JP2000229969A - 1-methylcarbapenem derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having excellent antibacterial activity, low in toxicity and useful as an antibacterial agent for treating bacterial infectious diseases. SOLUTION: A compound of formula I (n is 2-4; R1 and R2 are each H or a 1-4C alkyl; R3 is H or a 1-4C alkyl and R4 is H, a 1-4C alkyl or the like, or R3 and R4 are each a 2-6C alkylene capable of bonding to each other directly or via one oxygen or the like), for example, (1R,5S,6S)-2-[(2S,4S)-2-[(3S)-3-(2- aminoethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine-4-ylthio]-6-[(1R)-1-hyd roxyethyl]-1- methyl-1-carbapen-2-em-3-carboxylic acid. A compound of formula I is obtained by reacting a compound of formula II (L is a leaving group; R10 is a carboxyl protecting group) with a compound of the formula RpSH (Rp is R which may be protected when R contains OH or the like; R is a substituting group on the S on the 2-position side of a compound of formula I) in an inert solvent in the presence of a base and subsequently removing the blocking group.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a 1-methylcarbapenem compound having excellent antibacterial activity, a pharmaceutically acceptable salt or derivative thereof, and a method for preventing or treating bacterial infectious diseases containing them as an active ingredient. Pharmaceutical compositions, their use for the manufacture of a medicament for the prevention or treatment of bacterial infections, a method for preventing or treating bacterial infections by administering a pharmacologically effective amount thereof to a warm-blooded animal, or a method thereof. It relates to a manufacturing method.

[0002]

2. Description of the Related Art Meropenem (US Pat. No. 5,122,604), which is a 1-methylcarbapenem compound, is used in clinical practice as an antibacterial agent that is stable in vivo and effective against β-lactam resistant bacteria. In recent years, the appearance of a meropenem-resistant strain has been recognized in Pseudomonas aeruginosa and the like. Therefore, development of a carbapenem derivative having a stronger and more balanced antibacterial activity against a wide range of bacteria, including Pseudomonas aeruginosa, which is resistant to meropenem, is desired.

[0003]

As a result of various studies on the 1-methylcarbapenem compound for many years, the inventors have found that the compound (I) of the present invention has a stronger antibacterial activity than the conventional 1-methylcarbapenem derivative. And also exhibited excellent antibacterial activity against Pseudomonas aeruginosa and the like which are resistant to meropenem. Furthermore, the compound (I) of the present invention has low toxicity,
The present inventors have found that the present invention is effective as an antibacterial agent for treating or preventing (particularly treating) bacterial infections, and have completed the present invention.

[0004] Japanese Patent Application Laid-Open No. 5-310740 and WO
97/41123 disclose 1-methylcarbapenem compounds having a structure similar to that of the present invention (compounds in which n is 0 or 1 in the general formula (I)). Shows excellent antibacterial activity as compared with the compound.

[0005]

The present invention provides a compound represented by the general formula (I):

[0006]

Embedded image And a pharmacologically acceptable salt or derivative thereof.

In the formula, n represents 2, 3 or 4, R ¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
R ² is the same or different among n repeating units,
A hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
R ³ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R ⁴ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms having a substituent The group includes a hydroxyl group, a halogen atom, a carbamoyl group, a carbamoyl group substituted with an alkyl group having 1 to 4 carbon atoms, a carbamoyloxy group, a carbamoyloxy group substituted with an alkyl group having 1 to 4 carbon atoms, to 4 alkoxy group, an amino group substituted with an amino group or having 1 to 4 alkyl groups atoms), a cycloalkyl group, or the formula -C (= NH) group represented by R ⁵ (wherein , R ⁵ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an amino group), or R ³ and R ⁴ may be mutually bonded groups, ,
Carbon number 2 which may be via a nitrogen atom or a sulfur atom
To 6 alkylene groups (the nitrogen atom has 1 to 4 carbon atoms)
May be substituted with one or more alkyl groups).

In the above, R ¹ , R ² , R ³ , R ⁴ and R
"C1-C4 alkyl group" in the definition of ⁵
Is a linear or branched alkyl group having 1 to 4 carbon atoms, such as a methyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl group. It is a methyl or ethyl group, more preferably a methyl group.

A “halogen atom” in the definition of R ⁴ is
For example, a fluorine, chlorine or bromine atom can be mentioned, and a fluorine atom is preferable.

The "carbamoyl group substituted by an alkyl group having 1 to 4 carbon atoms" in the definition of R ⁴ includes, for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and diethylcarbamoyl, and preferably methylcarbamoyl. A carbamoyl or dimethylcarbamoyl group;

The "carbamoyloxy group substituted by an alkyl group having 1 to 4 carbon atoms" in the definition of R ⁴ includes, for example, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy and diethylcarbamoyloxy groups. And preferably a methylcarbamoyloxy or dimethylcarbamoyloxy group.

In the definition of R ⁴ , “formula —C (＝ NH) R ⁵
Examples of the “group represented by” include formimidoyl, acetimidoyl, propioimidoyl and amidino groups, and are preferably formimidoyl, acetimidoyl or amidino groups.

The "amino group substituted by an alkyl group having 1 to 4 carbon atoms" in the definition of R ⁴ includes, for example, methylamino, ethylamino, dimethylamino and diethylamino groups. Or a dimethylamino group.

In the definition of R ⁴ , “formula —C (＝ NH) R ⁵
Examples of the `` amino group substituted with a group represented by Amino or guanidino group.

As the "alkoxy group having 1 to 4 carbon atoms" in the definition of R ⁴ , for example, methoxy, ethoxy,
Propoxy and butoxy groups can be mentioned, preferably a methoxy group.

The "substituent" in the "alkyl group having 1 to 4 carbon atoms having a substituent" in the definition of R ⁴ is preferably a hydroxyl group, a fluorine atom, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, carbamoyloxy, methoxy, , Amino, methylamino or dimethylamino groups.

The "alkyl group having 1 to 4 carbon atoms having a substituent" in the definition of R ⁴ includes, for example, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, fluoro Methyl, difluoromethyl, trifluoromethyl, 2-
Fluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-
Chloroethyl, carbamoylmethyl, N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl,
2-carbamoylethyl, 2- (N-methylcarbamoyl) ethyl, 2- (N, N-dimethylcarbamoyl) ethyl, 2-carbamoyloxyethyl, 2- (N, N-
Dimethylcarbamoyloxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-aminoethyl, 3-aminopropyl, 2-aminopropyl, 2- (methylamino) ethyl, 3- (methylamino) propyl, 2- ( Examples thereof include dimethylamino) ethyl and 3- (dimethylamino) propyl groups, preferably 2-hydroxyethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, carbamoylmethyl, and 2-carbamoylethyl. , N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, 2-methoxyethyl, 2-carbamoyloxyethyl, 2-aminoethyl, 2- (methylamino) ethyl or 2- (dimethylamino) ethyl, More preferably, 2-hydroxyethyl, carbamoylmethyl, 2-a Aminoethyl or 2- a (methylamino) ethyl group.

"Cycloalkyl group" in the definition of R ⁴
Is a cycloalkyl group having 3 to 6 carbon atoms, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, preferably a cyclopropyl or cyclobutyl group, more preferably a cyclopropyl group It is.

"Alkylene group" of "alkylene group having 2 to 6 carbon atoms which may be through one oxygen atom, nitrogen atom or sulfur atom" in the definition of the group wherein R ³ and R ⁴ are bonded to each other Is a linear or branched alkylene group having 2 to 6 carbon atoms, for example, ethylene, propylene,
Examples include trimethylene, 1-methyltrimethylene, 2-methyltrimethylene, tetramethylene, 1-methyltetramethylene, 2-methyltetramethylene, pentamethylene groups and the like.

The alkylene group may be linked via one oxygen atom, nitrogen atom or sulfur atom. Examples of such an alkylene group include ethyleneoxyethyl (CH ₂ C
H ₂ OCH ₂ CH ₂ ), ethyleneaminoethyl (CH ₂ CH ₂ NHCH ₂ C
H ₂ ), ethyleneanopropyl (CH ₂ CH ₂ NHCH ₂ CH ₂ CH ₂ ),
And ethylenethioethyl (CH ₂ CH ₂ SCH ₂ CH ₂ ) group.

The nitrogen atom which may be interposed in the alkylene group may be substituted by an alkyl group having 1 to 4 carbon atoms, and the alkyl group is preferably a methyl group.

The above-mentioned "alkylene group having 2 to 6 carbon atoms which may be linked via one oxygen atom, nitrogen atom or sulfur atom" includes, for example, ethylene, trimethylene, tetramethylene, pentamethylene, ethyleneoxyethyl, ethylene Thioethyl, ethyleneaminoethyl, ethyleneaminopropyl, ethylene (methylamino) ethyl, ethylene (ethylamino) ethyl, ethylene (methylamino) propyl, and the like, preferably trimethylene, tetramethylene, pentamethylene, and the like. Ethyleneoxyethyl, ethylenethioethyl, ethyleneaminoethyl,
An ethylene (methylamino) ethyl or ethyleneaminopropyl group, more preferably a tetramethylene group.

N is preferably 2 or 3, and more preferably 2.

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

R ² 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 ³ 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 ⁴ is preferably a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms having a substituent A (the substituent A is a hydroxyl group, a fluorine atom, carbamoyl, methylcarbamoyl, shown dimethylcarbamoyl, carbamoyloxy, methoxy, amino, methylamino or dimethylamino group), a cycloalkyl group or the formula -C (= NH) group (wherein represented by R ^5, R ⁵
Represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an amino group).

R ⁴ is more preferably a hydrogen atom and a carbon number of 1
To 4 alkyl groups or a group represented by the formula —C (ＮＨNH) R ⁵ (wherein, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an amino group).

R ⁴ is more preferably a compound of the formula -C (= N
H) a group represented by R ⁵ (wherein R ⁵ is a hydrogen atom and has 1 carbon atom)
To 4 alkyl groups or amino groups).

R ⁴ is particularly preferably a formimidoyl, acetimidoyl or amidino group.

R ⁴ is most preferably an amidino group.

The compound (I) of the present invention can be converted into a "pharmaceutically acceptable salt or derivative" if necessary.

"Pharmacologically acceptable salts" include, for example, hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate,
Minerates such as nitrates; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate; oxalate, tartrate, citrate, maleate , Succinate, acetate,
Acid addition salts such as organic acid salts such as benzoate, mandelate, ascorbate, lactate, gluconate, malate, glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, asparagine Amino acid salts such as acid salts, or inorganic salts such as lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts or salts with organic bases such as ammonium salts, triethylamine salts, diisopropylamine salts, and cyclohexylamine salts. And hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-
Toluenesulfonate, oxalate, tartrate, citrate, acetate, lactate, glutamate, aspartate, sodium, potassium, ammonium or triethylamine salts, more preferably the hydrochloride, Sulfate, methanesulfonate, citrate, acetate or lactate, particularly preferably hydrochloride or sulfate.

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

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

Examples of the above “C _1-6 acyloxy C _1-4 alkyl group” include, for example, pivaloyloxymethyl, isobutyryloxymethyl, 1- (isobutyryloxy) ethyl, acetoxymethyl, (Acetoxy) ethyl,
1-methylcyclohexylcarbonyloxymethyl, 1
-Methylcyclopentylcarbonyloxymethyl.

