JP2000038387A - Tricyclic carbapenems - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel compound that has high anti-microbial activity, is stable to dehydropeptidase I and shows high urinary content. SOLUTION: This is a novel compound represented by formula I [A is a heteroaryl monocyclic thio group that is represented by formula II (R1 and R2 are each a 1-6C alkyl, a 3-6C cycloalkyl or the like), or contains 1-3N, O or S atoms], its derivatives, their salts, typically (4R, 8S, 9R, 10 S)-4-(dibenzylamino-thiocarbonyl)thiomethyl-10-[(R)-1-hydroxyethyl]-11 -oxo-1- azatricyclo[7.2.0.03.8]undeca-2-ene-2-carboxylic acid. This compound is prepared by sulfonylation of a compound of formula III before the sulfonylated product is allowed to react with a compound of the formula: Hap (Ap may be protected, when A includes hydroxyl or amino group), allowing the resultant intermediate to react with a compound of the formula: XCOCOOR14 (R14 is a protecting group of carboxyl; X is a halogen or the like) followed by ring closure reaction and final deprotection of the resultant intermediate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a tricyclic carbapenem compound having excellent antibacterial activity.

[0002]

2. Description of the Related Art Thienamycin derivatives have excellent antibacterial activity, but are degraded by dehydropeptidase-I, which is an inactivating enzyme for thienamycin derivatives present in the human body, and lose their activity. Low (H. Kroppetal., Antimi).
crob. Agents Chemother. , 22
62, (1982); R. Norrby et
al. , Ibid. , 23 , 300 (1983)).

On the other hand, tricyclic β-lactam compounds are disclosed in JP-A-3-167187 and JP-A-4-1783.
Some compounds are reported in, for example, JP-A-89-89 and the like. Compounds belonging to this family are called tribactam or trinem, in which compound A represented by the following chemical formula
Is well known (Di Modugno eta)
l. , Antimicrob. Agents Chem
other. , 38 , 2362 (1994)).

[0004]

Embedded image

[0005]

Although thienamycin derivatives generally exhibit excellent antibacterial activity, they have problems of chemical stability and dehydropeptidase-I, while trinem derivatives represented by compound A have a dehydropeptidase-type. Although it has good stability against I, it has a disadvantage that its antibacterial activity is slightly inferior to that of the thienamycin derivative. Therefore, the appearance of a trinem compound having good stability against dehydropeptidase-I and exhibiting excellent antibacterial activity has been desired.

[0006] The present inventors have conducted various studies to solve these drawbacks, and found that the novel tricyclic heterocyclic derivative (I), its pharmaceutically acceptable salts and derivatives have strong antibacterial activity, and have a high dehydropeptidase activity. The present invention was found to be stable to I and high in urine, and completed the present invention.

[0007]

The tricyclic carbapenem compound of the present invention has the general formula

[0008]

Embedded image Having.

In the formula (I), A represents the following (A1), (A
2) represents a group selected from (A3), (A4), (A5) and (A6). (A1) is a general formula

[0010]

Embedded imageAnd a group represented by the formula:¹And R^TwoAre the same or
Differently, (1) C which may have a substituent_1-6Alkyl group (the substituent may be hydroxy, cyano, carbamoyl,
Ruboxy, amino, mono- or di-C_1-4Alkyl
Amino, halogen, C_1-4Alkoxy, C_1-4Alkyl
E, mono- or di-C_1-4Alkylcarbamoyl,
C_1-4Alkoxycarbonyl or C_1-6Cycloalkyl
(2) C_3-6Cycloalkyl group (3) C optionally having substituent (s)_6-13Aryl group (the substituent is halogen, hydroxy, hydroxy C
_1-4Alkyl, carbamoyl, carboxy, C_1-4Arco
Xycarbonyl, sulfamoyl, C_1-4Alkoxy,
Cyano, oxo, nitro, amino, mono- or di-
C_1-4Alkylamino, C_1-4Alkylthio, mono-young
Kuha-C_1-4Alkylcarbamoyl, C _1-4Alkyl,
C substituted with halogen_1-4Alkyl, methylene dioki
C, optionally substituted C_6-10Aryl (the substituent
Is sulfamoyl, halogen or C_1-4Alkoxy
Or 1 to 3 nitrogen, oxygen or sulfur atoms
Represents a 5- or 6-membered heteroaryl monocyclic ring) (4) C which may have a substituent_7-17An aralkyl group (the substituent is the same as the above-mentioned (3)_6-13Of the aryl group
(Shows the same group as the substituent) (5) Nitrogen, oxygen or
5- or 6-membered heteroaryl containing 1 to 3 sulfur atoms
Or a benzene ring or a pyridine ring
A condensed heteroaryl fused ring group (wherein the substituent is_1-4Alkyl, hydroxy C_1-4Archi
Carbamoyloxy C_1-4Alkyl, halogen, mosquito
Rubamoyl, carboxy, C_1-4Alkoxycarboni
Le, sulfamoyl, C_1-4Alkoxy, mono-young
Is Di-C_1-4Alkylcarbamoyl, C_1-4Alkyl
E, optionally substituted C_6-10Aryl (the substituent
Is sulfamoyl, halogen or C_1-4Alkoxy
Or 1 to 3 nitrogen, oxygen or sulfur atoms
(Shows a 5- or 6-membered heteroaryl monocycle contained) (6) Nitrogen, oxygen or
5- or 6-membered hetero ant containing 1 to 3 sulfur atoms
Monocyclic C_1-4Alkyl or benzene ring with them
Or a heteroaryl fused ring C in which a pyridine ring is fused_1-4
Alkyl group (the substituent is the same as the substituent in the above (5))
Or (7) R¹And R^TwoTogether with the N atom to which they are attached
The benzene ring or the
A 4- to 7-membered cyclic amino optionally condensed with a lysine ring
Group forming (the substituent is halogen, hydroxy, C_1-4Archi
Le, hydroxy C_1-4Alkyl, carbamoyl, C_1-4A
Lucoxy, C_6-10Aryl, or nitrogen, oxygen or
5- or 6-membered hetero ant containing 1 to 3 sulfur atoms
(A2) is a group having a substituent
Containing 1 to 3 nitrogen, oxygen or sulfur atoms
Having heteroaryl monocyclic thio or benzene with them
Heteroaryl condensed ring with fused ring or pyridine ring
A thio group, and the substituent includes (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) a C_1-4Alkanesulfonyl group (5) C_3-6Cycloalkyl group (6) carboxy group (7) C_1-4Alkoxycarbonyl group (8) C which may have a substituent_1-4Alkyl group (the substituent is hydroxy, halogen, carbamoyl,
Cyano, carboxy, amino, C_1-4Alkoxy, C_1-4
Alkylthio, mono- or di-C_1-4Alkyl cal
Bamoyl (C_1-4Alkyl is hydroxy or carb
Optionally substituted with bamoyl), C_1-4Alkoxy
Carbonyl, C_3-6Cycloalkyl, mono- or di
-C_1-4Alkylamino (the C_1-4Alkyl is hydroxy
Si, carbamoyl, carboxy, amino or mono-young
Or Di-C_1-4May be substituted with alkylamino
I), Tri-C_1-4Alkyl ammonium (C_1-4Archi
Is substituted with hydroxy, carbamoyl or carboxy.
5) containing 1 to 3 N atoms
Or a 6-membered heteroaryl monocyclic ring (the N atom is C_1-4A
May be quaternized by substitution with alkyl), C_1-4A
Lucanesulfonylamino or nitrogen, oxygen or sulfur
4- to 7-membered heterocyclyl containing one or two atoms
(9) an amino group which may have a substituent (the substituent may be C_1-10Alkanoyl, C_3-6Cycloal
Kill, C which may be substituted_1-4Alkyl (the substituent
Is halogen, hydroxy, amino, mono- or di-
-C_1-4Alkylamino, carbamoyl or carboxy
Denote C), optionally substituted C_6-10Aryl cal
Bonyl (the substituent is halogen, C_1-4Alkyl or
C_1-4Represents alkoxy), optionally substituted C
_6-10Aryl (the substituent is halogen, C_1-4Archi
Le, C_1-4Alkoxy, amino or mono- or di
-C_1-4Alkylamino), which may be substituted
C_7-14Aralkyl (the substituent is halogen, C_1-4A
Luquil, C_1-4Represents alkoxy or carbamoyl
Carbamoyl which may be substituted (the substituent
Is C_1-4Alkyl or C_6-10Aryl))
Optionally substituted thiocarbamoyl wherein the substituent is
_1-4Alkyl or C_6-10Aryl)), substituted
May be C_6-10Arylsulfonyl (the substituent is
C_1-4Alkyl, halogen or C_1-4Shows alkoxy
C), optionally substituted C_1-4Alkylsulfonyl
(The substituents represent halogen), and may be substituted.
5 to 1 containing 1 to 3 nitrogen, oxygen or sulfur atoms
Or a 6-membered heteroaryl monocyclic ring wherein the substituent is_{1- Four}Al
Kill or C_1-4Optionally substituted with alkoxy
Phenyl), containing 1 to 3 nitrogen, oxygen or sulfur atoms
5- or 6-membered heteroaryl monocyclic C having_{1- Four}Archi
, Sulfamoyl, or optionally substituted nitrogen
5 containing 1-3 elemental, oxygen or sulfur atoms or
6-membered heteroaryl monocyclic carbonyls or
Heteroaryl condensed with fused zen or pyridine ring
Fused ring carbonyl (the substituent is C_1-4Alkyl or ha
A hydrogen atom, wherein the heteroaryl monocycle contains an N atom.
If the N atom is C_1-4Quaternized by substitution with alkyl
), C_2-5Alkenyl, amino C_1-10Al
Canoyl or one or more nitrogen, oxygen or sulfur atoms
Or a 4- to 7-membered heterocyclylcarbonyl containing two or more
(10) a carbamoyl group which may have a substituent (the substituent is a carbamoyl group which may be substituted;_1-4Alkyl
(The substituent may be halogen, hydroxy, amino, mono-
Or di-C_1-4Alkylamino or carbamoyl
Or substituted phenyl (the substituted
The group is halogen, C_1-4Alkyl, C_1-4Alkoxy or
Is C_1-4(11) a sulfamoyl group which may have a substituent (wherein the substituent is an optionally substituted C_1-4Alkyl (the
And the substituent represents hydroxy or amino). (12) Nitrogen, oxygen or an optionally substituted substituent
4- to 7-membered heterocyclyl containing one or two sulfur atoms
Rylcarbonyl group (the substituent may be hydroxy, amino, mono- or di-
-C_1-4Alkylamino, halogen, cyano, carbamo
Yl, carboxy, optionally substituted C_{1- Four}Archi
(The substituents are amino, hydroxy, carbamoyl,
Represents carboxy or phenyl), even if substituted
Good phenyl (the substituents are halogen, C_1-4Archi
Le, C_1-4Alkoxy or C_1-4Represents alkylthio)
And when the heterocyclyl contains an N atom,
May be substituted to be quaternized, and
When the heterocyclyl contains an S atom, the S atom
Is oxo converted to sulfoxide or sulfone,
(13) C optionally having substituent (s)_6-10Aryl group (the substituent is halogen, carbamoyl, sulfamoy,
Le, C_1-4Alkoxy, C_1-4Alkylthio, substituted
May be C_1-4Alkyl (the substituent is hydroxy,
Amino, mono- or di-C_1-4Alkyl amino, mosquito
Ruboxy, carbamoyl, sulfamoyl, tri-C
_1-4Alkyl ammonium (C_1-4Alkyl is hydroxy
May be substituted with carbamoyl or halogen
Or a 4- to 7-membered cyclic amino group (the cyclic amino group is
C_1-4May be substituted with alkyl and may be quaternized)
Benzene ring or pyridyl, which may be substituted
Nitrogen, oxygen or sulfur atom which may be condensed with
4- to 7-membered heterocyclyl containing 1 or 2
The substituent is an optionally substituted C_1-4Alkyl (the
Substituents are amino, hydroxy, carbamoyl, carboxyl
Or heterosulfamoyl).
When Ryl contains an N atom, the N atom is replaced
It may be quaternized, and the heterocyclyl may have S
When an atom is contained, its S atom is
Which may be a hydroxide or a sulfone),
Optionally substituted amino (the substituent is carbamoyl, sulfo
Amoyl, C_1-4Alkanoyl or substituted
Good C_1-4Alkyl (the substituent is amino, hydroxy,
Si, carbamoyl, carboxy or sulfamoyl
), Carbamoyl which may be substituted
(Equivalent to the above (10)) or may be substituted
Containing four to three nitrogen, oxygen or sulfur atoms
7-membered heterocyclylcarbonyl (same as (12) above)
(14) nitrogen or oxygen, which may have a substituent,
Is a 5- or 6-membered heteroatom containing 1 to 3 sulfur atoms
Reel single ring or benzene ring or pyridine with them
A heteroaryl fused ring group in which a ring is fused (the substituent is_1-4Alkyl, C_1-4Alkoxy, substituted
C that may be_{1- Four}Alkyl (the substituent is carbo
Xy, carbamoyl or hydroxy), carb
Moyl, mono- or di-C_1-4Alkyl carbamoy
, Halogen, cyano, phenyl which may be substituted
(The substituent is halogen, C_1-4Alkyl, C_1-4Arco
Kishi or C_1-4Represents alkylthio),
When the lower aryl contains an N atom, the N atom is substituted.
(15) C which may have a substituent_7-14An aralkyl group (the substituent is halogen, amino, mono- or di-
C_1-4Alkylamino, C_1-4Alkyl, C_1-4Alkoki
Si, C_1-4Alkylthio, C_1-4Alkanoylamino, mosquito
(Shows rubamoyl or sulfamoyl) (16) Nitrogen, oxygen or optionally substituted
Is a heteroaryl monocyclic C containing 1 to 3 sulfur atoms
_1-4Alkyl or their benzene ring or pyridi
Heterocyclic fused ring C fused with a heterocyclic ring_1-4Alkyl
Group (the substituent is halogen, C_1-4Alkyl or C_1-4A
(Shows lucoxy) (17) C optionally having substituent (s)_1-4Alkoxy group (the substituent represents hydroxy or amino) (18) C which may have a substituent_1-4Alkylthio
Group (the substituent is cyano, C_6-10Aryl, carbamoy
(19) represents C, hydroxy or carboxy.) (19) C_3-6Cycloalkylthio group or (20) C which may have a substituent_6-10Arylthio
Group (the substituent is C_1-4Alkyl, C_1-4Alkoxy, C
_1-4Alkoxy C_1-4Represents alkyl or halogen)
And (A3) is a general formula

[0011]

Embedded image Wherein n represents 1, 2 or 3, and R ⁸ represents (1) a hydrogen atom, (2) a C _1-4 alkyl group which may have a substituent (the The substituent represents hydroxy, amino or carbamoyl. (3) Allyl group (4) C _6-10 aryl group which may have a substituent (The substituent is halogen, amino, mono- or di-
C _1-4 alkylamino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkanoylamino, carbamoyl or sulfamoyl) (5) It may have a substituent A heteroaryl monocyclic ring containing 1 to 3 nitrogen, oxygen or sulfur atoms or a heteroaryl condensed ring obtained by condensing the same with a benzene ring or a pyridine ring (the substituent is halogen, C _1-4 alkyl or C _{1 -4} an alkoxy) (6) which may have a substituent C _7-14 aralkyl group (said substituents are halogen, amino, mono- - or di -
C _1-4 alkylamino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkanoylamino, carbamoyl or sulfamoyl) (7) It may have a substituent A heteroaryl monocyclic C _1-4 containing 1 to 3 nitrogen, oxygen or sulfur atoms
Alkyl or a heteroaryl condensed ring C _1-4 alkyl group obtained by condensing them with a benzene ring or a pyridine ring (the substituents represent halogen, C _1-4 alkyl or C _1-4 alkoxy) or (8) C _{3 -6} cycloalkyl group; and R ⁹ represents (1) an optionally substituted amino group (the substituent is an optionally substituted C _1-4 alkyl (the substituent is hydroxy , Carboxy or carbamoyl)) or (2) 4 to 4 containing one or two nitrogen, oxygen or sulfur atoms containing an optionally substituted N atom.
A 7-membered heterocyclyl group (the substituent represents C _1-4 alkyl);
4) is a general formula

[0012]

Embedded image Wherein R ^10a and R ^10b are the same or different, and are (1) hydrogen atom (2) halogen atom (3) hydroxy group (4) C _1-4 alkyl group (5) C _1-4 alkoxy group (6) optionally substituted amino group (the substituent may be C _1-4 alkyl or optionally substituted alkanoyl (the substituent may be amino or mono- or di -C _1-4 shows the alkylamino showing a)) (7) carboxyl group (8) C _1-4 alkoxycarbonyl group (9) which may have a substituent carbamoyl group (the substituents, C ( _{Shows 1-4} alkyl) (10) sulfamoyl group which may have a substituent (the substituent shows C _1-4 alkyl) (11) C _1-4 alkane sulfonyl group or (12) ureido And (A5) is a group represented by the general formula

[0013]

Embedded image Wherein R ¹¹ represents (1) a hydrogen atom, (2) a C _1-4 alkyl group which may have a substituent (the substituent may be a hydroxy, amino, mono- Or di-C _1-4 alkylamino, carbamoyl, mono- or di-C _1-4 alkylcarbamoyl, halogen or carboxy) (3) C _1-4 alkanoyl group (4) even if it has a substituent A good carbamoyl group (the substituent represents C _1-4 alkyl) (5) a C _6-10 aryl group _optionally having a substituent (the substituent is halogen, amino, mono- or di-
C _1-4 alkylamino, C _1-4 alkyl, hydroxy, C
_{Represents 1-4} alkoxy, C _1-4 alkylthio, C _1-4 alkanoylamino, carbamoyl or sulfamoyl) (6) Contains 1 to 3 nitrogen, oxygen or sulfur atoms which may have a substituent 5- or 6-membered heteroaryl monocyclic ring or a heteroaryl condensed ring group in which a benzene ring or a pyridine ring is condensed (the substituent is halogen, C _1-4 alkyl or C _1-4 alkoxy) (7) Substitution A C _7-14 aralkyl group which may have a group (the substituent is halogen, amino, mono- or di-
C _1-4 alkylamino, C _1-4 alkyl, hydroxy, C
_{Represents 1-4} alkoxy, C _1-4 alkylthio, C _1-4 alkanoylamino, carbamoyl or sulfamoyl) or (8) contains 1 to 3 nitrogen, oxygen or sulfur atoms which may have a substituent Heteroaryl monocyclic C _1-4
Alkyl or a heteroaryl condensed ring C _1-4 alkyl group in which a benzene ring or a pyridine ring is condensed with the alkyl (the substituent is halogen, C _1-4 alkyl or C _1-4 alkoxy), and (A6) Is of the formula -N (R ^a )
Represents a group represented by SO ₂ R ^b , wherein R ^a and R ^b are
The same or different, (1) hydrogen atom, (2) C _1-6 alkyl group, (3) C _6-10 aryl group which may have a substituent (the substituent is halogen, C _{1- 4} alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _7-14 aralkylthio groups) (4) Contains 1 to 3 nitrogen, oxygen or sulfur atoms which may have a substituent Heteroaryl monocyclic C _1-4
Alkyl or a heteroaryl condensed ring C _1-4 alkyl group in which a benzene ring or a pyridine ring is condensed thereto (the substituent is halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _{7 -14} aralkylthio group) or R ^a and R ^b together form (1) a C _2-4 alkylene group (2) a naphthylene group which may have a substituent (the substituted The group represents a halogen, a C _1-4 alkyl, a C _1-4 alkoxy or a C _1-4 alkylthio group).

In the description of the above formula (I), "C _1-6 alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl,
2-methylbutyl, 3-methylbutyl, 2,2-dimethylethyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-
A dimethylbutyl group and the like can be mentioned.
_1-4 alkyl group ", more preferably a methyl, ethyl or n-propyl group, most preferably a methyl or ethyl group. .

The “C _1-4 alkyl group” is a group having 1 to 4 carbon atoms.
Means a linear or branched alkyl group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or t-butyl group, preferably Is a methyl or ethyl group.

The "C _2-4 alkylene group" means a linear or branched alkylene group having 2 to 4 carbon atoms, such as ethylene, trimethylene or tetramethylene. Is a trimethylene group.

"C _2-5 alkenyl group" means a linear or branched alkenyl group having 2 to 5 carbon atoms, and examples thereof include vinyl, propenyl, butenyl and pentenyl groups. Preferably, it is a propenyl (especially 2-propenyl) group.

The "C _3-6 cycloalkyl group" has 3 carbon atoms.
Means from 6 to 6 cyclic alkyl groups, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, preferably cyclopentyl or cyclohexyl group.

"C _1-4 alkoxy group" means a linear or branched alkoxy group having 1 to 4 carbon atoms, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-alkoxy. Butyloxy, isobutyloxy, se
Examples thereof include a c-butyloxy or t-butyloxy group, preferably a methoxy or ethoxy group.

"C _1-4 alkylthio group" means a linear or branched alkylthio group having 1 to 4 carbon atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio. , Isobutylthio, sec-butylthio or t-butylthio group, preferably a methylthio or ethylthio group.

The "C _1-4 alkoxycarbonyl group" means a carbonyl group substituted with the aforementioned "C _1-4 alkoxy group", for example, methoxycarbonyl, ethoxycarbonyl, n- propyloxycarbonyl, isopropyloxycarbonyl , N-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl or
A t-butyloxycarbonyl group can be mentioned, preferably a methoxycarbonyl or ethoxycarbonyl group.

As the "halogen atom", for example, a fluorine, chlorine, bromine or iodine atom can be mentioned.
Preferably it is a fluorine or chlorine atom.

The “C _6-13 aryl group” has 6 to 1 carbon atoms.
It means three monocyclic to tricyclic aromatic hydrocarbon groups, for example, a phenyl, 1-naphthyl, 2-naphthyl or fluorenyl group, preferably a " _C6-10 aryl group". And more preferably a phenyl group.

The “C _6-10 aryl group” has 6 to 1 carbon atoms.
0 monocyclic or bicyclic aromatic hydrocarbon group,
For example, a phenyl, 1-naphthyl or 2-naphthyl group can be mentioned, and a phenyl group is preferable.

The “C _6-10 arylthio group” is the same as the aforementioned “C 6
" _10-10 aryl group" means a thio group substituted by, for example, phenylthio, 1-naphthylthio or 2-naphthylthio group, preferably phenylthio group.

"C_7-17The “aralkyl group” is the same as the aforementioned “C_6-13
The aforementioned “C” substituted with an “aryl group” _1-4Alkyl group ''
Means, for example, benzyl, phenethyl, phenylpro
Pill, phenylbutyl, naphthylmethyl, naphthylethyl
, Naphthylpropyl, naphthylbutyl, fluorenyl
Methyl, fluorenylethyl, fluorenylpropyl,
Or a fluorenylbutyl group.
Is "C_7-14An aralkyl group, and more preferably an aralkyl group.
C substituted with nyl_1-4Alkyl group ", most suitable
Is a benzyl or phenethyl group.

"C_7-14The “aralkyl group” is the same as the aforementioned “C_6-10
The aforementioned “C” substituted with an “aryl group” _1-4Alkyl group ''
Means, for example, benzyl, phenethyl, phenylpro
Pill, phenylbutyl, naphthylmethyl, naphthylethyl
, Naphthylpropyl or naphthylbutyl groups
And preferably “C substituted with phenyl”_1-4A
Alkyl group '', more preferably benzyl or phenene.
It is a tyl group.

A "5- or 6-membered heteroaryl monocyclic group containing 1 to 3 nitrogen, oxygen or sulfur atoms" is a 5 or 6-membered heteroaryl monocyclic group containing 1 to 3 nitrogen, oxygen or sulfur atoms.
Membered aromatic heterocyclic group means, for example, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrazyl, pyridazinyl, pyrimidinyl group, and preferably imidazolyl, Triazolyl,
Furyl, thienyl, thiazolyl, thiadiazolyl, pyridyl or pyrazyl groups.

"Heteroaryl condensed ring group in which a 5- or 6-membered heteroaryl monocyclic ring containing 1 to 3 nitrogen, oxygen or sulfur atoms and a benzene or pyridine ring are condensed"
Means a bi- or tricyclic aromatic hetero-fused ring group in which the aforementioned “5- or 6-membered heteroaryl monocyclic ring” and a benzene ring or a pyridine ring are condensed, for example, indolyl, benzimidazolyl, benzothiazolyl, benzothienyl,
Benzofuranyl, quinolyl, isoquinolyl, thiazolo [4,5-c] pyridyl, thiazolo [5,4-c] pyridyl, thiazolo [4,5-b] pyridyl, imidazolopyridyl, triazolopyridyl, dibenzofuranyl group, etc. Preferred are indolyl, benzimidazolyl, benzothiazolyl, benzothienyl, quinolyl, thiazolo [4,5-c] pyridyl, thiazolo [5
4-c] pyridyl or thiazolo [4,5-b] pyridyl group.

The "5- or 6-membered heteroaryl monocyclic C _1-4 alkyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms" is the above-mentioned "5- or 6-membered heteroaryl monocyclic group".
In substituted means above "C _1-4 alkyl group], preferably a imidazolylmethyl, thiazolylmethyl, Chiazoriruechiru, thiadiazolyl methyl, pyridylmethyl or pyridylethyl group.

"A heteroaryl condensed ring C _1-4 wherein a 5- or 6-membered heteroaryl monocyclic ring containing 1 to 3 nitrogen, oxygen or sulfur atoms and a benzene or pyridine ring are condensed.
The “alkyl group” is the aforementioned “C _1-4 alkyl group” substituted with the aforementioned “heteroaryl condensed ring group in which a 5- or 6-membered heteroaryl monocyclic ring and a benzene or pyridine ring are condensed”
And is preferably an indolylmethyl, quinolylmethyl, benzimidazolylmethyl or benzothiazolylmethyl group.

The term "5- or 6-membered heteroaryl monocyclic thio group containing 1 to 3 nitrogen, oxygen or sulfur atoms" means a thio group substituted with the aforementioned "5- or 6-membered heteroaryl monocyclic group". And preferably 5-tetrazolylthio, 2-
A thiazolylthio or 2-thiadiazolylthio group;

The “heteroaryl condensed ring thio group in which a 5- or 6-membered heteroaryl monocyclic ring containing 1 to 3 nitrogen, oxygen or sulfur atoms and a benzene or pyridine ring are condensed” is the above-mentioned “5- or 6-membered heteroaryl A thio group substituted by a "heteroaryl condensed ring group in which a single ring and a benzene or pyridine ring are condensed", and is preferably 2-benzimidazolylthio, 2-benzothiazolylthio, thiazolo [4,5-c A pyridin-2-ylthio, thiazolo [5,4-c] pyridin-2-ylthio or thiazolo [5,4-b] pyridin-2-ylthio group.

"R ¹ and R ² may have a substituent together with the N atom to which they are bonded, and may be a 4- to 7-membered ring which may be condensed with a benzene ring or a pyridine ring. Examples of "4- to 7-membered cyclic amino" in "amino-forming group" include, for example, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 1-homopiperazinyl, 4-morpholinyl, 4-thiomorpholinyl group And is preferably a 1-pyrrolidinyl or 1-piperidinyl group.

The "4- to 7-membered cyclic amino fused to a benzene ring or a pyridine ring" includes isoindolyl,
2,3-dihydroindolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 2,3-dihydro-1H-pyrrolo [3,4-
c] a pyridyl group, preferably an isoindolyl group.

[0036] "Hydroxy C _1-4 alkyl group" or "C _1-4 alkyl group substituted by hydroxy" refers to above which is substituted with a hydroxyl group "C _1-4 alkyl group], for example, hydroxymethyl , Hydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxyethyl,
Examples thereof include a dihydroxypropyl or dihydroxybutyl group, preferably a hydroxymethyl, 2-hydroxyethyl, 3-hydroxyethyl or 2,3-dihydroxypropyl group.

The “C _1-4 alkyl group substituted with a halogen” is the same as the “C _1-4 alkyl group substituted with the aforementioned halogen atom”.
_1-4 alkyl group], for example, fluoromethyl,
Difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, perfluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, perfluoropropyl, fluorobutyl, perfluorobutyl, Chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl, chloropropyl, dichloropropyl, trichloropropyl, chlorobutyl, bromomethyl, dibromomethyl, bromoethyl, dibromoethyl, bromopropyl, bromobutyl and the like, Preferably trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, chloromethyl,
2-chloroethyl or 3-chloropropyl group,
More preferably, it is a trifluoromethyl or 2-fluoroethyl group.

The term “carbamoyl C _1-4 alkyl group” or “C _1-4 alkyl group substituted with carbamoyl” means the aforementioned “C _1-4 alkyl group substituted with a carbamoyl group”, for example, carbamoyl Examples include a methyl, carbamoylethyl, carbamoylpropyl or carbamoylbutyl group, preferably a carbamoylmethyl or 2-carbamoylethyl group.

"Carboxy C _1-4 alkyl group" or "C _1-4 alkyl group substituted by carboxy" means the above-mentioned "C _1-4 alkyl group substituted by carboxy group". Mention may be made of methyl, carboxyethyl, carboxypropyl or carboxybutyl groups, preferably carboxymethyl or 2-carboxyethyl groups.

"Cyano C _1-4 alkyl group" or "C _1-4 alkyl group substituted with cyano" means the above-mentioned "C _1-4 alkyl group substituted with cyano group", for example, cyanomethyl , Cyanoethyl, cyanopropyl or cyanobutyl group, preferably cyanomethyl or 2-cyanoethyl group.

"Amino C _1-4 alkyl group" or "C _1-4 alkyl group substituted with amino" means the above-mentioned "C _1-4 alkyl group substituted with amino group". Examples include a methyl, aminoethyl, aminopropyl or aminobutyl group, preferably an aminomethyl or 2-aminoethyl group.

"Mono- or di-C _1-4 alkylcarbamoyl group" means a carbamoyl group substituted by the above-mentioned "C _1-4 alkyl", for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl , Dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl or dibutylcarbamoyl group, preferably methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl or diethylcarbamoyl group.

"Mono- or di- _C1-4 alkylamino group" means an amino group substituted with the above-mentioned " _C1-4 alkyl", for example, methylamino, ethylamino, propylamino, butylamino , Dimethylamino, diethylamino, dipropylamino or dibutylamino group, and is preferably a methylamino, ethylamino, dimethylamino or diethylamino group.

The above - C _1-4 alkyl moiety of the "mono- or di -C _1-4 alkylamino group" is hydroxy, carbamoyl, carboxy, amino or mono - substituted by or di -C _1-4 alkylamino In some cases, for example, 2-hydroxyethylamino, methyl (2-hydroxyethyl) amino, di (2-hydroxyethyl) amino, carbamoylmethylamino, methyl (carbamoylmethyl) amino, 2-carbamoylethylamino, methyl (2 -Carbamoylethyl) amino, carboxymethylamino, methyl (carboxymethyl) amino, 2-
Carboxyethylamino, methyl (2-carboxyethyl) amino, 2-aminoethylamino, methyl (2-aminoethyl) amino, 2-methylaminoethylamino,
Methyl (2-methylaminoethyl) amino, 2-dimethylaminoethylamino, methyl (2-dimethylaminoethyl) amino group and the like can be mentioned, and preferably, 2-hydroxyethylamino, methyl (2-hydroxyethyl) Amino, di (2-hydroxyethyl) amino, carbamoylmethylamino, methyl (carbamoylmethyl)
Amino, carboxymethylamino or methyl (carboxymethyl) amino group.

The "mono - or C _1-4 alkyl group substituted with a di -C _1-4 alkylamino", above - "C replaced by" mono- or di -C _1-4 alkylamino group "
_{A `` 1-4} alkyl '' group means, for example, methylaminoethyl, ethylaminoethyl, propylaminoethyl, butylaminoethyl, dimethylaminoethyl, diethylaminoethyl, dipropylaminoethyl, dibutylaminoethyl, methylaminopropyl, ethylamino Propyl,
Propylaminopropyl, butylaminopropyl, dimethylaminopropyl, diethylaminopropyl, dipropylaminopropyl, dibutylaminopropyl, methylaminobutyl, dimethylaminobutyl group and the like, preferably methylaminoethyl, ethylaminoethyl, It is a dimethylaminoethyl or diethylaminoethyl group.

The term "carbamoyloxyoxy C _1-4 alkyl group" means the above-mentioned "C _1-4 alkyl group" substituted by a carbamoyloxyoxy group, for example, carbamoyloxymethyl, carbamoyloxyethyl, carbamoyloxypropyl Or a carbamoyloxybutyl group can be mentioned, and it is preferably a 2-carbamoyloxyethyl group.

The "C _1-4 alkane sulfonyl group" means a sulfonyl group substituted by the above-mentioned "C _1-4 alkyl group", for example, methanesulfonyl, ethanesulfonyl, propanesulfonyl or butanesulfonyl group. And preferably a methanesulfonyl or ethanesulfonyl group.

The "C _6-10 arylsulfonyl group" means a sulfonyl group substituted with the aforementioned "C _6-10 aryl group", for example, benzenesulfonyl, be mentioned 1-naphthalenesulfonyl or 2-naphthalenesulfonyl group And preferably a benzenesulfonyl group.

"Tri-C _1-4 alkylammonio group"
Represents a quaternary amino group substituted with three of the above-mentioned “C _1-4 alkyl”, for example, trimethylammonio, triethylammonio, tripropylammonio, tributylammonio, N, N-dimethyl- Examples thereof include an N-ethylammonio group, and a trimethylammonio group is preferable.

In the above “tri-C _1-4 alkylammonio group”, the C _1-4 alkyl group is hydroxy, carbamoyl,
When substituted with carboxy, amino or halogen, for example, N, N-dimethyl-N- (2-hydroxyethyl) ammonio, N, N-dimethyl-N-
(Carbamoylmethyl) ammonio, N, N-dimethyl-N- (carboxymethyl) ammonio, N, N-dimethyl-N- (2-aminoethyl) ammonio or N, N
An N-dimethyl-N- (2-fluoroethyl) ammonio group can be mentioned.

The "C _1-10 alkanoyl group" means an alkanoyl group having 1 to 10 carbon atoms, such as formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl or octanoyl. Preferably, it is an acetyl group.

"Amino C _1-10 alkanoyl group" means the above-mentioned "C _1-10 alkanoyl group" substituted with an amino group, for example, aminoacetyl, aminopropionyl, aminobutyryl, aminopentanoyl, aminohexanoyl , Aminoheptanoyl or aminooctanoyl group, preferably an aminoacetyl group.

As the "5- or 6-membered heteroaryl monocyclic group containing 1 to 3 N atoms", for example, a pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl or pyrazyl group can be mentioned. Is a pyridyl, imidazolyl or triazolyl group.

Examples of the case where the N atom of the above “5- or 6-membered heteroaryl monocyclic group containing 1 to 3 N atoms” is substituted with C _1-4 alkyl and quaternized, 1-methyl-2-pyridyl, 1-methyl-3-pyridyl, 1-methyl-4-pyridyl, 3-methyl-1-
An imidazolyl or 4-methyl-1-triazolyl group can be mentioned.

[0055] "C _6-10 arylcarbonyl group" means a carbonyl group substituted by the above "C _6-10 aryl group", for example, be mentioned benzoyl, 1-naphthylcarbonyl or 2-naphthyl group And preferably a benzoyl group.

The "5- or 6-membered heteroaryl monocyclic carbonyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms" is the above-mentioned "5- or 6-membered heteroaryl monocyclic group".
And includes, for example, 2-thienylcarbonyl, 2-furylcarbonyl, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl group and the like, preferably 4-pyridyl It is a carbonyl group.

The 5- or 6-membered heteroaryl monocyclic carbonyl group of the above "5- or 6-membered heteroaryl monocyclic carbonyl group" has an N atom, and the N atom is substituted by C _1-4 alkyl to form a quaternary. For example, if
1-methyl-2-pyridiniocarbonyl, 1-methyl-
A 2-pyridiniocarbonyl or 1-methyl-4-pyridiniocarbonyl group can be mentioned.

A “4- to 7-membered heterocyclyl group containing one or two nitrogen, oxygen or sulfur atoms” is one or two
Nitrogen, oxygen or sulfur atom containing an aliphatic heteromonocyclic group, for example, azetidinyl, pyrrolidinyl,
Examples include piperidyl, piperazinyl, homopiperazinyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, and thiomorpholinyl groups, preferably azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl group.

"4- to 7-membered heterocyclylcarbonyl group containing one or two nitrogen, oxygen or sulfur atoms"
Means a carbonyl group substituted with the aforementioned `` 4- to 7-membered heterocyclyl group '', for example, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidylylcarbonyl, piperazinylcarbonyl, homopiperazinylcarbonyl, tetrahydrofuran Carbonyl, tetrahydrothienylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, etc., and preferably 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidylcarbonyl, -Piperazinylcarbonyl, 4-morpholinylcarbonyl, 4-thiomorpholinylcarbonyl, 2-azetidinylcarbonyl, 2-pyrrolidinylcarbonyl or 2-piperidylcarbonyl.

The case where the heterocyclyl moiety of the above “4 to 7-membered heterocyclylcarbonyl group” has an N atom and is substituted and quaternized is, for example, 4,4-dimethyl-1-piperazinio Carbonyl, 4-methyl-4
Carbamoylmethyl-1-piperaziniocarbonyl,
4-methyl-4- (2-carbamoylethyl) -1-piperaziniocarbonyl, 4-methyl-4-carboxymethyl-1-piperaziniocarbonyl, 4-methyl-4-
(2-hydroxyethyl) -1-piperaziniocarbonyl, 4-methyl-4- (2-aminoethyl) -1-piperaziniocarbonyl, 1,1-dimethyl-2-azetidinylcarbonyl, 1,1 -Dimethyl-2-pyrrolidinylcarbonyl or 1,1-dimethyl-2-piperidylcarbonyl group.

In the case where the “4- to 7-membered heterocyclylcarbonyl group” or the heterocyclyl portion of the “4- to 7-membered heterocyclyl group” has a sulfur atom and is oxidized to be a sulfoxide or a sulfone, 4-thiomorpholine Examples thereof include those in which a sulfur atom of a carbonyl group or a 4-thiomorpholinyl group is oxidized to sulfoxide or sulfone.

The "4- to 7-membered cyclic amino group" includes, for example, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 1-homopiperazinyl,
Examples thereof include a 4-morpholinyl and 4-thiomorpholinyl group, preferably a 1-pyrrolidinyl or 1-piperidinyl group.

The case where the N atom of the above “4- to 7-membered cyclic amino group” is quaternized by substitution with C _1-4 alkyl includes, for example, 1-methyl-1-pyrrolidinio,
-Methyl-1-piperidinio, 4-methyl-4-morpholinio, and 4-methyl-4-thiomorpholinio groups, and preferably 1-methyl-1-pyrrolidinio or 1-methyl-1-piperidinio group. .

The “tricyclic carbapenem compound represented by the general formula (I)” of the present invention can be a “pharmaceutically acceptable derivative” thereof, if necessary.

The “pharmacologically acceptable derivative thereof” refers to a group capable of forming the original compound or a salt thereof by cleavage by a chemical or biological method such as hydrolysis in a human or animal body (forming a so-called prodrug). And carboxyl group, hydroxyl group, amino group and the like of compound (I) are protected by an ester or amide derivative, and whether such a derivative is orally or intravenously administered to an experimental animal such as a rat or a mouse. It can be determined by administering by injection, then examining the body fluid of the animal and detecting the parent compound or its salt. Such carboxyl groups, hydroxyl groups,
Examples of the protecting group such as an amino group include groups known in the field of medicinal chemistry, for example, C _1-6 acyloxy C _1-4 alkyl group, C _1-6 alkoxycarbonyloxy C _1-4 alkyl group, phthalidyl group, 5-methyl-2-oxo-1,3-
Examples thereof include a dioxolen-4-ylmethyl group, an acyl group, a C _1-6 alkoxycarbonyl group, and an amino C _1-6 acyl group.

The “C _1-6 acyloxy C _1-4 alkyl group” includes, for example, pivaloyloxymethyl, isobutyryloxymethyl, 1- (isobutyryloxy) ethyl, acetoxymethyl, 1- (Acetoxy) ethyl,
1-methylcyclohexylcarbonyloxymethyl, 1
-Methylcyclopentylcarbonyloxymethyl.

"C _1-6 alkoxycarbonyloxy C _1-4"
Examples of the “alkyl group” include t-butoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl,
(Isopropoxycarbonyloxy) ethyl, 1- (t
-Butoxycarbonyloxy) ethyl, 1- (cyclohexyloxycarbonyloxy) ethyl and 1- (cyclopentyloxycarbonyloxy) ethyl groups.

As the “acyl group”, for example, acetyl,
C _1-20 alkanoyl groups such as propionyl, butyryl, pentanoyl, hexanoyl, octanoyl, decanoyl, dodecanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl groups, benzoyl, C _6-10 arylcarbonyl groups such as naphthoyl, 5- or 6-membered heteroarylcarbonyl groups containing 1 to 3 nitrogen, oxygen or sulfur atoms such as pyridylcarbonyl and thienylcarbonyl.

The “C _1-6 alkoxycarbonyl group” includes, for example, methoxycarbonyl, ethoxycarbonyl,
And propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl, octadecyloxycarbonyl and the like.

Examples of the “amino C _1-6 acyl group” include amino acid groups such as glycyl, alanyl, β-alanyl, leucyl, isoleucyl, phenylalanyl, histidyl, asparagyl, prolyl and lysyl.

A preferred protecting group among the above is 5-methyl-2
-Oxo-1,3-dioxolen-4-ylmethyl, acetoxymethyl, pivaloyloxymethyl, 1-methylcyclohexylcarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl or 1- (cyclohexyloxycarbonyloxy) ethyl group It is.

The “tricyclic carbapenem compounds represented by the general formula (I)” and “pharmacologically acceptable derivatives thereof” may be optionally substituted with “pharmacologically acceptable salts thereof”.
Can be

"Pharmacologically acceptable salts thereof" include, for example, hydrochloride, hydrobromide, hydroiodide, phosphate,
Mineral salts such as sulfates and nitrates; methanesulfonates,
Sulphonates such as ethanesulphonate, benzenesulphonate, p-toluenesulphonate; oxalates;
Tartrate, citrate, maleate, succinate, acetate, benzoate, mandelate, ascorbate,
Lactate, gluconate, acid addition salts such as organic acid salts such as malate, glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, amino acid salts such as aspartates, or lithium salts, It can be an inorganic salt such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt or a salt with an organic base such as an ammonium salt, a triethylamine salt, a diisopropylamine salt, a cyclohexylamine salt, preferably a hydrochloride, a bromide. Hydrochloride, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, oxalate, tartrate, citrate, acetate, lactate, glutamate, aspartate, sodium salt, Potassium salt, ammonium salt or triethylamine salt, more preferably sodium salt, hydrochloride or sulfate A.

The compound (I) of the present invention absorbs water by leaving it in the air, freeze-drying from an aqueous solution, or recrystallizing to form adsorbed water,
It may be a hydrate, and such salts are also included in the present invention.

Among the compounds represented by the general formula (I) of the present invention, preferred compounds include the following compounds.

Preferred compounds wherein A is (A1) are
A compound of (A1-1), and more preferably (A1-
The compound of 2), most preferably the compound of (A1-3). (A1-1) A is represented by (A1), R ¹ and R ² are the same or different, and (1) a C _1-4 alkyl group which may have a substituent (the substituent is Hydroxy, cyano, carbamoyl, amino or mono- or di-C _1-4 alkylamino) (2) C _3-6 cycloalkyl group (3) C _6-13 aryl group which may have a substituent (The substituent may be a halogen, carbamoyl, C _1-4 alkoxy, oxo, C _1-4 alkyl, C _6-10 aryl or a 5- or 6-membered heteroaryl unit containing 1 to 3 nitrogen, oxygen or sulfur atoms. (Shows a ring) (4) C _7-17 aralkyl group which may have a substituent (the substituent is the same as the substituent in the above (3)) (5) It has a substituent 5- or 6-membered containing 1 to 3 nitrogen, oxygen or sulfur atoms Roariru monocyclic or heteroaryl fused Hajime Tamaki thereof with a benzene ring or pyridine ring is fused (the substituent represents C _1-4 alkyl, halogen, carbamoyl or C _1-4 alkoxy) (6) have a substituent A heteroaryl monocyclic C _1-4 containing 1 to 3 nitrogen, oxygen or sulfur atoms which may be
Alkyl or a heteroaryl condensed ring C _1-4 alkyl group obtained by condensing them with a benzene or pyridine ring (the substituents are the same as the substituents in the above (5)); or (7) R ¹ and R ² Is a group which forms a 4- to 7-membered cyclic amine which may have a substituent together with the N atom to which they are bonded and which may be condensed with a benzene ring (the substituent is a halogen atom) , Hydroxy, C _1-4 alkyl, hydroxy C _1-4 alkyl, C _6-10 aryl or a 5- or 6-membered heteroaryl monocyclic ring having 1 to 3 nitrogen, oxygen or sulfur atoms). (A1-2) A is represented by (A1), and R ¹ and R ² are the same or different and each may have a substituent, a methyl, ethyl or propyl group (the substituent is hydroxy, Carbamoyl, amino, methylamino or dimethylamino), which may have a substituent, phenyl, naphthyl, pyridyl, thiazolyl, imidazolyl,
A thiadiazolyl, benzyl, phenethyl, naphthylmethyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, thiazolylethyl or thiadiazolylmethyl group (wherein the substituent represents fluorine, chlorine, methyl, methoxy or carbamoyl), or R ¹ and R ² are Azetidine, pyrrolidine, piperidine, piperazine, homopiperazine, isoindoline, 2,3-dihydroindole, 1,2,3, which may have a substituent together with the N atom to which they are bonded. Groups forming a 4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline or 2,3-dihydro-1H-pyrrolo [3,4-c] pyridine ring (the substituents are fluorine, chlorine, hydroxy , Methyl, ethyl, hydroxymethyl, 2-hydroxyethyl, Le, pyridyl, showing the imidazolyl or triazolyl group), compound. (A1-3) A is represented by (A1), and R ¹ and R ² are the same or different, and may have a substituent, a methyl or ethyl group (the substituent is hydroxy, carbamoyl, Amino, methylamino or dimethylamino), a phenyl, pyridyl, thiazolyl, imidazolyl, benzyl, phenethyl, pyridylmethyl, imidazolylmethyl or thiazolylmethyl group which may have a substituent (the substituent is fluorine, chlorine , Methyl, methoxy or carbamoyl), or R ¹ and R
² is a group which forms an azetidine, pyrrolidine, piperidine, piperazine or homopiperazine ring which may have a substituent together with the N atom to which they are bonded (the substituent is fluorine, chlorine, A hydroxy, methyl, ethyl, hydroxymethyl, 2-hydroxyethyl, phenyl, pyridyl or imidazolyl group).

Preferred compounds wherein A is (A2) are
(A2a), (A2b), (A2c), (A2d),
It is a compound of (A2e).

Regarding (A2a), more preferably (A2a)
a-1), most preferably (A2a-
2), (A2a-3) or (A2a-4).

Regarding (A2b), more preferably (A2b)
b-1), most preferably (A2b-2)
Is a compound of

Regarding (A2c), more preferably (A2c)
It is a compound of c-1).

