 3-172 2-NHBoc} -3-SH-Prn - (cHxln-4) -CH 2 - 3-173 2-NHBoc-3-SH-Prn _{-CH 2 - (cHxln-4)} - 3-174 2-NHBoc-3-SH-Prn -CH 2 - (cHxln-2) -CH 2 - 3-175 2-NHBoc-3-SH-Prn -CH 2 _{- (cHxln-3) -CH 2} - 3-176 2-NHBoc-3-SH-Prn -CH 2 - (cHxln-4) -CH 2 - 3-177 2-NHBoc-3-SH-Prn -CH 2 - (cHxln-4) - ( CH 2) 2 - 3-178 2-NHBoc-3-SH-Prn - (cPnln-3) -CH 2 - 3-179 2-NHBoc-3-SH-Prn -CH 2 - (cPnln-3) - 3-180 2-NHBoc-3-SH-Prn -CH 2 - (cPnln-2) -CH 2 - 3-181 2-NHBoc-3-SH-Prn -CH 2 - (cPnln _{-3) -CH 2 - 3-182 2-} NHBoc-3-SH-Prn -CH 2 - (cPnln-3) - (CH 2) 2 - 3-183 2-NHBoc-4-SH-Btyl - (CH _{2) 2 - 3-184 2-NHBoc} -4-SH-Btyl -CH (Me) CH 2 - 3-185 2-NHBoc-4-SH-Btyl - (cHxln-4) -CH 2 - 3-186 2 -NHBoc-4-SH-Btyl -CH 2 - (cHxln-4) - 3-187 2-NHBoc-4-SH-Btyl -CH 2 - (cHxln-2) -CH 2 - 3-188 2-NHBoc- _{4-SH-Btyl -CH 2 -} (cHxln-3) -CH 2 - 3-189 2-NHBoc-4-SH-Btyl -CH 2 - (cHxln-4) -CH 2 - 3-190 3-NHBoc- 4-SH-Btyl - (CH 2) 2 - 3-191 3-NHBoc-4-SH-Btyl -CH (Me) CH 2 - 3-192 3-NHBoc-4-SH-Btyl - (cHxln-4) _{-CH 2 - 3-193 3-NHBoc-} 4-SH-Btyl -CH 2 - (cHxln-4) - 3-194 3-NHBoc-4-SH-Btyl -CH 2 - (cHxln-4) -CH 2 - 3-195 2-NHBoc-5- SH-Val - (CH 2) 2 - 3-196 2-NHBoc-5 -SH-Val -CH (Me) CH 2 - 3-197 2-NHBoc-5-SH-Val -CH 2 - (cHxln-4) -CH 2 - 3-198 2-NHBoc-6-SH-Hxn - _{(CH 2) 2 - 3-199 2} -NHBoc-6-SH-Hxn -CH (Me) CH 2 - 3-200 2-NHBoc-6-SH-Hxn -CH 2 - (cHxln-4) -CH 2 - 3-201 2-NHMe-3- SH-Prn - (CH 2) 2 - 3-202 2-NHMe-3-SH-Prn -CH (Me) CH 2 - 3-203 2-NHMe-3-SH _{-Prn -CH 2 - (cHxln-4} ) -CH 2 - 3-204 2-NHMe-4-SH-Btyl -CH (Me) CH 2 - 3-205 3-NHMe-4-SH-Btyl -CH ( Me) CH ₂ -3-206 2-NHEt-3-SH-Prn-(CH ₂ ) ₂ -3-207 2-NHEt-3-SH-Prn -CH (Me) CH ₂ -3-208 2-NHEt _{-3-SH-Prn -CH 2 -} (cHxln-4) -CH 2 - 3-209 2-NHEt-4-SH-Btyl -CH (Me) CH 2 - 3-210 3-NHEt-4-SH- Btyl -CH (Me) CH _2-3 -211 2-NMe ₂ -3-SH-Prn-(CH ₂ ) ₂ -3-212 2-NMe ₂ -3-SH-Prn -CH (Me) CH _{2- 3-213 2-NMe 2 -3-SH} -Prn -CH 2 - (cHxln-4) -CH 2 - 3-214 2-NMe 2 -4-SH-Btyl -CH (Me) CH 2 - 3-215 _{3-NMe 2 -4-SH-} Btyl -CH (Me) CH 2 - 3-216 2-NMeAc-3-SH-Prn -CH (Me) CH 2 - 3-217 2-NMeAc-4-SH-Btyl _{-CH (Me) CH 2 - 3-218} 2-NMeBoc-3-SH-Prn -CH (Me) CH 2 - 3-219 2-SAc-Ac - (CH 2) 2 - 3-220 2-SAc- _{Ac -CH (Me) CH 2 -} 3-221 2-SAc-Ac -CH 2 - (cHxln-4) -CH 2 - 3-222 2-Me-2-SAc-Ac -(CH ₂ ) ₂ -3-223 2-Me-2-SAc-Ac -CH (Me) CH ₂ -3-224 2-Me-2-SAc-Ac -CH _2- (cHxln-4) -CH _{2 - 3-225 3-SAc-Prn} - (CH 2) 2 - 3-226 3-SAc-Prn - (CH 2) 3 - 3-227 3-SAc-Prn -CH (Me) CH 2 - 3- 228 3-SAc-Prn - ( cHxln-4) - 3-229 3-SAc-Prn - (cHxln-4) -CH 2 - 3-230 3-SAc-Prn -CH 2 - (cHxln-4) - 3 _{-231 3-SAc-Prn -CH 2} - (cHxln-2) -CH 2 - 3-232 3-SAc-Prn -CH 2 - (cHxln-3) -CH 2 - 3-233 3-SAc-Prn - _{CH 2 - (cHxln-4)} -CH 2 - 3-234 3-SAc-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 3-235 3-SAc-Prn - (cPnln-3) _{-CH 2 - 3-236 3-SAc-} Prn -CH 2 - (cPnln-3) - 3-237 3-SAc-Prn -CH 2 - (cPnln-2) -CH 2 - 3-238 3-SAc- _{prn -CH 2 - (cPnln-3} ) -CH 2 - 3-239 2-Me-3-SAc-prn - (CH 2) 2 - 3-240 2-Me-3-SAc-prn - (CH 2) _{3 - 3-241 2-Me-3} -SAc-Prn -CH (Me) CH 2 - 3-242 2-Me-3-SAc-Prn - (cHxln-4) - 3-243 2-Me-3- SAc-Prn - (cHxln-4 ) -CH 2 - 3-244 2-Me-3-SAc-Prn -CH 2 - (cHxln-4) - 3-245 2-Me-3-SAc-Prn -CH 2 _{- (cHxln-2) -CH 2} - 3-246 2-Me-3-SAc-Prn -CH 2 - (cHxln-3) -CH 2 - 3-247 2-Me-3-SAc-Prn -CH 2 _{- (cHxln-4) -CH 2} - 3-248 2-Me-3-SAc-Prn -CH 2 - (cHxln-4) - (CH 2) 2 - 3-249 2-Me-3 -SAc-Prn - (cPnln-3 ) -CH 2 - 3-250 2-Me-3-SAc-Prn -CH 2 - (cPnln-3) - 3-251 2-Me-3-SAc-Prn -CH _{2 - (cPnln-2) -CH} 2 - 3-252 2-Me-3-SAc-Prn -CH 2 - (cPnln-3) -CH 2 - 3-253 3-Me-3-SAc-Prn - ( _{CH 2) 2 - 3-254 3-} Me-3-SAc-Prn -CH (Me) CH 2 - 3-255 3-Me-3-SAc-Prn -CH 2 - (cHxln-4) -CH 2 - 3-256 2-Et-3-SAc -Prn - (CH 2) 2 - 3-257 2-Et-3-SAc-Prn -CH (Me) CH 2 - 3-258 2-Et-3-SAc- _{prn -CH 2 - (cHxln-4} ) -CH 2 - 3-259 4-SAc-Btyl - (CH 2) 2 - 3-260 4-SAc-Btyl -CH (Me) CH 2 - 3-261 4- _{SAc-Btyl -CH 2 - (cHxln} -4) -CH 2 - 3-262 2-Me-4-SAc-Btyl - (CH 2) 2 - 3-263 2-Me-4-SAc-Btyl -CH ( _{Me) CH 2 - 3-264 2-} Me-4-SAc-Btyl -CH 2 - (cHxln-4) -CH 2 - 3-265 3-Me-4-SAc-Btyl -CH (Me) CH 2 - 3-266 4-Me-4-SAc -Btyl -CH (Me) CH 2 - 3-267 5-SAc-Val -CH (Me) CH 2 - 3-268 2-Me-5-SAc-Val -CH (Me) CH ₂ -3-269 5-Me-5-SAc-Val -CH (Me) CH ₂ -3-270 6-SAc-Hxn -CH (Me) CH ₂ -3-271 2-NH _2- 3-SAc-Prn - (CH 2) 2 - 3-272 2-NH 2 -3-SAc-Prn -CH (Me) CH 2 - 3-273 2-NH 2 -3-SAc-Prn - (cHxln- _{4) -CH 2 - 3-274 2-} NH 2 -3-SAc-Prn -CH 2 - (cHxln-4) - 3-275 2-NH 2 -3-SAc-Prn -CH 2 - (cHxl _{n-2) -CH 2 - 3-276} 2-NH 2 -3-SAc-Prn -CH 2 - (cHxln-3) -CH 2 - 3-277 2-NH 2 -3-SAc-Prn -CH 2 _{- (cHxln-4) -CH 2} - 3-278 2-NH 2 -4-SAc-Btyl - (CH 2) 2 - 3-279 2-NH 2 -4-SAc-Btyl -CH (Me) CH 2 _{- 3-280 2-NH 2 -4-} SAc-Btyl -CH 2 - (cHxln-4) -CH 2 - 3-281 3-NH 2 -4-SAc-Btyl -CH (Me) CH 2 - 3- _{282 2-NH 2 -5-SAc} -Val -CH (Me) CH 2 - 3-283 2-NHAc-3-SAc-Prn - (CH 2) 2 - 3-284 2-NHAc-3-SAc-Prn -CH (Me) CH ₂ -3-285 2-NHAc-3-SAc-Prn-(cHxln-4) -CH ₂ -3-286 2-NHAc-3-SAc-Prn -CH _2- (cHxln-4 ) - 3-287 2-NHAc-3 -SAc-Prn -CH 2 - (cHxln-4) -CH 2 - 3-288 2-NHAc-4-SAc-Btyl -CH (Me) CH 2 - 3-289 3-NHAc-4-SAc- Btyl -CH (Me) CH 2 - 3-290 2-NHBoc-3-SAc-Prn - (CH 2) 2 - 3-291 2-NHBoc-3-SAc-Prn -CH (Me) CH ₂ -3-292 2-NHBoc-3-SAc-Prn-(cHxln-4) -CH ₂ -3-293 2-NHBoc-3-SAc-Prn -CH _2- (cHxln-4)- 3-294 2-NHBoc-3-SAc -Prn -CH 2 - (cHxln-4) -CH 2 - 3-295 2-NHBoc-4-SAc-Btyl -CH (Me) CH 2 - 3-296 3- NHBoc-4-SAc-Btyl -CH (Me) CH 2 - 3-297 2-NHMe-3-SAc-Prn -CH (Me) CH 2 - 3-298 2-NHEt-3-SAc-Prn -CH ( Me) CH ₂ -3-299 2-NMe ₂ -3-SAc-Prn -CH (Me) CH ₂ -3-300 2-NMeAc -3-SAc-Prn -CH (Me ) CH 2 - 3-301 2-NMeBoc-3-SAc-Prn -CH (Me) CH 2 - 3-302 2-SPrn-Ac -CH (Me) CH 2 - 3-303 2-Me-2-SPrn -Ac -CH (Me) CH 2 - 3-304 3-SPrn-Prn - (CH 2) 2 - 3-305 3-SPrn-Prn -CH (Me) CH 2 - 3-306 3-SPrn-Prn -CH 2 - (cHxln-4) -CH 2 - 3-307 2-Me-3-SPrn-Prn - (CH 2) 2 - 3-308 2-Me-3- SPrn-Prn -CH (Me) CH 2 - 3-309 2-Me-3-SPrn-Prn -CH 2 - (cHxln-4) -CH 2 - 3-310 3-Me-3-SPrn-Prn -CH _{(Me) CH 2 - 3-311 2} -Et-3-SPrn-Prn -CH (Me) CH 2 - 3-312 4-SPrn-Btyl -CH (Me) CH 2 - 3-313 2-Me-4 -SPrn-Btyl -CH (Me) CH 2 - 3-314 3-Me-4-SPrn-Btyl -CH (Me) CH 2 - 3-315 4-Me-4-SPrn-Btyl -CH (Me) CH _{2 - 3-316 2-NH 2 -3} -SPrn-Prn - (CH 2) 2 - 3-317 2-NH 2 -3-SPrn-Prn -CH (Me) CH 2 - 3-318 2-NH 2 _{-3-SPrn-Prn -CH 2 -} (cHxln-4) -CH 2 - 3-319 2-NHAc-3-SPrn-Prn -CH (Me) CH 2 - 3-320 2-NHBoc-3-SPrn- _{prn -CH (Me) CH 2 -} 3-321 2-NHMe-3-SPrn-prn -CH (Me) CH 2 - 3-322 2-NHEt-3-SPrn-prn -CH (Me) CH 2 - 3 _{-323 2-NMe 2 -3-SPrn} -Prn -CH (Me) CH 2 - 3-324 3-SBrn-Prn -CH (Me) CH 2 - 3-325 2-Me-3-SBrn-Prn -CH (Me) CH ₂ -3-326 2-NH ₂ -3-SBrn-Prn -CH (Me) CH ₂ -3-327 2-SBoz _{-Ac -CH (Me) CH 2 -} 3-328 2-Me-2-SBoz-Ac -CH (Me) CH 2 - 3-329 3-SBoz-Prn - (CH 2) 2 - 3-330 3- SBoz-Prn -CH (Me) CH 2 - 3-331 3-SBoz-Prn -CH 2 - (cHxln-4) -CH 2 - 3-332 2-Me-3-SBoz-Prn - (CH 2) 2 - 3-333 2-Me-3- SBoz-Prn -CH (Me) CH 2 - 3-334 2-Me-3-SBoz-Prn -CH 2 - (cHxln-4) -CH 2 - 3-335 4 -SBoz-Btyl -CH (Me) CH 2 - 3-336 2-NH 2 -3-SBoz-Prn - (CH 2) 2 - 3-337 2-NH 2 -3-SBoz-Prn -CH (Me) _{CH 2 - 3-338 2-NH 2} -3-SBoz-Prn -CH 2 - (cHxln-4) -CH 2 - 3-339 2-NH 2 -4-SBoz-Btyl -CH (Me) CH 2 - 3-340 2-NHAc-3-SBoz -Prn - (CH 2) 2 - 3-341 2-NHAc-3-SBoz-Prn -CH (Me) CH 2 - 3-342 2-NHAc-3-SBoz- _{prn -CH 2 - (cHxln-4} ) -CH 2 - 3-343 2-NHBoc-3-SBoz-prn - (CH 2) 2 - 3-344 2-NHBoc-3-SBoz-prn -CH (Me) _{CH 2 - 3-345 2-NHBoc-} 3-SBoz-Prn -CH 2 - (cHxln-4) -CH 2 - 3-346 2- (2-ThiCOS) -Ac -CH (Me) CH 2 - 3- 347 2-Me-2- (2 -ThiCOS) -Ac -CH (Me) CH 2 - 3-348 3- (2-ThiCOS) -Prn - (CH 2) 2 - 3-349 3- (2-ThiCOS _{) -Prn -CH (Me) CH 2} - 3-350 3- (2-ThiCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 3-351 2-Me-3- (2-ThiCOS) _{-Prn - (CH 2) 2 -} 3-352 2-Me-3- (2-ThiCOS) -Prn -CH (Me) CH 2 - 3 -353 2-Me-3- (2 -ThiCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 3-354 4- (2-ThiCOS) -Btyl -CH (Me) CH 2 - 3- 355 2-NH ₂ -3- (2-ThiCOS) -Prn-(CH ₂ ) ₂ -3-356 2-NH ₂ -3- (2-ThiCOS) -Prn -CH (Me) CH ₂ -3-357 _{2-NH 2 -3- (2-} ThiCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 3-358 2-NHAc-3- (2-ThiCOS) -Prn -CH (Me) CH 2 - 3-359 2-NHBoc-3- ( 2-ThiCOS) -Prn -CH (Me) CH 2 - 3-360 2- (2-FurCOS) -Ac -CH (Me) CH 2 - 3-361 2- Me-2- (2-FurCOS) -Ac -CH (Me) CH 2 - 3-362 3- (2-FurCOS) -Prn - (CH 2) 2 - 3-363 3- (2-FurCOS) -Prn _{-CH (Me) CH 2 - 3-364} 3- (2-FurCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 3-365 2-Me-3- (2-FurCOS) -Prn - _{(CH 2) 2 - 3-366 2} -Me-3- (2-FurCOS) -Prn -CH (Me) CH 2 - 3-367 2-Me-3- (2-FurCOS) -Prn -CH 2 - _{(cHxln-4) -CH 2 -} 3-368 4- (2-FurCOS) -Btyl -CH (Me) CH 2 - 3-369 2-NH 2 -3- (2-FurCOS) -Prn - (CH 2 _{) 2 - 3-370 2-NH 2} -3- (2-FurCOS) -Prn -CH (Me) CH 2 - 3-371 2-NH 2 -3- (2-FurCOS) -Prn -CH 2 - ( _{cHxln-4) -CH 2 - 3-372} 2-NHAc-3- (2-FurCOS) -Prn -CH (Me) CH 2 - 3-373 2-NHBoc-3- (2-FurCOS) -Prn -CH (Me) CH ₂ -3-374 2- (4-PyrCOS) -Ac -CH (Me) CH ₂ -3-375 2-Me-2- (4-PyrCOS) -Ac -CH (Me) CH ₂ - 3-376 3- (4-PyrCOS) -Prn - (CH 2) 2 - 3-377 3- (4-PyrCOS) -Prn -CH (Me) CH 2 - 3-378 3- (4-PyrCOS) _{-Prn -CH 2 - (cHxln-4} ) -CH 2 - 3-379 2-Me-3- (4-PyrCOS) -Prn - (CH 2) 2 - 3-380 2-Me-3- (4- PyrCOS) -Prn -CH (Me) CH 2 - 3-381 2-Me-3- (4-PyrCOS) -Prn -CH 2 - (cHxln-4) -CH 2 - 3-382 3-Me-3- (4-PyrCOS) -Prn -CH (Me) CH ₂ -3-383 4- (4-PyrCOS) -Btyl -CH (Me) CH ₂ -3-384 2-NH ₂ -3- (4-PyrCOS) -Prn-(CH ₂ ) ₂ -3-385 2-NH ₂ -3- (4-PyrCOS) -Prn -CH (Me) CH ₂ -3-386 2-NH ₂ -3- (4-PyrCOS)- _{prn -CH 2 - (cHxln-4} ) -CH 2 - 3-387 2-NHAc-3- (4-PyrCOS) -Prn -CH (Me) CH 2 - 3-388 2-NHBoc-3- (4- PyrCOS) -Prn -CH (Me) CH 2 - 3-389 2-SH-Ac -CH (Et) CH 2 - 3-390 2-SH-Ac -CH (Pr) CH 2 - 3-391 2-SH _{-Ac -CH (Bu) CH 2 -} 3-392 2-SH-Ac -CH (iBu) CH 2 - 3-393 2-SAc-Ac -CH (Et) CH 2 - 3-394 2-SAc-Ac _{-CH (Pr) CH 2 - 3-395} 2-SAc-Ac -CH (Bu) CH 2 - 3-396 2-SAc-Ac -CH (iBu) CH 2 - 3-397 2-NH 2 -2- SH-Ac -CH (Me) CH 2 - 3-398 2-NH 2 -2-SH-Ac -CH (Et) CH 2 - 3-399 2-NH 2 -2-SH-Ac -CH (Pr) _{CH 2 - 3-400 2-NH 2} -2-SH-Ac -CH (Bu) CH 2 - 3-401 2-NH 2 -2-SH-Ac -CH (iBu) CH 2 - 3-402 2- NHAc-2-SH-A _{c -CH (Me) CH 2 -} 3-403 2-NHAc-2-SH-Ac -CH (Et) CH 2 - 3-404 2-NHAc-2-SH-Ac -CH (Pr) CH 2 - 3 -405 2-NHAc-2-SH -Ac -CH (Bu) CH 2 - 3-406 2-NHAc-2-SH-Ac -CH (iBu) CH 2 - 3-407 2-NH 2 -2-SAc _{-Ac -CH (Me) CH 2 -} 3-408 2-NH 2 -2-SAc-Ac -CH (Et) CH 2 - 3-409 2-NH 2 -2-SAc-Ac -CH (Pr) CH _{2 - 3-410 2-NH 2 -2} -SAc-Ac -CH (Bu) CH 2 - 3-411 2-NH 2 -2-SAc-Ac -CH (iBu) CH 2 - 3-412 2-NHAc -2-SAc-Ac -CH (Me ) CH 2 - 3-413 2-NHAc-2-SAc-Ac -CH (Et) CH 2 - 3-414 2-NHAc-2-SAc-Ac -CH (Pr _{) CH 2 - 3-415 2-NHAc} -2-SAc-Ac -CH (Bu) CH 2 - 3-416 2-NHAc-2-SAc-Ac -CH (iBu) CH 2 - 3-417 3-SH _{-Prn -CH (Et) CH 2 -} 3-418 3-SH-Prn -CH (Pr) CH 2 - 3-419 3-SH-Prn -CH (Bu) CH 2 - 3-420 3-SH-Prn _{-CH (iBu) CH 2 - 3-421} 3-SAc-Prn -CH (Et) CH 2 - 3-422 3-SAc-Prn -CH (Pr) CH 2 - 3-423 3-SAc-Prn -CH _{(Bu) CH 2 - 3-424 3} -SAc-Prn -CH (iBu) CH 2 - 3-425 2-Me-3-SH-Prn -CH (Et) CH 2 - 3-426 2-Me-3 -SH-Prn -CH (Pr) CH 2 - 3-427 2-Me-3-SH-Prn -CH (Bu) CH 2 - 3-428 2-Me-3-SH-Prn -CH (iBu) CH _{2 - 3-429 2-Me-3} -SAc-Prn -CH (Me) CH 2 - 3-430 2-Me-3-SAc-Prn -CH (Et) CH 2 - 3-431 2-Me-3 -SAc-Prn -CH (Pr) CH _{2 - 3-432 2-Me-3} -SAc-Prn -CH (Bu) CH 2 - 3-433 2-Me-3-SAc-Prn -CH (iBu) CH 2 - 3-434 2-NH 2 - 3-SH-Prn -CH (Bu ) CH 2 - 3-435 2-NH 2 -3-SH-Prn -CH (iBu) CH 2 - 3-436 2-NHAc-3-SH-Prn -CH (Et _{) CH 2 - 3-437 2-NHAc} -3-SH-Prn -CH (Pr) CH 2 - 3-438 2-NHAc-3-SH-Prn -CH (Bu) CH 2 - 3-439 2-NHAc -3-SH-Prn -CH (iBu ) CH 2 - 3-440 2-NH 2 -3-SAc-Prn -CH (Et) CH 2 - 3-441 2-NH 2 -3-SAc-Prn -CH _{(Pr) CH 2 - 3-442 2} -NH 2 -3-SAc-Prn -CH (Bu) CH 2 - 3-443 2-NH 2 -3-SAc-Prn -CH (iBu) CH 2 - 3- 444 2-NHAc-3-SAc -Prn -CH (Me) CH 2 - 3-445 2-NHAc-3-SAc-Prn -CH (Et) CH 2 - 3-446 2-NHAc-3-SAc-Prn _{-CH (Pr) CH 2 - 3-447} 2-NHAc-3-SAc-Prn -CH (Bu) CH 2 - 3-448 2-NHAc-3-SAc-Prn -CH (iBu) CH 2 - ── ────────────────────────────────.

