WO2001057041A1 - 1-methylcarbapenem compounds - Google Patents

Abstract

1-Methylcarbapenem compounds of the general formula (I) having excellent antimicrobial activities, pharmacologically acceptable prodrugs thereof, or pharmacologically acceptable salts of both, (I) wherein R1 is alkyl or the like; R?2 and R3¿ are each independently hydrogen or the like; R4 is hydrogen or the like; R5 is a group having the formula: -C(=NH)R6 (wherein R6 is amino or the like); n is 0, 1 or 2; and A is alkylene or the like.

Description

 Specification

[Technical field]

 The present invention relates to a 1-methylcarbazanem compound having excellent antibacterial activity, a pharmacologically acceptable prodrug thereof, a pharmacologically acceptable salt thereof, and a medicament containing them as an active ingredient (particularly an antibacterial agent). ), Compositions containing them for treating or preventing bacterial infections, their use for producing medicaments for treating or preventing bacterial infections, and methods for treating bacterial infections thereby; [Background] on prevention methods

 Conventionally, various 1-methylcarbavenem compounds are known as antibacterial agents that are stable in vivo and effective against ^ -lactam-resistant bacteria. For example, Japanese Patent Application Laid-Open No. 5-294969 discloses a compound having a terminal amino group.

However, in recent years, the emergence of strains resistant to the conventional antibacterial agents of Pseudomonas aeruginosa has been recognized. Further, the conventional force Rubape Nemu antimicrobial agents, drawbacks earthenware pots have the show renal toxicity, was force ^s.

 Therefore, the problem to be solved by the present invention is to have a more potent and balanced antibacterial activity against a wide range of bacteria including Pseudomonas aeruginosa showing such resistance, to have excellent pharmacokinetics, and An object of the present invention is to provide a safe lenvanem derivative having low nephrotoxicity.

[Disclosure of the Invention]

 The inventors of the present invention have conducted various studies on 1-methylcarbapenem compounds over many years, and as a result, it has been found that compound (I) of the present invention having a strong basic group at the terminal is resistant to conventional anti-bacterial antifungal agents It has been found that it exhibits excellent antibacterial activity against a wide range of bacteria including these. Furthermore, the compound (I) of the present invention exhibits excellent pharmacokinetics such as a long half-life in blood and has low toxicity including nephrotoxicity, and thus is an antibacterial agent for treating and preventing (particularly treating) bacterial infections. The present inventors have found that they are effective as agents and completed the present invention.

 The present invention has the general formula

OH CH ₃ ~ ⁿ

 NCO—A-N

COOH Or a pharmacologically acceptable prodrug thereof or a pharmacologically acceptable salt thereof.

 Where:

R ¹ represents a hydrogen atom or a _ ₆ alkyl group,

1¾ ² and 1? ³ are independently a hydrogen atom or a (^ _ ₆ alkyl group,

R ⁴ represents a hydrogen atom or a _ ₆ alkyl group,

R ⁵ is a group [wherein having the formula one C (= NH) R ^6, R ⁶ is a hydrogen atom, _ ₆ alkyl group or a group of the formula - group (wherein represented by NR ⁷ R ^8, R ⁷ and R ⁸ independently represents a hydrogen atom or an alkyl group. ]

 n represents 0, 1 or 2,

A represents a _ds alkylene group (the alkylene group may be via an oxygen atom or a sulfur atom, and may be substituted with an amino group, a hydroxyl group, or a phenyl group). In the above,

`` (^ Alkyl group) '' in the definition of RR ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁸ represents a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, for example, Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, s-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl Sohexyl), 3-methylpentyl, 2-methylpentyl, 1-methylpentyl (s-hexyl), 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2 -Dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl groups, preferably a C 4 alkyl group, more preferably a methyl or ethyl group, Is a methyl group .

Examples of the “group represented by the formula —C (= NH) R ⁶ ” in the definition of R ⁵ include, for example, formimidoyl, acetateimidoyl, propioimidoyl, amidino, methylamidino, dimethylamidino, and the like. Preferably, it is a formimidoyl, acetimidoyl or amidino group, most preferably an amidino group.

Examples of the “group represented by the formula —NR ⁷ R ⁸ ” in the definition of R ⁶ include, for example, amino, methylamino, ethylamino, propylamino, butylamino, dimethylamino and dimethylamino. And getylamino groups, and preferably an amino or methylamino group.

The “ ₈ alkylene group” in the definition of A represents a linear, branched or cyclic divalent saturated hydrocarbon group having 1 to 8 carbon atoms, for example, methylene (—CH ₂ —), ethylene (— CH ₂ CH _2- ), trimethylene (-CH ₂ C¾CH _2- ), tetramethylene (-CH ₂ CH ₂ C CH _2- ), pentamethylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH _2- ), methyl methylene (- CH (C¾) -) , propylene _{(-CH (CH 3) CH 2} -) and 1,4 - can be exemplified hexylene group, etc. cyclohexylene.

The above "_ ₈ alkylene group", which may be through an oxygen atom or a sulfur atom, for example, the formula _{- CH 2 OCH 2 CH 2 -} , -CH 2 CH 2 OCH 2 C -, - CH (CH 3) 0CH ₂ CH ₂ —, —CH ₂ SCH ₂ CH ₂ —, —C C¾SCH ₂ CH ₂ —, —CH (CH ₃ ) SC CH ₂ — and the like.

Further, the above-mentioned “Cu alkylene group” may be replaced by an amino group, a hydroxyl group or a phenyl group, and may be, for example, a group represented by the formula —CH ₂ CH (OH) CH ₂ —, —C¾CH (NH ₂ ) CH ₂ — , -CH ₂ CH (C Ph) CH _2- and the like.

R ¹ is preferably a hydrogen atom, a methyl group or an ethyl group, more preferably a hydrogen atom or a methyl group, and most preferably a methyl group.

R ² and R ³ are preferably independently a hydrogen atom, a methyl group or an ethyl group, more preferably independently a hydrogen atom or a methyl group, and most preferably both are hydrogen atoms.

R ⁴ is preferably a hydrogen atom, a methyl group or an ethyl group, more preferably a hydrogen atom or a methyl group, and most preferably a hydrogen atom.

R ⁵ is preferably a formimidoyl, an acetimidoyl or an amidino group, and more preferably an amidino group.

 n is preferably 1 or 2.

A is preferably methylene (- (¾-), methylmethylene _{(-CH (CH 3) -)} , ethylene _{(- CH 2 CH 2 -)} , trimethylene (-CH ₂ CH ₂ C -) or 2-arsenide Dorokishi Doo Rimechiren _{(- CH 2 CH (0H)} CH 2 -) a group, more preferably methylene (-CH ₂ -), methylmethylene _{(- CH (CH 3) -} ) or ethylene (- CH ₂ CH ₂ -) group, and most methylene (- Oh in) group - CH _2.

“Pharmaceutically acceptable prodrug” of compound (I) means that the original compound or its salt is produced by cleavage in a human or animal body by a chemical or biological method such as hydrolysis. Esters and amide derivatives in which the carboxy, hydroxyl, and amino groups of compound (I) are protected by a group that forms (a group that forms a so-called prodrug). Such a derivative can be determined by orally or intravenously administering to an experimental animal such as a rat mouse, and then examining the body fluid of the animal to detect the original compound or its salt. More can be determined. Examples of such a carboxyl group, hydroxyl group and amino group-protecting group include groups known in the field of medicinal chemistry, for example, an acyloxy C _w alkyl group, a (^ ₆ alkoxycarbonyloxy C ₄ alkyl group, and phthalidyl. group, 5-methylcarbamoyl Lou 2 Okiso -1, 3-Jiokisoren - 4 Irumechiru group, Ashiru group, d_ ₆ Arukokishikaru Boniru group, may be mentioned Amino d_ ₆ Ashiru group.

Is a "^ _ ₆ Ashiruokishi _ ₄ alkyl group" described above, for example, Bibaroiruoki Shimechiru, isobutyryl O carboxymethyl, 1- (isobutyryl O carboxymethyl) Echiru, Aseto Kishimechiru, 1- (§ Se butoxy) Echiru, 1-methylcyclohexylcarbonyloxymethyl, 1-methylcyclopentylcarbonyloxymethyl.

Examples of “(: alkoxycarbonyl d_ ₄ alkyl group” include, for example, t-butoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (Isopropoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, and 1- (cyclopentyloxycarbonyloxy) ethyl group. To

Examples of the “acyl group” include acetyl, propionyl, butyryl, pentanoyl, hexanoyl, octanoyl, decanoyl, dodecanoyl, tetradecanol, hexadecanyl, octadecanol, and alkanol groups such as ₂₀ alkanol, benzoyl and benzoyl. And a 5- or 6-membered heterocarbonyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms, such as C ₆ _ _{1 ()} arylcarbonyl group, pyridylcarbonyl and phenylcarbonyl.

Examples of the “d- ₆ alkoxycarbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl, octadecyl And a carbonyl group. Examples of the "amino ( ₆ acyl group)" include, for example, amino acid groups such as glycyl, alanyl, β-ryanyl, leucyl, isoleucyl, fenylalanil, histidyl, asparagyl, prolyl, and lysyl.

 More preferred protecting groups among the above are 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, acetooxymethyl, pivaloyloxymethyl, 1-methylcyclohexylcarbonyloxymethyl And 1- (isopropoxycarbonyloxy) ethyl or 1- (cyclohexyloxycarbonyloxy) ethyl group, which are preferably used as a protecting group for a carboxy group to form an ester derivative.

 The compound (I) of the present invention and a pharmacologically acceptable prodrug thereof can form a "pharmacologically acceptable salt" as required.

“Pharmacologically acceptable salts” include, for example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate; methanesulfonic acid, ethanesulfonic acid Sulphonates such as, benzene sulphonic acid, Ρ-toluene sulphonic acid; oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate, mandelate, ascorbic acid Acid addition salts such as organic acids such as salts, lactates, gluconates and malates; amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate, and aspartate; lithium salts Inorganic salts such as sodium, potassium, calcium, and magnesium salts; and ammonium, triethylamine, and diisopropylamine salts; Examples thereof include salts with an organic base such as chlorohexylamine, and preferably, hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, and ρ-toluenesulfonate , Oxalate, tartrate, citrate, acetate, lactate, glutamate, asparaginate, sodium, potassium, ammonium or triethylamine, and more preferably hydrochloride, sulfuric acid Salt, methanesulfonate, citrate, acetate or lactate, most preferably hydrochloride or sulfate. '' The compound (1) of the present invention, its pharmacologically acceptable prodrugs and their pharmacologically acceptable salts can be prepared by leaving in the air, freeze-drying from an aqueous solution, or recrystallization. However, such hydrates that may absorb water and become adsorbed water or form hydrates are also included in the present invention. In addition, the compound (I) of the present invention absorbs certain other solvents and may form a solvate. Such solvates are also included in the present invention.

 Since the compound of the present invention has an asymmetric carbon, various isomers exist. Each of them, or mixtures thereof in any proportion, are encompassed by the present invention. Such a stereoisomer may be obtained by using a stereospecific raw material compound, or by synthesizing the compound according to the present invention using asymmetric synthesis or asymmetric induction, or by synthesizing the compound according to the present invention. If desired, it can be obtained by division using a conventional optical division method or separation method.

 As the compound (I), among these isomers, the isomer represented by the following formula (la) is most preferred.

 Among the compounds represented by the general formula (I), the following compounds are preferred.

(I) a compound wherein R ¹ is a hydrogen atom or a methyl group,

(2) a compound wherein R ¹ is a methyl group,

(3) R ² and R ^{3 forces?,} Compounds are independently hydrogen atom or a methyl group,

(4) a compound wherein R ² and R ³ are both hydrogen atoms;

(5) continuous ^four?, Represent hydrogen atom or a methyl group,

(6) compounds wherein R ⁴ is a hydrogen atom,

(7) continuous ^five?, Horumui Mi Doyle, compounds which are § cell Toys Mi Doyle or amidino group,

(8) R ⁵ ^ a compound which is an amidino group,

 (9) a compound that is n-force, 1 or 2,

^? (1 0) Hachika, methylene (-CH ₂ -), methylmethylene (- CH (CH ₃₎ -), ethylene (-CH ₂ CH ₂ -) trimethylene _{(- CH 2 CH 2 C -} ) or 2- A compound that is a hydroxytrimethylene (—CH ₂ CH (0H) CH ₂ —) group,

(II) A is methylene (-CH ₂ -), methylmethylene _{(- CH (CH 3) -} ) or ethylene A compound which is a (-CH ₂ CH _2- ) group,

(1 2) A is methylene (- CH ₂ -) compound is a group.

 Compounds obtained by arbitrarily combining suitable substituents in the above are more preferable, and examples thereof include the following compounds.

(1 3) R ¹ force represents a hydrogen atom or a methyl group,

R ² and R ^{3 forces?} Independently represents a hydrogen atom or a methyl group,

R ^{4 represents} a hydrogen atom or a methyl group,

Five ^ Horumui Mi Doyle, shows the Asetoimi Doyle or amidino group, n ^force?, Represents 1 or 2,

A is methylene (- CH ₂ -), methylmethylene _{(- CH (CH 3) -} ) or ethylene (- CH ₂ CH ₂ -) compound of the proximal.

(14) R ¹ represents a hydrogen atom or a methyl group,

R ² and R ³ independently represent a hydrogen atom or a methyl group,

R ⁴ force, showing hydrogen atom,

1? ^Five?, Shows the Amijino group,

 n Indicates force 1 or 2,

A force, methylene (- CH ₂ -) compound of the proximal.

(15) R ¹ represents a methyl group,

R ² and R ³ forces independently represent a hydrogen atom or a methyl group,

1 ^ ⁴ hydrogen atoms,

R ⁵ represents an amidino group,

 n represents 1 or 2,

A is a compound in which A represents a methylene (-CH _2- ) group. The compound (I) of the present invention can be specifically exemplified in Table 1. The compound (I) of the present invention is not limited to these exemplified compounds.

 1]

_End

 o. K n D3

 Lpd N A

1 H 1 HH-then H ₂ _ then (= NhUH

 (u

IH 1 HH-CH ₂ -H

 s n (\ λτττ

H 1 n H-LH ₂ -H

4 H 1 -H H ₃ H -CH ₂ -H H (= UH

5 H 12-H ₃ H -CH ₂ -H (= NH) H ₃

0 H 12-H ₃ H-CH ₂ -H = H) H ₂

7 H 1 d-shi H ₃ H-shi H ₂ -HU

no

8 H 1 3-H ₃ H-CH ₂ -H then (= hU then H ₃

9 H 1 3-CH ₃ H -CH ₂ -HC (= NH) NH ₂

10 H 1 2-CH3 5-CH3-CH ₂ -HC (= NH) H

13 H 1 HH-CH ₂ -CH ₃ C (= NH) H

14 H 1 HH-CH ₂ -CH ₃ C (= NH) CH ₃

15 H 1 HH-CH ₂ -CH ₃ C (-NH) NH ₂

16 H 1 HH -CH (CH ₃ ) -HC (= NH) H

17 H 1 HH -CH (CH ₃ ) -HC (= NH) CH ₃

18 H 1 HH -CH (CH ₃ ) -HC (= NH) NH ₂

20 H 1 2-CH3 H -CH (CH ₃ )-HC (= NH) CH ₃ H 1 2-CH ₃ H-CH (CH ₃ )-HC (= NH) NH ₂

H 1 3-CH3 H-CH (CH ₃ )-HC (= NH) CH ₃

H 1 3-CH3 H-CH (CH ₃ )-HC (= NH) NH ₂

H 1 2-CH3 5-CH3 -CH (CH ₃ ) -HC (= NH) H

H 1 2-CH3 5-CH3-CH (CH ₃ )-HC (= NH) CH ₃

H 1 2-CH3 5-CH3 -CH (CH ₃ ) -HC (= NH) NH ₂

H 1 HH-CH (CH ₃ )-CH ₃ C (= thigh) H

H 1 HH -CH (CH ₃ )-CH ₃ C (= NH) CH ₃

H 1 HH-CH (CH ₃ )-CH ₃ C (= NH) NH ₂

H 1 HH -CH ₂ CH ₂ -HC (= NH) H

H 1 HH -CH ₂ CH ₂ -HC (= NH) CH ₃

H 1 HH -CH ₂ CH ₂ -HC (= NH) NH ₂

H 1 2-CH3 H -CH ₂ CH ₂ -HC (= NH) H

H 1 2-CH3 H -CH ₂ CH ₂ -HC (= NH) CH ₃

H 1 3-CH3 H-C CH ₂ -HC (= NH) CH ₃

H 1 3-CH3 H-CH ₂ CH Factory HC (= NH) NH ₂

H 1 2-CH3 5-CH3 -CH ₂ CH ₂ -HC (= NH) CH ₃

H 1 2-CH3 5-CH3 -Cn ₂ VH ₂ -HC (= NH) NH ₂

H 1 HH -v ^ h ₂ CH ₂ -CH ₃ C (= NH) H

H 1 HH-Cn ₂ C¾-CH ₃ C (= NH) CH ₃

H 1 HH-し Η ₂ (¾- CH ₃ C (= NH) NH ₂

H 1 HH-H H <JCH ヮ₂ -HC (= NH) H

H 1 HH one H ₂ Gh one HC (= NH) CH ₃

H 1 HH -H H C -HC (= NH) NH ₂

H 1 2-CH3 H-C then (¾-HC (= NH) H H 2-CH ₃ H -CH ₂ CH ₂ CH ₂ -HC (= NH) CH ₃

H 3-CH3 H-CH ₂ CH ₂ CH ₂ -HC (= NH) CH ₃ H 3-CH3 H -CH H ₂ CH ₂ -HC (= NH) NH ₂ H 2-CH3 5-CH3 -CH H _{2 CH 2 - HC (= NH)} HH 2-CH3 5-CH3 -CH 2 CH H 2 - HC (= NH) CH 3 H 2-CH3 5-CH3 -CH2CH CH2- HC (= NH) NH 2 HHH CH 3 C (= NH) HHHH -CH ₂ CH, CH ₂ -CH ₃ C (= NH) CH ₃