Regarding (A2d), more preferably (A2d)
d-1), most preferably (A2d-2)
Is a compound of

Regarding (A2e), more preferably (A2e)
e-1), most preferably (A2e-2)
Is a compound of (A2a) A is a general formula

[0083]

Embedded image In the formula, R ³ and R ⁴ are the same or different and each represents (1) a hydrogen atom, (2) a cyano group, (3) a C _1-4 alkylsulfonyl group, or (4) a C ₁ which may have a substituent. _-4 alkyl group (the substituent is hydroxy, halogen, carbamoyl,
Cyano, carboxy, amino, mono- or di-C
_1-4 alkylamino, C _1-4 alkoxy, C _1-4 alkylthio, mono- or di-C _1-4 alkylcarbamoyl, C _1-4 alkoxycarbonyl or C _1-6 cycloalkyl) (5) Substitution An amino group optionally having a group (the substituent represents an optionally substituted C _1-4 alkyl (the substituent represents hydroxy, carbamoyl or carboxy)); An optionally substituted carbamoyl group (the substituent is an optionally substituted C _1-4 alkyl (the substituent represents amino, hydroxy or mono- or di-C _1-4 alkylamino) or Optionally substituted phenyl (the substituent represents halogen, C _1-4 alkyl, C _1-4 alkoxy or C _1-4 alkylthio); (7) optionally substituted Nitrogen, oxygen or sulfur source A 4- to 7-membered heterocyclylcarbonyl group containing 1 or 2 offspring (the substituent may be hydroxy, amino, mono- or di-C _1-4 alkylamino, halogen, cyano, carbamoyl, carboxy, good C _1-4 alkyl (the substituent, amino, hydroxy, carbamoyl,
Carboxy or phenyl), optionally substituted phenyl (the substituents represent halogen, C _1-4 alkyl, C _1-4 alkoxy or C _1-4 alkylthio)
Wherein, when the heterocyclyl contains an N atom, the N atom may be substituted to be quaternized;
When the heterocyclyl contains an S atom, the S atom may be oxo-modified to form a sulfoxide or a sulfone. (8) a C _6-10 aryl group which may have a substituent (the substituent is , Halogen, carbamoyl, sulfamoyl, C _1-4 alkoxy, optionally substituted C _1-4 alkyl (the substituent is hydroxy, amino, mono- or di-C _1-4 alkylamino, carboxy, carbamoyl, tri -C _{1 -4} alkyl ammonio (the C _1-4 alkyl, hydroxy, optionally substituted carbamoyl or halogen), or 4 to 7 membered cyclic amino group (the cyclic amino group with _1-4 alkyl Substituted or quaternized)), one or more nitrogen, oxygen or sulfur atoms which may be substituted and may be condensed with a benzene or pyridine ring. 4 to 7 membered heterocyclyl (wherein the substituent containing two is, optionally substituted C _1-4 alkyl (the substituent represents amino, hydroxy, carbamoyl, shown carboxy or sulfamoyl),
When the heterocyclyl contains an N atom, the N atom may be substituted to be quaternized. When the heterocyclyl contains an S atom, the S atom is oxo-modified to form a sulfoxide or a sulfone. Optionally substituted), optionally substituted amino (the substituent is carbamoyl, sulfamoyl or optionally substituted C _1-4 alkyl (the substituent is amino, hydroxy, carbamoyl, carboxy or sulfamoyl) Show)
Carbamoyl which may be substituted (same meaning as in the above (6)), or nitrogen which may be substituted;
4 to 7 containing 1 or 2 oxygen or sulfur atoms
Or a (9) 5- or 6-membered heteroaryl monocyclic ring having 1 to 3 nitrogen, oxygen or sulfur atoms which may have a substituent Or a heteroaryl condensed ring group in which a benzene ring or a pyridine ring is fused thereto (the substituent is an optionally substituted C _1-4 alkyl (the substituent represents carboxy, carbamoyl or hydroxy), carbamoyl, Mono- or di-C
_1-4 alkylcarbamoyl, halogen, cyano, optionally substituted phenyl (the substituent is halogen, C
_{Represents 1-4} alkyl, C _1-4 alkoxy or C _1-4 alkylthio), and when the heteroaryl contains an N atom, the N atom may be substituted and quaternized). A compound that is a group represented by｝. (A2a-1) In (A2a), R ³ and R ⁴ are the same or different and are each a hydrogen atom, a cyano group, a methanesulfonyl or ethanesulfonyl group, or a methyl, ethyl or propyl which may have a substituent. Group (the substituent represents hydroxy, fluorine, chlorine, carbamoyl, cyano or carboxy), an amino group which may have a substituent (the substituent is methyl, ethyl, 2-hydroxyethyl, carbamoylmethyl , 2-carbamoylethyl, carboxymethyl or 2-carboxyethyl), a carbamoyl group which may have a substituent (the substituent is methyl, ethyl, 2-aminoethyl, 2-hydroxyethyl, Methylaminoethyl, 2-dimethylaminoethyl and phenyl), which may have a substituent, 1-azeti Having a dinocarbonyl, 1-pyrrolidinocarbonyl or 1-piperidinocarbonyl group (the substituents represent hydroxy, amino, methylamino, dimethylamino, diethylamino, fluorine, cyano, carbamoyl or carboxy); May be one
-Piperazinocarbonyl group (the substituent represents methyl, ethyl, 2-hydroxyethyl, 2-aminoethyl, carbamoylmethyl, 2-carbamoylethyl, carboxymethyl or benzyl, and the 4-position N atom of piperazine is 4 May be substituted), 4-morpholinocarbonyl or 4-thiomorpholinocarbonyl group (S atom of the thiomorpholine may be oxo-modified to be sulfoxide or sulfone), and may have a substituent. Phenyl group (the substituent is fluorine, chlorine, carbamoyl, sulfamoyl, methoxy, ethoxy, optionally substituted methyl or ethyl (the substituent is hydroxy,
Amino, methylamino, ethylamino, dimethylamino, dimethylamino, carboxy, carbamoyl, trimethylammonio, 2-hydroxyethyldimethylammonio, carbamoylmethyldimethylammonio, 2-
Fluoroethyldimethylammonio, 1-methylpyrrolidinio or 1-methylpiperidinio), azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,
Homopiperazinyl, isoindolinyl, 2,3-dihydroindolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 2,
3-dihydro-1H-pyrrolo [3,4-c] pyridyl,
An optionally substituted amino (the substituent represents sulfamoyl, carbamoyl, methyl, ethyl, 2-hydroxyethyl, 2-aminoethyl, carbamoylmethyl or carboxymethyl), an optionally substituted carbamoyl group (the The substituent represents methyl, ethyl, 2-aminoethyl, 2-hydroxyethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, or phenyl), optionally substituted, 1-azetidinocarbonyl,
Pyrrolidinocarbonyl or 1-piperidinocarbonyl group (the substituent is hydroxy, amino, methylamino,
Dimethylamino, diethylamino, fluorine, cyano, carbamoyl or carboxy), an optionally substituted 1-piperazinocarbonyl group (the substituent is methyl, ethyl, 2-hydroxyethyl, 2-aminoethyl, carbamoyl Methyl, 2-carbamoylethyl, carboxymethyl or benzyl; the 4-position N atom of the piperazine may be quaternized; a 4-morpholinocarbonyl or 4-thiomorpholinocarbonyl group (the S atom of the thiomorpholine is Which may be oxolated to be a sulfoxide or a sulfone), or a thienyl, furanyl, pyrrolyl, thiazolyl, pyridyl, pyrazyl, indolyl, benzimidazolyl, benzothiazolyl group (optionally substituted) The group is
Methyl, ethyl, propyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, hydroxymethyl, 2-hydroxyethyl,
Carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, fluorine, chlorine, cyano or phenyl, and when the heteroaryl contains an N atom,
The N atom of which may be substituted and quaternized). (A2a-2) In (A2a), R ³ and R ⁴ are the same or different and each is hydrogen atom, cyano, methanesulfonyl, ethanesulfonyl, methyl, ethyl, propyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxy Propyl, carbamoylmethyl, 2-carbamoylmethyl, cyanomethyl, 2-cyanoethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, 2-hydroxyethylamino, carbamoylmethylamino, 2-carbamoylethylamino, carboxymethylamino or 2 A compound which is a carboxyethylamino group. (A2a-3) In (A2a), R ³ is a hydrogen atom,
A methyl or ethyl group, R ⁴ is carbamoyl,
Methylcarbamoyl, (2-aminoethyl) carbamoyl, (2-hydroxyethyl) carbamoyl, (2-methylaminoethyl) carbamoyl, (2-dimethylaminoethyl) carbamoyl, phenylcarbamoyl, 1-
Azetidinocarbonyl, 3-hydroxy-1-azetidinocarbonyl, 3-amino-1-azetidinocarbonyl, 3-methylamino-1-azetidinocarbonyl, 1
-Pyrrolidinocarbonyl, 3-hydroxy-1-pyrrolidinocarbonyl, 3-amino-1-pyrrolidinocarbonyl, 3-methylamino-1-pyrrolidinocarbonyl, 2
-Carbamoyl-1-pyrrolidinocarbonyl, 1-piperidinocarbonyl, 4-hydroxy-1-piperidinocarbonyl, 4-methylamino-1-piperidinocarbonyl, 1-piperazinocarbonyl, 4-methyl- 1-piperazinocarbonyl, 4- (2-hydroxyethyl) -1
A compound which is a piperazinocarbonyl, a 4,4-dimethyl-1-piperaziniocarbonyl, a 4-morpholinocarbonyl or a 4-thiomorpholinocarbonyl group; (A2a-4) In (A2a), R ³ is a hydrogen atom, a methyl or ethyl group, and R ⁴ is phenyl,
4-fluorophenyl, 4-carbamoylphenyl, 2
-Pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-4-pyridinio, 1-carbamoylmethyl-4-pyridinio, 2-pyrazyl, 2-benzothiazolyl or 2
-A compound which is a benzimidazolyl group. (A2b) A is a general formula

[0084]

Embedded image In the formula, R ^5a and R ^5b are the same or different and are (1) hydrogen atom (2) halogen atom (3) nitro group (4) carboxy group (5) amino group (6) ureido group (7) sulfo group Famoylamino group (8) C _1-4 alkyl group which may have a substituent (the substituent may be halogen, hydroxy, amino, mono-
Or di -C _1-4 alkylamino (said C _1-4 alkyl, amino, hydroxy, optionally substituted carbamoyl or carboxy), tri -C _1-4 alkyl ammonio (said C _{1 -4} alkyl May be substituted with hydroxy, carbamoyl or carboxy), or a 5- or 6-membered heteroaryl monocyclic ring containing 1 to 3 N atoms (the N atoms being substituted with C _1-4 alkyl to form a quaternary (9) an amino group which may have a substituent (the substituent is a C _1-4 alkyl, a C _6-10 arylcarbonyl, a C _6-10 aryl, a hydroxy C _1-4 alkyl, carbamoyl C _1-4 alkyl, C _1-10 alkanoyl, C _1-4
Alkanesulfonyl, or 5 or 6 containing 1-3 optionally substituted nitrogen, oxygen or sulfur atoms
Membered heteroaryl monocyclic carbonyl or a heteroaryl condensed ring carbonyl obtained by condensing them with a benzene ring or a pyridine ring (the substituent represents C _1-4 alkyl or halogen, and when the heteroaryl monocyclic ring contains an N atom, The N atom may be quaternized by substitution by C _1-4 alkyl), C _2-5 alkenyl, amino C _1-10 alkanoyl, or containing one or two nitrogen, oxygen or sulfur atoms (Shows a 4- to 7-membered heterocyclylcarbonyl group) (10) a carbamoyl group which may have a substituent (the substituent is a C _1-4 alkyl, a hydroxy C _1-4 alkyl or an amino C _1-4 alkyl; (11) Sulfamoyl group which may have a substituent (the substituent is C _1-4 alkyl, hydroxy C _1-4 alkyl or amino C _1-4 alkyl) (12) a C _1-4 alkoxy group which may have a substituent (the substituent represents hydroxy or amino) or (13) a nitrogen, oxygen or sulfur atom which may have a substituent A 4- to 7-membered heterocyclylcarbonyl group containing 1 or 2 (the substituent may be hydroxy, amino, mono- or di-C _1-4 alkylamino, halogen, cyano, carbamoyl, carboxy, optionally substituted C _{1- 4} alkyl (the substituent, amino, hydroxy, carbamoyl,
Carboxy or phenyl), optionally substituted phenyl (the substituents represent halogen, C _1-4 alkyl, C _1-4 alkoxy or C _1-4 alkylthio)
Wherein, when the heterocyclyl contains an N atom, the N atom may be substituted and may be quaternized; and when the heterocyclyl contains an S atom, the S atom is oxo-formed to form a sulfoxide or Sulfone). A compound that is a group represented by｝. (A2b-1) In (A2b), R ^5a and R ^5b are
Same or different, hydrogen atom, fluorine, chlorine, nitro, carboxy group, methyl or ethyl group which may have a substituent (the substituent is fluorine, chlorine, hydroxy, amino, methylamino, ethylamino, Dimethylamino, diethylamino, 2-aminoethylamino, 2-
Hydroxyethylamino, carbamoylmethylamino,
Carboxymethylamino, N- (2-aminoethyl)-
N-methylamino, N- (2-hydroxyethyl) -N
-Methylamino, N-carbamoylmethyl-N-methylamino, bis (2-hydroxyethyl) amino, trimethylammonio, 2-hydroxydimethylammonio,
Carbamoylmethyldimethylammonio or imidazolyl, triazolyl or pyridyl (the N atom may be substituted by methyl and may be quaternized), an amino group which may have a substituent (the substituent is Methyl,
Ethyl, benzoyl, phenyl, acetyl, octanoyl, methanesulfonyl, pyridinecarbonyl (the N atom of the pyridine may be quaternized by being substituted by methyl) or quinolinecarbonyl); A carbamoyl group (the substituent is methyl,
Ethyl, 2-hydroxyethyl or 2-aminoethyl), a sulfamoyl group which may have a substituent (the substituent represents methyl, ethyl, 2-hydroxyethyl or 2-aminoethyl), A methoxy or ethoxy group which may have a substituent (the substituent represents hydroxy or amino), 1-azetidinocarbonyl, 1-pyrrolidinocarbonyl or 1-pi which may have a substituent; A peridinocarbonyl group (the substituent is
Hydroxy, amino, methylamino, dimethylamino,
Diethylamino, fluorine, cyano, carbamoyl or carboxy), a 1-piperazinocarbonyl group which may have a substituent (the substituent is methyl, ethyl,
2-hydroxyethyl, 2-aminoethyl, carbamoylmethyl, 2-carbamoylethyl, carboxymethyl or benzyl, wherein the 4-position N atom of piperazine is 4
A 4-morpholinocarbonyl or 4-thiomorpholinocarbonyl group (the S atom of the thiomorpholine may be oxoated to be a sulfoxide or a sulfone). (A2b-2) In (A2b), R ^5a is a hydrogen atom, and R ^5b is a hydrogen atom, 5-trifluoromethyl,
5-chloro, 6-nitro, 6-methoxy, 6-amino,
6-ureido, 5-hydroxymethyl, 5- (3-methyl-1-imidazoliomethyl), 6-benzoylamino, 6-sulfamoylamino, 6-hydroxymethyl, 6-carboxy, 6-methylamino, 6 -Dimethylamino, 6- (2-hydroxyethoxy), 6- (2-
Aminoethoxy), 6-nicotinoylamino, 6-isonicotinoylamino, 6-picolinoylamino, 6-
(1-methyl-4-pyridiniocarbonyl), 6- (1
-Methyl-3-pyridiniocarbonyl), 6- (1-methyl-2-pyridiniocarbonyl), 6- (1-piperazinylcarbonyl), 6- (2-hydroxyethylcarbamoyl), 6- ( 2-aminoethylcarbamoyl),
5-aminomethyl, 5-methylaminomethyl, 5-dimethylaminomethyl, 5-trimethylammoniomethyl,
5- (2-hydroxyethylamino) or 5- (3-
A methyl-1-imidazoliomethyl) group. (A2c) the compound, wherein A is a 2-thiazolylthio group fused to a pyridine ring. (A2c-1) In (A2c), A represents thiazolo [4,5-c] pyridin-2-ylthio, thiazolo [5,4-c] pyridin-2-ylthio or thiazolo [5,4-b] pyridine A compound which is a 2-ylthio group. (A2d) A is a general formula

[0085]

Embedded image中 where R⁶Is (1) hydrogen atom (2) C which may have a substituent_1-4Alkyl group (the substituent is hydroxy, halogen, amino, or
Mono- or di-C _1-4Alkylamino (the C_1-4Al
Kills include hydroxy, carbamoyl, amino or mono
-Or di-C_1-4Substituted with alkylamino
(3) amino group which may have a substituent (the substituent may be C_1-4Alkanoyl, C_3-6Cycloalkyl
, Optionally substituted C_1-4Alkyl (the substituent
Is halogen, hydroxy, amino, mono- or di-
-C_1-4Alkylamino or carbamoyl),
Heteroarylcarbonyl, optionally substituted C
_6-10Arylcarbonyl (the substituent is halogen, C
_1-4Alkyl or C_1-4Represents alkoxy), substituted
May be C _6-10Aryl (the substituent is halogen,
C_1-4Alkyl, C_1-4Alkoxy, amino or mono-
Or di-C_1-4Alkylamino)), substituted
May be C_7-14Aralkyl (the substituent is halogen
N, C_1-4Alkyl, C_1-4Alkoxy or carbamoy
Carbamoyl (optionally substituted)
The substituent is C_1-4Alkyl or C_6-10Shows aryl
), Optionally substituted thiocarbamoyl (the substituted
The group is C_1-4Alkyl or C_6-10Aryl))
C which may be replaced_6-10Arylsulfonyl (substituted
The group is C_1-4Alkyl, halogen or C_1-4Alkoxy
Represents an optionally substituted C)_1-4Alkylsulfo
Nyl (the substituent represents halogen),
Contains 1 to 3 nitrogen, oxygen or sulfur atoms
A 5- or 6-membered heteroaryl monocyclic ring wherein the substituent is_1-4A
Lucil or C_1-4May be substituted with alkoxy
Represents phenyl) or a nitrogen, oxygen or sulfur atom
5 or 6 membered heteroaralkyl containing 1 to 3
(4) C which may have a substituent_1-4Alkylthio group (the substituent is cyano, C_6-10Aryl, carbamoy
(5) C_3-6Cycloalkylthio group (6) C optionally having substituent (s)_6-10Arylthio group (the substituent is C_1-4Alkyl, C_1-4Alkoxy, C
_1-4Alkoxy C_1-4(Shows alkyl or halogen) (7) C which may have a substituent_6-10Aryl group (the substituent is carbamoyl, C_1-4Alkoxy or
(Indicating halogen) (8) C_6-10Aralkyl groups (9) containing 1 to 3 nitrogen, oxygen or sulfur atoms
5- or 6-membered heteroaryl monocyclic ring or
Heteroaryl condensed with fused zen or pyridine ring
Condensed group (10) Contains 1 to 3 nitrogen, oxygen or sulfur atoms
Heteroaryl monocyclic C _1-4Alkyl or those and
Heteroaryl fused with benzene ring or pyridine ring
Fused ring C_1-4Alkyl group (11) carbamoyl group which may have a substituent (the substituent is a carbamoyl group which may be substituted;_1-4Alkyl
(The substituent may be halogen, hydroxy, amino, mono-
Or di-C_1-4Alkylamino or carbamoyl
Or (12) optionally substituted nitrogen, oxygen or
4- to 7-membered heterocyclyl containing one or two sulfur atoms
Rylcarbonyl group (the substituent may be hydroxy, amino, mono- or di-
-C_1-4Alkylamino, halogen, cyano, carbamo
Yl, carboxy, optionally substituted C_{1- Four}Archi
(The substituents are amino, hydroxy, carbamoyl,
Represents carboxy or phenyl), even if substituted
Good phenyl (the substituents are halogen, C_1-4Archi
Le, C_1-4Alkoxy or C_1-4Represents alkylthio)
And when the heterocyclyl contains an N atom,
May be substituted to be quaternized, and
When heterocyclyl contains an S atom, the S atom is
Even if it is oxo-ized to sulfoxide or sulfone
Good). A compound that is a group represented by｝. (A2d-1) In (A2d), R⁶Is a hydrogen atom,
Methyl, ethyl or propyl which may have a substituent
Group (the substituent is hydroxy, fluorine, chlorine,
No, methylamino, ethylamino, dimethylamino, di
Ethylamino, 2-aminoethylamino, 2-hydroxy
Ciethylamino, carbamoylmethylamino, carboxy
Cimethylamino, N- (2-aminoethyl) -N-methyl
Ruamino, N- (2-hydroxyethyl) -N-methyl
Amino, N-carbamoylmethyl-N-methylamino,
Bis (2-hydroxyethyl) amino), a substituent
An amino group which may have (the substituent is acetyl,
Optionally substituted methyl or ethyl (the substituent
Is fluorine, chlorine, hydroxy, amino, methylamino
, Ethylamino, dimethylamino, diethylamino
Or carbamoyl), pyridinecarbonyl, substituted
Optionally substituted benzoyl (the substituent is fluorine, salt
Represents methyl, methyl or methoxy),
Good phenyl, biphenyl or naphthyl (substituent
Represents fluorine, chlorine, methyl or methoxy),
Optionally substituted benzyl (the substituent is fluorine, salt
Represents methyl, methoxy or carbamoyl),
Optionally substituted carbamoyl (the substituent is methyl
, Ethyl or phenyl), even if substituted
Good thiocarbamoyl, wherein the substituent is methyl, ethyl or
Represents phenyl), optionally substituted benzenes
Rufonyl (the substituent is methyl, fluorine, chlorine or
Represents toxic), optionally substituted methyl or
Ethylsulfonyl (the substituents represent fluorine), thia
Zole, pyridine, benzothiazole, pyridylmethy
, Thienylmethyl, furfurylmethyl or benzoyl
Midazol-2-ylethyl), having a substituent
An optionally substituted methylthio or ethylthio group (the substituent
Is cyano, phenyl, carbamoyl, hydroxy or
Represents carboxy), cyclopentylthio or cyclo
Rohexylthio group, phenyl optionally having substituent (s)
A thio group (the substituent is methyl, methoxy, fluorine or
Chlorine)), a phenyl group which may have a substituent
(The substituent is carbamoyl, methoxy, fluorine or
Chlorine)), benzyl, pyridyl or thienyl
Group, a carbamoyl group which may have a substituent (the
The group is optionally substituted methyl or ethyl (such as
Substituents are halogen, hydroxy, amino, methylamino
, Ethylamino, dimethylamino, diethylamino
Or carbamoyl), which may have a substituent.
1-azetidinocarbonyl, 1-pyrrolidinocarbo
Nil or 1-piperidinocarbonyl group (the substituent is
Hydroxy, amino, methylamino, dimethylamino,
Diethylamino, fluorine, cyano, carbamoyl or
Represents carboxy), 1-py which may have a substituent
A perazinocarbonyl group (the substituent is methyl, ethyl,
2-hydroxyethyl, 2-aminoethyl, carbamoy
Methyl, 2-carbamoylethyl, carboxymethyl
Or benzyl, wherein the 4-position N atom of the piperazine is 4
Graded) or 4-morpholinocarboni
Or 4-thiomorpholinocarbonyl group (the thiomol
The S atom of holin is oxoated to give a sulfoxide or
Which may be rufone). (A2d-2) In (A2d), R⁶But hydrogen field
Child, methyl, phenyl, 4-pyridyl, methylthio, 4
-Methylphenylthio, 2-benzthiazolylamino,
2-naphthylamino, 4-fluorobenzoylamino,
Phenylthio, nicotinoylamino, isonicotinoyl
Amino, picolinoylamino, trifluoromethyl, amino
Mino, 2-thiazolylamino, 2-hydroxyethylthio
E, benzylthio, 2-fluoroethylamino, 2-a
Minoethylamino, methanesulfonylamino, triflu
Oromethanesulfonylamino or carbamoylmethyl
A compound that is an amino group. (A2e) A is a general formula

[0086]

Embedded image In the formula, R ⁷ represents (1) a C _1-4 alkyl group which may have a substituent (the substituent is carboxy, C _1-4 alkylsulfonylamino, carbamoyl, mono- or di-C _{1 -4} alkylcarbamoyl (the _C1-4 alkyl may be substituted by hydroxy or carbamoyl), amino,
Mono- or di-C _1-4 alkylamino, hydroxy, C _1-4 alkoxy, C _3-6 cycloalkyl or 4- to 6-membered heterocyclyl containing one or two nitrogen, oxygen or sulfur atoms. ) A C _6-10 aryl group which may have a substituent (the substituent may be a halogen, amino, mono- or di-
C _1-4 alkylamino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkanoylamino, carbamoyl or sulfamoyl) (3) It may have a substituent A 5- or 6-membered heteroaryl monocyclic ring containing 1 to 3 nitrogen, oxygen or sulfur atoms or a heteroaryl condensed ring obtained by condensing the same with a benzene ring or a pyridine ring (the substituent is halogen, C _1-4 Alkyl or C _1-4 alkoxy) (4) a C7-C14 aralkyl group which may have a substituent (the substituent may be halogen, amino, mono- or di-
C _1-4 alkylamino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkanoylamino, carbamoyl or sulfamoyl) (5) It may have a substituent A heteroaryl monocyclic C containing 1 to 3 nitrogen, oxygen or sulfur atoms
_1-4 alkyl or a heteroaryl condensed ring C _1-4 alkyl group in which a benzene ring or a pyridine ring is condensed thereto (the substituent represents halogen, C _1-4 alkyl or C _1-4 alkoxy) or (6 ) C _3-6 cycloalkyl group. A compound that is a group represented by｝. (A2e-1) In (A2e), R ⁷ is a C _1-4 alkyl group optionally having a substituent (the substituent is carboxy, methanesulfonylamino, carbamoyl, methylcarbamoyldimethylcarbamoyl, 2-hydroxy Ethylcarbamoyl, N- (2-hydroxyethyl) -N
-Methylcarbamoyl, amino, methylamino, ethylaminodimethylamino, diethylamino or hydroxy), a phenyl or naphthyl group which may have a substituent (the substituent is fluorine, chlorine, amino, methylamino, Ethylamino, dimethylamino, diethylamino, methyl, methoxy, methylthio, acetylamino, carbamoyl or sulfamoyl; a pyridyl group which may have a substituent (the substituent represents fluorine, chlorine, methyl or methoxy) ), A benzyl or phenethyl group which may have a substituent (the substituent is fluorine, chlorine, amino, methylamino, ethylamino, dimethylamino, diethylamino, methyl, methoxy, methylthio, acetylamino, carbamoyl or sulfamoyl) Shows ), Which may have a substituent pyridylmethyl or pyridylethyl group (said substituents are fluorine, chlorine, a methyl or methoxy), or cyclopentyl or compounds cyclohexyl. (A2e-2) In (A2e), R ⁷ is phenyl,
3-pyridyl, 3-methylphenyl, 3-fluorophenyl, 3,5-difluorobenzyl, carbamoylmethyl, 2- (methanesulfonylamino) ethyl, methyl,
4-dimethylaminophenyl, benzyl, 4-carbamoylphenyl, 4-sulfamoylphenyl, N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, 2-aminoethyl, carboxymethyl, N-
(2-hydroxyethyl) carbamoyl or N- (2
-Hydroxyethyl) -N-methylcarbamoylmethyl group.

Preferred compounds wherein A is (A3) are
(A3-1), and more preferably (A3-1)
It is a compound of 2). (A3-1) A is represented by (A3), n is 1 or 2, R ⁸ is a hydrogen atom, a methyl or ethyl group which may have a substituent (the substituent is Hydroxy, amino or carbamoyl), an allyl group, an optionally substituted phenyl or naphthyl group (the substituent represents fluorine, chlorine, methyl or methoxy), or an optionally substituted A good pyridyl, thiazolyl or benzothiazolyl group (the substituent represents fluorine, chlorine, methyl or methoxy), an optionally substituted benzyl or phenethyl group (the substituent is fluorine, chlorine, methyl or methoxy) A) optionally substituted pyridylmethyl, thiazolylmethyl, benzothiazolylmethyl or thiadiazolylmethyl group (the substituent is fluorine, chlorine A methyl or methoxy),
Or a cyclopentyl or cyclohexyl group, wherein R ⁹ is an optionally substituted amino group (the substituent is methyl, ethyl, 2-hydroxyethyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl or 2 -Represents carbamoylethyl),
Or a compound which is a pyrrolidine, piperidine, piperazine, morpholine, or thiomorpholine group (the substituent represents methyl or ethyl) which may have a substituent. (A3-2) A is represented by (A3), and n is 1 or 2
R ⁸ is a hydrogen atom, methyl, ethyl, 2-hydroxyethyl, 2-aminoethyl, carbamoylmethyl, allyl, phenyl, naphthyl, pyridyl, thiazolyl, benzothiazolyl, benzyl, phenethyl, pyridylmethyl, thiazolylmethyl, benzothia A zolylmethyl, thiadiazolylmethyl or cyclohexyl group, wherein R ⁹ is amino, methylamino, dimethylamino,
2-hydroxyethylamino, carboxymethylamino, carbamoylmethylamino, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl,
A compound which is a methylpiperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl group.

Preferred compounds wherein A is (A4) are
(A4-1), and more preferably (A4-1)
It is a compound of 2). (A4-1) A is represented by (A4), and R ^10a and R ^10b
Are the same or different and are a hydrogen atom, a fluorine or chlorine atom, a hydroxy group, a methyl or ethyl group, a methoxy or ethoxy group, an amino group which may have a substituent (the substituent is methyl, ethyl, acetyl , Aminoacetyl, N-methylaminoacetyl or N, N-dimethylaminoacetyl), a carboxy group, a methoxycarbonyl or ethoxycarbonyl group, a carbamoyl group which may have a substituent (the substituent is methyl or A compound which represents ethyl), a sulfamoyl group which may have a substituent (the substituent represents methyl or ethyl), a methyl or ethylsulfonyl group, or a ureido group. (A4-2) A is represented by (A4), and R ^10a and R ^10b
Are the same or different and are a hydrogen atom, a fluorine atom, a chlorine atom, hydroxy, methyl, methoxy, amino, methylamino, dimethylamino, acetylamino, aminoacetylamino, (N-methylaminoacetyl) amino,
(N, N-dimethylaminoacetyl) a compound which is an amino, carboxy, ethoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, sulfamoyl, methylsulfamoyl or methylsulfonyl group.

Preferred compounds wherein A is (A5) are
(A5-1), and more preferably (A5-1)
It is a compound of 2). (A5-1) A is represented by (A5), and R ¹¹ is a hydrogen atom, a methyl or ethyl group which may have a substituent (the substituent is hydroxy, amino, methylamino, ethylamino , Dimethylamino, diethylamino, carbamoyl, methylcarbamoyl, dimethylcarbamoyl,
Fluorine, chlorine or carboxy), an acetyl or propionyl group, a carbamoyl group which may have a substituent (the substituent represents methyl or ethyl), a C _6- which may have a substituent ₁₀ aryl groups (the substituents represent fluorine, chlorine, amino, methylamino, ethylamino, dimethylamino, diethylamino, methyl, ethyl, hydroxy, methoxy, ethoxy, methylthio, acetylamino, carbamoyl or sulfamoyl), substituents A thiazolyl or thiadiazolyl group which may have a substituent (the substituent represents fluorine, chlorine, methyl, ethyl or methoxy), or a benzyl or phenethyl group which may have a substituent (the substituent is Fluorine, chlorine, amino, methylamino, ethylamino, dimethylamino, diethyl Amino, methyl, ethyl, hydroxy, methoxy, ethoxy, methylthio, acetylamino, showing a carbamoyl or sulfamoyl), compound. (A5-2) A is represented by (A5), and R ¹¹ is methyl, ethyl, 2-hydroxyethyl, 2-aminoethyl, 2-methylaminoethyl, 2- (dimethylamino)
Ethyl, carbamoylmethyl, dimethylcarbamoylmethyl, 2-fluoroethyl, carboxymethyl, acetyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, phenyl, 4-chlorophenyl, 2,4-dimethylphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-hydroxyphenyl, 2-thiazolyl, 4
-Methylthiazol-2-yl, 2-methyl-1,3,4
-A compound which is a thiadiazol-5-yl or benzyl group.

Preferred compounds wherein A is (A6) are
(A6-1), more preferably (A6-1)
It is a compound of 2). (A6-1) A is represented by (A6), and R ^a and R
^b is the same or different and is a hydrogen atom, methyl, optionally substituted phenyl or optionally substituted benzothiazolyl group, or R ^a and R ^b are taken together as 1,8-naphthylene A compound that is a group. (A6-2) A is represented by (A6), and R ^a and R
Compounds in which ^b is the same or different and is phenyl or an optionally substituted benzothiazolyl group, or R ^a and R ^b together are a 1,8-naphthylene group.

In the compound represented by the general formula (I) of the present invention, the configuration at the 9-position and the 10-position are (9R, 10S) which is the same configuration as that of thienamycin.
The configuration at the α-position having a hydroxyl group of the position substituent is the R configuration,
Regarding the 8-position and 4-position, one or a mixture of isomers is shown. Preferred isomers are those in which the 8-position is in the S configuration. Specific examples of suitable compounds in the general formula (I) are shown in Tables 1 to 9 below. The abbreviations used in the table are as follows.

Me: methyl Et: ethyl nPr: normal propyl iPr: isopropyl nBu: normal butyl iBu: isobutyl sBu: secondary butyl tBu: tertiary butyl nPen: normal pentyl cPen: cyclopentyl nHex: normal hexyl cHex: cyclohexyl Nh : Naphthyl Imd: imidazolyl Trz: 1,2,4-triazolyl BiPh: biphenyl Pyd: pyridyl Thz: thiazolyl Tdz: 1,3,4-thiadiazolyl BThz: benzothiazolyl Qn: quinolyl Cbz: carbazolyl Dbf: dibenzofuranyl Oxn: oxobenzoyl : Fluorenyl PydThz: pyridothiazolyl Bn: benzyl PHE: phenethyl Thn: thienyl Fur: Ranyl Azt: azetidinyl Pyr: pyrrolidinyl Pip: piperidinyl Piz: piperazinyl Mor: morpholinyl Tmr: thiomorpholinyl Prz: pyrazinyl BImd: benzimidazolyl Ind: indolyl Ac: acetyl BThn: benzothienyl

[0093]

[Table 1]

[0094]