Among the above exemplified compounds, preferred compounds are
Compound Nos. 1-3, 1-8, 1-16, 1-21, 1-
29, 1-32, 1-43, 1-55, 1-57, 1-
60, 1-71, 1-85, 1-90, 1-98, 1-
103, 1-111, 1-124, 1-129, 1-1
37, 1-142, 1-150, 1-167, 1-17
8, 1-184, 1-187, 1-198, 1-21
2, 1-217, 1-224, 1-242, 1-24
7, 1-255, 1-267, 1-294, 1-30
5, 1-337, 1-359, 1-364, 1-36
7, 1-372, 1-389, 1-403, 1-40
6, 1-417, 1-435, 1-440, 1-46
8, 1-498, 1-549, 1-555, 1-56
0, 1-572, 1-593, 1-596, 1-61
6, 1-627, 1-642, 1-651, 1-68
1, 1-701, 1-705, 1-706, 1-71
3, 1-729, 1-733, 1-738, 1-73
9, 1-743, 1-745, 1-751, 2-2, 2,
-5, 2-13, 2-18, 2-28, 2-33, 2-
47, 2-65, 2-84, 2-109, 2-139,
2-144, 2-164, 2-220, 2-227, 2
-233, 2-241, 2-247, 2-257, 2-
303, 2-311, 2-319, 2-341, 2-3
49, 2-366, 2-396, 2-426, 2-43
1, 2-438, 2-448, 3-2, 3-10, 3-
18, 3-28, 3-47, 3-84, 3-95, 3-
139, 3-144, 3-220, 3-227, 3-2
33, 3-241, 3-247, 3-254, 3-28
4, 3-287, 3-305, 3-306, 3-31
9, 3-3331, 3-333, 3-341, 3-35
4, 3-363, 3-394, 3-424, 3-42
6, 3-428, 3-444 or 3-448, and more preferable compounds are Compound Nos. 1-3 and 1-2.
9, 1-32, 1-43, 1-55, 1-57, 1-6
0, 1-71, 1-85, 1-90, 1-98, 1-1
67, 1-212, 1-242, 1-247, 1-35
9, 1-364, 1-367, 1-389, 1-40
3, 1-406, 1-468, 1-498, 1-54
9, 1-555, 1-616, 1-627, 1-68
1, 1-701, 1-706, 1-729, 1-73
3, 2-5, 2-18, 2-139, 2-227, 2-
233, 2-241, 2-247, 2-426, 2-4
31, 2-438, 2-448, 3-28, 3-13
9, 3-144, 3-220, 3-227, 3-23
3, 3-241, 3-247, 3-284, 3-28
7, 3-319, 3-331, 3-394, 3-424
Or a compound of 3-444, and a particularly preferable compound is compound No. 1-57: 1- (3-mercapto-2-methylpropionyl) -L-proline-N- (1-methyl-
2-nitroxyethyl) amide, Compound No. 1-364: 1-acetylthioacetyl-L
-Proline-N- (4-nitroxymethylcyclohexylmethyl) carboxamide, Compound No. 1-403: 1- (3-acetylthio-2-
Methylpropionyl) -L-proline-N- (1-methyl-2-nitroxyethyl) amide, Compound No. 2-233: 3- (3-acetylthiopropionyl) -oxazolidin-4-yl-N- (4- Nitroxymethylcyclohexylmethyl) amide, Compound No. 2-241: 3- (3-acetylthio-2-)
Methylpropionyl) -oxazolidin-4-yl-N
-(1-methyl-2-nitroxyethyl) amide, compound number 2-431: 3- (3-acetylthio-2-
Methylpropionyl) -oxazolidin-4-yl-N
-(1-propyl-2-nitroxyethyl) amide, compound No. 3-233: 3- (3-acetylthiopropionyl) -thiazolidine-4-yl-N- (4-nitroxymethylcyclohexylmethyl) amide, compound No. 3-241: 3- (3-acetylthio-2-
Methylpropionyl) -thiazolidin-4-yl-N-
(1-methyl-2-nitroxyethyl) amide, Compound No. 3-247: 3- (3-acetylthio-2-
Methylpropionyl) -thiazolidin-4-yl-N-
(4-nitroxymethylcyclohexylmethyl) amide or Compound No. 3-284: 3- (2-acetylamino-3)
-Acetylthiopropionyl) -thiazolidine-4-yl-N- (1-methyl-2-nitroxyethyl) amide.

[0033]

BEST MODE FOR CARRYING OUT THE INVENTION The compound having the general formula (I), which is an active ingredient of the present invention, can be easily produced according to the following method.

[0034]

Embedded image

In the chemical formulas described in the above process, R ¹ , A and X have the same meanings as described above.
¹ a is a mercapto group contained in R ^1, an amino group and mono -C ₁ -C ₆ alkylamino group is, respectively, protected mercapto groups, protected mono -C ₁ which amino group and protected In addition to being a —C ₆ alkylamino group, it has the same meaning as R ^1, and R ⁴ represents a protecting group for an amino group (having the same meaning as described above).

The protecting group for the mercapto group is, for example, the above-mentioned C
₁ -C ₆ aliphatic acyl group, the C ₂ -C ₇ alkoxycarbonyl group, the optionally substituted C ₇ -C ₁₁ ants - ylcarbonyl group, the optionally substituted 5 or 6-membered aromatic heterocyclic carbonyl And preferably acetyl, t-
Butoxycarbonyl or benzoyl group.

Method A is a method for producing compound (I). Step A1 is a step for producing a compound having the general formula (I), and in an inert solvent, a compound having the general formula (II) or a reactive derivative thereof (acid halides, mixed acid anhydrides or active esters) ) And a compound having the general formula (III) or an acid addition salt thereof (for example, a mineral acid salt such as hydrochloride, nitrate or sulfate), and if desired, the amino group or imino of the compound (a) obtained Reaction for removing the protecting group of the group (-NH-), (b) reaction for removing the protecting group for the mercapto group, (c) reaction for protecting the amino group or imino group, and (d) reaction for acylating the mercapto group Is achieved by appropriately performing the following.

The reaction between compound (II) and compound (III) is carried out, for example, by an acid halide method, a mixed acid anhydride method, an active ester method or a condensation method. In the acid halide method, the compound (II) is reacted with a halogenating agent (eg, thionyl chloride, oxalic acid chloride, phosphorus pentachloride, etc.) in an inert solvent to produce an acid halide, and the acid halide and the compound (III) ) Or an acid addition salt thereof in an inert solvent in the presence or absence (preferably in the presence) of a base,
It is achieved by reacting. 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; and alkali metal carbonates such as sodium carbonate and potassium carbonate. Possible and preferred are organic amines, particularly preferably triethylamine.