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

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

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

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

More preferred protecting groups among the above are 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, acetoxymethyl, pivaloyloxymethyl, 1-
Methylcyclohexylcarbonyloxymethyl, 1-
(Isopropoxycarbonyloxy) ethyl or 1-
(Cyclohexyloxycarbonyloxy) ethyl groups, which are preferably used as protecting groups for carboxy groups to form ester derivatives.

The compound (I) of the present invention represents one or a mixture of isomers. Preferred among these isomers are the R-configuration at the 1-position of the carbapenem skeleton, the 5-position and the 6-position.
The position is a (5S, 6S) configuration which is the same configuration as that of thienamycin, and examples thereof include compounds in which the configuration of the α-carbon having a hydroxyl group at the 6-position substituent is the R configuration.

The 2- and 4-positions of the 2-substituted pyrrolidin-4-yl group preferably have a (2S, 4S) configuration. In addition, the 3-position configuration of the 3-substituted pyrrolidin-1-yl group is not particularly limited.

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

(1) Compounds wherein n is 2 or 3.

(2) Compounds wherein n is 2.

(3) Compounds wherein R ¹ is a hydrogen atom, a methyl group or an ethyl group.

(4) The compound wherein R ¹ is a hydrogen atom or a methyl group.

(5) The compound wherein R ² is a hydrogen atom, a methyl group or an ethyl group.

(6) The compound wherein R ² is a hydrogen atom or a methyl group.

(7) The compound wherein R ² is a hydrogen atom.

(8) The compound wherein R ³ is a hydrogen atom, a methyl group or an ethyl group.

(9) The compound wherein R ³ is a hydrogen atom or a methyl group.

(10) The compound wherein R ³ is a hydrogen atom.

(11) R ⁴ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms having a substituent (the substituent is a hydroxyl group, a fluorine atom, carbamoyl, methylcarbamoyl) , Dimethylcarbamoyl,
A carbamoyloxy, methoxy, amino, methylamino or dimethylamino group), a cycloalkyl group or a group represented by the formula —C (＝ NH) R ⁵ (wherein R ⁵ is a hydrogen atom, and has 1 to 4 carbon atoms); Which represents one or more alkyl groups or amino groups).

(12) R ⁴ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a group represented by the formula —C (＝ NH) R ⁵ (wherein R ⁵ is a hydrogen atom, Or 4 to 4 alkyl groups or amino groups).

[0057] (13) R ⁴ is a group (wherein, R ⁵ represents a hydrogen atom, 1 to 4 carbon alkyl group or an amino group having a carbon number) of the formula -C (= NH) R ⁵ in Certain compounds.

(14) R ⁴ is a formimidyl group,
A compound which is an acetimidoyl group or an amidino group.

(15) The compound wherein R ⁴ is an amidino group.

Compounds obtained by arbitrarily combining the substituents and the like in the compounds of the above (1) to (15) are more preferable. Examples of such compounds include the following compounds.

(16) n is 2 or 3, and R ¹
Is a hydrogen atom or a methyl group, R ² is a hydrogen atom or a methyl group, R ³ is a hydrogen atom or a methyl group, R ⁴ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms. or the formula -C (= NH) group (wherein, R ⁵ is a hydrogen atom, a 1 to 4 carbon alkyl group or an amino group carbon atoms) represented by R ⁵ compound is.

(17) n is 2 or 3, and R ¹
Is a hydrogen atom or a methyl group, R ² is a hydrogen atom, R ³ is a hydrogen atom, and R ⁴ is a group represented by the formula —C (= N
H) a group represented by R ⁵ (wherein R ⁵ is a hydrogen atom and has 1 carbon atom)
Or 4 to 4 alkyl groups or amino groups).

(18) n is 2, R ¹ is a hydrogen atom or a methyl group, R ² is a hydrogen atom,
R ³ is a hydrogen atom, R ⁴ is a formimidyl group,
A compound which is an acetimidoyl group or an amidino group.

(19) n is 2, R ¹ is a hydrogen atom or a methyl group, R ² is a hydrogen atom,
A compound in which R ³ is a hydrogen atom and R ⁴ is an amidino group.

Compounds suitable as compounds having the general formula (I) are specifically exemplified in Tables 1 and 2. [Table 1]

[0066]