_{HHH - CH (C) CH 2} - HC (= NH) HHHH -CH (CH 3) CH 2 - HC (= NH) CH 3 HHH -CH (CH 3) CH 2 - HC (= NH) NH 2

HHH--HC (= NH) NH ₂ HHH -CH ₂ CH (0H) CH ₂ -HC (= NH) HHHH -CH ₂ CH (0H) CH ₂ -HC (= NH) CH ₃ HHH -CH ₂ CH ( 0H) CH ₂ -HC (= NH) NH ₂ HHH -CH ₂ 0CH ₂ C -HC (= NH) HHHH -C 0CH ₂ CH ₂ -HC (= NH) CH ₃ HHH-(¾0 (¾ (¾-HC (= NH) NH ₂ HHH -CH2SCH2CH2- HC () H

HHH-0¾5 (¾ (¾-HC (= NH) NH ₂ HHH -CH (CH ₃ ) 0CH ₂ CH ₂ -HC (= NH) HHHH-CH (CH ₃ ) 0CH ₂ CH ₂ -HC (= NH) CH ₃ HHH -CH (CH ₃ ) OCH ₂ CH ₂ -HC (= NH) NH ₂ 79 HHH -CH (CH ₃ ) SCH ₂ CH ₂ -HC (= NH) H

80 H 1 HH -CH (CH ₃ ) SCH ₂ CH ₂ -HC (= NH) CH ₃

81 H 1 HH-CH (C) SC CH ₂ -HC (= NH) NH ₂

_{82 H 1 HH - CH 2 0CH} 2 CH 2 CH 2 - HC (= NH) H

83 H 1 HH-CH ₂ 0-HC (= NH) CH ₃

84 H 1 HH-CH ₂₀ 0 HC (= NH) H ₂

85 H 1 HH-CH ₂ SCH ₂ CH ₂ CH ₂ -HC (= NH) H

86 H 1 HH -CH2SCH2CHCH2-HC (= NH) CH ₃

87 H 1 HH-Cn ₂ oCh CH ₂ H ₂ -HC (= NH) NH ₂

88 H 2 HH-CH ₂ -HC (= NH) H

89 H 2 HH -CH ₂ -HC (= NH) CH ₃

90 H 2 HH-C-HC (= NH) H ₂

91 H 2 HH -CH ₂ -CH ₃ C (= NH) H

92 H 2 HH -CH ₂ -CH ₃ C (= NH) CH ₃

93 H 2 HH -C¾-CH ₃ C (= NH) NH ₂

94 H 2 HH -CH (CH ₃ ) -HC (= NH) H

95 H 2 HH -CH (CH ₃ )-HC (= NH) CH ₃

96 H 2 HH -CH (CH ₃ ) -HC (= NH) NH ₂

97 H 2 HH -CH (CH ₃ )-CH ₃ C (= NH) H

98 H 2 HH -CH (CH ₃ )-CH ₃ C (= NH) CH ₃

99 H 2 HH -CH (CH ₃ )-CH ₃ C (= NH) NH ₂

100 H 2 HH ~ CH ₂ CH ₂ -HC (= NH) H

101 H 2 HH-CH ₂ CH ₂ -HC (= NH) CH ₃

102 H 2 HH-CH ₂ CH ₂ -HC (= NH) NH ₂

103 H 2 HH -CH ₂ CH ₂ -CH ₃ C (= NH) H

104 H 2 HH -CH ₂ CH ₂ -CH ₃ C (= NH) CH ₃

105 H 2 HH--CH ₃ C (= NH) NH,

106 H 2 H H--H C (= NH) H

107 H 2 HH-CC CH factory HC (= NH) CH ₃ 108 H 2 HH -CH ₂ CH ₂ CH ₂ -HC (= NH) NH ₂

109 H 2 HH -CH2CH2CH2- CH ₃ C (= NH) H

110 H 2 HH--CH ₃ C (= NH) CH ₃

111 H 2 HH--CH ₃ C (= NH) NH ₂

112 H 2 HH -CH (CH ₃ ) CH ₂ -HC (= NH) H

113 H 2 HH -CH (CH ₃ ) CH ₂ -HC (= NH) CH ₃

114 H 2 HH -CH (CH ₃ ) CH ₂ -HC (= NH) NH ₂

115 H 2 HH -CH ₂ CH ₂ CH ₂ CH ₂ -HC (= NH) H

116 H 2 HH-CH ₂ CH ₂ CH ₂ CH ₂ -HC (= NH) CH ₃

117 H 2 HH-CH ₂ CH ₂ CH ₂ CH ₂ -HC (= NH) NH ₂

118 H 2 HH -CH ₂ CH (0H) CH ₂ -HC (= NH) H

119 H 2 HH-C CH (0H) C-HC (= NH) CH ₃

120 H 2 HH -CH ₂ CH (0H) CH ₂ -HC (= NH) NH ₂

_{121 H 2 HH - CH 2 0CH} 2 CH 2 - HC (= NH) H

_{122 H 2 HH - CH 2 0CH} 2 CH 2 - HC (= NH) CH 3

_{123 H 2 HH -CH 2 0CH 2} CH 2 - HC (= NH) NH 2

124 H 2 HH -CH ₂ SCH ₂ CH ₂ -HC (= NH) H

125 H 2 HH -CH2SCH ₂ CH ₂ ~ HC (= NH) CH ₃

126 H 2 HH -CH ₂ SCH ₂ CH ₂ -HC (= NH) NH ₂

_{127 H 2 HH -CH (CH 3} ) 0CH 2 CH 2 - HC (= NH) H

_{128 H 2 HH -CH (CH 3} ) 0CH 2 CH 2 - HC (= NH) CH 3

129 H 2 HH - CH (C ) 0CH 2 CH 2 - HC (= NH) NH 2

130 H 2 HH -CH (CH ₃ ) SCH ₂ CH ₂ -HC (= NH) H

131 H 2 HH -CH (CH ₃ ) SCH ₂ CH ₂ -HC (= H) CH ₃

132 H 2 HH -CH (CH ₃ ) SCH ₂ CH ₂ -HC (= NH) NH ₂

133 H 2 H H-CH2OCH2CH2CH2-H C (= NH) H

134 H 2 HH-CH 0C CH ₂ CH ₂ -HC (= NH) CH ₃

135 H 2 HH-CH 0CH ₂ CH ₂ CH ₂ -HC (= NH) NH ₂

136 H 2 HH-Cr¾¾Cri2 Ch HC (= NH) H 137 H 2 HH -Cn ₂ CHgCH ₂ CH2-HC (= NH) CH ₃

138 H 2 HH -CH2SCHCH2CH2-HC (= NH) NH ₂

139 CH ₃ 1 HH -CH ₂ -HC (= NH) H

140 CH ₃ 1 HH-CH ₂ -HC (= NH) CH ₃

141 CH ₃ 1 HH-CH ₂ -HC (= NH) NH ₂

_{142 CH 3 1 2-CH 3} H - CH 2 - HC (= H) H

146 CH ₃ 1 3-CH3 H-CH ₂ -HC (= NH) CH ₃

148 CH ₃ 1 2-CH3 5-CH3 -CH ₂ -HC (= NH) H

149 CH ₃ 1 2-CH3 5-CH3 -CH ₂ -HC (= NH) CH ₃

150 CH ₃ 1 2-CH3 5-CH3-CH—HC (= NH) NH ₂

151 CH ₃ 1 HH -CH ₂ -CH ₃ C (= NH) H

152 CH ₃ 1 HH-CH ₂ -CH ₃ C (= NH) CH ₃

153 CH ₃ 1 HH-CH factory CH ₃ C (= NH) NH ₂

154 CH ₃ 1 HH -CH (CH ₃ ) -HC (= NH) H

155 CH ₃ 1 HH -CH (CH ₃ )-HC (= NH) CH ₃

156 CH ₃ 1 HH-CH (CH ₃ ) -HC (= NH) NH ₂

157 CH ₃ 1 2-CH3 H-CH (CH ₃ )-HC (= NH) H

158 CH ₃ 1 2-CH3 H -CH (CH ₃ ) -HC (= NH) CH ₃

159 CH ₃ 1 2-CH3 H -CH (CH ₃ ) -HC (= NH) NH ₂

160 CH ₃ 1 3-CH3 H -CH (CH ₃ ) -HC (= NH) H

161 CH ₃ 1 3-CH3 H -CH (CH ₃ ) -HC (= NH) CH ₃

162 CH ₃ 1 3-CH3 H-CH (CH ₃ ) -HC (= NH) NH ₂

163 CH ₃ 1 2-CH3 5-CH3-CH (CH ₃ ) -HC (= NH) H

164 CH ₃ 1 2-CH3 5- CH ₃ -CH (CH ₃ )-HC (= NH) CH ₃

165 C¾ 1 2-CH3 5-CH3-CH (CH ₃ ) -HC (= NH) NH ₂ 166 CH ₃ 1 HH-CH (CH ₃ )-CH ₃ C (= NH) H

167 CH ₃ 1 HH -CH (CH ₃ )-CH ₃ C (= NH) CH ₃

168 CH ₃ 1 HH -CH (CH ₃ )-CH ₃ C (= NH) NH ₂

169 CH ₃ 1 HH-CH ₉ CH ₂ -HC (= NH) H

171 CH ₃ 1 HH-CH ₂ CH ₂ -HC (= NH) NH ₂

172 CH ₃ 1 2-CH ₃ H -CH ₂ CH ₂ -HC (= NH) H

173 CH ₃ 1 2-CH3 H -CH ₂ CH ₂ -HC (= NH) CH ₃

174 CH ₃ 1 2-CH ₃ H-CH ₂ CH ₂ -HC (= NH) NH ₂

175 CH ₃ [3-CH3 H-Οί ₂ (¾-HC (= NH) H

176 CH ₃ L 3-CH3 H -CH ₂ CH ₂ -HC (= NH) CH ₃

177 CH ₃ -L 3-CH3 H -CH ₂ CH ₂ ~ HC (= NH) NH ₂

178 CH ₃ -I 2-CH3 5-CH3-CH ₂ CH ₂ -HC (= NH) H

179 CH ₃ -L 2-CH3 5-CH3-CH ₂ CH ₂ -HC (= NH) CH ₃

180 CH ₃ -L 2-CH3 5-CH3 -CH ₂ CH ₂ -HC (= NH) NH ₂

181 CH ₃ : LHH-CH ₂ CH ₂ -CH ₃ C (= NH) H

182 CH ₃ : LHH-CH ₂ CH ₂ -CH ₃ C (= NH) CH ₃

183 CH ₃ : ί HH-CH ₂ CH ₂ -CH ₃ C (= NH) NH ₂

185 CH ₃ ] ί HH -CH ₂ CH ₂ CH ₂ -HC (= NH) CH ₃

186 CH ₃ JLHH -CH ₂ CH ₂ CH ₂ -HC (= NH) NH ₂

187 CH ₃ J. 2-CH3 H-CH ₂ CH ₂ CH ₂ -HC (= NH) H

188 CH ₃ ]. 2-CH3 H-CH ₉ CH ₂ CH ₂ -HC (= NH) CH ₃

189 CH ₃ ] 2-CH3 H -CHCH H- HC (= NH) NH ₂

190 CH ₃ I 3-CH3 H -CH CH2CH-HC (= NH) H

191 CH ₃ ] 3-CH3 H -CH ₂ CH ₂ CH-HC (= NH) CH ₃

192 CH ₃ ] 3-CH3 H-CH ₂ C (¾-HC (= NH) NH ₂

193 CH ₃ 1 2-CH3 5-CH3-Cr-H ₂ CH ₂ -HC (= NH) H

194 CH ₃ 1 2-CH3 5-CH3 -CH ₂ CH ₂ CH ₂ -HC (= NH) CH ₃ 195 CH ₃ 1 2-CH ₃ -CH3-CH ₂ CH ₂ CH ₂ -HC (= NH) NH ₂

196 CH ₃ 1 HH -CH ₂ CH ₂ CH ₂ -CH ₃ C (= NH) H

197 CH ₃ 1 HH -CH ₂ CH ₂ CH ₂ -CH ₃ C (= NH) CH ₃

198 CH ₃ 1 HH-H ₂ -CH ₃ C (= NH) NH ₂

199 CH ₃ 1 HH-CH (CH ₃ ) CH ₂ -HC (= NH) H

200 CH ₃ 1 HH-CH (CH ₃ ) C¾-HC (= NH) CH ₃

201 CH ₃ 1 HH -CH (CH ₃ ) CH ₂ -HC (= H) NH ₂

202 CH ₃ 1 HH-CH ₂ CH ₂ CH ₂ C-HC (= NH) H

204 CH ₃ 1 HH 1 xi ₂ Ch r! ₂ Ch ₂ HC (= NH) NH ₂

205 CH ₃ 1 HH -CH ₂ CH (0H) CH ₂ -HC (= NH) H

206 CH ₃ 1 HH -CH ₂ CH (0H) CH ₂ -HC (= NH) CH ₃

207 CH ₃ 1 HH-CH ₂ CH (0H) CH ₂ -HC (= NH) NH ₂

208 CH ₃ 1 HH-CH ₂ 0CH ₂ CH ₂ -HC (= H) H

209 CH ₃ 1 HH -CH ₂ 0CH ₂ CH ₂ -HC (= NH) CH ₃

210 CH ₃ 1 HH-(¾0 (¾ (¾-HC (= NH) NH ₂

211 CH ₃ 1 HH-Cn ₂ C CH2-HC (= NH) H

212 CH ₃ 1 HH-C SC¾CH ₂ -HC (= NH) CH ₃

213 CH ₃ 1 HH xi ₂ S xi ^ CF ^ —HC (= NH) NH ₂

214 CH ₃ 1 HH-CH (CH ₃ ) 0CH ₂ C¾-HC (= NH) H

_{215 CH 3 1 HH -CH (CH} 3) 0CH 2 CH 2 - HC (= NH) CH 3

_{216 CH 3 1 HH -CH (CH} 3) 0CH 2 CH 2 - HC (= NH) NH 2

217 CH ₃ 1 HH -CH (CH ₃ ) SCH ₂ CH ₂ -HC (= NH) H

218 CH ₃ 1 HH -CH (CH ₃ ) SCH ₂ CH ₂ -HC (= NH) CH ₃

219 CH ₃ 1 HH -CH (CH ₃ ) SCH ₂ CH ₂ -HC (= NH) NH ₂

_{220 CH 3 1 HH -CH 2 0CH} 2 CH 2 CH 2 - HC (= NH) H

221 CH ₃ 1 HH -CH ₂ 0CH ₂ CH ₂ CH ₂ -HC (= NH) CH ₃

222 CH ₃ 1 HH -CH ₂ OCH ₂ CH ₂ CH ₂ -HC (= NH) NH ₂

223 CH ₃ 1 HH-CH ₂ SCH ₂ CH ₂ CH ₂ -HC JP l / 00664

16

224 CH, 1 HH - CH2SCH2CH2CH one - HC (= NH) CH ₃

225 CH ₃ 1 HH-. 2 ^> (¾ (¾01 ₂ -HC (= NH) H ₂

226 CH, 6 2 HH-CH ₂ -HC (= NH) H

228 C¾ 2 HH-C¾-HC (= NH) NH ₂

229 CH, 2 HH-CH ₂ -CH ₃ C (= NH) H

230 CH, 2 HH-C-CH ₃ C (= NH) CH ₃

231 CH ^L , 2 HH -CH ₂ -CH ₃ C (= NH) NH ₂

232 CH, 2 H H-CH (C)-H C (= NH) H

233 CH *, 2 HH-CH (CH ₃ )-HC (= NH) CH ₃

234 CH, 2 HH-CH (CH ₃ )-HC (= NH) NH ₂

235 2 HH-CH (CH ₃ )-CH ₃ C (= NH) H

236 CH, 2 HH-CH (CH ₃ )-CH ₃ C (= NH) CH ₃

237 CH, 2 HH -CH (CH ₃ )-CH ₃ C (= NH) NH ₂

238 CH, 2 HH-Ch ₂ Cn ₂ -HC (= NH) H

239 CH ₃ 2 HH -CH ₂ v ^ h ₂ -HC (= NH) CH ₃

240 2 HH -Ch ₂ Cn ₂ -HC (= NH) NH ₂

241 CH ₃ 2 HH -Ch ₂ Cn ₂ -CH ₃ C (= NH) H

242 CH, 2 HH Cn ₂ H ヮ-CH ₃ C (= NH) CH ₃

243 2 HH-CH ₂ ri ₂ -CH ₃ C (= NH) NH ₂

244 2 HH-CH ₂ then i HC (= NH) H

245 2 HH-Ch ₂ then r! ₂ CH HC (= NH) CH ₃

246 2 HH--HC (= NH) NH ₂

And ⁿ 3

CH ₃ C (= NH) H

248 CH ₃ 2 HH-CH ₂ ri ₂ CH CH ₃ C (= NH) CH ₃

249 CH ₃ 2 HH-CH r ^ CH- CH ₃ C (= NH) NH ₂

250 CH ₃ 2 HH -CH (CH ₃ ) CH ₂ -HC (= NH) H

251 CH ₃ 2 HH -CH (CH ₃ ) CH ₂ -HC (= NH) CH ₃

252 CH ₃ 2 HH-CH (C¾) C-HC (= NH) NH ₂ 253 CH ₃ 2 HH-CH2CH2CH2CH2-HC (= NH) H

254 CH ₃ 2 HH-CH2CH2CH2CH2-HC (= NH) CH ₃

255 CH ₃ 2 HH-CH2CH2CH2CH2-HC (= NH) NH ₂

256 CH ₃ 2 HH-CH ₂ CH (0H) CH ₂ -HC (= NH) H

257 CH ₃ 2 HH -CH ₂ CH (OH) CH ₂ -HC (= H) CH ₃ 258 CH ₃ 2 HH-CH ₂ CH (0H) CH ₂ -HC (= NH) NH ₂ 259 CH ₃ 2 HH- CH ₂ OCn2 H-HC (= NH) H

_{260 CH 3 2 HH -CH 2 0CH} 2 CH 2 - HC (= H) CH 3 261 CH 3 2 HH - CH 2 0CH 2 CH 2 - HC (= H) NH 2 262 CH 3 2 HH -CHOSL, H 2 CH ₂ -HC (= NH) H

263 CH ₃ 2 HH-CH ₉ Cr Γ¾-HC (= NH) CH ₃ 264 CH ₃ 2 HH-CH ₂ CH-HC (= NH) NH ₂ 265 CH ₃ 2 HH -CH (CH ₃ ) 0CH ₂ CH ₂ -HC (= NH) H