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, and tetrachloromethane. 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-
Pyrrolidone, amides such as hexamethylphosphoramide, sulfoxides such as dimethyl sulfoxide, preferably hydrocarbons, halogenated hydrocarbons or ethers, more preferably, Ethers (particularly preferably tetrahydrofuran). The reaction temperature varies depending on the types of the starting compounds (II) and (III) and the solvent, but the reaction between the halogenating agent and the compound (II) and the reaction between the acid halide and the compound (III) are usually -20 ° C. To 150 ° C, preferably the reaction between the halogenating agent and the compound (II) is from -10 ° C to 50 ° C, and the reaction between the acid halide and the compound (III) is from 0 ° C to 100 ° C. Although the reaction time varies depending on the reaction temperature and the like, both reactions are usually 15 minutes to 24 hours (preferably 30 minutes to 16 hours).

In the mixed acid anhydride method, halogenocarbonate C ₁ -C
₆ alkyl, di-C ₁ -C ₆ alkyl cyanophosphoric acid or di-C ₆ -C ₁₀ aryl phosphoryl azide and compound (I
This is achieved by reacting I) to produce a mixed acid anhydride and reacting the mixed acid anhydride with compound (III) or an acid addition salt thereof. The reaction for preparing the mixed acid anhydride include methyl chlorocarbonate, ethyl chlorocarbonate, chlorocarbonate, isobutyl, C ₁ -C ₆ alkyl halogeno carbonate as chlorocarbonate hexyl (preferably, ethyl chloroformate or chlorocarbonate, isobutyl), Di-C ₁ -C ₆ alkyl cyanophosphate or diphenylphosphate azide, such as dimethylcyanophosphate, diethylcyanophosphate, dihexylcyanophosphate, azide of di- (p-nitrophenyl) phosphate,
Di -C ₆ -C ₁₀ aryl phosphate azide such as Jinafuchirurin acid azide (preferably, diphenylphosphoric acid azide)
And compound (II), 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 varies depending on the type of the starting compound (II) and the solvent, but is usually from -20 ° C to 50 ° C (preferably from 0 ° C to 30 ° C).
° C). The reaction time varies depending on the reaction temperature, etc.
Usually 15 minutes to 24 hours (preferably 30 minutes to 1 hour
6 hours).

The reaction between the mixed acid anhydride and the compound (III) or an acid addition salt thereof is carried out in an inert solvent in the presence or absence (preferably in the presence) of a base and used. The base and the inert solvent are the same as those used in the above-mentioned acid halide method. The reaction temperature is determined based on the amount of the starting compound (III).
And usually varies from -20 ° C to 1 ° C.
00 ° 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 30 minutes to 16 hours).
When di-C ₁ -C ₆ alkyl cyanophosphoric acid or di-C ₆ -C ₁₀ aryl phosphoric acid azide is used in the present method, compound (II) and compound (III) are converted in the presence of a base. It can also be reacted directly.

In the active ester method, a condensing agent (for example, dicyclohexylcarbodiimide, carbonyldiimidazo-
Compound (II) in the presence of an active ester (for example, an N-hydroxy compound such as N-hydroxysuccinimide or N-hydroxybenzotriazole) to produce an active ester. However, this is achieved by reacting the active ester with compound (III) or an acid addition salt thereof. The reaction for producing the active ester is preferably performed 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 depends on the starting compounds (II) and (III).
In the active esterification reaction, the temperature is usually −20 ° C. to 50 ° C. (preferably −10 ° C. to 30 ° C.), and the active ester compound and the compound (II)
In the reaction with I), the reaction temperature is from -20 ° C to 50 ° C (preferably-
10 ° C. to 30 ° C.). Although the reaction time varies depending on the reaction temperature and the like, 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-
(N, N-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, etc.] in the presence of compound (II) and compound (III) or an acid addition salt thereof. This reaction is carried out in the same manner as the above-mentioned reaction for producing an active ester. The desired reaction (a) for removing the protecting group for the amino group or imino group, which depends on the type of the protecting group, is generally carried out as follows by a method well known in the art. When the protecting group for the amino group or the imino group is a C ₁ -C ₆ aliphatic acyl group or a C ₂ -C ₇ alkoxycarbonyl group,
The substituent is removed by reacting the corresponding compound with an acid or base in the presence of an aqueous solvent. The acid used is usually used as an acid, and is not particularly limited as long as it does not inhibit the reaction.
Sulfuric acid, phosphoric acid, inorganic acids such as hydrobromic acid, particularly preferably hydrochloric acid, the base used is not particularly limited as long as it does not affect the other parts of the compound However, preferably, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide Alkali metal hydroxides or ammonia such as aqueous ammonia and concentrated ammonia-methanol, and particularly preferably ammonia.

It should be noted that isomerization may occur in hydrolysis with a base. The inert solvent used in the above reaction is not particularly limited as long as it is used in a usual hydrolysis reaction, and examples thereof include alcohols such as methanol and ethanol, tetrahydrofuran, and dioxane. Like
It may be an organic solvent such as ters or a mixed solvent of water and the above organic solvent, and is preferably a hydrated alcohol or a hydrated ether. The reaction temperature and reaction time vary depending on the starting material, the solvent and the acid or base used, and are not particularly limited. However, in order to suppress a side reaction, the reaction temperature is usually -10 ° C to 150 ° C (preferably 0 to 100 ° C
° C), and the reaction time is usually 30 minutes to 20 hours (preferably 1 hour to 10 hours).

An amino- or imino-protecting group is represented by the formula -S
When it is _a group having iR ³ _a R ³ _b R ³ _c (wherein, R ³ _a , R ³ _b and R ³ _c have the same meanings as described above),
The substituent is removed by reacting the corresponding compound with a compound that produces a fluoride anion, such as tetrabutylammonium fluoride, in an inert solvent.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction, but ethers such as tetrahydrofuran and dioxane are preferred. The reaction temperature and the reaction time are not particularly limited, but the reaction temperature is usually -10 ° C to 50 ° C (preferably 0 ° C
To 30 ° C.), and the reaction time is usually 2 hours to 2 hours.
4 hours (preferably 10 to 18 hours).

When the protecting group for the amino group or imino group is C _6-
When it is a C ₁₀ arylmethyl group or a C ₆ -C ₁₀ arylmethoxycarbonyl group, the corresponding compound is usually contacted with a reducing agent (including catalytic reduction) or an oxidizing agent in an inert solvent. By doing so, the substituent is removed. The inert solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in this reaction. Examples thereof include alcohols such as methanol and ethanol, diethyl ether, and tetrahydrofuran. , Ethers such as dioxane, aromatic hydrocarbons such as toluene, benzene, xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, and acetic acid. Fatty acids or a mixed solvent of these organic solvents and water, preferably alcohols.

The catalyst to be used is not particularly limited as long as it is usually used for a catalytic reduction reaction.
It can be palladium-carbon, Raney-nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate, preferably palladium-carbon.

The pressure of hydrogen is not particularly limited, but is usually 1
To 10 atm (preferably 1 to 3 atm). The reaction temperature and the reaction time vary depending on the type of the starting material, the solvent and the catalyst, and the like.
The temperature is 0 ° C. (preferably 0 ° C. to 50 ° C.), and the reaction time is usually 30 minutes to 10 hours (preferably 1 hour to 5 hours).

In the removal with an oxidizing agent, the inert solvent used is not particularly limited as long as it does not participate in the reaction. For example, ketones such as acetone, methylene chloride, chloroform and carbon tetrachloride Such as halogenated hydrocarbons, nitriles such as acetonitrile,
Diethyl ether, tetrahydrofuran, ethers such as dioxane, dimethylformamide, dimethylacetamide, amides such as hexamethyl phosphorotriamide and sulfoxides such as dimethyl sulfoxide or a mixed solvent of these organic solvents, Preferably, they are amides or sulfoxides. The oxidizing agent used is not particularly limited as long as it is a compound used for the oxidation.For example, potassium persulfate, alkali metal persulfate such as sodium persulfate, ammonium cerium nitrate (CAN), 2 , 3-Dichloro-5,6-dicyano-p
-Benzoquinone (DDQ), preferably ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-
It is dicyano-p-benzoquinone (DDQ). The reaction temperature and the reaction time vary depending on the type of the starting material, the solvent and the catalyst, and the like, but the reaction temperature is usually -10C to 150C (preferably 0C to 50C), and the reaction time is Normal,
10 minutes to 24 hours (preferably 30 minutes to 10 hours)
It is.

When the amino- or imino-protecting group is a t-butyl group, a t-butoxycarbonyl group, a methoxybenzyl group or a methoxybenzyloxycarbonyl group, the corresponding compound is usually reacted with an acid in an inert solvent. The reaction removes the substituent. If the inert solvent used in the above reaction is inert to this reaction,
Although not particularly limited, for example, ethers such as ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, and aromatic hydrocarbons such as benzene, toluene and xylene And preferably ethers. The acid used is usually used as an acid and is not particularly limited as long as it does not inhibit the reaction. An acid or an organic acid such as p-toluenesulfonic acid, preferably an inorganic acid (particularly preferably hydrochloric acid). The reaction temperature and the reaction time are not particularly limited, but the reaction temperature is usually −10 ° C. to 50 ° C. (preferably 0 ° C. to 30 ° C.), and the reaction time is usually 30 ° C.
Minutes to 50 hours (preferably 1 hour to 2 hours).

The desired (b) reaction for removing the protecting group for the mercapto group is generally carried out by a method well known in the art, and for example, in an inert solvent,
It is carried out by subjecting the obtained compound to alkaline hydrolysis. The alkali used in the above reaction is, for example, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or an alkali metal carbonate such as sodium carbonate or potassium carbonate. Things.

The inert solvent used in the above reaction is not particularly limited as long as it does not participate in this reaction. Examples thereof include diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol. , Ethers such as dimethyl ether, alcohols such as methanol, ethanol, and propanol, formamide, dimethylformamide,
It may be an amide such as dimethylacetamide, hexamethylene phosphate triamide, and preferably ethers or alcohols. The reaction temperature and the reaction time are not particularly limited, but the reaction temperature is usually -10 ° C to 100
° C (preferably 0 ° C to 30 ° C), and the reaction time is:
Usually, it is 5 minutes to 10 hours (preferably 30 minutes to 5 hours).

The desired reaction (c) for protecting an amino group or an imino group depends on the kind of the protecting group, but is generally carried out by a method well known in the art, and is carried out in an inert solvent in an inert solvent. In the presence or absence (preferably in the presence), the obtained compound is represented by the general formula R ⁴ —Y (X) wherein R ⁴ is as defined above, and Y is
A halogen atom (preferably a chlorine atom, a bromine atom or an iodine atom) is shown. By reacting with a compound having the following formula: The base used is not particularly limited as long as it does not affect the other parts of the compound.Examples include sodium methoxide, alkali metal alkoxides such as sodium ethoxide, lithium carbonate, sodium carbonate, and carbonate. It can be alkali metal carbonates such as potassium, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or amines such as triethylamine, N, N-dimethylaniline, pyridine, and the like. Are amines.

The inert solvent used in the above reaction is not particularly limited as long as it does not take part in the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, diethyl ether Ter, diisopropyl ether, tetrahydrofuran, dioxane,
Ethers such as dimethoxyethane, diethylene glycol, dimethyl ether, methanol, ethanol,
It may be an alcohol such as propanol, preferably an ether or an alcohol. The reaction temperature and reaction time are not particularly limited, but the reaction temperature is usually-
The temperature is 10 ° C to 100 ° C (preferably 0 ° C to 30 ° C), and the reaction time is usually 30 minutes to 10 hours (preferably 1 hour to 5 hours).

[0057] The reaction to acylate the mercapto group is desired (d) the reaction generally in the art are carried out by known methods, in an inert solvent, the general formula and the resulting compound R ² _a -OH (XI) (wherein, R ² _a is. of the same meaning as the group formed by removing a hydrogen atom from the R ²⁾ presence of a compound with a base having, carried out by reacting. The inert solvent used in the above reaction is not particularly limited as long as it is inert to the reaction. For example, hydrocarbons such as hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2 Halogenated hydrocarbons such as dichloroethane and carbon tetrachloride, ethers such as ether, tetrahydrofuran and dioxane, ketones such as acetone, N, N-dimethylformamide, N, N-dimethylacetamide , N-methyl-2-pyrrolidone, amides such as hexamethylphosphoramide, and sulfoxides such as dimethyl sulfoxide, and are preferably halogenated hydrocarbons (particularly preferably, dichloromethane). . The base used in the above reaction is, for example,
Sodium methoxide, alkali metal alkoxides such as sodium ethoxide, lithium carbonate, sodium carbonate, alkali metal carbonates such as potassium carbonate,
Lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide or triethylamine,
N, N-dimethylaniline, pyridine, 4-N, N-
Tertiary amines such as (dimethylamino) pyridine, preferably tertiary amines, and particularly preferably a combination of pyridine and 4-N, N- (dimethylamino) pyridine is there.

After completion of the reaction, the target compound (I) of each reaction
Is collected from the reaction mixture according to a conventional method. For example,
After filtering off the insoluble matter as appropriate, filtering the precipitated crystals or filtering out the insoluble matter as appropriate, neutralizing as appropriate, evaporating the solvent, adding water, and adding ethyl acetate or the like. After extraction with a water-immiscible organic solvent and drying, the solvent can be obtained by distilling off the extraction solvent. If necessary, it can be further purified by a conventional method, for example, recrystallization, column chromatography or the like.

Method B is a method for separately producing compound (I). Step B1 is a step of producing a compound having the general formula (V), wherein the compound (II) or a reactive derivative thereof (acid halides, mixed acid anhydrides or active esters) is mixed in an inert solvent with a compound of the general formula (V). It is achieved by reacting a compound having (IV) or an acid addition salt thereof. In this step, for example, an acid halide method, a mixed acid anhydride method, an active ester method or a condensation method can be used.
This is performed in the same manner as in the previous stage of the process.

Step B2 is a step of preparing a compound having the general formula (I), in which the compound having the general formula (V) is reacted with a nitrating agent in a solvent-free or inert solvent, and if necessary, a) a reaction for removing the protecting group for the amino group or imino group of the obtained compound, (b) a reaction for removing the protecting group for the mercapto group, (c) a reaction for protecting the amino group or the imino group, and (d) a reaction for protecting the amino group or the imino group. It is achieved by appropriately performing a reaction for acylating a group, and the desired reaction is performed in the same manner as in the latter stage of the above-mentioned Method A, Step A1. The nitrating agent used can be, for example, fuming nitric acid, nitrocoridium tetrafluoroboron, thionyl chloride nitric acid, thionyl nitric acid, nitronium tetrafluoroboron, preferably fuming nitric acid, nitrocorridium tetrafluoroboron or Thionyl chloride nitric acid.

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, 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, and preferably
It is a halogenated hydrocarbon, an ether, a nitrile or an amide, and particularly preferably a nitrile. The reaction temperature varies depending on the type of the starting compound (II) and the nitrating agent, but is usually -20 ° C to 50 ° C (preferably,
Around room temperature). The reaction time varies depending on the reaction temperature and the like, but is usually 30 minutes to 24 hours (preferably 1 hour to 10 hours).

After completion of the reaction, the target product of each reaction is collected from the reaction mixture according to a conventional method. For example, the precipitated crystals are filtered or appropriately neutralized, the solvent is distilled off, water is added, the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate, dried, and extracted. It can be obtained by evaporating the solvent, and if necessary, can be further purified by a conventional method, for example, recrystallization, column chromatography or the like.

Method C is a method for separately producing compound (I). The step C1 is a step for producing a compound having the general formula (VII), wherein the compound having the general formula (VI) is prepared in an inert solvent.
Or a reactive derivative thereof and a compound (II)
It is achieved by reacting I) or an acid addition salt thereof. For example, a mixed acid anhydride method, an active ester method, or a condensation method can be used.