Embedded image -------------------------------------------------- ------- No. R ¹ R ² ------------------------------------- -------------------- 1-1 HH 1-2 H Me 1-3 H Et 1-4 H nPr 1-5 H iPr 1-6 H nBu 1 -7 H iBu 1-8 H sBu 1-9 H tBu 1-10 H nPen 1-11 H cPen 1-12 H nHex 1-13 H cHex 1-14 Me Me 1-15 Me Et 1-16 Me nPr 1 -17 Me iPr 1-18 Me nBu 1-19 Me iBu 1-20 Me sBu 1-21 Me tBu 1-22 Me nPen 1-23 Me cPen 1-24 Me nHex 1-25 Me cHex 1-26 Et Me 1 -27 Et Et 1-28 Et nPr 1-29 Et iPr 1-30 Et nBu 1-31 Et iBu 1-32 Et sBu 1-33 Et tBu 1-34 Et nPen 1-35 Et cPen 1-36 Et nHex 1 -37 Et cHex 1-38 nPr nPr 1-39 iPr iPr 1-40 nBu nBu 1-41 CH ₂ CH ₂ F Me 1-42 CH ₂ CH ₂ F Et 1-43 CH ₂ CN Me 1-44 CH ₂ CN Et 1-45 CH ₂ CH ₂ CN Me 1-46 CH ₂ CH ₂ CN Et 1-47 CH ₂ COOH Me 1-48 CH ₂ COOH Et 1-49 CH ₂ CH ₂ COOH Me 1-50 CH ₂ CH ₂ COOH Et 1-51 CH ₂ CONH ₂ Me 1-52 CH ₂ CONH ₂ Et 1-53 CH ₂ CH ₂ CONH ₂ Me 1-54 CH ₂ CH ₂ CONH ₂ Et 1-55 CH ₂ CH ₂ OH Me 1-56 CH ₂ CH ₂ OH Et 1-57 CH ₂ CH ₂ NH ₂ Me 1-58 CH ₂ CH ₂ NH ₂ Et 1-59 CH ₂ CH ₂ NHMe Me 1-60 CH ₂ C H ₂ NHMe Et 1-61 CH ₂ CH ₂ NMe ₂ Me 1-62 CH ₂ CH ₂ NMe ₂ Et 1-63 CH ₂ CH ₂ NHEt Me 1-64 CH ₂ CH ₂ NHEt Et 1-65 CH ₂ CH ₂ NEt ₂ Me 1-66 CH ₂ CH ₂ NEt ₂ Et 1-67 Ph Me 1-68 Ph Et 1-69 Ph CH ₂ CH ₂ F 1-70 Ph CH ₂ CN 1-71 Ph CH ₂ CH ₂ CN 1-72 Ph CH ₂ COOH 1-73 Ph CH ₂ CH ₂ COOH 1-74 Ph CH ₂ CONH ₂ 1-75 Ph CH ₂ CH ₂ CONH ₂ 1-76 Ph CH ₂ CH ₂ OH 1-77 Ph CH ₂ CH ₂ CH ₂ OH 1-78 Ph CH ₂ CH ₂ NH ₂ 1-79 Ph CH ₂ CH ₂ NHMe 1-80 Ph CH ₂ CH ₂ NMe ₂ 1-81 Ph CH ₂ CH ₂ NHEt 1-82 Ph CH ₂ CH ₂ NEt ₂ 1 -83 1-Np Me 1-84 1-Np Et 1-85 1-Np CH ₂ CH ₂ F 1-86 1-Np CH ₂ CH ₂ CN 1-87 1-Np CH ₂ CH ₂ OH 1-88 1 -Np CH ₂ CH ₂ CH ₂ OH 1-89 1-Np CH ₂ COOH 1-90 1-Np CH ₂ CONH ₂ 1-91 2-Np Me 1-92 2-Np Et 1-93 2-Np CH ₂ CH ₂ F 1-94 2-Np CH ₂ CH ₂ CN 1-95 2-Np CH ₂ CH ₂ OH 1-96 2-Np CH ₂ CH ₂ CH ₂ OH 1-97 2-Np CH ₂ COOH 1-98 2-Np CH ₂ CONH ₂ 1-99 3-F-Ph Me 1-100 3-F-Ph Et 1-101 3-F-Ph CH ₂ CH ₂ F 1-102 3-F-Ph CH ₂ CH ₂ CN 1-103 3-F-Ph CH ₂ CH ₂ OH 1-104 3-F-Ph CH ₂ CH ₂ CH ₂ OH 1-105 3-F-Ph CH ₂ COOH 1-106 3-F-Ph CH ₂ CONH ₂ 1- 107 4-F-Ph Me 1-108 4-F-Ph Et 1-109 4-F-Ph CH ₂ CH ₂ F 1-110 4-F-Ph CH ₂ CH ₂ CN 1-111 4-F-Ph CH ₂ CH ₂ OH 1-112 4-F-Ph CH ₂ CH ₂ CH ₂ OH 1-113 4-F-Ph CH ₂ COOH 1-114 4-F-Ph CH ₂ CONH ₂ 1-115 3-Cl- Ph Me 1-116 3-Cl-Ph Et 1-117 3-Cl-Ph CH ₂ CH ₂ F 1-118 3-Cl-Ph CH ₂ CH ₂ CN 1-119 3-Cl-Ph CH ₂ CH ₂ OH 1-120 3-Cl-Ph CH ₂ CH ₂ CH ₂ OH 1-121 3-Cl-Ph CH ₂ COOH 1-122 3-Cl-Ph CH ₂ CONH ₂ 1-123 4-Cl-Ph Me 1-124 4-Cl-Ph Et 1-125 4-Cl-Ph CH ₂ CH ₂ F 1-126 4-Cl-Ph CH ₂ CH ₂ CN 1-127 4-Cl-Ph CH ₂ CH ₂ OH 1-128 4- Cl-Ph CH ₂ CH ₂ CH ₂ OH 1-129 4-Cl-Ph CH ₂ COOH 1-130 4-Cl-Ph CH ₂ CONH ₂ 1-131 3-CF ₃ -Ph Me 1-132 3-CF ₃ -Ph Et 1-133 3-CF ₃ -Ph CH ₂ CH ₂ F 1-134 3-CF ₃ -Ph CH ₂ CH ₂ CN 1-135 3-CF ₃ -Ph CH ₂ CH ₂ OH 1-136 3- CF ₃ -Ph CH ₂ CH ₂ CH ₂ OH 1-137 3-CF ₃ -Ph CH ₂ COOH 1-138 3-CF ₃ -Ph CH ₂ CONH ₂ 1-139 4-CF ₃ -Ph Me 1-140 4 -CF ₃ -Ph Et 1-141 4-CF ₃ -Ph CH ₂ CH ₂ F 1-142 4-CF ₃ -Ph CH ₂ CH ₂ CN 1-143 4-CF ₃ -Ph CH ₂ CH ₂ OH 1- 144 4-CF ₃ -Ph CH ₂ CH ₂ CH ₂ OH 1-145 4-CF ₃ -Ph CH ₂ COOH 1-146 4-CF ₃ -Ph CH ₂ CONH ₂ 1-147 4-CONH ₂ -Ph Me 1-148 4-CONH ₂ -Ph Et 1-149 4-CONH ₂ -Ph CH ₂ CH ₂ F 1-150 4-CONH ₂ -Ph CH ₂ CH ₂ CN 1-151 4-CONH ₂ -Ph CH ₂ CH ₂ OH 1-152 4-CONH ₂ -Ph CH ₂ CH ₂ CH ₂ OH 1-153 4-CONH ₂ -Ph CH ₂ COOH 1-154 4-CONH ₂ -Ph CH ₂ CONH ₂ 1-155 4-SONH ₂ -Ph Me 1-156 4-SONH ₂ -Ph Et 1-157 4-SONH ₂ -Ph CH ₂ CH ₂ F 1-158 4-SONH ₂ -Ph CH ₂ CH ₂ CN 1-159 4-SONH ₂ -Ph CH ₂ CH ₂ OH 1-160 4-SONH ₂ -Ph CH ₂ CH ₂ CH ₂ OH 1-161 4-SONH ₂ -Ph CH ₂ COOH 1-162 4-SONH ₂ -Ph CH ₂ CONH ₂ 1-163 4-COOH-Ph Me 1-164 4-COOH-Ph Et 1-165 4-COOH-Ph CH ₂ CH ₂ F 1-166 4-COOH -Ph CH ₂ CH ₂ CN 1-167 4-COOH-Ph CH ₂ CH ₂ OH 1-168 4-COOH-Ph CH ₂ CH ₂ CH ₂ OH 1-169 4-COOH-Ph CH ₂ COOH 1-170 4 -COOH-Ph CH ₂ CONH ₂ 1-171 4-OMe-Ph Me 1-172 4-OMe-Ph Et 1-173 4-OMe-Ph CH ₂ CH ₂ F 1-174 4-OMe-Ph CH ₂ CH ₂ CN 1-175 4-OMe-Ph CH ₂ CH ₂ OH 1-176 4-OMe-Ph CH ₂ CH ₂ CH ₂ OH 1-177 4-OMe-Ph CH ₂ COOH 1-178 4-OMe-Ph CH ₂ CONH ₂ 1-179 4-NMe ₂ -Ph Me 1-180 4-NMe ₂ -Ph Et 1-181 4-NMe ₂ -Ph CH ₂ CH ₂ F 1-182 4-NMe ₂ -Ph CH ₂ CH ₂ CN 1-183 4-NMe ₂ -Ph CH ₂ CH ₂ OH 1-184 4-NMe ₂ -Ph CH ₂ CH ₂ CH ₂ OH 1-185 4-NMe ₂ -Ph CH ₂ COOH 1-186 4- NMe ₂ -Ph CH ₂ CONH ₂ 1-187 4-Imd-Ph Me 1-188 4-Imd-Ph Et 1-189 4-Imd-Ph CH ₂ CH ₂ F 1-190 4-Imd-Ph CH ₂ CH ₂ CN 1-191 4-Imd-Ph CH ₂ CH ₂ OH 1-192 4-Imd-Ph CH ₂ CH ₂ CH ₂ OH 1-193 4-Imd-Ph CH ₂ COOH 1-194 4-Imd-Ph CH ₂ CONH ₂ 1-195 4-Trz-Ph Me 1-196 4-Trz-Ph Et 1-197 4-Trz-Ph CH ₂ CH ₂ F 1-198 4-Trz-Ph CH ₂ CH ₂ CN 1-199 4-Trz-Ph CH ₂ CH ₂ OH 1-200 4-Trz-Ph CH ₂ CH ₂ CH ₂ OH 1-201 4-Trz-Ph CH ₂ COOH 1-202 4-Trz-Ph CH ₂ CONH ₂ 1- 203 4-BiPh Me 1-204 4-BiPh Et 1-205 4-BiPh CH ₂ CH ₂ F 1-206 4-BiPh CH ₂ CH ₂ CN 1-207 4-BiPh CH ₂ CH ₂ OH 1-208 4- BiPh CH ₂ CH ₂ CH ₂ OH 1-209 4-BiPh CH ₂ COOH 1-210 4-BiPh CH ₂ CONH ₂ 1-211 2-Pyd Me 1-212 2-Pyd Et 1-213 2-Pyd CH ₂ CH ₂ F 1-214 2-Pyd CH ₂ CH ₂ CN 1-215 2-Pyd CH ₂ CH ₂ OH 1-216 2-Pyd CH ₂ CH ₂ CH ₂ OH 1-217 2-Pyd CH ₂ COOH 1-218 2 -Pyd CH ₂ CONH ₂ 1-219 3-Pyd Me 1-220 3-Pyd Et 1-221 3-Pyd CH ₂ CH ₂ F 1-222 3-Pyd CH ₂ CH ₂ CN 1-223 3-Pyd CH ₂ CH ₂ OH 1-224 3-Pyd CH ₂ CH ₂ CH ₂ OH 1-225 3-Pyd CH ₂ COOH 1-226 3-Pyd CH ₂ CONH ₂ 1-227 4-Pyd Me 1-228 4-Pyd Et 1-229 4-Pyd CH ₂ CH ₂ F 1-230 4-Pyd CH ₂ CH ₂ CN 1-231 4-Pyd CH ₂ CH ₂ OH 1-232 4-Pyd CH ₂ CH ₂ CH ₂ OH 1-233 4-Pyd CH ₂ COOH 1-234 4-Pyd CH ₂ CONH ₂ 1-235 2-Thz Me 1-236 2-Thz Et 1-237 2-Thz CH ₂ CH ₂ F 1-238 2-Thz CH ₂ CH ₂ CN 1-239 2-Thz CH ₂ CH ₂ OH 1-240 2-Thz CH ₂ CH ₂ CH ₂ OH 1-241 2-Thz CH ₂ COOH 1-242 2-Thz CH ₂ CONH ₂ 1-243 4, 5-diMe-2-Thz Me 1-244 4,5-diMe-2-Thz Et 1-245 4,5-diMe-2-Thz CH ₂ CH ₂ F 1-246 4,5-diMe-2-Thz CH ₂ CH ₂ CN 1-247 4,5-diMe-2-Thz CH ₂ CH ₂ OH 1-248 4,5-diMe-2-Thz CH ₂ CH ₂ CH ₂ OH 1-249 4,5-diMe- 2-Thz CH ₂ COOH 1-250 4,5-diMe-2-Thz CH ₂ CONH ₂ 1-251 4-Ph-2-Thz Me 1-252 4-Ph-2-Thz Et 1-253 4-Ph -2-Thz CH ₂ CH ₂ F 1-254 4-Ph-2-Thz CH ₂ CH ₂ CN 1-255 4-Ph-2-Thz CH ₂ CH ₂ OH 1-256 4-Ph-2-Thz CH ₂ CH ₂ CH ₂ OH 1-257 4-Ph-2-Thz CH ₂ COOH 1-258 4-Ph-2-Thz CH ₂ CONH ₂ 1-259 4-Ph-5-Me-2-Thz Me 1- 260 4-Ph-5-Me-2-Thz Et 1-261 4-Ph-5-Me-2-Thz CH ₂ C H ₂ F 1-262 4-Ph-5-Me-2-Thz CH ₂ CH ₂ CN 1-263 4-Ph-5-Me-2-Thz CH ₂ CH ₂ OH 1-264 4-Ph-5- Me-2-Thz CH ₂ CH ₂ CH ₂ OH 1-265 4-Ph-5-Me-2-Thz CH ₂ COOH 1-266 4-Ph-5-Me-2-Thz CH ₂ CONH ₂ 1-267 5-CONH ₂ -2-Thz Me 1-268 5-CONH ₂ -2-Thz Et 1-269 5-CONH ₂ -2-Thz CH ₂ CH ₂ F 1-270 5-CONH ₂ -2-Thz CH ₂ CH ₂ CN 1-271 5-CONH ₂ -2-Thz CH ₂ CH ₂ OH 1-272 5-CONH ₂ -2-Thz CH ₂ CH ₂ CH ₂ OH 1-273 5-CONH ₂ -2-Thz CH ₂ COOH 1-274 5-CONH ₂ -2-Thz CH ₂ CONH ₂ 1-275 2-Tdz Me 1-276 2-Tdz Et 1-277 2-Tdz CH ₂ CH ₂ F 1-278 2-Tdz CH ₂ CH ₂ CN 1-279 2-Tdz CH ₂ CH ₂ OH 1-280 2-Tdz CH ₂ CH ₂ CH ₂ OH 1-281 2-Tdz CH ₂ COOH 1-282 2-Tdz CH ₂ CONH ₂ 1-283 5- SEt-2-Tdz Me 1-284 5-SEt-2-Tdz Et 1-285 5-SEt-2-Tdz CH ₂ CH ₂ F 1-286 5-SEt-2-Tdz CH ₂ CH ₂ CN 1-287 5-SEt-2-Tdz CH ₂ CH ₂ OH 1-288 5-SEt-2-Tdz CH ₂ CH ₂ CH ₂ OH 1-289 5-SEt-2-Tdz CH ₂ COOH 1-290 5-SEt-2 -Tdz CH ₂ CONH ₂ 1-291 5-CONH ₂ -2-Tdz Me 1-292 5-CONH ₂ -2-Tdz Et 1-293 5-CONH ₂ -2-Tdz CH ₂ CH ₂ F 1-294 5 -CONH ₂ -2-Tdz CH ₂ CH ₂ CN 1-295 5-CONH ₂ -2-Tdz CH ₂ CH ₂ OH 1-296 5-CONH ₂ -2-Tdz CH ₂ CH ₂ CH ₂ OH 1-297 5-CONH ₂ -2-Tdz CH ₂ COOH 1-298 5-CONH ₂ -2-Tdz CH ₂ CONH ₂ 1- 299 5-Me-2-Tdz Me 1-300 5-Me-2-Tdz Et 1-301 5-Me-2-Tdz CH ₂ CH ₂ F 1-302 5-Me-2-Tdz CH ₂ CH ₂ CN 1-303 5-Me-2-Tdz CH ₂ CH ₂ OH 1-304 5-Me-2-Tdz CH ₂ CH ₂ CH ₂ OH 1-305 5-Me-2-Tdz CH ₂ COOH 1-306 5- Me-2-Tdz CH ₂ CONH ₂ 1-307 5-Ph-2-Tdz Me 1-308 5-Ph-2-Tdz Et 1-309 5-Ph-2-Tdz CH ₂ CH ₂ F 1-310 5 -Ph-2-Tdz CH ₂ CH ₂ CN 1-311 5-Ph-2-Tdz CH ₂ CH ₂ OH 1-312 5-Ph-2-Tdz CH ₂ CH ₂ CH ₂ OH 1-313 5-Ph- 2-Tdz CH ₂ COOH 1-314 5-Ph-2-Tdz CH ₂ CONH ₂ 1-315 5- (3-Pyd) -2-Tdz Me 1-316 5- (3-Pyd) -2-Tdz Et 1-317 5- (3-Pyd) -2-Tdz CH ₂ CH ₂ F 1-318 5- (3-Pyd) -2-Tdz CH ₂ CH ₂ CN 1-319 5- (3-Pyd) -2 -Tdz CH ₂ CH ₂ OH 1-320 5- (3-Pyd) -2-Tdz CH ₂ CH ₂ CH ₂ OH 1-321 5- (3-Pyd) -2-Tdz CH ₂ COOH 1-322 5- (3-Pyd) -2-Tdz CH ₂ CONH ₂ 1-323 5- (4-Pyd) -2-Tdz Me 1-324 5- (4-Pyd) -2-Tdz Et 1-325 5- (4 -Pyd) -2-Tdz CH ₂ CH ₂ F 1-326 5- (4-Pyd) -2-Tdz CH ₂ CH ₂ CN 1-327 5- (4-Pyd) -2-Tdz CH ₂ CH ₂ OH 1-328 5- (4-Pyd) -2-Tdz CH ₂ CH ₂ CH ₂ OH 1-329 5- (4-Pyd) -2-Tdz CH ₂ COOH 1-330 5- (4-Pyd) -2-Tdz CH ₂ CONH ₂ 1-331 2-BThz Me 1-332 2-BThz Et 1-333 2-BThz CH ₂ CH ₂ F 1-334 2-BThz CH ₂ CH ₂ CN 1-335 2-BThz CH ₂ CH ₂ OH 1-336 2-BThz CH ₂ CH ₂ CH ₂ OH 1-337 2 -BThz CH ₂ COOH 1-338 2-BThz CH ₂ CONH ₂ 1-339 6-OMe-2-BThz Me 1-340 6-OMe-2-BThz Et 1-341 6-OMe-2-BThz CH ₂ CH ₂ F 1-342 6-OMe-2-BThz CH ₂ CH ₂ CN 1-343 6-OMe-2-BThz CH ₂ CH ₂ OH 1-344 6-OMe-2-BThz CH ₂ CH ₂ CH ₂ OH 1 -345 6-OMe-2-BThz CH ₂ COOH 1-347 6-OMe-2-BThz CH ₂ CONH ₂ 1-348 6-MeSO ₂ -2-BThz Me 1-349 6-MeSO ₂ -2-BThz Et 1-350 6-MeSO ₂ -2-BThz CH ₂ CH ₂ F 1-351 6-MeSO ₂ -2-BThz CH ₂ CH ₂ CN 1-352 6-MeSO ₂ -2-BThz CH ₂ CH ₂ OH 1- 353 6-MeSO ₂ -2-BThz CH ₂ CH ₂ CH ₂ OH 1-354 6-MeSO ₂ -2-BThz CH ₂ COOH 1-355 6-MeSO ₂ -2-BThz CH ₂ CONH ₂ 1-356 6- CONH ₂ -2-BThz Me 1-357 6-CONH ₂ -2-BThz Et 1-358 6-CONH ₂ -2-BThz CH ₂ CH ₂ F 1-359 6-CONH ₂ -2-BThz CH ₂ CH ₂ CN 1-360 6-CONH ₂ -2-BThz CH ₂ CH ₂ OH 1-361 6-CONH ₂ -2-BThz CH ₂ CH ₂ CH ₂ OH 1-362 6-CONH ₂ -2-BThz CH ₂ COOH 1 -363 6-CONH ₂ -2-BThz CH ₂ CONH ₂ 1-364 6-Qn Me 1-365 6-Qn Et 1-366 6-Qn CH ₂ CH ₂ F 1-367 6-Qn CH ₂ CH ₂ CN 1- 368 6-Qn CH ₂ CH ₂ OH 1-369 6-Qn CH ₂ CH ₂ CH ₂ OH 1-370 6-Qn CH ₂ COOH 1-371 3-Cbz Me 1-372 3-Cbz Et 1-373 3- Cbz CH ₂ CH ₂ F 1-374 3-Cbz CH ₂ CH ₂ CN 1-375 3-Cbz CH ₂ CH ₂ OH 1-376 3-Cbz CH ₂ CH ₂ CH ₂ OH 1-377 3-Cbz CH ₂ COOH 1-378 9-Me-3-Cbz CH ₂ CONH ₂ 1-379 9-Me-3-Cbz Me 1-380 9-Me-3-Cbz Et 1-381 9-Me-3-Cbz CH ₂ CH ₂ F 1-382 9-Me-3-Cbz CH ₂ CH ₂ CN 1-383 9-Me-3-Cbz CH ₂ CH ₂ OH 1-384 9-Me-3-Cbz CH ₂ CH ₂ CH ₂ OH 1- 385 9-Me-3-Cbz CH ₂ COOH 1-386 9-Me-3-Cbz CH ₂ CONH ₂ 1-387 2-Dbf Me 1-388 2-Dbf Et 1-389 2-Dbf CH ₂ CH ₂ F 1-390 2-Dbf CH ₂ CH ₂ CN 1-391 2-Dbf CH ₂ CH ₂ OH 1-392 2-Dbf CH ₂ CH ₂ CH ₂ OH 1-393 2-Dbf CH ₂ COOH 1-394 2-Dbf CH ₂ CONH ₂ 1-395 9-Ox-2-Fln Me 1-396 9-Ox-2-Fln Et 1-397 9-Ox-2-Fln CH ₂ CH ₂ F 1-398 9-Ox-2- Fln CH ₂ CH ₂ CN 1-399 9-Ox-2-Fln CH ₂ CH ₂ OH 1-400 9-Ox-2-Fln CH ₂ CH ₂ CH ₂ OH 1-401 9-Ox-2-Fln CH ₂ COOH 1-402 9-Ox-2-Fln CH ₂ CONH ₂ 1-403 2-PydThz M e 1-404 2-PydThz Et 1-405 2-PydThz CH ₂ CH ₂ F 1-406 2-PydThz CH ₂ CH ₂ CN 1-407 2-PydThz CH ₂ CH ₂ OH 1-408 2-PydThz CH ₂ CH ₂ CH ₂ OH 1-409 2-PydThz CH ₂ COOH 1-410 2-PydThz CH ₂ CONH ₂ 1-411 Bn Me 1-412 Bn Et 1-413 Bn CH ₂ CH ₂ F 1-414 Bn CH ₂ CH ₂ CN 1-415 Bn CH ₂ CH ₂ OH 1-416 Bn CH ₂ CH ₂ CH ₂ OH 1-417 Bn CH ₂ COOH 1-418 Bn CH ₂ CONH ₂ 1-419 PHE Me 1-420 PHE Et 1-421 PHE _{CH 2 CH 2 F 1-422 PHE CH} 2 CH 2 CN 1-423 PHE CH 2 CH 2 OH 1-424 PHE CH 2 CH 2 CH 2 OH 1-425 PHE CH 2 COOH 1-426 PHE CH 2 CONH 2 1 -427 CH ₂ (1-Np) Me 1-428 CH ₂ (1-Np) Et 1-429 CH ₂ (1-Np) CH ₂ CH ₂ F 1-430 CH ₂ (1-Np) CH ₂ CH ₂ CN 1-431 CH ₂ (1-Np) CH ₂ CH ₂ OH 1-432 CH ₂ (1-Np) CH ₂ CH ₂ CH ₂ OH 1-433 CH ₂ (1-Np) CH ₂ COOH 1-434 CH ₂ (1-Np) CH ₂ CONH ₂ 1-435 CH ₂ (2-Np) Me 1-436 CH ₂ (2-Np) Et 1-437 CH ₂ (2-Np) CH ₂ CH ₂ F 1-438 CH ₂ (2-Np) CH ₂ CH ₂ CN 1-439 CH ₂ (2-Np) CH ₂ CH ₂ OH 1-440 CH ₂ (2-Np) CH ₂ CH ₂ CH ₂ OH 1-441 CH ₂ ( 2-Np) CH ₂ COOH 1-442 CH ₂ (2-Np) CH ₂ CONH ₂ 1-443 CH ₂ CH ₂ (1-Np) Me 1-444 CH ₂ CH ₂ (1-Np) Et 1-445 CH ₂ CH ₂ (1-Np) CH ₂ CH ₂ F 1-446 CH ₂ CH ₂ (1-Np) CH ₂ CH ₂ CN 1-447 CH ₂ CH ₂ ( 1-Np) CH ₂ CH ₂ OH 1-448 CH ₂ CH ₂ (1-Np) CH ₂ CH ₂ CH ₂ OH 1-449 CH ₂ CH ₂ (1-Np) CH ₂ COOH 1-450 CH ₂ CH ₂ (1-Np) CH ₂ CONH ₂ 1-451 CH ₂ CH ₂ (2-Np) Me 1-452 CH ₂ CH ₂ (2-Np) Et 1-453 CH ₂ CH ₂ (2-Np) CH ₂ CH ₂ F 1-454 CH ₂ CH ₂ (2-Np) CH ₂ CH ₂ CN 1-455 CH ₂ CH ₂ (2-Np) CH ₂ CH ₂ OH 1-456 CH ₂ CH ₂ (2-Np) CH ₂ CH ₂ CH ₂ OH 1-457 CH ₂ CH ₂ (2-Np) CH ₂ COOH 1-458 CH ₂ CH ₂ (2-Np) CH ₂ CONH ₂ 1-459 3-F-Bn Me 1-460 3- F-Bn Et 1-461 3-F-Bn CH ₂ CH ₂ F 1-462 3-F-Bn CH ₂ CH ₂ CN 1-463 3-F-Bn CH ₂ CH ₂ OH 1-464 3-F- Bn CH ₂ CH ₂ CH ₂ OH 1-465 3-F-Bn CH ₂ COOH 1-466 3-F-Bn CH ₂ CONH ₂ 1-467 4-F-Bn Me 1-468 4-F-Bn Et 1 -469 4-F-Bn CH ₂ CH ₂ F 1-470 4-F-Bn CH ₂ CH ₂ CN 1-471 4-F-Bn CH ₂ CH ₂ OH 1-472 4-F-Bn CH ₂ CH ₂ CH ₂ OH 1-473 4-F-Bn CH ₂ COOH 1-474 4-F-Bn CH ₂ CONH ₂ 1-475 3-Cl-Bn Me 1-476 3-Cl-Bn Et 1-477 3-Cl -Bn CH ₂ CH ₂ F 1-478 3-Cl-Bn CH ₂ CH ₂ CN 1-479 3-Cl-Bn CH ₂ CH ₂ OH 1-480 3-Cl -Bn CH ₂ CH ₂ CH ₂ OH 1-481 3-Cl-Bn CH ₂ COOH 1-482 3-Cl-Bn CH ₂ CONH ₂ 1-483 4-Cl-Bn Me 1-484 4-Cl-Bn Et 1-485 4-Cl-Bn CH ₂ CH ₂ F 1-486 4-Cl-Bn CH ₂ CH ₂ CN 1-487 4-Cl-Bn CH ₂ CH ₂ OH 1-488 4-Cl-Bn CH ₂ CH ₂ CH ₂ OH 1-489 4-Cl-Bn CH ₂ COOH 1-490 4-Cl-Bn CH ₂ CONH ₂ 1-500 3-CF ₃ -Bn Me 1-501 3-CF ₃ -Bn Et 1-502 3-CF ₃ -Bn CH ₂ CH ₂ F 1-503 3-CF ₃ -Bn CH ₂ CH ₂ CN 1-504 3-CF ₃ -Bn CH ₂ CH ₂ OH 1-505 3-CF ₃ -Bn CH ₂ CH ₂ CH ₂ OH 1-506 3-CF ₃ -Bn CH ₂ COOH 1-507 3-CF ₃ -Bn CH ₂ CONH ₂ 1-508 4-CF ₃ -Bn Me 1-509 4-CF ₃ -Bn Et 1-510 4-CF ₃ -Bn CH ₂ CH ₂ F 1-511 4-CF ₃ -Bn CH ₂ CH ₂ CN 1-512 4-CF ₃ -Bn CH ₂ CH ₂ OH 1-513 4-CF _3- Bn CH ₂ CH ₂ CH ₂ OH 1-514 4-CF ₃ -Bn CH ₂ COOH 1-515 4-CF ₃ -Bn CH ₂ CONH ₂ 1-516 4-CONH ₂ -Bn Me 1-517 4-CONH ₂ -Bn Et 1-518 4-CONH ₂ -Bn CH ₂ CH ₂ F 1-519 4-CONH ₂ -Bn CH ₂ CH ₂ CN 1-520 4-CONH ₂ -Bn CH ₂ CH ₂ OH 1-521 4- CONH ₂ -Bn CH ₂ CH ₂ CH ₂ OH 1-522 4-CONH ₂ -Bn CH ₂ COOH 1-523 4-CONH ₂ -Bn CH ₂ CONH ₂ 1-524 4-SONH ₂ -Bn Me 1-525 4 -SONH ₂ -Bn Et 1-526 4-SONH ₂ -Bn CH ₂ CH ₂ F 1-527 4-SONH ₂ -Bn CH ₂ CH ₂ CN 1-528 4-SONH ₂ -Bn CH ₂ CH ₂ OH 1-529 4-SONH ₂ -Bn CH ₂ CH ₂ CH ₂ OH 1-530 4-SONH ₂ -Bn CH ₂ COOH 1-531 4-SONH ₂ -Bn CH ₂ CONH ₂ 1-532 4-COOH-Bn Me 1-533 4-COOH-Bn Et 1-534 4- COOH-Bn CH ₂ CH ₂ F 1-535 4-COOH-Bn CH ₂ CH ₂ CN 1-536 4-COOH-Bn CH ₂ CH ₂ OH 1-537 4-COOH-Bn CH ₂ CH ₂ CH ₂ OH 1 -538 4-COOH-Bn CH ₂ COOH 1-539 4-COOH-Bn CH ₂ CONH ₂ 1-540 4-COOEt-Bn Me 1-541 4-COOEt-Bn Et 1-542 4-COOEt-Bn CH ₂ CH ₂ F 1-543 4-COOEt-Bn CH ₂ CH ₂ CN 1-544 4-COOEt-Bn CH ₂ CH ₂ OH 1-545 4-COOEt-Bn CH ₂ CH ₂ CH ₂ OH 1-546 4-COOEt -Bn CH ₂ COOH 1-547 4-COOEt-Bn CH ₂ CONH ₂ 1-548 4-OMe-Bn Me 1-549 4-OMe-Bn Et 1-550 4-OMe-Bn CH ₂ CH ₂ F 1- 551 4-OMe-Bn CH ₂ CH ₂ CN 1-552 4-OMe-Bn CH ₂ CH ₂ OH 1-553 4-OMe-Bn CH ₂ CH ₂ CH ₂ OH 1-554 4-OMe-Bn CH ₂ COOH 1-555 4-OMe-Bn CH ₂ CONH ₂ 1-556 4-NMe ₂ -Bn Me 1-557 4-NMe ₂ -Bn Et 1-558 4-NMe ₂ -Bn CH ₂ CH ₂ F 1-559 4 -NMe ₂ -Bn CH ₂ CH ₂ CN 1-560 4-NMe ₂ -Bn CH ₂ CH ₂ OH 1-561 4-NMe ₂ -Bn CH ₂ CH ₂ CH ₂ OH 1-562 4-NMe ₂ -Bn CH ₂ COOH 1-563 4-NMe ₂ -Bn CH ₂ CONH ₂ 1-564 4-Imd-Bn Me 1-565 4-Imd-Bn Et 1-566 4-Imd-Bn CH ₂ CH ₂ F 1 -567 4-Imd-Bn CH ₂ CH ₂ CN 1-568 4-Imd-Bn CH ₂ CH ₂ OH 1-569 4-Imd-Bn CH ₂ CH ₂ CH ₂ OH 1-570 4-Imd-Bn CH ₂ COOH 1-571 4-Imd-Bn CH ₂ CONH ₂ 1-572 4-Trz-Bn Me 1-573 4-Trz-Bn Et 1-574 4-Trz-Bn CH ₂ CH ₂ F 1-575 4-Trz -Bn CH ₂ CH ₂ CN 1-576 4-Trz-Bn CH ₂ CH ₂ OH 1-577 4-Trz-Bn CH ₂ CH ₂ CH ₂ OH 1-578 4-Trz-Bn CH ₂ COOH 1-579 4 -Trz-Bn CH ₂ CONH ₂ 1-580 CH ₂ (2-Pyd) Me 1-581 CH ₂ (2-Pyd) Et 1-582 CH ₂ (2-Pyd) CH ₂ CH ₂ F 1-583 CH ₂ (2-Pyd) CH ₂ CH ₂ CN 1-584 CH ₂ (2-Pyd) CH ₂ CH ₂ OH 1-585 CH ₂ (2-Pyd) CH ₂ CH ₂ CH ₂ OH 1-586 CH ₂ (2- Pyd) CH ₂ COOH 1-587 CH ₂ (2-Pyd) CH ₂ CONH ₂ 1-589 CH ₂ (3-Pyd) Me 1-590 CH ₂ (3-Pyd) Et 1-591 CH ₂ (3-Pyd ) CH ₂ CH ₂ F 1-592 CH ₂ (3-Pyd) CH ₂ CH ₂ CN 1-593 CH ₂ (3-Pyd) CH ₂ CH ₂ OH 1-594 CH ₂ (3-Pyd) CH ₂ CH ₂ CH ₂ OH 1-595 CH ₂ (3-Pyd) CH ₂ COOH 1-596 CH ₂ (3-Pyd) CH ₂ CONH ₂ 1-597 CH ₂ (4-Pyd) Me 1-598 CH ₂ (4-Pyd ) Et 1-599 CH ₂ (4-Pyd) CH ₂ CH ₂ F 1 -600 CH ₂ (4-Pyd) CH ₂ CH ₂ CN 1-601 CH ₂ (4-Pyd) CH ₂ CH ₂ OH 1-602 CH ₂ (4-Pyd) CH ₂ CH ₂ CH ₂ OH 1-603 CH ₂ (4-Pyd) CH ₂ COOH 1-604 CH ₂ (4-Pyd) CH ₂ CONH ₂ 1-605 CH ₂ (2-Thn) Me 1-606 CH ₂ (2-Thn) Et 1-607 CH ₂ (2-Thn) CH ₂ CH ₂ F 1-608 CH ₂ (2-Thn) CH ₂ CH ₂ CN 1-609 CH ₂ (2-Thn) CH ₂ CH ₂ OH 1-610 CH ₂ (2-Thn) CH ₂ CH ₂ CH ₂ OH 1-611 CH ₂ (2-Thn) CH ₂ COOH 1-612 CH ₂ (2-Thn) CH ₂ CONH ₂ 1-613 CH ₂ (2-Fur) Me 1-614 CH ₂ (2-Fur) Et 1-615 CH ₂ (2-Fur) CH ₂ CH ₂ F 1-616 CH ₂ (2-Fur) CH ₂ CH ₂ CN 1-617 CH ₂ (2-Fur) CH ₂ CH ₂ OH 1-618 CH ₂ (2-Fur) CH ₂ CH ₂ CH ₂ OH 1-619 CH ₂ (2-Fur) CH ₂ COOH 1-620 CH ₂ (2-Fur) CH ₂ CONH ₂ 1-621 CH ₂ CH ₂ (2-Pyd) Me 1-622 CH ₂ CH ₂ (2-Pyd) Et 1-623 CH ₂ CH ₂ (2-Pyd) CH ₂ CH ₂ F 1-624 CH ₂ CH ₂ (2-Pyd) CH ₂ CH ₂ CN 1-625 CH ₂ CH ₂ (2-Pyd) CH ₂ CH ₂ OH 1-626 CH ₂ CH ₂ (2-Pyd) CH ₂ CH ₂ CH ₂ OH 1-627 CH ₂ CH ₂ (2 -Pyd) CH ₂ COOH 1-628 CH ₂ CH ₂ (2-Pyd) CH ₂ CONH ₂ 1-629 CH ₂ CH ₂ (3-Pyd) Me 1-630 CH ₂ CH ₂ (3-Pyd) Et 1- 631 CH ₂ CH ₂ (3-Pyd) CH ₂ CH ₂ F 1- 632 CH ₂ CH ₂ (3-Pyd) CH ₂ CH ₂ CN 1-633 CH ₂ CH ₂ (3-Pyd) CH ₂ CH ₂ OH 1-634 CH ₂ CH ₂ (3-Pyd) CH ₂ CH ₂ CH ₂ OH 1-635 CH ₂ CH ₂ (3-Pyd) CH ₂ COOH 1-636 CH ₂ CH ₂ (3-Pyd) CH ₂ CONH ₂ 1-637 CH ₂ CH ₂ (4-Pyd) Me 1-638 CH ₂ CH ₂ (4-Pyd) Et 1-639 CH ₂ CH ₂ (4-Pyd) CH ₂ CH ₂ F 1-640 CH ₂ CH ₂ (4-Pyd) CH ₂ CH ₂ CN 1-641 CH ₂ CH ₂ ( 4-Pyd) CH ₂ CH ₂ OH 1-642 CH ₂ CH ₂ (4-Pyd) CH ₂ CH ₂ CH ₂ OH 1-643 CH ₂ CH ₂ (4-Pyd) CH ₂ COOH 1-644 CH ₂ CH ₂ (4-Pyd) CH ₂ CONH ₂ 1-645 CH ₂ CH ₂ (2-Thn) Me 1-646 CH ₂ CH ₂ (2-Thn) Et 1-647 CH ₂ CH ₂ (2-Thn) CH ₂ CH ₂ F 1-648 CH ₂ CH ₂ (2-Thn) CH ₂ CH ₂ CN 1-649 CH ₂ CH ₂ (2-Thn) CH ₂ CH ₂ OH 1-650 CH ₂ CH ₂ (2-Thn) CH ₂ CH ₂ CH ₂ OH 1-651 CH ₂ CH ₂ (2-Thn) CH ₂ COOH 1-652 CH ₂ CH ₂ (2-Thn) CH ₂ CONH ₂ 1-653 CH ₂ CH ₂ (2-Fur) Me 1 -654 CH ₂ CH ₂ (2-Fur) Et 1-655 CH ₂ CH ₂ (2-Fur) CH ₂ CH ₂ F 1-656 CH ₂ CH ₂ (2-Fur) CH ₂ CH ₂ CN 1-657 CH ₂ CH ₂ (2-Fur) CH ₂ CH ₂ OH 1-658 CH ₂ CH ₂ (2-Fur) CH ₂ CH ₂ CH ₂ OH 1-659 CH ₂ CH ₂ (2-Fur) CH ₂ COOH 1-660 CH ₂ CH ₂ (2-Fur) CH ₂ CONH ₂ 1-661 CH ₂ CH ₂ (4-Me-5-Thz) Me 1-662 CH ₂ CH ₂ (4-Me-5-Thz) Et 1-663 CH ₂ CH ₂ (4-Me- 5-Thz) CH ₂ CH ₂ F 1-664 CH ₂ CH ₂ (4-Me-5-Thz) CH ₂ CH ₂ CN 1-665 CH ₂ CH ₂ (4-Me-5-Thz) CH ₂ CH ₂ OH 1-666 CH ₂ CH ₂ (4-Me-5-Thz) CH ₂ CH ₂ CH ₂ OH 1-667 CH ₂ CH ₂ (4-Me-5-Thz) CH ₂ COOH 1-668 CH ₂ CH ₂ (4-Me-5-Thz) CH ₂ CONH ₂ 1-669 CH ₂ (2-Thz) Me 1-670 CH ₂ (2-Thz) Et 1-671 CH ₂ (2-Thz) CH ₂ CH ₂ F 1-672 CH ₂ (2-Thz) CH ₂ CH ₂ CN 1-673 CH ₂ (2-Thz) CH ₂ CH ₂ OH 1-674 CH ₂ (2-Thz) CH ₂ CH ₂ CH ₂ OH 1-675 CH ₂ (2-Thz) CH ₂ COOH 1-676 CH ₂ (2-Thz) CH ₂ CONH ₂ 1-677 CH ₂ (5-Imd) Me 1-678 CH ₂ (5-Imd) Et 1-679 CH ₂ (5-Imd) CH ₂ CH ₂ F 1-680 CH ₂ (5-Imd) CH ₂ CH ₂ CN 1-681 CH ₂ (5-Imd) CH ₂ CH ₂ OH 1-682 CH ₂ (5-Imd ) CH ₂ CH ₂ CH ₂ OH 1-683 CH ₂ (5-Imd) CH ₂ COOH 1-684 CH ₂ (5-Imd) CH ₂ CONH ₂ 1-685 Ph Bn 1-686 Ph 4-F-Bn 1 -687 Ph 4-CONH ₂ -Bn 1-688 Ph 4-SO ₂ NH ₂ -Bn 1-689 Ph 4-OMe-Bn 1-690 Ph 4-Me-Bn 1-691 Ph CH ₂ (1-Np) 1-692 Ph CH ₂ (2-Np) 1-693 Ph CH ₂ (2-Pyd) 1-694 Ph CH ₂ (3-Pyd) 1-69 5 Ph CH ₂ (4-Pyd) 1-696 Ph CH ₂ (2-Thn) 1-697 Ph CH ₂ (2-Fur) 1-698 Ph CH ₂ (4-Imd) 1-699 Ph CH ₂ (2 -Thz) 1-700 Ph PHE 1-701 Ph CH ₂ CH ₂ (1-Np) 1-702 Ph CH ₂ CH ₂ (2-Np) 1-703 Ph CH ₂ CH ₂ (2-Pyd) 1-704 Ph CH ₂ CH ₂ (3-Pyd) 1-705 Ph CH ₂ CH ₂ (4-Pyd) 1-706 Ph CH ₂ CH ₂ (2-Thn) 1-707 Ph CH ₂ CH ₂ (2-Fur) 1 -708 Ph CH ₂ CH ₂ (4-Imd) 1-709 Ph CH ₂ CH ₂ (2-Thz) 1-710 Ph CH ₂ CH ₂ (4-Me-5-Thz) 1-711 Bn Bn 1-712 Bn CH ₂ (2-Pyd) 1-713 Bn CH ₂ (3-Pyd) 1-714 Bn CH ₂ (4-Pyd) 1-715 CH ₂ (2-Pyd) CH ₂ (2-Pyd) 1-716 CH ₂ (3-Pyd) CH ₂ (3-Pyd) 1-717 CH ₂ (4-Pyd) CH ₂ (4-Pyd) 1-718 CH ₂ (2-Thn) CH ₂ (2-Thn) 1- _{719 CH 2 (2-Fur)} CH 2 (2-Fur) 1-720 -CH 2 CH 2 CH 2 - 1-721 -CH 2 CH 2 CH 2 CH 2 - 1-722 -CH 2 CH 2 CH (OH _{) CH 2 - 1-723 -CH 2 CH} 2 CH (NH 2) CH 2 - 1-724 -CH 2 CH 2 CH 2 CH (COOH) - 1-725 -CH 2 CH 2 CH 2 CH (CONH 2) _{- 1-726 -CH 2 CH 2 CH 2} CH (COOEt) - 1-727 -CH 2 CH 2 CH 2 CH 2 CH 2 - 1-728 -CH 2 CH 2 CH (OH) CH 2 CH 2 - 1- _{729 -CH 2 CH 2 CH (NH} 2) CH 2 CH 2 - 1-730 -CH 2 CH = CHCH 2 - 1-731 -CH 2 CH 2 OCH 2 _{CH 2 - 1-732 -CH 2 CH 2} SCH 2 CH 2 - 1-733 -CH 2 CH 2 NHCH 2 CH 2 - 1-734 -CH (Me) CH 2 NHCH 2 CH 2 - 1-735 -CH 2 _{CH (Me) NHCH 2 CH 2} - 1-736 -CH 2 CH (Me) NHCH (Me) CH 2 - 1-737 -CH 2 CH (Me) NHCH 2 CH (Me) - 1-738 -CH 2 CH _{2 N (Me) CH 2 CH} 2 - 1-739 -CH 2 CH 2 N (Et) CH 2 CH 2 - 1-740 -CH 2 CH 2 N (CH 2 CH 2 OH) CH 2 CH 2 - 1- _{741 -CH 2 CH 2 N (Ph} ) CH 2 CH 2 - 1-742 -CH 2 (1,2-Ph) CH 2 - 1-743 -CH 2 (1,2-Ph) CH 2 CH 2 - 1 -744 - (1,2-Ph) CH 2 CH 2 CH 2 - 1-745 -CH 2 (1,2-Pyd) CH 2 - 1-746 -CH 2 (3,4-Pyd) CH 2 - - -------------------------------------------------- ------

[0095]

[Table 2]

[0096]

Embedded image -------------------------------------------------- ------- No. R ³ R ⁴ ------------------------------------- -------------------- 2-1 HH 2-2 Me H 2-3 Et H 2-4 H Me 2-5 H Et 2-6 Me Me 2 -7 Et Et 2-8 CN H 2-9 NH ₂ H 2-10 NHMe H 2-11 NMe ₂ H 2-12 NHSO ₂ Me H 2-13 SO ₂ Me H 2-14 Ph H 2-15 H CF ₃ 2-16 H CH ₂ OH 2-17 H CH ₂ CONH ₂ 2-18 H CH ₂ NH ₂ 2-19 H CH ₂ NHMe 2-20 H CH ₂ NMe ₂ 2-21 H CH ₂ NHCH ₂ CH ₂ OH 2-22 H CH ₂ NHCH ₂ COOH 2-23 H CH ₂ NHCH ₂ CONH ₂ 2-24 H CH ₂ NHCH ₂ CH ₂ NH ₂ 2-25 H CH ₂ NHCH ₂ CH ₂ NHMe 2-26 H CH ₂ NHCH ₂ CH ₂ NMe ₂ 2-27 H CH ₂ N (CH ₃ ) CH ₂ CH ₂ OH 2-28 H CH ₂ N (CH ₃ ) CH ₂ CONH ₂ 2-29 H CH ₂ N (CH ₃ ) CH ₂ CH ₂ NH ₂ 2-30 H CH ₂ N (CH ₂ CH ₂ OH) ₂ 2-31 H COOEt 2-32 H CONH ₂ 2-33 H CONHMe 2-34 H CONHEt 2-35 H CONMe ₂ 2-36 H CONEt ₂ 2-37 H CONHPh 2-38 H CO (1-Azt) 2-39 H CO (1-Pyr) 2-40 H CO (3-OH-1-Pyr) 2-41 H CO (3-NH _2- 1-Pyr) 2-42 H CO (3-NHMe-1-Pyr) 2-43 H CO (3-Cl-1-Pyr) 2-44 H CO (3-CN-1-Pyr) 2-45 H CO (3-COOH-1-Pyr) 2-46 H CO (3-CONH ₂ -1-Pyr) 2-47 H CO (1-Pip) 2-48 H CO (4-O H-1-Pip) 2-49 H CO (4-NH ₂ -1-Pip) 2-50 H CO (1-Piz) 2-51 H CO (4-Me-1-Piz) 2-52 H CO (4,4-diMe-1-Piz) 2-53 H CO (4-Ph-1-Piz) 2-54 H CO (4-CH ₂ CH ₂ OH-1-Piz) 2-55 H CO (4 -CH ₂ COOH) 1-Piz) 2-56 H CO (4-CH ₂ CONH ₂ -1-Piz) 2-57 H CO (4-Me-4-CH ₂ CH ₂ OH-1-Piz) 2- 58 H CO (4-Me-4-CH ₂ COOH-1-Piz) 2-59 H CO (4-Me-4-CH ₂ CONH ₂ -1-Piz) 2-60 H CO (4-Mor) 2 -61 H CO (4-Tmr) 2-62 H Ph 2-63 H 4-F-Ph 2-64 H 4-Me-Ph 2-65 H 4-MeO-Ph 2-66 H 4-CF _3- Ph 2-67 H 4-CH ₂ OH-Ph 2-68 H 4-NH ₂ -Ph 2-69 H 4-NHMe-Ph 2-70 H 4-NMe ₂ -Ph 2-71 H 4-NHCH ₂ CH ₂ OH-Ph 2-72 H 4-NHCH ₂ COOH-Ph 2-73 H 4-NHCH ₂ CONH ₂ -Ph 2-74 H 4-NHCH ₂ CH ₂ NH ₂ -Ph 2-75 H 4-NHCH ₂ CH ₂ NHMe-Ph 2-76 H 4-NHCH ₂ CH ₂ NMe ₂ -Ph 2-77 H 4-N (Me) CH ₂ CH ₂ OH-Ph 2-78 H 4-N (Me) CH ₂ CONH _2- Ph 2-79 H 4-N (Me) CH ₂ CH ₂ NH ₂ -Ph 2-80 H 4-N (CH ₂ CH ₂ OH) ₂ -Ph 2-81 H 4-CH ₂ NH ₂ -Ph 2- 82 H 4-CH ₂ NHMe-Ph 2-83 H 4-CH ₂ NMe ₂ -Ph 2-84 H 4-CH ₂ NHCH ₂ CH ₂ OH-Ph 2-85 H 4-CH ₂ NHCH ₂ COOH-Ph 2 -86 H 4-CH ₂ NHCH ₂ CONH ₂ -Ph 2-87 H 4-CH ₂ NHCH ₂ CH ₂ NH ₂ -Ph 2-88 H 4 -CH ₂ NHCH ₂ CH ₂ NHMe-Ph 2-89 H 4-CH ₂ NHCH ₂ CH ₂ NMe ₂ -Ph 2-90 H 4-CH ₂ N (Me) CH ₂ CH ₂ OH-Ph 2-91 H 4 -CH ₂ N (Me) CH ₂ CONH ₂ -Ph 2-92 H 4-CH ₂ N (Me) CH ₂ CH ₂ NH ₂ -Ph 2-93 H 4-CH ₂ N (CH ₂ CH ₂ OH) ₂ -Ph 2-94 H 4-CH ₂ N ⁺ Me ₃ -Ph 2-95 H 4-CH ₂ N ⁺ (Me) ₂ CH ₂ CH ₂ OH-Ph 2-96 H 4-CH ₂ N ⁺ (Me) ₂ CH ₂ CONH ₂ -Ph 2-97 H 4-CH ₂ (1-Pyr) -Ph 2-98 H 4-CH ₂ (3-OH-1-Pyr) -Ph 2-99 H 4-CH ₂ ( 1-Me-1-Pyr) -Ph 2-100 H 4-CH ₂ (1-Pip) -Ph 2-101 H 4-CH ₂ (3-OH-1-Pip) -Ph 2-102 H 4- CH ₂ (1-Me-1-Pip) -Ph 2-103 H 4-SO ₂ NH ₂ -Ph 2-104 H 4-COOEt-Ph 2-105 H 4-CONH ₂ -Ph 2-106 H 4- CONHMe-Ph 2-107 H 4-CONHEt-Ph 2-108 H 4-CONMe ₂ -Ph 2-109 H 4-CONEt ₂ -Ph 2-110 H 4-CONHPh-Ph 2-111 H 4-CO (1 -Azt) -Ph 2-112 H 4-CO (1-Pyr) -Ph 2-113 H 4-CO (3-OH-1-Pyr) -Ph 2-114 H 4-CO (3-NH _2- 1-Pyr) -Ph 2-115 H 4-CO (3-NHMe-1-Pyr) -Ph 2-116 H 4-CO (3-Cl-1-Pyr) -Ph 2-117 H 4-CO ( 3-CN-1-Pyr) -Ph 2-118 H 4-CO (3-COOH-1-Pyr) -Ph 2-119 H 4-CO (3-CONH ₂ -1-Pyr) -Ph 2-120 H 4-CO (1-Pip) -Ph 2-121 H 4-CO (4-OH-1-Pip) -Ph 2-122 H 4-CO (4-NH ₂ -1-Pip) -Ph 2- 123 H 4-CO (1-Piz) -Ph 2-124 H 4-CO (4-Me-1-Piz) -Ph 2-125 H 4-CO (4,4-diMe-1-Piz) -Ph 2- 126 H 4-CO (4-Ph-1-Piz) -Ph 2-127 H 4-CO (4-CH ₂ CH ₂ OH-1-Piz) -Ph 2-128 H 4-CO (4-CH ₂ COOH-1-Piz) -Ph 2-129 H 4-CO (4-CH ₂ CONH ₂ -1-Piz) -Ph 2-130 H 4-CO (4-Me-4-CH ₂ CH ₂ OH-1 -Piz) -Ph 2-131 H 4-CO (4-Me-4-CH ₂ COOH-1-Piz) -Ph 2-132 H 4-CO (4-Me-4-CH ₂ CONH ₂ -1- Piz) -Ph 2-133 H 4-CO (4-Mor) -Ph 2-134 H 4-CO (4-Tmr) -Ph 2-135 H 4-NHCONH ₂ -Ph 2-136 H 2-Pyd 2 -137 H 1-Me-2-Pyd 2-138 H 1-CH ₂ CH ₂ OH-2-Pyd 2-139 H 1-CH ₂ COOH-2-Pyd 2-140 H 1-CH ₂ CONH ₂ -2 -Pyd 2-141 H 3-Pyd 2-142 H 1-Me-3-Pyd 2-143 H 1-CH ₂ CH ₂ OH-3-Pyd 2-144 H 1-CH ₂ COOH-3-Pyd 2- 145 H 1-CH ₂ CONH ₂ -3-Pyd 2-146 H 4-Pyd 2-147 H 1-Me-4-Pyd 2-148 H 1-CH ₂ CH ₂ OH-4-Pyd 2-149 H 1 -CH ₂ COOH-4-Pyd 2-150 H 1-CH ₂ CONH ₂ -4-Pyd 2-151 H 2-Prz 2-152 H 5-Ph-2-Prz 2-153 H 2-Thn 2-154 H 2-BImd 2-155 H 2-BThz 2-156 H 3-Ind -------------------------------- -------------------------

[0097]

[Table 3]

[0098]