266 CH ₃ 2 HH -CH (CH ₃ ) 0CH ₂ CH ₂ -HC (= NH) CH ₃ 267 CH ₃ 2 HH -CH (CH ₃ ) 0CH ₂ CH ₂ -HC (= NH) NH ₂ 268 CH ₃ 2 HH -CH (CH ₃ ) SCH ₂ CH ₂ -HC (= NH) H

269 CH ₃ 2 HH-CH (CH ₃ ) SCH ₂ CH ₂ -HC (= NH) CH ₃ 270 CH ₃ 2 HH -CH (CH ₃ ) SCH ₂ CH ₂ -HC (= NH) NH ₂ 271 CH ₃ 2 HH -CH0CH ₂ CH ₂ CH ₂ -HC (= NH) H

272 CH ₃ 2 HH -CH _{2 0} CH ₂ CH ₂ CH ₂ -HC (= NH) CH ₃ 273 CH ₃ 2 HH -CH ₂ 0CH ₂ CH ₂ CH ₂ -HC (= Heat) NH ₂ 274 CH ₃ 2 HH- CH ₂ SCH ₂ CH ₂ CH ₂ -HC (= NH) H

_{275 CH 3 2 HH -CH2SCH2CH2CH2- HC (} = NH) CH 3 276 CH 3 2 HH -CH2SCH2CH2CH2- HC (= NH) NH 2 In addition, among the compounds exemplified in the table above, preferably

2- [2- [4- (2-guanidinoacetyl) pidazine-1-ylcarbonyl] pyrrolidine-4-ylthio] — 6- [1-hydroxyxethyl] -1-methyl-1-buta-2 -Em-3-carboxylic acid (compound of Ex. No. 3), 2- [2- [4- [2- (1-Methylguanidino) acetyl] piperazine-1-ylcarbonylpyrrolidine-4-ylthio] — 6- [1-Hydroxyshetyl] -1-methyl-1-capryl -2-Em

-3-carboxylic acid (compound of Ex. No. 15),

 2- [2- [4- (2-Guanidino-2-methylacetyl) pidazine-1-ylcarbonyl] piperidine-1-ylthio] — 6- [1-Hydroxityl] -1-methyl-1-force Lubapen-2-em-3-carboxylic acid (compound of Ex. No. 18),

 2 -— [2- [4- (3-Guanidinopropanoyl) pidazine-1-ylcarbonyl] pyrrolidin-4-ylthio] -6- [1-hydroxyxethyl] -1-methyl-1-capryl -2-em-3-force rubonic acid (compound of Ex. No. 33),

 2- [2- [4- (2-guanidinoacetyl) -3-methylbiperazine-1-ylcarbonyl] pyrrolidine-1-4-ylthio] -6- [1-hydroxyxethyl] -1-methyl-1-capryl -2-em-3 -capillonic acid (compound of Ex. No. 9),

 2— [2- [4- (2-Guanidinoacetyl) homopidrazine-1-ylcarbonyl] pyrrolidin _4-ylthio] -6- [1-hydroxyxethyl] -1-methyl-1-methyll-bapen-2 -Em-3-force rubonic acid (compound of Ex. No. 90),

 2- [2- [4-[(2-guanidinoacetyl) pidazine-1-ylcarbonyl] -1-methylpi-lysine—4-ylthio] -6— [1-hydroxyxethyl] -1-methyl-1 —Power Lubapen— 2-Em

-3-Rubonic acid (compound of Exhibit No. 141),

 2- [2- [4- [2- (1-Methylguanidino) acetyl] pidazine-1-ylcarbonyl] -1-methylpyrrolidine-4-ylthio] -6- [1-hydroxyxethyl] -1-methyl- 1-potassium pen-2-ene-3-carboxylic acid (compound of Ex. No. 1553),

 2- [2- [4- (2-guanidino-2-methylacetyl) piperazine-1-ylcarbonyl]-1-methylpyrrolidine-4-ylthio]-6- [1-hydroxyxethyl]-1-methyl-1 -Carban-2-em-3-carboxylic acid (compound of Ex. No. 156),

 2- [2- [4- (3-Guanidinopropanoyl) piperazine-1-ylcarbonyl] -1-methylpyrrolidine-4-ylthio] -6- [1-Hydroxityl] -1-methyl- 1-Lyvapene- 2-em-3-carboxylic acid (compound of Ex. No. 17 1),

2- [2- [4- (2-guanidinoacetyl) -3-methylbiperazine-1-ylcarbonyl] -1-methylpyrrolidine-4-ylthio] -6- [1-hydroxyxyl] -1-methyl-1 -Carba N-2-em-3-carboxylic acid (compound of Ex. No. 147),

 2— [2- [4- (2-Guanidinoacetyl) homopirazine-1-ylcarbonyl] -1-methylpyrrolidine-4-ylthio] -6- [1-Hydroxitytyl] -1-methyl- It is 1-force lubapen-2-em_3-carboxylic acid (compound of Ex. No. 228).

 More preferably,

 2- [2- [4- (2-guanidinoacetyl) pyrazine-1-ylcarbonyl] pyrrolidine-4-ylthio] -6- [1-hydroxyxethyl] -1-methyl-1 -Em-3-carboxylic acid (compound of Ex. No. 3),

 2- [2- [4- [2- (1-Methylguanidino) acetyl] piperazine-1-ylcarbonyl] piπlysine-1-ylthio] -6-[1-hydroxyxethyl] -1-methyl-1-capryl -2-Em-3 -Rubonic acid (compound of Ex. 15),

 2- [2- [4- (2-guanidino-2-methylacetyl) pidazine-1-ylcarbonyl] piperidine-4-ylthio] -6- [1-hydroxyxethyl] -1-methyl-1-force Lubapen-2-em-3-carboxylic acid (compound of Ex. No. 18),

 2- [2- [4- (3-guanidinopropanoyl) piperazine-1-ylcarbonyl] pyrrolidin-4-ylthio] -6- [1-hydroxyxethyl] -1-methyl-1-capryl -2-em-3 -force rubonic acid (compound of Ex. No. 33),

 2- [2- [4- (2-guanidinoacetyl) pidazine-1-ylcarbonyl] -1-methylpiperidine-4-ylthio] -1-6- [1-hydroxyxethyl] -1-methyl-1 -Kylbenapen-2-em-3-carboxylic acid (compound of Ex. No. 141),

 2- [2- [4- [2- (1-Methylguanidino) acetyl] piperazine-1-ylcarbonyl] -1-methylpyrrolidine-4-ylthio] -6- [1-hydroxyxethyl] -1-methyl-1- Lenno, 'pen-2-em-3-carboxylic acid (compound of Ex. No. 1553),

 2- [2- [4- (2-Guanidino-2-methylacetyl) pidazine-1-ylcarbonyl] -1-methylpyrrolidine-4-ylthio] -6- [1-hydroxyxethyl] -1-methyl-1 -Carban-2-em-3-carboxylic acid (compound of Ex. No. 156); and

2- [2- [4- (3-guanidinopropanoyl) pidazine-1-ylcarbonyl] -1-methylpyrrolidine-4-ylthio] -6- [1-hydroxyxethyl] -1- Methyl-1-carbyl-2-em-3-carboxylic acid (compound of Ex. No. 1771). Most preferably

 (1R, 5S, 6S)-2-[(2S, 4S)-2- [4- (2-guanidinoacetyl) pidazine-1-ylcarbonyl] pyrrolidine- 4-ylthio] -6-[( 1R) -1-Hydroxityl]-1-methyl-1 -force Lubapen-2-em-3-carboxylic acid (compound of Example 1),

 (1R, 5S, 6S)-2-[(2S, 4S) -2- [4- (2-guanidinoacetyl) -3-methylbiperazine-1-ylcarbonyl] pyrrolidine-4-ylthio] -6-[( 1R) -1 -Hydroxitytyl]-1-methyl_1_potassyl-2-ene-3-carboxylic acid (compound of Example 3),

 (1 55,65) -2-[(25,45) -2- [4- (2-guanidinoacetyl) homopidrazin-1-yl carbonyl] pyrrolidine—4-ylthio] -6-[( lR) -1-Hydroxityl] -1-methyl-1 monolubapen-2-heme-3-carboxylic acid (compound of Example 5),

 (1R, 5S, 6S) -2-[(2S, 4S) -2- [4- (2-guanidinoacetyl) pyrazine-1-ylcarbonyl] -1-methylpyrrolidine-1-ylthio-6 -[(1R)-1-hydroxyxethyl] -1-methyl-1-l-levapen-21-em-3-carboxylic acid (compound of Example 2),

 (1R, 5S, 6S)-2-[(2S, 4S) -2- [4- (2-guanidinoacetyl) -3-methylbiperazine-1-ylcarbonyl] -1-methylpyrrolidine-4-ylthio]- 6-[(1R) -1-hydroxylmethyl-1--1-l-levapen-2-em-3-carboxylic acid (compound of Example 4),

(1R, 5S, 6S) -2- [(2S, 4S) -2- [4- (2-guanidinoacetyl) homopyrazine-1-yl carbonyl]-1-methylpyrrolidine-4- Ylchi ^]-6-[(1R) -1-hydroxyxetyl] -1_methyl-1-potassium 2-vam-3-carboxylic acid (compound of Example 6).

The 1-methylcarbanemine derivative having the general formula (I) of the present invention can be produced by the following method ^{. In} the following description, the 2-position side chain of the compound represented by the general formula (I) The substituent of the sulfur atom is represented by R, and the general formula (I) is abbreviated as follows.

 The compound having the general formula (I) of the present invention can be produced according to the following method.

 [Method A]

 Method A is a method for producing a 1-methylcarbazanem derivative having the general formula (I) by condensing the compound of the general formula (II) and the compound of the general formula (III) and removing a protecting group as necessary. Is the law.

In the above formula, R ^1Q represents a carboxyl protecting group, L represents a leaving group, and Rp represents R which may have a protecting group.

The "protective group for carboxy group" of R ^10, for example methyl, Echiru, t - _ ₄ alkyl group such as butyl; benzyl, 4-main Tokishibenjiru, 4 two Torobenjiru, 2-two preparative port base Njiru A benzyl group optionally having such a substituent; a benzhydryl group; an aryl group optionally having a substituent at the 2-position such as aryl, 2-chloroaryl, and 2-methylaryl; 2,2,2-trichloro Halogenoethyl groups such as ethyl, 2,2-dibromoethyl and 2,2,2-tribromoethyl; and 2-trimethylsilylethyl groups And is preferably a 4-nitrobenzyl or benzyl group.

A “leaving group” is a group having the formula —OR ¹¹ or —S (O) R ^12, for example.

R ¹¹ is methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, prono, Sulphonyl, isoprono, Alkanesulfonyl groups such as phenylsulfonyl and butanesulfonyl groups; phenylsulfonyl, tolylsulfonyl and naphthylsulfonyl. Arylsulfonyl groups; dialkylphosphoryl groups such as dimethylphosphoryl, methylphosphoryl, dipropylphosphoryl, diisopropylphosphoryl, dibutylphosphoryl, dipentylphosphoryl, dihexylphosphoryl; and diphenylphosphoryl, ditolylphosphoryl there may be mentioned di--C ₆ _ ₁₀ § reel phosphoryl group, preferably a Jifue two Ruhosuhoriru group.

R ¹² is a methyl-, ethyl-, propyl-, isopropyl-like ( _4- alkyl group; fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoropropyl, difluoromethyl, difluoroethyl, dichloroethyl, trifluoromethyl, trifluoromethyl, trifluoromethyl, etc. _4- alkyl group; 2-acetylaminoethyl group; 2-acetylaminovinyl group; phenyl and naphthyl which may have a substituent, aryl group (where the aryl groups are the same or different and 1 to 3 And the substituent may be a halogen atom such as fluorine, chlorine, or bromine; a C _w alkyl group such as methyl, ethyl, propyl, or isopropyl; methoxy, ethoxy, propoxy, d_ ₄ alkoxy groups such as isopropoxy; main Tokishikarubo Include hydroxyl group and Shiano groups; (; _ ₄ alkyl C) force Rubamoiru group; nitro group -, Le, ethoxycarbonyl, t - like butoxycarbonyl (C _ ₄ alkoxy!) Carbonyl group force Rubamoiru, mono- - or di And a heteroaryl group which may have one or two nitrogen atoms such as pyridyl and pyrimidinyl which may have a substituent (the heteroaryl group may be the same or different and has one to three nitrogen atoms). The substituent may be a halogen atom such as fluorine, chlorine, or bromine; a ( ₄ alkyl group such as methyl, ethyl, propyl, or isopropyl; methoxy, ethoxy, or propoxy). (C! _ ₄ alkoxy) carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, and t-butoxycarbonyl ; Carbamoyl, mono- or di- (Ci- ₄ alkyl) carbamoyl group; nitro group; hydroxyl group and cyano group. ).

 The protecting group which Rp may have is a protecting group for a hydroxyl group, an amino group or an imino group.

The “protecting group for the hydroxyl group” contained in Rp includes, for example, tri-(^ _ ₄ alkylsilyl groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl; benzyloxycarbonyl, 4-nitrobenzyl) Optionally substituted benzyloxycarbonyl groups such as methoxycarbonyl, 4-chlorobenzyloxycarbonyl, and 4-methoxybenzyloxycarbonyl (the substituent is nitro, methyl, chlorine or methyl) An aryloxycarbonyl group which may be substituted at the 2-position such as aryloxycarbonyl, 2-chloroallyloxycarbonyl and 2-methylaryloxycarbonyl. Group is chlorine or methyl); position 2 such as trimethylsilylethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl Is a tri-Cw alkylsilyl or chlorine-substituted ethyloxycarbonyl group, and is preferably a 4-dihydroxybenzyl or a 4-dibenzyloxycarbonyl group.

 The “protecting group for amino or amino group” contained in Rp includes, for example, 2-substituted substituents such as aryloxycarbonyl, 2-chloroallyloxycarbonyl, and 2-methylaryloxycarbonyl. Aryloxycarbonyl group (the substituent is chlorine or methyl); benzyloxycarbonyl, 4-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-cyclobenzyloxy An optionally substituted benzyloxycarbonyl group such as carbonyl or 4-dihydroxybenzyloxycarbonyl (the substituent is methyl, methoxy, chlorine or nitro) is mentioned. Preferably, it is an aryloxycarbonyl group or a 4-to-2 opening benzyloxycarbonyl group, more preferably a 4-to-2 opening benzyloxycarbonyl group. Is a group.

Method A comprises reacting a compound having the formula (II) with a compound having the formula (III) in the presence of a base to produce a compound having the formula (IV) (Step A1), and then removing the protecting group. This is a method for producing a compound (I) by subjecting it to a reaction (Step A2). Further, the obtained compound (I) Can be converted as necessary into a pharmacologically acceptable salt or derivative by a method obvious to those skilled in the art. Hereinafter, each step will be described.

 (Step A 1)

Step A1 is a step of producing a compound having the general formula (IV), in which the compound (II) is reacted with a mercaptan derivative having the general formula (III) in an inert solvent in the presence of a base. Achieved by Incidentally, L has the formula -. Is a group represented by OR ^11, the compounds of formula (II) as the departure material, DH Shih et al., Produced by the method described in Heterocycles 21, 29 (1984) You. L has the formula - if S (0) Ru Oh a group represented by R ^12, the starting compound ([pi) is prepared according to the process disclosed in JP 62- 30781 JP. The mercaptan derivative having the general formula (III), which is a synthetic intermediate, can be produced by Method B described below.

(1) L force ', is a group of the formula one OR ¹¹

 The solvent used is not particularly limited as long as it does not inhibit the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, and chloroform; and solvents such as acetonitrile. Trils; amides such as Ν, Ν-dimethylformamide and Ν, Ν-dimethylacetamide; esters such as ethyl acetate and methyl acetate; ethers such as getyl ether, tetrahydrofuran, and dioxane Preferred are acetonitrile, Ν, Ν-dimethylformamide and tetrahydrofuran, and more preferred is acetonitrile.

 The base used in this step is not particularly limited as long as it is generally used in organic synthesis. Preferably, organic amines such as triethylamine and diisopropylethylamine; and lithium carbonate and carbonate An inorganic base such as sodium can be mentioned, and preferred is diisopropylethylethylamine.

 Although the reaction temperature is not particularly limited, the reaction is usually carried out at −20 ° C. to 40 ° C. (preferably −10 ° C. to 20 ° C.).

 The reaction time is 30 minutes to 108 hours (preferably 1 hour to 18 hours).

(2) L force ⁵ ', the formula - S (0) is a group represented by R ¹²

The solvent to be used is not particularly limited as long as it does not inhibit the reaction. For example, tetrahydrofuran, acetonitril, dimethylformamide, dimethylsulfo Oxide, water and a mixed solvent thereof can be mentioned, and preferred is acetonitrile.

 The base used is not particularly limited as long as it does not affect the other parts of the compound, particularly the -lactam ring.Examples include diisopropylethylamine, triethylamine, N-methylpiperidine, and 4-dimethylamine. Organic bases such as minopyridine; and inorganic bases such as potassium carbonate and sodium bicarbonate can be mentioned, and preferred is diisopropylpropylethylamine.

 The reaction temperature is not particularly limited, but it is preferable to carry out the reaction at a relatively low temperature in order to suppress a side reaction, usually from 120 ° C to 40 ° C (preferably from 10 ° C to 20 ° C). C)

The reaction time, mainly on the reaction temperature, the force depends on the type of reaction ^reagent?, It is usually for 15 minutes to 7 5 hours (preferably 3 0 minutes to 1 8 hours).

 After the completion of the reaction of (1) or (2), the target compound (IV) of this step 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. Further, if desired, the target compound (IV) can be subjected to the next step without isolation.

 (Step A 2)

 Step A2 is a step of converting compound (IV) to compound (I) and is achieved by removing the protecting group of the compound.

The removal of the protecting group depends on the type, but is generally performed by a method used in the field of synthetic organic chemistry (Greene & Wuts, Protective Groups in Organic Synthesis, 2nd Edition, 1991, John Wiley & Sons, Inc.) ₀

(1) Protecting group R ^{10 A} benzyl group or a benzhydryl group which may have a substituent such as benzyl or 4-nitrobenzyl, and a hydroxyl group, an amino group and an imino group contained in Rp. The protecting group of the group may have a substituent such as benzyl or 4-nitrobenzyl, or may have a substituent such as benzyloxycarbonyl or 4-dibenzobenzyloxycarbonyl. Benzyloxycarbonyl group which may be In the case of, the protecting group can be removed by reacting with hydrogen and a reducing agent using a catalytic reduction catalyst or metal sulfide.