Step C2 is a step for producing a compound having the general formula (VIII), and the compound (V) is prepared in an inert solvent.
This step is achieved by removing the protecting group for the amino group in II), and this step is carried out in the same manner as the reaction (a) for removing the protecting group for the amino group or imino group in the above-mentioned Method A, Step A1.

Step C3 is a step for producing a compound having the general formula (I), and the compound (VII) is prepared in an inert solvent.
I) or an acid addition salt thereof (for example, a mineral acid salt such as hydrochloride, nitrate, sulfate) and a compound having the general formula (IX), and if necessary, (a) an amino group of the obtained compound Alternatively, a reaction for removing the protecting group of the imino group, (b) a reaction for removing the protecting group for the mercapto group, (c) a reaction for protecting the amino group or the imino group, and (d) a reaction for acylating the mercapto group are appropriately performed. This is carried out in the same manner as in the method A, step A1.

The starting compounds (II) and (VI) are known or are easily produced according to known methods or methods similar thereto. [For example, Chemical Abstracts, Vol. 88, 7376, 1977: Chem. Abstr.,
88 , 7376 (1977), Biochemistry, Volume 16, Volume 54
84, 1977: Biochemistry, 16 , 5484 (1977),
Chemical Pharmaceutical Brettan, Vol. 30, p. 440, 1982: Chem. Pharm. Bull., 30 , 440.
(1982), The Journal of Medicinal Chemistry, Vol. 29, p. 784, 1986: J. M.
ed. Chem., 29 , 784 (1986), tetrahedron, No. 50
Volume, 13493, 1994: Tetrahedron, 50 , 1
3493 (1994), The Journal of American Chemical Society, Vol. 79, pp. 6180, 1957
Year: J. Am. Chem. Soc., 79 , 6180 (1957), The Journal of Medicinal Chemistry, 37.
3707, 1994: J. Med. Chem., 37 , 3.
707 (1994), etc.].

The starting compound (III) is known or is easily produced according to a known method or a method analogous thereto. [For example, Chemical Abstracts, No. 88
Volume, 7376, 1978: Chem. Abstr., 88 , 7376 (1
978), JP-A-5-213910 and the like].

The starting compound (IV) is known or is easily produced according to a known method or a method analogous thereto. [For example, Chemical Abstracts, Vol. 61,
9415, 1964: Chem. Abstr., 61 , 9415 (196
4), tetrahedron, vol. 47, p. 8177, 199
One year: Tetrahedron, 47 , 8177 (1991), Tetrahedron Letters, Vol. 28, p. 6069, 1987: Te
trahedron Letters, 28 , 6069 (1987), Tetrahedron Letters, Vol. 29, p. 1265, 1988: T
etrahedron Letters, 29 , 1265 (1988), The Journal of American Chemical Society, 113
Volume, 8980, 1991: J. Am. Chem. Soc., 1
13 , 8980 (1991), The Journal of Organic Chemistry, 47, 3016, 1982
Year: J. Org. Chem., 47 , 3016 (1982), etc.].

The starting compound (IX) is known or is easily produced according to a known method or a method analogous thereto. [For example, The Journal of American Chemical Society, Vol. 75, pp. 913, 1953
Year: J. Am. Chem. Soc., 75 , 913 (1953), The Journal of Organic Chemistry, Volume 30,
2839, 1965: J. Org. Chem., 30 , 2839.
(1965), The Journal of Organic Chemistry, 58, 3731, 1993: J.
Org. Chem., 58 , 3731 (1993) etc.].

The starting compound (III) can also be produced by the following method.

[0071]

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[0072]

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[0073]

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[0074]

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In the above formula, A has the same meaning as described above, and Aa is a C ₁ -C ₇ alkylene group (C ₁ -C
₍₈₎ methylene is removed from an alkylene group, and a linear or branched alkylene group having 1 to 7 carbon atoms) or a compound of the formula -B
-D-Ea- wherein B and D have the same meanings as described above, and Ea is a single bond or a C ₁ -C ₅ alkylene group (methylene is removed from the C ₁ -C ₆ alkylene group) And a linear or branched alkylene group having 1 to 5 carbon atoms). And Ab represents the above C _1-
A C ₆ alkylene group or a formula -Ba-D-Ea- (wherein D
And Ea have the same meanings as described above, and Ba represents a single bond or the C ₁ -C ₅ alkylene group. Wherein Ac ′ is the aforementioned C ₁ -C ₆ alkylene group or a formula —B—D—Eb—, wherein B and D have the same meanings as described above, and Eb is A bond or a C ₁ -C ₄ alkylene group (a linear or branched alkylene group having 1 to 4 carbon atoms, obtained by removing ethylene from the C ₁ -C ₆ alkylene group). It represents a group having a], Ad, the C ₁ -C ₇ (wherein, Ba, D and E. Showing the same meanings as defined above) alkylene group or the formula -Ba-D-E- having Ae represents a C ₁ -C ₄ alkylene group or a formula -B-D-Ec- (where B and D are
It has the same meaning as described above, and Ec represents a single bond or the C ₁ -C ₂ alkylene group. Represents a group having
R ⁵ is a hydrogen atom, the above-mentioned C ₁ -C ₆ alkyl group or the above-mentioned C ₁ -C ₆ aliphatic acyl group (preferably acetyl, propionyl, butyryl or isobutyryl group, particularly preferably isobutyryl group). are shown, R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or a protecting group of the amino group (except when R ⁶ and R ⁷ is a protecting group for amino group.), R ⁶ a represents a cyano group or a carbamoyl group, R ⁸ is cyano or the formula -CH (CO ₂ R ⁵ a)
₂ (wherein, R ⁵ a is a hydrogen atom or a C ₁ -C ₆ alkyl group.) Indicates, R ⁹ is a hydroxyl protecting group (e.g.,
2-tetrahydrofuryl, 2-tetrahydropyranyl,
5- to 6-membered cyclic ether groups such as 4-methoxy-2-tetrahydropyranyl and 2-tetrahydrothiopyranyl; tri-C ₁ -C ₄ alkylsilyl groups such as trimethylsilyl, triethylsilyl and t-butyldimethylsilyl; benzyl, methylbenzyl, methoxybenzyl, fluorobenzyl, chloro C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or halogen optionally substituted benzyl group such as benzyl, benzyloxycarbonyl, methyl benzyloxycarbonyl, C ₁ -C such as methoxybenzyloxycarbonyl, fluorobenzyloxycarbonyl, chlorobenzyloxycarbonyl
_It may be a benzyloxycarbonyl group optionally substituted with ₆ alkyl, C ₁ -C ₆ alkoxy or halogen, preferably a 2-tetrahydropyranyl, t-butyldimethylsilyl or p-methoxybenzyloxycarbonyl group. is there. ) And R ¹⁰ represent a cyano group or an azide group, and Ya represents the halogen atom (preferably chlorine or bromine atom), a C ₁ -C ₆ alkylsulfonyloxy group (preferably methanesulfonyloxy or ethane). A sulfonyloxy group) or a C ₆ -C ₁₀ arylsulfonyloxy group (preferably a benzenesulfonyloxy or toluenesulfonyloxy group), p represents an integer of 0 to 1, and q represents an integer of 2 to 3. Is shown.

Method D is a method for producing compound (III). Step D1 is a step for producing a compound having the general formula (IVa), and in an inert solvent (preferably an ether such as ether or tetrahydrofuran), the amino having the general formula (XII) The carboxylic acids are combined with a reducing agent (preferably, a borohydride compound such as sodium borohydride or sodium cyanoborohydride) at 0 ° C to 50 ° C.
The reaction is carried out at 30 ° C. (preferably around room temperature) for 30 minutes to 10 hours (preferably 1 hour to 5 hours). If desired, in an inert solvent (preferably ethers such as ether and tetrahydrofuran, alcohols such as methanol and ethanol),
The amino group can be protected by reacting with the compound (X) in the presence or absence of a base (preferably, amines such as triethylamine and pyridine). The reaction is performed in the same manner as in the reaction (c) for protecting a group or an imino group.

Step D2 is a step of preparing compound (III), which is carried out by nitrating compound (IVa) and, if desired, removing an amino-protecting group. It is performed in the same manner as in the first step of the step B2. The desired reaction of removing the protecting group for the amino group is carried out in the same manner as the reaction (a) for removing the protecting group for the amino group or imino group in Step A1 of Method A after the above reaction.

In the method E, the compound (IVa) is reacted with a compound of the formula
A group having R ⁶ R ⁷ N— (wherein R ⁶ and R ⁷ have the same meanings as described above) is an amino group, and Aa
But (wherein, Ab is. Showing the same meanings as defined above) wherein -CH ₂ Ab-compound is a group having a (IV
b) is a method for separately producing the same. The step E1 is a step for producing a compound (IVb). In an inert solvent (preferably, ethers such as ether and tetrahydrofuran), the compound having the general formula (XIII) is reduced with a reducing agent (for example, Include sodium borohydride, borohydride compounds such as sodium cyanoborohydride,
Aluminum hydride compounds such as lithium aluminum hydride, preferably lithium aluminum hydride)
And 0 ° C to 150 ° C (preferably 30 ° C to 100 ° C).
C.) for 15 minutes to 10 hours (preferably 30 minutes to 5 hours). Further, the compound (IV)
b) is manufactured.

In the method F, the compound (XII) is treated with Aa
But the formula _{-Ac '- (CH 2) p-} ( wherein, Ac' and p
Has the same meaning as described above. This is a method for producing a compound (XIIa) which is a group having the following formula: The step F1 is a step of producing a compound having the general formula (XIV), wherein the compound having the general formula (IVc) is dissolved in an inert solvent (preferably, ethers such as ether and tetrahydrofuran, methylene chloride, In the presence or absence of halogenated hydrocarbons such as chloroform), bases (preferably amines such as triethylamine and pyridine), thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, Halides such as methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, benzenesulfonyl bromide, p-toluene sulfonyl chloride or methanesulfonic anhydride, ethanesulfonic anhydride, benzenesulfonic anhydride, p-toluenesulfonic anhydride, etc. Sulfonic anhydride and 0 ° C to 50 ° C
The reaction is carried out (preferably around room temperature) for 30 minutes to 10 hours (preferably 1 hour to 5 hours). Further, the obtained sulfonyloxy compound is placed in an inert solvent (preferably, a ketone such as acetone, an amide such as dimethylformamide or dimethylacetamide), an alkali metal such as sodium bromide or sodium iodide. The corresponding halide can also be produced by reacting the halide at 0 ° C. to 50 ° C. (preferably around room temperature) for 30 minutes to 20 hours (preferably 1 hour to 10 hours).

Step F2 is a step of preparing a compound having the general formula (XV). amides such as acetamide), lithium cyanide, sodium cyanide, alkali metal cyanides such as potassium cyanide or the formula _{^{M + - CH (CO 2 R}} 5 a) 2 ( wherein,
R ⁵ a have the same meanings as described above, M represents an alkali metal atom. The reaction is carried out at 0 ° C. to 50 ° C. (preferably around room temperature) for 30 minutes to 10 hours (preferably 1 hour to 5 hours). This step is also preferably performed in the presence of sodium iodide.

The step F3 is a step of producing the compound (XIIa). In the compound (XV), the compound in which R ⁸ is a cyano group is dissolved in an aqueous solution of an acid (preferably hydrochloric acid, nitric acid or sulfuric acid). A mineral acid) at 0 ° C. to 150 ° C. (preferably 30 ° C. to 120 ° C.) for 30 minutes to 10 hours (preferably 1 hour to 5 hours) to give compound (XIIa) , R ⁵ are hydrogen atoms and p is 0, and the compound (X
In V), R ⁸ has the formula -CH- (CO ₂ R ⁵ a)
₂ (wherein, R ⁵ a is. Showing the same meanings as defined above) and a group having a compound, if desired, the following reaction conditions, i.e., an inert solvent (preferably, water ether, water Hydrated ethers such as tetrahydrofuran, hydrated alcohols such as hydrated methanol and hydrated ethanol), bases (preferably alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide); 30 ° C. to 10 ° C. (preferably around room temperature)
The reaction is carried out for a period of time (preferably 1 hour to 5 hours) to hydrolyze, and then in an inert solvent (preferably an aromatic hydrocarbon such as benzene, toluene, or xylene) at 50 ° C. to 200 ° C. ℃ (preferably 100 ℃ ~ 1
(50 ° C.) for 30 minutes to 10 hours (preferably 1 hour to 5 hours) to give Compound (XIIa)
In the above, a compound wherein R ⁵ is a hydrogen atom and p is 1 is produced. Further, if desired, the obtained carboxylic acid compound is dissolved in an inert solvent (preferably, ethers such as ether and tetrahydrofuran) in diazomethane,
Diazo C ₁ -C such as diazoethane, diazohexane
₆ alkyl and 0 ° C to 50 ° C (preferably around room temperature)
For 5 minutes to 2 hours (preferably 10 minutes to 1 hour), or a C ₁ -C ₆ alcohol such as methanol, ethanol or hexanol, and the method A
By reacting in the same manner as in the first step the active ester method, it is possible to produce the corresponding esters, the carboxylic acid compound, a halogeno carbonate C ₁ -C ₆ alkyl A
The corresponding acyl compound can be produced by reacting in the same manner as in the reaction for producing the mixed acid anhydride in the step A1 of the method.

In Method G, compound (XIIa) was prepared by adding p
Is a method for separately producing the compound (XIIb) wherein is 1. The step G1 is a step of producing a compound having the general formula (XVI), wherein the compound having the general formula (XIIc) is dissolved in an inert solvent (preferably ethers such as ether and tetrahydrofuran, methylene chloride, In the presence or absence of halogenated hydrocarbons such as chloroform) and bases (preferably amines such as triethylamine, pyridine and N-methylmorpholine), methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate ,
C ₁ -C ₆ alkyl halogenocarbonate such as hexyl chlorocarbonate at −50 ° C. to 50 ° C. (preferably −20 ° C. to 0 ° C.) for 30 minutes to 10 hours (preferably 1 hour to 5 hours) Time), reacting the resulting compound in an inert solvent (preferably ethers such as ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and chloroform), diazomethane and -50
30 ° C. to 50 ° C. (preferably −20 ° C. to 0 ° C.)
The reaction is carried out for a period of from minutes to 10 hours (preferably from 1 hour to 5 hours).

The step G2 is a step of producing the compound (XIIb). The compound (XVI) is prepared by reacting the compound (XVI) with silver carboxylate such as silver acetate or silver benzoate, silver methanesulfonate, silver benzenesulfonate, p-toluene. In the presence of silver sulfonates such as silver sulfonate, silver powder, silver compounds such as silver oxide (preferably silver benzoate or silver oxide), and in the presence of organic amines (eg, triethylamine, pyridine, etc.) Or a large excess of water or C ₁ -C ₆ also serving as an inert solvent in the absence of
Alcohol and 0 ° C to 50 ° C (preferably around room temperature)
The reaction is performed by reacting for 30 minutes to 10 hours (preferably 1 hour to 5 hours).
A compound in which R ⁵ is a hydrogen atom is produced, and a compound in which R ⁵ is a C ₁ -C ₆ alkyl group is produced by reaction with a C ₁ -C ₆ alcohol. The obtained carboxylic acid can be esterified or acylated in the same manner as in the above-mentioned Method F, Step F3.

In the method H, the compound (IVa) is treated with R ⁶
Is a method for producing a compound (IVd) which is a hydrogen atom. The step H1 is a step of producing a compound having the general formula (XVIII), which is achieved by protecting the hydroxyl group of the compound having the general formula (XVII), and the reaction for protecting the hydroxyl group varies depending on the type of the protecting group. Is carried out by a reaction well known in the field of synthetic organic chemistry.