Embedded image -------------------------------------------------- ------- No. R ^5a R ^5b ------------------------------------- -------------------- 3-1 HH 3-2 H 4-F 3-3 H 4-Cl 3-4 H 4-Me 3-5 H 4 -OMe 3-6 H 4-OCH ₂ CH ₂ OH 3-7 H 4-OCH ₂ CH ₂ NH ₂ 3-8 H 4-CF ₃ 3-9 H 4-CH ₂ OH 3-10 H 4-NO ₂ 3-11 H 4-NH ₂ 3-12 H 4-NHMe 3-13 H 4-NMe ₂ 3-14 H 4-NHCH ₂ CH ₂ OH 3-15 H 4-NHCH ₂ COOH 3-16 H 4-NHCH ₂ CONH ₂ 3-17 H 4-NHCH ₂ CH ₂ NH ₂ 3-18 H 4-NHCH ₂ CH ₂ NHMe 3-19 H 4-NHCH ₂ CH ₂ NMe ₂ 3-20 H 4-N (Me) CH _{2 CH 2 OH 3-21 H 4-N} (Me) CH 2 CONH 2 3-22 H 4-N (Me) CH 2 CH 2 NH 2 3-23 H 4-N (CH 2 CH 2 OH) 2 3- 24 H 4-N ⁺ Me ₃ 3-25 H 4-N ⁺ (Me) ₂ CH ₂ CH ₂ OH 3-26 H 4-N ⁺ (Me) ₂ CH ₂ CONH ₂ 3-27 H 4-NHAc 3- _{28 H 4-NHCOC 3 H 7} 3-29 H 4-NHCOC 5 H 11 3-30 H 4-NHCOC 7 H 15 3-31 H 4-NHCOC 9 H 19 3-32 H 4-NHCOPh 3-33 H 4 -NHCO (3,4-diOH-Ph) 3-34 H 4-NHCO (3,4-diOMe-Ph) 3-35 H 4-NHCO (3,4,5-triOH-Ph) 3-36 H 4 -NHCO (3,4,5-triOMe-Ph) 3-37 H 4-NHCO (2-Pyd) 3-38 H 4-NHCO (1-Me-2-Pyd) 3-39 H 4-NHCO (1 -CH ₂ CONH ₂ -2-Pyd) 3-40 H 4-NHCO (1-CH ₂ CH ₂ OH-2-P yd) 3-41 H 4-NHCO (3-Pyd) 3-42 H 4-NHCO (1-Me-3-Pyd) 3-43 H 4-NHCO (1-CH ₂ CONH ₂ -3-Pyd) 3 -44 H 4-NHCO (1-CH ₂ CH ₂ OH-3-Pyd) 3-45 H 4-NHCO (4-Pyd) 3-46 H 4-NHCO (1-Me-4-Pyd) 3-47 H 4-NHCO (1-CH ₂ CONH ₂ -4-Pyd) 3-48 H 4-NHCO (1-CH ₂ CH ₂ OH-4-Pyd) 3-49 H 4-NHPh 3-50 H 4-NHCONH ₂ 3-51 H 4-NHSO ₂ NH ₂ 3-52 H 4-NHSO ₂ Me 3-53 H 4-CH ₂ NH ₂ 3-54 H 4-CH ₂ NHMe 3-55 H 4-CH ₂ NMe ₂ 3 -56 H 4-CH ₂ NHCH ₂ CH ₂ OH 3-57 H 4-CH ₂ NHCH ₂ COOH 3-58 H 4-CH ₂ NHCH ₂ CONH ₂ 3-59 H 4-CH ₂ NHCH ₂ CH ₂ NH ₂ 3 -60 H 4-CH ₂ NHCH ₂ CH ₂ NHMe 3-61 H 4-CH ₂ NHCH ₂ CH ₂ NMe ₂ 3-62 H 4-CH ₂ N (Me) CH ₂ CH ₂ OH 3-63 H 4-CH ₂ N (Me) CH ₂ CONH ₂ 3-64 H 4-CH ₂ N (Me) CH ₂ CH ₂ NH ₂ 3-65 H 4-CH ₂ N (CH ₂ CH ₂ OH) ₂ 3-66 H 4- CH ₂ N ⁺ Me ₃ 3-67 H 4-CH ₂ N ⁺ (Me) ₂ CH ₂ CH ₂ OH 3-68 H 4-CH ₂ N ⁺ (Me) ₂ CH ₂ CONH ₂ 3-69 H 4-CH ₂ (1-Pyr) 3-70 H 4-CH ₂ (3-OH-1-Pyr) 3-71 H 4-CH ₂ (1-Me-1-Pyr) 3-72 H 4-CH ₂ (1 -Pip) 3-73 H 4-CH ₂ (3-OH-1-Pip) 3-74 H 4-CH ₂ (1-Me-1-Pip) 3-75 H 4-CH ₂ (1-Imd) 3-76 H 4-CH ₂ (3-Me-1-Imd) 3-77 H 4-CH ₂ (1-Trz) 3 _{-78 H 4-CH 2 (4} -Me-1-Trz) 3-79 H 4-SO 2 NH 2 3-80 H 4-SO 2 NMe 2 3-81 H 4-SO 2 NHCH 2 CH 2 OH 3 -82 H 4-SO ₂ NHCH ₂ CH ₂ NH ₂ 3-83 H 4-COOH 3-84 H 4-COOEt 3-85 H 4-CONH ₂ 3-86 H 4-CONHMe 3-87 H 4-CONHEt 3 -88 H 4-CONMe ₂ 3-89 H 4-CONEt ₂ 3-90 H 4-CONHPh 3-91 H 4-CO (1-Azt) 3-92 H 4-CO (1-Pyr) 3-93 H 4-CO (3-OH-1-Pyr) 3-94 H 4-CO (3-NH ₂ -1-Pyr) 3-95 H 4-CO (3-NHMe-1-Pyr) 3-96 H 4 -CO (3-Cl-1-Pyr) 3-97 H 4-CO (3-CN-1-Pyr) 3-98 H 4-CO (3-COOH-1-Pyr) 3-99 H 4-CO (3-CONH ₂ -1-Pyr) 3-100 H 4-CO (1-Pip) 3-101 H 4-CO (4-OH-1-Pip) 3-102 H 4-CO (4-NH ₂ 3-103 H 4-CO (1-Piz) 3-104 H 4-CO (4-Me-1-Piz) 3-105 H 4-CO (4,4-diMe-1-Piz ) 3-106 H 4-CO (4-Ph-1-Piz) 3-107 H 4-CO (4-CH ₂ CH ₂ OH-1-Piz) 3-108 H 4-CO (4-CH ₂ COOH -1-Piz) 3-109 H 4-CO (4-CH ₂ CONH ₂ -1-Piz) 3-110 H 4-CO (4-Me-4-CH ₂ CH ₂ OH-1-Piz) 3- 111 H 4-CO (4-Me-4-CH ₂ COOH-1-Piz) 3-112 H 4-CO (4-Me-4-CH ₂ CONH ₂ -1-Piz) 3-113 H 4-CO (4-Mor) 3-114 H 4-CO (4-Tmr) 3-115 H 5-F 3-116 H 5-Cl 3-117 H 5-Me 3-118 H 5-OMe 3-119 H 5 -OCH ₂ CH ₂ OH 3-120 H 5-OCH ₂ CH ₂ NH ₂ 3-121 H 5-CF ₃ 3-122 H 5-CH ₂ OH 3-123 H 5-NO ₂ 3-124 H 5-NH ₂ 3-125 H 5-NHMe 3-126 H 5-NMe ₂ 3 -127 H 5-NHCH ₂ CH ₂ OH 3-128 H 5-NHCH ₂ COOH 3-129 H 5-NHCH ₂ CONH ₂ 3-130 H 5-NHCH ₂ CH ₂ NH ₂ 3-131 H 5-NHCH ₂ CH ₂ NHMe 3-132 H 5-NHCH ₂ CH ₂ NMe ₂ 3-133 H 5-N (Me) CH ₂ CH ₂ OH 3-134 H 5-N (Me) CH ₂ CONH ₂ 3-135 H 5-N (Me) CH ₂ CH ₂ NH ₂ 3-136 H 5-N (CH ₂ CH ₂ OH) ₂ 3-137 H 5-N ⁺ Me ₃ 3-138 H 5-N ⁺ (Me) ₂ CH ₂ CH ₂ OH 3-139 H 5-N ⁺ (Me) ₂ CH ₂ CONH ₂ 3-140 H 5-NHAc 3-141 H 5-NHCOC ₃ H ₇ 3-142 H 5-NHCOC ₅ H ₁₁ 3-143 H 5- NHCOC ₇ H ₁₅ 3-144 H 5-NHCOC ₉ H ₁₉ 3-145 H 5-NHCOPh 3-146 H 5-NHCO (3,4-diOH-Ph) 3-147 H 5-NHCO (3,4-diOMe -Ph) 3-148 H 5-NHCO (3,4,5-triOH-Ph) 3-149 H 5-NHCO (3,4,5-triOMe-Ph) 3-150 H 5-NHCO (2-Pyd ) 3-151 H 5-NHCO (1-Me-2-Pyd) 3-152 H 5-NHCO (1-CH ₂ CONH ₂ -2-Pyd) 3-153 H 5-NHCO (1-CH ₂ CH ₂ OH-2-Pyd) 3-154 H 5-NHCO (3-Pyd) 3-155 H 5-NHCO (1-Me-3-Pyd) 3-156 H 5-NHCO (1-CH ₂ CONH ₂ -3 -Pyd) 3-157 H 5-NHCO (1-CH ₂ CH ₂ OH-3-Pyd) 3-158 H 5-NHCO (4-Pyd) 3-159 H 5-NHCO (1-Me-4-Pyd ) 3-160 H 5-NHC O (1-CH ₂ CONH ₂ -4-Pyd) 3-161 H 5-NHCO (1-CH ₂ CH ₂ OH-4-Pyd) 3-162 H 5-NHPh 3-163 H 5-NHCONH ₂ 3- 164 H 5-NHSO ₂ NH ₂ 3-165 H 5-NHSO ₂ Me 3-166 H 5-CH ₂ NH ₂ 3-167 H 5-CH ₂ NHMe 3-168 H 5-CH ₂ NMe ₂ 3-169 H 5-CH ₂ NHCH ₂ CH ₂ OH 3-170 H 5-CH ₂ NHCH ₂ COOH 3-171 H 5-CH ₂ NHCH ₂ CONH ₂ 3-172 H 5-CH ₂ NHCH ₂ CH ₂ NH ₂ 3-173 H 5-CH ₂ NHCH ₂ CH ₂ NHMe 3-174 H 5-CH ₂ NHCH ₂ CH ₂ NMe ₂ 3-175 H 5-CH ₂ N (Me) CH ₂ CH ₂ OH 3-176 H 5-CH ₂ N ( _{Me) CH 2 CONH 2 3-177 H} 5-CH 2 N (Me) CH 2 CH 2 NH 2 3-178 H 5-CH 2 N (CH 2 CH 2 OH) 2 3-179 H 5-CH 2 N ⁺ Me ₃ 3-180 H 5-CH ₂ N ⁺ (Me) ₂ CH ₂ CH ₂ OH 3-181 H 5-CH ₂ N ⁺ (Me) ₂ CH ₂ CONH ₂ 3-182 H 5-CH ₂ (1 -Pyr) 3-183 H 5-CH ₂ (3-OH-1-Pyr) 3-184 H 5-CH ₂ (1-Me-1-Pyr) 3-185 H 5-CH ₂ (1-Pip) 3-186 H 5-CH ₂ (3-OH-1-Pip) 3-187 H 5-CH ₂ (1-Me-1-Pip) 3-188 H 5-CH ₂ (1-Imd) 3-189 H 5-CH ₂ (3-Me-1-Imd) 3-190 H 5-CH ₂ (1-Trz) 3-191 H 5-CH ₂ (4-Me-1-Trz) 3-192 H 5- SO ₂ NH ₂ 3-193 H 5-SO ₂ NMe ₂ 3-194 H 5-SO ₂ NHCH ₂ CH ₂ OH 3-195 H 5-SO ₂ NHCH ₂ CH ₂ NH ₂ 3-196 H 5-COOH 3- 197 H 5-COOEt 3-198 H 5-CONH ₂ 3-199 H 5-CONHMe 3-200 H 5-CONHEt 3-201 H 5-CONMe ₂ 3-202 H 5-CONEt ₂ 3-203 H 5-CONHPh 3- 204 H 5-CO (1-Azt) 3-205 H 5-CO (1-Pyr) 3-206 H 5-CO (3-OH-1-Pyr) 3-207 H 5-CO (3-NH ₂ -1-Pyr) 3-208 H 5-CO (3-NHMe-1-Pyr) 3-209 H 5-CO (3-Cl-1-Pyr) 3-210 H 5-CO (3-CN-1 -Pyr) 3-211 H 5-CO (3-COOH-1-Pyr) 3-212 H 5-CO (3-CONH ₂ -1-Pyr) 3-213 H 5-CO (1-Pip) 3- 214 H 5-CO (4-OH-1-Pip) 3-215 H 5-CO (4-NH ₂ -1-Pip) 3-216 H 5-CO (1-Piz) 3-217 H 5-CO (4-Me-1-Piz) 3-218 H 5-CO (4,4-diMe-1-Piz) 3-219 H 5-CO (4-Ph-1-Piz) 3-220 H 5-CO (4-CH ₂ CH ₂ OH-1-Piz) 3-221 H 5-CO (4-CH ₂ COOH-1-Piz) 3-222 H 5-CO (4-CH ₂ CONH ₂ -1-Piz) 3-223 H 5-CO (4-Me-4-CH ₂ CH ₂ OH-1-Piz) 3-224 H 5-CO (4-Me-4-CH ₂ COOH-1-Piz) 3-225 H 5-CO (4-Me-4-CH ₂ CONH ₂ -1-Piz) 3-226 H 5-CO (4-Mor) 3-227 H 5-CO (4-Tmr) 3-228 H 6-F 3-229 H 6-Cl 3-230 H 6-Me 3-231 H 6-OMe 3-232 H 6-OCH ₂ CH ₂ OH 3-233 H 6-OCH ₂ CH ₂ NH ₂ 3-234 H 6- CF ₃ 3-235 H 6-CH ₂ OH 3-236 H 6-NO ₂ 3-237 H 6-NH ₂ 3-238 H 6-NHMe 3-239 H 6-NMe ₂ 3-240 H 6-NHCH ₂ CH ₂ OH 3-241 H 6-NHCH ₂ COOH 3-242 H 6-NHCH ₂ CONH ₂ 3-243 H 6-NHCH ₂ CH ₂ NH ₂ 3-244 H 6-NHCH ₂ CH ₂ NHMe 3-245 H 6-NHCH ₂ CH ₂ NMe ₂ 3-246 H 6-N (Me) CH ₂ CH ₂ OH 3-247 H 6-N (Me) CH ₂ CONH ₂ 3-248 H 6-N (Me) CH ₂ CH ₂ NH ₂ 3-249 H 6 -N (CH ₂ CH ₂ OH) ₂ 3-250 H 6-N ⁺ Me ₃ 3-251 H 6-N ⁺ (Me) ₂ CH ₂ CH ₂ OH 3-252 H 6-N ⁺ (Me) ₂ CH ₂ CONH ₂ 3-253 H 6-NHAc 3-254 H 6-NHCOC ₃ H ₇ 3-255 H 6-NHCOC ₅ H ₁₁ 3-256 H 6-NHCOC ₇ H ₁₅ 3-257 H 6-NHCOC ₉ H ₁₉ 3-258 H 6-NHCOPh 3-259 H 6-NHCO (3,4-diOH-Ph) 3-260 H 6-NHCO (3,4-diOMe-Ph) 3-261 H 6-NHCO (3,4 , 5-triOH-Ph) 3-262 H 6-NHCO (3,4,5-triOMe-Ph) 3-263 H 6-NHCO (2-Pyd) 3-264 H 6-NHCO (1-Me-2 -Pyd) 3-265 H 6-NHCO (1-CH ₂ CONH ₂ -2-Pyd) 3-266 H 6-NHCO (1-CH ₂ CH ₂ OH-2-Pyd) 3-267 H 6-NHCO ( 3-Pyd) 3-268 H 6-NHCO (1-Me-3-Pyd) 3-269 H 6-NHCO (1-CH ₂ CONH ₂ -3-Pyd) 3-270 H 6-NHCO (1-CH ₂ CH ₂ OH-3-Pyd) 3-271 H 6-NHCO (4-Pyd) 3-272 H 6-NHCO (1-Me-4-Pyd) 3-273 H 6-NHCO (1-CH ₂ CONH ₂ -4-Pyd) 3-274 H 6-NHCO (1-CH ₂ CH ₂ OH-4-Pyd) 3-275 H 6-NHPh 3-276 H 6-NHCONH ₂ 3-277 H 6-NHSO ₂ NH ₂ 3-278 H 6-NHS O ₂ Me 3-279 H 6-CH ₂ NH ₂ 3-280 H 6-CH ₂ NHMe 3-281 H 6-CH ₂ NMe ₂ 3-282 H 6-CH ₂ NHCH ₂ CH ₂ OH 3-283 H 6 -CH ₂ NHCH ₂ COOH 3-284 H 6-CH ₂ NHCH ₂ CONH ₂ 3-285 H 6-CH ₂ NHCH ₂ CH ₂ NH ₂ 3-286 H 6-CH ₂ NHCH ₂ CH ₂ NHMe 3-287 H 6 -CH ₂ NHCH ₂ CH ₂ NMe ₂ 3-288 H 6-CH ₂ N (Me) CH ₂ CH ₂ OH 3-289 H 6-CH ₂ N (Me) CH ₂ CONH ₂ 3-290 H 6-CH ₂ N (Me) CH ₂ CH ₂ NH ₂ 3-291 H 6-CH ₂ N (CH ₂ CH ₂ OH) ₂ 3-292 H 6-CH ₂ N ⁺ Me ₃ 3-293 H 6-CH ₂ N ⁺ ( (Me) ₂ CH ₂ CH ₂ OH 3-294 H 6-CH ₂ N ⁺ (Me) ₂ CH ₂ CONH ₂ 3-295 H 6-CH ₂ (1-Pyr) 3-296 H 6-CH ₂ (3- OH-1-Pyr) 3-297 H 6-CH ₂ (1-Me-1-Pyr) 3-298 H 6-CH ₂ (1-Pip) 3-299 H 6-CH ₂ (3-OH-1 -Pip) 3-300 H 6-CH ₂ (1-Me-1-Pip) 3-301 H 6-CH ₂ (1-Imd) 3-302 H 6-CH ₂ (3-Me-1-Imd) 3-303 H 6-CH ₂ (1-Trz) 3-304 H 6-CH ₂ (4-Me-1-Trz) 3-305 H 6-SO ₂ NH ₂ 3-306 H 6-SO ₂ NMe ₂ 3-307 H 6-SO ₂ NHCH ₂ CH ₂ OH 3-308 H 6-SO ₂ NHCH ₂ CH ₂ NH ₂ 3-309 H 6-COOH 3-310 H 6-COOEt 3-311 H 6-CONH ₂ 3 -312 H 6-CONHMe 3-313 H 6-CONHEt 3-314 H 6-CONMe ₂ 3-315 H 6-CONEt ₂ 3-316 H 6-CONHPh 3-317 H 6-CO (1-Az t) 3-318 H 6-CO (1-Pyr) 3-319 H 6-CO (3-OH-1-Pyr) 3-320 H 6-CO (3-NH ₂ -1-Pyr) 3-321 H 6-CO (3-NHMe-1-Pyr) 3-322 H 6-CO (3-Cl-1-Pyr) 3-323 H 6-CO (3-CN-1-Pyr) 3-324 H 6 -CO (3-COOH-1-Pyr) 3-325 H 6-CO (3-CONH ₂ -1-Pyr) 3-326 H 6-CO (1-Pip) 3-327 H 6-CO (4- OH-1-Pip) 3-328 H 6-CO (4-NH ₂ -1-Pip) 3-329 H 6-CO (1-Piz) 3-330 H 6-CO (4-Me-1-Piz ) 3-331 H 6-CO (4,4-diMe-1-Piz) 3-332 H 6-CO (4-Ph-1-Piz) 3-333 H 6-CO (4-CH ₂ CH ₂ OH 3-334 H 6-CO (4-CH ₂ COOH-1-Piz) 3-335 H 6-CO (4-CH ₂ CONH ₂ -1-Piz) 3-336 H 6-CO ( 4-Me-4-CH ₂ CH ₂ OH-1-Piz) 3-337 H 6-CO (4-Me-4-CH ₂ COOH-1-Piz) 3-338 H 6-CO (4-Me- 4-CH ₂ CONH ₂ -1-Piz) 3-339 H 6-CO (4-Mor) 3-340 H 6-CO (4-Tmr) 3-341 H 7-F 3-342 H 7-Cl 3 -343 H 7-Me 3-344 H 7-OMe 3-345 H 7-OCH ₂ CH ₂ OH 3-346 H 7-OCH ₂ CH ₂ NH ₂ 3-347 H 7-CF ₃ 3-348 H 7- CH ₂ OH 3-349 H 7-NO ₂ 3-350 H 7-NH ₂ 3-351 H 7-NHMe 3-352 H 7-NMe ₂ 3-353 H 7-NHCH ₂ CH ₂ OH 3-354 H 7 -NHCH ₂ COOH 3-355 H 7-NHCH ₂ CONH ₂ 3-356 H 7-NHCH ₂ CH ₂ NH ₂ 3-357 H 7-NHCH ₂ CH ₂ NHMe 3-358 H 7-NHCH ₂ CH ₂ NMe ₂ 3 -359 H 7- N (Me) CH ₂ CH ₂ OH 3-360 H 7-N (Me) CH ₂ CONH ₂ 3-361 H 7-N (Me) CH ₂ CH ₂ NH ₂ 3-362 H 7-N (CH ₂ CH ₂ OH) ₂ 3-363 H 7-N ⁺ Me ₃ 3-364 H 7-N ⁺ (Me) ₂ CH ₂ CH ₂ OH 3-365 H 7-N ⁺ (Me) ₂ CH ₂ CONH ₂ 3-366 H 7-NHAc 3-367 H 7- NHCOC 3 H 7 3-368 H 7-NHCOC 5 H 11 3-369 H 7-NHCOC 7 H 15 3-370 H 7-NHCOC 9 H 19 3-371 H 7- NHCOPh 3-372 H 7-NHCO (3,4-diOH-Ph) 3-373 H 7-NHCO (3,4-diOMe-Ph) 3-374 H 7-NHCO (3,4,5-triOH-Ph ) 3-375 H 7-NHCO (3,4,5-triOMe-Ph) 3-376 H 7-NHCO (2-Pyd) 3-377 H 7-NHCO (1-Me-2-Pyd) 3-378 H 7-NHCO (1-CH ₂ CONH ₂ -2-Pyd) 3-379 H 7-NHCO (1-CH ₂ CH ₂ OH-2-Pyd) 3-380 H 7-NHCO (3-Pyd) 3- 381 H 7-NHCO (1-Me-3-Pyd) 3-382 H 7-NHCO (1-CH ₂ CONH ₂ -3-Pyd) 3-383 H 7-NHCO (1-CH ₂ CH ₂ OH-3 -Pyd) 3-384 H 7-NHCO (4-Pyd) 3-385 H 7-NHCO (1-Me-4-Pyd) 3-386 H 7-NHCO (1-CH ₂ CONH ₂ -4-Pyd) 3-387 H 7-NHCO (1-CH ₂ CH ₂ OH-4-Pyd) 3-388 H 7-NHPh 3-389 H 7-NHCONH ₂ 3-390 H 7-NHSO ₂ NH ₂ 3-391 H 7 -NHSO ₂ Me 3-392 H 7-CH ₂ NH ₂ 3-393 H 7-CH ₂ NHMe 3-394 H 7-CH ₂ NMe ₂ 3-395 H 7-CH ₂ NHCH ₂ CH ₂ OH 3-396 H 7-CH ₂ NHCH ₂ COOH 3-397 H 7-CH ₂ NHCH ₂ CONH ₂ 3-398 H 7-CH ₂ NHCH ₂ CH ₂ NH ₂ 3-399 H 7-CH ₂ NHCH ₂ CH ₂ NHMe 3-400 H 7-CH ₂ NHCH ₂ CH ₂ NMe ₂ 3-401 H 7-CH ₂ N (Me) CH ₂ CH ₂ OH 3-402 H 7-CH ₂ N (Me) CH ₂ CONH ₂ 3-403 H 7-CH ₂ N (Me) CH ₂ CH ₂ NH ₂ 3-404 H 7-CH ₂ N (CH ₂ CH ₂ OH) ₂ 3-405 H 7-CH ₂ N ⁺ Me ₃ 3-406 H 7-CH ₂ N ⁺ (Me) ₂ CH ₂ CH ₂ OH 3 -407 H 7-CH ₂ N ⁺ (Me) ₂ CH ₂ CONH ₂ 3-408 H 7-CH ₂ (1-Pyr) 3-409 H 7-CH ₂ (3-OH-1-Pyr) 3-410 H 7-CH ₂ (1-Me-1-Pyr) 3-411 H 7-CH ₂ (1-Pip) 3-412 H 7-CH ₂ (3-OH-1-Pip) 3-413 H 7- CH ₂ (1-Me-1-Pip) 3-414 H 7-CH ₂ (1-Imd) 3-415 H 7-CH ₂ (3-Me-1-Imd) 3-416 H 7-CH ₂ ( 1-Trz) 3-417 H 7-CH ₂ (4-Me-1-Trz) 3-418 H 7-SO ₂ NH ₂ 3-419 H 7-SO ₂ NMe ₂ 3-420 H 7-SO ₂ NHCH ₂ CH ₂ OH 3-421 H 7-SO ₂ NHCH ₂ CH ₂ NH ₂ 3-422 H 7-COOH 3-423 H 7-COOEt 3-424 H 7-CONH ₂ 3-425 H 7-CONHMe 3-426 H 7-CONHEt 3-427 H 7-CONMe ₂ 3-428 H 7-CONEt ₂ 3-429 H 7-CONHPh 3-430 H 7-CO (1-Azt) 3-431 H 7-CO (1-Pyr ) 3-432 H 7-CO (3-OH-1-Pyr) 3-433 H 7-CO (3-NH ₂ -1-Pyr) 3-434 H 7-CO (3-NHMe-1-Pyr) 3-435 H 7-CO (3-Cl-1-Pyr) 3- 436 H 7-CO (3-CN-1-Pyr) 3-437 H 7-CO (3-COOH-1-Pyr) 3-438 H 7-CO (3-CONH ₂ -1-Pyr) 3-439 H 7-CO (1-Pip) 3-440 H 7-CO (4-OH-1-Pip) 3-441 H 7-CO (4-NH ₂ -1-Pip) 3-442 H 7-CO ( 1-Piz) 3-443 H 7-CO (4-Me-1-Piz) 3-444 H 7-CO (4,4-diMe-1-Piz) 3-445 H 7-CO (4-Ph- 1-Piz) 3-446 H 7-CO (4-CH ₂ CH ₂ OH-1-Piz) 3-447 H 7-CO (4-CH ₂ COOH-1-Piz) 3-448 H 7-CO ( _{4-CH 2 CONH 2 -1-} Piz) 3-449 H 7-CO (4-Me-4-CH 2 CH 2 OH-1-Piz) 3-450 H 7-CO (4-Me-4-CH ₂ COOH-1-Piz) 3-451 H 7-CO (4-Me-4-CH ₂ CONH ₂ -1-Piz) 3-452 H 7-CO (4-Mor) 3-453 H 7-CO ( 4-Tmr) 3-454 5-OMe 6-OMe 3-455 5-F 6-F 3-456 5-Cl 6-Cl 3-457 5-Me 6-Me ---------- -----------------------------------------------

[0099]

[Table 4]

[0100]

Embedded image -------------------------------------------------- ------- No. A -------------------------------------------------------- ----------------- 4-1 S-2-Thz [4,5-c] Pyd 4 4-2 S-2-Thz [5,4-c] Pyd 4 -3 S-2-Thz [5,4-b] Pyd ----------------------------------- ----------------------

[0101]

[Table 5]

[0102]

Embedded image -------------------------------------------------- ------- No. R ⁶ --------------------------------------- ------------------ 5-1 H 5-2 F 5-3 Cl 5-4 Me 5-5 Et 5-6 nPr 5-7 nBu 5-8 iBu 5-9 tBu 5-10 CH ₂ OH 5-11 CH ₂ CH ₂ OH 5-12 CF ₃ 5-13 CH ₂ CH ₂ F 5-14 CH ₂ COOH 5-15 CH ₂ CONH ₂ 5-16 CH ₂ CN 5-17 CH ₂ NH ₂ 5-18 CH ₂ NHMe 5-19 CH ₂ NMe ₂ 5-20 CH ₂ CH ₂ NH ₂ 5-21 CH ₂ CH ₂ NHMe 5-22 CH ₂ CH ₂ NMe ₂ 5-23 CH ₂ NHCH ₂ CH ₂ OH 5-24 CH ₂ NHCH ₂ COOH 5-25 CH ₂ NHCH ₂ CONH ₂ 5-26 CH ₂ NHCH ₂ CH ₂ NH ₂ 5-27 CH ₂ NHCH ₂ CH ₂ NHMe 5-28 CH ₂ NHCH ₂ CH ₂ NMe ₂ 5-29 CH ₂ N (Me) CH ₂ CH ₂ OH 5-30 CH ₂ N (Me) CH ₂ CONH ₂ 5-31 CH ₂ N (Me) CH ₂ CH ₂ NH ₂ 5-32 CH ₂ N (CH ₂ CH ₂ OH) ₂ 5-33 SMe 5-34 SEt 5-35 SnPr 5-36 SnBu 5-37 SiBu 5-38 StBu 5-39 SCH ₂ OH 5-40 SCH ₂ CH ₂ OH 5 _{-41 SCF 3 5-42 SCH 2 CH 2} F 5-43 SCH 2 COOH 5-44 SCH 2 CONH 2 5-45 SCH 2 CN 5-46 SCH 2 NH 2 5-47 SCH 2 NHMe 5-48 SCH 2 NMe ₂ 5-49 SCH ₂ CH ₂ NH ₂ 5-50 SCH ₂ CH ₂ NHMe 5-51 SCH ₂ CH ₂ NMe ₂ 5-52 ScPen 5-53 ScHex 5-54 SPh 5-55 S (1-Np) 5- 56 S (2-N p) 5-57 S (4-BiPh) 5-58 S (2-F-Ph) 5-59 S (3-F-Ph) 5-60 S (4-F-Ph) 5-61 S (2 -Me-Ph) 5-62 S (3-Me-Ph) 5-63 S (4-Me-Ph) 5-64 S (2-OMe-Ph) 5-65 S (3-OMe-Ph) 5 -66 S (4-OMe-Ph) 5-67 NH ₂ 5-68 NHMe 5-69 NMe ₂ 5-70 NHCH ₂ CH ₂ OH 5-71 NHCH ₂ CH ₂ F 5-72 NHCH ₂ COOH 5-73 NHCH ₂ CONH ₂ 5-74 NHCH ₂ CH ₂ NH ₂ 5-75 NHCH ₂ CH ₂ NHMe 5-76 NHCH ₂ CH ₂ NMe ₂ 5-77 N (Me) CH ₂ CH ₂ OH 5-78 N (Me) CH _{2 CONH 2 5-79 N (Me) CH} 2 CH 2 NH 2 5-80 N (CH 2 CH 2 OH) 2 5-81 NHcPen 5-82 NHcHex 5-83 NHAc 5-84 NHCOC 3 H 7 5-85 NHCOC ₅ H ₁₁ 5-86 NHCOC ₇ H ₁₅ 5-87 NHCOC ₉ H ₁₉ 5-88 NHCOPh 5-89 NHCO (2-F-Ph) 5-90 NHCO (3-F-Ph) 5-91 NHCO (4- F-Ph) 5-92 NHCO (2-Me-Ph) 5-93 NHCO (3-Me-Ph) 5-94 NHCO (4-Me-Ph) 5-95 NHCO (2-OMe-Ph) 5- 96 NHCO (3-OMe-Ph) 5-97 NHCO (4-OMe-Ph) 5-98 NHCO (3,4-diOH-Ph) 5-99 NHCO (3,4-diOMe-Ph) 5-100 NHCO (3,4,5-triOH-Ph) 5-101 NHCO (3,4,5-triOMe-Ph) 5-102 NHCO (2-Pyd) 5-103 NHCO (1-Me-2-Pyd) 5- 104 NHCO (1-CH ₂ CONH ₂ -2-Pyd) 5-105 NHCO (1-CH ₂ CH ₂ OH-2-Pyd) 5-106 NHCO (3-Pyd) 5-107 NHCO (1-Me-3 -Pyd) 5-108 NHCO (1-CH ₂ CONH ₂ -3-Pyd) 5 -109 NHCO (1-CH ₂ CH ₂ OH-3-Pyd) 5-110 NHCO (4-Pyd) 5-111 NHCO (1-Me-4-Pyd) 5-112 NHCO (1-CH ₂ CONH _2- 4-Pyd) 5-113 NHCO (1-CH ₂ CH ₂ OH-4-Pyd) 5-114 NHPh 5-115 NH (1-Np) 5-116 NH (2-Np) 5-117 NH (4- BiPh) 5-118 NH (2-F-Ph) 5-119 NH (3-F-Ph) 5-120 NH (4-F-Ph) 5-121 NH (2-Me-Ph) 5-122 NH (3-Me-Ph) 5-123 NH (4-Me-Ph) 5-124 NH (2-OMe-Ph) 5-125 NH (3-OMe-Ph) 5-126 NH (4-OMe-Ph) ) 5-127 NHBn 5-128 NH (4-F-Bn) 5-129 NH (4-Cl-Bn) 5-130 NH (4-Me-Bn) 5-131 NH (4-OMe-Bn) 5 -132 NH (4-CONH ₂ -Bn) 5-133 NH (2-Thz) 5-134 NH (2-BThz) 5-135 NH (2-Pyd) 5-136 NH (3-Pyd) 5-137 NH (4-Pyd) 5-138 NHCONH 2 5-139 NHCONHMe 5-140 NHCONHPh 5-141 NHCSNH 2 5-142 NHCSNHMe 5-143 NHCSNHPh 5-144 NHSO 2 NH 2 5-145 NHSO 2 NHMe 5-146 NHSO 2 NHPh 5-147 NHSO ₂ Me 5-148 NHSO ₂ CF3 5-149 NHSO ₂ Ph 5-150 NHSO ₂ (4-F-Ph) 5-151 NHSO ₂ (4-Cl-Ph) 5-152 Ph 5-153 1-Np 5-154 2-Np 5-155 4-BiPh 5-156 2-NH ₂ -Ph 5-157 3-NH ₂ -Ph 5-158 4-NH ₂ -Ph 5-159 2-F-Ph 5-160 3-F-Ph 5-161 4-F-Ph 5-162 2-Cl-Ph 5-163 3-Cl-Ph 5-164 4-Cl-Ph 5-165 2-Me-Ph 5- 166 3-Me-Ph 5-167 4-Me-P h 5-168 2-OMe-Ph 5-169 3-OMe-Ph 5-170 4-OMe-Ph 5-171 Bn 5-172 2-F-Bn 5-173 3-F-Bn 5-174 4- F-Bn 5-175 2-Me-Bn 5-176 3-Me-Bn 5-177 4-Me-Bn 5-178 2-OMe-Bn 5-179 3-OMe-Bn 5-180 4-OMe- Bn 5-181 2-Pyd 5-182 3-Pyd 5-183 4-Pyd 5-184 2-Thn 5-185 2-Prz 5-186 5-Me-2-Prz 5-187 2-Thz 5-188 2-Thd 5-189 CH ₂ (2-Pyd) 5-190 CH ₂ (3-Pyd) 5-191 CH ₂ (4-Pyd) 5-192 COOH 5-193 COOEt 5-194 CONH ₂ 5-195 CONHMe 5-196 CONHEt 5-197 CONMe ₂ 5-198 CONEt ₂ 5-199 CONHCH ₂ CH ₂ OH 5-200 CONHCH ₂ CH ₂ F 5-201 CONHCH ₂ CONH ₂ 5-202 CONHCH ₂ CH ₂ NH ₂ 5-203 CONHCH ₂ CH ₂ NHMe 5-204 CONHCH ₂ CH ₂ NMe ₂ 5-205 CON (Me) CH ₂ CH ₂ OH 5-206 CON (Me) CH ₂ CONH ₂ 5-207 CON (Me) CH ₂ CH ₂ NH ₂ 5 -208 CONHPh 5-209 CO (1-Azt) 5-210 CO (1-Pyr) 5-211 CO (3-OH-1-Pyr) 5-212 CO (3-NH ₂ -1-Pyr) 5- 213 CO (3-NHMe-1-Pyr) 5-214 CO (3-Cl-1-Pyr) 5-215 CO (3-CN-1-Pyr) 5-216 CO (3-COOH-1-Pyr) 5-217 CO (3-CONH ₂ -1-Pyr) 5-218 CO (1-Pip) 5-219 CO (4-OH-1-Pip) 5-220 CO (4-NH ₂ -1-Pip) 5-221 CO (1-Piz) 5-222 CO (4-Me-1-Piz) 5-223 CO (4,4-diMe-1-Piz) 5-224 CO (4-Ph-1-Piz) _{5-225 CO (4-CH 2 CH} 2 OH-1-Piz) 5-226 CO (4-CH 2 COOH-1-Piz) 5-227 CO (4-CH 2 CONH 2 -1-Piz) 5- 228 CO (4-Me-4-CH ₂ CH ₂ OH-1-Piz) 5-229 CO (4-Me-4-CH ₂ COOH-1-Piz) 5-230 CO (4-Me-4-CH ₂ CONH ₂ -1-Piz) 5-231 CO (4-Mor) 5-232 CO (4-Tmr) ------------------------ ---------------------------------

[0103]

[Table 6]

[0104]

Embedded image -------------------------------------------------- ------- No. R ⁷ --------------------------------------- ------------------ 6-1 Me 6-2 Et 6-3 nPr 6-4 iPr 6-5 nBu 6-6 iBu 6-7 tBu 6-8 CH ₂ CH ₂ OH 6-9 CH ₂ CH ₂ CH ₂ OH 6-10 CH ₂ CH (OH) CH ₂ OH 6-11 CH ₂ COOH 6-12 CH ₂ CH ₂ COOH 6-13 CH ₂ CONH ₂ 6-14 CH ₂ CONH ₂ 6-15 CH ₂ CONHMe 6-16 CH ₂ CONHEt 6-17 CH ₂ CONMe ₂ 6-18 CH ₂ CONEt ₂ 6-19 CH ₂ CONHCH ₂ CH ₂ OH 6-20 CH ₂ CONHCH ₂ CONH ₂ 6 -21 CH ₂ CON (Me) CH ₂ CH ₂ OH 6-22 CH ₂ CON (Me) CH ₂ CONH ₂ 6-23 CH ₂ CH ₂ CONH ₂ 6-24 CH ₂ CH ₂ CONH ₂ 6-25 CH ₂ CH ₂ CONHMe 6-26 CH ₂ CH ₂ CONHEt 6-27 CH ₂ CH ₂ CONMe ₂ 6-28 CH ₂ CH ₂ CONEt ₂ 6-29 CH ₂ CH ₂ NH ₂ 6-30 CH ₂ CH ₂ NHMe 6-31 CH ₂ CH ₂ NHEt 6-32 CH ₂ CH ₂ NMe ₂ 6-33 CH ₂ CH ₂ NEt ₂ 6-34 CH ₂ CH ₂ NHCH ₂ CONH ₂ 6-35 CH ₂ CH ₂ N (Me) CH ₂ CONH ₂ 6-36 CH ₂ CH ₂ NHSO ₂ Me 6-37 cPen 6-38 cHex 6-39 Ph 6-40 1-Np 6-41 2-Np 6-42 4-NH ₂ -Ph 6-43 4-NHMe-Ph 6- 44 4-NMe ₂ -Ph 6-45 4-NHAc-Ph 6-46 4-CONH ₂ -Ph 6-47 4-SO ₂ NH ₂ -Ph 6-48 2-F-Ph 6-49 3-F- Ph 6-50 4-F-Ph 6-51 2,4-diF-Ph 6-52 2-Cl-Ph 6-53 3-Cl-Ph 6-54 4-Cl-Ph 6-55 2,4-diCl-Ph 6-56 2-Me -Ph 6-57 3-Me-Ph 6-58 4-Me-Ph 6-59 2,4-diMe-Ph 6-60 2-OMe-Ph 6-61 3-OMe-Ph 6-62 4-OMe -Ph 6-63 Bn 6-64 CH ₂ (1-Np) 6-65 CH ₂ (2-Np) 6-66 4-NH ₂ -Bn 6-67 4-NHMe-Bn 6-68 4-NMe ₂ -Bn 6-69 4-NHAc-Bn 6-70 4-CONH ₂ -Bn 6-71 4-SO ₂ NH ₂ -Bn 6-72 2-F-Bn 6-73 3-F-Bn 6-74 4 -F-Bn 6-75 2,4-diF-Bn 6-76 2-Cl-Bn 6-77 3-Cl-Bn 6-78 4-Cl-Bn 6-79 2,4-diCl-Bn 6- 80 2-Me-Bn 6-81 3-Me-Bn 6-82 4-Me-Bn 6-83 2,4-diMe-Bn 6-84 2-OMe-Bn 6-85 3-OMe-Bn 6- 86 4-OMe-Bn 6-87 PHE 6-88 CH ₂ CH ₂ (1-Np) 6-89 CH ₂ CH ₂ (2-Np) 6-90 4-NH ₂ -PHE 6-91 4-NHMe- PHE 6-92 4-NMe ₂ -PHE 6-93 4-NHAc-PHE 6-94 4-CONH ₂ -PHE 6-95 4-SO ₂ NH ₂ -PHE 6-96 2-F-PHE 6-97 3 -F-PHE 6-98 4-F-PHE 6-99 2,4-diF-PHE 6-100 2-Cl-PHE 6-101 3-Cl-PHE 6-102 4-Cl-PHE 6-103 2 , 4-diCl-PHE 6-104 2-Me-PHE 6-105 3-Me-PHE 6-106 4-Me-PHE 6-107 2,4-diMe-PHE 6-108 2-OMe-PHE 6- 109 3-OMe-PHE 6-110 4-OMe-PHE 6-111 2-Pyd 6-112 3-Pyd 6-113 4-Pyd 6-114 CH ₂ (2-Pyd) 6-115 CH ₂ (3- Pyd) 6-116 CH ₂ (4 -Pyd) 6-117 CH ₂ CH ₂ (2-Pyd) 6-118 CH ₂ CH ₂ (3-Pyd) 6-119 CH ₂ CH ₂ (4-Pyd) ----------- ----------------------------------------------

[0105]

[Table 7]

[0106]