 Reducing agents include, for example, hydrogen and catalytic reduction catalysts such as palladium-carbon; and alkali metal sulfides such as sodium sulfide or lithium sulfide, preferably hydrogen and / or It is a carbon catalyst.

The solvent used is not particularly limited as long as it does not participate in the reaction, especially but not exclusively a force ⁵ ', preferably alcohols such as methanol, ethanol; as tetrahydrofuran, ethers such as di-O-hexane; or of It is a mixed solvent of an organic solvent and water. The reaction temperature is usually from 0 ° C to 50 ° C (preferably from 10 ° C to 40 ° C), and the reaction time varies depending on the type of the starting compound and the reducing agent, usually from 5 minutes to 12 hours. Time (preferably 30 minutes to 4 hours).

(2) the protecting group R ¹⁰ is Ariru, 2-chloroallyl, 2 - if a 2-position may Ariru group optionally substituted as Mechiruariru, and hydroxyl group contained in Rp, the amino group and I amino group When the protecting group is a substituted or unsubstituted aryloxycarbonyl group such as aryloxycarbonyl, 2-chloroallyloxycarbonyl, or 2-methylaryloxycarbonyl, bis (triphenyl) Phosphine) palladium oxide-tributyltin hydride, tetrakis (triphenylphosphine), Palladiums such as radium-tributyltin hydride-trialkyltin hydrides or tetrakis (triphenylphosphine) palladium-2-ethylhexanoic acid or sodium 2-ethylhexanoate The protective group can be removed by reacting with a deprotecting agent such as a palladium monoorganic carboxylic acid metal salt such as

 The deprotecting agent is preferably bis (triphenylphosphine) norradium chloride-tributyltin hydride or tetrakis (triphenylphosphine) no, “radium-2-ethylhexanoate”. It is.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction. Examples thereof include halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, and ethyl acetate. Esters; ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane; nitriles such as acetonitrile; Alcohols such as ethanol, ethanol and propanol; water; and a mixed solvent thereof, preferably methylene chloride, ethyl acetate or a mixed solvent thereof.

 Although the reaction temperature is not particularly limited, it is generally carried out at a temperature of from 120 ° C to 100 ° C (preferably from 0 ° C to 60 ° C), and the reaction time is usually from 30 minutes to 48 hours (preferably). 30 minutes to 12 hours.

(3) When the protecting group R ¹⁰ is a halogenoethyl group such as 2,2-dibromoethyl and 2,2,2-trichloroethyl, a metal such as zinc and an acid such as acetic acid or hydrochloric acid are used. The protective group can be removed by reacting with a reducing agent. Suitable reducing agents are zinc and acetic acid.

 The solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and fatty acids such as acetic acid. And a mixed solvent of these organic solvents and water.

The reaction temperature is usually 0 ° C to 4 0 ° C (preferably 1 0 a to 3 0 ° to 0, while during the reaction depends on the type of the starting compound and the reducing agent ^forces?, Usually 5 minutes to 1 2 Time (preferably 30 minutes to 4 hours).

 After the completion of the above reactions (1) to (3), the target compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off insolubles from the reaction mixture and then distilling off the solvent.

 The target compound (I) thus obtained can be purified, if necessary, by a conventional method such as a recrystallization method, preparative thin-layer chromatography, column chromatography and the like.

The 1-methylcarbapanem compound having the general formula (I) thus obtained can be used, if necessary, according to methods or techniques known in the field of medicinal chemistry, in particular, / 3-lactam antibiotics. It can be converted into a derivative such as an ester that undergoes hydrolysis in vivo as a pharmacologically acceptable prodrug, and can be purified as a pharmacologically acceptable salt. In addition, a pharmacologically acceptable prodrug is used in place of the carboxyl-protecting R ^{1 Q} group as the starting material (化合物). Compound (IV) can also be obtained using a compound protected with a desired protecting group (for example, a bivaloyloxymethyl group and the like).

 A mercaptan derivative having the general formula (III), which is a synthetic intermediate, can be produced by the following Method B.

[Method B] Step B 1

In the above formula, R ² , R ³ , R ⁴ , n and A have the same meaning as described above. R ⁵ p represents an optionally R ⁵ may have a protecting group, R ^{1 3} represents a protecting group of a mercapto group, R ¹ is a protecting group, or (^ _ ₆ alkyl amino group.

The protecting group for R ⁵ p has the same meaning as the protecting group for imino or amino which is the protecting group for Rp.

Protecting group of the mercapto group of R ^{1 3} represents a protecting group can be selectively removed while maintaining the protective group of R ⁵ p and R ¹ p. Such protecting groups include, for example, an optionally substituted benzyl group such as 4-methoxybenzyl; and an optionally substituted alkenyl group such as formyl, acetyl, chloroacetyl and trichloroacetyl. And is preferably 4-methoxybenzyl or acetyl.c

The protecting group for the amino group in Rip has the same meaning as the protecting group for the amino group which is the protecting group for Rp.

 In the method B, a compound having the formula (V) is produced by condensing a compound having the formula (VI) with a compound having the formula (VII) (Step B1), and then the protecting group for the mercapto group is removed. This is a method for producing a compound having the general formula (III) by selective removal (Step B2). Hereinafter, each step will be described.

(Step B 1) Step B1 is a step for producing a compound having the formula (V), in which the compound (VI) is reacted with the general formula (VII) with a condensing agent in an inert solvent, preferably in the presence of a base. This is achieved by The compound (VI) can be produced by the method described in Isao Kawamoto, Synlett, pp. 575-577 (1995) or JP-A-2-3687, or a method analogous to the method described. Compound (VII) can be produced by Method C described below.

 The inert solvent used is not particularly limited as long as it does not inhibit the reaction. For example, halogenated hydrocarbons such as dichloromethane and dichloroethane; ketones such as acetone and 2-propanone; dimethyl sulfoxide and the like Sulfoxides; amides such as N, N-dimethylformamide; nitriles such as acetonitrile; and ethers such as ethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxetane. And preferably sulfoxides or nitriles, and more preferably dimethyl sulfoxide or acetonitrile.

 The condensing agent to be used is not particularly limited as long as it is used for forming an amide bond in organic synthesis.For example, dicyclohexyl carbodiimide, diisopropyl pillcarbodiimide, N-ethyl-Ν'- Examples thereof include (3-dimethylaminopropyl) carbodiimide, carbonyldiimidazole, and bivaloyl chloride, and preferably carbodiimidazole or pivaloyl chloride.

 Examples of the base used include organic amines such as triethylamine, diisopropylethylamine, dicyclohexylamine, pyridine, lutidine, 4- (dimethylamino) pyridine, diazabicycloundecene, and diazabicyclononene. And preferably with triethylamine or diisopropylethylamine.

 The reaction temperature is usually from 0 ° C to 40 ° C (preferably from 10 ° C to 30 ° C), and the reaction time varies depending on the type of the starting compound and the reducing agent. 2 hours (preferably 30 minutes to 4 hours).

After completion of the reaction, compound (V) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent under reduced pressure, adding a water-immiscible solvent such as ethyl acetate to the residue and washing with water, and then distilling off the solvent. The desired compound (V) thus obtained can be used, if necessary, in a conventional manner such as a recrystallization method, preparative thin-layer chromatography, It can be purified by, for example, column chromatography.

 (Step B 2)

 Step B1 is a step of producing compound (III), which is achieved by selectively removing a mercapto group-protecting group by reacting a deprotecting reagent in an inert solvent. .

 The removal of the protecting group varies depending on the type, but is generally performed by a method used in the field of synthetic organic chemistry (Greene & Wuts, Protective Groups in Organic Synthesis, 2nd Edition, 1991, John Wiley). & Sons, 丄 nc.).

(1) protecting group R ^{1 3} force? In the case of a benzyl group which may have a substituent such as 1,4-methoxybenzyl, the protecting group can be removed with an acid in an inert solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction. Examples thereof include hydrocarbons such as benzene, toluene, and anisol; and halogenated hydrocarbons such as dichloromethane and dichloroethane. it can.

 Examples of the acid used include mineral acids such as hydrochloric acid and sulfuric acid; sulfonic acids such as P-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and camphorsulfonic acid; carboxylic acids such as trifluoroacetic acid; A mixed acid can be mentioned, and a mixed acid of trifluoromethanesulfonic acid and trifluoroacetic acid is preferable.

 The reaction temperature is usually 0 ° C to 50 ° C (preferably 0 ° C to room temperature), and the reaction time varies depending on the type of the starting compound and the reducing agent, but is usually 30 minutes to 12 hours (preferably 30 minutes to 4 hours).

(2) Protecting Group When the protecting group is an alkanoyl group such as R ¹³ -acetyl, the protecting group can be removed with a salt or base of a hydrazine compound in an inert solvent. As the salt of the hydrazine compound, for example, hydrazine-acetic acid, N, N-dimethylhydrazine'acetic acid can be used, and hydrazine.acetic acid is preferable. The solvent used in this case is not particularly limited as long as it does not inhibit the reaction. For example, halogenated hydrocarbons such as dichloromethane and dichloroethane; sulfoxides such as dimethyl sulfoxide; N, N-dimethyl Amides such as formamide and N, N-dimethylacetamide can be mentioned, and amides are preferred. The reaction temperature is not particularly limited, but is usually from o ° C to room temperature (preferably room temperature). The reaction time varies depending on the solvent, the reaction temperature and the type of the reaction reagent, but is usually from 30 minutes to 24 hours. Time (preferably 1 to 8 hours).

 Examples of the base used include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, and calcium hydroxide; and alkali metal alcoholates such as sodium methoxide. And preferably sodium methoxide. In this case, the solvent used includes alcohols such as methanol and ethanol, and is preferably methanol.

 Although the reaction temperature is not particularly limited, it is generally −10 ° C. to room temperature (preferably 0 ° C.). The reaction time varies depending on the solvent, the reaction temperature and the type of the reaction reagent, but is usually 30 minutes. To 24 hours (preferably 1 to 8 hours).

After completion of the reaction, the mercaptopyrrolidine compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent from the reaction mixture under reduced pressure. The obtained compound can be purified, if necessary, by a conventional method such as a recrystallization method or column chromatography. The mercaptopyrrolidine compound (III) obtained by this method can be used as a raw material in the above-mentioned Step A1 without isolation from the reaction solution.

Compound (VII), which is a synthetic intermediate, can be produced by the following Method C,

[Method C]

In the above formula, R ² , R ³ > RR ⁵ p, n and A have the same meaning as described above. R ^{1 4} and R ^{1 5} represents a protecting group of the Amino group, L ¹ represents a leaving group.

R ¹⁴ is a protecting group for an amino group and is a protecting group which can be selectively removed while maintaining R which is a protecting group for a secondary amino group. Examples of such a protecting group include an aryloxycarbonyl group which may be substituted at the 2-position such as aryloxycarbonyl, 2-chloroallyloxycarbonyl and 2-methylaryloxycarbonyl ( The substituent is chlorine or methyl); benzyloxycarbonyl, 4-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, And an optionally substituted benzyloxycarbonyl group such as benzyloxycarbonyl (the substituent is methyl, methoxy, chlorine or nitro). A benzyloxycarbonyl group, and more preferably a benzyloxycarbonyl group.

R ¹⁵ is a protecting group for a secondary amino group in the ring, and is a protecting group that can be selectively removed while maintaining the protecting group for R ⁵ p. Such protecting groups include, for example, 2,2,2, -trichloroethyloxycarbonyl, diphenylmethyloxycarbonyl, an optionally substituted alkyloxycarbonyl group such as t-butyloxycarbonyl (the substituent is a halogen atom or a phenyl group), and preferably t-butyloxycarbonyl .

Leaving group in L ¹ is mainly not particularly limited as long as it varies depending on the type in R ⁵ R ⁶ used Oite usually organic synthetic chemistry, for example pyrazole, methyl Chio, main butoxy, amino, etc. And preferably pyrazole or methylthio.

 In the method C, the compound (X) is produced by condensing the compound (VIII) with the compound (IX) (Step C1), and the compound is selectively removed by removing the protecting group of the terminal amino group. Preparation of (XI) (Step C2), reaction of compound (XI) with compound (XII) to prepare compound (XIII) (Step C3), and then protection of the secondary amino group in the ring This is a method for producing a compound (VII) by selectively removing a group (Step C4). Hereinafter, each step will be described.

 (Step C 1)

Step C1 is a step of producing compound (X), and is accomplished by condensing compound (VIII) and compound (IX) in an inert solvent using a condensing agent. Compound (VIII) can be commercially available or can be produced by a method obvious to those skilled in the art. For example, a precursor of compound (VIII), which is an amino acid having no protecting group, can be obtained by the Gabriel synthesis method (see JWLOTO et al., J. Org. Chem., 47, pp. 2027-2033 (1982)). then compound (VIII) is obtained by introducing R ^{1 4} is a protecting group to Amino group by methods obvious to those skilled in the art (H.Kruse et, J.Org.Chem., 50, pp2792-2794 ( 1985 year )), An alkyl group can be introduced as R ⁴ if necessary by a method obvious to those skilled in the art. Compound (IX) can also be commercially available or can be produced by a method obvious to those skilled in the art. For example, a cyclic dimine compound obtained by condensing an alkylenediamine derivative and an alkyldione compound is reduced (see D. Giardina et al., J. Med. Chem., 36, pp 690-698 (1993)), or a pyridazine derivative. Decomposition of compound (IX) by reducing its body with nickel-aluminum alloy in hydrobromic acid (see G. unn, J. Org. Chem., 52, ppl043-1046 (1987)). A protected form is obtained, which can be selectively introduced into one of the ring secondary amines by a method obvious to those skilled in the art. (See D. Giardina et al., J. Med. Chem., 36, pp. 690-698 (1993)) to obtain the compound (IX).

 The inert solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably a dry solvent, for example, nitriles such as acetonitrile; hydrocarbons such as hexane, cyclohexane, benzene, and toluene. Dry solvents of halogenated hydrocarbons such as dichloromethane and dichloroethane; and preferred is dry acetate nitrile.

 Examples of the condensing agent to be used include 1, カ ル -carbodildimidazole, dicyclohexylcarbodiimid, diisopropylcarbodiimid, and triphenylphosphine-carbon tetrachloride. '-It is a carbonidimidazole.

 Although the reaction temperature is not particularly limited, it is usually 10 ° C to 40 ° C (preferably 10 ° C to room temperature ° C), and the reaction time depends on the type of the solvent, the reaction temperature and the type of the reaction reagent. Different forces Usually between 30 minutes and 24 hours (preferably between 1 and 9 hours). After completion of the reaction, compound (X) is collected from the reaction mixture according to a conventional method. For example, the solvent can be obtained by distilling off the solvent from the reaction mixture under reduced pressure, adding water-immiscible ethyl acetate and the like, washing with saturated saline and the like, and concentrating the organic solvent. The obtained compound can be purified, if necessary, by a conventional method such as a recrystallization method and column chromatography.

 (Step C 2)

Step C2 is a step of producing compound (XI). In a solvent, in the presence of a catalyst and a hydrogen donor, R ¹⁴ which is a protecting group for a terminal amino group in the structure of compound (X) is selectively used. It is achieved by removing

 Examples of the solvent used include water; alcohols such as methanol and ethanol; hydrocarbons such as hexane, cyclohexane, benzene and toluene; or, ethyl ether, tetrahydrofuran, 1,4-dioxane, Ethers such as 2-dimethyloxetane are preferred, and alcohols are preferred.

Examples of the catalyst include palladium catalysts such as palladium carbon, palladium black, and palladium hydroxide; platinum catalysts such as platinum oxide; and rhodium alumina and the like. Rhodium catalysts and the like are preferable, and a palladium catalyst (particularly palladium carbon) is preferable.

 Examples of the hydrogen donor include hydrogen gas, formic acid, sodium formate, ammonium formate, and the like. Hydrogen gas is preferred.

 The reaction temperature for the hydrogenolysis is usually between 0 ° C and room temperature (preferably room temperature), and the reaction time depends on the protective groups that are mainly to be removed, usually between 10 minutes and 8 hours (preferably 30 to 2 hours).

 After completion of the reaction, compound (XI) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off the catalyst and concentrating the filtrate under reduced pressure. The obtained compound (XI) can be used as a starting material in Step C3 without further purification. C (Step C3)

 Step C3 is a step of producing compound (XIII), and is accomplished by condensing compound (XI) and compound (XII) in a solvent.

 Solvents used include, for example, halogenated hydrocarbons such as dichloromethane and dichloroethane; ketones such as acetone and 2-propanone; sulfoxides such as dimethyl sulfoxide; amides such as N, N-dimethylformamide; Nitriles such as acetonitrile; and ethers such as geethylether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxetane, and the like, preferably ethers, and more preferably ethers Is tetrahydrofuran.

 The reaction temperature is usually from 0 ° C to room temperature (preferably room temperature), and the reaction time is mainly different depending on the reaction reagent. The reaction time is usually 10 minutes to 8 hours (preferably 30 to 2 hours). It is.

 After completion of the reaction, compound (XIII) is collected from the reaction mixture according to a conventional method. For example, the solvent can be obtained by distilling off the solvent under reduced pressure, adding a solvent that does not mix with water such as ethyl acetate, and washing with an aqueous solvent. The obtained compound (XIII) can be purified, if necessary, by a conventional method such as a recrystallization method or column chromatography.

 (Step C4)

Step C4 is a step of producing compound (VII), in which the protecting group for the secondary amino group in the ring of compound (XIII) is selectively removed by operating a deprotecting reagent in a solvent. Is achieved by

 Solvents used are, for example, halogenated hydrocarbons such as dichloromethane and dichloroethane; ketones such as acetone and 2-propanone; esters such as ethyl acetate; alcohols such as methanol and ethanol; Examples thereof include ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxetane, and preferred is dichloromethane or ethyl acetate.

 Examples of the deprotecting reagent used include mineral acids such as hydrochloric acid and sulfuric acid; sulfonic esters such as methanesulfonic acid ester, trifluoromethanesulfonic acid ester and toluenesulfonic acid ester; and carboxylic acids such as trifluoroacetic acid. Hydrochloric acid or trifluoroacetic acid is preferred, and hydrochloric acid is more preferred.

 The reaction temperature is usually from o ° C to room temperature (preferably room temperature), and the reaction time is mainly from 10 minutes to 8 hours (preferably 30 to 2 hours), depending mainly on the reaction reagent. .