When the protecting group is a 5- or 6-membered cyclic ether group, it is preferably in an inert solvent (preferably ether, ethers such as tetrahydrofuran, methylene chloride,
Halogenated hydrocarbons such as chloroform), acids (for example, mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid), and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid. Is reacted with an unsaturated cyclic ether such as dihydrofuran, dihydropyran, 4-methoxydihydropyran or dihydrothiopyran at 0 ° C to 50 ° C (preferably around room temperature) in the presence of hydrochloric acid). For 30 minutes to 5 hours (preferably 1 hour to 2 hours), the hydroxyl group can be protected.

When the protecting group is a tri-C ₁ -C ₄ alkylsilyl group, an optionally substituted benzyl group or an optionally substituted benzyloxycarbonyl group,
In an inert solvent (preferably ethers such as ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and chloroform, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethylsulfoxide) In the presence of a base (preferably, an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride, or an amine such as triethylamine, pyridine or N-methylmorpholine), the corresponding compound is converted to trimethylsilyl. Chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldimethylsilyl bromide, benzyl chloride, benzyl bromide, methylbenzyl chloride, methoxybenzyl chloride, fluorobenzyl chloride, chlorobe Jirukurorido, benzyloxycarbonyl chloride, methyl benzyloxycarbonyl chloride, methoxybenzyloxycarbonyl chloride,
Halides such as fluorobenzyloxycarbonyl chloride and chlorobenzyloxycarbonyl chloride;
The reaction is carried out at 0 ° C. to 50 ° C. (preferably around room temperature) for 30 minutes to 24 hours (preferably 1 hour to 20 hours).

Step H2 is a step of producing a compound having the general formula (XIX), which is achieved by halogenation or sulfonylation. This step is carried out in the same manner as in the above-mentioned Method F, Step F1.

Step H3 is a step of preparing a compound having the general formula (XX) in an inert solvent (preferably an ether such as ether or tetrahydrofuran, or an amide such as dimethylformamide or dimethylacetamide). , Sulfoxides such as dimethyl sulfoxide),
Compound (XIX) is reacted with an alkali metal cyanide such as lithium cyanide, sodium cyanide and potassium cyanide or an alkali metal azide such as lithium azide, sodium azide and potassium azide at 0 ° C. to 200 ° C.
C. (preferably 50.degree. C. to 150.degree. C.) for 15 minutes to 20 hours (preferably 30 minutes to 10 hours).

The step H4 is a step for producing a compound having the general formula (XXI), which is achieved by reducing the compound (XX). This step is carried out in the same manner as the above-mentioned Method E, step E1. From compounds where R ¹⁰ is azide, A is Ad
Compound is is prepared from the compound R ¹⁰ is cyano, compounds wherein A is a group having the formula -CH ₂ -Ad- is manufactured.

Step H5 is a step of producing compound (IVd), which is accomplished by removing the hydroxyl-protecting group of compound (XXI) and, if desired, protecting the amino group.

The protecting group for the hydroxyl group is removed by a method usually used in the field of synthetic organic chemistry. When the protecting group is a 5- or 6-membered cyclic ether group, a methoxybenzyl group or a methoxybenzyloxycarbonyl group, the substituent is removed by reacting the corresponding compound with an acid. The removal reaction is carried out in the same manner as the removal reaction in the case where the protecting group such as an amino group in the reaction (a) of the step A1 of Method A is a t-butyl group or the like. When the protecting group is a trisubstituted silyl group, the corresponding compound is converted to a fluoride anion such as tetrabutylammonium fluoride in an inert solvent (preferably, ethers such as tetrahydrofuran and dioxane). The substituent is removed by reacting the resulting compound with -10 ° C to 50 ° C (preferably 0 ° C to 30 ° C) for 2 hours to 24 hours (preferably 10 hours to 18 hours). Is done.

When the protecting group is a benzyl group which may be substituted or a benzyloxycarbonyl group which may be substituted, the substituent is removed by subjecting the corresponding compound to catalytic reduction. The reaction is carried out according to Method A
The reaction is performed in the same manner as in the removal reaction of the one-step reaction (a) in which the protecting group such as an amino group is an optionally substituted benzyl group or the like. The reaction for protecting the amino group is carried out according to Method A
The reaction is carried out in the same manner as in one-step reaction (c).

Method I is a method for producing a compound having the general formula (IVe) contained in the compound (IV). I
One step is a step of producing a compound having the general formula (XXIII). The compound having the general formula (XXII) is mixed with concentrated ammonia at 0 ° C. to 50 ° C. (preferably around room temperature).
30 minutes to 20 hours (preferably 1 hour to 10 hours)
Time) to carry out the reaction.

Step I2 is a step of producing compound (IVe), which is achieved by reducing compound (XXIII). This step is carried out in the same manner as in the above-mentioned Method E, step E1.

Method J is a method for producing a compound having the general formula (IVf) contained in compound (IV). Jth
One step is a step of producing a compound having the general formula (XXV), which is achieved by reacting a compound having the general formula (XXIV) with concentrated ammonia in the same manner as in the above-mentioned Method I, Step I1. Step J2 is a step of producing compound (IVf), which is performed by reducing compound (XXV). This step is performed in the same manner as in the aforementioned Method E, step E1.

Method K is a method for producing a compound having the general formula (IVg) contained in compound (IV). Kth
One step is a step of producing a compound having the general formula (XXVII) in an inert solvent (preferably, halogenated hydrocarbons such as dichloromethane and chloroform, amides such as dimethylformamide and dimethylacetamide; Sulfoxides such as dimethylsulfoxide), a compound having the general formula (XXVI), an oxidizing agent (for example, chromic acid-pyridine, dimethylsulfoxide-oxalic acid chloride, dimethylsulfoxide-chlorine gas, dimethylsulfoxide-trifluoroacetic anhydride, Succinimide dimethylsulfonium chloride, preferably dimethylsulfoxide-oxalic acid chloride);
The reaction is carried out at 0 ° C. to 50 ° C. (preferably around room temperature) for 15 minutes to 20 hours (preferably 30 minutes to 10 hours).

Step K2 is a step of preparing a compound having the general formula (XXVIII). Below (preferably, 1,5-diazabicyclo [4.3.0] non-5-
Ene, strong base amines such as 1,8-diazabicyclo [5.4.0] undes-7-ene, alkyllithiums such as butyllithium), formula (R ¹¹ ) ₃ P ⁺ (CH
_{2) qOH} Y ^-. (Wherein, Y and q have the same meanings as described above, R ¹¹ is a compound having a) showing a C ₆ -C ₁₀ aryl group, -20 ° C. to 0.99 ° C. ( The reaction is preferably performed at 0 ° C. to 100 ° C. for 1 hour to 10 days (preferably 5 hours to 7 days).

The K3 step is a step of producing the compound (IVg). The compound (XXVIII) is reacted with the reaction (a) for removing the protecting group for the amino group or imino group in the step A1 of the above-mentioned Method A.
It is carried out by catalytic reduction in the same manner as described above.

Method L is a method for producing a compound having the general formula (IVh) contained in compound (IV). L-th
One step is a step of producing a compound having the general formula (XXVIa), which is achieved by reducing a compound having the general formula (XIId). This step is performed in the same manner as in the above-mentioned Method D, Step D1.

The L2 step is a step of producing the compound (XXVIIa), which is achieved by oxidizing the compound (XXVIa). This step is carried out in the same manner as in the K step K1 of Method K.

Step L3 is a step for producing a compound (IVh) in an inert solvent (preferably ethers such as ether and tetrahydrofuran).
Ia) is treated with a Grignard reagent such as methylmagnesium chloride, methylmagnesium bromide at -20 ° C.
The reaction is carried out at 10 to 50 ° C (preferably 0 ° C to 30 ° C) for 10 minutes to 5 hours (preferably 15 minutes to 2 hours).

After completion of the reaction, the target compound of each reaction is collected from the reaction mixture according to a conventional method. For example, the precipitated crystals are filtered or, if there is any insoluble matter, appropriately filtered off.If the reaction solution is acidic or alkaline, the reaction solution is appropriately neutralized, water is added, and ethyl acetate is added. After extraction with such a water-immiscible organic solvent and drying, it can be obtained by distilling off the extraction solvent.If necessary, it can be further purified by a conventional method, for example, recrystallization, column chromatography or the like. it can.

Starting compounds (XII), (XIII),
(XVII), (XXII) and (XXIV) are known or are easily prepared by known methods [eg Chemical Abstracts, Vol. 64, 3379
f, 1966: Chem. Abst., 64 , 3379f (1966), Chemish Berichte, 67, 1783, 1934.
Year: Chemische, Berichte, 67 , 1783 (1934);
Berichte, vol. 71, p. 759, 1938: Chemi
sche, Berichte, 71 , 759 (1938), Journal of
American Chemical Society, Vol. 62, No. 2
891, 1940: J. Am. Chem. Soc., 62 , 2891.
(1940), Journal of American Chemical
Society, 82, 3257, 1960:
J. Am. Chem. Soc., 82 , 3257 (1960), Journal of the American Chemical Society, Vol. 88, p. 3522, 1966: J. Am. Chem. Soc., 88 . , 3522
(1966), tetrahedron, vol. 21, p. 2725, 1
965: Tetrahedron, 21 , 2725 (1965), Tetrahedron, 48, 9753, 1992: Tertrahe
dron, 48 , 9753 (1992), etc.].

The above-mentioned formula (I) which is an active ingredient of the present invention.
The compound having a or a pharmacologically acceptable salt thereof has an excellent collateral vasodilatory effect, has no side effects such as headache, dizziness, tachycardia or adverse effects on the digestive organs, liver, bones, etc. Since it does not receive a passage effect, it is useful as a therapeutic or preventive agent (preferably, a therapeutic agent) for angina pectoris.

When the compound (I), which is an active ingredient of the present invention, and a pharmacologically acceptable salt thereof are used as a therapeutic or prophylactic agent for angina pectoris, the compound itself or an appropriate pharmacologically acceptable salt is used. Mixed with excipients, diluents and the like, and administered orally by tablets, capsules, granules, powders or syrups, or parenterally by injections (preferably orally). it can.

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 per dose
(Preferably 0.5 mg), the upper limit of 100 mg (preferably 50 mg) is desirably administered to an adult 1 to 6 times per day depending on the symptoms.

[0107]

The present invention will be described in more detail with reference to the following Examples, Reference Examples, Test Examples and Formulation Examples, but the scope of the present invention is not limited thereto.

Example 1 1-[(2S) -2-methyl-3-mercaptopropionyl] -L-proline-N- (2-nitroxyethyl)
Amide (Exemplified Compound No. 1-55) 1.0 g of 1-[(2S) -2-methyl-3-mercaptopropionyl] -L-proline and 0.79 g of 2-
Nitroxyethylamine hydrochloride was suspended in 20 ml of anhydrous tetrahydrofuran, 2.3 ml of triethylamine and 1.2 ml of diphenylphosphoric acid azide were added under ice cooling and stirring, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 0.75 g of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.21 (3H, d, J = 6.
6Hz), 1.55 (1H, t, J = 7.9Hz), 1.80-2.25 (3H, m), 2.30-2.
60 (2H, m), 2.75-3.05 (2H, m), 3.40-3.75 (4H, m), 4.40-
4.70 (3H, m), 6.82 (0.1H, bs), 7.52 (0.9H, bs).

Example 2 1-[(2S) -3-mercapto-2-methylpropionyl] -L-proline-N- (1-methyl-2-nitroxyethyl) amide (Exemplified Compound No. 1-57) 0 0.81 g of 1-[(2S) -3-mercapto-2-methylpropionyl] -L-proline and 0.70 g of 1
The reaction was carried out in the same manner as in Example 1 using -methyl-2-nitroxyethylamine hydrochloride, and purification was performed to obtain 0.45 g of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.10-1.35 (6H,
m), 1.53 (1H, t, J = 7.9Hz), 1.70-2.23 (3H, m), 2.30-2.55
(2H, m), 2.75-2.98 (2H, m), 3.45-3.70 (2H, m), 4.18-4.70
(4H, m), 7.42 (1H, d, J = 5.9Hz).

Example 3 1-[(2S) -3-mercapto-2-methylpropionyl] -L-proline-N-[(1S) -1-methyl-
2-Nitrooxyethyl] amide (Exemplary Compound No. 1-5
7) Using 1.80 g of 1-[(2S) -3-mercapto-2-methylpropionyl] -L-proline and 1.56 g of (1S) -1-methyl-2-nitroxyethylamine hydrochloride, The reaction was carried out and purified in the same manner as in Example 1 to obtain 649 mg of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.10-1.30 (6H,
m), 1.53 (1H, t, J = 8.0Hz), 1.70-2.25 (3H, m), 2.35-2.55
(2H, m), 2.75-2.98 (2H, m), 3.50-3.70 (2H, m), 4.20-4.52
(3H, m), 4.55-4.65 (1H, m), 7.32 (1H, d, J = 7.2Hz).

Example 4 1-[(2S) -3-acetylthio-2-methylpropionyl] -L-proline-N-[(1S) -1-methyl-2-nitroxyethyl] amide (Exemplary Compound No. 1) −
403) 649 mg of 1-[(2S) -3-mercapto-2-methylpropionyl] -L-proline-N- of Example 3
[(1S) -1-Methyl-2-nitroxyethyl] amide is dissolved in 10 ml of dichloromethane, 0.21 ml of acetic anhydride and 0.18 ml of pyridine are added under ice-cooling and stirring, and the mixture is added at room temperature for 1 hour 15 hours. For a minute. Further, a catalytic amount of 4-dimethylaminopyridine was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent:
(Cyclohexane / ethyl acetate = 1/4).
Crystallization was performed with hexane-isopropyl ether, and the crystals were collected by filtration to obtain 536 mg of the title compound as colorless crystals. Melting point: 77-79C. NMR spectrum (CDCl ₃ ) δ ppm: 1.10-1.30 (6H,
m), 1.75-2.20 (3H, m), 2.33 (3H, s), 2.30-2.43 (1H, m),
2.75-2.90 (1H, m), 2.92-3.18 (2H, m), 3.45-3.65 (2H, m),
4.15-4.63 (4H, m), 7.28 (1H, d, J = 5.3Hz).

Example 5 1-[(2S) -3-mercapto-2-methylpropionyl] -L-proline-N-[(1R) -1-methyl-
2-Nitrooxyethyl] amide (Exemplary Compound No. 1-5
7) Using 2.00 g of 1-[(2S) -3-mercapto-2-methylpropionyl] -L-proline and 1.72 g of (1R) -1-methyl-2-nitroxyethylamine hydrochloride, The reaction was carried out and purified in the same manner as in Example 1 to obtain 711 mg of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.10-1.35 (6H,
m), 1.53 (1H, t, J = 8Hz), 1.70-2.25 (3H, m), 2.40-2.55 (2
H, m), 2.75-3.00 (2H, m), 3.50-3.70 (2H, m), 4.15-4.45 (2
H, m), 4.55-4.70 (2H, m), 7.42 (1H, d, J = 7.1Hz).