Embedded image -------------------------------------------------- ------- No. n R ⁸ R ⁹ ------------------------------------ --------------------- 7-1 2 H NH ₂ 7-2 2 H NHMe 7-3 2 H NHEt 7-4 2 H NMe ₂ 7-5 2 H NEt ₂ 7-6 2 H NHCH ₂ CH ₂ OH 7-7 2 H NHCH ₂ COOH 7-8 2 H NHCH ₂ CONH ₂ 7-9 2 HN (Me) CH ₂ CH ₂ OH 7-10 2 HN ( Me) CH ₂ COOH 7-11 2 HN (Me) CH ₂ CONH ₂ 7-12 2 HN (CH ₂ CH ₂ OH) ₂ 7-13 2 H 1-Pyr 7-14 2 H 1-Pip 7-15 2 H 1-Piz 7-16 2 H 4-Me-1-Piz 7-17 2 H 4-Mor 7-18 2 H 4-Tmr 7-19 1 H 2-Pyr 7-20 1 H 2-Pip 7- 21 1 H 3-Mor 7-22 1 H 3-Tmr 7-23 1 H 3-Pyr 7-24 1 H 3-Pip 7-25 2 Me NH 2 7-26 2 Me NHMe 7-27 2 Me NHEt 7 -28 2 Me NMe ₂ 7-29 2 Me NEt ₂ 7-30 2 Me NHCH ₂ CH ₂ OH 7-31 2 Me NHCH ₂ COOH 7-32 2 Me NHCH ₂ CONH ₂ 7-33 2 Me N (Me) CH _{2 CH 2 OH 7-34 2 Me N} (Me) CH 2 COOH 7-35 2 Me N (Me) CH 2 CONH 2 7-36 2 Me N (CH 2 CH 2 OH) 2 7-37 2 Me 1- Pyr 7-38 2 Me 1-Pip 7-39 2 Me 1-Piz 7-40 2 Me 4-Me-1-Piz 7-41 2 Me 4-Mor 7-42 2 Me 4-Tmr 7-43 1 Me 2-Pyr 7-44 1 Me 2-Pip 7-45 1 Me 3-Mor 7-46 1 Me 3-Tmr 7-47 1 Me 3-Pyr 7-48 1 Me 3-Pip 7 -49 2 Et NH ₂ 7-50 2 Et NHMe 7-51 2 Et NHEt 7-52 2 Et NMe ₂ 7-53 2 Et NEt ₂ 7-54 2 Et NHCH ₂ CH ₂ OH 7-55 2 Et NHCH ₂ COOH 7-56 2 Et NHCH ₂ CONH ₂ 7-57 2 Et N (Me) CH ₂ CH ₂ OH 7-58 2 Et N (Me) CH ₂ COOH 7-59 2 Et N (Me) CH ₂ CONH ₂ 7- 60 2 Et N (CH ₂ CH ₂ OH) ₂ 7-61 2 Et 1-Pyr 7-62 2 Et 1-Pip 7-63 2 Et 1-Piz 7-64 2 Et 4-Me-1-Piz 7- 65 2 Et 4-Mor 7-66 2 Et 4-Tmr 7-67 1 Et 2-Pyr 7-68 1 Et 2-Pip 7-69 1 Et 3-Mor 7-70 1 Et 3-Tmr 7-71 1 Et 3-Pyr 7-72 1 Et 3 -Pip 7-73 2 CH 2 CH 2 OH NH 2 7-74 2 CH 2 CH 2 OH NHMe 7-75 2 CH 2 CH 2 OH NHEt 7-76 2 CH 2 CH ₂ OH NMe ₂ 7-77 2 CH ₂ CH ₂ OH NEt ₂ 7-79 2 CH ₂ CH ₂ OH NHCH ₂ CH ₂ OH 7-80 2 CH ₂ CH ₂ OH NHCH ₂ COOH 7-81 2 CH ₂ CH ₂ OH NHCH ₂ CONH ₂ 7-82 2 CH ₂ CH ₂ OH N (Me) CH ₂ CH ₂ OH 7-83 2 CH ₂ CH ₂ OH N (Me) CH ₂ COOH 7-84 2 CH ₂ CH ₂ OH N (Me _{) CH 2 CONH 2 7-85 2 CH} 2 CH 2 OH N (CH 2 CH 2 OH) 2 7-86 2 CH 2 CH 2 OH 1-Pyr 7-87 2 CH 2 CH 2 OH 1-Pip 7-88 2 CH ₂ CH ₂ OH 1-Piz 7-89 2 CH ₂ CH ₂ OH 4-Me-1-Piz 7-90 2 CH ₂ CH ₂ OH 4-Mor 7-91 2 CH ₂ CH ₂ OH 4-Tmr 7 -92 1 CH ₂ CH ₂ OH 2-Pyr 7-93 1 CH ₂ CH ₂ OH 2-Pip 7-94 1 CH ₂ CH ₂ OH 3-Mor 7-95 1 CH ₂ CH ₂ OH 3-Tmr 7-96 1 CH ₂ CH _{2 OH 3-Pyr 7-97 1 CH 2} CH 2 OH 3-Pip 7-98 2 CH 2 CONH 2 NH 2 7-99 2 CH 2 CONH 2 NHMe 7-100 2 CH 2 CONH 2 NHEt 7-101 2 CH 2 CONH ₂ NMe ₂ 7-102 2 CH ₂ CONH ₂ NEt ₂ 7-103 2 CH ₂ CONH ₂ NHCH ₂ CH ₂ OH 7-104 2 CH ₂ CONH ₂ NHCH ₂ COOH 7-105 2 CH ₂ CONH ₂ NHCH ₂ CONH ₂ 7-106 2 CH ₂ CONH ₂ N (Me) CH ₂ CH ₂ OH 7-107 2 CH ₂ CONH ₂ N (Me) CH ₂ COOH 7-108 2 CH ₂ CONH ₂ N (Me) CH ₂ CONH ₂ 7- 109 2 CH ₂ CONH ₂ N (CH ₂ CH ₂ OH) ₂ 7-110 2 CH ₂ CONH ₂ 1-Pyr 7-111 2 CH ₂ CONH ₂ 1-Pip 7-112 2 CH ₂ CONH ₂ 1-Piz 7- 113 2 CH ₂ CONH ₂ 4-Me-1-Piz 7-114 2 CH ₂ CONH ₂ 4-Mor 7-115 2 CH ₂ CONH ₂ 4-Tmr 7-116 1 CH ₂ CONH ₂ 2-Pyr 7-117 1 CH ₂ CONH ₂ 2-Pip 7-118 1 CH ₂ CONH ₂ 3-Mor 7-119 1 CH ₂ CONH ₂ 3-Tmr 7-120 1 CH ₂ CONH ₂ 3-Pyr 7-121 1 CH ₂ CONH ₂ 3- Pip 7-122 2 CH ₂ CH ₂ NH ₂ NH ₂ 7-123 2 CH ₂ CH ₂ NH ₂ NHMe 7-124 2 CH ₂ CH ₂ NH ₂ NHEt 7-125 2 CH ₂ CH ₂ NH ₂ NMe ₂ 7-126 2 CH ₂ CH ₂ NH ₂ NEt ₂ 7-127 2 CH ₂ CH ₂ NH ₂ NHCH ₂ CH ₂ OH 7-128 2 CH ₂ CH ₂ NH ₂ NHCH ₂ COOH 7-129 2 CH ₂ CH ₂ NH ₂ NHCH ₂ CONH ₂ 7-130 2 CH ₂ CH ₂ NH ₂ N (Me) CH ₂ CH ₂ OH 7-131 2 CH ₂ CH ₂ NH ₂ N (Me) CH ₂ COOH 7-132 2 CH ₂ CH ₂ NH ₂ N (Me) CH ₂ CONH ₂ 7-133 2 CH ₂ CH ₂ NH ₂ N (CH ₂ (CH ₂ OH) ₂ 7-134 2 CH ₂ CH ₂ NH ₂ 1-Pyr 7-135 2 CH ₂ CH ₂ NH ₂ 1-Pip 7-136 2 CH ₂ CH ₂ NH ₂ 1-Piz 7-137 2 CH ₂ CH ₂ NH ₂ 4-Me-1-Piz 7-138 2 CH ₂ CH ₂ NH ₂ 4-Mor 7-139 2 CH ₂ CH ₂ NH ₂ 4-Tmr 7-140 1 CH ₂ CH ₂ NH ₂ 2-Pyr 7-141 1 CH ₂ CH ₂ NH ₂ 2-Pip 7-142 1 CH ₂ CH ₂ NH ₂ 3-Mor 7-143 1 CH ₂ CH ₂ NH ₂ 3-Tmr 7-144 1 CH ₂ CH ₂ NH ₂ 3 -Pyr 7-145 1 CH ₂ CH ₂ NH ₂ 3-Pip 7-146 2 CH ₂ CH = CH ₂ NH ₂ 7-147 2 CH ₂ CH = CH ₂ NHMe 7-148 2 CH ₂ CH = CH ₂ NHEt 7 -149 2 CH ₂ CH = CH ₂ NMe ₂ 7-150 2 CH ₂ CH = CH ₂ NEt ₂ 7-151 2 CH ₂ CH = CH ₂ NHCH ₂ CH ₂ OH 7-152 2 CH ₂ CH = CH ₂ NHCH ₂ COOH 7-153 2 CH ₂ CH = CH ₂ NHCH ₂ CONH ₂ 7-154 2 CH ₂ CH = CH ₂ N (Me) CH ₂ CH ₂ OH 7-155 2 CH ₂ CH = CH ₂ N (Me) CH ₂ COOH 7-156 2 CH ₂ CH = CH ₂ N (Me) CH ₂ CONH ₂ 7-157 2 CH ₂ CH = CH ₂ N (CH ₂ CH ₂ OH) ₂ 7-158 2 CH _{2 CH = CH 2 1-Pyr} 7-159 2 CH 2 CH = CH 2 1-Pip 7-160 2 CH 2 CH = CH 2 1-Piz 7-161 2 CH 2 CH = CH 2 4-Me-1- Piz 7-162 2 CH ₂ CH = CH ₂ 4-Mor 7-163 2 CH ₂ CH = CH ₂ 4-Tmr 7-164 1 CH ₂ CH = CH ₂ 2-Pyr 7-165 1 CH ₂ CH = CH ₂ 2-Pip 7-166 1 CH ₂ CH = CH ₂ 3-Mor 7-167 1 CH ₂ CH = CH ₂ 3-Tmr 7-168 1 CH ₂ CH = CH ₂ 3-Pyr 7-169 1 CH ₂ CH = CH ₂ 3-Pip 7-170 2 Ph NH ₂ 7-171 2 Ph NHMe 7-172 2 Ph NHEt 7-173 2 Ph NMe ₂ 7-174 2 Ph NEt ₂ 7-175 2 Ph NHCH ₂ CH ₂ OH 7- 176 2 Ph NHCH ₂ COOH 7-177 2 Ph NHCH ₂ CONH ₂ 7-178 2 Ph N (Me) CH ₂ CH ₂ OH 7-179 2 Ph N (Me) CH ₂ COOH 7-180 2 Ph N (Me) CH ₂ CONH ₂ 7-181 2 Ph N (CH ₂ CH ₂ OH) ₂ 7-182 2 Ph 1-Pyr 7-183 2 Ph 1-Pip 7-184 2 Ph 1-Piz 7-185 2 Ph 4-Me -1-Piz 7-186 2 Ph 4-Mor 7-187 2 Ph 4-Tmr 7-188 1 Ph 2-Pyr 7-189 1 Ph 2-Pip 7-190 1 Ph 3-Mor 7-191 1 Ph 3 -Tmr 7-192 1 Ph 3-Pyr 7-193 1 Ph 3-Pip 7-194 2 1-Np NH 2 7-195 2 1-Np NHMe 7-196 2 1-Np NHEt 7-197 2 1-Np _{NMe 2 7-198 2 1-Np NEt} 2 7-199 2 1-Np NHCH 2 CH 2 OH 7-200 2 1-Np NHCH 2 COOH 7-201 2 1-Np NHCH 2 CONH 2 7-202 2 1- Np N (Me) CH ₂ CH ₂ OH 7- 203 2 1-Np N (Me ) CH 2 COOH 7-204 2 1-Np N (Me) CH 2 CONH 2 7-205 2 1-Np N (CH 2 CH 2 OH) 2 7-206 2 1-Np 1-Pyr 7-207 2 1-Np 1-Pip 7-208 2 1-Np 1-Piz 7-209 2 1-Np 4-Me-1-Piz 7-210 2 1-Np 4-Mor 7-211 2 1-Np 4-Tmr 7-212 1 1-Np 2-Pyr 7-213 1 1-Np 2-Pip 7-214 1 1-Np 3-Mor 7-215 1 1-Np 3-Tmr 7-216 1 1-Np 3-Pyr 7-217 1 1-Np 3-Pip 7-218 2 2-Np NH ₂ 7-219 2 2-Np NHMe 7-220 2 2-Np NHEt 7-221 2 2-Np NMe ₂ 7-222 2 2-Np NEt ₂ 7-223 2 2-Np NHCH ₂ CH ₂ OH 7-224 2 2-Np NHCH ₂ COOH 7-225 2 2-Np NHCH ₂ CONH ₂ 7-226 2 2-Np _{N (Me) CH 2 CH 2} OH 7-227 2 2-Np N (Me) CH 2 COOH 7-228 2 2-Np N (Me) CH 2 CONH 2 7-229 2 2-Np N (CH 2 CH ₂ OH) ₂ 7-230 2 2-Np 1-Pyr 7-231 2 2-Np 1-Pip 7-232 2 2-Np 1-Piz 7-233 2 2-Np 4-Me-1-Piz 7- 234 2 2-Np 4-Mor 7-235 2 2-Np 4-Tmr 7-236 1 2-Np 2-Pyr 7-237 1 2-Np 2-Pip 7-238 1 2-Np 3-Mor 7- 239 1 2-Np 3-Tmr 7-240 1 2-Np 3-Pyr 7-241 1 2-Np 3-Pip 7-242 2 2-Thz NH ₂ 7-243 2 2-Thz NHMe 7-244 2 2 -Thz NHEt 7-245 2 2-Thz NMe 2 7-246 2 2-Thz NEt 2 7-247 2 2-Thz NHCH 2 CH 2 OH 7-248 2 2-Thz NHCH 2 COOH 7-2 49 2 2-Thz NHCH ₂ CONH ₂ 7-250 2 2-Thz N (Me) CH ₂ CH ₂ OH 7-251 22 2-Thz N (Me) CH ₂ COOH 7-252 2 2-Thz N (Me) CH ₂ CONH ₂ 7-253 2 2-Thz N (CH ₂ CH ₂ OH) ₂ 7-254 2 2-Thz 1-Pyr 7-255 2 2-Thz 1-Pip 7-256 2 2-Thz 1-Piz 7-257 2 2-Thz 4-Me-1-Piz 7-258 2 2-Thz 4-Mor 7-259 2 2-Thz 4-Tmr 7-260 1 2-Thz 2-Pyr 7-261 1 2- Thz 2-Pip 7-262 1 2-Thz 3-Mor 7-263 1 2-Thz 3-Tmr 7-264 1 2-Thz 3-Pyr 7-265 1 2-Thz 3-Pip 7-266 2 2- _{Tdz NH 2 7-267 2 2-Tdz} NHMe 7-268 2 2-Tdz NHEt 7-269 2 2-Tdz NMe 2 7-270 2 2-Tdz NEt 2 7-271 2 2-Tdz NHCH 2 CH 2 OH 7 _{-272 2 2-Tdz NHCH 2 COOH} 7-273 2 2-Tdz NHCH 2 CONH 2 7-274 2 2-Tdz N (Me) CH 2 CH 2 OH 7-275 2 2-Tdz N (Me) CH 2 COOH 7-276 2 2-Tdz N (Me) CH ₂ CONH ₂ 7-277 2 2-Tdz N (CH ₂ CH ₂ OH) ₂ 7-278 2 2-Tdz 1-Pyr 7-279 2 2-Tdz 1- Pip 7-280 2 2-Tdz 1-Piz 7-281 2 2-Tdz 4-Me-1-Piz 7-282 2 2-Tdz 4-Mor 7-283 2 2-Tdz 4-Tmr 7-284 1 2 -Tdz 2-Pyr 7-285 1 2-Tdz 2-Pip 7-286 1 2-Tdz 3-Mor 7-287 1 2-Tdz 3-Tmr 7-288 1 2-Tdz 3-Pyr 7-289 1 2 -Tdz 3-Pip 7-290 2 2-Pyd NH ₂ 7-291 2 2-Pyd NHMe 7-292 2 2-Pyd NHEt 7-293 2 2-Pyd NMe ₂ 7-294 2 2-Pyd NEt ₂ 7-295 2 2-Pyd NHCH ₂ CH ₂ OH 7-296 2 2-Pyd NHCH ₂ COOH 7-297 2 2-Pyd NHCH ₂ CONH ₂ 7-298 2 2-Pyd N (Me) CH ₂ CH ₂ OH 7-299 2 2-Pyd N (Me) CH ₂ COOH 7-300 2 2-Pyd N (Me) CH ₂ CONH ₂ 7-301 2 2-Pyd N (CH ₂ CH ₂ OH) ₂ 7-302 2 2-Pyd 1-Pyr 7-303 2 2-Pyd 1-Pip 7-304 2 2-Pyd 1-Piz 7-305 2 2-Pyd 4 -Me-1-Piz 7-306 2 2-Pyd 4-Mor 7-307 2 2-Pyd 4-Tmr 7-308 1 2-Pyd 2-Pyr 7-309 1 2-Pyd 2-Pip 7-310 1 2-Pyd 3-Mor 7-311 1 2-Pyd 3-Tmr 7-312 1 2-Pyd 3-Pyr 7-313 1 2-Pyd 3-Pip 7-314 2 3-Pyd NH 2 7-315 2 3 -Pyd NHMe 7-316 2 3-Pyd NHEt 7-317 2 3-Pyd NMe ₂ 7-318 2 3-Pyd NEt ₂ 7-319 2 3-Pyd NHCH ₂ CH ₂ OH 7-320 2 3-Pyd NHCH ₂ COOH 7-321 2 3-Pyd NHCH ₂ CONH ₂ 7-322 2 3-Pyd N (Me) CH ₂ CH ₂ OH 7-323 2 3-Pyd N (Me) CH ₂ COOH 7-324 2 3-Pyd N _{(Me) CH 2 CONH 2 7-325} 2 3-Pyd N (CH 2 CH 2 OH) 2 7-326 2 3-Pyd 1-Pyr 7-327 2 3-Pyd 1-Pip 7-328 2 3-Pyd 1-Piz 7-329 2 3-Pyd 4-Me-1-Piz 7-330 2 3-Pyd 4-Mor 7-331 2 3-Pyd 4-Tmr 7-332 1 3-Pyd 2-Pyr 7-333 1 3-Pyd 2-Pip 7-334 1 3-Pyd 3-Mor 7-335 1 3-Pyd 3-Tmr 7-336 1 3-Pyd 3-Pyr 7-337 1 3-Pyd 3-Pip 7-338 2 4-Pyd NH ₂ 7-339 2 4-Pyd NHMe 7-340 2 4-Pyd NHEt 7-341 2 4 -Pyd NMe ₂ 7-342 2 4-Pyd NEt ₂ 7-343 2 4-Pyd NHCH ₂ CH ₂ OH 7-344 2 4-Pyd NHCH ₂ COOH 7-345 2 4-Pyd NHCH ₂ CONH ₂ 7-346 2 4-Pyd N (Me) CH 2 CH 2 OH 7-347 2 4-Pyd N (Me) CH 2 COOH 7-348 2 4-Pyd N (Me) CH 2 CONH 2 7-349 2 4-Pyd N ( (CH ₂ CH ₂ OH) ₂ 7-350 2 4-Pyd 1-Pyr 7-351 2 4-Pyd 1-Pip 7-352 2 4-Pyd 1-Piz 7-353 2 4-Pyd 4-Me-1- Piz 7-354 2 4-Pyd 4-Mor 7-355 2 4-Pyd 4-Tmr 7-356 1 4-Pyd 2-Pyr 7-357 1 4-Pyd 2-Pip 7-358 1 4-Pyd 3- Mor 7-359 1 4-Pyd 3-Tmr 7-360 1 4-Pyd 3-Pyr 7-361 1 4-Pyd 3-Pip 7-362 2 2-BThz NH ₂ 7-363 2 2-BThz NHMe 7- 364 2 2-BThz NHEt 7-365 2 2-BThz NMe ₂ 7-366 2 2-BThz NEt ₂ 7-367 2 2-BThz NHCH ₂ CH ₂ OH 7-368 2 2-BThz NHCH ₂ COOH 7-369 2 2-BThz NHCH ₂ CONH ₂ 7-370 2 2-BThz N (Me) CH ₂ CH ₂ OH 7-371 2 2-BThz N (Me) CH ₂ COOH 7-372 2 2-BThz N (Me) CH ₂ CONH ₂ 7-373 2 2-BThz N (CH ₂ CH ₂ OH) ₂ 7-374 2 2-BThz 1-Pyr 7-375 2 2-BThz 1-Pip 7-376 2 2-BThz 1-Piz 7- 377 2 2-BThz 4-Me-1-Piz 7-378 2 2-BThz 4-Mor 7-379 2 2-BThz 4-Tmr 7-380 1 2-BThz 2-Pyr 7-381 1 2-BThz 2-Pip 7-382 1 2-BThz 3-Mor 7-383 1 2-BThz 3-Tmr 7-384 1 2-BThz 3-Pyr 7-385 1 2-BThz 3-Pip 7-386 2 2-BThn NH ₂ 7-387 2 2-BThn NHMe 7-388 2 2- BThn NHEt 7-389 2 2-BThn NMe ₂ 7-390 2 2-BThn NEt ₂ 7-391 2 2-BThn NHCH ₂ CH ₂ OH 7-392 2 2-BThn NHCH ₂ COOH 7-393 2 2-BThn NHCH ₂ CONH ₂ 7-394 2 2-BThn N (Me) CH ₂ CH ₂ OH 7-395 2 2-BThn N (Me) CH ₂ COOH 7-396 2 2-BThn N (Me) CH ₂ CONH ₂ 7- 397 2 2-BThn N (CH ₂ CH ₂ OH) ₂ 7-398 2 2-BThn 1-Pyr 7-399 2 2-BThn 1-Pip 7-400 2 2-BThn 1-Piz 7-401 2 2- BThn 4-Me-1-Piz 7-402 2 2-BThn 4-Mor 7-403 2 2-BThn 4-Tmr 7-404 1 2-BThn 2-Pyr 7-405 1 2-BThn 2-Pip 7- 406 1 2-BThn 3-Mor 7-407 1 2-BThn 3-Tmr 7-408 1 2-BThn 3-Pyr 7-409 1 2-BThn 3-Pip 7-410 2 Bn NH 2 7-411 2 Bn NHMe 7-412 2 Bn NHEt 7-413 2 Bn NMe ₂ 7-414 2 Bn NEt ₂ 7-415 2 Bn NHCH ₂ CH ₂ OH 7-416 2 Bn NHCH ₂ COOH 7-417 2 Bn NHCH ₂ CONH ₂ 7- 418 2 Bn N (Me) CH 2 CH 2 OH 7-419 2 Bn N (Me) CH 2 COOH 7-420 2 Bn N (Me) CH 2 CONH 2 7-421 2 Bn N (CH 2 CH 2 OH ) ₂ 7-422 2 Bn 1-Pyr 7-423 2 Bn 1-Pip 7-424 2 Bn 1-Piz 7-425 2 Bn 4-Me-1-Piz 7-426 2 Bn 4-Mor 7-427 2 Bn 4-Tmr 7-428 1 Bn 2-Pyr 7-429 1 Bn 2-Pip 7-430 1 Bn 3-Mor 7-431 1 Bn 3-Tmr 7-432 1 Bn 3-Pyr 7-433 1 Bn 3 -Pip 7-434 2 CH ₂ (1-Np) NH ₂ 7-435 2 CH ₂ (1-Np) NHMe 7-436 2 CH ₂ (1-Np) NHEt 7-437 2 CH ₂ (1-Np) NMe ₂ 7-438 2 CH ₂ (1-Np) NEt ₂ 7-439 2 CH ₂ (1-Np) NHCH ₂ CH ₂ OH 7-440 2 CH ₂ (1-Np) NHCH ₂ COOH 7-441 2 CH ₂ (1-Np) NHCH ₂ CONH ₂ 7-442 2 CH ₂ (1-Np) N (Me) CH ₂ CH ₂ OH 7-443 2 CH ₂ (1-Np) N (Me) CH ₂ COOH 7- _{444 2 CH 2 (1-Np} ) N (Me) CH 2 CONH 2 7-445 2 CH 2 (1-Np) N (CH 2 CH 2 OH) 2 7-446 2 CH 2 (1-Np) 1- Pyr 7-447 2 CH ₂ (1-Np) 1-Pip 7-448 2 CH ₂ (1-Np) 1-Piz 7-449 2 CH ₂ (1-Np) 4-Me-1-Piz 7-450 2 CH ₂ (1-Np) 4-Mor 7-451 2 CH ₂ (1-Np) 4-Tmr 7-452 1 CH ₂ (1-Np) 2-Pyr 7-453 1 CH ₂ (1-Np) 2-Pip 7-454 1 CH ₂ (1-Np) 3-Mor 7-455 1 CH ₂ (1-Np) 3-Tmr 7-456 1 CH ₂ (1-Np) 3-Pyr 7-457 1 CH ₂ (1-Np) 3-Pip 7-458 2 CH ₂ (2-Np) NH ₂ 7-459 2 CH ₂ (2-Np) NHMe 7-460 2 CH ₂ (2-Np) NHEt 7-461 2 CH ₂ (2-Np) _{NMe 2 7-462 2 CH 2 (2} -Np) NEt 2 7-463 2 CH 2 (2-Np) NHCH 2 CH 2 OH 7-464 2 CH 2 (2-Np) NHCH 2 COOH 7-465 2 CH ₂ (2-Np) NHCH ₂ CONH ₂ 7-466 2 CH ₂ (2-Np) N (Me) CH ₂ CH ₂ OH 7-467 2 CH ₂ (2-Np) N (Me) CH ₂ COOH 7- _{468 2 CH 2 (2-Np} ) N (Me) CH 2 CONH 2 7-469 2 CH 2 (2-Np) N (CH 2 CH 2 OH) 2 7-470 2 CH 2 (2-Np) 1- Pyr 7-471 2 CH ₂ (2-Np) 1-Pip 7-472 2 CH ₂ (2-Np) 1-Piz 7-473 2 CH ₂ (2-Np) 4-Me-1-Piz 7-474 2 CH ₂ (2-Np) 4-Mor 7-475 2 CH ₂ (2-Np) 4-Tmr 7-476 1 CH ₂ (2-Np) 2-Pyr 7-477 1 CH ₂ (2-Np) 2-Pip 7-478 1 CH ₂ (2-Np) 3-Mor 7-479 1 CH ₂ (2-Np) 3-Tmr 7-480 1 CH ₂ (2-Np) 3-Pyr 7-481 1 CH ₂ (2-Np) 3-Pip 7-482 2 CH ₂ (2-Thz) NH ₂ 7-483 2 CH ₂ (2-Thz) NHMe 7-484 2 CH ₂ (2-Thz) NHEt 7-485 2 _{CH 2 (2-Thz) NMe} 2 7-486 2 CH 2 (2-Thz) NEt 2 7-487 2 CH 2 (2-Thz) NHCH 2 CH 2 OH 7-488 2 CH 2 (2-Thz) NHCH ₂ COOH 7-489 2 CH ₂ (2-Thz) NHCH ₂ CONH ₂ 7-490 2 CH ₂ (2-Thz) N (Me) CH ₂ CH ₂ OH 7-491 2 CH ₂ (2-Thz) N ( _{Me) CH 2 COOH 7-492 2 CH} 2 (2-Thz) N (Me) CH 2 CONH 2 7-493 2 CH 2 (2-Thz) N (CH 2 CH 2 OH) 2 7-494 2 CH 2 (2-Thz) 1-Pyr 7-495 2 CH ₂ (2-Thz) 1-Pip 7-496 2 CH ₂ (2-Thz) 1-Piz 7-497 2 CH ₂ (2-Thz) 4-Me -1-Piz 7-498 2 CH ₂ (2-Thz) 4-Mor 7-499 2 CH ₂ (2-Thz) 4-Tmr 7-500 1 CH ₂ (2-Thz) 2-Pyr 7-501 1 CH ₂ (2-Thz) 2-Pip 7-502 1 CH ₂ (2-Thz) 3-Mor 7-503 1 CH ₂ (2-Thz) 3-Tmr 7-504 1 CH ₂ (2-Thz) 3 _{-Pyr 7-505 1 CH 2 (2-} Thz) 3-Pip 7-506 2 CH 2 (2-Tdz) NH 2 7-507 2 CH 2 (2-Tdz) NHMe 7-508 2 CH 2 (2- Tdz) NHEt 7-509 2 CH ₂ (2-Tdz) NMe ₂ 7-510 2 CH ₂ (2-Tdz) NEt ₂ 7-511 2 CH ₂ (2-Tdz) NHCH ₂ CH ₂ OH 7-512 2 CH _{2 (2-Tdz) NHCH 2} COOH 7-513 2 CH 2 (2-Tdz) NHCH 2 CONH 2 7-514 2 CH 2 (2-Tdz) N (Me) CH 2 CH 2 OH 7-515 2 CH 2 (2-Tdz) N (Me ) CH 2 COOH 7-516 2 CH 2 (2-Tdz) N (Me) CH 2 CONH 2 7-517 2 CH 2 (2-Tdz) N (CH 2 CH 2 OH) ₂ 7-518 2 CH ₂ (2-Tdz) 1-Pyr 7-519 2 CH ₂ (2-Tdz) 1-Pip 7-520 2 CH ₂ (2-Tdz) 1-Piz 7-521 2 CH ₂ ( 2-Tdz) 4-Me-1-Piz 7-522 2 CH ₂ (2-Tdz) 4-Mor 7-523 2 CH ₂ (2-Tdz) 4-Tmr 7-524 1 CH ₂ (2-Tdz) 2-Pyr 7-525 1 CH ₂ (2-Tdz) 2-Pip 7-526 1 CH ₂ (2-Tdz) 3-Mor 7-527 1 CH ₂ (2-Tdz) 3-Tmr 7-528 1 CH ₂ (2-Tdz) 3-Pyr 7-529 1 CH ₂ (2-Tdz) 3-Pip 7-530 2 CH ₂ (2-Pyd) NH ₂ 7-531 2 CH ₂ (2-Pyd) NHMe 7-532 2 CH ₂ (2 _{-Pyd) NHEt 7-533 2 CH 2 (} 2-Pyd) NMe 2 7-534 2 CH 2 (2-Pyd) NEt 2 7-535 2 CH 2 (2-Pyd) NHCH 2 CH 2 OH 7-536 2 _{CH 2 (2-Pyd) NHCH} 2 COOH 7-537 2 CH 2 (2-Pyd) NHCH 2 CONH 2 7-538 2 CH 2 (2-Pyd) N (Me) CH 2 CH 2 OH 7-539 2 CH _{2 (2-Pyd) N (} Me) CH 2 COOH 7-540 2 CH 2 (2-Pyd) N (Me) CH 2 CONH 2 7-541 2 CH 2 (2-Pyd) N (CH 2 CH 2 OH ) ₂ 7-542 2 CH ₂ (2-Pyd) 1-Pyr 7-543 2 CH ₂ (2-Pyd) 1-Pip 7-544 2 CH ₂ (2-Pyd) 1-Piz 7-545 2 CH ₂ (2-Pyd) 4-Me-1-Piz 7-546 2 CH ₂ (2-Pyd) 4-Mor 7-547 2 CH ₂ (2-Pyd) 4-Tmr 7-548 1 CH ₂ (2-Pyd ) 2-Pyr 7-549 1 CH ₂ (2-Pyd) 2-Pip 7-550 1 CH ₂ (2-Pyd) 3-Mor 7-551 1 CH ₂ (2-Pyd) 3-Tmr 7-552 1 _{CH 2 (2-Pyd) 3} -Pyr 7-553 1 CH 2 (2-Pyd) 3-Pip 7-554 2 CH 2 (3-Pyd) NH 2 7-555 2 CH 2 (3-Pyd) NHMe 7 -556 2 CH ₂ (3-Pyd) NHEt 7-557 2 CH ₂ (3-Pyd) NMe ₂ 7-558 2 CH ₂ (3-Pyd) NEt ₂ 7-559 2 CH ₂ (3-Pyd) NHCH ₂ CH ₂ OH 7-560 2 CH ₂ (3-Pyd) NHCH ₂ COOH 7-561 2 CH ₂ (3-Pyd) NHCH ₂ CONH ₂ 7-562 2 CH ₂ ( 3-Pyd) N (Me) CH ₂ CH ₂ OH 7-563 2 CH ₂ (3-Pyd) N (Me) CH ₂ COOH 7-564 2 CH ₂ (3-Pyd) N (Me) CH ₂ CONH ₂ 7-565 2 CH ₂ (3-Pyd) N (CH ₂ CH ₂ OH) ₂ 7-566 2 CH ₂ (3-Pyd) 1-Pyr 7-567 2 CH ₂ (3-Pyd) 1-Pip 7- 568 2 CH ₂ (3-Pyd) 1-Piz 7-569 2 CH ₂ (3-Pyd) 4-Me-1-Piz 7-570 2 CH ₂ (3-Pyd) 4-Mor 7-571 2 CH ₂ (3-Pyd) 4-Tmr 7-572 1 CH ₂ (3-Pyd) 2-Pyr 7-573 1 CH ₂ (3-Pyd) 2-Pip 7-574 1 CH ₂ (3-Pyd) 3-Mor 7-575 1 CH ₂ (3-Pyd) 3-Tmr 7-576 1 CH ₂ (3-Pyd) 3-Pyr 7-577 1 CH ₂ (3-Pyd) 3-Pip 7-578 2 CH ₂ (4 -Pyd) NH ₂ 7-579 2 CH ₂ (4-Pyd) NHMe 7-580 2 CH ₂ (4-Pyd) NHEt 7-581 2 CH ₂ (4-Pyd) NMe ₂ 7-582 2 CH ₂ (4 -Pyd) NEt ₂ 7-583 2 CH ₂ (4-Pyd) NHCH ₂ CH ₂ OH 7-584 2 CH ₂ (4-Pyd) NHCH ₂ COOH 7-585 2 CH ₂ (4-Pyd) NHCH ₂ CONH ₂ 7-586 2 CH ₂ (4-Pyd) N (Me) CH ₂ CH ₂ OH 7-587 2 CH ₂ (4-Pyd) N (Me) CH ₂ COOH 7-588 2 CH ₂ (4-Pyd) N (Me) CH ₂ CONH ₂ 7-589 2 CH ₂ (4-Pyd) N (CH ₂ CH ₂ OH) ₂ 7-590 2 CH ₂ (4-Pyd) 1-Pyr 7-591 2 CH ₂ (4- Pyd) 1-Pip 7-592 2 CH ₂ (4-Pyd) 1-Piz 7-593 2 CH ₂ (4-Pyd) 4-Me-1-Piz 7-594 2 CH ₂ (4-Pyd) 4- Mor 7-595 2 CH ₂ (4-Pyd) 4-Tmr 7-596 1 CH ₂ (4-Pyd) 2-Pyr 7-597 1 CH ₂ (4-Pyd) 2-Pip 7-598 1 CH ₂ (4-Pyd) 3-Mor 7-599 1 CH ₂ (4-Pyd) 3-Tmr 7-600 1 CH ₂ (4-Pyd) 3-Pyr 7-601 1 CH ₂ (4-Pyd) 3-Pip 7-602 2 CH _{2 (2-BThz) NH 2} 7-603 2 CH 2 (2-BThz) NHMe 7-604 2 CH 2 (2-BThz) NHEt 7-605 2 CH 2 (2-BThz) NMe 2 7-606 2 CH ₂ (2-BThz) NEt ₂ 7-607 2 CH ₂ (2-BThz) NHCH ₂ CH ₂ OH 7-608 2 CH ₂ (2-BThz) NHCH ₂ COOH 7-609 2 CH ₂ (2-BThz) NHCH ₂ CONH ₂ 7-610 2 CH ₂ (2-BThz) N (Me) CH ₂ CH ₂ OH 7-611 2 CH ₂ (2-BThz) N (Me) CH ₂ COOH 7-612 2 CH ₂ (2- BThz) N (Me) CH ₂ CONH ₂ 7-613 2 CH ₂ (2-BThz) N (CH ₂ CH ₂ OH) ₂ 7-614 2 CH ₂ (2-BThz) 1-Pyr 7-615 2 CH ₂ (2-BThz) 1-Pip 7-616 2 CH ₂ (2-BThz) 1-Piz 7-617 2 CH ₂ (2-BThz) 4-Me-1-Piz 7-618 2 CH ₂ (2-BThz ) 4-Mor 7-619 2 CH ₂ (2-BThz) 4-Tmr 7-620 1 CH ₂ (2-BThz) 2-Pyr 7-621 1 CH ₂ (2-BThz) 2-Pip 7-622 1 CH ₂ (2-BThz) 3-Mor 7-623 1 CH ₂ (2-BThz) 3-Tmr 7-624 1 CH ₂ (2-BThz) 3-Pyr 7-625 1 CH ₂ (2-BThz) 3 -Pip 7-626 2 CH ₂ (2-BThn) NH ₂ 7-627 2 CH ₂ (2-BThn) NHMe 7-628 2 CH ₂ (2-BThn) NHEt 7-629 2 CH ₂ (2-BThn) NMe ₂ 7-630 2 CH ₂ (2-BThn) NEt ₂ 7-631 2 CH ₂ (2-BThn) NHCH ₂ CH ₂ OH 7-632 2 CH ₂ ( 2-BThn) NHCH ₂ COOH 7-633 2 CH ₂ (2-BThn) NHCH ₂ CONH ₂ 7-634 2 CH ₂ (2-BThn) N (Me) CH ₂ CH ₂ OH 7-635 2 CH ₂ (2 _{-BThn) N (Me) CH 2} COOH 7-636 2 CH 2 (2-BThn) N (Me) CH 2 CONH 2 7-637 2 CH 2 (2-BThn) N (CH 2 CH 2 OH) 2 7 -638 2 CH ₂ (2-BThn) 1-Pyr 7-639 2 CH ₂ (2-BThn) 1-Pip 7-640 2 CH ₂ (2-BThn) 1-Piz 7-641 2 CH ₂ (2- (BThn) 4-Me-1-Piz 7-642 2 CH ₂ (2-BThn) 4-Mor 7-643 2 CH ₂ (2-BThn) 4-Tmr 7-644 1 CH ₂ (2-BThn) 2- Pyr 7-645 1 CH ₂ (2-BThn) 2-Pip 7-646 1 CH ₂ (2-BThn) 3-Mor 7-647 1 CH ₂ (2-BThn) 3-Tmr 7-648 1 CH ₂ ( 2-BThn) 3-Pyr 7-649 1 CH ₂ (2-BThn) 3-Pip ----------------------------- ----------------------------

[0107]

[Table 8]

[0108]

Embedded image -------------------------------------------------- ------- No. R ^10a R ^10b ------------------------------------- -------------------- 8-1 HH 8-2 H 3-F 8-3 H 4-F 8-4 H 3-Cl 8-5 H 4 -Cl 8-6 H 3-Me 8-7 H 4-Me 8-8 H 3-OMe 8-9 H 4-OMe 8-10 H 3-OH 8-11 H 4-OH 8-12 H 3- NH ₂ 8-13 H 4-NH ₂ 8-14 H 3-NHMe 8-15 H 4-NHMe 8-16 H 3-NMe ₂ 8-17 H 4-NMe ₂ 8-18 H 3-NHCONH ₂ 8- 19 H 4-NHCONH ₂ 8-20 H 3-NHAc 8-21 H 4-NHAc 8-22 H 3-NHCOCH ₂ NH ₂ 8-23 H 4-NHCOCH ₂ NH ₂ 8-24 H 3-NHCOCH ₂ NHMe 8 -25 H 4-NHCOCH ₂ NHMe 8-26 H 3-NHCOCH ₂ NMe ₂ 8-27 H 4-NHCOCH ₂ NMe ₂ 8-28 H 3-COOH 8-29 H 4-COOH 8-30 H 3-COOEt 8 -31 H 4-COOEt 8-32 H 3-CONH ₂ 8-33 H 4-CONH ₂ 8-34 H 3-CONHMe 8-35 H 4-CONHMe 8-36 H 3-CONMe ₂ 8-37 H 4- CONMe ₂ 8-38 H 3-SO ₂ NH ₂ 8-39 H 4-SO ₂ NH ₂ 8-40 H 3-SO ₂ NHMe 8-41 H 4-SO ₂ NHMe 8-42 H 3-SO ₂ NMe ₂ 8-43 H 4-SO ₂ NMe ₂ 8-44 H 3-SO ₂ Me 8-45 H 4-SO ₂ Me 8-46 4-Me 5-Me 8-47 4-OMe 5-OMe 8-48 4 -F 5-F 8-49 4-Cl 5-Cl ------------------------------------ ---------------------

[0109]

[Table 9]

[0110]

Embedded image -------------------------------------------------- ------- No. R ¹¹ --------------------------------------- ------------------ 9-1 H 9-2 Me 9-3 Et 9-4 nPr 9-5 iPr 9-6 nBu 9-7 iBu 9-8 sBu 9-9 tBu 9-10 CF ₃ 9-11 CH ₂ CH ₂ F 9-12 CH ₂ COOH 9-13 CH ₂ CH ₂ COOH 9-14 CH ₂ CONH ₂ 9-15 CH ₂ CH ₂ CONH ₂ 9-16 CH ₂ CONHMe 9-17 CH ₂ CH ₂ CONHMe 9-18 CH ₂ CONMe ₂ 9-19 CH ₂ CH ₂ CONMe ₂ 9-20 CH ₂ CH ₂ OH 9-21 CH ₂ CH ₂ CH ₂ OH 9-22 CH ₂ CH (OH) CH ₂ OH 9-23 CH ₂ CH ₂ NH ₂ 9-24 CH ₂ CH ₂ NHMe 9-25 CH ₂ CH ₂ NMe ₂ 9-26 Ac 9-27 COEt 9-28 CONH ₂ 9-29 CONHMe 9-30 CONMe ₂ 9-31 Ph 9-32 4-BiPh 9-33 1-Np 9-34 2-Np 9-35 2-F-Ph 9-36 3-F-Ph 9-37 4-F- Ph 9-38 2,4-diF-Ph 9-39 2-Cl-Ph 9-40 3-Cl-Ph 9-41 4-Cl-Ph 9-42 2,4-diCl-Ph 9-43 2- Me-Ph 9-44 3-Me-Ph 9-45 4-Me-Ph 9-46 2,4-diMe-Ph 9-47 2-OMe-Ph 9-48 3-OMe-Ph 9-49 4- OMe-Ph 9-50 3,4-diOMe-Ph 9-51 2-OH-Ph 9-52 3-OH-Ph 9-53 4-OH-Ph 9-54 3,4-diOH-Ph 9-55 Bn 9-56 CH ₂ (4-BiPh) 9-57 CH ₂ (1-Np) 9-58 CH ₂ (2-Np) 9-59 2-F-Bn 9-60 3-F-Bn 9-61 4-F-Bn 9-62 2,4-diF-Bn 9-63 2-Cl-Bn 9-64 3-Cl-Bn 9-65 4-Cl-Bn 9-66 2,4-diCl-Bn 9-67 2-Me-Bn 9-68 3-Me-Bn 9-69 4-Me-Bn 9-70 2,4-diMe-Bn 9-71 2-OMe-Bn 9-72 3-OMe-Bn 9-73 4-OMe-Bn 9-74 3,4-diOMe-Bn 9-75 2-OH -Bn 9-76 3-OH-Bn 9-77 4-OH-Bn 9-78 3,4-diOH-Bn 9-79 2-Pyr 9-80 3-Pyr 9-81 4-Pyr 9-82 2 -Thz 9-83 4-Me-2-Thz 9-84 4,5-diMe-2-Thz 9-85 2-Tdz 9-86 5-Me-2-Tdz 9-87 2-BThz ---- -------------------------------------------------- --- In the above table, preferably, compound numbers 1-14, 1-43, 1-47, 1-51,
1-55, 1-57, 1-68, 1-70, 1-72,
1-74, 1-76, 1-78, 1-83, 1-84,
1-87, 1-91, 1-95, 1-98, 1-99,
1-100, 1-103, 1-105, 1-106, 1
-107, 1-108, 1-111, 1-114, 1-
115, 1-116, 1-119, 1-122, 1-1
23, 1-124, 1-127, 1-131, 1-13
2, 1-147, 1-148, 1-155, 1-15
6, 1-171, 1-172, 1-179, 1-18
0, 1-187, 1-188, 1-203, 1-20
4, 1-211, 1-212, 1-219, 1-22
0, 1-227, 1-228, 1-231, 1-23
4, 1-235, 1-236, 1-243, 1-24
4, 1-251, 1-252, 1-267, 1-26
8, 1-275, 1-276, 1-299, 1-30
0, 1-307, 1-308, 1-315, 1-31
6,1-323,1-324,1-331,1-33
2,1-335,1-338,1-348,1-34
9, 1-356, 1-357, 1-364, 1-36
5, 1-371, 1-372, 1-379, 1-38
0, 1-387, 1-388, 1-395, 1-39
6, 1-403, 1-404, 1-411, 1-41
2, 1-419, 1-420, 1-427, 1-42
8, 1-435, 1-436, 1-443, 1-44
4, 1-451, 1-452, 1-459, 1-46
0, 1-467, 1-468, 1-475, 1-47
6, 1-483, 1-484, 1-508, 1-50
9, 1-516, 1-517, 1-524, 1-52
5, 1-548, 1-549, 1-556, 1-55
7, 1-564, 1-565, 1-572, 1-57
3, 1-580, 1-581, 1-589, 1-59
0, 1-597, 1-598, 1-605, 1-60
6, 1-613, 1-614, 1-621, 1-62
2, 1-629, 1-630, 1-637, 1-63
8, 1-645, 1-646, 1-653, 1-65
4, 1-661, 1-662, 1-669, 1-67
0, 1-677, 1-678, 1-685, 1-69
3, 1-698, 1-699, 1-703, 1-70
8, 1-711, 1-712, 1-715, 1-72
0, 1-721, 1-722, 1-723, 1-72
5, 1-728, 1-731, 1-732, 1-73
3, 1-734, 1-738, 1-740, 1-74
1, 1-742, 2-1, 2-2, 2-3, 2-6, 2,
-14, 2-15, 2-17, 2-32, 2-37, 2
-39, 2-47, 2-50, 2-51, 2-52, 2
-53, 2-60, 2-61, 2-62, 2-63, 2
-70, 2-94, 2-103, 2-105, 2-12
0, 2-123, 2-133, 2-134, 2-13
6, 2-137, 2-141, 2-142, 2-14
6, 2-147, 2-151, 3-1, 3-2, 3-
3, 3-10, 3-11, 3-12, 3-13, 3-2
4, 3-27, 3-29, 3-32, 3-37, 3-3
8, 3-41, 3-42, 3-45, 3-46, 3-5
0, 3-51, 3-52, 3-66, 3-76, 3-8
5, 3-88, 3-92, 3-93, 3-94, 3-1
00, 3-101, 3-102, 3-103, 3-10
4, 3-105, 3-107, 3-113, 3-11
4, 3-115, 3-124, 3-137, 3-14
0, 3-142, 3-145, 3-150, 3-15
1, 3-154, 3-155, 3-158, 3-15
9, 3-179, 3-189, 3-205, 3-20
6, 3-207, 3-216, 3-217, 3-21
8, 3-226, 3-227, 3-236, 3-23
7, 3-250, 3-253, 3-255, 3-25
8, 3-263, 3-264, 3-267, 3-26
8, 3-271, 3-272, 3-292, 3-30
2, 3-311, 3-318, 3-319, 3-32
0, 3-326, 3-329, 3-330, 3-33
1,3-339,3-340,4-1,4-2,4-
3, 5-4, 5-33, 5-34, 5-54, 5-5
6, 5-57, 5-60, 5-88, 5-102, 5-
103, 5-106, 5-107, 5-110, 5-1
11, 5-114, 5-116, 5-117, 5-15
2, 5-161, 5-171, 5-183, 5-20
8, 5-210, 5-218, 5-222, 5-22
3, 5-224, 5-231, 5-232, 6-1, 6
-39, 6-50, 6-63, 6-87, 6-113,
7-2, 7-168, 7-170, 7-171, 7-1
88, 7-195, 7-219, 7-243, 7-26
7, 7-291, 7-315, 7-316, 7-33
9, 7-363, 7-387, 7-411, 7-43
5, 7-449, 7-483, 7-507, 7-53
1, 7-555, 7-579, 7-603, 7-62
7, 8-1, 8-3, 8-5, 8-13, 8-21, 8
-48, 9-2, 9-26, 9-31, 9-41, 9-
Compounds of Nos. 45, 9-49, 9-55, 9-61 or 9-65 can be mentioned, and more preferably, compound numbers 1-67, 1-68, 1-99, 1-10
0, 1-107, 1-108, 1-116, 1-13
2, 1-147, 1-148, 1-180, 1-18
7, 1-188, 1-204, 1-212, 1-22
0, 1-228, 1-235, 1-236, 1-33
1, 1-332, 1-685, 1-693, 1-71
1, 1-712, 2-14, 2-62, 2-94, 3-
1, 3-2, 3-3, 3-11, 3-45, 3-46,
3-145, 3-150, 3-151, 3-154, 3
-155, 3-158, 3-159, 3-179, 3-
236, 3-237, 3-250, 3-258, 3-2
63, 3-264, 3-267, 3-268, 3-27
1, 3-272, 3-292, 5-4, 5-54, 5-
114, 5-152, 5-171, 6-39, 6-6
3, 7-171, 7-195, 7-243, 7-36
3, 7-411, 8-1, 9-2, 9-31 or 9-
55 compounds can be mentioned. Particularly preferred compounds include the following compounds. 1. (4R, 8S, 9R, 10S) -4- (dibenzylaminothiocarbonyl) thiomethyl-10-[(R)-
1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2
1.-carboxylic acid [(4R) isomer of exemplary compound 1-711] (4R, 8S, 9R, 10S) -4-[(N-ethyl-N-phenylamino) thiocarbonyl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7 .2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [exemplified compound 1-68
(4R) isomer] (4R, 8S, 9R, 10S) -10-[(R)-
1-hydroxyethyl] -4-[(N-methyl-N-phenylamino) thiocarbonyl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2 -Carboxylic acid [exemplary compound 1-67
(4R) isomer] of (4R, 8S, 9R, 10S) -10-[(R)-
1-hydroxyethyl] -4-[(N-3-fluorophenyl-N-methylamino) thiocarbonyl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.
0 ^3,8 ] undec-2-ene-2-carboxylic acid [(4R) isomer of exemplary compound 1-99] 5. (4R, 8S, 9R, 10S) -10-[(R)-
1-hydroxyethyl] -4-[(N-2-thiazolyl-N-methylamino) thiocarbonyl] thiomethyl-1
1-oxo-1-azatricyclo [7.2.0.
0 ^3,8 ] undec-2-ene-2-carboxylic acid [(4R) isomer of exemplified compound 1-235] (4R, 8S, 9R, 10S) -4-[(N-2-
Benzothiazolyl-N-methylamino) thiocarbonyl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.
0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [(4R) isomer of exemplary compound 1-331] 7. (4R, 8S, 9R, 10S) -10-[(R)-
1-hydroxyethyl] -4 - [(N-4- (1- imidazolyl) phenyl -N- methylamino) thiocarbonyl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^{3, 8]} 7. Undec-2-ene-2-carboxylic acid [(4R) isomer of exemplified compound 1-187] (4R, 8S, 9R, 10S) -4-[(N-benzyl-N-phenylamino) thiocarbonyl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-
Oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [Exemplified compound 1-6
85 (4R) isomer] 9. (4R, 8S, 9R, 10S) -4-[(N-benzyl-N-2-pyridylmethylamino) thiocarbonyl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1- Azatricyclo [7.2.
0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [(4R) isomer of exemplified compound 1-712] (4R, 8S, 9R, 10S) -10-[(R)
-1-Hydroxyethyl] -4- [2- (5-phenyl) thiazolyl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [(4R) isomer of exemplary compound 2-14] (4R, 8S, 9R, 10S) -10-[(R)
-1-Hydroxyethyl] -4- [2- (4-phenyl) thiazolyl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [(4R) isomer of exemplary compound 2-62] (4R, 8S, 9R, 10S) -10-[(R)
-1-Hydroxyethyl] -4- (6-nitrobenzothiazol-2-yl) thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2- Carboxylic acid [Exemplified compound 3-236 (4R)
Isomer] 13. (4R, 8S, 9R, 10S) -4- (2-benzothiazolyl) thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 13.] Undec-2-ene-2-carboxylic acid [(4R) isomer of exemplified compound 3-1] (4R, 8S, 9R, 10S) -4- (6-Aminobenzothiazol-2-yl) thiomethyl-10-
[(R) -1-hydroxyethyl] -11-oxo-1
-Azatricyclo [7.2.0.0 ^3,8 ] undeca-2
-Ene-2-carboxylic acid [(4 of Exemplified Compound 3-237)
R) Isomer] 15. (4R, 8S, 9R, 10S) -4- [6- (4
-Pyridylcarbonylamino) benzothiazol-2-yl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.
0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [(4R) isomer of exemplified compound 3-271] 16. (4R, 8S, 9R, 10S) -4- [6- (1
-Methylpyridinio-4-ylcarbonylamino) benzothiazol-2-yl] thiomethyl-10-[(R)-
1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2
-Carboxylic acid [(4R) isomer of exemplified compound 3-272] (4R, 8S, 9R, 10S) -4- [6- (3
-Pyridylcarbonylamino) benzothiazol-2-yl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.
0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [(4R) isomer of exemplified compound 3-267] (4R, 8S, 9R, 10S) -4- [6- (1
-Methylpyridinio-3-ylcarbonylamino) benzothiazol-2-yl] thiomethyl-10-[(R)-
1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2
-Carboxylic acid [(4R) isomer of exemplified compound 3-268] (4R, 8S, 9R, 10S) -4- [6- (2
-Pyridylcarbonylamino) benzothiazol-2-yl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.
0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [(4R) isomer of exemplified compound 3-263] 20. (4R, 8S, 9R, 10S) -4- [6- (1
-Methylpyridinio-2-ylcarbonylamino) benzothiazol-2-yl] thiomethyl-10-[(R)-
1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2
-Carboxylic acid [(4R) isomer of exemplary compound 3-264] (4R, 8S, 9R, 10S) -10-[(R)
-1-hydroxyethyl] -4- [5-methyl-1,
3,4-thiadiazol-2-yl] thiomethyl-11-
Oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [exemplified compound 5-4
(4R) isomer of the formula] (4R, 8S, 9R, 10S) -10-[(R)
-1-hydroxyethyl] -4- [5-phenyl-1,
3,4-thiadiazol-2-yl] thiomethyl-11-
Oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [exemplified compound 5-1]
52 (4R) isomer] 23. (4R, 8S, 9R, 10S) -10-[(R)
-1-Hydroxyethyl] -4- (1-phenyltetrazol-5-yl) thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-en-2-carboxylic 23. Acid [(4R) isomer of exemplified compound 6-39] (4R, 8S, 9R, 10S) -10-[(R)
-1-Hydroxyethyl] -4- (1-methylhydantoin-3-yl) methyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2
-Carboxylic acid [(4R) isomer of exemplified compound 9-2] (4R, 8S, 9R, 10S) -10-[(R)
-1-Hydroxyethyl] -4- (phthalimido) methyl-11-oxo-1-azatricyclo [7.2.0.
[0 ^3,8 ] undec-2-ene-2-carboxylic acid [(4R) isomer of exemplified compound 8-1] (4R, 8S, 9R, 10S) -4- [6- (benzoylamino) benzothiazol-2-yl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-
Oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [exemplified compound 3-2
58 (4R) isomer] 27. (4R, 8S, 9R, 10S) -4- [5- (4
-Pyridylcarbonylamino) benzothiazol-2-yl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.
0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [(4R) isomer of exemplified compound 3-158] 28. (4R, 8S, 9R, 10S) -4- [5 (3-
Pyridylcarbonylamino) benzothiazol-2-yl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.
0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [(4R) isomer of exemplified compound 3-154] 29. (4R, 8S, 9R, 10S) -4- [5 (2-
Pyridylcarbonylamino) benzothiazol-2-yl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.
0.0 ^3,8 ] undec-2-ene-2-carboxylic acid [(4R) isomer of exemplified compound 3-150]

[0111]

DETAILED DESCRIPTION OF THE INVENTION Tricyclic carbapenems having the general formula (I) can be prepared by the following methods (Method A, Method B and Method C).
Method).

[0112]

Embedded image In the above formula, A has the same meaning as described above, R ¹² represents a “protecting group for a hydroxyl group”, and R ¹³ represents a “C _1-4 alkyl group optionally substituted with halogen” or “C _{1 -4 C6-10} aryl group _optionally substituted with alkyl ''
R ¹⁴ represents a “protecting group for a carboxy group”, and Ap represents A which may be protected when A contains a hydroxyl group, an amino group, an imino group or a carboxy group. Also, A
Is a group having a quaternary ammonium group or a pyridinio group, Ap includes a group having a corresponding tertiary amino group or pyridyl group.

The “protecting group for hydroxyl group” for R ¹² includes, for example, a tri-C _1-4 alkylsilyl group such as trimethylsilyl, triethylsilyl and t-butyldimethylsilyl; benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, An optionally substituted benzyloxycarbonyl group such as -chlorobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, wherein the substituent is nitro, methyl, chlorine or methoxy; allyloxycarbonyl, 2-chloroallyl Oxycarbonyl, 2
An allyloxycarbonyl group which may be substituted at the 2-position such as -methylallyloxycarbonyl, wherein the substituent is chlorine or methyl; trimethylsilylethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl Examples thereof include an ethyloxycarbonyl group substituted at the 2-position with tri-C _1-4 alkylsilyl or chlorine, preferably a tri-C _1-4 alkylsilyl group or an allyl optionally substituted at the 2-position. It is an oxycarbonyl group, more preferably a t-butyldimethylsilyl group or an allyloxycarbonyl group, and most preferably a t-butyldimethylsilyl group.

As the “C _1-4 alkyl group _optionally substituted with halogen” for R ¹³ , for example, methyl, ethyl,
Propyl, isopropyl, trifluoromethyl and butyl can be mentioned, preferably a methyl or trifluoromethyl group.

Examples of the “C _6-10 aryl group _optionally substituted with C _1-4 alkyl” for R ¹³ include phenyl,
A tolyl or naphthyl group can be mentioned, and a phenyl group is preferable.

R ^{13 as a} whole is preferably a methyl or phenyl group, more preferably a methyl group.

The “protecting group for carboxyl group” for R ¹⁴ is a protecting group usually used in the field of synthetic organic chemistry, and is substituted at the 2-position such as allyl, 2-chloroallyl and 2-methylallyl. An optionally substituted allyl group (the substituent is chlorine or methyl); an optionally substituted benzyl group such as benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl, and 4-nitrobenzyl (The substituent is methyl, methoxy, chlorine or nitro); or a benzhydryl group, preferably an optionally substituted allyl group or an optionally substituted benzyl group, More preferred is an allyl or 4-nitrobenzyl group, particularly preferred is an allyl group.

As a protecting group for a hydroxyl group, imino, amino or carboxy group contained in Ap, a protecting group usually used in the field of synthetic organic chemistry can be used.

Among these, "protecting group for hydroxyl group" and "protecting group for carboxy group" are as defined above. As the "protecting group for imino or amino group", for example, allyloxycarbonyl, 2-chloroallyloxycarbonyl,
Allyloxycarbonyl group which may be substituted at the 2-position such as -methylallyloxycarbonyl (the substituent is chlorine or methyl); benzyloxycarbonyl, 4-methylbenzyloxycarbonyl, 4-methoxybenzyloxy A benzyloxycarbonyl group which may be substituted such as carbonyl, 4-chlorobenzyloxycarbonyl, and 4-nitrobenzyloxycarbonyl (the substituent is methyl, methoxy, chlorine or nitro); Is an allyloxycarbonyl group or a 4-nitrobenzyloxycarbonyl group, more preferably an allyloxycarbonyl group.

In the method A, a compound having the formula (II) is reacted with a sulfonylating agent in the presence of a base to produce a compound having the formula (III) (Step A1). Reacting with a compound having the formula HAp in the presence of a base to produce a compound having the formula (IV) (A2
Step), then in the presence of a base, of the formula XCOCOOR ¹⁴ (where X represents a leaving group such as halogen (eg a chlorine atom) or imidazolyl, and R ¹⁴ is as defined above)
To produce a compound having the formula (V) (Step A3), followed by a ring closure reaction to produce a compound having the formula (VI) (Step A4), and finally to protection. This is a method for producing a compound having the general formula (I) by removing the group and converting it into a pharmacologically acceptable salt or an ester which undergoes hydrolysis in vivo as necessary (Step A5). Hereinafter, each step will be described in detail. (Step A1) Sulfonylation Step A1 is a step of producing a compound having the formula (III) by reacting a compound having the formula (II) with a sulfonylating agent in an inert solvent in the presence of a base. is there. still,
The compound having the formula (II) as a starting material is referred to in Reference Example 1.
Synthesized according to the following procedure.

Sulfonylating agents include, for example, C _1-4 such as methanesulfonyl chloride and ethanesulfonyl chloride.
Alkanesulfonyl halides; benzenesulfonyl chloride, p- toluenesulfonyl chloride methyl with optionally substituted C _{6- 10} aryl sulfonyl halide, such as chloride; methanesulfonic anhydride, trifluoromethanesulfonic anhydride, such as anhydrous ethanesulfonic acid C _1-4 alkanesulfonic anhydride _optionally substituted with halogen;
C _6-10 arylsulfonic acid anhydrides which may be substituted with methyl, such as benzenesulfonic acid anhydride and p-toluenesulfonic acid anhydride, are preferably methanesulfonyl chloride or p-toluenesulfonyl chloride.

The solvent used is not particularly limited as long as it does not participate in the reaction. Examples thereof include ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, nitriles such as acetonitrile, and ethyl acetate. Esters, amides such as N, N-dimethylformamide or N, N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide, preferably tetrahydrofuran or acetonitrile.