 After completion of the reaction, compound (VII) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent under reduced pressure and washing with a solvent which does not dissolve the compound (VII) such as ethyl acetate or ether. The obtained compound (VII) can be used as a starting material in Step B1 without further purification.

 The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof includes, for example, Gram-positive bacteria such as Staphylococcus aureus and Bacillus subtilis, Escherichia coli, Shigella, Klebsiella pneumoniae, deformed bacteria, Serratia, Enterobacter, Shows strong and balanced antibacterial activity against a wide range of pathogens including gram-negative bacteria such as Pseudomonas aeruginosa and anaerobic bacteria such as Pacteroides fragilis, and is resistant to melopenem, a potent antibacterial agent. It also has excellent antibacterial activity against Pseudomonas aeruginosa. In addition, the compound (I) of the present invention exhibits excellent pharmacokinetics such as a long half-life in blood, and has low renal toxicity. Therefore, the compound of the present invention having the general formula (I), a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof is useful as a medicament, and is particularly useful for inhibiting bacterial infections caused by various pathogenic bacteria. It is useful as an antibacterial agent for treatment or prevention (preferably treatment).

Compound (I) or its pharmacologically acceptable prodrug or their pharmacologically acceptable When the salt to be used is used as a medicament, especially as an antibacterial agent, it is mixed with itself or an appropriate pharmacologically acceptable excipient, diluent, etc., to give tablets, capsules, granules, powders Alternatively, it can be administered orally with a syrup or the like or parenterally with an injection or the like.

These preparations may contain excipients (e.g., lactose, sucrose, glucose, mannitol, sugar derivatives such as sorbitol; corn starch, potato starch, α-starch, dextrin, carboxymethyl starch, etc.). Starch derivatives; crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally cross-linked carboxymethylcellulose sodium and other cellulosic derivatives; gum arabic; dextran; pullulan Silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate silicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; Sulphate derivatives such as sodium chloride, binders (eg, the above-mentioned excipients; gelatin; polyvinylpyrrolidone; macrogol, etc.); disintegrants (eg, the above-mentioned excipients; cross-force lumelo) Monosodium, sodium carboxymethyl starch, chemically modified starch such as cross-linked polyvinyl pyrrolidone, starch, cellulose derivatives, etc., lubricants (eg, talc; stearic acid; calcium stearate; magnesium stearate) Metal salts of stearate, such as gum; Colloidal force; Big gum; Beads, waxes such as gay wax; boric acid; glycol; carboxylic acids, such as fumaric acid and adipic acid; Sodium carboxylate; sulfates such as sodium sulfate; leucine; lauryl Lauryl sulfates such as sodium sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (eg, methylparaben, pulpylparaben) Alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; phenols such as phenol and cresol; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc.), Flavoring agents (eg, commonly used sweeteners, acidulants, flavors, etc.), suspending agents (eg, polysorbate 80, carboxymethylcell mouth) —Manufactured in a known manner using additives such as sodium, diluents, and formulation solvents (eg, water, ethanol, glycerin, etc.).

The dosage may vary depending on the symptoms, age, etc. of the patient (warm-blooded animal, especially human). In the case of oral administration, the lower limit is 10 mg (preferably 50 mg) and the upper limit is 200 Omg (preferably). In the case of intravenous administration, the lower limit is 1 Omg (preferably lO Omg) and the upper limit is 3000 mg (preferably 200 Omg) per dose. It is desirable to administer 1 to 6 times daily depending on the symptoms.

[Best Mode for Carrying Out the Invention]

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples and Formulation Examples, and the scope of the present invention is not limited thereto. Incidentally, using trimethyl chill silyl propionic acid Natoriumu d ₄ unless otherwise specified in the measurement of the heavy water for nuclear magnetic resonance scan Bae-vector in the Examples and Reference Examples in the internal standard, tetramethylsilane in other solvents Was used as an internal standard. In the following, PMZ indicates a 4-methoxybenzyl group, PNZ indicates a 4-dimethoxybenzyloxycarbonyl group, and CBZ indicates a benzyloxycarbonyl group.

 Example 1

 (1 R, 5 S, 6 S) 1-2-[(2 S, 4 S)-2-[4-1 (2-guanidinoacetyl) piperazine 1 -ylcarbonyl] pyrrolidine-1 -ylthio] 1 6-[ (1 R) — 1-Hydroxityl] — 1-Methyl-1 1-Lenopen 2- 2-Emu 3 3-Lubonic acid

 (1) (2 S, 4 S) — 2— [4- [2- [2,3-bis (412-trobenzoyloxycarbonyl) guanidino-acetyl-pyrazine-1-ylcarbonyl] 1-41 (4-Methoxybenzyl) thiol (412 trobenzyloxycarbonyl) pyrrolidine (1.64 g) and anisol (1.38 ml) were added to a mixture of trifluoroacetic acid (1.38 ml) under ice cooling. 6.47m1) and trifluoromethanesulfonic acid

(295 ^ 1) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. 1,2-Dichloroethane was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was washed with ether and hexane, and then dissolved in dichloromethane. The solution was washed with saturated sodium bicarbonate solution, water, and saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then subjected to colorless amorphous 4 dog (2S, 4S) —2- [2 -— [2,3-bis (4-nitrobenzene ziroxycarbonyl) guanidino] acetyl] piperazine-1-ylcarbonyl——4-mercapto-1 -— (4-nitrobenzoyloxycarbonyl) Pyrrolidin (1.39 g) was obtained. Infrared absorption spectrum (KBr) cm- ¹ : 3317, 1737, 1710, 1648, 1608, 1554, 1522, 1495, 1432, 1407, 1347.

Nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) <Jppm} : i.54-1.73 (1H, m), 1.83-2.03 (1H, m), 2.53-2.83 (1H, m), 3.21-4.03 (11H , m), 4.05-4.35 (2H, m), 4.61-4.76 (1H, m), 5.01-5.38 (6H, m), 7.40-7.62 (6H, m), 8.13-8.30 (6H, m).

MS spectrum m / z: 852 (M + l) ⁺ .

 (2) (1 R, 5 R, 6 S) _ 6— [(1 R) 1 1—Hydroxityl] — 1 1 Methyl-2-diphenylphosphoryloxy 1 1 1 Lubapen 1 2-Emu 3 To a suspension of carboxylic acid 412 trobenzyl ester (1.00 g) in dry acetonitrile (12 ml) was added under ice-cooling N, N-diisopropylethylamine (2941) and Example 1 A solution of the compound (1.37 g) obtained in Step (1) (1.87 g) in dry acetonitrile (18 ml) and N, N-dimethylformamide (3 ml) was added dropwise and reacted overnight with. . The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, an aqueous saturated sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (benzene: acetonitrile = 6: 4, benzene: acetonitrile = 1: 1 followed by acetate nitrile) to give a pale yellow amorphous (1R, 5S, 6S) ) — 2— [(2 S, 4 S) 1 2— [4-1] [2— [2,3-bis (412-trobenzoyloxycarbonyl) guanidino] acetyl] piperazine-1—ylcarbonyl] 1 1 — (4 — benzoyloxycarbonyl) pyrrolidine-1-4-ylthio] -1 6 — [(1 R) 1 1-hydroxyl]-1-methyl-1 1—l-lubapen-1 2—em-1 3—carbon There was obtained 412 trobenzyl ester of the acid (910 mg).

Infrared absorption spectrum (KBr) cm " ¹ : 3337, 1775, 1712, 1648, 1608, 1554, 1522, 1495, 1432, 1407, 1377, 1347.

Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) 0, ppm: 1.28 (3H, d, J = 7.2 Hz), 1.37 (3H, d, J = 6.2 Hz), 1.86-2.08 (1H, m), 2.60 -2.82 (1H, m), 3.23-3.98 (11H, m), 4.02-4.10 (1H, m), 4.13-4.35 (5H, m), 4.67-4.82 (1H, m), 5.03-5.53 (8H, m), 7.39-7.71 (8H, m), 8.14-8.31 (8H, m).

MS spectrum m / z: 1196 (M + l) +. (3) Example 1 A solution of the compound (888 mg) obtained in item (2) (88 mg) in tetrahydrofuran (24 ml) -water (12 ml) was added with 7.5% palladium-carbon catalyst. (65 Omg), and hydrogen was absorbed for 2 hours while stirring at 30 ° C and normal pressure. The catalyst was filtered off, the filtrate was washed with ether, and concentrated under reduced pressure (20 ml). The residue was subjected to reverse phase silica gel column chromatography [Cosmo Seal 75 C18 PREP (Nacalai Tester)], and eluted with acetonitrile-water. The fractions containing the desired compound were combined, concentrated under reduced pressure, and lyophilized to give the title compound (153 mg) as a powder.

Infrared absorption scan Bae-vector (KBr) Les ^{cm- 1: 3337, 1754, 1646} , 1437, 1387, 1284, 1247. UV absorption-spectrum ls e _{max (H 2 0) nm:} 229.7 (ε = 9400).

Nuclear magnetic resonance scan Bae-vector _{(400MHz, D 2 0) Sppm} : 1.22 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.2 Hz), 1.60-1.69 (1H, m), 2.70 -2.83 (1H, m), 3.05-3.22 (2H, m),

3.36-3.46 (2H, m), 3.51-3.88 (9H, m), 4.12-4.32 (5H, m).

 MS spectrum m / z: 524 (M + l) +.

Elemental analysis (calculated as _{C 22 H 33 N 7 0 6} S'3 / 2H 2 0)

 Calculated: C, 47.99%; H, 6.59%; N, 17.81%; S, 5.82%.

Found: C, 47.73%; H, 6.28%; N, 17.71%; S, 5.96% ₀ Example 2

 (1 R, 5 S, 6 S)-2-[(2 S, 4 S) — 2— [4-I- (2-guanidinoa cetyl) piperazine-1 1-ylcarbonyl] 1 1 1-Methylpyrrolidine-1 4-ylthio ] ー 6— [(1 R) 1 1 —Hydroxityl] 1 1-Methyl- 1 1-Lubapene 1-2-1-M-1--3-Carboxylic acid

(1) (2 S, 4 S) 1-2-[4-[2-[2, 3 _ bis (4-nitrobenzoyloxycarbonyl) guanidino] acetyl] piperazine-1 -ylcarbonyl Hydrazine · acetic acid (125 mg) was added to a solution of 14-acetylthio-11-methylpyrrolidine (822 mg) in N, N-dimethylformamide (16 ml), and the mixture was stirred at room temperature for 4 hours. Add (1R, 5R, 6S) -16-[(1R) 1-1-Hydroxkisethyl] 1-1-methyl-2-diphenylphosphoryloxy-1-11-lubaben-2-hem_3 —Carboxylic acid 4-nitrobenzyl ester (672 mg) and N, N-diisopropylethylamine (0.62 ml) were added, and the mixture was reacted at 130 ° C. for 3 days. The reaction mixture was added to a 1% aqueous sodium hydrogen carbonate solution, and the precipitated crystals were collected by filtration and washed with water. The obtained powder was dissolved in tetrahydrofuran: ethyl acetate = 3: 7, washed with a saturated aqueous solution of sodium hydrogencarbonate, water, and saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (5% methanol / ethyl acetate, 10% methanol / ethyl acetate, followed by 20% methanol / ethyl acetate) to give a pale yellow amorphous (1R, 5S , 6 S)-2-[(2 S, 4 S) 1 2-[4-[2-[2, 3-bis (4-nitrobenzilooxycarbonyl) guanidino] acetyl] piperazine 1 -ylcarbone 1—Methylpyrrolidine-1-ylthio] —6 — [(1 R) —1—Hydroxyethyl] —1—Methyl-1—1-Lubapen—2-Emu3—Carboxylic acid (0.81) was obtained.

Infrared absorption vector (KBr) cm- ¹ : 3314, 1771, 1740, 1710, 1645, 1609, 1554, 1522, 1494, 1433, 1378, 1347.

Nuclear magnetic resonance spectrum _{(270 MHz, CDC1 3) (} Jppm: 1.18-1.43 (6H, m), 1.76-1.92 (1H, m), 2.35 (3H, s), 2.60-2.77 (2H, m), 3.07 -4.33 (18H, m), 5.14-5.63 (6H, m), 7.56 (4H, d, J = 8.7 Hz), 7.60-7.74 (2H, m), 8.13-8.30 (6H, m), 9.30-9.50 (1H, br), 11.66 (1H, s).

 MS spectrum m / z: 1031 (M + l)

(2) Example 2—A solution of the compound (0.79 g) obtained in (1) in tetrahydrofuran (20 ml) —water (12 ml) was added to a 7.5% palladium-carbon catalyst (0 ml). 79 g) was added, and hydrogen was absorbed for 2 hours while stirring at 35 ° C. and normal pressure. The catalyst was filtered off, the filtrate was washed with ether and concentrated under reduced pressure (2 Om 1). The residue was subjected to reversed-phase silica gel column chromatography “Cosmo Seal 75 C 1 8 PRE P (Naka G) and eluted with acetonitrile-water. The fractions containing the desired compound were combined, concentrated under reduced pressure, and lyophilized to give the title compound (256 mg) as a powder.

Infrared absorption spectrum (KBr) cm- ¹ : 3347, 1755, 1648, 1439, 1386, 1312, 1284, 1245.

UV absorption scan Bae-vector _{Amax (H 2 0) nm:} 300.3 (ε = 9300).

Nuclear magnetic resonance scan Bae-vector _{(400MHz, D 2 0) Sppm} : 1.21 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.2 Hz), 1.60-1.75 (1H, m), 2.32 (3H, s), 2.75-2.95 (2H, m), 3.13 (1H, d = 106 Hz), 3.30-3.46 (2H, m), 3.48-3.93 (fan, m), 4.16-4.35 (4H, m ).

MS spectrum m / z: 538 (M + l) ⁺ .

Elemental analysis (calculated as _{C 23 H 35 N 7 0 6} S'17 / 6H 2 0)

 Calculated: C, 46.93%; H, 6.96%; N, 16.66%; S, 5.45%.

 Found: C, 46.71%; H, 6.60%; N, 16.54%; S, 5.59%. Example 3

 (1 R, 5 S, 6 S) 1 2— [(2 S, 4 S) 1 2— [4-1 (2-guanidinoacetyl) 1-3-Methylbiperazine-1 1-ylcarbonyl] pyrrolidine 1-4-ylthio] 1 6— [(1 R) 1-1-Droxityl] 1-1-methyl-1-lubapen-1-2-emu 3-l-rubonic acid

(1) (1 R, 5 R, 6 S) 1 6— [(1 R) — 1-Droxitytyl] 1 1 1 Methyl 2-diphenylphosphoryloxy 1 1—Power Lubapen 1 2—Emu 3 _Power Rubonic acid 4-nitrobenzyl ester (1.68 g) and (2S, 4S) 12- [4-1-1 [2- [2,3-bis (412-trobenziloxycarbonyl) guanidino] ] Acetyl] 1-Methylbiperazine-1-ylcarbonyl] —4-Mercapto 11- (4-nitrobenzyloxycarbonyl) pyrrolidine (2.46 g) To a solution of NN-dimethylformamide (40 ml) was added NN-diisopropylditylamine (0.59 ml), and the mixture was reacted at -30 ° C for 3 days. The reaction mixture was poured into a 1% aqueous sodium hydrogen carbonate solution, and the precipitated powder was collected by filtration, washed with water, and dissolved in ethyl acetate. Next, the ethyl acetate solution was washed with water, a saturated aqueous solution of sodium bicarbonate, and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (5% methanol Z). Ethyl acetate followed by 10% methanolic ethyl acetate) to give a pale yellow amorphous (1R, 5S, 6S) —2 — [(2S, 4S) 1-2— [4— [ 2- [23-bis (4-nitrobenzoyloxycarbonyl) guanidino] acetyl] -13-methylbiperazin-1-ylcarbonyl-11-11 (4-nitrobenzyloxycarbonyl) pyrrolidine-1-ylthio ] — 6— [(1 R) — 1-Hydroxityl] — 1-Methyl — 1-Lubaven-1 2-Em-3-3-Rubonic Acid 4-12

(3.09 g) was obtained.

Infrared absorption spectrum (KBr) cm- ¹ : 3316, 1774, 1738, 1712, 1647 1608, 1553, 1552, 1496 1431 1407 1378 1347 1286.

Nuclear magnetic resonance spectrum _{(400 MHz, DMSO- d 6)} <ppm:? 0.71 - 1.35 (9H m) 1.52- 2.02 (2H, m), 2.47-3.43 (6H m) 3.70-4.62 (10H, m), 4.68-5.53 (10H, m 7.41-7.79 (8H m), 8.15-8.32 (8H m), 8.93-9.08 (1H br), 11.55 (1H s.

MS spectrum m / z: 1209 (+ l) ⁺ .

 (2) A solution of the compound (1.50 g) obtained in Example 3- (1) (1.50 g) in tetrahydrofuran (50 ml) -water (30 ml) was added with a 7.5% palladium-carbon catalyst (1.50 g). g), absorb hydrogen for 2 hours while stirring at 30 ° C and normal pressure, and treat in the same manner as in Example 11- (3) to give the title compound (38) as a pale yellow powder. 8 mg).

Infrared absorption spectrum (KBr) cm- ¹ : 3342, 1753 1645, 1415, 1386.

UV absorption spectrum scan _{max (H 2 0) nm:} 299.8 (ε = 9700).

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, D 2 0)} ^ ppm! 1.10-1.36 (9H, m), 1.50-1.75 (1H, m), 2.68-2.98 (1H, m), 3.03-4.46 (17H m).

MS spectrum m / z: 538 (M + l) +. Elemental analysis (calculated as _{C 23 H 35 N 7 0 6} S'3H 2 0)

 Calculated: C, 46.69%; H, 6.98%; N, 16.57%; S, 5.42%.

 Found: C, 46.52%; H, 6.34%; N, 16.65%; S, 5.58%. Example 4

 (1 R, 5 S, 6 S)-2-[(2 S, 4 S) — 2— [4- (2-guanidinoacetyl) 1-3-methylbiperazine-1-ylcarbonyl] 1-methylpyrrolidin-1 4-ylthio ] 1 6— [(1 R) 1 1—Hydroxityl] 1 1—Methyl- 1 1 Lubapen 1 2 1 Chem 1 3—Luvonic acid

 (1) (2 S, 4 S) —2— [4— [2— [2,3-bis (4-nitrobenzyloxycarbonyl) guanidino] acetyl] -13-methylbiperazine-1-ylcarbonyl] —4 Hydrazine · acetic acid (223 mg) was added to a solution of 1-acetylthio-1-methylpyrrolidine (1.50 g) in N, N-dimethylformamide (30 ml), and the mixture was stirred at room temperature for 2 hours. Add (1 R, 5 R, 6 S) — 6 — [(1 R) 1-1-hydroxyloxytyl) 1-methyl-2-diphenylphosphoryloxy 1 1-lubapen 1-2-emu 3-carboxylic acid to the reaction mixture 4 12 Trobenzyl ester (1.