Example 6 1-[(2S) -3-acetylthio-2-methylpropionyl] -L-proline-N-[(1R) -1-methyl-2-nitroxyethyl] amide (Exemplary Compound No. 1) −
403) 711 mg of 1-[(2S) -3-mercapto-2-methylpropionyl] -L-proline-N- of Example 5
[(1R) -1-Methyl-2-nitroxyethyl] amide, 0.23 ml of acetic anhydride and 0.20 ml of pyridine were reacted and purified in the same manner as in Example 4, and the title compound was purified as colorless crystals. 566 mg was obtained. Melting point: 61-63 [deg.] C. NMR spectrum (CDCl ₃ ) δ ppm: 1.12-1.32 (6H,
m), 1.70-2.20 (3H, m), 2.33 (3H, s), 2.40-2.53 (1H, m),
2.75-2.90 (1H, m), 2.92-3.15 (2H, m), 3.45-3.65 (2H, m),
4.18-4.40 (2H, m), 4.45-4.65 (2H, m), 7.38 (1H, d, J = 8H
z).

Example 7 1- (3-acetylthiopropionyl) -L-proline-N-[(1S) -1-methyl-2-nitroxyethyl] amide (Exemplary Compound No. 1-375) (7a) 1 -T-butoxycarbonyl-L-proline-
N-[(1S) -1-methyl-2-nitroxyethyl]
Amide 5.0 g of 1-t-butoxycarbonyl-L-proline and 4.4 g of (1S) -1-methyl-2-nitroxyethylamine hydrochloride are suspended in 100 ml of anhydrous tetrahydrofuran, and the suspension is stirred under ice cooling. 9.7 ml of triethylamine and 6.0 ml of diphenylphosphate azide were added, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 1/1) to obtain 5.3 g of the title compound as colorless crystals. Melting point: 122 DEG C. (decomposition). NMR spectrum (CDCl ₃ ) δ ppm: 1.23 (3H, d, J = 6.
6Hz), 1.47 (9H, s), 1.75-2.45 (4H, m), 3.20-3.55 (2H,
m), 4.13-4.53 (4H, m), 6.09 (0.3H, bs), 7.25 (0.7H, b
s). (7b) 1- (3-acetylthiopropionyl) -L-
Proline-N-[(1S) -1-methyl-2-nitroxyethyl] amide (Exemplary Compound No. 1-375) 1-t-butoxycarbonyl-L-proline-N-[(of Example 7 (a) 0.50 g of 1S) -1-methyl-2-nitroxyethyl] amide was dissolved in 5 ml of a 4N hydrochloric acid-dioxane solution, and the mixture was stirred at room temperature for 40 minutes. The solvent was distilled off under reduced pressure, toluene was added to the obtained residue, and the mixture was azeotropically dried. To this, 0.28 g of 3-acetylthiopropionic acid and 20 ml of anhydrous tetrahydrofuran were added, and under ice-cooling and stirring, 0.7 ml of triethylamine and 0.4 ml of diphenylphosphoric acid azide were added, followed by stirring at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent:
(Ethyl acetate) to give a pale yellow oil. The oil was crystallized from isopropyl ether to give the title compound (0.30 g) as colorless crystals. Melting point: 56-58 [deg.] C (decomposition). NMR spectrum (CDCl ₃ ) δ ppm: 1.24 (3H, d, J = 6.
7Hz), 1.65-2.56 (4H, m), 2.33 (3H, s), 2.65 (2H, t, J = 6.7
Hz), 3.16 (2H, t, J = 6.7Hz), 3.30-3.60 (2H, m), 4.15-4.58
(4H, m), 7.25 (1H, d, J = 8.7Hz).

Example 8 1-[(2R) -2-acetylamino-3-mercaptopropionyl] -L-proline-N-[(1S) -1-
Methyl-2-nitroxyethyl] amide (Exemplary Compound No. 1-242) 1.00 g of 1- (t-butoxycarbonyl) -L-proline-N-[(1S) -1-methyl of Example (7a) -2-Nitrooxyethyl] amide was dissolved in 10 ml of a 4N hydrochloric acid-dioxane solution and stirred at room temperature for 40 minutes. The solvent was distilled off under reduced pressure, toluene was added to the obtained residue, and the mixture was azeotropically dried. To this, 0.62 g of N-acetyl-L-cysteine and 40 ml of anhydrous tetrahydrofuran were added, and further, under ice-cooling and stirring, 1.4 ml of triethylamine and 0.8 ml of diphenylphosphoric azide were added.
Stir at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 19/1) to obtain a pale yellow oil. Further, this oily substance was separated and purified by silica gel column chromatography (elution solvent: ethyl acetate) to give the title compound as a colorless oily substance.
0 mg was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.24 (3H, d, J = 6.
9Hz), 1.74 (1H, t, J = 8.7Hz), 1.88-2.35 (4H, m), 2.02 (3
H, s), 2.91 (2H, dd, J = 6.3Hz, J = 8.8Hz), 3.65-3.85 (2H,
m), 4.20-4.65 (4H, m), 4.90-5.00 (1H, m), 6.50 (1H, d, J =
7.9Hz), 6.78 (1H, d, J = 7.6Hz).

Example 9 3-[(2S) -2-methyl-3-acetylthiopropionyl] thiazolidine- (4R) -4-yl-N- (trans-4-nitroxymethylcyclohexylmethyl)
Carboxamide (Exemplified Compound No. 3-247) 1.00 g of 3-[(2S) -2-methyl-3-acetylthiopropionyl] -thiazolidine- (4R) -4-
Carboxylic acid and 0.891 g of trans-4-nitroxymethylcyclohexylmethylamine hydrochloride of Reference Example 4 were combined with 1
Suspended in 00 ml of anhydrous tetrahydrofuran, and stirred under ice-cooling with 1.51 ml of triethylamine and 0.93 m
l of diphenylphosphoric acid azide was added and stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 1/1) to obtain 650 mg of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 0.85-1.15 (4H,
m), 1.24 (3H, d, J = 6Hz), 1.32-1.95 (6H, m), 2.35 (3H, s),
2.55-3.68 (7H, m), 4.26 (2H, d, J = 6.5Hz), 4.40-4.83 (2H, m
m), 4.95-5.05 (1H, m), 6.38 (0.2H, bs), 6.80 (1H, bs).

Example 10 1- (2-acetylthioacetyl) -L-proline-N
-(Trans-4-nitroxymethylcyclohexylmethyl) carboxamide (Exemplified Compound No. 1-364) (10a) 1- (t-butoxycarbonyl) -L-proline-N- (trans-4-nitroxymethylcyclohexylmethyl) Carboxamide 3.0 g of 1- (t-butoxycarbonyl) -L-proline and 3.76 g of trans-4-nitroxymethylcyclohexylmethylamine hydrochloride of Reference Example 4 are suspended in 60 ml of anhydrous tetrahydrofuran, and stirred under ice-cooling. , 5.8
ml of triethylamine and 3.6 ml of diphenylphosphate azide were added, and the mixture was stirred at room temperature for 5.5 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 1).
/ 1) to separate and purify the title compound as colorless crystals.
41 g were obtained. Melting point: 117-119 [deg.] C (decomposition). NMR spectrum (CDCl ₃ ) δ ppm: 0.80-1.10 (4H,
m), 1.32-2.00 (6H, m), 1.46 (9H, s), 2.00-2.50 (2H, m),
3.09 (2H, bs), 3.41 (2H, bs), 4.20-4.35 (1H, m), 4.26 (2H,
d, J = 6.5Hz), 6.16 (0.2H, bs), 7.06 (0.8H, bs). (10b) 1- (2-acetylthioacetyl) -L-proline-N- (trans-4-nitroxymethylcyclohexylmethyl) carboxamide (Exemplified Compound No. 1-
364) 1.00 g of 1- (t-butoxycarbonyl) -L-proline-N- (trans-4-nitroxymethylcyclohexylmethyl) carboxamide of Example (10a) is dissolved in 10 ml of 4N hydrochloric acid-dioxane solution. And stirred at room temperature for 40 minutes. The solvent was distilled off under reduced pressure, and toluene was further added to the residue, followed by azeotropic drying. 0.69g 2 for residue
-Acetylthioacetic acid and 40 ml of anhydrous tetrahydrofuran were added, further, under ice-cooling and stirring, 1.30 ml of triethylamine and 0.82 ml of diphenylphosphoric acid azide were added, and the mixture was stirred at room temperature for 17 hours. The solvent is distilled off under reduced pressure,
The residue was separated and purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain a pale yellow oil.
This oil was crystallized from isopropyl ether,
0.29 g of the title compound was obtained as colorless crystals. Melting point: 99-101 ° C (decomposition). NMR spectrum (CDCl ₃ ) δ ppm: 1.80-2.15 (4H,
m), 1.35-2.52 (10H, m), 2.40 (3H, s), 2.95-3.15 (2H,
m), 3.50-3.85 (4H, m), 4.26 (2H, d, J = 6.5Hz), 4.53-4.63
(1H, m), 6.53 (0.1H, bs), 7.00 (0.9H, bs).

Example 11 1-[(2R) -2-acetylamino-3-acetylthiopropionyl] -L-proline-N- (trans-4
-Nitroxymethylcyclohexylmethyl) carboxamide (Exemplary Compound No. 1-498) (11a) 1-[(2R) -2-acetylamino-3-
Mercaptopropionyl] -L-proline-t-butyl ester 1.00 g of N-acetyl-L-cysteine and 1.00 g
g of L-proline-t-butyl ester were suspended in 20 ml of anhydrous tetrahydrofuran and stirred under ice-cooling at 1.70.
ml of triethylamine and 1.60 ml of diphenylphosphoric acid azide were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 0.32 g of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 1.
90-2.30 (5H, m), 2.01 (3H, s), 2.75-2.98 (2H, m), 3.65-
3.90 (2H, m), 4.35-4.45 (1H, m), 4.95-5.05 (1H, m), 6.90
(1H, d, J = 8.1Hz). (11b) 1-[(2R) -2-acetylamino-3-
Acetylthiopropionyl] -L-proline-t-butyl ester 7.5 g of 1-[(2R) -2-acetylamino-3-mercaptopropionyl] -L-proline-t-butyl ester of Example (11a) The residue was dissolved in 75 ml of pyridine, 4.5 ml of acetic anhydride was added under ice-cooling and stirring, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water and extracted with dichloromethane. The extract was washed with aqueous citric acid and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was separated and purified by silica gel column chromatography (elution solvent: ethyl acetate), and further, silica gel column chromatography (elution solvent: dichloromethane / methanol = 97.5 / 2.5). And 2.86 g of the title compound was obtained as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 1.
85-2.40 (4H, m), 1.98 (3H, s), 2.36 (3H, s), 2.94 (1H, dd, J
= 9.4Hz, J = 14.1Hz), 3.40-3.98 (3H, m), 4.30-4.40 (1H,
m), 4.90-5.00 (1H, m), 6.40 (1H, d, J = 8.4Hz). (11c) 1-[(2R) -2-acetylamino-3-
Acetylthiopropionyl] -L-proline 0.86 g of 1-[(2R) -2- of Example (11b).
Acetylamino-3-acetylthiopropionyl] -L
-Proline-t-butyl ester was dissolved in 8.6 ml of trifluoroacetic acid and stirred at room temperature for 1.5 hours. Under reduced pressure, the solvent was distilled off, and diethyl ether was added to the residue.
A pale yellow powder was obtained. Further, recrystallization from ethanol gave 0.19 g of the title compound as colorless columnar crystals. Melting point: 180-181 ° C (decomposition). NMR spectrum (d ₆ -DMSO) δ ppm: 1.82 (3H, s),
1.80-2.25 (4H, m), 2.33 (3H, s), 2.80-3.75 (4H, m), 4.18
-4.28 (1H, m), 4.50-4.75 (1H, m), 8.32 (1H, d, J = 8.4Hz)
. (11d) 1-[(2R) -2-acetylamino-3-
Acetylthiopropionyl] -L-proline-N- (trans-4-nitroxymethylcyclohexylmethyl)
Carboxamide (Exemplified Compound No. 1-498) 0.70 g of 1-[(2R) -2 of Example (11c)
-Acetylamino-3-acetylthiopropionyl]-
L-proline and 0.62 g of trans-4 of Reference Example 4
-Suspending nitroxymethylcyclohexylmethylamine hydrochloride in 28 ml of anhydrous tetrahydrofuran,
Under ice cooling and stirring, 1.0 ml of triethylamine and 0.6 m
l of diphenylphosphoric acid azide was added and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 9: 1) to obtain 100 mg of the title compound as colorless needles. Melting point: 137-139 [deg.] C (decomposition). NMR spectrum (d ₆ -DMSO) δ ppm: 0.80-1.45 (5
H, m), 1.55-2.20 (9H, m), 1.82 (3H, s), 2.33 (3H, s), 2.75
-3.80 (6H, m), 4.18-4.28 (1H, m), 4.35 (1.8H, d, J = 6Hz),
4.51 (0.2H, d, J = 6Hz), 4.60-4.73 (1H, m), 7.65-7.75 (0.
9H, m), 7.85-7.95 (0.1H, m), 8.07 (0.1H, d, J = 8Hz), 8.30
(0.9H, d, J = 8.5Hz).

Example 12 1- (2-acetylthioacetyl) -L-proline-N
-[(1S) -1-methyl-2-nitroxyethyl] amide (Exemplified Compound No. 1-359) 1.0 g of 1-t-butoxycarbonyl-L-proline-N-[(of Example (7a) 1S) -1-Methyl-2-
The nitroxyethyl] amide was dissolved in 10 ml of a 4N hydrochloric acid-dioxane solution and stirred at room temperature for 40 minutes. The solvent was distilled off under reduced pressure, and toluene was further added to the residue, followed by azeotropic drying. 1.02 g of 2-acetylthioacetic acid and 40
To the mixture were added 1.3 ml of triethylamine and 0.82 ml of diphenylphosphoryl azide under ice-cooling and stirring, followed by stirring at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 0.24 g of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.22 (3H, d, J = 7H
z), 1.85-2.50 (4H, m), 2.40 (3H, s), 3.50-3.82 (4H, m),
4.18-4.60 (4H, m), 6.99 (1H, d, J = 7.2Hz).

Example 13 1- (3-Acetylthiopropionyl) -L-proline-N- (trans-4-nitroxymethylcyclohexylmethyl) carboxamide (Exemplified Compound No. 1-38)
9) 0.27 g of dicyclohexylammonium 1- (3
-Acetylthiopropionyl) -L-prolinate and 0.156 g of trans-4-nitroxymethylcyclohexylmethylamine hydrochloride of Reference Example 4 were suspended in 5 ml of anhydrous dimethylformamide and stirred under ice-cooling with stirring for 0.26 g.
5 ml of triethylamine and 0.164 ml of diphenylphosphoric azide were added, and the mixture was stirred at room temperature for 4 hours and 25 minutes.
After completion of the reaction, the mixture was diluted with 150 ml of ethyl acetate, washed with aqueous citric acid, brine, aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent:
Separation and purification with ethyl acetate) gave 0.19 g of the title compound as colorless crystals. Melting point: 92-94 [deg.] C. NMR spectrum (CDCl ₃ ) δ ppm: 0.85-1.15 (4H,
m), 1.35-1.55 (1H, m), 1.60-2.25 (8H, s), 2.34 (3H, s),
2.40-2.50 (1H, m), 2.64 (2H, t, J = 7Hz), 3.00-3.20 (2H, m
m), 3.16 (2H, t, J = 7Hz), 3.30-3.55 (2H, m), 4.26 (2H, d, J =
6.5Hz), 4.57 (1H, d, J = 7Hz), 7.19 (1H, bs).