The base to be used is not particularly limited as long as it does not affect the other parts of the compound, particularly the β-lactam ring. And an organic base such as, for example, triethylamine or diisopropylethylamine.

Although the reaction temperature is not particularly limited, it is usually
The reaction is carried out at 20 ° C. to room temperature (preferably 0 ° C. to room temperature), and the reaction time is 30 minutes to 48 hours (preferably 30 minutes to 1 hour).
0 hours).

After completion of the reaction, the target compound (II)
I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling a solvent from the reaction mixture, washing with water, and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step A2) Substitution (Ap formation) reaction Step A2 is a step of reacting compound (III) with a compound of formula A in the presence of a base.
In this step, the compound (IV) is reacted with a compound represented by pH (wherein the Ap portion is as defined above) to obtain a compound (IV).

Solvents used include, for example, amides such as N, N-dimethylformamide or N, N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, nitriles such as acetonitrile, and esters such as ethyl acetate. And ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, preferably N, N-dimethylformamide, N, N-dimethylacetamide or dimethylsulfoxide.

The base used is, for example, triethylamine, diisopropylethylamine, pyridine or 4
Organic bases such as dimethylaminopyridine or inorganic bases such as sodium, sodium or potassium carbonate, preferably triethylamine or diisopropylethylamine.

The reaction temperature is not particularly limited, but is usually -2.
The reaction is performed at 0 ° C to 100 ° C (preferably room temperature to 60 ° C), and the reaction time is 30 minutes to 48 hours (preferably 30 minutes to 10 hours).

After completion of the reaction, the target compound (IV) of the reaction is usually
Collected from the reaction mixture according to the method. For example, a reaction mixture
To the residue obtained by distilling off the solvent of the combined liquid or the reaction mixture
Add an organic solvent that does not mix with water, wash with water, and evaporate the solvent.
It is obtained by doing. The obtained target compound is necessary
The conventional method, such as recrystallization, reprecipitation or chromatography
It can be further purified by a fee or the like. (Step A3) Oxalylation reaction In step A3, compound (IV) is reacted with a compound of formula XC in the presence of a base.
OCOOR¹⁴(Where X is a halogen (eg, chlorine atom)
Or a leaving group such as imidazolyl; ¹⁴Is mentioned above
With the compound represented by the formula
This is a step of manufacturing (V).

Examples of the compound represented by the formula XCOCOOR ¹⁴ include allyl oxalyl chloride, benzyl oxalyl chloride, p-nitrobenzyl oxalyl chloride, and preferably allyl oxalyl chloride.

The solvent used is, for example, methylene chloride,
Chloroform, halogenated hydrocarbons such as 1,2-dichloroethane, nitriles such as acetonitrile,
Esters such as ethyl acetate, tetrahydrofuran,
Examples include ethers such as dioxane or 1,2-dimethoxyethane, preferably methylene chloride or chloroform.

The base used is, for example, triethylamine, diisopropylethylamine, pyridine or 4-ethylamine.
Organic bases such as dimethylaminopyridine;
Preferably it is triethylamine or diisopropylethylamine.

Although the reaction temperature is not particularly limited, it is usually -20.
C. to 60.degree. C. (preferably 0.degree. C. to room temperature), and the reaction time is 30 minutes to 24 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the desired product (V) of the reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. (Step A4) Ring Closure Reaction Step A4 is a step of subjecting compound (V) to a ring closure reaction in a molecule using a trivalent phosphorus compound to produce compound (VI).

Examples of the trivalent phosphorus compound to be used include tri-C _1-4 alkyl phosphites such as triethyl phosphite, trimethyl phosphite, tripropyl phosphite and tributyl phosphite; Di C _1-4 alkyl (C _1-4 alkyl) phosphonites such as diethylmethylphosphonite and diethylethylphosphonite, and preferably triethyl phosphite, trimethyl phosphite, diethylmethylphosphonite or diethyl It is ethylphosphonite.

Examples of the solvent used include aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene, aliphatic hydrocarbons such as cyclohexane and decalin, dioxane, tetrahydrofuran and 1,2-diethoxyethane. Examples of such ethers include toluene, xylene and mesitylene.

Although the reaction temperature is not particularly limited, it is generally carried out at 40 ° C. to 200 ° C. (preferably 40 ° C. to 160 ° C.)
The reaction time is 30 minutes to 24 hours (preferably 30 minutes to 2 hours).
4 hours).

After completion of the reaction, the target product (VI) of the reaction was
The residue obtained by distilling off the solvent from the reaction solution can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When A is a group having a quaternary ammonium or pyridinio group, the compound (V
I) is reacted with a desired alkyl halide or the like to obtain a quaternized compound (VI). (Step A5) Deprotection reaction Step A5 includes a step of protecting a hydroxyl group R ^{12 of} compound (VI),
When a protecting group is contained in the protecting groups R ¹⁴ and Ap of the carboxy group, these protecting groups are removed to produce the desired compound (I).

The removal of the protecting groups contained in the protecting groups R ¹² , R ¹⁴ and Ap varies depending on the kind thereof, but is generally carried out by a method known in the art (“Protective Groups in O
rganic Synthesis, 2nd Edition "Ed. by TWGreene a
nd PGMWuts, 1991, John Wiley & Sons, Inc.).

The protecting groups contained in the protecting groups R ¹² and Ap are
In the case of a tri-C _1-4 alkylsilyl group such as trimethylsilyl, triethylsilyl and t-butyldimethylsilyl, examples of the deprotecting agent include ammonium hydrogen fluoride,
Examples thereof include an organic fluorine compound such as tetrabutylammonium fluoride and an inorganic fluorine compound such as potassium fluoride, and are preferably ammonium hydrogen fluoride or tetrabutylammonium fluoride.

The solvent used depends on the type of the deprotecting agent, but ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, amides such as dimethylformamide, sulfoxides such as dimethylsulfoxide, Nitriles such as acetonitrile, methylene chloride, chloroform or 1,2
Hydrogen halides such as -dichloroethane, preferably tetrahydrofuran or dimethylformamide.

Although the reaction temperature is not particularly limited, it is usually -20.
C. to 100.degree. C. (preferably 0.degree. C. to 60.degree. C.)
The reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the deprotected compound is collected from the reaction mixture according to a conventional method, and then, when Ap contains a protecting group, the protecting group can be removed and the protecting group R ¹⁴ can be removed. .

The protecting groups contained in the protecting groups R ¹² and Ap are
Trimethylsilylethyloxycarbonyl, 2,2,2
When the 2-position such as a trichloroethyloxycarbonyl group is an ethyloxycarbonyl group substituted with tri-C _1-4 alkylsilyl or chlorine, the deprotecting agent may be a Lewis acid such as boron trifluoride etherate. And metal-organic acids such as zinc-acetic acid, preferably boron trifluoride etherate or zinc-acetic acid.

The solvent used depends on the type of the deprotecting agent, but includes hydrogen halides such as chloroform or 1,2-dichloroethane, esters such as ethyl acetate, tetrahydrofuran, dioxane or 1,2-dimethoxy. Ethers such as ethane, nitriles such as acetonitrile, and alcohols such as methanol, ethanol or propanol, preferably methylene chloride, ethyl acetate or tetrahydrofuran.

Although the reaction temperature is not particularly limited, it is usually -20.
C. to 100.degree. C. (preferably 0.degree. C. to 60.degree. C.)
The reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the deprotected compound is collected from the reaction mixture according to a conventional method, and then, when Ap contains a protecting group, the protecting group can be removed and the protecting group R ¹⁴ can be removed. .

When the protecting group R ¹² is allyloxycarbonyl, 2
When the protecting group R ¹⁴ is an allyloxycarbonyl group which may be substituted at the 2-position such as -chloroallyloxycarbonyl or 2-methylallyloxycarbonyl (the substituent is chlorine or methyl), When the 2-position is an allyl group which may be substituted such as 2-chloroallyl or 2-methylallyl (the substituent is chlorine or methyl), and when the protecting group contained in Ap is allyl, 2-chloroallyl, An allyl group which may be substituted at the 2-position such as 2-methylallyl (the substituent is chlorine or methyl) or allyloxycarbonyl;
In the case of an allyloxycarbonyl group which may be substituted at the 2-position such as -chloroallyloxycarbonyl or 2-methylallyloxycarbonyl (the substituent is chlorine or methyl), the deprotecting agent may be bis Palladiums-trialkyltin hydrides such as (triphenylphosphine) palladium chloride-tributyltin hydride, tetrakis (triphenylphosphine) palladium-tributyltin hydride or tetrakis (triphenylphosphine) palladium-2
-Palladiums such as potassium ethylhexanoate or sodium 2-ethylhexanoate-alkali metal salts of organic carboxylic acids, preferably bis (triphenylphosphine) palladium chloride-tributyltin hydride or tetrakis (triphenylphosphine)
Potassium palladium-2-ethylhexanoate.

The solvent used is not particularly limited as long as it does not participate in this reaction, but halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane, and esters such as ethyl acetate. Ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, nitriles such as acetonitrile, methanol, ethanol or propanol.
Examples thereof include alcohols such as toluene, water and a mixed solvent thereof, and preferably methylene chloride, ethyl acetate or a mixed solvent thereof.

The reaction temperature is not particularly limited, but is usually -20 ° C.
To 100 ° C. (preferably 0 ° C. to 60 ° C.), and the reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the deprotected compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by removing the insoluble material precipitated from the reaction mixture by filtration and then distilling off the solvent.

When the protecting group R ¹² is benzyloxycarbonyl,
When it is an optionally substituted benzyloxycarbonyl group such as 4-nitrobenzyloxycarbonyl,
Protecting group R ¹⁴ is benzyl, 4-nitro case optionally be an optionally substituted benzyl group or benzhydryl group, and the protecting group contained in Ap benzyloxycarbonyl, such as benzyl, such as 4-nitrobenzyloxycarbonyl Aralkyloxycarbonyl group, benzyl, 4
In the case of an optionally substituted benzyl group such as nitrobenzyl or a benzhydryl group, the deprotecting agent may be hydrogen and a catalytic reduction catalyst such as palladium-carbon or an alkali metal sulfide such as sodium sulfide or potassium sulfide. And preferably hydrogen and palladium-carbon.

The solvent to be used is not particularly limited as long as it does not participate in the reaction, but halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane, and esters such as ethyl acetate. Ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, nitriles such as acetonitrile, methanol, ethanol or propanol.
Alcohol or water or a mixed solvent thereof, preferably tetrahydrofuran or a mixed solvent of tetrahydrafuran and water.

The reaction temperature is not particularly limited, but it is usually from room temperature to 100 ° C. (preferably from room temperature to 60 ° C.), and the reaction time is usually from 30 minutes to 48 hours (preferably from 30 minutes to 20 hours).
Time).

After completion of the reaction, compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off the catalyst used for the reaction and the precipitated insoluble matter from the reaction mixture, and then distilling off the solvent.

When a protecting group removed by the same deprotecting agent is used for R ¹² , R ¹⁴ or Ap, those protecting groups can be removed simultaneously.

The compound (I) thus obtained is
If necessary, it can be purified by a conventional method such as a recrystallization method, column chromatography, preparative liquid chromatography and the like. Further, if necessary, it can be converted into a derivative such as an ester which is hydrolyzed in a living body by a conventional method (Japanese Patent Laid-Open No. 5-50204), and purified as a pharmaceutically acceptable salt by a conventional method. Can be.

On the other hand, the tricyclic carbapenem compound having the general formula (I) of the present invention can also be produced by the following method (Method B).

[0160]

Embedded image In the above formula, R ¹² , R ¹⁴ , A and Ap have the same meanings as described above in Method A. Hereinafter, each step will be described. (Step B1) Ap Condensation Reaction Step B1 converts a compound having the general formula (VII) into a compound having the formula A
In this step, a compound represented by the formula (VI) is produced by reacting a compound represented by pH (wherein the Ap portion is as defined above). The starting material (VI
I) is produced according to Reference Example 2.

A is the above (A1), (A2), (A
In the case corresponding to the group represented by 4) or (A5), this step is accomplished by a reaction known as Mitsunobu reaction in an inert solvent.

The solvent to be used is not particularly limited as long as it does not participate in the reaction. Examples thereof include ethers such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane and nitriles such as acetonitrile. Is tetrahydrofuran.

The condensing agent used is a combination of phosphines and azodicarboxylic esters such as triphenylphosphine-diethylazodicarboxylate, and preferably triphenylphosphine-diethylazodicarboxylate. It is.

The reaction temperature is not particularly limited, but is preferably at a relatively low temperature in order to suppress a side reaction, and is usually at -60 ° C to room temperature (preferably -40 ° C to room temperature).

The reaction time varies depending mainly on the reaction temperature and the type of the reaction reagent, but is usually from 15 minutes to 75 hours (preferably from 30 minutes to 6 hours).

After completion of the reaction, the desired compound (VI)
Can be collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When A is a group having a quaternary ammonium group or a pyridinio group, compound (VI) can be prepared by a conventional method.
Is reacted with a desired alkyl halide or the like to obtain a quaternized compound (VI). (Step B2) Deprotection Reaction Step B2 is a step of producing a compound (I) by removing the protecting group contained in the compound (VI), and is achieved according to the method of the above-mentioned step A5.

Further, the tricyclic carbapenem compound having the general formula (I) of the present invention can also be produced by the following method (Method C).

[0169]

Embedded image In the above formula, R ¹² , R ¹⁴ , A and Ap have the same meanings as described above in Method A.

In this synthesis method, a compound having the general formula (VII) is subjected to an oxidation reaction to produce a compound having the formula (VIII) (Step C1), and then a compound represented by the formula Ap-H (as described above) Is condensed in the presence of a reducing agent to produce a compound having the formula (VI) (Step C2), and finally removing the protecting group to produce a compound having the general formula (I) (C3) Step). In this synthesis method, A is (A
It is used when it is a group represented by 3). Hereinafter, each step will be described. (Step C1) Oxidation Reaction Step C1 is a step of reacting compound (VII) with an oxidizing agent to produce a compound having formula (VIII).

The oxidizing agent is, for example, dimethyl sulfoxide-
Oxalyl chloride, dimethylsulfoxide-an oxidizing agent using a dimethylsulfoxide-based reagent such as trifluoroacetic anhydride in the presence of an organic base or a chromic acid-based oxidizing agent such as pyridinium chlorochromate, and preferably dimethylsulfoxide- Oxalyl chloride.

The organic base used is not particularly limited as long as it does not affect the other parts of the compound. Examples thereof include organic bases such as triethylamine, diisopropylamine and N-methylpiperidine. Is triethylamine.

The solvent used is not particularly limited as long as it does not participate in the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane, tetrahydrofuran, dioxane or 1,2-dimethoxy Ethers such as ethane, ketones such as acetone or methyl ethyl ketone, nitriles such as acetonitrile, amides such as dimethylformamide or dimethylacetamide, sulfoxides such as dimethylsulfoxide or a mixed solvent thereof, Preferably it is methylene chloride or tetrahydrofuran.

The reaction temperature is not particularly limited, but is usually -75 ° C to room temperature (preferably -60 ° C) in order to suppress side reactions.
To room temperature). The reaction time varies depending on the reaction temperature and the type of the reaction reagent, but is usually 15 minutes to 48 hours (preferably 30 minutes to 12 hours).

After the completion of the reaction, the compound (VIII) obtained by this reaction is collected according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. Compound (VII)
I) can be further purified, if necessary, by conventional methods, for example by recrystallization, reprecipitation or chromatography. (Step C2) Ap condensation reaction Step C2 is a step of producing compound (VI) by subjecting compound (VIII) to a condensation reaction with a compound represented by the formula Ap-H in the presence of a reducing agent. .

The reducing agent to be used includes, for example, sodium cyanoborohydride, hydrogen-palladium carbon catalyst or hydrogen-platinum oxide, preferably sodium cyanoborohydride.

The solvent to be used is not particularly limited as long as it does not participate in the reaction. For example, alcohols such as methanol, ethanol or propanol, ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, acetonitrile Such as nitriles, water or a mixed solvent thereof, and is preferably methanol or ethanol.

The reaction temperature is not particularly limited, but is usually -20 ° C to 40 ° C (preferably 0 ° C to room temperature) in order to suppress a side reaction. The reaction time varies depending on the reaction temperature and the type of the reaction reagent, but is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours).

After completion of the reaction, the desired compound (VI)
Is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

When A is a group having a quaternary ammonium group or a pyridinio group, compound (VI) can be prepared by a conventional method.
Is reacted with a desired alkyl halide or the like to obtain a quaternized compound (VI). (Step C3) Deprotection Reaction Step C3 is a step of producing the compound (I) by removing the protecting group contained in the compound (VI), and is achieved according to the method of the above-mentioned step A5.

The compound having the general formula (I) thus produced by the method A, the method B or the method C may be, if necessary, known in the field of medicinal chemistry, particularly β-lactam antibiotics. It can be converted into a derivative such as an ester that undergoes hydrolysis in vivo and purified as a pharmacologically acceptable salt, according to a certain method or technique.

The tricyclic carbapenem compound of the present invention having the general formula (I), a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof exhibits excellent antibacterial activity against various pathogenic bacteria, In particular, it showed strong antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Accordingly, such compound (I), a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof is useful as a medicament, and particularly useful as an antibacterial agent for treating or preventing a bacterial infection.

When Compound (I), a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof is used as an antibacterial agent, the compound itself or an appropriate pharmaceutically acceptable excipient may be used. And diluents and the like, and can be administered orally by tablets, capsules, granules, powders or syrups or parenterally by intravenous injection, intramuscular injection and the like.

These preparations may 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 hydroxypropyl cellulose, hydroxy Cellulose derivatives such as propylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate; Silicate derivatives such as magnesium metasilicate aluminate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; Agent Gelatin; polyvinylpyrrolidone;
Maglogol, etc.), disintegrants (for example, the above-mentioned excipients; croscarmellose sodium, carboxymethyl starch)
Disodium, chemically modified starch such as crosslinked polyvinylpyrrolidone, starch, cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; metal stearate such as calcium stearate, magnesium stearate; colloidal silica) Luxes such as bee gum and gay wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylate salts such as sodium benzoate; sulfate salts such as sodium sulfate; Lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (such as methylparaben and propylparaben) Paraoxybenzoic acid esters; chlorobutanol, Alcohols such as benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; Flavoring agents (for example, commonly used sweeteners, sour agents, flavors, etc.), suspending agents (for example, polysorbate 80, sodium carboxymethyl cellulose), diluents, solvents for preparations (for example, Water, ethanol, glycerin and the like) are used and manufactured by a known method.

The dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 10 mg (preferably 50 mg) and the upper limit is 2000 mg (preferably 10 mg).
00 mg), in the case of intravenous administration, a lower limit of 10 mg (preferably 50 mg) and an upper limit of 3000 mg (preferably 2000 mg) are administered to an adult 1 to 6 times per day depending on the symptoms. It is desirable to do.

[0186]

EXAMPLES The present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples and Formulation Examples, but the scope of the present invention is not limited thereto. Incidentally, trimethylsilyl propionic acid sodium -d ₄ unless otherwise specified for the measurement of heavy water for nuclear magnetic resonance spectra in the Examples and Reference Examples using the internal standard tetramethylsilane as the internal standard in the other solvents It measured using. Example 1 (4S, 8S, 9R, 10S) -4-dimethylaminothiocarbonylthiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^[3,8 ] Sodium undec-2-ene-2-carboxylate

[0187]

Embedded image (1) (4S, 8S, 9R, 10S) -10-[(R)
-(T-butyldimethylsilyloxy) ethyl] -4-
4-Nitrobenzyl dimethylaminothiocarbonylthiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate Obtained in Reference Example 3- (2). Compound (300 mg) was dissolved in 10 ml of toluene, and zinc dimethyldithiocarbamate (260 mg) and triphenylphosphine (742) were dissolved.
mg), 40% diethyl azodicarboxylate toluene solution (1.28 ml) was added, and the mixture was stirred for 1.5 hours at room temperature. A small amount of water was added to the reaction solution, and extracted with ethyl acetate (20
ml × 2), dried over Na ₂ SO ₄ , and the solvent was distilled off under reduced pressure. The obtained residue is subjected to column chromatography (silica gel 30 g, hexane: ethyl acetate = 2.5: 1).
To give a mixture (414 mg) of the title compound and zinc dimethyldithiocarbamate as an oil.

Infrared absorption spectrum (neat) ν _max c
m ^-1 : 2931, 2857, 1777, 1723,1524, 1284 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.08 (6H, s), 0.88 (9H, s), 1.19 ~ 2.00 (6H, m)
, 1.23 (3H, d, J = 6.1Hz), 3.13 ~ 3.30 (1H, m), 3.21 (1H,
dd, J = 5.9,3.1Hz), 3.32 (3H, s), 3.43-3.71 (2H, m),
3.54 (3H, s), 3.93-4.07 (1H, m), 4.09-4.30 (2H, m),
5.25 (1H, d, J = 13.9Hz), 5.43 (1H, d, J = 13.9Hz), 7.65
(1H, d, J = 8.7 Hz), 8.21 (1H, d, J = 8.7 Hz). (2) (4S, 8S, 9R, 10S) -4-dimethylaminothiocarbonylthiomethyl-10-[(R ) -Hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate 4-nitrobenzyl Obtained in Example 1- (1). The compound (414 mg) was dissolved in tetrahydrofuran (2 ml), and acetic acid (204 m
g), a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (2.83 ml) was added, and the mixture was reacted in a refrigerator for 6 days. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate (20 ml × 3), and the organic layer was washed with water and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (silica gel 12.5 g, hexane: ethyl acetate = 1: 5 → 1: 8) to give the title compound (17
5 mg) as an oil.

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 1.24 to 1.48 (1H, m), 1.33 (3H, d, J =
6.4Hz), 1.25 ~ 2.02 (5H, m), 3.18 ~ 3.38 (2H, m), 3.
30 (3H, s), 3.42 ~ 3.58 (1H, m), 3.75 (1H, dd, J = 13.0,9.
6Hz), 3.92 ~ 4.07 (1H, m), 4.19 (1H, dd, J = 10.3,3.1Hz)
, 4.15 ~ 4.32 (1H, m), 5.24 (1H, d, J = 13.7Hz), 5.47 (1
H, d, J = 13.7Hz), 7.65 (1H, d, J = 8.7Hz), 8.22 (1H, d, J =
8.7 Hz). (3) (4S, 8S, 9R, 10S) -4-dimethylaminothiocarbonylthiomethyl-10-[(R) -hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0 .0 ^3,8 ] Sodium undec-2-ene-2-carboxylate The compound (70 mg) obtained in Example 1- (2) was dissolved in tetrahydrofuran (7 ml), water (3 ml), sodium hydrogen carbonate ( 12 mg), 10% Pd-C (15
0 mg), and the atmosphere in the system was replaced with hydrogen, followed by vigorous stirring at 30 ° C. for about 1 hour. The solvent was removed by filtration, and the obtained filtrate was subjected to ethyl acetate: diisopropyl ether = 2:
The mixture was extracted with the mixed solvent of No. 1 and the aqueous layer was collected and concentrated. This concentrated solution is subjected to column chromatography (Cosmo Seal 75C).
18-PREP10g, acetonitrile: water = 0: 10
0 → 20: 80) to give the desired compound (20 mg) as a lyophilized powder.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 3390, 2928, 1752, 1591, 1395, 1255 Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.21 ~ 1.38 (1H, m), 1.27 (3H, d, J = 6.4Hz), 1.55 ~
1.80 (3H, m), 1.83 to 1.94 (2H, m), 3.17 to 3.37 (1H, m)
, 3.35 to 3.58 (2H, m), 3.39 (3H, s), 3.52 (3H, s),
3.67 to 3.79 (2H, m), 4.13 (1H, dd, J = 10.3,3.0Hz), 4.2
Example 2 (4S, 8S, 9R, 10S) -4-dibenzylaminothiocarbonylthiomethyl-10-[(R) -1-hydroxyethyl]- Sodium 11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate

[0191]

Embedded image (1) (4S, 8S, 9R, 10S) -10-[(R)
-1- (t-butyldimethylsilyloxy) ethyl]-
4-dibenzylaminothiocarbonylthiomethyl-11
-Oxo-1-azatricyclo [7.2.0.0 ^3,8 ]
4-Nitrobenzyl undec-2-ene-2-carboxylate Example 1 using the compound (250 mg) obtained in Reference Example 3- (2) and zinc dibenzyldithiocarbamate.
By performing the same reaction and isolation operation as in (1), the title compound (287 mg) was obtained as an amorphous.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 2930, 2857, 1777, 1721, 1523, 1347, 1285 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.09 (6H, s), 0.88 (9H, s), 1.24 (3H, d, J = 6.3H
z), 1.29-2.05 (6H, m), 3.15-3.42 (2H, m), 3.66 (1
H, dd, J = 13.2,6.3Hz), 3.82 (1H, dd, J = 13.2,9.7Hz), 3.
99 to 4.29 (3H, m), 4.72 to 4.94 (2H, m), 5.14 (1H, d, J =
13.9Hz), 5.17 to 5.44 (2H, m), 5.33 (1H, d, J = 13.9Hz)
, 7.08 〜 7.39 (10H, m), 7.58 (2H, d, J = 8.7Hz), 8.14
(2H, d, J = 8.7 Hz). (2) (4S, 8S, 9R, 10S) -4-dibenzylaminothiocarbonylthiomethyl-10-[(R) -1
-Hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-
Carboxylic acid 4-nitrobenzyl Using the compound (380 mg) obtained in Example 2- (1), the same reaction as in Example 1- (2) and an isolation operation were performed to obtain the title compound (223 mg). ) Obtained as an oil.

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 1.21 to 2.05 (6H, m), 1.34 (3H, d, J =
6.4Hz), 3.25-3.39 (1H, m), 3.26 (1H, dd, J = 6.2,3.1H
z), 3.63 (1H, dd, J = 13.1,5.7Hz), 3.91 (1H, dd, J = 13.1,1
0.2Hz), 3.98-4.13 (1H, m), 4.19 (1H, dd, J = 10.2,3.0H
z), 4.26 (1H, qd, J = 6.4,6.2Hz), 4.82 (2H, m), 5.15 (1
H, d, J = 13.7Hz), 5.30 (2H, m), 5.36 (1H, d, J = 13.7Hz),
7.08 ~ 7.42 (10H, m), 7.57 (2H, d, J = 8.7Hz), 8.14 (2H, d,
J = 8.7 Hz). (3) (4S, 8S, 9R, 10S) -4-dibenzylaminothiocarbonylthiomethyl-10-[(R) -1
-Hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-
Sodium carboxylate Using the compound (94 mg) obtained in Example 2- (2), the same reaction and isolation procedure as in Example 1- (3) was performed to obtain the desired compound (35 mg) as a lyophilized powder. .

Infrared absorption spectrum (KBr) ν _max cm
^-1: 3415, 2928, 1750, 1589, 1400, 1218 Nuclear magnetic resonance spectrum (400MHz, D ₂ O + DMS
_{O-d 6) δppm: 1.07~1.23} (1H, m), 1.12 (3H, d, J =
6.1Hz), 1.31 to 1.85 (5H, m), 2.86 to 3.05 (2H, m), 3.
48 to 3.63 (2H, m), 3.84 to 3.94 (2H, m), 4.03 to 4.17
(1H, m), 4.92 (1H, d, J = 6.5Hz), 5.00 (1H, d, J = 6.5Hz),
5.20 (1H, d, J = 5.3Hz), 5.32 (1H, d, J = 5.3Hz), 7.15 〜
7.45 (10H, m). Example 3 (4S, 8S, 9R, 10S) -4- (N-ethyl-N
-Phenylamino) thiocarbonylthiomethyl-10-
[(R) -1-hydroxyethyl] -11-oxo-1
-Azatricyclo [7.2.0.0 ^3,8 ] undeca-2
-Ene-2-carboxylic acid

[0195]

Embedded image (1) (4S, 8S, 9R, 10S) -10-[(R)
-1- (t-butyldimethylsilyloxy) ethyl]-
4- (N-ethyl--N- phenylamino) thiocarbonyl thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^{3, 8]} undec-2-ene-2-carboxylic acid 4-nitrobenzyl Compound (250 mg) obtained in Reference Example 3- (2) and N
By performing the same reaction and isolation operation as in Example 1- (1) using zinc -ethyl-N-phenylthiocarbamate, the title compound (297 mg) was obtained as an amorphous substance.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 2931, 2857, 1777, 1722, 1524, 1346, 1281 Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.09 (6H, s), 0.88 (9H, s), 1.19 to 1.92 (6H, m)
, 1.22 (3H, d, J = 6.3Hz), 1.25 (3H, t, J = 7.1Hz), 3.07
~ 3.21 (1H, m), 3.18 (1H, dd, J = 5.7,3.3Hz), 3.42 ~ 3.
62 (2H, m), 3.74-3.92 (1H, m), 4.07-4.42 (3H, m),
4.22 (1H, qd, J = 6.3,5.7Hz), 5.20 (1H, d, J = 3.9Hz), 5.3
6 (1H, d, J = 3.9Hz), 7.07 to 7.22 (2H, m), 7.32 to 7.51
(3H, m), 7.60 (1H, d, J = 8.7 Hz), 8.20 (1H, d, J = 8.7 Hz). (2) (4S, 8S, 9R, 10S) -4- (N-ethyl- N-phenylamino) thiocarbonylthiomethyl-
4-nitrobenzyl 10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate Example 3- The same reaction and isolation procedure as in Example 1- (2) were performed using the compound (350 mg) obtained in (1) to give the title compound (210 mg) as an oil.

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 1.25 (3H, t, J = 7.0 Hz), 1.32 (3H, d,
J = 6.3Hz), 1.21 ~ 1.95 (6H, m), 3.14 ~ 3.28 (1H, m),
3.23 (1H, dd, J = 6.1,3.2Hz), 3.46 (1H, dd, J = 13.2,7.2Hz)
, 3.59 (1H, dd, J = 13.2,8.7Hz), 3.77 〜3.92 (1H, m),
4.17 (1H, dd, J = 7.2,3.2Hz), 4.21 to 4.43 (2H, m), 5.21
(1H, d, J = 13.4Hz), 5.38 (1H, d, J = 13.4Hz), 7.08 to 7.2
2 (2H, m), 7.34 to 7.55 (3H, m), 7.79 (2H, d, J = 8.7Hz),
8.20 (2H, d, J = 8.7Hz). (3) (4S, 8S, 9R, 10S) -4- (N-ethyl-N-phenylamino) thiocarbonylthiomethyl-
10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid In Example 3- (2) The same reaction and isolation procedure as in Example 1- (3) were performed using the obtained compound (97 mg),
The target compound (39 mg) was obtained.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 3397, 2932, 1745, 1594, 1397, 1274 Nuclear magnetic resonance spectrum (400 MHz, D ₂ O + DMS
_{O-d 6) δppm: 1.04~1.25} (1H, m), 1.12 (3H, t, J =
6.9Hz), 1.13 (3H, d, J = 6.1Hz), 1.41 ~ 1.79 (5H, m),
2.93 to 3.05 (1H, m), 3.12 to 3.21 (1H, m), 3.34 to 3.5
0 (2H, m), 3.56-3.72 (1H, m), 3.88-3.95 (1H, m),
4.06 (1H, qd, J = 6.3,6.1Hz), 4.08-4.31 (2H, m), 7.14
Example 4. (4S, 8S, 9R, 10S) -4- (benzothiazol-2-yl) thiomethyl-10-[(R) -1 -Hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate potassium

[0199]

Embedded image (1) (4S, 8S, 9R, 10S) -4- (benzothiazol-2-yl) thiomethyl-10-[(R) -1
-(T-butyldimethylsilyloxy) ethyl] -11
-Oxo-1-azatricyclo [7.2.0.0 ^3,8 ]
Allyl undec-2-ene-2-carboxylate The compound (250 mg) obtained in Reference Example 2- (2) and 2
Example 1 using mercaptobenzothiazole
The same reaction and isolation procedure as in (1) was performed to obtain a mixture (395 mg) of the title compound, triphenylphosphine, and 2-mercaptobenzothiazole.

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 0.05 (3H, s), 0.06 (3H, s), 0.87 (9
H, s), 1.18 to 2.07 (6H, m), 1.22 (3H, d, J = 6.2Hz), 3.
08 ~ 3.22 (2H, m), 3.57 (1H, dd, J = 12.9,6.7Hz), 3.74 (1
H, dd, J = 12.9,9.5Hz), 3.99 (1H, dd, J = 10.5,3.2Hz), 4.
02 to 4.21 (2H, m), 4.61 to 4.69 (2H, m), 5.12 to 5.39 (2
H, m), 5.78 to 5.96 (1H, m), 7.24 to 7.45 (2H, m), 7.7
0 to 7.88 (2H, m). (2) (4S, 8S, 9R, 10S) -4- (benzothiazol-2-yl) thiomethyl-10-[(R) -1
-Hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-
Allyl carboxylate By performing the same reaction and isolation operation as in Example 1- (2) using the compound (390 mg) obtained in Example 4- (1), the title compound (172 mg) was obtained as an oil. Obtained.

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 1.16 to 2.08 (6H, m), 1.30 (3H, d, J =
6.2Hz), 3.12 ~ 3.39 (2H, m), 3.59 (1H, dd, J = 12.9,6.8H
z), 3.72 (1H, dd, J = 12.9,9.4Hz), 4.01 ~ 4.27 (3H, m),
4.54 to 4.74 (2H, m), 5.12 to 5.38 (2H, m), 5.78 to 5.97
(1H, m), 7.24 to 7.47 (2H, m), 7.71 to 7.89 (2H, m). (3) (4S, 8S, 9R, 10S) -4- (benzothiazol-2-yl) thiomethyl-10 -[(R) -1
-Hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-
Potassium carboxylate The compound (85 mg) obtained in Example 4- (2) was dissolved in a mixed solvent of dichloromethane (3 ml) and ethyl acetate (3 ml), and potassium 2-ethylhexanoate (3
3 mg), triphenylphosphine (10 mg), tetrakistriphenylphosphine palladium (4.2 m
g) was added and stirred at 0 ° C. for 1.5 hours. Hexane was added to the reaction solution, and extracted three times with water (20 ml × 3). The aqueous layer is concentrated under reduced pressure, and the concentrate is purified by column chromatography (Cosmosil 75C18-PREP 7.5 g, acetonitrile: water = 0: 100 → 25: 75, increasing the concentration of acetonitrile stepwise), (44m
g) was obtained as a lyophilized powder.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 3414, 2928, 1754, 1590, 1427, 1392, 996. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 0.98 (3H, d, J = 6.4 Hz), 1.01 to 1.31 (1H, m), 1.42
~ 1.60 (3H, m), 1.62 ~ 1.78 (2H, m), 2.81 ~ 2.89 (1H, m
m), 3.08 (1H, dd, J = 6.0,3.0Hz), 3.21 (1H, dd, J = 13.1,
4.9Hz), 3.61 (1H, dd, J = 13.1,11.2Hz), 3.67〜3.77 (1
H, m), 3.89 (1H, qd, J = 6.4,6.0Hz), 7.21 ~ 7.28 (1H, m)
, 7.33 to 7.39 (1H, m), 7.69 (1H, d, J = 8.0Hz), 7.74 (1H
Example 5 (8S, 9R, 10S) -10-[(R) -1-hydroxyethyl] -4- [2- (N-methyl) aminoethyl] aminomethyl- 11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid monohydrochloride

[0203]

Embedded image (1) (3R, 4R) -4-[(2R) -6- [N'-
[2- (N-allyloxycarbonyl-N-methyl) aminoethyl] -N'-allyloxycarbonyl] aminomethylcyclohexanone-2-yl] -3-[(R)
-1- (t-Butyldimethylsilyloxy) ethyl] azetidin-2-one The compound (711 mg) obtained in Reference Example 1- (8) was dissolved in tetrahydrofuran (10 ml), and triethylamine (233 mg) was added under ice-cooling. Methanesulfonyl chloride (2
52 mg) and stirred for about 1 hour. After removing the insoluble matter by filtration, the solvent was distilled off under reduced pressure to obtain a methanesulfonic acid ester intermediate. This was dissolved in dimethylformamide (10 ml) and N-allyloxycarbonyl-
A DMF solution (10 ml) of N-methylethylenediamine (633 mg) and triethylamine (203 mg) were added, and the mixture was stirred at room temperature. Allyl oxalyl chloride (482m
g) and triethylamine (203 mg), a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 ml × 3). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (silica gel 75 g, hexane: ethyl acetate = 1: 3) to give the title compound (385 mg, 6α form: 6β form = 4).
5:55) as an oil.

The nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 0.06 (3H, s), 0.07 (3H, s), 0.87 (9
H, s), 1.09 to 1.44 (1H, m), 1.46 to 2.28 (6H, m), 2.5
2 ~ 3.01 (2H, m), 2.93,2.96 (3H, bs × 2), 3.11 ~ 3.60
(6H, m), 4.12 to 4.28 (2H, m), 4.47 to 4.62 (4H, m), 5.
12 to 5.38 (4H, m), 5.74,5.81 (1H, brs × 2), 5.80 to 6.
02 (2H, m). (2) (8S, 9R, 10S) -4- [N '-[2-
(N-allyloxycarbonyl-N-methyl) aminoethyl] -N'-allyloxycarbonyl] aminomethyl-10-[(R) -1- (t-butyldimethylsilyloxy) ethyl] -11-oxo-1 -Allyl azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate The compound (450 mg) obtained in Example 5- (1) was dissolved in dichloromethane (5 ml), and iced. Under cooling, triethylamine (157 mg) and allyl oxalyl chloride were added, and 4
Stirred for 0 minutes. PH 7 phosphate buffer was added to the reaction solution,
The mixture was extracted with ethyl acetate (50 ml × 3), and the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (silica gel 15 g, hexane: ethyl acetate = 1: 1) to obtain an intermediate (525 mg). This was dissolved in mesitylene (30 ml), diethylethylphosphonite (342 mg) was added, the mixture was refluxed at 180 ° C. for 5 hours, and mesitylene was distilled off under reduced pressure. : Ethyl acetate = 2: 1 → 1: 1) to give the title compound (175 mg, 4α form: 4β form = 6).
7:33) as an oil.

Nuclear magnetic resonance spectrum (270 MHz, C
DCL ₃ ) δppm: 0.07 (6H, s), 0.88 (9H, s), 1.22 (3
(H, d, J = 6.2Hz), 1.12 to 2.12 (6H, m), 2.63 to 3.72 (9H,
m), 2.94 (3H, brs), 4.07 ~ 4.25 (2H, m), 4.49 ~ 4.82
(6H, m), 5.12 to 5.48 (6H, m), 5.82 to 6.04 (3H, m). (3) (8S, 9R, 10S) -4- [N '-[2-
(N-allyloxycarbonyl-N-methyl) aminoethyl] -N'-allyloxycarbonyl] aminomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2. 0.0 ^3,8 ] undec-2-ene-2-carboxylic acid allyl Example 5-
The same reaction and isolation procedure as in Example 1- (2) were performed using the compound (170 mg) obtained in (2) to give the title compound (97 mg) as an oil.

A nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 1.19 to 2.20 (9H, m), 2.35 to 3.99
(9H, m), 2.94 (3H, brs), 4.05-4.35 (2H, m), 4.50-
4.89 (6H, m), 5.13 to 5.50 (6H, m), 5.81 to 6.08 (3H,
m). (4) (8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4- [2- (N-methyl) aminoethyl] aminomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-
Carboxylic acid monohydrochloride The compound (90 mg) obtained in Example 5- (3) was dissolved in dichloromethane (3 ml), and the solution was cooled with ice (50 ml).
l), ammonium chloride (18 mg), bis (triphenylphosphine) palladium (II) chloride (2.3 m
g), tri-n-butyltin hydride (240 mg) was added, and the mixture was stirred for 40 minutes. Water was added to the reaction solution for extraction, and the aqueous layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (Cosmoseal 75C18-PREP 5 g, water: acetonitrile = 100: 0 → 99: 1) to obtain the target compound (18 mg, a mixture of 4α-form and 4β-form) as a lyophilized powder. .

Nuclear magnetic resonance spectrum (400 MHz, D
₂ O) δ ppm: 0.95 to 1.35 (1H, m), 1.08 (3H, d, J = 6.4H
z), 1.40-1.95 (5H, m), 2.56-3.34 (8H, m), 2.63 (3
H, s), 3.18 (1H, dd, J = 6.0,2.8Hz), 3.94 (1H, dd, J = 9.7,
Example 6 (8S, 9R, 10S) -4- [N-allyl-N-
[(R) -Pyrrolidinyl-3-yl] methyl] aminomethyl-10-[(R) -1-hydroxyethyl] -11
-Oxo-1-azatricyclo [7.2.0.0 ^3,8 ]
Undec-2-ene-2-carboxylic acid

[0208]

Embedded image (1) (3R, 4R) -4-[(2R) -6- [N-allyloxycarbonyl-N-[(R) -1-allyloxycarbonylpyrrolidinyl-3-yl] methyl] aminomethylcyclohexanone -2-yl] -3-[(R)-
1- (t-butyldimethylsilyloxy) ethyl] azetidin-2-one Using the compound obtained in Reference Example 1- (8) and (S) -1-allyloxycarbonyl-3-aminomethylpyrrolidine, The same reaction and isolation procedure as in Example 5- (1) were carried out to give the title compound (769 mg, 6α-form: 6β-form = 1: 9)
Was obtained as amorphous.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 3290, 2933, 1763, 1704, 1409. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.06 (3H, s), 0.07 (3H, s), 0.87 (9H, s), 1.05
~ 2.22 (9H, m), 1.22 (3H, d, J = 6.4Hz), 2.49 ~ 3.61 (10
H, m), 3.99 to 4.26 (2H, m), 4.45 to 4.71 (4H, m), 5.15
~ 5.38 (4H, m), 5.67 ~ 5.77 (1H, m), 5.82 ~ 6.04 (2H, m
m). (2) (8S, 9R, 10S) -4- [N-allyloxycarbonyl-N-[(R) -1-allyloxycarbonylpyrrolidinyl-3-yl] methyl] aminomethyl-
Allyl 10-[(R) -1- (t-butyldimethylsilyloxy) ethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate Using the compound (760 mg) obtained in Example 6- (1) and performing the same method and isolation operation as in Example 5- (2), the title compound (158 mg) was obtained as an oil.

Infrared absorption spectrum (neat) ν _max c
m ^-1 : 2932, 2858, 1777, 1701,1407, 1279, 1254
, 836, 776. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.07 (6H, s), 0.88 (9H, s), 1.12 ~ 2.05 (9H, m)
, 1.22 (3H, d, J = 6.5Hz), 2.68〜3.72 (7H, m), 3.88 〜
4.24 (4H, m), 4.39 〜4.81 (6H, m), 5.12 〜5.50 (6H, m)
, 5.80-6.08 (3H, m). (3) (8S, 9R, 10S) -4- [N-allyloxycarbonyl-N-[(R) -1-hydroxyethyl]]
11-oxo-1-azatricyclo [7.2.0.0
Allyl [ ^3,8 ] undec-2-ene-2-carboxylate The same reaction and isolation procedure as in Example 5- (3) is carried out using the compound (153 mg) obtained in Example 6- (2). This gave the title compound (97 mg) as an oil.

Infrared absorption spectrum (neat) ν _max c
m ^-1 : 3448, 2938, 1773, 1699, 1413, 1279, 756. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 1.24 to 2.15 (12H, m), 2.78 to 3.72 (9H, m), 3.9
1 to 4.30 (3H, m), 4.45 to 4.89 (6H, m), 5.12 to 5.50 (6
H, m), 5.82 to 6.08 (3H, m). (4) (8S, 9R, 10S) -4- [N-allyl-N
-[(R) -pyrrolidinyl-3-yl] methyl] aminomethyl-10-[(R) -1-hydroxyethyl] -1
1-oxo-1-azatricyclo [7.2.0.
[0 ^3,8 ] undec-2-ene-2-carboxylic acid Using the compound (90 mg) obtained in Example 6- (3), the same reaction and isolation procedure as in Example 5- (4) were carried out. ,
The target compound (8.3 mg) was obtained as a lyophilized powder.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 3381, 2930, 1756, 1598, 1448, 1396. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 0.74 to 2.16 (9H, m), 1.08 (3H, d, J = 6.3Hz), 2.20 to
3.81 (13H, m), 3.87〜4.12 (2H, m), 5.02 〜5.20 (2H, m)
, 5.62 to 5.89 (1H, m). Example 7 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -11-oxo-4-phthalimidomethyl-azatricyclo [7.2.0.0 ^{3, 8]} undec-2-ene-2-carboxylate

[0213]

Embedded image (1) (4S, 8S, 9R, 10S) -10-[(R)
-1- (t-butyldimethylsilyloxy) ethyl]-
11-oxo-4-phthalimidomethyl-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2
-Carboxylic acid 4-nitrobenzyl The same reaction and isolation procedure as in Example 1- (1) was carried out using phthalimide and the compound (300 mg) obtained in Reference example 3- (2) to give the title compound (157 mg) Was obtained as an oil.

Infrared absorption spectrum (neat) ν _max c
m ^-1 : 2932, 1776, 1720, 1524,1396, 1347, 837. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.09 (6H, s), 0.89 (9H, s), 1.17 to 2.01 (6H, m)
, 1.24 (3H, d, J = 6.0Hz), 3.22 (1H, dd, J = 6.0,3.3Hz),
3.32 to 3.49 (1H, m), 3.77 to 3.85 (1H, m), 3.95 to 4.32
(4H, m), 5.00 (1H, d, J = 13.8Hz), 5.16 (1H, d, J = 13.8Hz)
, 7.48 (1H, d, J = 8.9Hz), 7.64〜7.73 (2H, m), 7.74 〜
7.89 (4H, m), 8.11 (2H, d, J = 8.9Hz). (2) (4S, 8S, 9R, 10S) -10-[(R)
-1-Hydroxyethyl] -11-oxo-4-phthalimidomethyl-1-azatricyclo [7.2.0.0
^[3,8 ] Undec-2-ene-2-carboxylic acid 4-nitrobenzyl The same reaction and isolation as in Example 1- (2) using the compound (212 mg) obtained in Example 7- (1). The operation was performed to obtain the title compound (104 mg) as an oily substance.

Infrared absorption spectrum (neat) ν _max c
m ^-1 : 3468, 2936, 1773, 1717,1522, 1397, 1348
724. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 1.25 to 2.21 (6H, m), 1.33 (3H, d, J = 6.2Hz), 3.
26 (1H, dd, J = 6.1,3.2Hz), 3.42 ~ 3.58 (1H, m), 3.71 ~
3.88 (1H, m), 4.01 to 4.19 (2H, m), 4.20 to 4.35 (1H, m)
, 4.24 (1H, dd, J = 10.4,3.2Hz), 4.99 (1H, d, J = 13.6Hz)
, 5.19 (1H, d, J = 13.6Hz), 7.46 (2H, d, J = 8.6Hz), 7.65
Up to 7.89 (4H, m), 8.10 (2H, d, J = 8.6Hz). (3) (4S, 8S, 9R, 10S) -10-[(R)
-1-Hydroxyethyl] -11-oxo-4-phthalimidomethyl-1-azatricyclo [7.2.0.0
^[3,8 ] Sodium undec-2-ene-2-carboxylate Using the compound (98 mg) obtained in Example 7- (2), the same reaction and isolation procedure as in Example 1- (3). Was carried out to obtain the desired product (51 mg) as a lyophilized powder.

Infrared absorption spectrum (KBr) ν _max cm
^-1: 3403, 2930, 1752, 1716, 1597, 1399, 721. Nuclear Magnetic Resonance Spectrum (400MHz, D ₂ O) δpp
m: 1.21 ~ 1.91 (6H, m), 1.27 (3H, d, J = 6.4Hz), 3.30 ~
3.45 (1H, m), 3.40 (1H, dd, J = 5.9,3.2Hz), 3.71 (1H, dd,
J = 13.5,4.7Hz), 3.67-3.87 (1H, m), 4.08 (1H, dd, J = 1
3.5,11.8Hz), 4.13 (1H, d, J = 10.6,3.3Hz), 4.21 (1H, q
d, J = 6.4, 5.9 Hz), 7.77 to 7.92 (4H, m). Example 8 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4- (1-methylhydantoin-
Potassium ³ -yl) methyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate

[0219]

Embedded image (1) (4S, 8S, 9R, 10S) -10-[(R)
-1- (t-butyldimethylsilyloxy) ethyl]-
4- (1-methylhydantoin-3-yl) methyl-1
1-oxo-1-azatricyclo [7.2.0.
[ ^3,8 ] allyl undec-2-ene-2-carboxylate The compound (250 mg) obtained in Reference Example 2- (2) and 1
By performing the same reaction and isolation operation as in Example 1- (1) using -methylhydantoin, the title compound (2
64 mg) as an oil.