20 g) and N, N-diisopropylethylamine (0.46 ml) were added, reacted at 130 ° C for 2 days, and treated in the same manner as in Example 2 (1). To give a pale yellow amorphous (1R, 5S, 6S)-2-[(2S, 4S) 1 2-[4-[2-[2,

3-bis (4-nitrobenzyloxycarbonyl) guanidino] acetyl] -1-methylbiperazine-1-1-ylcarbonyl] 1-1-methylpyrrolidine-14-ylthio] —6 -— ((1R) — [1-Hydroxityl] -1-methyl-1-1-l-lubapen-12-emu-3-carboxylic acid 4-nitrobenzyl ester (1.70 g) was obtained.

Infrared absorption spectrum (KBr) y cm- ¹ : 3315, 1772, 1739, 1645, 1609, 1552, 1522, 1495, 1432, 1378, 1347, 1325, 1286.

Nuclear magnetic resonance spectrum _{(400 MHz, CDC1 3) ^} pm: 1.07-1.47 (9H, m), 1.67-1.95 (2H, m), 2.29-2.43 (3H, m), 2.55-3.80 (10H, m) , 3.90-5.06 (8H, m), 5.15-5.55 (6H, m), 7.48-7.73 (6H, m), 8.15-8.30 (6H, m), 9.45 (1H, s), 11.66 (1H, s) .

MS spectrum m / z: 1045 (M + l) ⁺ .

 (2) Example 4 A solution of the compound obtained in step (1) (1.68 g) in tetrahydrofuran (42 ml) -water (34 ml) was added to a solution of 7.5% palladium carbon catalyst (1. 68 g), absorb hydrogen for 2 hours while stirring at 35 ° C and normal pressure, and treat in the same manner as in Example 11- (2) to give a pale yellow powder. Compound (593 mg) was obtained.

Infrared absorption spectrum (KBr) vcm- ¹ : 3337, 1756, 1646, 1450, 1436, 1384, 1308, 1277, 1246, 1219, 1179, 1149.

Ultraviolet absorption-spectrum ls e _{max (H 2 0) nm:} 301.3 (ε = 10400).

Nuclear magnetic resonance scan Bae-vector _{(400MHz, D 2 0) 8} ppm: 1.07-1.38 (9H, m), 1.52-1.80 (1H, m), 2.20-2.47 (3H, m), 2.73-2.95 (2H, m), 3.00-3.73 (8H, m), 3.80-3.98 (1H, m), 4.03-4.47 (6H, m).

MS spectrum m / z: 552 (M + l) ⁺ .

Elemental analysis (calculated as _{C 24 H 37 N 7 0 6} S'3 / 2H 2 0)

 Calculated: C, 49.81%; H, 6.97%; N, 16.94%; S, 5.54%.

Found: C, 49.48%; H, 6.43%; N, 17.00%; S, 5.24%.

Example 5

 (1 R, 5 S, 6 S)-2 [(2 S, 4 S)-2-[4- (2-guanidinoacetyl) homopidazine 1 -ylcarbonyl] pyrrolidine-1 -ylthio] 1-6-[(1 R) 1 1 _Hydro — 1 —Methyl-1 1) Levapen 1 2 — Chem 1 3 —Carboxylic acid

(1) (2 S, 4 S) — 2— [4-1- [2- [2,3-bis (412-trobenzoyloxycarbonyl) guanidino] acetyl] Homopyrazine-1—ylcarbyl] — 4— (4-Methoxybenzyl) thiol 1 — (4-Nitrobenzyloxycarbonyl) pyrrolidine (900 mg) and anisol (0.99 ml) were added to a mixture under ice-cooling. Trifluoroacetic acid (4.96 ml) and trifluoromethanesulfonic acid (0.16 ml) were added dropwise, and the mixture was stirred at room temperature for 1 hour. Xylene was added to the reaction mixture and concentrated under reduced pressure. The residue was triturated with ether and hexane, washed, and dried under reduced pressure. The obtained powder and (1 R, 5 R, 6 S) — 6 — [(1 R) — 1 —hydroxyethyl] 1 1 —methyl-1-diphenylphosphoryloxy 1 1 —l-lappapen 1 2 N-N-N-Diisopropylethylamine (0.1-mL) was added to a solution of 4-nitrobenzyl ester (54 mg) in N, N-dimethylformamide (10 ml). 6 ml) and reacted at 0 ° C overnight. The reaction mixture was poured into a 1% aqueous sodium hydrogen carbonate solution, and the precipitated powder was collected by filtration, washed with water, dissolved in THF, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (acetonitrile) to give a pale yellow amorphous (1R, 5S, 6S)-2-[(2S, 4S) — 2— [4— [2 — [2,3_Bis (4-2-trobenzoyloxycarbonyl) guanidino] acetyl] homopirazine-111-ylcarbonyl] -111- (4-nitrobenzyloxycarbonyl) pyrrolidine-l-ylthio] — 6 — [(1 R) — 1 —Hydroxityl] 1 1 —Methyl 1 1 Power Lubapen-1-emu-3-potassium ribonate 4-nitrobenzyl ester (605 mg) was obtained.

Infrared absorption spectrum (KBr) cm- ¹ : 3341, 1773 1738 1711 1647 1608, 1553, 1522, 1493, 1431 1406 1377 1347 1286 1210.

Nuclear magnetic resonance spectrum _{(400 MHz DMS0-d 5)} δ ppm: 1.15 (6H, d J = 5.8 Hz), 1.46-1.88 (3H m), 2.72-2.93 (1H, ra), 3.06-4.28 (17H m ), 4.55-4.85 (1H m), 4.95-5.50 (8H m), 7.38-7.76 (8H, m), 8.10-8.30 (8H, m).

MS spectrum m / z: 1210 (M + l) ⁺ .

 (2) 20% palladium hydroxide-carbon was added to a solution of the compound (600 mg) obtained in Example 5_ (1) (600 mg) in tetrahydrofuran (12 ml) _water (12 ml). After adding a catalyst (60 Omg) and absorbing hydrogen for 2 hours while stirring at 35 ° C and normal pressure, the mixture was treated in the same manner as in Example 11- (2) to obtain a powder. The title compound (129 mg) was obtained.

Infrared absorption spectrum (KBr) cm- ^L : 3343 1753 1646 1482 1430, 1387 1281, 1262 1225 1183 1151.

Nuclear magnetic resonance spectrum (400MHz, 0) ppm: 1.21 (3H dd J = 7.2, 1.0 Hz), 1.30 (3H, d J = 6.4 Hz), 1.35-1.65 (1H, m), 1.73-2.00 ( 2H, m), 2.65-2.82 (1H m), 3.03-3.23 (2H, m), 3.33-4.35 (16H m).

MS spectrum m / z: 538 (M + l) ⁺ .

Elemental analysis (calculated as C ₂₃ H ₃₅ N ₇ 0 ₆ S'2¾0)

 Calculated: C, 48.16%; H 6.85%; N, 17.09%.

 Found: C, 48.25%; H 6.89%; N 17.28% Example 6

(1 R 5 S, 6 S) 1 2— [(2 S, 4 S) 1 2— [4— (2-guanidinoacetyl) homopidazine 1 1-ylcarbonyl] 1 1 1-Methylpyrrolidine 1-4-ylthio] 1 6— [(1 R) — 1-Hydroxityl] 1 1-Methyl- 1 1-Luba Pen 1- 2-Em-1 3--Rubonic acid

 (1) (2 S, 4 S) — 4-acetylthio-1-1-methyl-2- [4-1- [2- [3- (412-trobensiloxycarbonyl) guanidino] acetyl〗 homopiperazine-1-1-ylcarbonyl] To a solution of pyrrolidine (900 mg) in methanol (9 ml) was added sodium methoxide (84.6 mg) under ice-cooling, and the mixture was stirred at 0 ° C for 1 hour. Further, sodium methoxide (169.2 mg) was added, and the mixture was stirred at 0 ° C for 3 hours. To the reaction mixture was added 4N-hydrogen chloride / ethyl acetate (1.6 ml), and the mixture was concentrated under reduced pressure. Residue, (1 R, 5 R, 6 S) — 6— [(1 R) — 1-hydroxyethyl] — 1-methyl-2-diphenylphosphoryloxy 1-l-l-l-bapene 1—2-emu 3— A solution of 4-nitrobenzyl ester of carboxylic acid (951 mg) and N, N-diisopropylethylamine (0.56 ml) in N, N-dimethylformamide (9 ml) was heated to 0 °. Reaction at C overnight. The reaction mixture was added to a 1 o / o aqueous sodium hydrogen carbonate solution, and the precipitated crystals were collected by filtration, washed with water, dissolved in THF, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (acetonitrile: methanol = 3: 1), and then powdered with acetonitrile-isopropyl ether to obtain a pale yellow amorphous (1R, 5S, 6S) 6— [(1 R) 1 1-Hydroxityl] 1 1-Methyl-2 — [(2 S, 4 S) — 2— [4— [2— [3— (4-Nitrobenzyloxycarbonyl) guanidino ] Acetyl] Homopyrazine-1 -ylcarbonyl]-1 -methylpyrrolidine-14 -ylthio] 1-1-l-rubapene 1-2-em-1-3-r-rubonic acid 4-1 2-Trobenzylester (450 mg) Obtained.

Infrared absorption spectrum (KBr) level cm- ¹ : 3385, 1768, 1704, 1647, 1608, 1522, 1489, 1454, 1435, 1378, 1347, 1279, 1210, 1182, 1135, 1104.

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, DMS0-d 6} ) ^ ppm: 1.00-1.27 (6H, m), 1.47-1.98 (3H, m), 2.03-4.25 (22H, m), 5.05-5.50 ( 4H, m), 6.90-7.28 (4H, m), 7.53- 7.78 (2H, m), 8.16-8.20 (2H, m). MS spectrum m / z: 866 (M + l) ⁺ .

 (2) Example 6—A solution of the compound (400 mg) obtained in (1) in tetrahydrofuran (20 ml) —water (20 ml) was added with a 20% palladium hydroxide carbon catalyst. (4 O Omg), absorb hydrogen for 4 hours while stirring at 35 ° C and normal pressure, and treat in the same manner as in Example 1-1 (2) to obtain a powdery title. The compound (122 mg) was obtained.

Infrared absorption spectrum (KBr) cm- ¹ : 3350, 1755, 1648, 1487, 1454, 1434, 1385, 1256, 1221, 1182, 1148, 1095.

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, D 2 0)} Sppm: 1.20 (3H, dd, J = 7.1, 3.8 Hz), 1.30 (3H, d, J = 6.3 Hz), 1.43-1.61 (1H, m ), 1.71-2.03 (2H, m), 2.15-2.44 (2H, m), 2.70-4.00 (wind m), 4.10-4.32 (4H, m).

Elemental analysis (calculated as the _{C 24 H 37 N 7 0 6} S'1.5H 2 0)

 Calculated: C, 49.81%; H, 6.97%; N, 16.94%; S, 5.54%.

 Found: C, 49.82%; H, 6.72%; N, 15.81%; S, 5.27%. Reference example 1

 (2S, 4S) 1 2— [4- [2— [2,3_bis (4-nitrobenzyloxycarbonyl) guanidino] acetyl] pidazine-1 1-ylcarbonyl] 1-41

(4-Methoxybenzyl) Thio-111 (412-Trobenzoyloxycarbonyl) Pialysine

To a solution of (1 N-CBZ-glycine (110 g) in dry acetonitrile (13 ml)) was added 1,2-carbodildimidazole (892 mg), and the mixture was stirred at room temperature for 30 minutes. A solution of N-Boc-piperazine (93 1 mg) in dry acetonitrile (15 ml) was added, and the mixture was stirred for 1.5 hours.The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue to dissolve the residue. Saturated aqueous potassium hydrogen sulfate solution, saturated salt The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, then hexane: ethyl acetate = 3: 7) to give a colorless powder of 4- (2-benzyloxycarbo). (2 L-amino) acetyl-1 (t-butyloxycarbonyl) piperazine (1.7 g) was obtained.

Infrared absorption spectrum (KBr) cm- ¹ : 3324 1719 1699, 1643 1514, 1482 1455, 1447, 1408, 1367.

Nuclear magnetic resonance spectrum _{(270 MHz CDC1 3) <^} ppm: 1.47 (9H s), 3.22-3.50 (6Η m), 3.53-3.66 (2Η m), 4.03 (2Η d J = 4.2 Hz), 5.13 (2Η , s 5.71-5.83 (1H br), 7.28-7.42 (5H, m).

 MS spectrum m / z: 377 (M + l) +.

 (2) Reference Example 1- A solution of the compound (1.68 g) obtained in (1) (1.68 g) in ethanol (25 ml) and methanol (8 ml) was dissolved in a 7.5% palladium-carbon catalyst (0.8 g). ) Was added, and hydrogen was absorbed for 10 minutes while stirring at normal temperature and normal pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain 1_ (2-aminoacetyl) 14- (t-butyloxycarbonyl) pidazine (980 mg) as a colorless powder.

Infrared absorption spectrum (KBr) cm- ¹ : 3352, 1689, 1658 1604, 1465 1427, 1364, 1331 1288 1240, 1177 1134.

Nuclear magnetic resonance spectrum (270 MHz, CDCI3) <? Ppm: 1.47 (9Hs), 3.28-3.50 (8Hm), 3.55-3.77 (2H, m).

 MS spectrum m / z: 244 (Μ + 1) + ·

(3) In a nitrogen stream, a solution of the compound obtained in Reference Example 1- (2) (730 mg) in tetrahydrofuran (15 m 1) was added to a solution of 1- [N ¹ , N ² -bis (4-ni). Trobenzyloxycarbonyl)] amidino-l-pyrazol (1.27 g) at room temperature

Stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, dissolved by adding ethyl acetate (1 000 ml), washed with water, a saturated aqueous solution of potassium hydrogen sulfate, and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, hexane: ethyl acetate = 4: 6, and then hexane: ethyl acetate = 2: 8) to give a colorless amorphous product. — [2 _ [2 3—B Four

52 (4-12 trobenzyloxycarbonyl) guanidino] acetyl] -11- (t-butyloxycarbonyl) piperazine (1.68 g) was obtained.

Infrared absorption spectrum (KBr) level cnr ¹ : 3308, 1740, 1697, 1647, 1627, 1553, 1524, 1458, 1416, 1378, 1367, 1347.

Nuclear magnetic resonance scan Bae-vector _{(270 MHz, CDC1 3) ^} ppm: 1.47 (9H, s), 3.30-3.50 (6H, m), 3.57-3.70 (2H, m), 4.17-4.28 (2H, m) , 5.23 (2H, s), 5.31 (2H, s), 7.55 (4H, d, J = 8.6 Hz), 8.14-8.28 (4H, m), 9.36-9.47 (1H, br), 11.55-11.70 (1H , Br).

MS spectrum m / z: 644 (M + l) ⁺ .

 (4) To a solution of the compound (1.66 g) obtained in Reference Example 1 (3) (6 ml) in dichloromethane (8 ml) was added trifluoroacetic acid (4 ml) in a nitrogen stream under ice-cooling. For 1 hour. 1,2-Dichloroethane was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was triturated with ether, separated by decantation and dried under reduced pressure.

One [2- [2,3-bis (4-nitrobenzyloxycarbonyl) guanidino] acetyl] piperazine trifluoroacetate (2.26 g) was obtained.

Infrared absorption scan Bae-vector ^{(KBr) cm- 1: 1735,} 1671, 1648, 1627, 1611, 1557, 1524. Nuclear Magnetic Resonance scan Bae-vector _{(270 MHz, DMSO-d 6} ) ^ pm: 3.00-3.26 ( 4H, m), 3.48-3.76 (4H, m), 4.27 (2H, d, J = 3.9 Hz), 5.21 (2H, s), 5.39 (2H, s), 7.62 (2H, d, J = 8.7 Hz) ), 7.71 (2H, d, J = 8.7 Hz), 8.17-8.32 (4H, m), 8.74-9.07 (3H, m), 11.30-11.70 (1H, br).

 MS spectrum m / z: 544 (M + l) +.

(5) (2 S, 4 S) — 4- (4-Methoxybenzylthio) 111 (4-Nitoxybenzyloxycarbonyl) pyrrolidine-12-Carbonic acid (1.21 g) To a suspension of dried acetonitrile (12 ml) in water was added 1,1,1-carbonyldiimidazole (459 mg), and the mixture was stirred at room temperature for 1 hour, and then N, N-diisopropylethylamine Acetonitrile (15 ml) and N, N-dimethylformamide (20 ml) of the compound (2.261 g) obtained in Reference Example 11 (4) The solution was added and reacted at room temperature overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Shrank. The residue was subjected to silica gel column chromatography (ethyl acetate, followed by 5% methanol / ethyl acetate) to give the title compound (1.65 g) as a colorless amorphous.

Infrared absorption scan Bae-vector (KBr) Les ^{cm- 1: 3308, 1737, 1711} , 1648, 1609, 1553, 1521. Nuclear Magnetic Resonance spectrum _{(400 MHz, CDC1 3) 0} , ppm: 1.73-1.93 (1H, m), 2.38-2.53 (1H, m), 3.03-3.17 (1H, m), 3.21-3.93 (15H, m), 4.15-4.32 (2H, m), 4.51- 4.66 (1H, m), 5.00- 5.38 (6H, m), 6.82-6.90 (2H ₍ m), 7.18-7.28 (2H, m), 7.38-7.50 (2H, m), 7.55 (4H, d, J = 8.6 Hz), 8.18-8.30 ( 6H, m).