Example 14 1-[(2S) -3-mercapto-2-methylpropionyl] -L-proline-N- (trans-4-nitroxymethylcyclohexylmethyl) carboxamide (Exemplified Compound No. 1-71) 14a) 1-[(2S) -3-t-butoxycarbonylthio-2-methylpropionyl] -L-proline-N
-(Trans-4-nitroxymethylcyclohexylmethyl) carboxamide 1.0 g of 1-[(2S) -3-mercapto-2-methylpropionyl] -L-proline and 1.24 g of trans-4- of Reference Example 4. Nitroxymethylcyclohexylmethylamine hydrochloride was suspended in 20 ml of anhydrous tetrahydrofuran. Further, under ice-cooling and stirring, 1.92 ml of triethylamine and 1.19 ml of diphenylphosphoric acid azide were added, followed by stirring at room temperature for 3 hours. The insoluble matter is filtered, and under reduced pressure,
The solvent was distilled off from the filtrate, and the residue was separated and purified by silica gel column chromatography (elution solvent: ethyl acetate).
0.34 g of a colorless oil was obtained. This oil was dissolved in 15 ml of dichloromethane, 0.30 ml of di-t-butyl dicarbonate and a catalytic amount of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 1 hour and 15 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 = 1: 1) to give 0.35 g of the title compound as a colorless oil.
Obtained. NMR spectrum (CDCl ₃ ) δ ppm: 0.85-1.12 (4H,
m), 1.20 (3H, d, J = 6.3Hz), 1.30-2.20 (10H, m), 1.49 (9H,
s), 2.40-2.52 (1H, m), 2.80-3.20 (4H, m), 3.45-3.63 (2
H, m), 4.25 (2H, d, J = 6.5Hz), 4.62 (1H, d, J = 6.5Hz), 7.27
(1H, bs). (14b) 1-[(2S) -3-mercapto-2-methylpropionyl] -L-proline-N- (trans-4
-Nitroxymethylcyclohexylmethyl) carboxamide (Exemplified Compound No. 1-71) 322 mg of 1-[(2S) -2- of Example (14a)
Methyl-3-t-butoxycarbonylthiopropionyl] -L-proline-N- (trans-4-nitroxymethylcyclohexylmethyl) carboxamide
of 4N hydrochloric acid-dioxane was added and dissolved, and the mixture was stirred at room temperature for 3 hours and 10 minutes. Furthermore, 10 ml of 4N hydrochloric acid-
A dioxane solution was added, and the mixture was stirred at room temperature for 1 hour and 20 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 = 2: 1) to obtain 147 mg of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 0.80-1.10 (4H,
m), 1.18 (3H, d, J = 6.6Hz), 1.30-2.25 (10H, m), 2.30-2.6
0 (2H, m), 2.75-3.20 (4H, m), 3.50-3.70 (2H, m), 4.25 (1H,
d, J = 6.5Hz), 4.65 (1H, d, J = 7.8Hz), 6.48 (0.1H, bs), 7.2
7 (0.9H, bs).

Example 15 (4S)-[3-[(2S) -3-acetylthio-2-
Methylpropionyl]] oxazolidin-4-yl-N
-[(1S) -1-methyl-2-nitroxyethyl] carboxamide (Exemplary Compound No. 2-241) Dissolve 0.21 g of sodium hydroxide in 2.5 ml of water, and add 0.525 g with stirring under ice-cooling. Of L-serine and 0.41
Then, 37 ml of 37% formalin water was added, and the mixture was stirred at room temperature for 16 hours. Further, under ice-cooling and stirring, 1.26 g of sodium bicarbonate was added, and then 1.039 g of (2S) -3-acetylthio-2
A solution of -methylpropionyl chloride dissolved in 1.0 ml of dioxane was added, and the mixture was stirred at room temperature for 4 hours. The reaction was diluted with 50 ml of water and washed with ethyl acetate.
25 ml of 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate.
Dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.221 g of an oil. 10m of this oil
dissolved in anhydrous tetrahydrofuran, 0.313 g of (1S) -1-methyl-2-nitroxyethylamine hydrochloride, 0.84 ml of triethylamine and 0.48 m
1 of diphenylphosphoric acid azide was added and stirred at room temperature overnight. After diluting with 150 ml of ethyl acetate and washing sequentially with 0.2 N hydrochloric acid, water, saturated aqueous sodium bicarbonate and saturated saline,
Dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 1: 1 to 1: 3).
The title compound was converted into colorless crystals by 0.265.
g was obtained. Melting point: 83-84 [deg.] C. NMR spectrum (CDCl ₃ ) δ ppm: 1.10-1.35 (6H,
m), 2.34 (3H, s), 2.50-2.70 (1H, m), 2.90-3.15 (2H, m),
4.00-4.15 (1H, m), 4.20-4.70 (4H, m), 4.95 (1H, bs), 5.0
8 (1H, d, J = 3.9Hz), 7.20 (1H, bs).

Example 16 (4S) -3- (3-Acetylthiopropionyl) oxazolidin-4-yl-N-[(1S) -1-methyl-
2-Nitrooxyethyl] carboxamide (Exemplified Compound No. 2-227) 0.525 g of L-serine and 0.41 ml of 37% formalin water, 0.882 g of 3-acetylthiopropionyl chloride and 0.156 g of (1S) Using -1-methyl-2-nitroxyethylamine hydrochloride as in Example 15, the title compound was converted into colorless crystals in 0.1%.
78 g were obtained. Melting point: 89-90C. NMR spectrum (CDCl ₃ ) δ ppm: 1.26 (3H, d, J = 6.
8Hz), 2.34 (3H, s), 2.50-2.70 (2H, m), 3.17 (2H, t, J = 6.7H
z), 3.98-4.10 (1H, m), 4.20-4.65 (5H, m), 4.95 (2H, q, J =
3.8Hz, J = 6.5Hz), 7.18 (1H, d, J = 5.8Hz).

Example 17 (4S)-[3-[(2S) -3-acetylthio-2-
Methylpropionyl]] oxazolidin-4-yl-N
-(Trans-4-nitroxymethylcyclohexylmethyl) carboxamide (Exemplified Compound No. 2-247) 0.442 g of dicyclohexylammonium [3-[(2S) -3-acetylthio-2-methylpropionyl]] oxazolidine of Reference Example 5 Using -4-carboxylate and 0.224 g of trans-4-nitroxymethylcyclohexylmethylamine hydrochloride of Reference Example 4 in the same manner as in the final step of Example 15, 0.272 g of the title compound was obtained as colorless crystals. Obtained. Melting point: 79-80C. NMR spectrum (CDCl ₃ ) δ ppm: 0.85-1.15 (4H,
m), 1.23 (3H, d, J = 6.9Hz), 1.35-1.95 (6H, m), 2.34 (3H,
s), 2.50-2.70 (1H, m), 2.90-3.20 (4H, m), 4.00-4.15 (1
H, m), 4.26 (2H, d, J = 6.4Hz), 4.58-4.72 (2H, m), 4.93 (1
H, d, J = 3.5Hz), 5.09 (1H, d, J = 3.5Hz), 7.12 (1H, bs).

Example 18 (4S)-(3-Acetylthiopropionyl) oxazolidin-4-yl-N- (trans-4-nitroxymethylcyclohexylmethyl) carboxamide (Exemplified Compound No. 2-233) Reference of 0.428 g 0.428 g and 0.224 g of dicyclohexylammonium (3-acetylthiopropionyl) oxazolidine-4-carboxylate of Example 6
Using trans-4-nitroxymethylcyclohexylmethylamine hydrochloride of Reference Example 4 in the same manner as in the final step of Example 15, the title compound was converted into colorless crystals in 0.2%.
88 g were obtained. Melting point: 92-93C. NMR spectrum (CDCl ₃ ) δ ppm: 0.90-1.15 (4H,
m), 1.40-1.95 (6H, m), 2.35 (3H, s), 2.50-2.75 (2H, m),
3.05-3.25 (4H, m), 3.98-4.10 (1H, m), 4.27 (2H, d, J = 6.4H
z), 4.55-4.68 (2H, m), 4.90-5.00 (2H, m), 7.08 (1H, b
s).

Example 19 (4S)-[3-[(2S) -3-acetylthio-2-
Methylpropionyl]] oxazolidin-4-yl-N
-[(1S) -1-propyl-2-nitroxyethyl]
Carboxamide (Exemplified Compound No. 2-431) 0.442 g of dicyclohexylammonium (4S)-[3-[(2S) -3-acetylthio- of Reference Example 5
2-Methylpropionyl]] oxazolidine-4-carboxylate and 0.184 g of (1S) -1-propyl-2-nitroxyethylamine hydrochloride as in the last step of Example 15 to give the title compound 0.208 g of colorless crystals were obtained. Melting point: 97-98C. NMR spectrum (CDCl ₃ ) δ ppm: 0.91 (3H, t, J = 7H
z), 1.20-1.60 (4H, m), 1.23 (3H, d, J = 6.9Hz), 2.34 (3H,
s), 2.50-2.70 (1H, m), 2.95-3.20 (2H, m), 4.00-4.75 (6
H, m), 4.93 (1H, bs), 5.08 (1H, d, J = 4Hz), 7.21 (1H, bs).

Example 20 (4R)-[3-[(2S) -3-acetylthio-2-
Methylpropionyl]] thiazolidin-4-yl-N-
[(1S) -1-methyl-2-nitroxyethyl] carboxamide (Exemplified Compound No. 3-241) 500 mg of dicyclohexylammonium (4R)
Example 1 using-[3-[(2S) -3-acetylthio-2-methylpropionyl]] thiazolidine-4-carboxylate and 205 mg of (1S) -1-methyl-2-nitroxyethylamine hydrochloride. In the same way as
121 mg of the title compound were obtained as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.10-1.35 (6H,
m), 2.34 (3H, s), 2.85-3.20 (4H, m), 3.45-3.60 (1H, m),
4.20-4.55 (4H, m), 4.77 (1H, d, J = 8.8Hz), 4.90-5.00 (1H,
m), 6.81 (1H, bs).

Example 21 (4R) -3- (3-Acetylthiopropionyl) thiazolidine-4-yl-N-[(1S) -1-methyl-2
-Nitroxyethyl] carboxamide (Exemplified Compound No. 3-227) (21a) dicyclohexylammonium (4R)-
3- (3-acetylthiopropionyl) thiazolidine-
4-Carboxylate 1.0 g of 3-acetylthiopropionic acid was dissolved in 20 ml of anhydrous tetrahydrofuran, and stirred under ice-cooling with stirring.
3 ml of triethylamine and 0.975 ml of isobutyl chloroformate were added, and the mixture was stirred at room temperature for 2 hours. Further, under ice-cooling and stirring, 1.01 g of (4R) -thiazolidine-4-
Carboxylic acid and 1.13 ml of triethylamine in 15
A solution dissolved in 1 ml of a mixed solution of 1: 2 dimethylformamide and water was added, and the mixture was stirred at room temperature overnight. The reaction solution was washed with ethyl acetate, adjusted to pH 1.0 with dilute aqueous hydrochloric acid, and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml of methanol, 2.5 g of diphenyldiazomethane was added, and the mixture was stirred at room temperature for 2 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 = 9: 1 to 2: 1).
0.70 g of diphenylmethyl ester was obtained. This diphenylmethyl ester was dissolved in 5 ml of a 4N hydrochloric acid-dioxane solution, and 2 ml of trifluoroacetic acid was added.
Stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure.
Toluene was added and azeotropically dried. The residue was dissolved in 50 ml of diethyl ether and adjusted to pH 8-9 by adding dicyclohexylamine to obtain 745 mg of the title compound as colorless crystals. Melting point: 172-175 [deg.] C (decomposition). (21b) (4R) -3- (3-acetylthiopropionyl) thiazolidin-4-yl-N-[(1S) -1-
Methyl-2-nitroxyethyl] carboxamide 350 mg of dicyclohexylammonium (4R) -3- (3-acetylthiopropionyl) thiazolidine-4-carboxylate of Example (21a) and 148
81 mg of the title compound was obtained as colorless crystals in the same manner as in Example 1 using mg of (1S) -1-methyl-2-nitroxyethylamine hydrochloride. Melting point: 70-72 ° C (decomposition). NMR spectrum (d ₆ -DMSO) δ ppm: 1.26 (3H, d, J =
6.9Hz), 2.34 (3H, s), 2.74 (2H, t, J = 6.6Hz), 3.05-3.40 (4
H, m), 3.56 (1H, dd, J = 3.5Hz, J = 11.8Hz), 4.20-4.80 (5H,
m), 4.90-5.00 (1H, m), 6.85 (1H, bs).

Example 22 390 mg of (4R) -3- (3-acetylthiopropionyl) thiazolidine-4-yl-N- (trans-4-nitroxymethylcyclohexylmethyl) carboxamide (Exemplified Compound No. 3-233) Dicyclohexylammonium (4R) -3- (3-acetylthiopropionyl) thiazolidine-4-carboxylate of Example (21a) and 217
161 mg of the title compound was obtained as colorless crystals in the same manner as in Example 1 by using mg of trans-4-nitroxymethylcyclohexylmethylamine hydrochloride of Reference Example 4. Melting point: 91-93C. NMR spectrum (CDCl ₃ ) δ ppm: 0.85-1.15 (4H,
m), 1.35-1.95 (6H, m), 2.35 (3H, s), 2.65-2.80 (2H, m),
2.95-3.40 (5H, m), 3.61 (1H, dd, J = 3.3Hz, J = 11.6Hz), 4.2
7 (2H, d, J = 6.4Hz), 4.38-4.78 (2H, m), 4.95-5.05 (1H, m),
6.76 (1H, bs).

Reference Example 1 trans-4-t-butoxycarbonylaminomethylcyclohexylcarboxylic acid 5.0 g of trans-4-aminomethylcyclohexylcarboxylic acid was dissolved in 50 ml of water, and 6.6 ml of triethylamine was added. 11.2 ml of di-t
A solution of -butyl dicarbonate in dioxane (20 ml) was added, and the mixture was stirred at room temperature for 3 hours. Under reduced pressure, dioxane was distilled off, and the aqueous solution was adjusted to pH 4.0 by adding aqueous citric acid, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain colorless crystals. Isopropyl ether was added to the crystals, and the crystals were collected by filtration and dried to obtain 7.0 g of the title compound as colorless crystals. Melting point: 126-128 [deg.] C. NMR spectrum (CDCl ₃ ) δ ppm: 0.85-1.05 (2H,
m), 1.30-1.60 (9H, m), 1.75-1.92 (2H, m), 1.95-2.12 (2H,
m), 2.18-2.35 (1H, m), 2.85-3.05 (2H, m), 4.60 (1H, bs)
.

Reference Example 2 trans-4-t-butoxycarbonylaminomethylcyclohexylmethanol 5.0 g of trans-4-t-butoxycarbonylaminomethylcyclohexylcarboxylic acid of Reference Example 1 was dissolved in anhydrous tetrahydrofuran (60 ml), and cooled with ice. Under stirring,
22.0 ml of a 1 mol solution of lithium aluminum hydride in tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 2 hours. Add excess sodium sulfate decahydrate to the reaction solution,
The insoluble material was filtered, and the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 2/1) to obtain 1.4 g of the title compound as colorless crystals. Melting point: 88-89C. NMR spectrum (CDCl ₃ ) δ ppm: 0.85-1.05 (4H,
m), 1.25-1.52 (11H, m), 1.75-1.90 (4H, m), 2.98 (2H, t, J =
6.4Hz), 3.45 (2H, d, J = 6.2Hz), 4.61 (1H, bs).