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 0.07 (3H, s), 0.08 (3H, s), 0.89 (9
H, s), 1.20-1.95 (6H, m), 1.23 (3H, d, J = 6.3Hz), 2.
94 (3H, s), 3.18 (1H, dd, J = 6.3,3.4Hz), 3.26 to 3.42 (1
H, m), 3.59 (1H, dd, J = 12.6,4.6Hz), 3.85 (1H, dd, J = 12.
6,10.9Hz), 3.87 to 4.01 (1H, m), 4.07 to 4.18 (1H, m),
4.19 (1H, dq, J = 6.3,6.3Hz), 4.61 to 4.78 (2H, m), 5.2
2 to 5.48 (2H, m), 5.89 to 6.04 (1H, m). (2) (4S, 8S, 9R, 10S) -10-[(R)
-1-Hydroxyethyl] -4- (1-methylhydantoin-3-yl) methyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2
-Allyl carboxylate Using the compound (295 mg) obtained in Example 8- (1), the same reaction and isolation procedure as in Example 1- (2) were performed to give the title compound (138 mg) as an oil. Obtained as material.

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 1.17 to 2.05 (6H, m), 1.31 (3H, d, J =
6.2Hz), 2.94 (3H, s), 3.23 (1H, dd, J = 6.2,3.2Hz), 3.
33 ~ 3.47 (1H, m), 3.58 (1H, dd, J = 11.7,3.4Hz), 3.76 (2
H, s), 3.85 to 4.02 (2H, m), 3.88 (1H, t, J = 11.3Hz), 4.
16 to 4.29 (2H, m), 4.60 to 4.77 (2H, m), 5.20 to 5.46
(2H, m), 5.88 to 6.07 (1H, m). (3) (4S, 8S, 9R, 10S) -10-[(R)
-Hydroxyethyl] -4- (1-methylhydantoin-3-yl) methyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid potassium The same reaction and isolation procedure as in Example 4- (3) were performed using the compound (120 mg) obtained in Example 8- (2) to give the desired compound (97 mg) as a lyophilized powder.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 3401, 2931, 1760, 1708, 1592, 1389. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.08 (3H, d, J = 6.4 Hz), 1.09 to 1.22 (1H, m), 1.34
~ 1.77 (5H, m), 2.75 (3H, s), 3.02 ~ 3.12 (1H, m), 3.2
3 (1H, dd, J = 6.0,3.4Hz), 3.33 (1H, dd, J = 13.5,4.3Hz),
3.50 ~ 3.57 (1H, m), 3.68 (1H, dd, J = 13.5,12.0Hz), 3.8
0 (3H, s), 3.94 (1H, dd, J = 10.6,3.3Hz), 4.03 (1H, qd, J =
Example 9 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4- (1-methyltetrazole-
5-yl) thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-en-2-
Potassium carboxylate

[0221]

Embedded image (1) (4S, 8S, 9R, 10S) -10-[(R)
-1- (t-butyldimethylsilyloxy) ethyl]-
4- (1-methyltetrazol-5-yl) thiomethyl-11-oxo-1-azatricyclo [7.2.0.0
^3,8 ] Allyl undec-2-ene-2-carboxylate The compound (175 mg) obtained in Reference Example 2- (2) and 5
By performing the same reaction and isolation operation as in Example 1- (1) using -mercapto-1-methyltetrazole, the title compound (113 mg) was obtained as an oil.

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 0.07 (3H, s), 0.08 (3H, s), 0.89 (9
H, s), 1.05 to 1.95 (6H, m), 1.22 (3H, d, J = 6.1Hz), 3.
02〜3.15 (1H, m), 3.17 (1H, dd, J = 6.3,3.2Hz), 3.46 〜
3.78 (2H, m), 3.87 (3H, s), 3.97 ~ 4.27 (2H, m), 4.03 (1
(H, dd, J = 10.4,3.3Hz), 4.57 ~ 4.82 (2H, m), 5.17 ~ 5.48
(2H, m), 5.80 to 6.02 (1H, m). (2) (4S, 8S, 9R, 10S) -10-[(R)
-1-Hydroxyethyl] -4- (1-methyltetrazol-5-yl) thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid Allyl Using the compound (130 mg) obtained in Example 9- (1) and performing the same reaction and isolation procedure as in Example 1- (2), the title compound (49 mg) was obtained as an oil. Was.

The nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 1.21 to 1.45 (1H, m), 1.32 (3H, d, J =
6.4Hz), 1.59 to 2.10 (5H, m), 3.11 to 3.27 (1H, m), 3.
22 (1H, dd, J = 6.5,3.3Hz), 3.57 (1H, dd, J = 12.9,5.7Hz),
3.74 (1H, dd, J = 12.9,10.7Hz), 3.86 (3H, s), 3.96-4.
16 (2H, m), 4.22 (1H, dq, J = 6.5,6.4Hz), 4.58 to 4.82 (2
H, m), 5.20 to 5.47 (2H, m), 5.84 to 6.02 (1H, m). (3) (4S, 8S, 9R, 10S) -10-[(R)
-1-Hydroxyethyl] -4- (1-methyltetrazol-5-yl) thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid Potassium The target compound (21 mg) was obtained as a lyophilized powder by performing the same reaction and isolation procedure as in Example 4- (3) using the compound (45 mg) obtained in Example 9- (2). Was.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 3371, 2930, 1754, 1590, 1391, 1252. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.01 to 1.15 (1H, m), 1.06 (3H, d, J = 6.4Hz), 1.38 to
1.75 (5H, m), 2.77 to 2.89 (1H, m), 3.15 (1H, dd, J = 6.2,
3.1Hz), 3.26 (1H, dd, J = 12.7,3.3Hz), 3.49 ~ 3.63 (2H,
m), 3.69 (1H, dd, J = 10.2,3.0Hz), 3.75 (3H, s), 3.99
(1H, qd, J = 6.4, 6.2 Hz). Example 10 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -11-oxo-4- (1-phenyltetrazol-5-yl) thiomethyl-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2
-Potassium carboxylate

[0225]

Embedded image (1) (4S, 8S, 9R, 10S) -10-[(R)
-1- (t-butyldimethylsilyl) oxyethyl]-
11-oxo-4- (1-phenyltetrazole-5
Yl) thiomethyl-1-azatricyclo [7.2.0.
[ ^3,8 ] allyl undec-2-ene-2-carboxylate The compound (150 mg) obtained in Reference Example 2- (2) and 1
The title compound (142 mg) was obtained as an oil by performing the same reaction and isolation procedure as in Example 1- (1) using -phenyl-5-mercaptotetrazole.

Infrared absorption spectrum (CHCl ₃ ) ν _max
cm ^-1 : 2933, 1775, 1717, 1601, 1501, 1286, 1
142. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.08 (3H, s), 0.09 (3H, s), 0.89 (9H, s), 1.12
~ 1.98 (6H, m), 1.23 (3H, d, J = 6.1Hz), 3.04 ~ 3.21 (1
H, m), 3.17 (1H, dd, J = 6.1,3.2Hz), 3.63 (1H, dd, J = 12.
8,6.2Hz), 3.74 (1H, dd, J = 12.8,10.1Hz), 3.99 ~ 4.12
(1H, m), 4.05 (1H, dd, J = 10.5,3.2Hz), 2.28 (1H, dq, J =
6.1,6.1Hz), 4.49〜4.71 (2H, m), 5.12 〜5.42 (2H, m)
, 5.76 to 5.97 (1H, m), 7.41 to 7.67 (5H, m). (2) (4S, 8S, 9R, 10S) -10-[(R)
-1-hydroxyethyl] -11-oxo-4- (1-
Allyl phenyltetrazol-5-yl) thiomethyl-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate Compound (105 mg) obtained in Example 10- (1) Was used to carry out the same reaction and isolation procedure as in Example 1- (1) to give the title compound (94 mg) as an oil.

The nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 1.32 (3H, d, J = 6.1 Hz), 1.18 to 1.4
7 (1H, m), 1.60 to 2.05 (5H, m), 3.12 to 3.29 (2H, m),
3.62 (1H, dd, J = 13.0,5.7Hz), 3.77 (1H, dd, J = 13.0,10.6H
z), 4.01-4.29 (3H, m), 4.48-4.72 (2H, m), 5.12
〜5.40 (2H, m), 5.75 〜5.95 (1H, m), 7.40 〜7.62 (5H, m
m). (3) (4S, 8S, 9R, 10S) -10-[(R)
-1-hydroxyethyl] -11-oxo-4- (1-
Potassium phenyltetrazol-5-yl) thiomethyl-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-en-2-carboxylate Compound obtained in Example 10- (2) (90 mg) Was used to carry out the same reaction and isolation procedure as in Example 4- (3) to obtain the desired compound (65 mg) as a lyophilized powder.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 3384, 2930, 1754, 1592, 1500, 1389, 765,
694. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.21 ~ 1.35 (1H, m), 1.26 (3H, d, J = 6.2Hz), 1.57 ~
1.93 (5H, m), 3.03-3.12 (1H, m), 3.34 (1H, dd, J = 6.0,
3.0Hz), 3.52 (1H, dd, J = 13.4,4.9Hz), 3.65 (1H, dd, J = 1
3.4,11.5Hz), 3.84 ~ 3.93 (1H, m), 3.97 (1H, dd, J = 10.1,
3.0Hz), 4.20 (1H, qd, J = 6.2,6.0Hz), 7.56 ~ 7.74 (5H,
m). Example 11 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4- [5-methyl-1,3,4-
Potassium thiadiazol-2-yl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate

[0229]

Embedded image (1) (4S, 8S, 9R, 10S) -10-[(R)
-(T-butyldimethylsilyloxy) ethyl] -4-
[5-methyl-1,3,4-thiadiazol-2-yl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^{3, 8]} undec-2-ene-2-carboxylic acid allyl Reference A compound (180 mg) obtained in Example 2- (2),
Using 5-methyl-1,3,4-thiadiazole-2-thiol, the same reaction and isolation procedure as in Example 1- (1) were performed to obtain the title compound (70 mg) as an oil.

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 0.07 (3H, s), 0.08 (3H, s), 0.89 (9
H, s), 1.09 to 2.05 (6H, m), 1.23 (3H, d, J = 6.3Hz), 2.
71 (3H, s), 3.03 to 3.20 (1H, m), 3.16 (1H, dd, J = 6.3,3.
3Hz), 3.55 (1H, dd, J = 12.7,6.5Hz), 3.70 (1H, dd, J = 12.
7,9.8Hz), 3.96 to 4.11 (1H, m), 4.06 (1H, dd, J = 10.3,
3.3Hz), 2.94 (1H, dq, J = 6.3,6.3Hz), 4.58 ~ 4.82 (2H,
m), 5.16 to 5.47 (2H, m), 5.86 to 6.02 (1H, m). (2) (4S, 8S, 9R, 10S) -10-[(R)
-Hydroxyethyl] -4- [5-methyl-1,3,4
-Thiadiazol-2-yl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid allyl obtained in Example 11- (1). The title compound (38 mg) was obtained as an oil by performing the same reaction and isolation operation as in Example 1- (2) using the compound (65 mg).

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 1.18 to 2.02 (6H, m), 1.33 (3H, d, J =
6.2Hz), 2.73 (3H, s), 3.11 to 3.32 (1H, m), 3.23 (1H,
dd, J = 6.6,3.2Hz), 3.52 (1H, dd, J = 12.8,6.0Hz), 3.77
(1H, dd, J = 12.8,10.3Hz), 3.96-4.17 (2H, m), 4.23 (1
(H, dq, J = 6.6,6.2Hz), 4.59 to 4.82 (2H, m), 5.19 to 5.4
9 (2H, m), 5.87 to 6.05 (1H, m). (3) (4S, 8S, 9R, 10S) -10-[(R)
-1-hydroxyethyl] -4- [5-methyl-1,
3,4-Thiadiazol-2-yl] thiomethyl-11
-Oxo-1-azatricyclo [7.2.0.0 ^3,8 ]
Potassium undec-2-ene-2-carboxylate By using the compound (35 mg) obtained in Example 11- (2), the same reaction and isolation procedure as in Example 4- (3) was carried out for the purpose. The compound (16 mg) was obtained.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 3383, 2928, 1754, 1592, 1388, 1252. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.06 (3H, d, J = 6.4Hz), 1.10-1.17 (1H, m), 1.43
〜1.57 (3H, m), 1.65 〜1.73 (2H, m), 2.54 (3H, s), 2.
80-2.88 (1H, m), 3.15 (1H, dd, J = 6.2,2.9Hz), 3.18 (1
H, dd, J = 13.2,4.6Hz), 3.61-3.68 (1H, m), 3.72 (1H, d
d, J = 10.2,3.1Hz), 4.01 (1H, qd, J = 6.4,6.2Hz). Example 12 (4S, 8S, 9R, 10S) -10-[(R) -1-
Potassium hydroxyethyl] -4- (6-nitrobenzothiazole) thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate

[0233]

Embedded image (1) (4S, 8S, 9R, 10S) -10-[(R)
-(T-butyldimethylsilyloxy) ethyl] -4-
Allyl (6-nitrobenzothiazole) thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate Obtained in Reference Example 2- (2) A compound (207 mg);
The title compound (100 mg) was obtained as an oil by performing the same reaction and isolation operation as in Example 1- (1) using 2-mercapto-6-nitrobenzothiazole.

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 0.05 (3H, s), 0.06 (3H, s), 0.87 (9
H, s), 1.22 (3H, d, J = 6.1Hz), 1.31 ~ 2.05 (6H, m), 3.0
9 ~ 3.20 (2H, m), 3.63 (1H, dd, J = 6.6,12.9Hz), 3.76 (1
H, dd, J = 9.4,12.9Hz), 4.06 (1H, dd, J = 3.2,10.5Hz), 4.
00-4.25 (2H, m), 4.58-4.75 (2H, m), 5.12-5.42 (2
H, m), 5.78 to 5.98 (1H, m), 7.89 (1H, d, J = 8.9Hz), 8.
30 (1H, d, J = 2.3,8.9Hz), 8.67 (1H, d, J = 2.3Hz). (2) (4S, 8S, 9R, 10S) -10-[(R)
-1-Hydroxyethyl] -4- (6-nitrobenzothiazole) thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-
Allyl carboxylate Using the compound (150 mg) obtained in Example 12- (1) and performing the same reaction and isolation procedure as in Example 1- (2), the title compound (79 mg) was converted to an oily substance. As obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _max
cm ^-1 : 2933, 1775, 1717, 1341. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 1.31 (3H, d, J = 6.2Hz), 1.25 ~ 2.14 (6H, m),
3.12 to 3.28 (1H, m), 3.24 (1H, dd, J = 3.2,6.6Hz), 3.65
(1H, dd, J = 6.9,12.9Hz), 3.74 (1H, dd, J = 9.4,12.9Hz),
4.08 〜4.19 (2H, m), 4.22 (1H, qd, J = 6.2,6.6Hz), 4.57
〜4.75 (2H, m), 5.12 〜5.40 (2H, m), 5.79 〜5.96 (1
H, m), 7.90 (1H, d, J = 9.0Hz), 8.31 (1H, dd, J = 2.2,9.0H
z), 8.67 (1H, d, J = 2.2 Hz). (3) (4S, 8S, 9R, 10S) -10-[(R)
-1-Hydroxyethyl] -4- (6-nitrobenzothiazole) thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-
Potassium carboxylate By using the compound (76 mg) obtained in Example 12- (2) and performing the same reaction and isolation procedure as in Example 4- (3), the target compound (48 mg) was lyophilized to give a powder. As obtained.

Infrared absorption spectrum (KBr) ν _max cm
^-1: 3419, 2929, 1754, 1591, 1400, 1340. Nuclear Magnetic Resonance Spectrum (270MHz, D ₂ O + DMS
_{O-d 6) δppm: 1.17~1.40} (1H, m, J = 6.4Hz), 1.60
~ 1.97 (5H, m), 3.12 ~ 3.17 (1H, m), 3.34 (1H, dd, J =
3.0,5.9Hz), 3.50 (1H, dd, J = 5.3,13.1Hz), 3.78 (1H, d
d, J = 10.9,13.1Hz), 3.86 (1H, dd, J = 3.0,10.2Hz), 3.91
~ 3.98 (1H, m), 4.14 (1H, dq, J = 5.9,6.4Hz), 7.86 (1H, d,
J = 8.9Hz), 8.30 (1H, dd, J = 2.2,8.9Hz), 8.76 (1H, d, J =
Example 13 (4S, 8S, 9R, 10S) -4- (6-aminobenzothiazole) thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7 2.0.0 ^3,8 ] potassium undec-2-ene-2-carboxylate

[0237]

Embedded image (1) (4S, 8S, 9R, 10S) -4- (6-aminobenzothiazole) thiomethyl-10-[(R) -1
-(T-butyldimethylsilyloxy) ethyl] -11
-Oxo-1-azatricyclo [7.2.0.0 ^3,8 ]
Allyl undec-2-ene-2-carboxylate The compound (50 mg) obtained in Reference Example 2- (2) and 6
Using -amino-2-mercaptobenzothiazole,
By performing the same reaction and isolation operation as in Example 1- (1), the title compound (56 mg) was obtained as an oil.

Infrared absorption spectrum (CHCl ₃ ) ν _max
cm ^-1 : 3373, 2931, 1775, 1721, 1286, 1251. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.06 (6H, s), 0.88 (9H, s), 1.15-1.46 (1H, m)
, 1.22 (3H, d, J = 6.3Hz), 1.51 ~ 2.09 (5H, m), 3.00 ~
3.19 (1H, m), 3.15 (1H, dd, J = 3.2,6.7Hz), 3.49 (1H, dd,
J = 6.8,12.8Hz), 3.66 (1H, dd, J = 9.3,12.8Hz), 3.78 (2H, b
r), 3.99 (1H, dd, J = 3.2,10.5Hz), 3.95-4.19 (1H, m),
4.15 (1H, qd, J = 6.3,6.7Hz), 4.58 to 4.73 (2H, m), 5.1
2 to 5.42 (2H, m), 5.80 to 5.97 (1H, m), 6.75 (1H, dd, J =
2.3,8.6Hz), 6.99 (1H, d, J = 2.3Hz), 7.62 (1H, d, J = 8.6H
z). (2) (4S, 8S, 9R, 10S) -4- (6-aminobenzothiazole) thiomethyl-10-[(R) -1
-Hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-
Allyl carboxylate Using the compound (170 mg) obtained in Example 13- (1) and the same reaction and isolation procedure as in Example 1- (2), the title compound (102 mg) was converted into an oily substance. As obtained.

Nuclear magnetic resonance spectrum (400 MHz, C
DCl ₃ ) δ ppm: 1.30 (3H, d, J = 6.3 Hz), 1.20 to 2.0
2 (6H, m), 3.10-3.19 (1H, m), 3.19 (1H, dd, J = 3.2,6.6
Hz), 3.50 (1H, dd, J = 6.6,12.9Hz), 3.66 (1H, dd, J = 9.6,1
2.9Hz), 3.77 (2H, br), 4.01 (1H, dd, J = 3.1,10.3Hz),
3.99-4.12 (1H, m), 4.19 (1H, qd, 1H, J = 6.3,6.6Hz), 4.58
~ 4.73 (2H, m), 5.16 ~ 5.37 (2H, m), 5.81 ~ 5.93 (1H, m
m), 6.76 (1H, dd, J = 2.4,8.6Hz), 7.05 (1H, d, J = 2.4Hz)
, 7.68 (1H, d, J = 8.6Hz). (3) (4S, 8S, 9R, 10S) -4- (6-aminobenzothiazole) thiomethyl-10-[(R) -1
-Hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-
Potassium carboxylate Using the compound (100 mg) obtained in Example 13- (2), the target compound (51 mg) was lyophilized by performing the same reaction and isolation procedure as in Example 4- (3). As obtained.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 3342, 2928, 1751, 1590, 1390, 997. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.12 (3H, d, J = 6.4 Hz), 1.11 to 1.37 (1H, m), 1.60
~ 1.94 (5H, m), 2.91 ~ 3.00 (1H, m), 3.24 (1H, dd, J = 2.
9,6.0Hz), 3.32 (1H, dd, J = 4.8,13.3Hz), 3.47 (1H, dd, J
= 2.9,10.0Hz), 3.77 (1H, dd, J = 11.3,13.3Hz), 3.86 〜
3.94 (1H, m), 4.06 (1H, dq, J = 6.0,6.4Hz), 7.01 (1H, dd, J
= 2.2,8.7Hz), 7.28 (1H, d, J = 2.2Hz), 7.69 (1H, d, J = 8.7
Example 14 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4- [6- (4-pyridylcarbonylamino) benzothiazole] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid potassium

[0241]

Embedded image (1) (4S, 8S, 9R, 10S) -10-[(R)
-(T-butyldimethylsilyloxy) ethyl] -4-
Allyl [6- (4-pyridylcarbonylamino) benzothiazole] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate Example 13- ( The compound (320 mg) obtained in 1) was dissolved in dichloromethane (10 ml), and isonicotinoyl chloride hydrochloride (104 mg) and triethylamine (118 mg) were added under ice-cooling, followed by stirring for about 1 hour. Aqueous sodium bicarbonate and ethyl acetate (30 ml) were added to the reaction solution, and the mixture was extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was subjected to column chromatography (silica gel 10 g, ethyl acetate: methanol =
95: 5) to give the title compound (387 mg) as a white solid.

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 0.06 (6H, s), 0.87 (9H, s), 1.21 to
2.05 (6H, m), 3.07 to 3.21 (1H, m), 3.15 (1H, dd, J = 3.0,
6.6Hz), 3.56 (1H, dd, J = 6.8,12.8Hz), 3.69 (1H, dd, J =
9.2,12.8Hz), 3.95 to 4.19 (3H, m), 4.52 to 4.68 (2H,
m), 5.08-5.38 (2H, m), 7.46 (1H, dd, J = 2.1,8.8Hz),
7.75 (2H, d, J = 5.9Hz), 7.79 (1H, d, J = 8.8Hz), 8.39 (1H,
d, J = 2.1Hz), 8.44 (1H, s), 8.79 (2H, d, J = 5.9Hz). (2) (4S, 8S, 9R, 10S) -10-[(R)
-Hydroxyethyl] -4- [6- (4-pyridylcarbonylamino) benzothiazole] thiomethyl-11
Allyl oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate (2) Compound (410m) obtained in Example 14- (1)
Using g) and the same reaction and isolation procedure as in Example 1- (2), the title compound (240 mg) was obtained as an oil.

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 1.28 (3H, d, J = 6.4 Hz), 1.21 to 1.4
9 (1H, m), 1.54 to 2.16 (5H, m), 3.20 (1H, dd, J = 3.1,6.4
Hz), 3.14-3.29 (1H, m), 3.29 (1H, dd, J = 6.4,13.0Hz)
, 3.75 (1H, dd, J = 9.8,13.0Hz), 4.04 (1H, dd, J = 3.1,10.
4Hz), 4.03 ~ 4.20 (1H, m), 4.17 (1H, dq, J = 6.4,6.4Hz)
, 4.56 to 4.73 (2H, m), 5.12 to 5.38 (2H, m), 5.79 to
5.94 (1H, m), 7.43 (1H, dd, J = 2.1,8.7Hz), 7.74 (1H, d, J
= 6.0Hz), 7.80 (1H, d, J = 8.7Hz), 8.26 (1H, s), 8.35 (1H,
d, J = 2.1 Hz). (3) (4S, 8S, 9R, 10S) -10-[(R)
-1-Hydroxyethyl] -4- [6- (4-pyridylcarbonylamino) benzothiazole] thiomethyl-1
1-oxo-1-azatricyclo [7.2.0.
[0 ^3,8 ] Potassium undec-2-ene-2-carboxylate The same reaction and isolation procedure as in Example 4- (3) using the compound (90 mg) obtained in Example 14- (2). By performing the above, the target compound (62 mg) was obtained as a lyophilized powder.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 3290, 2929, 1752, 1672, 1584, 1531, 1444
, 1398. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.19 (3H, d, J = 6.4 Hz), 1.12 to 1.87 (6H, m), 2.86
~ 2.96 (1H, m), 3.19 (1H, dd, J = 5.8,12.5Hz), 3.29 (1H, d
d, J = 2.8,6.0Hz), 3.44 (1H, dd, J = 10.6,12.4Hz), 3.77
(1H, dd, J = 2.8,10.1Hz), 3.82 ~ 3.90 (1H, m), 4.11 (1H,
dq, J = 6.0,6.4Hz), 7.44 (1H, dd, J = 2.0,8.8Hz), 7.60 (1
H, d, J = 8.8Hz), 7.64 (2H, d, J = 5.9Hz), 7.98 (1H, d, J = 2.
0 Hz), 8.59 (2H, d, J = 5.9 Hz). Example 15 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4- [6- (1-methylpyridinio-4-ylcarbonylamino) benzothiazole] thiomethyl-11-oxo-1-azatricyclo [7.
2.0.0 ^3,8 ] undec-2-ene-2-carboxylate

[0245]

Embedded image The compound (90 mg) obtained in Example 14- (2) was dissolved in dichloromethane, methyl trifluoromethanesulfonate (28 mg) was added under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1.5 hours. . After confirming the disappearance of the starting materials, the same reaction and isolation procedure as in Example 4- (3) were performed to obtain the desired compound (39 mg).

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 3403, 2929, 1754, 1674, 1585, 1444, 1400. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δpp
m: 1.16 (3H, d, J = 6.4 Hz), 1.01 to 1.95 (6H, m), 2.93
~ 3.05 (1H, m), 3.23 ~ 3.38 (1H, m), 3.28 (1H, dd, J = 3.
1,5.9Hz), 3.61 to 3.72 (2H, m), 3.87 to 3.94 (1H, m),
4.09 (1H, dq, J = 5.9,6.4Hz), 4.49 (3H, s), 7.58 (1H, d
d, J = 1.9,8.9Hz), 7.74 (1H, d, J = 8.9Hz), 8.18 (1H, d, J =
1.9Hz), 8.40 (2H, d, J = 6.6Hz), 8.99 (2H, d, J = 6.6Hz). Embodiment 16 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4-[(6-methanesulfonylamino) benzothiazol-2-yl] thiomethyl-11
-Oxo-1-azatricyclo [7.2.0.0 ^3,8 ]
Potassium undec-2-ene-2-carboxylate and (4S, 8S, 9R, 10S) -4-[(6-N-
Allyl -N- methanesulfonylamino) benzothiazol-2-yl] thiomethyl -10 - [(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^{3, 8]} undec Potassium 2-ene-2-carboxylate

[0247]

Embedded image Under a nitrogen stream, the compound obtained in Example 13- (1) was
After methanesulfonylation, it is obtained by using the same method as in Example 1- (2) (4S, 8S, 9R, 10
S) -10-[(R) -1-Hydroxyethyl] -4-
[(6-methanesulfonylamino) benzothiazole-
2-yl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-en-2-
Example 4 using allyl carboxylate (110 mg)
By performing the same reaction and isolation procedure as in (3), (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4-[(6-methanesulfonylamino) benzothiazol-2-yl] thiomethyl-11
-Oxo-1-azatricyclo [7.2.0.0 ^3,8 ]
Potassium undec-2-ene-2-carboxylate (49m
g) and (4S, 8S, 9R, 10S) -4-[(6
-N-allyl-N-methanesulfonylamino) benzothiazol-2-yl] thiomethyl-10-[(R) -1
-Hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-
Potassium carboxylate (15 mg) was obtained as a lyophilized powder.

(4S, 8S, 9R, 10S) -10-
[(R) -1-hydroxyethyl] -4-[(6-methanesulfonylamino) benzothiazol-2-yl] thiomethyl-11-oxo-1-azatricyclo [7.
2.0.0 ^3,8 ] potassium undec-2-ene-2-carboxylate infrared absorption spectrum (KBr) cm ^-1: 3374, 2928, 1752,
1587, 1441, 1392, 1324, 1252, 1225, 1153. Nuclear magnetic resonance spectrum (400MHz, D ₂ O) d: 1.18 (3H, d,
J = 6.4Hz), 1.16-1.37 (1H, m), 1.59-1.96 (5H, m), 2.
98 ~ 3.07 (1H, m), 3.11 (3H, s), 3.28 (1H, dd, J = 6.0, 3.
2Hz), 3.40 (1H, dd, J = 13.2, 4.7Hz), 3.56-3.64 (1H,
m), 3.74 to 3.84 (1H, m), 3.86 to 3.95 (1H, m), 4.08 (1H,
qd, J = 6.4, 6.0Hz), 7.38 (1H, dd, J = 8.8, 2.2Hz), 7.8
7-7.78 (2H, m) (4S, 8S, 9R, 10S) -4-[(6-N-allyl-N-methanesulfonylamino) benzothiazole-
2-yl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.
2.0.0 ^3,8 ] undec-2-ene-2-carboxylate potassium Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) d: 1.19 (3H, d,
J = 6.5Hz), 1.14-1.38 (1H, m), 1.62-1.75 (2H, m), 1.
79 to 1.97 (1H, m), 3.03 to 3.14 (1H, m), 3.19 (3H, s),
3.29 (1H, dd, J = 6.4, 3.0Hz), 3.44 (1H, dd, J = 13.1,
4.6Hz), 3.64 (1H, dd, J = 10.2, 3.0Hz), 3.80〜3.96 (2H,
m), 4.07 (1H, qd, J = 6.5, 6.4Hz), 4.38 (2H, d, J = 6.0
Hz), 5.14 to 5.33 (2H, m), 5.83 to 5.97 (1H, m9, 7.56 (1
H, d, J = 8.7, 2.1Hz), 7.91 (1H, d, J = 8.7Hz), 8.01 (1
(H, d, J = 2.1 Hz) Example 17 (4S, 8S, 9R, 10S) -4-[(6-N, N-
Bismethanesulfonylamino) benzothiazole-2-
Yl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.
0.0 ^3,8 ] potassium undec-2-ene-2-carboxylate

[0249]

Embedded image Under a nitrogen stream, the compound obtained in Example 13- (1) was
After bismethanesulfonylation, it can be obtained by using the same method as in Example 1- (2) (4S, 8S, 9R,
10S) -4-[(6-N, N-bismethanesulfonylamino) benzothiazol-2-yl] thiomethyl-1
Using allyl 0-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate (50 mg), By performing the same reaction and isolation operation as in Example 4- (3), the desired compound (27 mg) was obtained as a lyophilized powder.

Infrared absorption spectrum (KBr) cm ^-1: 3375,
2930, 1752, 1589, 1438, 1369, 1161. Nuclear magnetic resonance spectrum (400MHz, D ₂ O) d: 1.20 (3H, d,
J = 6.4Hz), 1.17-1.35 (1H, m), 1.65-1.79 (3H, m), 1.
84 to 1.96 (2H, m), 3.07 to 3.17 (1H, m), 3.30 (1H, dd, J
= 6.3, 3.1Hz), 3.46 (1H, dd, J = 13.1, 4.5Hz), 3.60 (6
H, s), 3.65 (1H, dd, J = 10.2, 3.0Hz), 3.80 to 3.96 (2H,
m), 3.81 to 3.95 (2H, m), 4.07 (1H, qd, J = 6.4, 6.3Hz),
7.64 (1H, dd, J = 8.7, 2.2Hz), 7.98 (1H, d, J = 8.7Hz),
8.14 (1H, d, J = 2.2 Hz). Embodiment 18 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4-[(6-octanoylamino) benzothiazol-2-yl] thiomethyl-11
Potassium oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate

[0251]

Embedded image Under a nitrogen stream, the compound obtained in Example 13- (1) was
After octanoylation, it is obtained by using the same method as in Example 1- (2) (4S, 8S, 9R, 10S).
-10-[(R) -1-hydroxyethyl] -4-
[(6-Octanoylamino) benzothiazole-2-
Example 4- (3) using allyl (85 mg) of yl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate.
The target compound was obtained as a lyophilized powder by carrying out the same reaction and isolation procedure as in.

Infrared absorption spectrum (KBr) cm- ^1: 3297,
2928, 1754, 1663, 1583, 1533, 1446, 1400. Nuclear magnetic resonance spectrum (400MHz, D ₂ O) d: 1.22 (3H, d,
J = 6.1Hz), 0.61 to 1.85 (19H, m), 2.25 to 4.30 (9H, m),
7.10-8.25 (3H, m) Example 19 (4S, 8S, 9R, 10S) -4-[(6-benzoylamino) benzothiazol-2-yl] thiomethyl-
Potassium 10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate

[0253]

Embedded image Under a nitrogen stream, the compound obtained in Example 13- (1) was
After benzoylation, it is obtained by using the same method as in Example 1- (2) (4S, 8S, 9R, 10S)-.
4-[(6-benzoylamino) benzothiazole-2
-Yl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.
2.0.0 ^3,8 ] undec-2-ene-2-carboxylate (75 mg) was subjected to the same reaction and isolation procedures as in Example 4- (3) to give the desired compound (45
mg) as a lyophilized powder.

Infrared absorption spectrum (KBr) cm ^-1: 3308,
2929, 1752, 1652, 1580, 1529, 1445, 1398, 1253. Nuclear magnetic resonance spectrum (400MHz, D ₂ O) d: 1.19 (3H, d,
J = 6.3Hz), 1.15-1.37 (1H, m), 1.49-1.72 (3H, m), 1.
74 ~ 1.92 (2H, m), 2.87 ~ 2.97 (1H, m), 3.17 ~ 3.31 (2H, m
m), 3.50 to 3.62 (1H, m), 3.66 to 3.74 (1H, m), 3.82 to
3.90 (1H, m), 4.06 to 4.14 (1H, m), 7.46 to 8.09 (5H, m). Example 20 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4-[(6- (3,4,5-trimethoxybenzoyl) amino) benzothiazole-2-
Il] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate potassium

[0255]

Embedded image Under a nitrogen stream, the compound obtained in Example 13- (1) was
After 3,4,5-trimethoxybenzoylation, Example 1 was used.
It is obtained by using the same method as (2) (4
S, 8S, 9R, 10S) -10-[(R) -1-hydroxyethyl] -4-[(6- (3,4,5-trimethoxybenzoyl) amino) benzothiazol-2-yl] thiomethyl- Example 4- (3) using allyl 11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate (90 mg)
The target compound (56 mg) was obtained as a lyophilized powder by carrying out the same reaction and isolation procedures as in 1.

Infrared absorption spectrum (KBr) cm- ^1: 3396,
2933, 1752, 1652, 1587, 1500, 1336, 1226, 1128. Nuclear magnetic resonance spectrum (400MHz, D ₂ O) d: 1.20 (3H, d,
J = 6.5Hz), 1.15 ~ 1.32 (1H, m), 1.35 ~ 1.70 (3H, m), 1.
71 ~ 1.86 (2H, m), 2.83 ~ 2.96 (1H, m), 3.17 ~ 3.25 (1H,
m), 3.27 to 3.32 (1H, m), 3.35 to 3.47 (1H, m), 3.76 (3
H, m), 3.81 (6H, s), 4.08-4.16 (1H, m), 6.94 (2H, s),
7.43 to 7.60 (2H, m), 7.97 (1H, s). Example 21 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4- [6- (2-pyridylcarbonylamino) benzothiazol-2-yl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0
^3,8 ] potassium undec-2-ene-2-carboxylate

[0257]

Embedded image Under a nitrogen stream, the compound obtained in Example 13- (1) was
After 2-pyridylcarbonylation, it can be obtained by using the same method as in Example 1- (2) (4S, 8S, 9
R, 10S) -10-[(R) -1-hydroxyethyl] -4- [6- (2-pyridylcarbonylamino) benzothiazol-2-yl] thiomethyl-11-oxo-1-azatricyclo [7.2 .0.0 ^3,8 ] undec-2-ene-2-carboxylate (119 mg) was subjected to the same reaction and isolation procedure as in Example 4- (3) to give the desired compound (93 mg) Was obtained as a lyophilized powder.

Infrared absorption spectrum (KBr) cm ^-1: 3335,
2928, 1754, 1684, 1590, 1570, 1524, 1446, 1400.- Nuclear magnetic resonance spectrum (400MHz, D ₂ O) d: 1.20 (3H, d,
J = 6.4Hz), 1.15 ~ 1.33 (1H, m), 1.51 ~ 1.70 (3H, m), 1.
74 to 1.90 (2H, m), 2.90 to 2.96 (1H, m), 3.17 to 3.25 (1H,
m), 3.27 to 3.32 (1H, m), 3.35 to 3.47 (1H, m), 3.76 (3
H, m), 3.81 (6H, s), 4.08-4.16 (1H, m), 6.94 (2H, s),
7.43 to 7.60 (2H, m), 7.97 (1H, s). Example 22 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4- [6- (3-pyridylcarbonylamino) benzothiazol-2-yl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0
^3,8 ] potassium undec-2-ene-2-carboxylate

[0259]

Embedded image Under a nitrogen stream, the compound obtained in Example 13- (1) was
After 3-pyridylcarbonylation, it is obtained by using the same method as in Example 1- (2) (4S, 8S, 9
R, 10S) -10-[(R) -1-hydroxyethyl] -4- [6- (3-pyridylcarbonylamino) benzothiazol-2-yl] thiomethyl-11-oxo-1-azatricyclo [7.2 .0.0 ^3,8 ] undec-2-ene-2-carboxylate (96 mg) was subjected to the same reaction and isolation procedure as in Example 4- (3) to give the desired compound (59 mg). Was obtained as a lyophilized powder.

Infrared absorption spectrum (KBr) cm- ^1: 3405,
2929, 1752, 1669, 1590, 1533, 1524, 1445, 1399. Nuclear magnetic resonance spectrum (400MHz, D ₂ O) d: 1.19 (3H, d,
J = 6.2Hz), 1.14 ~ 1.34 (1H, m), 1.49 ~ 1.72 (3H, m), 1.
77 ~ 1.92 (2H, m), 2.88 ~ 3.02 (1H, m), 3.19 ~ 3.35 (2H, m
m), 3.49 to 3.58 (1H, m), 3.74 (1H, dd, J = 10.2, 2.7H
z), 3.83 to 3.90 (1H, m), 4.11 (1H, qd, J = 6.2, 6.1H
z), 7.42-7.57 (2H, m), 7.66 (1H, d, J = 8.8Hz), 8.01
(1H, s), 8.14 (1H, d, J = 8.0), 8.63, (1H, d, J = 4.7),
8.82 (1H, s). Example 23 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4- [6- (6-quinolinecarbonylamino) benzothiazol-2-yl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0
^3,8 ] potassium undec-2-ene-2-carboxylate

[0261]

Embedded image Under a nitrogen stream, the compound obtained in Example 13- (1) was
After 6-quinolylcarbonylation, it is obtained by using the same method as in Example 1- (2) (4S, 8S, 9
R, 10S) -10-[(R) -1-hydroxyethyl] -4- [6- (6-quinolinecarbonylamino) benzothiazol-2-yl] thiomethyl-11-oxo-1-azatricyclo [7.2 .0.0 ^3,8 ] undec-2-ene-2-carboxylate (174 mg) was subjected to the same reaction and isolation procedure as in Example 4- (3) to give the desired compound (130 mg). Was obtained as a lyophilized powder.

Infrared absorption spectrum (KBr) cm ^-1: 3308,
2928, 1752, 1658, 1580, 1530, 1444, 1398. Nuclear magnetic resonance spectrum (400MHz, D ₂ O) d: 1.21 (3H, d,
J = 6.2Hz), 1.09 to 1.82 (6H, m), 2.76 to 2.95 (2H, m), 3.
07-3.17 (1H, m), 3.26-3.34 (1H, m), 3.69-3.88 (2H,
m), 4.10-4.18 (1H, m), 7.20-8.16 (9H, m). Example 24 (4S, 8S, 9R, 10S) -4- [6-Glycylamino) benzothiazol-2-yl] thiomethyl- 10
-[(R) -1-hydroxyethyl] -11-oxo-
1-azatricyclo [7.2.0.0 ^3,8 ] undeca
2-ene-2-carboxylic acid

[0263]

Embedded image Under a nitrogen stream, the compound obtained in Example 13- (1) was
After (N-allyloxycarbonyl) glycylation, (4S, 8S, 9R, 10S) -4- [6-((N-allyloxycarbonyl) is obtained by using the same method as in Example 1- (2). ) Glycylamino) benzothiazol-2-yl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene- Example 5- (4) using allyl 2-carboxylate (88 mg)
The target compound (21 mg) was obtained as a lyophilized powder by carrying out the same reaction and isolation procedures as in 1.

Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) d:
1.15 to 1.39 (1H, m), 1.17 (3H, d, J = 6.1Hz), 1.55 to 1.7
8 (3H, m), 1.81 to 1.95 (2H, m), 2.98 to 3.10 (1H, m), 3.
23 ~ 3.33 (1H, m), 3.33 ~ 3.47 (1H, m), 3.55 ~ 3.65 (1H, m
m), 3.75 to 3.89 (1H, m), 3.89 to 3.96 (1H, m), 4.01 (2
H, s), 4.05-4.15 (1H, m), 7.49-7.55 (1H, m), 7.81
7.87.88 (1H, m), 8.06 to 8.12 (1H, m). Example 25 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4- [6- (S) -prolylaminobenzothiazol-2-yl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene- 2-carboxylic acid

[0265]

Embedded image Under a nitrogen stream, the compound obtained in Example 13- (1) was
After (S)-(N-allyloxycarbonyl) prolylation, (4S, 8S, 9R, 10S) -4- [6- is obtained by using the same method as in Example 1- (2).
((S)-(N-allyloxycarbonyl) prolylamino) benzothiazol-2-yl] thiomethyl-10
-[(R) -1-hydroxyethyl] -11-oxo-
1-azatricyclo [7.2.0.0 ^3,8 ] undeca
The target compound (34 mg) was obtained as a lyophilized powder by performing the same reaction and isolation operation as in Example 5- (4) using allyl 2-ene-2-carboxylate (210 mg).

Nuclear magnetic resonance spectrum (400 MHz, DMSO-d ₆ )
d: 1.10 (3H, d, J = 6.1Hz), 1.21-1.37 (1H, m), 1.47
~ 1.95 (8H, m), 2.09 ~ 2.21 (1H, m), 2.93 ~ 3.09 (2H, m
m), 3.10-3.27 (1H, m), 3.15 (1H, dd, J = 5.9, 3.3Hz),
3.55 to 3.70 (2H, m), 3.85 to 4.06 (2H, m), 3.91 (1H, d
d, J = 6.1, 5.9Hz), 3.98 (1H, dd, J = 3.1, 10.4Hz), 7.6
2 (1H, dd, J = 8.8, 1.8Hz), 7.77 (1H, d, J = 8.8Hz), 8.3
Example 26 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4- [6- (2-methylaminoethyl) aminobenzothiazol-2-yl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0
^3,8 ] Undec-2-ene-2-carboxylic acid

[0267]

Embedded image Under a nitrogen stream, the compound obtained in Example 13- (1) was
After 2- (N-allyloxycarbonyl-N-methyl) aminoethylation, (4S, 8S, 9R, 10S) -4 obtained by using the same method as in Example 1- (2).
-[6- (2- (N-allyloxycarbonyl-N-methyl) aminoethylamino) benzothiazol-2-yl] thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1- Azatricyclo [7.2.
0.0 ^3,8 ] undec-2-ene-2-carboxylate (78 mg) was subjected to the same reaction and isolation procedures as in Example 5- (4) to give the desired compound (21 m
g) was obtained as a lyophilized powder.

Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) d:
1.16 (3H, d, J = 6.3Hz), 1.17 ~ 1.34 (1H, m), 1.60 ~ 1.7
7 (3H, m), 1.80 to 1.94 (2H, m), 2.76 (3H, s), 2.92 to
3.03 (1H, m), 3.25 (1H, dd, J = 6.0, 2.9Hz), 3.28-3.3
6 (1H, m), 3.30 (2H, t, J = 5.9Hz), 3.49 (1H, dd, J = 1
0.1, 2.8Hz), 3.56 (2H, t, J = 5.9Hz), 3.74-3.84 (1H,
m), 3.85 to 3.94 (1H, m), 4.06 (1H, qd, J = 6.3, 6.0Hz),
6.97 (1H, dd, J = 8.8, 2.3Hz), 7.21 (1H, d, J = 2.3Hz),
7.71 (1H, d, J = 8.8Hz). Example 27 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4- [6- (2-pyridylmethylamino) benzothiazol-2-yl] thiomethyl-1
1-oxo-1-azatricyclo [7.2.0.
0 ^3,8 ] potassium undec-2-ene-2-carboxylate

[0269]

Embedded image Under a nitrogen stream, the compound obtained in Example 13- (1) was
After 2-pyridylmethylation, it is obtained by using the same method as in Example 1- (2) (4S, 8S, 9R, 1).
0S) -10-[(R) -1-hydroxyethyl] -4
-[6- (2-Pyridylmethylamino) benzothiazol-2-yl] thiomethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2
Example 4 using allyl carboxylate (79 mg)
The target compound (49 mg) was obtained as a lyophilized powder by performing the same reaction and isolation operation as in (3).

Infrared absorption spectrum (KBr) cm- ^1: 3383,
2928, 1752, 1603, 1593, 1448, 1393, 1252. Nuclear magnetic resonance spectrum (400MHz, D ₂ O) d: 1.15 to 1.35 (1
H, m), 1.16 (3H, d, J = 6.4Hz), 1.34 to 1.87 (5H, m), 2.
72 ~ 2.85 (2H, m), 3.15 ~ 3.25 (1H, m), 3.45 ~ 3.61 (1H,
m), 3.78 to 3.89 (1H, m), 3.95 to 4.07 (1H, m), 4.47 (2
H, br s), 6.92 to 7.02 (2H, m), 7.22 to 7.45 (2H, m), 7.
Example 28 (4S, 8S, 9R, 10S) -4- (benzothiazol-2-yl) aminomethyl-10-[(R) 1-Hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid sodium salt

[0271]

Embedded image It is obtained by using the compound obtained in Reference Example 2- (2) and benzothiazol-2-ylcarbamic acid allyl ester under a nitrogen stream and using the same method as in Example 1- (1) (4S , 8S, 9R, 10S) -4-
(N-allyloxycarbonyl-N-benzothiazol-2-yl) aminomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 Example 5 using allyl undec-2-ene-2-carboxylate (124 mg)
The same reaction and isolation operation as in (4) were performed, and an equivalent amount of sodium hydrogen carbonate was added during the isolation operation to obtain the desired compound (57 mg) as a lyophilized powder.

Infrared absorption spectrum (KBr) cm ^-1: 3267,
2925, 2852, 1752, 1599, 1552, 1447, 1400, 1252. Nuclear magnetic resonance spectrum (400MHz, D ₂ O) d: 1.23 to 1.44 (1
H, m), 1.25 (3H, d, J = 6.5Hz), 1.54 to 1.80 (3H, m), 1.
82 ~ 1.94 (2H, m), 3.17 ~ 3.29 (1H, m), 3.36 (1H, dd, J
= 6.3, 3.0Hz), 3.49-3.63 (1H, m), 3.68-4.86 (2H,
m), 4.01, (1H, dd, J = 10.2, 3.0Hz), 4.18 (1H, qd, J =
6.5, 6.2Hz), 7.16 to 7.22 (1H, m), 7.33 to 7.42 (1H, m),
7.49 (1H, d, J = 8.9 Hz), 7.69 (1H, d, J = 8.9 Hz). Example 29 (4S, 8S, 9R, 10S) -4- (6-fluorobenzothiazol-2-yl) Aminomethyl-10-
[(R) -1-hydroxyethyl] -11-oxo-1
-Azatricyclo [7.2.0.0 ^3,8 ] undeca-2
-Sodium ene-2-carboxylate

[0273]

Embedded image Using a compound obtained in Reference Example 2- (2) and 6-fluorobenzothiazol-2-ylcarbamic acid allyl ester under a nitrogen stream, using the same method as in Example 1- (1). (4S, 8S, 9R, 10
S) -4- (N-allyloxycarbonyl-N- (6-
Fluorobenzothiazol-2-yl)) aminomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene- The same reaction and isolation procedure as in Example 5- (4) was carried out using allyl 2-carboxylate (131 mg), and the desired compound (70 mg) was frozen by adding an equivalent amount of sodium hydrogen carbonate during the isolation procedure. Obtained as a dry powder.