MS spectrum m / z: 972 (M + l) +. Reference example 2

(2 S, 4 S)-2-[4- [2- [2,3-bis (4-nitrobenzyloxycarbonyl) guanidino] acetyl] piperazine-1-ylcarbonyl] — 4-acetylthiol 1 -methylpyrrolidine

 (1) A solution of the compound (1.286 g) obtained in Reference Example 1- (3) in tetrahydrofuran (3.2 ml) and acetonitrile (3.2 ml) in a nitrogen stream under ice-cooling To the mixture was added 4N hydrogen chloride Z-ethyl acetate (6.4 ml), and the mixture was stirred at room temperature for 4 hours. Ether was added to the reaction mixture, and the precipitated powder was collected by filtration, washed with ether, and obtained as a colorless powder of 11- [2- [2,3-bis (4-nitrobenzylsiloxycarbonyl) guanidino] acetyl. There was obtained piperazine hydrochloride (1.10 g).

Nuclear magnetic resonance scan Bae-vector _{(270 MHz, DMSO- d 4)} <5ppm: 3.00-3.20 (4H, m), 3.56-3.77 (4H, m), 4.27 (2H, d, J = 4.0 Hz), 5.21 (2H, s), 5.39 (2H, s), 7.62 (2H, d, J = 8.3 Hz), 7.71 (2H, d, J = 8.3 Hz), 8.20-8.32 (4H, m), 8.97 (1H, s), 9.32 (2H, s), 11.53 (1H, s).

MS spectrum m / z: 524 (M + l) ⁺ .

(2) In a nitrogen stream, under ice-cooling, (2 S, 4 S) — 4-acetylthio-1- 1 -methyl To a solution of 2-pyrrolidinecarboxylic acid (508 mg) in N, N-dimethylformamide (10 ml), add N, N-diisopropylethylamine (0.44 ml), and vivaloyl chloride (0.2 5 ml) was added dropwise and stirred for 30 minutes. Reference Example 2-N, N-dimethylformamide (10 ml) of the compound (1.10 g) obtained in (1) and N, N-diisopropylethylamine (1.1 ml) The solution was added and stirred for 2 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with 5% brine and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (5% methanol / ethyl acetate, followed by 10% methanol / ethyl acetate) to obtain the title compound (84.8 mg) as a pale yellow amorphous substance. .

Infrared absorption spectrum (KBr) cm " ¹ : 3307, 1739, 1646, 1553, 1522, 1432, 1378, 1347.

Nuclear magnetic resonance spectrum _{(400 MHz, CDC1 3) <} 5ppm: 1.80-1.90 (1H, m), 2.31 (3H, s), 2.36 (3H, s), 2.67-2.82 (2H, m), 2.98-3.10 (1H, m) '3.15-3.27 (1H, m), 3.34-4.03 (9H, m), 4.26 (2H, d, J = 3.6 Hz), 5.23 (2H, s), 5.32 (2H, s), 7.56 (4H, d, J = 8.7 Hz), 8.18-8.27 (4H, m), 9.30-9.50 (1H, br), 11.66 (1H, s). MS spectrum m / z: 729 (M + l) ⁺ . Reference example 3

(2 S, 4 S) 1 2— [4 1 [2— [2,3—bis (412 trobenzylyloxycarbonyl) guanidino] acetyl] 1-3-Methylbiperazine 1-ylcarbonyl] 1-4— (4- Methoxybenzyl) thio-1-1 (412-trobenzyloxycarbonyl) pyrrolidine

(1) To a solution of N-CBZ-glycine (4.33 g) in dry acetonitrile (90 ml); add I, 1,1-carbonyldiimidazole (4.03 g), and add the solution at 50 ° C. Stirred for 0 minutes. Add N—B 0 c—3-methylbiperazine (4.14 g) to the reaction mixture. Was added and the mixture was stirred at 50 ° C for 7 hours and at 70 ° C for 7 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue to dissolve the residue, and the mixture was washed with a saturated aqueous solution of citric acid, water, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. It was concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, then ethyl acetate) to give a colorless oily 4- (2-benzyloxycarbonylamino) acetyl-11- (t-butyloxycarbonyl) One 3-methylbiperazine (4.52 g) was obtained.

Infrared absorption spectrum (KBr) cm- ¹ : 3410, 3323, 1723, 1698, 1653, 1587, 1500, 1456, 1426, 1394.

Nuclear magnetic resonance spectrum _{(400 MHz, CDC1 3) ^} ppm: 1.06-1.34 (3H, m), 1.47 (9H, s), 2.67-3.09 (3H, m), 3.22-3.49 (1H, m), 3.70 -4.78 (5H, m), 5.13 (2H, s), 5.82 (1H, s), 7.25-7.42 (5H, m).

MS spectrum m / z: 392 (M + l) ⁺ .

 (2) Reference Example 3— To a solution of the compound (4.50 g) obtained in (1) (4.55 g) in ethanol (45 ml) was added 7.5% palladium on carbon catalyst (1.35 g), and the mixture was added to 30%. Hydrogen was absorbed for 30 minutes while stirring at normal temperature and ° C. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain colorless oily 4- (2-aminoacetyl) -11- (t-butyloxycarbonyl) -13-methylbiperazine (3.13 g).

Infrared absorption spectrum (KBr) V cm- ¹ : 3372, 1697, 1649, 1463, 1427, 1393, 1367, 1344, 1328, 1307, 1270.

Nuclear magnetic resonance spectrum (400 MHz, CDCI3) ^ ppm: 1.08-1.33 (3H, m), 1.47 (9H, s), 1.74 (2H, s), 2.68-3.10 (2H, m), 3.20-3.63 ( 3H, m), 3.76-4.85 (4H, m).

MS spectrum m / z: 258 (M + l) +.

(3) In a nitrogen stream, a solution of the compound (3.13 g) obtained in Reference Example 3- (2) in tetrahydrofuran (60 ml) was added to a solution of 1- [N ¹ , N ² -bis (4- Ditrobenzyloxycarbonyl)] amidino-1-pyrazole (4.83 g) was added, and the mixture was stirred at room temperature for 1.5 hours. The powder precipitated from the reaction mixture was collected by filtration and washed with ethyl acetate. The filtrate was washed with water, a saturated aqueous solution of potassium hydrogen sulfate, and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl acetate And then washed with ether. Powdered 4- [2- [2,3-bis (4-nitrobenzyloxycarbonyl) guanidino] acetyl] -11- (t-butyloxycarbonyl) -13-methylbiperazine was combined to obtain (6.08 g). Was.

Infrared absorption spectrum (KBr) vcm " ¹ : 3434, 3323, 1740, 1697, 1647, 1553, 1524, 1495, 1463, 1426, 1367, 1348, 1310, 1286.

Nuclear magnetic resonance spectrum (400 MHz, DMSO-dg) ^ ppm: 0.95-1.26 (3H, m), 1.41 (9H, s), 2.60-4.60 (9H, m), 5.20 (2H, s), 5.39 (2H, s), 7.62 (2H, d, J = 8.6 Hz), 7.71 (2H, d, J = 8.6 Hz), 8.23 (2H, d, J = 8.6 Hz), 8.26 (2H, d, J = 8.6 Hz), 9.01 (1H, s), 11.55 (1H, s).

MS spectrum m / z: 658 (M + l) ⁺ .

 (4) In a nitrogen stream, under ice-cooling, 4N hydrogen chloride Z-ethyl acetate (20 ml) was added to a dichloromethane (10 ml) solution of the compound (2.0 g) obtained in Reference Example 3— (3) under ice cooling. Was added and stirred at room temperature for 30 minutes. The powder precipitated from the reaction mixture was collected by filtration, washed with ether, dried under reduced pressure, and dried as a colorless powder, 1- [2- [2,3-bis (4--2-trobenzoyloxycarbonyl) guanidino] acetyl ] — 2-Methylbiperazine dihydrochloride (2.13 g) was obtained.

Infrared absorption spectrum (KBr) cm- ¹ : 3410, 1753, 1665, 1625, 1606, 1589, 1522, 1463, 1428, 1384, 1348, 1324, 1286, 1237, 1210.

Nuclear magnetic resonance spectrum (400 MHz, DMSO-c ^) ^ m: 1.20-1.50 (3H, m), 2.65-3.83 (5H, m), 4.08-4.83 (4H, m), 5.22 (2H, s), 5.40 (2H, s), 7.63 (2H, d, J = 8.6 Hz), 7.71 (2H, d, J = 8.6 Hz), 8.17-8.33 (4H, m).

 MS spectrum m / z: 558 (M + l) +.

(5) (2 S, 4 S) 14- (4-Methoxybenzylthio) 1-1- (4-tol-benzyloxycarbonyl) pyrrolidine-12-carboxylic acid (1.357 g) And a solution of N, N-diisopropylpyramine (0.635 ml) in N, N-dimethylformamide (27 ml) under ice-cooling with bivaloyl chloride (0.375 ml) Was added dropwise, and the mixture was stirred at 0 for 30 minutes. Then, N, N-diisopropylpyrutylamine (2.2 m 1) and the compound obtained in Reference Example 3— (4) (2.13 A solution of g) in N, N-dimethylformamide (12 ml) was added dropwise, and the mixture was stirred at 0 ° C for 2 hours. Vinegar in the reaction mixture Ethyl acid was added, and the mixture was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate) to give the title compound (2.85 g) as a colorless amorphous substance.

Infrared absorption spectra (KBr) cm- ¹ : 3430, 3316, 1737, 1710, 1649, 1609, 1584, 1552, 1521, 1497, 1430, 1407, 1378, 1347, 1323, 1286.

Nuclear magnetic resonance spectrum _{(400 MHz, CDC1 3) (} 5ppm: 0.85-1.45 (3H, m), 1.55-2.00 (1H, m), 2.31-4.87 (19H, m), 4.96-5.38 (6H, m) , 6.85 (2H, d, J = 8.4 Hz), 7.19-7.28 (2H, m), 7.32-7.61 (4H, m) 8.13-8.24 (6H, m), 9.32-9.52 (1H, b), 11.65 ( 1H, s).

MS spectrum m / z: 986 (M + l) ⁺ . Reference example 4

(2 S, 4 S) — 2 -— [4-—2- [2,3-bis (412-trobenzoyloxycarbonyl) guanidino] acetyl] — 3-methylpiperazine-1-ylcarbonyl] -14-acetylthio One-one-methylpyrrolidine

 (1) In a nitrogen stream and under ice-cooling, 4N hydrogen chloride Z ethyl acetate (20 ml) was added to a dichloromethane (10 ml) solution of the compound (2.00 g) obtained in Reference Example 3— (3) under ice-cooling. Was added and stirred at room temperature for 1 hour. Further, 4N hydrogen chloride Z-ethyl acetate (10 ml) was added, and the mixture was stirred at room temperature for 1 hour. Ether was added to the reaction mixture, and the precipitated powder was collected by filtration, washed with ether, dried under reduced pressure, and dried as a colorless powder of 1- [2- [2,3-bis (4-nitrobenzoyloxycarbonyl)]. [Guanidino] acetyl] 1-2-methylpiperazine dihydrochloride (2.16 g) was obtained.

(2) (2 S, 4 S) — 4-acetyl-thio-1-1-methylpyrrolidine- 12-carbonic acid (618 mg) and N, N-diisopyrupytilamine (0.635 ml) Of N, N-dimethylformamide (12m 1) in ice-cooled 37.5 ml) was added dropwise, and the mixture was stirred at 0 ° C. for 30 minutes, and then N, N-diisopropylpyramine (2.2 ml) and the compound obtained in Reference Example 4- (2) (2.16) g) in N, N-dimethylformamide (12 ml) was added dropwise, and the mixture was stirred at 0 ° C for 2 hours. Ethyl acetate was added to the reaction mixture, washed with water, a saturated aqueous solution of sodium hydrogencarbonate, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (10% methanol / ethyl acetate) to give the title compound (1.53 g) as a pale-yellow amorphous.

Infrared absorption vector (KBr) cm- ¹ : 3432, 1739, 1684, 1646, 1552, 1523, 1495, 1464, 1431, 1378, 1347, 1325, 1310, 1286.

Nuclear magnetic resonance spectrum _{(400 MHz, CDC1 3) ^} ppm: 1.10-1.35 (3H, m), 1.76-1.98 (1H, m), 2.26-2.43 (3H, m), 2.57-3.65 (9H, m) , 3.86-4.90 (8H, m), 5.23 (2H, s), 5.31 (2H, m), 7.56 (4H, d, J = 8.6 Hz), 8.18-8.28 (4H, m) 9.39-9.55 (1H, b), 11.66 (1H, s).

MS spectrum m / z: 743 (M + l) +. Reference example 5

 (2 S, 4 S) — 2— [4— [2— [2,3-bis (412-trobenzoyloxycarbonyl) guanidino] acetyl] Homopyrazine-1—ylcarbonyl] 1

4- (4-Methoxybenzyl) Thio 1- (4-nitrobenzoyloxycarbonyl) pyrrolidine

(1) To a solution of N-CBZ-glycine (547 mg) in dry acetonitrile (10 ml) was added 1,1, -carbonyldiimidazole (445 mg), and the mixture was stirred at room temperature for 1.5 hours. N-B0c-Homopyrazine (500 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. There was obtained (oxycarbonylamino) acetyl-1- (t-butyloxycarbonyl) homopiperazine (849 mg). Infrared absorption spectrum (KBr) cm- ¹ : 3567 3409, 3323 1724, 1693, 1653, 1587, 1498, 1480, 1455 1435, 1416, 1393, 1367.

Nuclear magnetic resonance spectrum _{(400 MHz, CD 3 0D)} ^ ppra: 1.40-1.52 (9H m), 1.69-1.94 (2H m), 3.33-3.67 (8H m), 3.96-4.05 (2H, m), 5.09 (2H, s), 7.25-4.42 (5H m).

MS spectrum m / z: 392 (M + l) ⁺ .

 (2) Reference Example 5—7.5% palladium-carbon catalyst (405 mg) was added to a solution of the compound (809 mg) obtained in (1) in ethanol (16 ml), and the mixture was added at 30: atmospheric pressure. After absorbing hydrogen for 1 hour while stirring with, the mixture was treated in the same manner as in Reference Example 2-(2) to give a colorless oil ¾ ^ 4- (2-aminoacetyl) -11- (t-butyloxycarbonyl) Homopirazine (49 1 mg) was obtained.

Infrared absorption spectrum (KBr) cm- ¹ : 3432, 3370, 3307 1692, 1650, 1481, 1418, 1392, 1367, 1336 1305, 1271 1245, 1169.

Nuclear magnetic resonance spectrum (400 MHz, CD3OD) ^ ppm: 1.40-1.50 (9H, m), 1.74-1.89 (2H m), 3.37-3.69 (10H, m).

MS spectrum m / z: 258 (M + l) ⁺ .

(3) In a stream of nitrogen, a solution of the compound (1.00 g) obtained in Reference Example 5— (2) (1.00 g) in tetrahydrofuran (20 ml) was added to a solution of 1- [N ¹ , N ² —bis (41-2 Trobenzyloxycarbonyl)] amidino 1-pyrazole (2.19 g) was added, and the mixture was stirred at room temperature for 5.5 hours. The powder precipitated from the reaction mixture was collected by filtration, washed with tetrahydrofuran, and then subjected to silica gel column chromatography (dichloromethane: methanol = 100: 3) to obtain powdery 4- [2— [2 3 —Bis (412-to-mouth benzyloxycarbonyl) guanidinodiacetyl] -111 (t-butyloxycarbonyl) homopiperazine (2.80 g) was obtained.

Infrared absorption spectrum (KBr) cm- ¹ : 3306, 1740, 1693, 1647, 1627, 1553, 1347, 1286, 1244 1212, 1163.

Nuclear magnetic resonance spectrum _{(400 MHz, CD 3 0D +} DMS0-d 6) δ ppm: 1.35-1.49 (9H m), 1.73-1.95 (2H, m), 3.33-3.68 (8H m), 4.18-4.33 ( 2H m), 5.18-5.30 (2H m), 5.39 (2H, s), 7.63 (2H d J = 8.6 Hz), 7.68 (2H d J = 8.6 Hz), 8.18-8.30 (4H, m).

 MS spectrum m / z: 658 (M + l) +.

 (4) 4N hydrogen chloride / ethyl acetate (14.3m) was added to a solution of the compound (2.50g) obtained in Reference Example 5- (3) in dichloromethane (25ml) in a nitrogen stream under ice-cooling. l) was added and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was suspended in methanol, triturated with ethyl acetate, and washed, to give a colorless powder 1- [2— [2,

3-bis (412-trobenzoyloxycarbonyl) guanidino] acetyl] homopiperazine 9/4 hydrochloride (1.74 g) was obtained.

Infrared absorption spectrum (KBr) cm: 1759, 1743, 1656, 1625, 1606, 1591, 1522, 1494, 1459, 1428, 1398, 1377, 1349.

Nuclear magnetic resonance spectrum _{(400 MHz, D 2 0 +} D S0-d 6) d ppm: 2.12-2.23 (2H, m), 3.42-3.90 (8H, m), 4.28-4.38 (2H, m), 5.25 (2H, s), 5.38 (2H, s), 7.56-7.71 (2H, m), 8.18-8.33 (4H, m).

MS spectrum m / z: 558 (M + l) ⁺ .

 (5) (2 S, 4 S) -4- (4-Methoxybenzylthio) 111- (4-nittobenzoyloxycarbonyl) pyrrolidine-1-2-ruthenic acid (375 mg) and N Pivaloyl chloride (0.1 ml) was added dropwise to a solution of, N-diisopropylpyramine (0.15 ml) in N, N-dimethylformamide (5 ml) under ice-cooling. After stirring at 30 ° C for 30 minutes, the N, N-diisopropylpyramine (0.75 ml) and the compound (529 mg) obtained in Reference Example 5 (4) N-dimethylformamide

(5 ml) solution was added dropwise, and the mixture was stirred at 0 ° C. for 3 hours, and then treated in the same manner as in Reference Example 3- (5) to obtain an amorphous title compound (869 mg).

Infrared absorption spectrum (KBr) cm- ¹ : 3306, 1739, 1710, 1647, 1627, 1609, 1552, 1521, 1429, 1406, 1346, 1286, 1246, 1204.