Reference Example 3 Trans-Nt-butoxycarbonyl-4-nitroxymethylcyclohexylmethylamine Under ice-cooling and stirring, 11.0 ml of anhydrous acetonitrile was added to 14.0 ml of anhydrous acetonitrile.
3 g of nitronium tetrafluoroborane and 1.19 g
Was added and stirred at the same temperature for 30 minutes, 1.2 g of trans-4-t-butoxycarbonylaminomethylcyclohexylmethanol of Reference Example 2 was added, and the mixture was stirred at room temperature for 1 hour and 10 minutes. . The solvent was distilled off under reduced pressure,
The obtained residue was dissolved in ethyl acetate, the insoluble matter was filtered,
The filtrate was evaporated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: cyclohexane /
Separation and purification with ethyl acetate (9/1) gave 1.1 g of the title compound as pale yellow crystals. Melting point: 65-67 [deg.] C. NMR spectrum (CDCl ₃ ) δ ppm: 0.85-1.13 (4H,
m), 1.44 (10H, m), 1.60-1.95 (5H, m), 2.98 (2H, t, J = 6.4H
z), 4.27 (2H, d, J = 6.4 Hz), 4.59 (1H, bs).

Reference Example 4 trans-4-Nitrooxymethylcyclohexylmethylamine hydrochloride 1.1 g of trans-Nt-butoxycarbonyl-4-nitroxymethylcyclohexylmethylamine of Reference Example 3 was added to 15 ml of 4N hydrochloric acid. -Dioxane solution was added and dissolved, followed by stirring at room temperature for 1 hour. The precipitated crystals were filtered, washed with dioxane and ether, further washed with ethanol and ether, and dried to obtain 0.25 g of the title compound as colorless crystals. Melting point: 166-168 [deg.] C (decomposition). NMR spectrum (CDCl ₃ ) δ ppm: 0.85-1.10 (4H,
m), 1.45-1.90 (6H, m), 2.62 (2H, d, J = 6.8Hz), 4.37 (2H, d,
J = 6.5Hz), 8.06 (3H, bs).

Reference Example 5 Dicyclohexylammonium (4S)-[3-
[(2S) -2-Methyl-3-acetylthiopropionyl]] oxazolidine-4-carboxylate 210 mg of sodium hydroxide was dissolved in 2.5 ml of water, and 525 mg of L-serine and 0 .41
Then, 37% formalin (ml) was added, and the mixture was stirred for 16 hours under ice cooling. Further, under ice-cooling, 1.26 g of baking soda and 1.04 g
(2S) -2-methyl-3-acetylthiopropionyl chloride in 1.0 ml of dioxane was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 50 ml of water and washed with ethyl acetate. 25 ml of 1N hydrochloric acid was added to the aqueous solution, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. 5m of 674mg residue
Dissolved in 1 l of ethyl acetate, 0.56 ml of dicyclohexylamine was added, and the precipitated crystals were filtered and washed with ethyl acetate to obtain 979 mg of the title compound as colorless crystals. Melting point: 190-193C. NMR spectrum (CDCl ₃ ) δ ppm: 1.10-2.05 (23H,
m), 2.30 (3H, s), 2.45-3.30 (6H, m), 4.10-4.50 (3H, m),
5.00-5.20 (2H, m).

Reference Example 6 Dicyclohexylammonium (4S) -3- (3-
(Acetylthiopropionyl) oxazolidine-4-carboxylate 210 mg of sodium hydroxide was dissolved in 2.5 ml of water, and under ice-cooling and stirring, 525 mg of L-serine and 0.41
To the mixture was added 37 ml of 37% formalin, and the mixture was stirred under ice cooling for 15 hours. Further, under ice-cooling, 1.26 g of sodium bicarbonate and 882 mg
1.0 m of 3-acetylthiopropionyl chloride
1 dioxane solution was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with 150 ml of ethyl acetate, and washed with 0.5N hydrochloric acid and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. 5 ml of the obtained oil
Was dissolved in ethyl acetate, and 0.85 ml of dicyclohexylamine was added. The precipitated crystals were filtered and washed with ethyl acetate to obtain 1.24 g of the title compound as colorless crystals. Melting point: 169-171 [deg.] C. NMR spectrum (CDCl ₃ ) δ ppm: 1.10-2.10 (20H,
m), 2.30 (3H, s), 2.45-2.75 (2H, m), 2.85-3.00 (2H, m),
3.15 (2H, t, J = 7Hz), 4.10-4.55 (3H, m), 5.02 (1H, d, J = 5H
z), 5.10 (1H, d, J = 5Hz).

Test Example 1 Collateral Vasodilatation Effect A beagle dog (male) weighing 9-13 kg was pentobarbital
Anesthesia was performed by intravenous injection of 30 mg / kg, and the experiment was performed under artificial respiration. To measure left carotid artery pressure, a polyethylene cannula (Atom vein catheter 2F) was retrograde inserted into one branch of the left thyroid artery. 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 through 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) According to this test, Examples 2, 4, 6, 9, 15, 18, 1
The compounds 9, 20, and 22 exhibited excellent effects (the compounds of Examples 4 and 6 exhibited an activity in which the CI (60) value at 0.3 mg / kg administration was 10 or more).

Formulation Example 1 Capsule Compound of Example 4 50.0 mg Lactose 128.7 Maize Starch 70.0 Magnesium Stearate 1.3 250 mg After mixing the powder of the above formulation and passing through a 60 mesh sieve, This powder is placed in a 250 mg No. 3 gelatin capsule to form a capsule.

Formulation Example 2 Tablet Compound of Example 4 50.0 mg Lactose 124.0 Maize Starch 25.0 Magnesium Stearate 1.0 200 mg Tablets 200 mg tablets. The tablets can be sugar-coated as needed.

[0139]

The compound having the general formula (I) or a pharmacologically acceptable salt thereof, which is an active ingredient of the present invention, shows excellent collateral vasodilation in a test using the carotid collateral system of an anesthetized dog. It has no side effects such as headache, dizziness, tachycardia or adverse effects on digestive organs, liver, bones, etc., and has no first-pass effect. Is extremely useful as a therapeutic agent).

Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 263/04 C07D 263/04 277/06 277/06 401/12 207 401/12 207 405/12 207 405/12 207 413/12 213 413 / 12 213 307 307 333 333 433 417/12 213 417/12 213 307 307 333 333 (72) Inventor Yasuo Ohata 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Shigeki Miyake 1-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Ryosuke Yorikan 1-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Norio Fukuda Tokyo 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd.

Claims (14)

[Claims] 1. A compound of the general formula [In the formula, X represents a methylene group, an oxygen atom or a sulfur atom, and R ¹ is a C ₂ -C ₈ alkanoyl group having a substituent. ² (where
R ² is a hydrogen atom; a C ₁ -C ₆ aliphatic acyl group; C ₂ -C ₇
Alkoxycarbonyl group; C ₁ -C ₆ alkyl, C ₁ -C ₆
C _7- which may be substituted by alkoxy or halogen
C ₁₁ arylcarbonyl group; or C ₁ -C ₆ alkyl, C
5- to 6-membered aromatic heterocyclic carbonyl group which may be substituted with _1- C ₆ alkoxy or halogen and contains 1 to 3 heteroatoms selected from the group consisting of heteroatoms consisting of nitrogen, oxygen and sulfur Is shown. ), And as desired, an amino group, a mono- or di-C ₁ -C ₆ alkylamino group, a protected amino group or a protected mono-C ₁ -C ₆ alkylamino group . A represents a C ₁ -C ₈ alkylene group or a formula -BDE- (where B and E are the same or different and are a single bond or C ₁ -C
Represents a ₆ alkylene group, and D represents a C ₃ -C ₆ cycloalkylene group which may be substituted with a C ₁ -C ₆ alkyl. ) Is shown. Or a pharmacologically acceptable salt thereof as an active ingredient. 2. The method according to claim 1, wherein R ¹ is a substituted C ₂ -C ₆ alkanoyl group wherein the substituent is an essential group represented by the formula —S—R ² (wherein
R ² is a hydrogen atom; a C ₁ -C ₆ alkanoyl group; C ₂ —
C ₅ alkoxycarbonyl group; C ₁ -C ₂ alkyl, C
₁ -C ₂ alkoxy, fluorine or optionally a benzoyl group optionally substituted by a chlorine; or methyl, methoxy, may be substituted by fluorine or chlorine, thienylcarbonyl, furylcarbonyl or pyridylcarbonyl group. )
Which is preferably an amino group, a mono-C ₁ -C ₄ alkylamino group, a di-C ₁ -C ₄ alkylamino group or a protected amino or mono-C ₁
-C ₄ alkylamino group (said protecting group, C ₁ -C ₄ alkanoyl group, C ₁ -C ₄ alkoxycarbonyl group, tri -C ₁ -C ₂ alkyl silyl group, t- butyl dimethyl silyl group, phenyl dimethylsilyl Group, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, benzyl group optionally substituted by fluorine or chlorine or C ₁ -C ₂ alkyl, C _1-
C ₂ alkoxy, a benzyloxycarbonyl group which may be substituted by fluorine or chlorine. ). Or a pharmacologically acceptable salt thereof as an active ingredient. 3. The method according to claim 1, wherein R ¹ is a substituted C ₂ -C ₆ alkanoyl group wherein the substituent is an essential group represented by the formula —SR ² (wherein
R ² is a hydrogen atom; C ₁ -C ₄ alkanoyl group; C ₂ -
C ₃ alkoxycarbonyl group; t-butoxycarbonyl group; a benzoyl group; with or methyl or chlorine may be substituted, a thienylcarbonyl, furylcarbonyl or pyridylcarbonyl group. And a group having an amino group, a methylamino group,
Ethylamino group, dimethylamino group, methylethylamino group or t-butyl, C ₁ -C ₄ alkanoyl or C
₁ -C is a ₄ alkoxycarbonyl protected amino or methylamino group with a carbonyl. Or a pharmacologically acceptable salt thereof as an active ingredient. 4. The method according to claim 1, wherein R ¹ is a C ₂ -C ₆ alkanoyl group having a substituent, wherein said substituent is essentially a compound of the formula —SR ² (wherein
R ² is a hydrogen atom; C ₁ -C ₄ alkanoyl group; C ₂ -
C ₃ alkoxycarbonyl group; t-butoxycarbonyl group; a benzoyl group; with or methyl or chlorine may be substituted, a thienylcarbonyl, furylcarbonyl or pyridylcarbonyl group. A group having amino, methylamino, dimethylamino, acetylamino, N-acetyl-N-methylamino, t-butoxycarbonylamino or Nt-
Butoxycarbonyl-N-methylamino group. Or a pharmacologically acceptable salt thereof as an active ingredient. 5. The method according to claim 1, wherein R ¹ is a substituted C ₂ -C ₄ alkanoyl group wherein the substituent is an essential group represented by the formula —S—R ² (wherein
R ² is a hydrogen atom or a C ₁ -C ₄ alkanoyl group. ), And the desired one is an amino, methylamino, dimethylamino, acetylamino or N-acetyl-N-methylamino group. Or a pharmacologically acceptable salt thereof as an active ingredient. 6. The method of claim 1, R ¹ is, C ₃ -C ₄ alkanoyl group [the substituent group having a substituent, as the indispensable formula -S-R ² (wherein,
R ² is a hydrogen atom or an acetyl group. ), And a desired group is an amino group or an acetylamino group. Or a pharmacologically acceptable salt thereof as an active ingredient. 7. The method of claim 1, wherein R ¹ is 3-mercaptopropionyl, 3-mercapto-2-methylpropionyl, 3-mercapto-3-methylpropionyl, 4-mercaptobutyryl, 3-mercapto-2-ethyl Propionyl, 2-amino-3-mercaptopropionyl, 2-acetylamino-3-mercaptopropionyl, 3-acetylthiopropionyl, 3
Thiazolidine which is -acetylthio-2-methylpropionyl, 3-acetylthio-3-methylpropionyl, 4-acetylthiobutyryl or 2-acetylamino-3-acetylthiopropionyl group or a pharmacologically acceptable salt thereof as an active ingredient An agent for preventing or treating angina pectoris. 8. The method of claim 1, wherein R ¹ is 3-mercapto-2-methylpropionyl,
-Amino-3-mercaptopropionyl, 2-acetylamino-3-mercaptopropionyl, 3-acetylthio-2-methylpropionyl or 2-acetylamino-
An agent for preventing or treating angina pectoris, comprising as an active ingredient a thiazolidine which is a 3-acetylthiopropionyl group or a pharmacologically acceptable salt thereof. 9. The method according to claim 1, wherein A is a C ₂ -C ₆ alkylene group or a group represented by the formula -B-D-E-
(Wherein B and E are the same or different and are each a single bond or C
₁ -C ₄ alkylene group, D is a C ₁ -C ₂ optionally substituted by alkyl C ₅ -C ₆ cycloalkylene group. Or a pharmacologically acceptable salt thereof as an active ingredient. 10. The method according to claim 1, wherein A is a C ₂ -C ₆ alkylene group or a group represented by the formula -B-D-E-
(Wherein, B is a single bond or a C ₁ -C ₄ alkylene group, D is a C ₅ -C ₆ cycloalkylene group optionally substituted with methyl, and E is a single bond, methylene, ethylene , A trimethylene or tetramethylene group.) Or a pharmacologically acceptable salt thereof as an active ingredient. 11. The method according to claim 1, wherein A is ethylene, methylethylene, trimethylene, ethylethylene, tetramethylene, propylethylene, butylethylene or isobutylethylene.
D-E- (wherein, B is a single bond, a methylene or ethylene group, D is a C ₅ -C ₆ cycloalkylene group, E is a single bond, methylene or ethylene group.)
An agent for preventing or treating angina pectoris, which comprises, as an active ingredient, a thiazolidine or a pharmacologically acceptable salt thereof, which is a group having: 12. The method according to claim 1, wherein A is ethylene, methylethylene, propylethylene,
Butylethylene or isobutylethylene group or formula-
B-DE- (wherein B is a methylene group, and D is
It is a cyclohexylene group, and E is a methylene group. Or a pharmacologically acceptable salt thereof as an active ingredient. 13. The preventive or therapeutic agent for angina pectoris according to claim 1, wherein A is a methylethylene group, thiazolidine or a pharmacologically acceptable salt thereof as an active ingredient. 14. A 1- (3-mercapto-2-methylpropionyl) -L-proline-N- (1-methyl-2-nitroxyethyl) amide, 1-acetylthioacetyl-L-proline-N- ( 4-
Nitroxymethylcyclohexylmethyl) carboxamide, 1- (3-acetylthio-2-methylpropionyl)-
L-proline-N- (1-methyl-2-nitroxyethyl) amide, 3- (3-acetylthiopropionyl) -oxazolidin-4-yl-N- (4-nitroxymethylcyclohexylmethyl) amide, 3- (3-acetylthio-2-methylpropionyl)-
Oxazolidin-4-yl-N- (1-methyl-2-nitroxyethyl) amide, 3- (3-acetylthio-2-methylpropionyl)-
Oxazolidin-4-yl-N- (1-propyl-2-
Nitroxyethyl) amide, 3- (3-acetylthiopropionyl) -thiazolidine-4-yl-N- (4-nitroxymethylcyclohexylmethyl) amide, 3- (3-acetylthio-2-methylpropionyl)-
Thiazolidine-4-yl-N- (1-methyl-2-nitroxyethyl) amide, 3- (3-acetylthio-2-methylpropionyl)-
Thiazolidine-4-yl-N- (4-nitroxymethylcyclohexylmethyl) amide or 3- (2-acetylamino-3-acetylthiopropionyl) -thiazolidin-4-yl-N- (1-methyl-2-nitro An agent for preventing or treating angina pectoris, which comprises (xethyl) amide or a pharmacologically acceptable salt thereof as an active ingredient.