Embedded image ――――――――――――――――――――――――――――――――――― No R ¹ R ² n R ³ R ⁴ ――――― ―――――――――――――――――――――――――――――― 1-1 HH 2 HH 1-2 HH 2 H CH ₃ 1-3 HH 2 H CH ₂ CH ₃ 1-4 HH 2 H CH ₂ CH ₂ CH ₃ 1-5 HH 2 H CH ₂ CH ₂ F 1-6 HH 2 H CH ₂ CF ₃ 1-7 HH 2 H CH ₂ CH ₂ OH 1- 8 HH 2 H CH ₂ CH ₂ OCH ₃ 1-9 HH 2 H CH ₂ CONH ₂ 1-10 HH 2 H CH ₂ CONHCH ₃ 1-11 HH 2 H CH ₂ CON (CH ₃ ) ₂ 1-12 HH 2 H CH ₂ CH ₂ CONH ₂ 1-13 HH 2 H CH ₂ CH ₂ CONHCH ₃ 1-14 HH 2 H CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-15 HH 2 H CH ₂ CH ₂ OCONH ₂ 1-16 HH 2 H CH ₂ CH ₂ OCONHCH ₃ 1-17 HH 2 H CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-18 HH 2 H CH ₂ CH ₂ NH ₂ 1-19 HH 2 H CH ₂ CH ₂ NHCH ₃ 1- 20 HH 2 H CH ₂ CH ₂ N (CH ₃ ) ₂ 1-21 HH 2 H c-Pro 1-22 HH 2 H c-But 1-23 HH 2 H c-Pen 1-24 HH 2 H c-Hex 1-25 HH 2 HC (= NH) H 1-26 HH 2 HC (= NH) CH ₃ 1-27 HH 2 HC (= NH) NH ₂ 1-28 HH 2 CH ₃ CH ₃ 1-29 HH 2 CH ₃ CH ₂ CH ₃ 1-30 HH 2 CH ₃ CH ₂ CH ₂ CH ₃ 1-31 HH 2 CH ₃ CH ₂ CH ₂ F 1-32 HH 2 CH ₃ CH ₂ CF ₃ 1-33 HH 2 CH ₃ CH ₂ CH ₂ OH 1-34 HH 2 CH ₃ CH ₂ CH ₂ OCH ₃ 1-35 HH 2 CH ₃ CH ₂ CONH ₂ 1-36 HH 2 CH ₃ CH ₂ CONHCH ₃ 1-37 HH 2 CH ₃ CH ₂ CON (CH ₃ ) ₂ 1-38 HH 2 CH ₃ CH ₂ CH ₂ CONH ₂ 1-39 HH 2 CH ₃ CH ₂ CH ₂ CONHCH ₃ 1 -40 HH 2 CH ₃ CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-41 HH 2 CH ₃ CH ₂ CH ₂ OCONH ₂ 1-42 HH 2 CH ₃ CH ₂ CH ₂ OCONHCH ₃ 1-43 HH 2 CH ₃ CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-44 HH 2 CH ₃ CH ₂ CH ₂ NH ₂ 1-45 HH 2 CH ₃ CH ₂ CH ₂ NHCH ₃ 1-46 HH 2 CH ₃ CH ₂ CH ₂ N (CH ₃ ) ₂ 1-47 HH 2 CH ₃ c-Pro 1-48 HH 2 CH ₃ c-But 1-49 HH 2 CH ₃ c-Pen 1-50 HH 2 CH ₃ c-Hex 1-51 HH 2 CH ₃ C (= NH) H 1-52 HH 2 CH ₃ C (= NH) CH ₃ 1-53 HH 2 CH ₃ C (= NH) NH ₂ 1-54 HH 2 CH ₂ CH ₃ CH ₂ CH ₃ 1-55 HH 2 CH ₂ CH ₃ CH ₂ CH ₂ CH ₃ 1-56 HH 2 CH ₂ CH ₃ CH ₂ CH ₂ F 1-57 HH 2 CH ₂ CH ₃ CH ₂ CF ₃ 1-58 HH 2 CH ₂ CH ₃ CH ₂ CH ₂ OH 1-59 HH 2 CH ₂ CH ₃ CH ₂ CH ₂ OCH ₃ 1-60 HH 2 CH ₂ CH ₃ CH ₂ CONH ₂ 1-61 HH 2 CH ₂ CH ₃ CH ₂ CONHCH ₃ 1-62 HH 2 CH ₂ CH ₃ CH ₂ CON (CH ₃ ) ₂ 1-63 HH 2 CH ₂ CH ₃ CH ₂ CH ₂ CONH ₂ 1-64 HH 2 CH ₂ CH ₃ C H ₂ CH ₂ CONHCH ₃ 1-65 HH 2 CH ₂ CH ₃ CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-66 HH 2 CH ₂ CH ₃ CH ₂ CH ₂ OCONH ₂ 1-67 HH 2 CH ₂ CH ₃ CH ₂ CH ₂ OCONHCH ₃ 1-68 HH 2 CH ₂ CH ₃ CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-69 HH 2 CH ₂ CH ₃ CH ₂ CH ₂ NH ₂ 1-70 HH 2 CH ₂ CH ₃ CH ₂ CH ₂ NHCH ₃ 1-71 HH 2 CH ₂ CH ₃ CH ₂ CH ₂ N (CH ₃ ) ₂ 1-72 HH 2 CH ₂ CH ₃ c-Pro 1-73 HH 2 CH ₂ CH ₃ c-But 1-74 HH 2 CH ₂ CH ₃ c-Pen 1-75 HH 2 CH ₂ CH ₃ c-Hex 1-76 HH 2 CH ₂ CH ₃ C (= NH) H 1-77 HH 2 CH ₂ CH ₃ C (= NH) CH ₃ 1-78 HH 2 CH ₂ CH ₃ C (= NH) NH ₂ 1-79 HH 2 CH ₂ CH ₂ 1-80 HH 2 CH ₂ CH ₂ CH ₂ 1-81 HH 2 CH ₂ CH ₂ CH ₂ CH ₂ 1-82 HH 2 CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ 1-83 HH 2 CH ₂ CH ₂ OCH ₂ CH ₂ 1-84 HH 2 CH ₂ CH ₂ SCH ₂ CH ₂ 1-85 HH 2 CH ₂ CH ₂ NHCH ₂ CH ₂ 1-86 HH 2 CH ₂ CH ₂ N (CH ₃ ) CH ₂ CH ₂ 1-87 HH 3 HH 1-88 HH 3 H CH ₃ 1-89 HH 3 H CH ₂ CH ₃ 1-90 HH 3 H CH ₂ CH ₂ CH ₃ 1-91 HH 3 H CH ₂ CH ₂ F 1-92 HH 3 H CH ₂ CF ₃ 1-93 HH 3 H CH ₂ CH ₂ OH 1-94 HH 3 H CH ₂ CH ₂ OCH ₃ 1-95 HH 3 H CH ₂ CONH ₂ 1-96 HH 3 H CH ₂ CONHCH ₃ 1-97 HH 3 H CH ₂ CON (CH ₃ ) ₂ 1-98 HH 3 H CH ₂ CH ₂ CONH ₂ 1-99 HH 3 H CH ₂ CH ₂ CONHCH ₃ 1-100 HH 3 H CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-101 HH 3 H CH ₂ CH ₂ OCONH ₂ 1-102 HH 3 H CH ₂ CH ₂ OCONHCH ₃ 1-103 HH 3 H CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-104 HH 3 H CH ₂ CH ₂ NH ₂ 1-105 HH 3 H CH ₂ CH ₂ NHCH ₃ 1 -106 HH 3 H CH ₂ CH ₂ N (CH ₃ ) ₂ 1-107 HH 3 H c-Pro 1-108 HH 3 H c-But 1-109 HH 3 H c-Pen 1-110 HH 3 H c- Hex 1-111 HH 3 HC (= NH) H 1-112 HH 3 HC (= NH) CH ₃ 1-113 HH 3 HC (= NH) NH ₂ 1-114 HH 3 CH ₃ CH ₃ 1-115 HH 3 CH ₃ CH ₂ CH ₃ 1-116 HH 3 CH ₃ CH ₂ CH ₂ CH ₃ 1-117 HH 3 CH ₃ CH ₂ CH ₂ F 1-118 HH 3 CH ₃ CH ₂ CF ₃ 1-119 HH 3 CH ₃ CH ₂ CH ₂ OH 1-120 HH 3 CH ₃ CH ₂ CH ₂ OCH ₃ 1-121 HH 3 CH ₃ CH ₂ CONH ₂ 1-122 HH 3 CH ₃ CH ₂ CONHCH ₃ 1-123 HH 3 CH ₃ CH ₂ CON ( CH ₃ ) ₂ 1-124 HH 3 CH ₃ CH ₂ CH ₂ CONH ₂ 1-125 HH 3 CH ₃ CH ₂ CH ₂ CONHCH ₃ 1-126 HH 3 CH ₃ CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-127 HH 3 CH ₃ CH ₂ CH ₂ OCONH ₂ 1-128 HH 3 CH ₃ CH ₂ CH ₂ OCONHCH ₃ 1-129 HH 3 CH ₃ CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-130 HH 3 CH ₃ CH ₂ CH ₂ NH ₂ 1-131 HH 3 CH ₃ CH ₂ CH ₂ NHCH ₃ 1-132 HH 3 CH ₃ CH ₂ CH ₂ N (CH ₃ ) ₂ 1-133 HH 3 CH ₃ c-Pro 1-134 HH 3 CH ₃ c-But 1-135 HH 3 CH ₃ c-Pen 1-136 HH 3 CH ₃ c- Hex 1-137 HH 3 CH ₃ C (= NH) H 1-138 HH 3 CH ₃ C (= NH) CH ₃ 1-139 HH 3 CH ₃ C (= NH) NH ₂ 1-140 HH 3 CH ₂ CH ₃ CH ₂ CH ₃ 1-141 HH 3 CH ₂ CH ₃ CH ₂ CH ₂ CH ₃ 1-142 HH 3 CH ₂ CH ₃ CH ₂ CH ₂ F 1-143 HH 3 CH ₂ CH ₃ CH ₂ CF ₃ 1-144 HH 3 CH ₂ CH ₃ CH ₂ CH ₂ OH 1-145 HH 3 CH ₂ CH ₃ CH ₂ CH ₂ OCH ₃ 1-146 HH 3 CH ₂ CH ₃ CH ₂ CONH ₂ 1-147 HH 3 CH ₂ CH ₃ CH ₂ CONHCH ₃ 1-148 HH 3 CH ₂ CH ₃ CH ₂ CON (CH ₃ ) ₂ 1-149 HH 3 CH ₂ CH ₃ CH ₂ CH ₂ CONH ₂ 1-150 HH 3 CH ₂ CH ₃ CH ₂ CH ₂ CONHCH ₃ 1 -151 HH 3 CH ₂ CH ₃ CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-152 HH 3 CH ₂ CH ₃ CH ₂ CH ₂ OCONH ₂ 1-153 HH 3 CH ₂ CH ₃ CH ₂ CH ₂ OCONHCH ₃ 1- 154 HH 3 CH ₂ CH ₃ CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-155 HH 3 CH ₂ CH ₃ CH ₂ CH ₂ NH ₂ 1-156 HH 3 CH ₂ CH ₃ CH ₂ CH ₂ NHCH ₃ 1-157 HH 3 CH ₂ CH ₃ CH ₂ CH ₂ N (CH ₃ ) ₂ 1-158 HH 3 CH ₂ CH ₃ c-Pro 1-159 HH 3 CH ₂ CH ₃ c-But 1-160 HH 3 CH ₂ CH ₃ c -Pen 1-161 HH 3 CH ₂ CH ₃ c-Hex 1-162 HH 3 CH ₂ CH ₃ C (= NH) H 1 -163 HH 3 CH ₂ CH ₃ C (= NH) CH ₃ 1-164 HH 3 CH ₂ CH ₃ C (= NH) NH ₂ 1-165 HH 3 CH ₂ CH ₂ 1-166 HH 3 CH ₂ CH ₂ CH ₂ 1-167 HH 3 CH ₂ CH ₂ CH ₂ CH ₂ 1-168 HH 3 CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ 1-169 HH 3 CH ₂ CH ₂ OCH ₂ CH ₂ 1-170 HH 3 CH ₂ CH ₂ SCH ₂ CH ₂ 1-171 HH 3 CH ₂ CH ₂ NHCH ₂ CH ₂ 1-172 HH 3 CH ₂ CH ₂ N (CH ₃ ) CH ₂ CH ₂ 1-173 HH 4 HH 1-174 HH 4 H CH ₃ 1-175 HH 4 H CH ₂ CH ₃ 1-176 HH 4 H CH ₂ CH ₂ CH ₃ 1-177 HH 4 H CH ₂ CH ₂ F 1-178 HH 4 H CH ₂ CF ₃ 1-179 HH 4 H CH ₂ CH ₂ OH 1-180 HH 4 H CH ₂ CH ₂ OCH ₃ 1-181 HH 4 H CH ₂ CONH ₂ 1-182 HH 4 H CH ₂ CONHCH ₃ 1-183 HH 4 H CH ₂ CON (CH ₃ ) ₂ 1-184 HH 4 H CH ₂ CH ₂ CONH ₂ 1-185 HH 4 H CH ₂ CH ₂ CONHCH ₃ 1-186 HH 4 H CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-187 HH 4 H CH ₂ CH ₂ OCONH ₂ 1-188 HH 4 H CH ₂ CH ₂ OCONHCH ₃ 1-189 HH 4 H CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-190 HH 4 H CH ₂ CH ₂ NH ₂ 1-191 HH 4 H CH ₂ CH ₂ NHCH ₃ 1-192 HH 4 H CH ₂ CH ₂ N (CH ₃ ) ₂ 1-193 HH 4 H c-Pro 1-194 HH 4 H c-But 1-195 HH 4 H c-Pen 1-196 HH 4 H c-Hex 1-197 HH 4 HC (= NH) H 1-198 HH 4 HC (= NH) CH ₃ 1-199 HH 4 HC (= NH) NH ₂ 1-200 HH 4 CH ₃ CH ₃ 1-201 HH 4 CH ₃ CH ₂ CH ₃ 1-202 HH 4 CH ₃ CH ₂ CH ₂ CH ₃ 1-203 HH 4 CH ₃ CH ₂ CH ₂ F 1-204 HH 4 CH ₃ CH ₂ CF ₃ 1-205 HH 4 CH ₃ CH ₂ CH ₂ OH 1-206 HH 4 CH ₃ CH ₂ CH ₂ OCH ₃ 1-207 HH 4 CH ₃ CH ₂ CONH ₂ 1-208 HH 4 CH ₃ CH ₂ CONHCH ₃ 1-209 HH 4 CH ₃ CH ₂ CON (CH ₃ ) ₂ 1-210 HH 4 CH ₃ CH ₂ CH ₂ CONH ₂ 1-211 HH 4 CH ₃ CH ₂ CH ₂ CONHCH ₃ 1-212 HH 4 CH ₃ CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-213 HH 4 CH ₃ CH ₂ CH ₂ OCONH ₂ 1-214 HH 4 CH ₃ CH ₂ CH ₂ OCONHCH ₃ 1-215 HH 4 CH ₃ CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-216 HH 4 CH ₃ CH ₂ CH ₂ NH ₂ 1-217 HH 4 CH ₃ CH ₂ CH ₂ NHCH ₃ 1-218 HH 4 CH ₃ CH ₂ CH ₂ N (CH ₃ ) ₂ 1-219 HH 4 CH ₃ c-Pro 1-220 HH 4 CH ₃ c-But 1-221 HH 4 CH ₃ c-Pen 1-222 HH 4 CH ₃ c-Hex 1-223 HH 4 CH ₃ C (= NH) H 1-224 HH 4 CH ₃ C (= NH) CH ₃ 1-225 HH 4 CH ₃ C (= NH) NH ₂ 1-226 HH 4 CH ₂ CH ₃ CH ₂ CH ₃ 1 -227 HH 4 CH ₂ CH ₃ CH ₂ CH ₂ CH ₃ 1-228 HH 4 CH ₂ CH ₃ CH ₂ CH ₂ F 1-229 HH 4 CH ₂ CH ₃ CH ₂ CF ₃ 1-230 HH 4 CH ₂ CH ₃ CH ₂ CH ₂ OH 1-231 HH 4 CH ₂ CH ₃ CH ₂ CH ₂ OCH ₃ 1-232 HH 4 CH ₂ CH ₃ CH ₂ CONH ₂ 1-233 HH 4 CH ₂ CH ₃ CH ₂ CONHCH ₃ 1-234 HH 4 CH ₂ CH ₃ CH ₂ CON (CH ₃ ) ₂ 1-235 HH 4 CH ₂ CH ₃ CH ₂ CH ₂ CONH ₂ 1-236 HH 4 CH ₂ CH ₃ CH ₂ CH ₂ CONHCH ₃ 1-237 HH 4 CH ₂ CH ₃ CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-238 HH 4 CH ₂ CH ₃ CH ₂ CH ₂ OCONH ₂ 1-239 HH 4 CH ₂ CH ₃ CH ₂ CH ₂ OCONHCH ₃ 1-240 HH 4 CH ₂ CH ₃ CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-241 HH 4 CH ₂ CH ₃ CH ₂ CH ₂ NH ₂ 1-242 HH 4 CH ₂ CH ₃ CH ₂ CH ₂ NHCH ₃ 1-243 HH 4 CH ₂ CH ₃ CH ₂ CH ₂ N (CH ₃ ) ₂ 1-244 HH 4 CH ₂ CH ₃ c-Pro 1-245 HH 4 CH ₂ CH ₃ c-But 1-246 HH 4 CH ₂ CH ₃ c-Pen 1-247 HH 4 CH ₂ CH ₃ c-Hex 1-248 HH 4 CH ₂ CH ₃ C (= NH) H 1-249 HH 4 CH ₂ CH ₃ C (= NH) CH ₃ 1-250 HH 4 CH ₂ CH ₃ C (= NH) NH ₂ 1-251 HH 4 CH ₂ CH ₂ 1-252 HH 4 CH ₂ CH ₂ CH ₂ 1 -253 HH 4 CH ₂ CH ₂ CH ₂ CH ₂ 1-254 HH 4 CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ 1-255 HH 4 CH ₂ CH ₂ OCH ₂ CH ₂ 1-256 HH 4 CH ₂ CH ₂ SCH ₂ CH ₂ 1-257 HH 4 CH ₂ CH ₂ NHCH ₂ CH ₂ 1-258 HH 4 CH ₂ CH ₂ N (CH ₃ ) CH ₂ CH ₂ 1-259 CH ₃ H 2 HH 1-260 CH ₃ H 2 H CH ₃ 1-261 CH ₃ H 2 H CH ₂ CH ₃ 1-262 CH ₃ H 2 H CH ₂ CH ₂ CH ₃ 1-263 CH ₃ H 2 H CH ₂ CH ₂ F 1-264 CH ₃ H 2 H CH ₂ CF ₃ 1-265 CH ₃ H 2 H CH ₂ CH ₂ OH 1-266 CH ₃ H 2 H CH ₂ CH ₂ OCH ₃ 1-267 CH ₃ H 2 H CH ₂ CONH ₂ 1-268 CH ₃ H 2 H CH ₂ CONHCH ₃ 1-269 CH ₃ H 2 H CH ₂ CON (CH ₃ ) ₂ 1-270 CH ₃ H 2 H CH ₂ CH ₂ CONH ₂ 1-271 CH ₃ H 2 H CH ₂ CH ₂ CONHCH ₃ 1-272 CH ₃ H 2 H CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-273 CH ₃ H 2 H CH _{2 CH 2 OCONH 2 1-274 CH 3 H} 2 H CH 2 CH 2 OCONHCH 3 1-275 CH 3 H 2 H CH 2 CH 2 OCON (CH 3) 2 1-276 CH 3 H 2 H CH 2 CH 2 NH 2 1-277 CH ₃ H 2 H CH ₂ CH ₂ NHCH ₃ 1-278 CH ₃ H 2 H CH ₂ CH ₂ N (CH ₃ ) ₂ 1-279 CH ₃ H 2 H c-Pro 1-280 CH ₃ H 2 H c-But 1-281 CH ₃ H 2 H c-Pen 1-282 CH ₃ H 2 H c-Hex 1-283 CH ₃ H 2 HC (= NH) H 1-284 CH ₃ H 2 HC (= NH ) CH ₃ 1-285 CH ₃ H 2 HC (= NH) NH ₂ 1-286 CH ₃ H 2 CH ₃ CH ₃ 1-287 CH ₃ H 2 CH ₃ CH ₂ CH ₃ 1-288 CH ₃ H 2 CH ₃ CH ₂ CH ₂ CH ₃ 1-289 CH ₃ H 2 CH ₃ CH ₂ CH ₂ F 1-290 CH ₃ H 2 CH ₃ CH ₂ CF ₃ 1-291 CH ₃ H 2 CH ₃ CH ₂ CH ₂ OH 1-292 CH ₃ H 2 CH ₃ CH ₂ CH ₂ OCH ₃ 1-293 CH ₃ H 2 CH ₃ CH ₂ CONH ₂ 1-294 CH ₃ H 2 CH ₃ CH ₂ CONHC H ₃ 1-295 CH ₃ H 2 CH ₃ CH ₂ CON (CH ₃ ) ₂ 1-296 CH ₃ H 2 CH ₃ CH ₂ CH ₂ CONH ₂ 1-297 CH ₃ H 2 CH ₃ CH ₂ CH ₂ CONHCH ₃ 1 -298 CH ₃ H 2 CH ₃ CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-299 CH ₃ H 2 CH ₃ CH ₂ CH ₂ OCONH ₂ 1-300 CH ₃ H 2 CH ₃ CH ₂ CH ₂ OCONHCH ₃ 1- 301 CH ₃ H 2 CH ₃ CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-302 CH ₃ H 2 CH ₃ CH ₂ CH ₂ NH ₂ 1-303 CH ₃ H 2 CH ₃ CH ₂ CH ₂ NHCH ₃ 1-304 CH ₃ H 2 CH ₃ CH ₂ CH ₂ N (CH ₃ ) ₂ 1-305 CH ₃ H 2 CH ₃ c-Pro 1-306 CH ₃ H 2 CH ₃ c-But 1-307 CH ₃ H 2 CH ₃ c -Pen 1-308 CH ₃ H 2 CH ₃ c-Hex 1-309 CH ₃ H 2 CH ₃ C (= NH) H 1-310 CH ₃ H 2 CH ₃ C (= NH) CH ₃ 1-311 CH ₃ H 2 CH ₃ C (= NH) NH ₂ 1-312 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CH ₃ 1-313 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CH ₂ CH ₃ 1-314 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CH ₂ F 1-315 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CF ₃ 1-316 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CH ₂ OH 1-317 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CH ₂ OCH ₃ 1-318 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CONH ₂ 1-319 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CONHCH ₃ 1-320 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CON (CH ₃ ) ₂ 1-321 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CH ₂ CONH ₂ 1-322 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CH ₂ CONHCH ₃ 1-323 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-324 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CH ₂ OCONH ₂ 1-325 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CH ₂ OCONHCH ₃ 1-326 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-327 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CH ₂ NH ₂ 1-328 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CH ₂ NHCH ₃ 1-329 CH ₃ H 2 CH ₂ CH ₃ CH ₂ CH ₂ N (CH ₃ ) ₂ 1-330 CH ₃ H 2 CH ₂ CH ₃ c -Pro 1-331 CH ₃ H 2 CH ₂ CH ₃ c-But 1-332 CH ₃ H 2 CH ₂ CH ₃ c-Pen 1-333 CH ₃ H 2 CH ₂ CH ₃ c-Hex 1-334 CH ₃ H 2 CH ₂ CH ₃ C (= NH) H 1-335 CH ₃ H 2 CH ₂ CH ₃ C (= NH) CH ₃ 1-336 CH ₃ H 2 CH ₂ CH ₃ C (= NH) NH ₂ 1-337 CH ₃ H 2 CH ₂ CH ₂ 1-338 CH ₃ H 2 CH ₂ CH ₂ CH ₂ 1-339 CH ₃ H 2 CH ₂ CH ₂ CH ₂ CH ₂ 1-340 CH ₃ H 2 CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ 1-341 CH ₃ H 2 CH ₂ CH ₂ OCH ₂ CH ₂ 1-342 CH ₃ H 2 CH ₂ CH ₂ SCH ₂ CH ₂ 1-343 CH ₃ H 2 CH ₂ CH ₂ NHCH ₂ CH ₂ 1- 344 CH ₃ H 2 CH ₂ CH ₂ N (CH ₃ ) CH ₂ CH ₂ 1-345 CH ₃ H 3 HH 1-346 CH ₃ H 3 H CH ₃ 1-347 CH ₃ H 3 H CH ₂ CH ₃ 1- 348 CH ₃ H 3 H CH ₂ CH ₂ CH ₃ 1-349 CH ₃ H 3 H CH ₂ CH ₂ F 1-350 CH ₃ H 3 H CH ₂ CF ₃ 1-351 CH ₃ H 3 H CH ₂ CH ₂ OH 1-352 CH ₃ H 3 H CH ₂ CH ₂ OCH ₃ 1-353 CH ₃ H 3 H CH ₂ CONH ₂ 1-354 CH ₃ H 3 H CH ₂ CONHCH ₃ 1-355 CH ₃ H 3 H CH ₂ CON (CH ₃ ) ₂ 1-356 CH ₃ H 3 H CH ₂ CH ₂ CONH ₂ 1-357 CH ₃ H 3 H CH ₂ CH ₂ CONHCH ₃ 1-358 CH ₃ H 3 H CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-359 CH ₃ H 3 H CH ₂ CH ₂ OCONH ₂ 1-360 CH ₃ H 3 H CH ₂ CH ₂ OCONHCH ₃ 1-361 CH ₃ H 3 H CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-362 CH ₃ H 3 H CH ₂ CH ₂ NH ₂ 1-363 CH ₃ H 3 H CH ₂ CH ₂ NHCH ₃ 1-364 CH ₃ H 3 H CH ₂ CH ₂ N (CH ₃ ) ₂ 1-365 CH ₃ H 3 H c-Pro 1-366 CH ₃ H 3 H c-But 1-367 CH ₃ H 3 H c-Pen 1-368 CH ₃ H 3 H c-Hex 1 -369 CH ₃ H 3 HC (= NH) H 1-370 CH ₃ H 3 HC (= NH) CH ₃ 1-371 CH ₃ H 3 HC (= NH) NH ₂ 1-372 CH ₃ H 3 CH ₃ CH ₃ 1-373 CH ₃ H 3 CH ₃ CH ₂ CH ₃ 1-374 CH ₃ H 3 CH ₃ CH ₂ CH ₂ CH ₃ 1-375 CH ₃ H 3 CH ₃ CH ₂ CH ₂ F 1-376 CH ₃ H 3 CH ₃ CH ₂ CF ₃ 1-377 CH ₃ H 3 CH ₃ CH ₂ CH ₂ OH 1-378 CH ₃ H 3 CH ₃ CH ₂ CH ₂ OCH ₃ 1-379 CH ₃ H 3 CH ₃ CH ₂ CONH ₂ 1- 380 CH ₃ H 3 CH ₃ CH ₂ CONHCH ₃ 1-381 CH ₃ H 3 CH ₃ CH ₂ CON (CH ₃ ) ₂ 1-382 CH ₃ H 3 CH ₃ CH ₂ CH ₂ CONH ₂ 1-383 CH ₃ H 3 CH ₃ CH ₂ CH ₂ CONHCH ₃ 1-384 CH ₃ H 3 CH ₃ CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-385 CH ₃ H 3 CH ₃ CH ₂ CH ₂ OCONH ₂ 1-386 CH ₃ H 3 CH ₃ CH ₂ CH ₂ OCONHCH ₃ 1-387 CH ₃ H 3 CH ₃ CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-388 CH ₃ H 3 CH ₃ CH ₂ CH ₂ NH ₂ 1-389 CH ₃ H 3 CH ₃ CH ₂ CH ₂ NHCH ₃ 1-390 CH ₃ H 3 CH ₃ CH ₂ CH ₂ N (CH ₃ ) ₂ 1-391 CH ₃ H 3 CH ₃ c-Pro 1-392 CH ₃ H 3 CH ₃ c-But 1-393 CH ₃ H 3 CH ₃ c-Pen 1-394 CH ₃ H 3 CH ₃ c-Hex 1-395 CH ₃ H 3 CH ₃ C (= NH) H 1-396 CH ₃ H 3 CH ₃ C (= NH) CH ₃ 1-397 CH ₃ H 3 CH ₃ C (= NH) NH ₂ 1-398 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CH ₃ 1- 399 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CH ₂ CH ₃ 1-400 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CH ₂ F 1-401 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CF ₃ 1-402 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CH ₂ OH 1-403 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CH ₂ OCH ₃ 1-404 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CONH ₂ 1-405 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CONHCH ₃ 1-406 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CON (CH ₃ ) ₂ 1-407 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CH ₂ CONH ₂ 1-408 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CH ₂ CONHCH ₃ 1-409 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-410 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CH ₂ OCONH ₂ 1-411 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CH ₂ OCONHCH ₃ 1-412 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-413 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CH ₂ NH ₂ 1-414 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CH ₂ NHCH ₃ 1-415 CH ₃ H 3 CH ₂ CH ₃ CH ₂ CH ₂ N (CH ₃ ) ₂ 1-416 CH ₃ H 3 CH ₂ CH ₃ c-Pro 1-417 CH ₃ H 3 CH ₂ CH ₃ c-But 1-418 CH ₃ H 3 CH ₂ CH ₃ c-Pen 1-419 CH ₃ H 3 CH ₂ CH ₃ c-Hex 1-420 CH ₃ H 3 CH ₂ CH ₃ C (= NH) H 1-421 CH ₃ H 3 CH ₂ CH ₃ C (= NH) CH ₃ 1-422 CH ₃ H 3 CH ₂ CH ₃ C (= NH) NH ₂ 1-423 CH ₃ H 3 CH ₂ CH ₂ 1-424 CH ₃ H 3 CH ₂ CH ₂ CH ₂ 1-425 CH ₃ H 3 CH ₂ CH ₂ CH ₂ CH ₂ 1-426 CH ₃ H 3 CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ 1-427 CH ₃ H 3 CH ₂ CH ₂ OCH ₂ CH ₂ 1-428 CH ₃ H 3 CH ₂ CH ₂ SCH ₂ CH ₂ 1-429 CH ₃ H 3 CH ₂ CH ₂ NHCH ₂ CH ₂ 1-430 CH ₃ H 3 CH ₂ CH ₂ N (CH ₃ ) CH ₂ CH ₂ 1-431 CH ₃ H 4 HH 1-432 CH ₃ H 4 H CH ₃ 1-433 CH ₃ H 4 H CH ₂ CH ₃ 1-434 CH ₃ H 4 H CH ₂ CH ₂ CH ₃ 1-435 CH ₃ H 4 H CH ₂ CH ₂ F 1-436 CH ₃ H 4 H CH ₂ CF ₃ 1-437 CH ₃ H 4 H CH ₂ CH ₂ OH 1-438 CH ₃ H 4 H CH ₂ CH ₂ OCH ₃ 1-439 CH ₃ H 4 H CH ₂ CONH ₂ 1-440 CH ₃ H 4 H CH ₂ CONHCH ₃ 1-441 CH ₃ H 4 H CH ₂ CON (CH ₃ ) ₂ 1-442 CH ₃ H 4 H CH ₂ CH ₂ CONH ₂ 1-443 CH ₃ H 4 H CH ₂ CH ₂ CONHCH ₃ 1-444 CH ₃ H 4 H CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-445 CH ₃ H 4 H CH ₂ CH ₂ OCONH ₂ 1-446 CH ₃ H 4 H CH ₂ CH ₂ OCONHCH ₃ 1-447 CH ₃ H 4 H CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-448 CH ₃ H 4 H CH ₂ CH ₂ NH ₂ 1-449 CH ₃ H 4 H CH ₂ CH ₂ NHCH ₃ 1-450 CH ₃ H 4 H CH ₂ CH ₂ N (CH ₃ ) ₂ 1-451 CH ₃ H 4 H c-Pro 1-452 CH ₃ H 4 H c-But _{1-453 CH 3 H 4 H c-} Pen 1-454 CH 3 H 4 H c-Hex 1-455 CH 3 H 4 HC (= NH) H 1-456 CH 3 H 4 HC (= NH) CH 3 1 -457 CH ₃ H 4 HC (= NH) NH ₂ 1-458 CH ₃ H 4 CH ₃ CH ₃ 1-459 CH ₃ H 4 CH ₃ CH ₂ CH ₃ 1-460 CH ₃ H 4 CH ₃ CH ₂ CH ₂ CH ₃ 1-461 CH ₃ H 4 CH ₃ CH ₂ CH ₂ F 1-462 CH ₃ H 4 CH ₃ CH ₂ CF ₃ 1-463 CH ₃ H 4 CH ₃ CH ₂ CH ₂ OH 1-464 CH ₃ H 4 CH ₃ CH ₂ CH ₂ OCH ₃ 1-465 CH ₃ H 4 CH ₃ CH ₂ CONH ₂ 1-466 CH ₃ H 4 CH ₃ CH ₂ CONHCH ₃ 1-467 CH ₃ H 4 CH ₃ CH ₂ CON (CH ₃ ) ₂ 1-468 CH ₃ H 4 CH ₃ CH ₂ CH ₂ CONH ₂ 1-469 CH ₃ H 4 CH ₃ CH ₂ CH ₂ CONHCH ₃ 1-470 CH ₃ H 4 CH ₃ CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-471 CH ₃ H 4 CH ₃ CH ₂ CH ₂ OCONH ₂ 1-472 CH ₃ H 4 CH ₃ CH ₂ CH ₂ OCONHCH ₃ 1-473 CH ₃ H 4 CH ₃ CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-474 CH ₃ H 4 CH ₃ CH ₂ CH ₂ NH ₂ 1-475 CH ₃ H 4 CH ₃ CH ₂ CH ₂ NHCH ₃ 1-476 CH ₃ H 4 CH ₃ CH ₂ CH ₂ N (CH ₃ ) ₂ 1-477 CH ₃ H 4 CH ₃ c-Pro 1-478 CH ₃ H 4 CH ₃ c-But 1-479 CH ₃ H 4 CH ₃ c-Pen 1-480 CH ₃ H 4 CH ₃ c-Hex 1-481 CH ₃ H 4 CH ₃ C (= NH) H 1-482 CH ₃ H 4 CH ₃ C (= NH) CH ₃ 1-483 CH ₃ H 4 CH ₃ C (= NH) NH ₂ 1-484 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CH ₃ 1-485 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CH ₂ CH ₃ 1-486 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CH ₂ F 1-487 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CF ₃ 1-488 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CH ₂ OH 1-489 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CH ₂ OCH ₃ 1-490 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CONH ₂ 1-491 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CONHCH ₃ 1-492 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CON ( CH ₃ ) ₂ 1-493 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CH ₂ CONH ₂ 1-494 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CH ₂ CONHCH ₃ 1-495 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CH ₂ CON (CH ₃ ) ₂ 1-496 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CH ₂ OCONH ₂ 1-497 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CH ₂ OCONHCH ₃ 1-498 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CH ₂ OCON (CH ₃ ) ₂ 1-499 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CH ₂ NH ₂ 1 -500 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CH ₂ NHCH ₃ 1-501 CH ₃ H 4 CH ₂ CH ₃ CH ₂ CH ₂ N (CH ₃ ) _{2 1} -502 CH ₃ H 4 CH ₂ CH ₃ c- Pro 1-503 CH ₃ H 4 CH ₂ CH ₃ c-But 1-504 CH ₃ H 4 CH ₂ CH ₃ c-Pen 1-505 CH ₃ H 4 CH ₂ CH ₃ c-Hex 1-506 CH ₃ H 4 CH ₂ CH ₃ C (= NH) H 1-507 CH ₃ H 4 CH ₂ CH ₃ C (= NH) CH ₃ 1-508 CH ₃ H 4 CH ₂ CH ₃ C (= NH) NH ₂ 1-509 CH ₃ H 4 CH ₂ CH ₂ 1-510 CH ₃ H 4 CH ₂ CH ₂ CH ₂ 1-511 CH ₃ H 4 CH ₂ CH ₂ CH ₂ CH ₂ 1-512 CH ₃ H 4 CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ 1-513 CH ₃ H 4 CH ₂ CH ₂ OCH ₂ CH ₂ 1-514 CH ₃ H 4 CH ₂ CH ₂ SCH ₂ CH ₂ 1-515 CH ₃ H 4 CH ₂ CH ₂ NHCH ₂ CH ₂ 1-516 CH ₃ H 4 CH ₂ CH ₂ N (CH ₃ ) CH ₂ CH ₂ ――――――――――――――――――――――――――――――――― --- Of the compounds exemplified in Table 1 above, more preferably, compound numbers 1-1, 1-2, 1-3, 1-5, 1-7, and 1
-8, 1-9, 1-18, 1-25, 1-26, 1-2
7, 1-28, 1-51, 1-52, 1-53, 1-8
7, 1-88, 1-91, 1-93, 1-95, 1-1
11, 1-112, 1-113, 1-114, 1-11
9, 1-137, 1-138, 1-139, 1-17
3, 1-174, 1-197, 1-198, 1-19
9, 1-200, 1-259, 1-260, 1-28
3, 1-284, 1-285, 1-286, 1-30
9, 1-310, 1-311, 1-345, 1-34
6, 1-369, 1-370, 1-371, 1-37
2, 1-395, 1-396, 1-397, 1-43
1, 1-432, 1-455, 1-456, 1-45
7, and 1-458.