Infrared absorption spectrum (KBr) cm ^-1: 3257,
2930, 2859, 1753, 1608, 1562, 1461, 1401, 1253. Nuclear magnetic resonance spectrum (400MHz, D ₂ O) d: 1.23 to 1.40 (1
H, m), 1.25 (3H, d, J = 6.4Hz), 1.55-1.79 (3H, m), 1.
80 ~ 1.96 (2H, m), 3.15 ~ 3.27 (1H, m), 3.36 (1H, dd, J
= 6.0, 3.0Hz), 3.53 (1H, dd, J = 12.3, 4.8Hz), 3.68〜
3.85 (2H, m), 4.01, (1H, dd, J = 10.2, 3.1Hz), 4.18 (1
(H, qd, J = 6.4, 6.0Hz), 7.07 ~ 7.14 (1H, m), 7.38 ~ 7.47
Example 30 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4- (6-nitrobenzothiazol-2-yl) -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylic acid sodium salt

[0275]

Embedded image Using a compound obtained in Reference Example 2- (2) and 6-nitrobenzothiazol-2-ylcarbamic acid allyl ester under a stream of nitrogen and using the same method as in Example 1- (1), (4S, 8S, 9R, 10
S) -4- (N-allyloxycarbonyl-N- (6-
Nitrobenzothiazol-2-yl)) aminomethyl-
Using allyl 10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate (131 mg), The same reaction and isolation procedure as in Example 5- (4) were carried out, and an equivalent amount of sodium hydrogen carbonate was added during the isolation procedure to obtain the desired compound (70 mg) as a lyophilized powder.

Infrared absorption spectrum (KBr) cm- ^1: 3369,
3247, 1754, 1608, 1554, 1507,1451, 1400, 1332, 1
. 299,1127 Nuclear magnetic resonance spectrum _{(400MHz, D 2 O) d} : 1.17~1.42 (1
H, m), 1.25 (3H, d, J = 6.4Hz), 1.54 to 1.97 (5H, m), 3.
17 ~ 3.31 (1H, m), 3.38 (1H, dd, J = 6.0, 3.0Hz), 3.46
~ 3.65 (1H, m), 3.71 ~ 3.87 (2H, m), 4.04, (1H, dd, J
= 10.2, 3.0Hz), 4.19 (1H, qd, J = 6.4, 6.0Hz), 7.40 (1H,
Example 31, (4S, 8S, 9R, 10S) -4- (2-benzimidazolyl) thiomethyl-10. -[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.
2.0.0 ^3,8 ] potassium undec-2-ene-2-carboxylate

[0277]

Embedded image The compound obtained in Reference Example 2- (2) under a stream of nitrogen, and
Example 1 using 2-mercaptobenzimidazole
It is obtained by using the same method as (1) (4
S, 8S, 9R, 10S) -4- (2-Benzimidazolyl) thiomethyl-10-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.
0.0 ^3,8 ] undec-2-ene-2-carboxylate (52 mg) was subjected to the same reaction and isolation procedure as in Example 4- (3). The target compound (42 mg) was obtained as a lyophilized powder by adding sodium hydrogen.

Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) d:
1.10 to 1.32 (1H, m), 1.14 (3H, d, J = 6.4Hz), 1.54 to 1.9
4 (5H, m), 2.82 ~ 2.93 (1H, m), 3.22 (1H, dd, J = 6.2,
3.0Hz), 3.25 to 3.41 (2H, m), 3.67 to 3.88 (2H, m), 4.02
(1H, qd, J = 6.4, 6.2Hz), 7.28 ~ 7.40 (2H, m), 7.56 ~
7.63 (2H, m). Example 32 (4S, 8S, 9R, 10S) -10-[(R) -1-
Hydroxyethyl] -4- (2H-naphtho <1,8-c
d> isothiazol-1,1-dioxide-2-yl)
Methyl-11-oxo-1-azatricyclo [7.2.
0.0 ^3,8 ] potassium undec-2-ene-2-carboxylate

[0279]

Embedded image It is obtained by using the compound obtained in Reference Example 2- (2) and 1,8-naphthosultam in a nitrogen stream and using the same method as in Example 1- (1) (4S, 8S, 9).
R, 10S) -10-[(R) -1-hydroxyethyl] -4- (2H-naphtho <1,8-cd> isothiazol-1,1-dioxide-2-yl) methyl-11
Allyl oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate (103 m
The target compound (66 mg) was obtained as a lyophilized powder by performing the same reaction and isolation operation as in Example 4- (3) using g).

Infrared absorption spectrum (KBr) cm- ^1: 3421,
. 2929, 1753 1591, 1554, 1386,1314,1174,1138 NMR spectrum _{(400MHz, D 2 O) d} : 1.17~1.40 (1
H, m), 1.28 (3H, d, J = 6.4Hz), 1.45 to 2.00 (5H, m), 3.
17 ~ 3.32 (1H, m), 3.39 (1H, dd, J = 6.0, 3.0Hz), 3.79
~ 3.96 (2H, m), 4.15, (1H, dd, J = 10.2, 3.0Hz), 4.23
(1H, qd, J = 6.4,6.0Hz), 6.88 ~ 7.00 (1H, m), 7.46 ~ 7.
61 (2H, m) .7.70-7.85 (1H, m), 8.00-8.20 (2H, m). Example 33 (4S, 8S, 9R, 10S) -4- (N-benzenesulfonyl-N-phenyl) Aminomethyl-10-
[(R) -1-hydroxyethyl] -11-oxo-1
-Azatricyclo [7.2.0.0 ^3,8 ] undeca-2
-Potassium ene-2-carboxylate

[0281]

Embedded image Example 1 was prepared using the compound obtained in Reference Example 2- (2) and N-phenylbenzenesulfonamide under a nitrogen stream.
-It is obtained by using the same method as (1) (4
S, 8S, 9R, 10S) -4- (N-benzenesulfonyl-N-phenyl) aminomethyl-10-[(R)-
1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2
Example 4 using allyl carboxylate (108 mg)
The same reaction and isolation procedure as in (3) was performed, and an equivalent amount of sodium hydrogen carbonate was added during the isolation procedure to obtain the desired compound (83 mg) as a lyophilized powder.

Infrared absorption spectrum (KBr) cm- ^1: 3403,
2930, 1753, 1593, 1492, 1448, 1392, 1348, 1165, 1
091. Nuclear magnetic resonance spectrum (400MHz, D ₂ O) d: 1.13 to 1.30 (1
H, m), 1.25 (3H, d, J = 6.3Hz), 1.36 to 1.85 (5H, m), 3.
27 (1H, dd, J = 6.1 2.8Hz), 3.45 ~ 3.56 (1H, m), 3.73 (1
H, J = 13.4, 5.3Hz), 3.82 (1H, dd, J = 9.8, 2.8Hz), 3.9
8 (1H, dd, J = 13.4, 11.0Hz), 4.18 (1H, qd, J = 6.3, 6.1
Hz), 7.04 to 7.14 (2H, m), 7.34 to 7.45 (3H, m), 7.55 to
7.79 (5H, m). Example 34 (4S, 8S, 9R, 10S) -4- (N- (2-benzylthiobenzothiazol-6-yl) -N-methanesulfonyl) aminomethyl-10-[( R) -1- hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0 ^{3, 8]} potassium undec-2-ene-2-carboxylic acid

[0283]

Embedded image The compound obtained in Reference Example 2- (2) and N- (2-benzylthiobenzothiazol-6-yl) under a stream of nitrogen
Obtained by using methanesulfonamide and using the same method as in Example 1- (1) (4S, 8S, 9
R, 10S) -4- (N- (2-benzylthiobenzothiazol-6-yl) -N-methanesulfonyl) aminomethyl-10-[(R) -1-hydroxyethyl] -1
1-oxo-1-azatricyclo [7.2.0.
[ ^3,8 ] Allyl undec-2-ene-2-carboxylate (145 mg) was reacted and isolated in the same manner as in Example 4- (3). Was added to give the desired compound (100 mg) as a lyophilized powder.

Infrared absorption spectrum (KBr) cm ^-1: 3407,
2928, 1753, 1593, 1442, 1394, 1338, 1151, 1085, 1
000. Nuclear magnetic resonance spectrum (400MHz, D ₂ O) d: 1.10-1.37 (1
H, m), 1.19 (3H, d, J = 6.3Hz), 1.38 to 1.80 (5H, m), 2.
58 ~ 2.84 (1H, m), 3.10 (3H, s), 3.18 ~ 3.27 (1H, m),
3.61 to 3.70 (1H, m), 3.80 to 3.95 (1H, m), 3.97 to 4.14 (2
H, m), 4.50 to 4.62 (2H, m), 7.27 to 7.43 (3H, m), 7.43
-7.57 (3H, m), 7.83-7.92 (2H, m). Reference Example 1 (3S, 4R) -3-[(R) -1- (t-butyldimethylsilyloxy) ethyl] -4-[( 2R, 6R)-
6- (hydroxymethyl) cyclohexanone-2-yl] azetidin-2-one (1) ethyl 2-hydroxycyclohexanecarboxylate ethyl 2-cyclohexanonecarboxylate (1
0.2 g) was dissolved in 200 ml of methanol.
Then, sodium borohydride (2.72 g) was added, and the mixture was stirred at the same temperature for 3 hours, and then heated to room temperature.
After treating with an appropriate amount of acetic acid, the reaction solution was diluted with water, extracted with ethyl acetate (200 ml × 4), the organic layer was washed with aqueous sodium hydrogen carbonate and saturated saline, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (400 g of silica gel,
Separation and purification with hexane: ethyl acetate = 3: 1 → 1: 2) gave the title compound (cis-form 5.47 g, trans-form 1.5).
9g) was obtained as a colorless oil.

Cis form infrared absorption spectrum (neat) ν _max cm ^-1 :
3513, 2937, 1713, 1185, 1040,
976. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 1.28 (3H, d, J = 7.0 Hz),
1.24-1.98 (8H, m), 2.48 (1H, d
dd, J = 11.3, 3.5 and 2.8H
z), 3.20 (1H, brd, J = 2.6 Hz),
4.11-4.18 (1H, m), 4.17 (2H,
q, J = 7.0 Hz).

Trans-form Infrared absorption spectrum (neat) ν _max cm ^-1 :
3448, 2936, 1733, 1180. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 1.28 (3H, t, J = 7.2 Hz),
1.14-1.45 (4H, m), 1.68-1.94
(2H, m), 1.95-2.09 (2H, m), 2.
25 (1H, ddd, J = 3.7, 9.8 and
12.1 Hz), 2.83 (1H, brs), 3.79
-3.84 (1H, m), 4.18 (2H, q, J =
7.2 Hz).

(2) Ethyl (1S, 2R) -2-acetoxycyclohexanecarboxylate The cis form (1.72 g) obtained in Reference Example 1- (1) was dissolved in a mixed solvent of 75 ml of tetrahydrofuran and 175 ml of vinyl acetate. Then, 10 g of immobilized lipase (LIP-301, manufactured by Toyobo Co., Ltd.) was added, and the mixture was stirred at 37 ° C. for 9 hours. The obtained residue was subjected to column chromatography (silica gel 100 g, hexane: ethyl acetate = 5: 1 → 3:
The product was separated and purified in 1) to give the title compound (710 mg) as a colorless oil, and the starting material (861 mg) was recovered.

Infrared absorption spectrum (neat) ν _max
cm ^-1 : 1238, 1250, 1740, 294
0. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 1.19-1.38 (1H, m), 1.2
3 (3H, t, J = 7.2 Hz), 1.41-1.65
(3H, m), 1.72-1.88 (3H, m), 1.
92-2.11 (1H, m), 2.03 (3H, s),
2.43-2.59 (1H, m), 4.02-4.21
(2H, m), 5.35-5.42 (1H, m).

Light intensity: [α] _D ²⁵ = -10.7 ° (C =
0.605, CHCl ₃ ). (3) (1R, 2R) -2-hydroxymethylcyclohexanol Lithium aluminum hydride (122 mg) was dissolved in tetrahydrofuran (5 ml), and a solution of the compound (690 mg) obtained in Reference Example 1- (2) in tetrahydrofuran ( 5 ml) was added dropwise at -70 ° C. The temperature was raised to 0 ° C., and lithium aluminum hydride (36 mg) was added.
Stirred for 0 minutes. Sodium sulfate decahydrate (1.56
g) was added, the resulting precipitate was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel 25 g, hexane: ethyl acetate = 1: 2) to give the title compound (395 m
g) was obtained as a colorless oil.

Infrared absorption spectrum (neat) ν _max
cm ^-1 : 3356,2931,2857,145
0. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 1.18-1.85 (9H, m), 2.2
4 (2H, brm), 3.76 (2H, d, J = 4.1)
Hz), 4.13-4.19 (1H, m).

Light intensity: [α] _D ²⁵ = −32.6 ° (C =
0.725, CHCl _3).

(4) (1R, 2R) -2-t-butyldimethylsilyloxymethylcyclohexanol The compound (380 mg) obtained in Reference Example 1- (3) was dissolved in dichloromethane, and t-butyldimethylsilyl chloride was dissolved. (506 mg), triethylamine (369 mg)
And 4-dimethylaminopyridine (20 mg) were added,
Stirred at room temperature for 2 hours. Aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 3). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (silica gel 50 g, hexane: ethyl acetate = 15: 1).
→ 9: 1) to give the title compound (610 mg) as a colorless oil.

Nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δ ppm: 0.07 (6H, s), 0.
90 (9H, s), 1.17-1.84 (9H, m),
3.35 (1H, brs), 3.72 (3H, dd, J
= 10.0 and 4.8 Hz), 3.81 (1H,
dd, J = 10.0 and 3.7 Hz), 4.09
-4.15 (1H, m).

Light intensity: [α] _D ²⁵ = -12.7 ° (C =
0.755, CHCl _3).

(5) (R) -2-t-butyldimethylsilyloxymethylcyclohexanone The compound (550 mg) obtained in Reference Example 1- (4) was treated with dichloromethane (5 m
l), molecular sieves 4A and pyridinium dichromate (93 mg) were added, and the mixture was stirred for 4.5 hours. The insolubles were removed by celite filtration, the filtrate was collected and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography to give the title compound (480 mg) as a colorless oil.

Infrared absorption spectrum (neat) ν _max
cm ^-1 : 2931, 2859, 1710, 125
4,1087,835. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.05 (6H, s), 0.88 (9H,
s), 1.30-1.48 (1H, m), 1.54-
1.76 (1H, m), 1.84-1.97 (1H,
m), 1.96-2.13 (1H, m), 2.24-
2.42 (2H, m), 2.42-2.56 (1H,
m), 3.56 (1H, dd, J = 10.3 and)
8.0 Hz), 3.98 (1H, dd, J = 4.7 a)
nd 10.4 Hz).

Light intensity: [α] _D ²⁵ = + 39.0 ° (C =
0.580, CHCl ₃ ).

(6) (R) -1-trimethylsilyloxy-2-t-butyldimethylsilyloxymethylcyclohexene The compound (400 mg) obtained in Reference Example 1- (5) was dissolved in tetrahydrofuran (2 ml), and lithium Bistrimethylsilylamide was added dropwise to a 1.0 M tetrahydrofuran solution (1.8 ml) at -78 ° C. One hour later, trimethylsilyl chloride (269 mg) was added to the reaction solution,
The temperature was raised to room temperature over 1 hour. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (silica gel 10).
g, hexane: ethyl acetate = 40: 1) to give the title compound (653 mg) as a colorless oil.

(7) (3S, 4R) -3-[(R) -1
-(T-butyldimethylsilyloxy) ethyl] -4-
[(2R, 6R) -6- (t-butyldimethylsilyloxymethyl) cyclohexanone-2-yl] azetidin-2-one (3S, 4R) -4-acetoxy-3-[(R) -1-
(T-Butyldimethylsilyloxy) ethyl] -1-trimethylsilylazetidin-2-one (653 mg) was dissolved in dichloromethane, and 4 ml of a dichloromethane solution of the compound obtained in Reference Example 7- (6) was added.
After adding 0 mg of zinc chloride, the mixture was stirred at room temperature for 3 hours. Aqueous sodium bicarbonate was added to the reaction solution, and the resulting insolubles were removed through celite, followed by extraction with ethyl acetate (50 ml × 3). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 10 ml of ethyl acetate,
After adding 5 g of silica gel and stirring for 2 hours and filtering, the solvent was distilled off and the residue was purified by column chromatography (silica gel 50 g, hexane: ethyl acetate = 3: 1 → 2: 1), and stereoselectively, The title compound was converted to white crystals (485).
mg).

Infrared absorption spectrum (KBr) ν _max c
m ^-1 : 3080, 2930, 1761, 1716,
1257, 836. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ
ppm: 0.04 (6H, s), 0.06 (3H,
s), 0.07 (3H, s), 0.88 (18H,
s), 1.17 (3H, d, J = 6.1 Hz), 1.6
6-2.09 (6H, m), 2.57-2.62 (1
H, m), 2.63-2.75 (1H, m), 2.87
(1H, dd, J = 4.3 and 2.4 Hz),
3.74 (1H, dd, J = 10.2 and 7.0
Hz), 3.90 (1H, dd, J = 10.2 and)
7.0 Hz), 4.09 (1H, dd, J = 5.4)
and 2.4 Hz), 4.21 (1H, dq, J =
6.1 and 4.3 Hz), 5.79 (1H, br)
s).

Light intensity: [α] _D ²⁵ = + 65.4 ° (C =
0.895, CHCl _3).

(8) (3S, 4R) -3-[(R) -1
-(T-butyldimethylsilyloxy) ethyl] -4-
[(2R, 6R) -6- (hydroxymethyl) cyclohexanone-2-yl] azetidin-2-one The compound (10.0 g) obtained in Reference Example 1- (7) was dissolved in dimethylformamide (100 ml). And ammonium hydrogen fluoride (1.34 g) were added and the mixture was stirred for about 2 days. Aqueous sodium bicarbonate was added for neutralization, and the mixture was extracted with ethyl acetate (250 m
After 1 × 3), the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to column chromatography (silica gel 350).
g, hexane: ethyl acetate = 1: 1 → 1: 4) to give the title compound (5.61 g).

Infrared absorption spectrum (KBr) ν _max c
m ^-1 : 3154, 3073, 2935, 1762,
1715. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.07 (6H, s), 0.88 (9H,
s), 1.11 (3H, d, J = 6.2 Hz), 2.0
5-1.64 (6H, m), 2.42 (1H, br)
s), 2.56-2.66 (2H, m), 2.93 (1
H, dd, J = 3.5 and 2.1 Hz), 3.6
9 (1H, dd, J = 11.2 and 4.6H
z), 3.82 (1H, dd, J = 11.2 and)
7.8 Hz), 4.08 (1H, dd, J = 7.9 a)
nd 2.1 Hz), 4.21 (1H, qd, J = 6.
1 and 3.5 Hz), 6.28 (1H, brs).

Light intensity: [α] _D ²⁵ = + 48.9 ° (C =
0.845, CHCl _3).

(9) (1S, 2R) -2-t-butyldimethylsilyloxymethylcyclohexanol ethyl 2-cyclohexanone carboxylate was converted to BI
Catalytic asymmetric hydrogenation using NAP-Ru (M. Ki
tamura et al., Tethredron Asymme
try, vol. 1, p. 1, 1990) (20 g, 87.5% ee) obtained from ethyl (1S, 2R) -2-acetoxycyclohexanecarboxylate.
Was dissolved in dichloromethane (200 ml), and acetic anhydride (13.0 g) and 4-dimethylaminopyridine (15.
6 g) and stirred for 1 hour, and the reaction solution was concentrated under reduced pressure.
The residue was extracted with ethyl acetate (700 ml × 3). The organic layer was washed sequentially with 1N hydrochloric acid and aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. By performing the same reaction and the same isolation operation as Reference Example 1- (3) without isolating and purifying the obtained acetyl derivative (26.9 g), (1S, 2R) -2- was obtained. A crude product of hydroxymethylcyclohexanol was obtained. This compound was subjected to the same reaction and isolation procedure as in Reference Example 1- (4) without isolation and purification to give the title compound (24.3 g) as a colorless oil.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δpp
m: 0.09 (3H, s), 0.10 (3H, s), 0.74-1.79 (8H, m), 0.91 (9
H, s), 1.92-2.02 (1H, m), 3.42-3.57 (1H, m), 3.58 (1H, dd,
J = 9.9,9.4Hz), 3.72 (1H, dd, J = 9.4,4.0Hz), 4.33 (1H, br
s). (10) Compound (7.14) obtained in Reference Example 1- (9).
g) was dissolved in 60 ml of dichloromethane, molecular sieve 4A (14.6 g), tetrapropylammonium perruthenate (513 mg), and N-methylmorpholine-N-oxide (5.13 g) were added, followed by stirring for 3 days. After removing insolubles by celite filtration, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (silica gel 400 g, hexane: ethyl acetate = 9: 1).
→ 5: 1) to give the desired compound (3.44 g, 86,
1% e. e. ) Got. This was in agreement with the compound obtained in Reference Example 1- (5) in both infrared absorption spectrum and nuclear magnetic resonance spectrum.

Optical rotation: [α] _D ²⁵ = 33.6 ° (C =
1.23. CHCl ₃ ). Reference Example 2 (4S, 8S, 9R, 10S) -10-[(R) -1-
Allyl (t-butyldimethylsilyloxy) ethyl] -4-hydroxymethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate (1) ( 4S, 8S, 9R, 10S) -10-[(R)
-1- (t-butyldimethylsilyloxyethyl) -4
Allyl -t-butyldimethylsilyloxymethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate Obtained in Reference Example 1- (7) The compound (1.68 g) was dissolved in dichloromethane (30 ml), and triethylamine (725 mg) and allyloxalyl chloride (796) were added under ice cooling.
mg) and stirred for 3 hours. 2-Propanol (84 mg) was added to the reaction solution, and after stirring for 15 minutes, the solvent was distilled off under reduced pressure. The obtained residue is subjected to column chromatography (silica gel 30 g, hexane: ethyl acetate = 3: 1).
To give an oil. This is toluene (30 ml)
And diethylethylphosphonite (1.60 g)
After stirring at 50 ° C. for 2 hours, the solvent was replaced with xylene and refluxed at 160 ° C. for 3 hours. Xylene was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (120 g of silica gel, hexane: ethyl acetate = 5:
Purification in 1) gave the title compound (1.72 g) as a colorless oil.

Infrared absorption spectrum (CHCl ₃ ) ν
_max cm ^-1 : 2932, 2859, 1771, 17
15, 1259, 1102. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.04 (3H, s), 0.07 (3H,
s), 0.87 (9H, s), 1.24 (3H, d, J
= 6.2 Hz), 1.21 to 2.04 (6H, m),
2.94-3.08 (1H, m), 3.17 (1H, d
d, J = 6.7 and 3.2 Hz), 3.67−
3.85 (3H, m), 4.08 (1H, dd, J = 1
0.5 and 3.2 Hz), 4.19 (1H, qu)
int, J = 6.2 Hz), 4.67 (1H, dd, J)
= 13.7 and 5.5 Hz), 4.78 (1H,
dd, J = 10.4 and 5.5 Hz), 5.24
(1H, d, J = 9.0 Hz), 5.42 (1H, d,
J = 17.2 Hz), 5.89-6.06 (1H,
m).

Light intensity: [α] _D ²⁵ = + 96.0 ° (C =
1.32, CHCl ₃ ).

(2) (4S, 8S, 9R, 10S) -1
0-[(R) -1- (t-butyldimethylsilyloxy) ethyl] -4-hydroxymethyl-11-oxo-
1-azatricyclo [7.2.0.0 ^3,8 ] undeca
Allyl 2-ene-2-carboxylate The compound (5.90 g) obtained in Reference Example 2- (1) was treated with D
It was dissolved in MF (60 ml), ammonium hydrogen fluoride (641 mg) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was neutralized by adding aqueous sodium hydrogen carbonate, and ethyl acetate (250 ml ×
Extracted in 4). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to column chromatography (silica gel 300).
g, hexane: ethyl acetate = 3: 2 → 1: 1) to give the title compound (2.22 g) as a colorless oil.

Infrared absorption spectrum (CHCl ₃ ) νm
axcm ^-1 : 2933,2859,1771,17
20. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.08 (6H, s), 0.88 (9H,
s), 1.16-1.92 (6H, m), 1.23 (3
H, d, J = 6.2 Hz), 2.97-3.10 (1
H, m), 3.20 (1H, dd, J = 6.3 and
3.4 Hz), 3.71-3.88 (3H, m),
4.16 (1H, dd, J = 10.6 and 3.4
Hz), 4.21 (1H, quint, J = 6.2H)
z), 4.69 (1H, dd, J = 13.6 and
5.5 Hz), 4.77 (1H, dd, J = 13.6)
and 5.2 Hz), 5.26 (1H, dd, J = 1)
0.6 and 1.2 Hz), 5.46 (1H, d
d, J = 17.2 and 1.2 Hz), 5.88−
6,04 (1H, m).

Light intensity: [α] _D ²⁶ = + 133.3 ° (C
= 0.780, CHCl ₃ ). Reference Example 3 (4S, 8S, 9R, 10S) -10-[(R) -1-
(T-butyldimethylsilyloxy) ethyl] -4-hydroxymethyl-11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-ene-2-carboxylate 4-nitrobenzyl ( 1) (4S, 8S, 9R, 10S) -10-[(R)
-1- (t-butyldimethylsilyloxy) ethyl]-
4-triethylsilyloxymethyl-11-oxo-1
-Azatricyclo [7.2.0.0 ^3,8 ] undeca-2
-Ene-2-carboxylic acid 4-nitrobenzyl (3S, 4R) -3-[(R) -1- (t-butyldimethylsilyloxy) ethyl] -4-[(2R, 6R)-
6- (Triethylsilyloxy) methylcyclohexanon-2-yl] azetidin-2-one (2.5 g) was subjected to the same reaction as in Reference Example 2- (1), except that 4-nitrobenzyloxalyl chloride was used instead of allyloxalyl chloride. And the same isolation procedure was performed to give the title compound (2.89 g) as a white solid.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 2953, 2878, 1776, 1712, 1526, 1347. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.08 (6H, s), 0.58 (6H, q, J = 7.9Hz), 0.87 (9H,
s), 0.93 (9H, t, J = 7.9Hz), 1.17 ~ 2.05 (6H, m), 1.23 (3
H, d, J = 6.2Hz), 2.97 to 3.11 (1H, m), 3.20 (1H, dd, J = 5.
9,3.3Hz), 3.69-3.86 (3H, m), 5.24 (1H, d, J = 14.0Hz)
, 5.45 (1H, d, J = 14.0Hz), 7.66 (1H, d, J = 8.9Hz), 8.21
(1H, d, J = 8.9Hz). Optical rotation [α] _D ²⁵ = 76.3 ° (C = 1.23, CH
Cl _3).

(2) (4S, 8S, 9R, 10S) -1
0-[(R) -1- (t-butyldimethylsilyloxy) ethyl] -4-hydroxymethyl-11-oxo-
1-azatricyclo [7.2.0.0 ^3,8 ] undeca
4-ene-2-carboxylic acid 4-nitrobenzyl Using the compound (2.7 g) obtained in Reference Example 3- (1), performing the same reaction and isolation procedure as in Reference Example 2- (2). As a result, the title compound (1.8 g) was obtained as an amorphous substance.

Infrared absorption spectrum (KBr) ν _max cm
^-1 : 3430, 2931, 1778, 1718, 1524, 1347, 1285
, 1144, 837. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ
ppm: 0.08 (6H, s), 0.87 (9H, s), 1.23 (3H, d, J = 6.3H
z), 1.27-1.97 (6H, m), 3.00-3.17 (1H, m), 3.24 (1
(H, dd, J = 5.5,3.4Hz), 3.72 to 3.93 (3H, m), 4.19 to 4.3
2 (2H, m), 5.26 (1H, d, J = 14.1Hz), 5.44 (1H, d, J = 14.1H
z), 7.67 (1H, d, J = 8.8 Hz), 8.22 (1 H, d, J = 8.8 Hz). Optical rotation [α] _D ²⁵ = 78.5 ° (C = 0.88, CH
Cl _3). Test Example 1 The compounds obtained in Examples were measured for their antibacterial activity against various pathogenic bacteria by an agar plate dilution method. Among these, Table 10 shows the minimum growth inhibitory concentration (MIC μg / ml) against Staphylococcus aureus including methicillin-resistant Staphylococcus aureus (MRSA).

[0316]

[Table 10]-------------------------MIC (μg / ml) ABC------------------------------------------------------------------------------- −−−−−−−−−−−−−−−−−−−−−−−−−− The compound of Example 3 0.02 0.1 1.5 The compound of Example 4 ≦ 0.01 0.02 1.5 Compound of Example 14 0.02 0.05 1.5 Comparative Compound A 0.02 0.05 12.5 ----------------------------- A: Staphylococcus aureus 209P B: Staphylococcus aureus 56R C: Staphylococcus aureus 535 (MRSA) The compounds of Examples 3, 4 and 14 are compared with Comparative Compound A. It exhibited excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), which is considered a clinical problem.

Formulation Example 1 Injection 500 mg of the compound of Example 1 is dissolved in 5 ml of distilled water for injection, passed through a filter for sterilization, and lyophilized to give a lyophilized preparation for injection.

Formulation Example 2 Capsule Compound of Example 1 50 mg Lactose 128 mg Maize Starch 70 mg Magnesium stearate 2 mg 250 mg After mixing the powder of the above formulation and passing through a 60-mesh sieve, the powder was mixed with 250 mg of No. 3 gelatin capsule. Into a capsule.

Formulation Example 3 Tablets Compound of Example 1 50 mg Lactose 126 mg Corn starch 23 mg Magnesium stearate 1 mg 200 mg The powder of the above formulation was mixed, wet-granulated using corn starch paste, dried, and pressed with a tablet machine. Lock it, 1
Tablets 200 mg tablets. The tablets can be sugar-coated as needed.

[0320]

Industrial Applicability The tricyclic carbapenem compound of the present invention having the general formula (I), a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof exhibits excellent antibacterial activity and inhibits β-lactamase. Have activity. That is, the compound (I) of the present invention includes, for example, Gram-positive bacteria such as Staphylococcus aureus and Enterococcus, Gram-negative bacteria such as Escherichia coli, Shigella, Klebsiella pneumoniae, deformed bacteria, Serratia, Enterobacter, and Bacteroides fragilis. It shows antibacterial activity against a wide range of pathogenic bacteria including anaerobic bacteria, and particularly shows strong antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), which has recently become a problem.
In addition, although thienamycin compounds are susceptible to metabolism by mammals, the compound (I) of the present invention also shows excellent stability against dehydropeptidase-I, which is known as an enzyme that catalyzes inactivation of thienamycin. The urine recovery rate is also high. Furthermore, compound (I) has low toxicity. Therefore, the tricyclic carbapenem compound of the present invention having the general formula (I) or a pharmacologically acceptable salt or derivative thereof is useful as a medicament, and in particular, an antibacterial agent for treating or preventing (preferably treating) a bacterial infection. Useful as an agent.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61K 31/433 A61K 31/41 604 31/4178 31/415 612 31/427 31/425 602 31/435 31/435 31 / 437 605 31/4439 31/44 613 31/454 31/445 614 31/4709 31/47 603 31/496 31/495 601 31/5377 31/535 606 31/541 31/54 601 C07D 513/04 343 C07D 513/04 343 (72) Inventor Yasuo Shimo 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Tetsu Oya 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. In the formula company

Claims (1)

[Claims] 1. A compound of the general formulaＡ In the formula, A represents the following (A1), (A2), (A3),
A group selected from (A4), (A5) and (A6)
Wherein (A1) has the general formulaAnd a group represented by the formula:¹And R^TwoAre the same or
Differently, (1) C which may have a substituent_1-6Alkyl group (the substituent may be hydroxy, cyano, carbamoyl,
Ruboxy, amino, mono- or di-C_1-4Alkyl
Amino, halogen, C_1-4Alkoxy, C_1-4Alkyl
E, mono- or di-C_1-4Alkylcarbamoyl,
C_1-4Alkoxycarbonyl or C_3-6Cycloalkyl
(2) C_3-6Cycloalkyl group (3) C optionally having substituent (s)_6-13Aryl group (the substituent is halogen, hydroxy, hydroxy C
_1-4Alkyl, carbamoyl, carboxy, C_1-4Arco
Xycarbonyl, sulfamoyl, C_1-4Alkoxy,
Cyano, oxo, nitro, amino, mono- or di-
C_1-4Alkylamino, C_1-4Alkylthio, mono-young
Kuha-C_1-4Alkylcarbamoyl, C _1-4Alkyl,
C substituted with halogen_1-4Alkyl, methylene dioki
C, optionally substituted C_6-10Aryl (the substituent
Is sulfamoyl, halogen or C_1-4Alkoxy
Or 1 to 3 nitrogen, oxygen or sulfur atoms
Represents a 5- or 6-membered heteroaryl monocyclic ring) (4) C which may have a substituent_7-17An aralkyl group (the substituent is the same as the above-mentioned (3)_6-13Of the aryl group
(Shows the same group as the substituent) (5) Nitrogen, oxygen or
5- or 6-membered heteroaryl containing 1 to 3 sulfur atoms
Or a benzene ring or a pyridine ring
A condensed heteroaryl fused ring group (wherein the substituent is_1-4Alkyl, hydroxy C_1-4Archi
Carbamoyloxy C_1-4Alkyl, halogen, mosquito
Rubamoyl, carboxy, C_1-4Alkoxycarboni
Le, sulfamoyl, C_1-4Alkoxy, mono-young
Is Di-C_1-4Alkylcarbamoyl, C_1-4Alkyl
E, optionally substituted C_6-10Aryl (the substituent
Is sulfamoyl, halogen or C_1-4Alkoxy
Or 1 to 3 nitrogen, oxygen or sulfur atoms
(Shows a 5- or 6-membered heteroaryl monocycle contained) (6) Nitrogen, oxygen or
5- or 6-membered hetero ant containing 1 to 3 sulfur atoms
Monocyclic C_1-4Alkyl or benzene ring with them
Or a heteroaryl fused ring C in which a pyridine ring is fused_1-4
Alkyl group (the substituent is the same as the substituent in the above (5))
Or (7) R¹And R^TwoTogether with the N atom to which they are attached
The benzene ring or the
A 4- to 7-membered cyclic amino optionally condensed with a lysine ring
Group forming (the substituent is halogen, hydroxy, C_1-4Archi
Le, hydroxy C_1-4Alkyl, carbamoyl, C_1-4A
Lucoxy, C_6-10Aryl, or nitrogen, oxygen or
5- or 6-membered hetero ant containing 1 to 3 sulfur atoms
(A2) is a group having a substituent
Containing 1 to 3 nitrogen, oxygen or sulfur atoms
Having heteroaryl monocyclic thio or benzene with them
Heteroaryl condensed ring with fused ring or pyridine ring
A thio group, and the substituent includes (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) a C_1-4Alkanesulfonyl group (5) C_3-6Cycloalkyl group (6) carboxy group (7) C_1-4Alkoxycarbonyl group (8) C which may have a substituent_1-4Alkyl group (the substituent is hydroxy, halogen, carbamoyl,
Cyano, carboxy, amino, C_1-4Alkoxy, C_1-4
Alkylthio, mono- or di-C_1-4Alkyl cal
Bamoyl (C_1-4Alkyl is hydroxy or carb
Optionally substituted with bamoyl), C_1-4Alkoxy
Carbonyl, C_3-6Cycloalkyl, mono- or di
-C_1-4Alkylamino (the C_1-4Alkyl is hydroxy
Si, carbamoyl, carboxy, amino or mono-young
Or Di-C_1-4May be substituted with alkylamino
I), Tri-C_1-4Alkyl ammonium (C_1-4Archi
Is substituted with hydroxy, carbamoyl or carboxy.
5) containing 1 to 3 N atoms
Or a 6-membered heteroaryl monocyclic ring (the N atom is C_1-4A
May be quaternized by substitution with alkyl), C_1-4A
Lucanesulfonylamino or nitrogen, oxygen or sulfur
4- to 7-membered heterocyclyl containing one or two atoms
(9) an amino group which may have a substituent (the substituent may be C_1-10Alkanoyl, C_3-6Cycloal
Kill, C which may be substituted_1-4Alkyl (the substituent
Is halogen, hydroxy, amino, mono- or di-
-C_1-4Alkylamino, carbamoyl or carboxy
Denote C), optionally substituted C_6-10Aryl cal
Bonyl (the substituent is halogen, C_1-4Alkyl or
C_1-4Represents alkoxy), optionally substituted C
_6-10Aryl (the substituent is halogen, C_1-4Archi
Le, C_1-4Alkoxy, amino or mono- or di
-C_1-4Alkylamino), which may be substituted
C_7-14Aralkyl (the substituent is halogen, C_1-4A
Luquil, C_1-4Represents alkoxy or carbamoyl
Carbamoyl which may be substituted (the substituent
Is C_1-4Alkyl or C_6-10Aryl))
Optionally substituted thiocarbamoyl wherein the substituent is
_1-4Alkyl or C_6-10Aryl)), substituted
May be C_6-10Arylsulfonyl (the substituent is
C_1-4Alkyl, halogen or C_1-4Shows alkoxy
C), optionally substituted C_1-4Alkylsulfonyl
(The substituents represent halogen), and may be substituted.
5 to 1 containing 1 to 3 nitrogen, oxygen or sulfur atoms
Or a 6-membered heteroaryl monocyclic ring wherein the substituent is_{1- Four}Al
Kill or C_1-4Optionally substituted with alkoxy
Phenyl), containing 1 to 3 nitrogen, oxygen or sulfur atoms
5- or 6-membered heteroaryl monocyclic C having_{1- Four}Archi
, Sulfamoyl, optionally substituted nitrogen, oxygen
Or a 5- or 6-membered Het containing 1 to 3 sulfur atoms
Loaryl monocyclic carbonyl or benzene ring
Or a fused heteroaryl ring fused with a pyridine ring
Bonyl (the substituent is C_1-4Alkyl or halogen
If the heteroaryl monocycle contains an N atom,
N atom is C_1-4Quaternized by substitution with alkyl
Good), C_2-5Alkenyl, amino C_1-10Arcanoy
Or one or two nitrogen, oxygen or sulfur atoms
Represents a 4- to 7-membered heterocyclylcarbonyl group
(10) a carbamoyl group which may have a substituent (the substituent is a carbamoyl group which may be substituted;_1-4Alkyl
(The substituent may be halogen, hydroxy, amino, mono-
Or di-C_1-4Alkylamino or carbamoyl
Or substituted phenyl (the substituted
The group is halogen, C_1-4Alkyl, C_1-4Alkoxy or
Is C_1-4(11) a sulfamoyl group which may have a substituent (wherein the substituent is an optionally substituted C_1-4Alkyl (the
And the substituent represents hydroxy or amino). (12) Nitrogen, oxygen or an optionally substituted substituent
4- to 7-membered heterocyclyl containing one or two sulfur atoms
Rylcarbonyl group (the substituent may be hydroxy, amino, mono- or di-
-C_1-4Alkylamino, halogen, cyano, carbamo
Yl, carboxy, optionally substituted C_{1- Four}Archi
(The substituents are amino, hydroxy, carbamoyl,
Represents carboxy or phenyl), even if substituted
Good phenyl (the substituents are halogen, C_1-4Archi
Le, C_1-4Alkoxy or C_1-4Represents alkylthio)
And when the heterocyclyl contains an N atom,
May be substituted to be quaternized, and
When the heterocyclyl contains an S atom, the S atom
Is oxo converted to sulfoxide or sulfone,
(13) C optionally having substituent (s)_6-10Aryl group (the substituent is halogen, carbamoyl, sulfamoy,
Le, C_1-4Alkoxy, C_1-4Alkylthio, substituted
May be C_1-4Alkyl (the substituent is hydroxy,
Amino, mono- or di-C_1-4Alkyl amino, mosquito
Ruboxy, carbamoyl, sulfamoyl, tri-C
_1-4Alkyl ammonium (C_1-4Alkyl is hydroxy
May be substituted with carbamoyl or halogen
Or a 4- to 7-membered cyclic amino group (the cyclic amino group is
C_1-4May be substituted with alkyl and may be quaternized)
Benzene ring or pyridyl, which may be substituted
Nitrogen, oxygen or sulfur atom which may be condensed with
4- to 7-membered heterocyclyl containing 1 or 2
The substituent is an optionally substituted C_1-4Alkyl (the
Substituents are amino, hydroxy, carbamoyl, carboxyl
Or heterosulfamoyl).
When Ryl contains an N atom, the N atom is replaced
It may be quaternized, and the heterocyclyl may have S
When an atom is contained, its S atom is
Which may be a hydroxide or a sulfone),
Optionally substituted amino (the substituent is carbamoyl, sulfo
Amoyl, C_1-4Alkanoyl or substituted
Good C_1-4Alkyl (the substituent is amino, hydroxy,
Si, carbamoyl, carboxy or sulfamoyl
), Carbamoyl which may be substituted
(Equivalent to the above (10)) or may be substituted
Containing four to three nitrogen, oxygen or sulfur atoms
7-membered heterocyclylcarbonyl (same as (12) above)
(14) nitrogen or oxygen, which may have a substituent,
Is a 5- or 6-membered heteroatom containing 1 to 3 sulfur atoms
Reel single ring or benzene ring or pyridine with them
A heteroaryl fused ring group in which a ring is fused (the substituent is_1-4Alkyl, C_1-4Alkoxy, substituted
C that may be_{1- Four}Alkyl (the substituent is carbo
Xy, carbamoyl or hydroxy), carb
Moyl, mono- or di-C_1-4Alkyl carbamoy
, Halogen, cyano, phenyl which may be substituted
(The substituent is halogen, C_1-4Alkyl, C_1-4Arco
Kishi or C_1-4Represents alkylthio),
When the lower aryl contains an N atom, the N atom is substituted.
(15) C which may have a substituent_7-14An aralkyl group (the substituent is halogen, amino, mono- or di-
C_1-4Alkylamino, C_1-4Alkyl, C_1-4Alkoki
Si, C_1-4Alkylthio, C_1-4Alkanoylamino, mosquito
(Shows rubamoyl or sulfamoyl) (16) Nitrogen, oxygen or optionally substituted
Is a heteroaryl monocyclic C containing 1 to 3 sulfur atoms
_1-4Alkyl or their benzene ring or pyridi
Heterocyclic fused ring C fused with a heterocyclic ring_1-4Alkyl
Group (the substituent is halogen, C_1-4Alkyl or C_1-4A
(Shows lucoxy) (17) C optionally having substituent (s)_1-4Alkoxy group (the substituent represents hydroxy or amino) (18) C which may have a substituent_1-4Alkylthio
Group (the substituent is cyano, C_6-10Aryl, carbamoy
(19) represents C, hydroxy or carboxy.) (19) C_3-6Cycloalkylthio group or (20) C which may have a substituent_6-10Arylthio
Group (the substituent is C_1-4Alkyl, C_1-4Alkoxy, C
_1-4Alkoxy C_1-4Represents alkyl or halogen)
And (A3) is a compound represented by the general formula:Wherein n represents 1, 2 or 3
Then R⁸Is (1) a hydrogen atom, (2) C which may have a substituent_1-4Alkyl group (the substituent is hydroxy, amino or carbamoyl
(3) Allyl group (4) C which may have a substituent_6-10Aryl group (the substituent may be halogen, amino, mono- or di-
C_1-4Alkylamino, C_1-4Alkyl, C_1-4Alkoki
Si, C_1-4Alkylthio, C_1-4Alkanoylamino, mosquito
(Shows rubamoyl or sulfamoyl) (5) Nitrogen, oxygen or optionally substituted
A heteroaryl monocyclic ring containing 1 to 3 sulfur atoms or
A benzene ring or pyridine ring condensed with them
A loaryl fused ring group (the substituent is halogen, C_1-4Alkyl or C_1-4A
(6) C which may have a substituent_7-14An aralkyl group (the substituent is halogen, amino, mono- or di-
C_1-4Alkylamino, C_1-4Alkyl, C_1-4Alkoki
Si, C_1-4Alkylthio, C_1-4Alkanoylamino, mosquito
(Shows rubamoyl or sulfamoyl) (7) Nitrogen, oxygen or optionally substituted
Heteroaryl monocyclic C containing 1 to 3 sulfur atoms_1-4
Alkyl or their benzene or pyridine ring
Fused to a heteroaryl fused ring C_1-4Alkyl group (the substituent is halogen, C_1-4Alkyl or C_1-4A
(Shows lucoxy) or (8) C_3-6A cycloalkyl group;⁹Is (1) an amino group which may have a substituent (the substituent is an optionally substituted C_1-4Alkyl
(The substituent may be hydroxy, carboxy or carbamo.
Or (2) nitrogen containing an N atom which may have a substituent.
4 to containing 1 or 2 elemental, oxygen or sulfur atoms
7-membered heterocyclyl group (the substituent is C_1-4Represents alkyl), and (A
4) has the general formula:And a group represented by the formula:^10aAnd R^10bAre the same
Or differently: (1) hydrogen atom (2) halogen atom (3) hydroxy group (4) C_1-4Alkyl group (5) C_1-4Alkoxy group (6) amino group optionally having substituent (s)_1-4Alkyl or substituted
Good alkanoyl, wherein the substituent is amino or mono-
Or Di-C_1-4(7) Carboxyl group (8) C_1-4Alkoxycarbonyl group (9) carbamoyl group which may have a substituent (the substituent is_1-4(Shows alkyl) (10) a sulfamoyl group which may have a substituent (the substituent is a C_1-4Represents alkyl) (11) C_1-4An alkanesulfonyl group or (12) a ureido group, and (A5) is a compound represented by the general formula:And a group represented by the formula:¹¹Is (1) a hydrogen atom, (2) C which may have a substituent_1-4Alkyl group (the substituent may be hydroxy, amino, mono- or di-
-C_1-4Alkylamino, carbamoyl, mono-young
Is Di-C_1-4Alkyl carbamoyl, halogen or potassium
(Shows ruboxy) (3) C_1-4Alkanoyl group (4) carbamoyl group which may have a substituent (the substituent is C_1-4(Indicating alkyl) (5) C optionally having substituent (s)_6-10Aryl group (the substituent may be halogen, amino, mono- or di-
C_1-4Alkylamino, C_1-4Alkyl, hydroxy, C
_1-4Alkoxy, C_1-4Alkylthio, C_1-4Arcanoy
(6) represents nitrogen, oxygen or an optionally substituted substituent;
5- or 6-membered hetero ant containing 1 to 3 sulfur atoms
Or a benzene or pyridine ring
Is a heteroaryl fused ring group wherein the substituent is halogen, C_1-4Alkyl or C_1-4A
(7) indicating an alkoxy group. (7) C which may have a substituent_7-14An aralkyl group (the substituent is halogen, amino, mono- or di-
C_1-4Alkylamino, C_1-4Alkyl, hydroxy, C
_1-4Alkoxy, C_1-4Alkylthio, C_1-4Arcanoy
Represents amino, carbamoyl or sulfamoyl) or (8) optionally substituted nitrogen, oxygen or
Heteroaryl monocyclic C containing 1 to 3 sulfur atoms_1-4
Alkyl or their benzene or pyridine ring
Fused to a heteroaryl fused ring C_1-4Alkyl group (the substituent is halogen, C_1-4Alkyl or C_1-4A
Alkoxy), and (A6) represents the formula -N (R^a)
SO_TwoR^bAnd a group represented by the formula:^aAnd R^bIs
Same or different, (1) hydrogen atom, (2) C_1-6A
Alkyl group, (3) C optionally having substituent (s)_6-10Ants
(The substituent is halogen, C_1-4Alkyl, C_1-4Arco
Kissi, C_1-4Alkylthio, C_7-14An aralkylthio group
(4) Nitrogen, oxygen or an optionally substituted substituent
Heteroaryl monocyclic C containing 1 to 3 sulfur atoms_1-4
Alkyl or their benzene or pyridine ring
Fused to a heteroaryl fused ring C_1-4Alkyl group (the substituent is halogen, C_1-4Alkyl, C_1-4Arco
Kissi, C_1-4Alkylthio, C_7-14An aralkylthio group
) Or R^aAnd R^bAre together, (1) C_2-4Alkylene group (2) naphthylene group which may have a substituent (the substituent is halogen, C_1-4Alkyl, C_1-4Arco
Kishi or C_1-4An alkylthio group). ｝
Having a tricyclic carbapenem compound, which is pharmacologically acceptable
Derivatives or pharmacologically acceptable salts thereof.