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, DMS0-d 6} ) 3 ppm: 1.38-1.85 (3H, m), 2.54-2.75 (1H, m), 2.94-4.32 ( weeks, m), 4.48-4.82 ( 1H, m), 4.92-5.43 (6H, m), 6.82-6.92 (2H, m), 7.18-7.30 (2H, m), 7.37-7.75 (6H, m), 8.09-8.31 (6H, m). MS spectrum m / z: 986 (M + l) +. Reference example 6

 (2 S, 4 S) 14-Acetylthio-1-1-methyl-2- [4- [2- [3-((412-trobenzylyloxycarbonyl) guanidino] acetyl] Homopyrazine-1-ylcarbonyl] pyrrolidine

 (1) In a nitrogen stream, the compound (500 mg) obtained in Reference Example 5- (2), N- (412-trobenzoyloxycarbonyl) -S-methylisothiourea (628 mg) and A mixture of ethanol (0.1 ml) was stirred at 80 ° C for 2 hours. Ethyl acetate (25 ml) and 1N hydrochloric acid (25 ml) were added to the reaction mixture, and the precipitated powder was collected by filtration, washed with water-monoethyl acetate, and dried in powder form. (412-benzyloxycarbonyl) guanidino] acetyl] 1-1 (t-butyloxycarbonyl) homopiperazine 5/3 hydrochloride (460 mg) was obtained.

Infrared absorption vector (KBr) cm- ¹ : 1750, 1689, 1655, 1615, 1588, 1525, 1482, 1424, 1390, 1367, 1347, 1301, 1239, 1166.

Nuclear magnetic resonance spectrum _{(400 MHz, CD 3 0D)} δ ppm: 1.35-1.52 (9H, m), 1.74-1.94 (2H, m), 3.37-3.93 (8H, m), 4.22-4.41 (2H, m ), 5.43 (2H, s), 7.68 (2H, d, J = 8.7 Hz), 8.27 (2H, d, J = 8.7 Hz).

 MS spectrum m / z: 479 (M + l) +.

 (2) 4N hydrogen chloride / ethyl acetate (3.3 ml) was added to a solution of the compound (46 mg) obtained in Reference Example 6- (1) in acetonitrile (5 ml) in a nitrogen stream under ice-cooling. Was added and stirred at room temperature for 1 hour. Ether was added to the reaction mixture, and the precipitated powder was collected by filtration, washed with ether, dried under reduced pressure, and dried as a colorless powder of 111- [2- (3- (412-trovenzyroxycarbonyl) guanidino] acetyl. Homopirazine dihydrochloride (405 mg) was obtained.

Infrared absorption scan Bae-vector ^{(KBr) V '1: 1747} , 1685, 1664, 1607, 1583, 1520, 1482, 1466, 1426, 1380, 1349, 1298, 1243.

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, D 2 0)} Sppm: 2.06-2.37 (2H, m), 3.32-3.94 (8H, m), 4.40 (2H, s), 5.42 (2H, s), 7.66 (2H, d, J = 8.7 Hz), 8.26-8.33 (2H, m).

MS spectrum m / z: 379 (M + l) ⁺ .

 (3) of (2 S, 4 S) — 4-acetylthio-1- 1-methylpyrrolidine-12-carbonic acid (17 Omg) and N, N-diisopropylpyruethylamine (0.15 m 1) Bivaloyl chloride (0.1 ml) was added dropwise to the N, N-dimethylformamide (5 ml) solution under ice cooling, and the mixture was stirred at 0 ° C for 30 minutes, and then N, N-diisopropylpyrethyla was added. A solution of N (0.3 ml) and the compound (38 Omg) obtained in Reference Example 6- (2) in N, N-dimethylformamide (5 ml) was cooled on ice and cooled at 0 ° C for 1 min. After stirring for 5 hours, the mixture was treated in the same manner as in Reference Example 41- (2) to obtain the title compound in an amorphous state (293 mg).

Infrared absorption spectrum (KBr) level cm ¹ : 3371, 3309, 1748, 1686, 1649, 1575, 1521, 1481, 1432, 1347, 1290, 1262, 1180, 1109.

Nuclear magnetic resonance scan Bae-vector _{(400 MHz, DMSO-d 6} ) δ ppm: 1.50-1.85 (1H, m), 2.15-4.15 (23H, m), 5.05-5.25 (2H, m), 7.55-7.65 ( 2H, m), 8.23 (2H, d, J = 8.6 Hz). MS spectrum m / z: 564 (M + l) +.

Test Example 1 In vitro activity test

 The antibacterial activity was measured by the agar plate dilution method, and the minimum inhibitory concentration (g / ml) for various pathogens was determined.

Preparation of inoculated bacterial solution: Tributosoyvion medium (manufactured by Eiken Chemical Co., Ltd.) was used. The following three bacterial species A to C were cultured at 37 ° C. for 18 to 20 hours. The culture was adjusted to 10 ⁷ cfu / ml and used as an inoculum.

 Test method: The test compound was adjusted to 2,000 with sterile distilled water, and this was further diluted by a factor of 2 to prepare each dilution solution. 1 ml of each of these dilution solutions was dispensed into a sterile plastic petri dish (manufactured by Terumo), and 9 ml of ordinary agar medium (manufactured by Eiken Chemical Co., Ltd.) was added and mixed to form a plate. One spot was inoculated with the inoculum using a nichrome wire loop. This was cultured at 37 ° C for 18 to 20 hours, and the minimum concentration of the drug that inhibited growth was defined as the minimum inhibitory concentration (g / ml). Table 2 shows the obtained results. In the table, specific bacteria A, B and C are as follows.

A: Staphylococcus aureus 209 P strain

B: E. coli NIHJ strain

C: Pseudomonas aeruginosa 100 1 strain

[Table 2] Minimum growth inhibitory concentration, μg / 1)

 A B C Compound of Example 1 ≤0.01; 0.01 0.05 Compound of Example 2 ≤0.01; 0.01 0.2

Test Example 2 In vivo activity

0.2 ml (D: 1, 0X10 ⁷ CFU / mouse, Ε: 2 · 10 ⁶ CFU / mouse, F: 9.2Χ10 ⁵ CFU / mouse) of each of the following three bacterial species D to F (ddY, SPF, male , 4 weeks old, day This SIX) was inoculated intraperitoneally to induce infection. Gastric mucin (Tokyo Kasei) was added to the bacterial solution of D to a concentration of 5%. Infected mice (7 mice / group) were subcutaneously administered 0.1 ml of the compound to be studied (a solution of a 2-fold serial dilution from a maximum dose of 6.25 mgAg) dissolved in sterile physiological saline 0 and 4 hours later. did. Probi t method from the survival rate of mice 7 days post infection (SAS preclinical package ver. 4. 1, SAS Insuteichi Ute Japan) ED ₅ obtained by. The values are shown in Table 2. In the table, the specific bacteria D to F are as follows.

 D: Staphylococcus aureus Smi th strain

 E: E. coli 704 strains

 F: Pseudomonas aeruginosa strain 10 08

 3]

(ED ₅₀ value img / kg / dose)

Compound specific test

 DEF Example 2 1.00 0.915 0.184 From Test Examples 1 and 2, the compounds of the present invention have excellent antibacterial activity against a wide range of bacteria including Pseudomonas aeruginosa, for which resistance is a problem. Became clear. Test Example 3 Blood concentration half-life and blood concentration

 The compound of Example 2 (10 mg / kg) was administered to mice (1 group, 3 animals, ddY male, manufactured by Japan SLC), rats (1 group, 3 animals, SD male, Charl Sliver), dogs (1 group) 3 animals, male, Nippon Agricultural Industry Co., Ltd.), Egret (3 animals per group, JW male, Funabashi Farm Co., Ltd.), Rinkuisaru (3 animals per group, male) The drug concentration in plasma at each blood sampling time after administration was measured by the bioassay method described below.

Bioassay method: The obtained plasma sample was diluted 2-fold with 500 mM M0PS (4-morpholinepropanesulfonic acid aqueous solution, pH 7) to obtain a measurement sample. As test bacteria Using Escherichia coli NIHJ and Antibiotic Medium 1 (manufactured by Diico) as medium, add about 30 samples for measurement to a paper disk (diameter 6 mm).

—Mounted Perdisk, incubated at 37 ° C for 18 hours, and measured the growth inhibition zone. The concentration of the sample solution was calculated by comparing the stop band of the separately prepared standard solution series with the stop band of the sample solution. The blood collection time points after various administrations are as follows.

Mouse 2, 5, 15, 30 minutes, 1 hour (5 time points)

 Rat 5, 15, 30 minutes, 1, 1.5, 2 hours (6 time points)

 Dog 5, 15, 30 minutes, 1, 1.5, 2, 3, 4 hours (8 time points)

 ゥ Egret 5, 15, 30 minutes, 1, 2, 3, 4 hours (7 time points)

Monkey Pre (for calibration curve), 5, 15, 30 minutes, 1, 2, 3, 4 hours (8 time points)

Table 4 shows the obtained pharmacokinetic parameters. In the table, T _1/2 represents the plasma concentration half-life, and AUC _{: NF} represents the area under the plasma concentration-time curve extrapolated to infinity time.

[¾4] Animal T _1/2 (hr) AUC _INF (^ g-hr / ml) Mouse 0.192 8.15

 Rat 0.265 11.5

 Egret 0.653 29.8

 Dog 1.017 46.4

 Monkey 1.503 53.9 Test Example 3 suggested that the compound of the present invention has a long half-life in blood concentration, so that its pharmacological effect is maintained for a long time, and it has been clarified that the compound can be an excellent drug. Test Example 4 蓄積 Accumulation in the heron renal cortex

Immediate intravenous injection (5 mg / kg) of the compound of Example 2 into perch (3 animals per group, male, manufactured by Funabashi Farm Co., Ltd.) under anesthesia, immediately followed by continuous infusion (0.5 mg / min) The drug concentrations in plasma and renal cortex at 0.5 and 1 hour after the start of administration were measured by HPLC. The result is displayed Write in 5 ₍

[Table 5] Sample time (hr) Drug concentration Plasma 0.5 22.5 (g / ml)

 1.0 Renal cortex 0.5 22.8 (/ g / g- tissue)

 1.0 22.8 CO (g / g-tissue)

(Renal cortex Z plasma) ratio 0.5 1.4 B

 1-

1.0 0.7 Test Example 4 shows that the compound of the present invention does not show renal toxicity because no significant transfer from plasma to renal cortex was observed and no renal accumulation was observed. It became clear that there was. 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 then lyophilized to give a lyophilized preparation for injection. Formulation Example 2 (Capsule)

 50 mg of the compound of Example 1

 Lactose 1 2 8 mg

 Tumorocco starch 70 mg

 Magnesium stearate 2 mg

 2 50 mg

After mixing the powder of the above formulation and passing through a 60 mesh sieve, Put into 0 mg No. 3 gelatin capsules to make a forcepsel.

 Formulation Example 3 (tablet)

 50 mg of the compound of Example 1

 Lactose 1 2 6 mg

 Tumoroko starch 2 3 mg

 Magnesium stearate 1 mg

 2 0 0 mg

 The powder of the above formulation is mixed, wet-granulated using corn starch paste, dried, and then tableted with a tableting machine to give a tablet of 20 Omg per tablet. These tablets can be sugar-coated if necessary.

[Industrial applicability]

 The 1-methylcarbazane compound having the above general formula (I), the pharmaceutically acceptable prodrug thereof, or the pharmaceutically acceptable salt thereof of the present invention has excellent antibacterial activity and has a half-life in blood. It shows excellent pharmacokinetics such as long term and low renal toxicity, so it is useful as a medicine (especially antibacterial agent).

Claims

68 Claims

 1. General formula (I)

 [Where,

R ¹ represents a hydrogen atom or a CI_ ₆ alkyl group,

1 ^ ² and 1? ³ are independently a hydrogen atom or a (^ _ ₆ alkyl group,

R ⁴ represents a hydrogen atom or a ^ alkyl group,

R ⁵ is a group having the formula —C (= NH) R ⁶ [wherein, R ⁶ is a hydrogen atom, CΊ: -6

Or the formula - group (wherein, R ⁷ and R s represents a hydrogen atom or a _ ₆ alkyl group independently.) Represented by NR ⁷ R ⁸ showing the. ]

 n represents 0, 1 or 2,

A represents (: ₈ alkylene group (the alkylene group may be via an oxygen atom or a sulfur atom, and may be substituted with an amino group, a hydroxyl group, or a phenyl group).] Or a pharmacologically acceptable prodrug thereof or a pharmacologically acceptable salt thereof.

2. In Claim 1,

A compound having R ¹ , a hydrogen atom or a methyl group, a pharmacologically acceptable open drug thereof, or a pharmacologically acceptable salt thereof.

3. In Claim 1,

 A compound having a 1 ^ -methyl group, a pharmacologically acceptable prodrug thereof, or a pharmacologically acceptable salt thereof.

4. In any one of claims 1 to 3,

A compound in which 2 and ^1-3 are each independently a hydrogen atom or a methyl group, a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 3, wherein 2 and 1 to ³ 'are both hydrogen atoms, a pharmacologically acceptable prodrug thereof, or a pharmacologically acceptable prodrug thereof. Acceptable salt.

6. In any one of claims 1 to 5,

A compound in which R ⁴ is a hydrogen atom or a methyl group, a pharmacologically acceptable open drug thereof, or a pharmacologically acceptable salt thereof.

7. In any one of claims 1 to 5,

R ⁴ if A compound which is a hydrogen atom, a pharmacologically acceptable prodrug thereof, or a pharmacologically acceptable salt thereof.

8. In any one of claims 1 to 7,

R ⁵ -A compound having a formimidoyl, an acetateimidoyl or an amidino group, a pharmacologically acceptable prodrug thereof, or a pharmacologically acceptable salt thereof.

9. In any one of claims 1 to 7,

A compound which is a 1 ^ ⁵ amidino group, a pharmacologically acceptable prodrug thereof, or a pharmacologically acceptable salt thereof.

10. The compound according to any one of claims 1 to 9, wherein the compound has an n-force of 1 or 2, a pharmacologically acceptable prodrug thereof, or a pharmacologically acceptable salt thereof.

1 1. In any one of claims 1 to 10,

A is methylene (- (¾-), methylmethylene (-CH ((¾) -) , ethylene (-CH ₂ C -), preparative Rimechiren _{(_CH 2 CH 2 CH 2 -} ) or 2-hydroxycarboxylic trimethylene (-C CH (0H) C¾-) group compounds, their pharmacologically acceptable prodrugs, or their pharmacologically acceptable Salt _c

1 2. In any one of claims 1 to 10,

^? A force, methylene (- CH ₂ -), methylmethylene _{(- CH (CH 3) -} ) or ethylene (- CH ₂ CH ₂ -) compound or prodrug thereof or a pharmaceutically thereof pharmacologically acceptable is a group Above acceptable salts.

1 3. In any one of claims 1 to 10,

A compound having a methylene (—CH ₂ —) group, a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof.

1 4. In Claim 1,

R ¹ represents a hydrogen atom or a methyl group,

R ² and R ³ independently represent a hydrogen atom or a methyl group,

R ⁴ represents a hydrogen atom or a methyl group,

R ^{5 represents a} force, formimidyl, acetateimidyl or an amidino group; n represents 1 or 2;

Hachika \ methylene (- CH ₂ -), methylmethylene (-CH (CH ₃₎ -) or ethylene (- CH ₂ CH ₂ -) compound showing a group or a pharmacologically acceptable prodrug thereof or a pharmacologically Acceptable salt.

1 5. In claim 1,

R ^Yuka?, Represents a methyl group,

R ² and R ³ independently represent a hydrogen atom or a methyl group,

Scale ^four?, It represents a hydrogen atom,

R ⁵ represents an amidino group,

n force ^? , 1 or 2

^? A force, methylene (- CH ₂ -) Purodo drag or pharmacologically acceptable salt thereof acceptable compound or a pharmacologically a group.

1 6.

 2- [2- [4- (2-guanidinoacetyl) pyrazine-1-ylcarbonyl] pyrrolidine-4-ylthio] -1-6- [1-hydroxyxethyl] -1-methyl-1 EM-3-Carbonic acid,

 2- [2- [4- [2- (1-Methylguanidino) acetyl] piperazine-1-ylcarbonyl] piperidine-4-ylthio] -6- [1-hydroxyxethyl] -1-methyl-1- Power Lubapen-2-Em-3-Power Rubinic Acid,

 2- [2- [4- (2-guanidino-2-methylacetyl) piperazine-1-ylcarbonyl] piperidine—4-ylthio] -6- [1-hydroxyxethyl] -1-methyl-1 -force Lubapen-2-Em-3-Luvric acid,

 2- [2- [4- [3- (3-guanidinopropanoyl) piperazine-1-ylcarbonyl] pyrrolidinin-4-ylthio] —6- [1-hydroxyxethyl] -1-methyl-1-capryl -2-em- 3-force rubonic acid,

 2-[2- [4- (2-guanidinoacetyl) piperazine-1-ylcarbonyl] -1 -methylpiperidine-4 -ylthio]-6- [ledroxyxethyl] -1-methyl-1-force Lubapen-2-Em-3-Luvric acid,

 2- [2- [4- [2- (1-Methylguanidino) acetyl] piperazine-1-ylcarbonyl] -1-methylpyrrolidine-4-ylthio] -6- [1-hydroxyxethyl] -1-methyl- 1-Power Luba Pen — 2-Em-3-Power Rubonic Acid,

 2- [2- [4- (2-Guanidino-2-methylacetyl) pidazine-1-ylcarbonyl] -1-methylpyrrolidine-4-ylthio] -6- [1-hydroxyxethyl] -1-methyl-1 -Carban-2-em-3-carboxylic acid, and

 2- [2- [4- (3-guanidinopropanoyl) pidazine-1-ylcarbonyl] — 1-methylpyrrolidine—4-ylthio] — 6- [1-hydroxyxethyl] -1- Methyl-1-l-rubapen-2-em-3-carboxylic acid,

Or a pharmacologically acceptable prodrug thereof or a pharmacologically acceptable salt thereof.

17. A compound according to any one of claims 1 to 16 or a pharmacologically acceptable prodrug thereof or a pharmacologically acceptable salt thereof as an active ingredient. Medicine.

18. The compound according to any one of claims 1 to 16 or a pharmacologically acceptable prodrug thereof or a pharmacologically acceptable salt thereof as an active ingredient. Antibacterial agent.

1 9. Bacterial infection containing a compound according to any one of claims 1 to 16 or a pharmacologically acceptable prodrug thereof or a pharmacologically acceptable salt thereof. A composition for treating or preventing a disease.

20. The compound according to any one of claims 1 to 16 for producing a medicament for treating or preventing a bacterial infection, or a pharmacologically acceptable prodrug thereof, or Use of those pharmacologically acceptable salts.

21. Bacterial infection caused by the compound according to any one of claims 1 to 16 or a pharmacologically acceptable prodrug thereof or a pharmacologically acceptable salt thereof. A method of treatment or prevention.