Among the above compounds, the compounds specified by the following chemical names are particularly preferred. Exemplified Compound 1-1 (Compound of Example 1) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (2-aminoethyl) pyrrolidine-1
-Ylcarbonyl] pyrrolidin-4-ylthio] -6
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapene-2-em-3-carboxylic acid Exemplified Compound 1-2 (Compound of Example 2) (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2- [(2S, 4S) -2-
[(3S) -3- (2-methylaminoethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio]
-1-carbapene-2-em-3-carboxylic acid Exemplified Compound 1-27 (Compound of Example 3) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (2-guanidinoethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid Exemplified Compound 1-285 (Compound of Example 4) (1R, 5S, 6S) -2 − [(2S, 4S) -2-
[(3S) -3- (2-guanidinoethyl) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-4-
Ilthio] -6-[(1R) -1-hydroxyethyl]
-1-Methyl-1-carbapene-2-em-3-carboxylic acid Exemplified compound 1-87 (compound of Example 5) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (3-aminopropyl) pyrrolidine-
1-ylcarbonyl] pyrrolidin-4-ylthio] -6
-[(1R) -1-hydroxyethyl] -1-methyl-
1-carbapen-2-em-3-carboxylic acid Exemplified Compound 1-88 (Compound of Example 6) (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2 − [(2S, 4S) -2-
[(3S) -3- (3-Methylaminopropyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylic acid Exemplified compound 1-113 (Example 7 Compound) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (3-guanidinopropyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio]
-6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid Exemplified Compound 1-371 (Compound of Example 8) (1R, 5S, 6S)- 2-[(2S, 4S) -2-
[(3S) -3- (3-guanidinopropyl) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-4
-Ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid Exemplified Compound 1-26 (Compound of Example 9) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (2-acetimidoylaminoethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine-4
-Ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid Exemplified Compound 1-284 (Compound of Example 10) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (3-acetimidoylethyl) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl- 1-carbapene-2-m-3-
Carboxylic acid Exemplified compound 1-112 (compound of Example 11) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (3-acetimidoylpropyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1
-Methyl-1-carbapen-2-em-3-carboxylic acid Exemplified Compound 1-370 (Compound of Example 12) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (3-acetimidoylpropyl) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl- 1-carbapene-2-M-3
-Carboxylic acid Exemplified compound 1-259 (compound of Example 13) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (2-aminoethyl) pyrrolidine-1
-Ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1
-Methyl-1-carbapene-2-em-3-carboxylic acid Exemplified Compound 1-260 (Compound of Example 14) (1R, 5S, 6S) -2-[(2S, 4S) -1-methyl-2- [(3S) -3- (2-methylaminoethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine-4
-Ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid Exemplified Compound 1-345 (Compound of Example 15) (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (3-aminopropyl) pyrrolidine-
1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl]-
1-methyl-1-carbapen-2-em-3-carboxylic acid Exemplified Compound 1-346 (Compound of Example 16) (1R, 5S, 6S) -2-[(2S, 4S) -1-methyl-2 -[(3S) -3- (3-methylaminopropyl) pyrrolidin-1-ylcarbonyl] pyrrolidine-4
-Iylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0068]

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, a compound having the general formula (I)
The -methylcarbapenem derivative can be produced by the following method. Abbreviated as follows.

[0069]

Embedded image The carbapenem compound of the general formula (I) has the general formula

[0070]

Embedded image (Wherein L represents a leaving group, and R ¹⁰ represents a carboxyl-protecting group) and a carbapenem compound represented by the general formula:

[0071]

Embedded image (In the formula, Rp represents R which may be protected when R contains a hydroxyl group, an amino group or an imino group.)
By reacting a mercaptan derivative represented by the following formula, and removing a protecting group as necessary.
In addition, it can be converted to a pharmacologically acceptable salt or derivative, if necessary.

In detail, the compound (I) of the present invention can be produced by the method shown below.

[0073]

Embedded image In the above formula, R ¹⁰ , L and Rp have the same meanings as described above.

The “protecting group for carboxy group” for R ¹⁰ includes, for example, a C _1-4 alkyl group such as methyl, ethyl or t-butyl; benzyl, 4-methoxybenzyl,
A benzyl group which may have a substituent such as 4-nitrobenzyl or 2-nitrobenzyl; a benzhydryl group; an allyl which may have a substituent at the 2-position such as allyl, 2-chloroallyl or 2-methylallyl Group; 2,
Examples include a halogenoethyl group such as 2,2-trichloroethyl, 2,2-dibromoethyl or 2,2,2-tribromoethyl or a 2-trimethylsilylethyl group, preferably 4-nitrobenzyl or benzyl. Group.

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

R ¹¹ represents a C _1-4 alkanesulfonyl group such as methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl or butanesulfonyl; a C 11 such as phenylsulfonyl, tolylsulfonyl or naphthylsulfonyl. _6-10 arylsulfonyl group; dimethylphosphoryl, diethylphosphoryl, dipropylphosphoryl,
Di-C _1-6 alkylphosphoryl groups such as diisopropylphosphoryl, dibutylphosphoryl, dipentylphosphoryl or dihexylphosphoryl or di-C such as diphenylphosphoryl or ditolylphosphoryl
_{6-10 represents an} arylphosphoryl group, preferably a diphenylphosphoryl group.

R ¹² is a C _1-4 alkyl group such as methyl, ethyl, propyl or isopropyl; fluoromethyl, chloromethyl, fluoroethyl, chloroethyl,
A halogeno-C _1-4 alkyl group such as fluoropropyl, difluoromethyl, difluoroethyl, dichloroethyl, trifluoromethyl or trifluoroethyl;
2-acetylaminoethyl group; 2-acetylaminovinyl group; a C _6-10 aryl group such as phenyl or naphthyl which may have a substituent (the aryl group is the same or different from one to three aryl groups shown below). The substituent may be a halogen atom such as fluorine, chlorine, bromine, or a C _1-4 such as methyl, ethyl, propyl, or isopropyl.
Alkyl groups; C _1-4 alkoxy groups such as methoxy, ethoxy, propoxy and isopropoxy; (C _1-4 alkoxy) carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl; carbamoyl, mono- or di- — (C _1-4 alkyl) carbamoyl group; nitro group; hydroxyl group or cyano group. ) Or a heteroaryl group optionally having 1 to 2 nitrogen atoms such as pyridyl or pyrimidinyl which may have a substituent (the heteroaryl group is the same or different from 1 to 3 substituents shown below) And the substituent may be a halogen atom or a C
_{1-4 represents} an alkyl group. ).

The "protecting group for hydroxyl group" contained in Rp includes, for example, trimethylsilyl, triethylsilyl, t-
A tri-C _1-4 alkylsilyl group such as butyldimethylsilyl; an optionally substituted benzyl such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, and 4-methoxybenzyloxycarbonyl An oxycarbonyl group (the substituent is nitro, methyl, chlorine or methoxy); an allyl which may be substituted at the 2-position such as allyloxycarbonyl, 2-chloroallyloxycarbonyl, 2-methylallyloxycarbonyl Oxycarbonyl group (the substituent is chlorine or methyl); 2-position such as trimethylsilylethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl is tri-C
Examples thereof include an ethyloxycarbonyl group substituted with _1-4 alkylsilyl or chlorine, preferably a 4-nitrobenzyl or 4-nitrobenzyloxycarbonyl group.

The “protecting group for imino or amino group” contained in R p includes, for example, allyloxycarbonyl,
An allyloxycarbonyl group which may be substituted at the 2-position such as 2-chloroallyloxycarbonyl, 2-methylallyloxycarbonyl (the substituent is chlorine or methyl); benzyloxycarbonyl, 4-methylbenzyl Oxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4
An optionally substituted benzyloxycarbonyl group such as -nitrobenzyloxycarbonyl, wherein the substituent is
Methyl, methoxy, chlorine or nitro), preferably an allyloxycarbonyl group or a 4-nitrobenzyloxycarbonyl group, more preferably 4
-Nitrobenzyloxycarbonyl group.

The process comprises reacting a compound having formula (II) with a compound having formula (III) in the presence of a base to produce a compound having formula (IV) (first step) and then protecting This is a method for producing a compound (I) by subjecting to a reaction for removing a group (Step A2). Incidentally, when L is a group of the formula -OR ^11, compounds of formula (II) as a starting material, DHShih et al., Heterocycles 21 , 29
(1984). L is the formula -S
(O) When it is a group represented by R ¹² , the starting compound (I
I) is produced according to the method disclosed in JP-A-62-30781. Hereinafter, each step will be described.

(First Step) In the first step, the general formula (IV)
In the step of producing a compound having the formula (I), the compound (II) is reacted with a mercaptan derivative having the general formula (III) in the presence of a base in an inert solvent.

(1) When L is a group represented by the formula —OR ^{11 The} solvent used is not particularly limited as long as it does not participate in the reaction. For example, methylene chloride, 1,2-dichloroethane,
Halogenated hydrocarbons such as chloroform, nitriles such as acetonitrile, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, esters such as ethyl acetate and methyl acetate, diethyl ether And ethers such as tetrahydrofuran and dioxane, preferably acetonitrile, N, N-dimethylformamide or tetrahydrofuran, and particularly preferably acetonitrile.

The base used in this step is not particularly limited, but is preferably an organic amine such as triethylamine or diisopropylethylamine or an inorganic base such as potassium carbonate or sodium carbonate. Diisopropylethylamine.

The reaction temperature is not particularly limited, but is usually -2.
It is carried out at 0 ° 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) When L is a group represented by the formula —S (O) R ^{12 The} solvent used is not particularly limited as long as it does not participate in the reaction. For example, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl Examples thereof include sulfoxide, water and a mixed solvent thereof, and preferably acetonitrile.

The base to be used is not particularly limited as long as it does not affect the other parts of the compound, particularly the β-lactam ring, and examples thereof include diisopropylethylamine, triethylamine, N-methylpiperidine, and 4-dimethylamino. Organic bases such as pyridine or inorganic bases such as potassium carbonate and sodium bicarbonate;
Preferably it is diisopropylethylamine.

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 side reactions, usually at a temperature of -20 ° C to 40 ° C (preferably -10 ° C to 20 ° C). Will be

The reaction time depends mainly on the reaction temperature and the type of the reaction reagent, but is usually from 15 minutes to 75 hours (preferably from 30 minutes to 18 hours).

After 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 used in a conventional manner if necessary, for example, recrystallization,
It can be further purified by reprecipitation or chromatography. If desired, the desired compound (I
V) can be subjected to the next step without isolation.

(Second Step) In the second step, compound (IV)
To the compound (I), which is achieved by removing the protecting group of the compound.

The removal of the protecting group varies depending on its type, but is generally performed by a method used in the field of synthetic organic chemistry (Greene & Wuts, P.S.
protective Groups in Organ
ic Synthesis, 2nd Edition,
1991, John Wiley & Sons, In
c. ).

(1) When the protecting group R ¹⁰ is a benzyl group or a benzhydryl group which may have a substituent such as benzyl or 4-nitrobenzyl, and the hydroxyl group, amino group and imino group contained in Rp A benzyl group wherein the protecting group of the group may have a substituent such as benzyl or 4-nitrobenzyl or a benzyloxycarbonyl group which may have a substituent such as benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl; In the case where, the protecting group can be removed by reacting with hydrogen and a reducing agent using a catalytic reduction catalyst or an alkali metal sulfide.

The reducing agent is, for example, hydrogen and palladium-
Mention may be made of a catalytic reduction catalyst such as carbon or an alkali metal sulfide such as sodium sulfide or potassium sulfide, preferably hydrogen and a palladium-carbon catalyst.

The solvent to be used is not particularly limited as long as it does not participate in the present reaction. Preferably, alcohols such as methanol and ethanol, tetrahydrofuran,
Ethers such as dioxane and mixed solvents of these organic solvents 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.
2 hours (preferably 30 minutes to 4 hours).

After completion of the reaction, the desired 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.

(2) When the protecting group R ¹⁰ is an allyl group which may be substituted at the 2-position such as allyl, 2-chloroallyl and 2-methylallyl, and the hydroxyl, amino and imino groups contained in Rp When the protecting group of the group is allyloxycarbonyl, 2-chloroallyloxycarbonyl,
-When the 2-position is an allyloxycarbonyl group which may be substituted, such as -methylallyloxycarbonyl,
Bis (triphenylphosphine) palladium chloride-
Palladium-trialkyltin hydrides such as tributyltin hydride, tetrakis (triphenylphosphine) palladium-tributyltin hydride or potassium tetrakis (triphenylphosphine) -2-ethylhexanoate or sodium 2-ethylhexanoate The protective group can be removed by reacting with a deprotecting agent such as a palladium-organic carboxylic acid alkali metal salt.

The deprotecting agent is preferably bis (triphenylphosphine) palladium chloride-tributyltin hydride or tetrakis (triphenylphosphine)
Potassium palladium-2-ethylhexanoate.

The solvent used is not particularly limited as long as it does not take part in the reaction. Halogenated hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane, and esters such as ethyl acetate. Ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, nitriles such as acetonitrile, alcohols such as methanol, ethanol or propanol, water or a mixed solvent thereof. , Ethyl acetate or a mixed solvent thereof.

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

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

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

As the reducing agent, zinc and acetic acid are preferred.

The solvent to be used is not particularly limited as long as it does not participate in the reaction. Preferably, alcohols such as methanol and ethanol, tetrahydrofuran,
They are ethers such as dioxane, fatty acids such as acetic acid, and mixed solvents of these organic solvents and water.

The reaction temperature is usually from 0 ° C. to 40 ° C. (preferably from 10 ° C. to 30 ° C.). The reaction time varies depending on the type of the starting compound and the reducing agent, but is usually from 5 minutes to 12 hours (preferably from 5 minutes to 12 hours). Is 30 minutes to 4 hours).

After completion of the reaction, the desired 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, thin-layer chromatography for preparative use, or column chromatography.

The thus obtained 1-methylcarbapenem compound having the general formula (I) may be optionally
According to methods or techniques known in the field of medicinal chemistry, particularly β-lactam antibiotics, they can be converted into derivatives such as esters that undergo hydrolysis in vivo, and as pharmacologically acceptable salts. It can be purified.

The raw material mercaptan compound (III) used in this method can be prepared by a known method, for example, I.P. Ka
wamoto et al. , Synlett, 199
5,575; JP-A-2-28180; JP-A-2-36
No. 87; JP-A-4-211083, JP-A-5-339
269 or JP-A-10-36370, or according to the method described in Reference Examples described later.

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, Shows strong and balanced antibacterial activity against a wide range of pathogens including Enterobacter, Gram-negative bacteria such as Pseudomonas aeruginosa and anaerobic bacteria such as Bacteroides fragilis, and against Meropenem-resistant Pseudomonas aeruginosa. Also exhibit excellent antibacterial activity. Further, the compound (I) of the present invention has high stability against β-lactamase, is stable against dehydropeptidase-I, and has a high urine recovery rate. Furthermore, the compound (I) of the present invention has excellent pharmacokinetics such as half-life in blood and has low toxicity to the kidney. Therefore, the compound of the present invention having the above general formula (I) or a pharmaceutically acceptable salt or derivative thereof is useful, for example, as a medicament, and in particular, treats or prevents (preferably, treats) bacterial infections caused by various pathogenic bacteria. ) Is useful as an antibacterial agent.

When the compound (I) and a pharmaceutically acceptable derivative or salt thereof are used as a medicament, particularly as an antibacterial agent, excipients, diluents, etc. per se or appropriate pharmaceutically acceptable ones are used. And administered orally using tablets, capsules, granules, powders, syrups and the like, or parenterally using injections and the like.

These preparations contain excipients (eg, lactose,
Sugar derivatives such as sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxy Cellulose derivatives such as propylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate; Silicate derivatives such as magnesium metasilicate aluminate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; Agent Gelatin; polyvinylpyrrolidone;
Macrogol, etc.), disintegrants (for example, the above-mentioned excipients; croscarmellose sodium, carboxymethyl starch)
Disodium, chemically modified starch such as crosslinked polyvinylpyrrolidone, starch, cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; metal stearate such as calcium stearate, magnesium stearate; colloidal silica) Bee gum; beeswax;
Waxes such as gay wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylate salts such as sodium benzoate; sulfate salts such as sodium sulfate; leucine; sodium lauryl sulfate; Lauryl sulfates such as magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (eg, paraoxybenzoic acid esters such as methylparaben and propylparaben) Chlorobutanol, benzyl alcohol
Alcohols such as phenylethyl alcohol;
Benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid and the like; flavoring agents (for example, commonly used sweeteners)
Additives such as acidulants, flavors, etc., suspending agents (eg, polysorbate 80, carboxymethyl cellulose sodium, etc.), diluents, formulation solvents (eg, water, ethanol, glycerin, etc.). And manufactured by a well-known method.

The dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 10 mg (preferably 50 mg) and the upper limit is 2000 mg (preferably 10 mg).
In the case of intravenous administration, the lower limit is 10 mg (preferably 100 mg) and the upper limit is 3000 mg per dose.
(Preferably 2000 mg) is desirably administered to an adult 1 to 6 times a day depending on the symptoms.

[0114]

EXAMPLES Examples, reference examples and test examples are given below.
The present invention will be described in more detail, but the scope of the present invention is not limited thereto. Incidentally, unless otherwise specified the nuclear magnetic resonance spectra, using trimethylsilyl propionic acid sodium -d ₄ for the measurement of heavy water as an internal standard substance, with tetramethylsilane as an internal standard in the other solvents.

Example 1 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (2-aminoethyl) pyrrolidine-1
-Ylcarbonyl] pyrrolidin-4-ylthio] -6
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapene-2-m-3-carboxylic acid

[0116]

Embedded image (1) (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid 4- Nitrobenzyl ester (713mg)
Was added to a solution of (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- under ice-cooling in a solution of dried dimethylformamide (5 ml).
[2- (4-Nitrobenzyloxycarbonyl) aminoethyl] pyrrolidin-1-ylcarbonyl] pyrrolidine (722 mg) in dry dimethylformamide (10 m
l) solution and diisopropylethylamine (0.21 m
l) was added and the mixture was stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate / methanol = 10/1, powdery (1R, 5S, 6S) -6-[(1R)-
1-hydroxyethyl] -1-methyl-2-[(2S,
4S) -1- (4-nitrobenzyloxycarbonyl)
-2-[(3S) -3- [2- (4-nitrobenzyloxycarbonyl) aminoethyl] pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylic The acid 4-nitrobenzyl ester (914 mg) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3414, 1773, 1713, 1648, 1607, 1522, 1445, 14
04, 1346. Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ pp
m: 1.24-1.29 (3H, m), 1.37 (3H, d, J = 6.1Hz), 1.42-
2.37 (7H, m), 2.60-2.74 (1H, m), 2.83-3.02 (1H, m), 3.
10-4.05 (10H, m), 4.22-4.30 (2H, m), 4.44-4.58 (1H,
m), 4.82-4.87 (1H, m), 5.00-5.53 (6H, m), 7.42-7.67 (6
H, m), 8.21-8.24 (6H, m). (2) The compound (913 mg) obtained in (1) was dissolved in tetrahydrofuran (12 ml) -water (6 ml),
A 10% palladium carbon catalyst (1.8 g) was added, and hydrogenation was performed at room temperature for 90 minutes. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure to remove tetrahydrofuran, washed with ether, and the aqueous layer was concentrated under reduced pressure. The residue is subjected to reverse phase column chromatography (Nacalai Tesque, Cosmoseal 75C18-PR
EP), and the fraction eluted with 10% acetonitrile-water was lyophilized to obtain a powdery target compound (124 mg).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3389, 1755, 1629, 1453, 1387, 1312. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δ ppm:
1.21 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.4Hz), 1.55-1.
90 (4H, m), 2.07-2.45 (2H, m), 2.70-2.82 (1H, m), 3.00
-3.28 (5H, m), 3.32-3.87 (6H, m), 3.95-4.07 (1H, m),
4.19-4.30 (2H, m). Example 2 (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -2-
[(3S) -3- (2-methylaminoethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio]
-1-carbapene-2-em-3-carboxylic acid

[0119]

Embedded image (2S, 4S) -4-mercapto-2-[(3S) -3
Implemented using-[2- [N-methyl-N- (4-nitrobenzyloxycarbonyl) amino] ethyl] pyrrolidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) -pyrrolidine (177 mg). Example 1
A powdery target compound (30 mg) was obtained in the same manner as in (1) and (2).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3318, 1758, 1632, 1604, 1455, 1385, 1314. Nuclear magnetic resonance spectrum (270 MHz, D ₂ O) δ ppm:
1.22 (3H, d, J = 7.1Hz), 1.30 (3H, d, J = 6.4Hz), 1.53-1.
91 (4H, m), 2.04-2.43 (3H, m), 2.73 (3H, s), 3.00-3.21
(4H, m), 3.33-3.89 (7H, m), 3.91-4.03 (1H, m), 4.17-
4.30 (2H, m). Example 3 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (2-guanidinoethyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio]-
6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid

[0121]

Embedded image (1) (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid 4- To a solution of nitrobenzyl ester (4.8 g) in acetonitrile (50 ml) was added (2S,
4S) -2-[(3S) -3- [2- [2,3-bis (4-nitrobenzyloxycarbonyl) guanidino]
Ethyl] pyrrolidin-1-ylcarbonyl] -4-mercapto-1- (4-nitrobenzyloxycarbonyl)
Acetonitrile (70 ml) of pyrrolidine (6.7 g)
The solution and diisopropylethylamine (1.4 ml) were added, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was concentrated under reduced pressure,
The residue was dissolved in ethyl acetate, washed with water and brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate / methanol = 19/1, powdery (1R, 5S, 6S) -2-[(2S, 4S) -2
-[(3S) -3- [2- [2,3-bis (4-nitrobenzyloxycarbonyl) guanidino] ethyl] pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R)- 1-hydroxyethyl] -1-
Methyl-1-carbapene-2-em-3-carboxylic acid
4-Nitrobenzyl ester (5.9 g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CD
Cl ₃ ) δ ppm: 1.25-1.30 (3H, m), 1.36 (3H, d, J = 6.2H
z), 1.48-2.40 (8H, m), 2.56-2.77 (1H, m), 2.88-3.04
(1H, m), 3.10-4.30 (13H, m), 4.43-4.60 (1H, m), 5.49
-5.53 (6H, m), 7.38-7.71 (6H, m), 8.13-8.36 (6H, m). (2) The compound (5.9 g) obtained in (1) was treated with tetrahydrofuran (250 ml) -water ( 160 ml), a 20% palladium hydroxide carbon catalyst (8.9 g) was added, and hydrogenation was performed at room temperature for 90 minutes. The catalyst is filtered off,
The filtrate was concentrated under reduced pressure to remove tetrahydrofuran, washed with ether, and the aqueous layer was concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography (manufactured by Nacalai Tesque, Cosmoseal 75C18PREP), and the fraction eluted with 10% acetonitrile-water was lyophilized to give the powdered target compound (1.1
3 g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3344, 1754, 1629, 1454, 1389, 1312. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δ ppm:
1.22 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.4Hz), 1.55-1.
80 (4H, m), 2.17-2.41 (2H, m), 2.69-2.81 (1H, m), 3.
02-3.85 (11H, m), 3.94-4.07 (1H, m), 4.19-4.28 (2H,
m). Example 4 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (2-guanidinoethyl) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-4-
Ilthio] -6-[(1R) -1-hydroxyethyl]
-1-Methyl-1-carbapene-2-em-3-carboxylic acid

[0124]

Embedded image (2S, 4S) -2-[(3S) -3- [2- [2,3
-Bis (4-nitrobenzyloxycarbonyl) guanidino] ethyl] pyrrolidin-1-ylcarbonyl] -4
Using -mercapto-1-methylpyrrolidine (887 mg), a powdery target compound (86 mg) was obtained in the same manner as in Example 3- (1) and (2).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3335, 1758, 1629, 1453, 1385, 1339, 1315. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δ ppm:
1.21 (3H, d, J = 7.3Hz), 1.30 (3H, d, J = 6.3Hz), 1.54-1.
77 (4H, m), 2.05-2.38 (2H, m), 2.30 (3H, s), 2.72-2.91
(2H, m), 3.03-3.17 (2H, m), 3.23-3.76 (7H, m), 3.77-
3.92 (2H, m), 4.17-4.28 (2H, m). Example 5 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (3-aminopropyl) pyrrolidine-
1-ylcarbonyl] pyrrolidin-4-ylthio] -6
-[(1R) -1-hydroxyethyl] -1-methyl-
1-carbapene-2-m-3-carboxylic acid

[0126]

Embedded image (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- [3
Example 3- (1) and (2) using-(4-nitrobenzyloxycarbonyl) aminopropyl] pyrrolidin-1-ylcarbonyl] pyrrolidine (664 mg).
In the same manner as in the above, a powdery target compound (175 mg) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3384, 1755, 1630, 1605, 1455, 1387, 1312. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δ ppm:
1.22 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.3Hz), 1.43-1.
82 (6H, m), 2.05-2.38 (2H, m), 2.69-2.80 (1H, m), 2.
97-3.23 (5H, m), 3.33-3.86 (6H, m), 3.94-4.05 (1H,
m), 4.18-4.28 (2H, m). Example 6 (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -2 −
[(3S) -3- (3-methylaminopropyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylic acid

[0128]

Embedded image (2S, 4S) -4-mercapto-2-[(3S) -3
Implemented using-[3-N-methyl-N- (4-nitrobenzyloxycarbonyl) aminopropyl] pyrrolidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (1.15 g) Example 3
A powdery target compound (261 mg) was obtained in the same manner as in (1) and (2).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3394, 1757, 1632, 1600, 1454, 1386, 1313. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δ ppm:
1.22 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.4Hz), 1.45-1.
80 (6H, m), 2.07-2.36 (2H, m), 2.68-2.78 (1H, m), 2.72
(3H, s), 3.00-3.32 (5H, m), 3.35-3.85 (6H, m), 3.94-
4.05 (1H, m), 4.18-4.28 (2H, m). Example 7 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (3-guanidinopropyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio]
-6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid

[0130]

Embedded image (2S, 4S) -2-[(3S) -3- [3- [2,3
-Bis (4-nitrobenzyloxycarbonyl) guanidino] propyl] pyrrolidin-1-ylcarbonyl]-
Example 3 using 4-mercapto-1- (4-nitrobenzyloxycarbonyl) -pyrrolidine (1.22 g)
A powdery target compound (224 mg) was obtained in the same manner as in (1) and (2).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3339, 1756, 1630, 1455, 1386, 1312. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δ ppm:
1.22 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.4Hz), 1.42-1.
72 (6H, m), 2.06-2.34 (2H, m), 2.69-2.80 (1H, m), 3.02
-3.85 (11H, m), 3.93-4.05 (1H, m), 4.24-4.33 (2H, m). Example 8 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (3-guanidinopropyl) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-4
-Iylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0132]

Embedded image (2S, 4S) -2-[(3S) -3- [3- [2,3
-Bis (4-nitrobenzyloxycarbonyl) guanidino] propyl] -4-mercapto-1-methylpyrrolidin-1-ylcarbonyl] pyrrolidine (1.03
Using g), a powdery target compound (291 mg) was obtained in the same manner as in Example 3- (1) and (2).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 3343, 1757, 1630, 1454, 1386, 1339, 1314. Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δ ppm:
1.20 (3H, d, J = 7.2Hz), 1.30 (3H, d, J = 6.2Hz), 1.40-1.
73 (6H, m), 2.04-2.40 (2H, m), 2.36 (3H, s), Example 9 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (2-acetimidoylaminoethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine-4
-Iylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0134]

Embedded image (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- [2
Example 3- (1) and (2) using-[(4-nitrotrondyloxycarbonyl) acetimidoyl] aminoethyl] pyrrolidin-1-ylcarbonyl] pyrrolidine
The target compound can be synthesized in the same manner as in the method described above. Example 10 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (3-acetimidoylethyl) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl- 1-carbapene-2-m-3-
carboxylic acid

[0135]

Embedded image (2S, 4S) -4-mercapto-1-methyl-2-
The method described in Examples 3- (1) and (2) using [(3S) -3- [2-[(4-nitrobenzyloxycarbonyl) acetimidoyl] aminoethyl] pyrrolidin-1-ylcarbonyl] pyrrolidine. The target compound can be synthesized in the same manner as described above. Example 11 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (3-Atomidoylpropyl) pyrrolidin-1-ylcarbonyl] pyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
Methyl-1-carbene-2-em-3-carboxylic acid

[0136]

Embedded image (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- [3
Using-[(4-nitrobenzyloxycarbonyl) acetimidoyl] aminopropyl] pyrrolidin-1-ylcarbonyl] pyrrolidine, the target compound was obtained in the same manner as described in Example 3- (1) and (2). Can be synthesized. Example 12 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (3-acetimidoylpropyl) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl- 1-carbapene-2-M-3
-Carboxylic acid

[0137]

Embedded image (2S, 4S) -2-[(3S) -3- [3-[(4-
Nitrobenzyloxycarbonyl) acetimidoyl]
Aminopropyl] pyrrolidin-1-ylcarbonyl]-
Using 1-methyl-4-mercaptopyrrolidine, the target compound can be synthesized in the same manner as described in Examples 3- (1) and (2). Example 13 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (2-aminoethyl) pyrrolidine-1
-Ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1
-Methyl-1-carbapene-2-em-3-carboxylic acid

[0138]

Embedded image (2S, 4S) -4-mercapto-1-methyl-2-
[(3S) -3- [2- (4-nitrobenzyloxycarbonyl) aminoethyl] pyrrolidin-1-ylcarbonyl] pyrrolidine was used in the same manner as described in Example 3- (1) and (2). To synthesize the target compound. Example 14 (1R, 5S, 6S) -2-[(2S, 4S) -1-methyl-2-[(3S) -3- (2-methylaminoethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine-4
-Iylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0139]

Embedded image (2S, 4S) -4-mercapto-1-methyl-2--2-
Example 3 using [(3S) -3- [2-N-methyl-N- (4-nitrobenzyloxycarbonyl) aminoethyl] pyrrolidin-1-ylcarbonyl] pyrrolidine.
The target compound can be synthesized in the same manner as in the methods described in (1) and (2). Example 15 (1R, 5S, 6S) -2-[(2S, 4S) -2-
[(3S) -3- (3-aminopropyl) pyrrolidine-
1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl]-
1-methyl-1-carbapene-2-em-3-carboxylic acid

[0140]

Embedded image (2S, 4S) -4-mercapto-1-methyl-2-
[(3S) -3- [3- (4-nitrobenzyloxycarbonyl) aminopropyl] pyrrolidin-1-ylcarbonyl] pyrrolidine was used in the same manner as in Example 3- (1) and (2). To synthesize the target compound. Example 16 (1R, 5S, 6S) -2-[(2S, 4S) -1-methyl-2-[(3S) -3- (3-methylaminopropyl) pyrrolidin-1-ylcarbonyl] pyrrolidine-4
-Iylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid

[0141]

Embedded image (2S, 4S) -4-mercapto-1-methyl-2-
[(3S) -3- [3- (4-nitrobenzyloxycarbonyl) aminopropyl] pyrrolidin-1-ylcarbonyl] pyrrolidine was used in the same manner as in Example 3- (1) and (2). To synthesize the target compound. Reference Example 1 (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- [2
-(4-Nitrobenzyloxycarbonyl) aminoethyl] pyrrolidin-1-ylcarbonyl] pyrrolidine (1) (3S) -1-t described in Japanese Patent Application No. 8-10736.
-Butoxycarbonyl-3-hydroxymethylpyrrolidine (5
08 mg) in 5 ml of dry acetonitrile, and triethylamine (0.46 ml), methanesulfonyl chloride
(0.22 ml), and the mixture was stirred at the same temperature for 10 minutes. After removing the solvent under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure. ) -1-t-Butoxycarbonyl-3- (methanesulfonyloxymethyl) pyrrolidine (839 mg) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ )
δ ppm: 1.46 (9H, s), 1.65-1.80 (1H, m), 1.98-2.10 (1
H, m), 2.57-2.68 (1H, m), 3.04 (3H, s), 3.08-3.21 (1
H, m), 3.30-3.60 (3H, m), 4.10-4.25 (2H, m). (2) (3S) -1-t-butoxycarbonyl- obtained in (1)
3-Methanesulfonyloxymethylpyrrolidine (29.9 g) was dissolved in 300 ml of dry acetonitrile, acetone cyanohydrin (24.5 ml) was added at room temperature, and the same temperature at room temperature for 20 minutes. 75 ml) solution was added. Thereafter, the reaction mixture was heated under reflux for 13 hours, returned to room temperature, and the solvent was removed under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed sequentially with water and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product (26.7 g) was subjected to silica gel column chromatography (n-hexane / methylene chloride / ethyl acetate = 3).
/ 1/1) to obtain powdery (3R) -1-t-butoxycarbonyl-3-cyanomethylpyrrolidine (21.4 g).

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ )
δ ppm: 1.46 (9H, s), 1.70-1.80 (1H, m), 2.05-2.20 (1
H, m), 2.35-2.59 (3H, m), 3.05-3.15 (1H, m), 3.30-3.4
2 (1H, m), 3.42-3.56 (1H, m), 3.56-3.67 (1H, m). (3) (3R) -1-t-butoxycarbonyl- obtained in (2)
3-cyanomethylpyrrolidine (6.04 g) was added to ethanol (121 m
l), ammonium acetate (4.42 g) was further dissolved, and hydrogenation was performed at room temperature for 2 hours in the presence of platinum oxide (3.02 g). After filtering off the catalyst and concentrating the reaction solution under reduced pressure,
The residue was dissolved in 2N hydrochloric acid, and the aqueous layer was washed with ethyl acetate. After that, the aqueous layer was made basic with potassium carbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and obtained as oily (3S) -1-t-butoxycarbonyl-3-aminoethylpyrrolidine. (6.91 g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ )
δ ppm: 1.46 (9H, s), 1.55-1.65 (2H, m), 1.95-2.05 (1
H, m), 2.60-2.70 (1H, m), 2.76 (1H, t, J = 7.4Hz), 2.
80-2.95 (1H, m), 3.61-3.18 (5H, m). (4) (3S) -1-t-butoxycarbonyl-3-aminoethylpyrrolidine (897 mg) obtained in (3)
Was dissolved in dimethylformamide (18 ml) and N, N-diisopropylethylamine (1.2 m
1), then 4-nitrobenzyloxycarbonyl chloride (901 mg) in dimethylformamide (6 ml)
The solution was added and stirred at the same temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, washed with water and brine, the organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give a powdery (3).
S) -1-t-Butoxycarbonyl-3- (4-nitrobenzyloxycarbonylaminoethyl) pyrrolidine (783 mg) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ )
δ ppm: 1.46 (6H, s), 1.58 (3H, s), 1.42-1.72 (2H,
m), 1.95-2.22 (3H, m), 2.81-2.97 (1H, m), 3.16-3.33
(3H, m), 3.34-3.63 (2H, m), 4.75-4.90 (1H, br s), 5.
19 (2H, s), 7.51 (2H, d, J = 8.6Hz), 8.22 (2H, d, J =
(8.6 Hz). (5) The compound (782 mg) obtained in (4) was dissolved in ethyl acetate (8 ml), 4N hydrogen chloride-ethyl acetate (9 ml) was added at room temperature, and the mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the powdery residue was washed with ether and filtered to obtain powdery (3R) -3- (4-nitrobenzyloxycarbonylaminoethyl) pyrrolidine hydrochloride (656 mg).

Nuclear magnetic resonance spectrum (400 MHz, CD
Cl ₃ ) δ ppm: 1.57-1.86 (6H, m), 2.10-2.44 (2H, m), 2.
34-2.98 (1H, m), 3.15-3.60 (5H, m), 5.19 (2H, s), 7.51
(2H, d, J = 8.5Hz), 8.22, 8.23 (2H, dx2, J = 8.5Hz), 9.6
7 (1H, brs). (6) (2S, 4S) -4- (4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl)-
Triethylamine (0.31 ml) and pivaloyl chloride (0.26 ml) were added to a solution of 2-pyrrolidinecarboxylic acid (889 mg) in tetrahydrofuran (6 ml) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. (5)
A solution of the compound (656 mg) obtained in (1) in dimethylformamide (6 ml) and N, N-diisopropylethylamine (2 ml) were added, and the mixture was stirred at 0 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with water, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give powdery (2S, 4S) -4-
(4-methoxybenzylthio) -1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- (4-
Nitrobenzyloxycarbonylaminoethyl) pyrrolidin-1-ylcarbonyl] pyrrolidine (866 mg)
I got

Nuclear magnetic resonance spectrum (270 MHz, CD
Cl ₃ ) δ ppm: 1.42-2.35 (6H, m), 2.39-2.53 (1H, m),
2.78-4.08 (9H, m), 3.73 (2H, s), 3.79 (3H, s), 4.30-
4.43 (1H, m), 4.78-4.93 (1H, m), 6.85 (2H, d, J = 8.6H
z), 7.24 (2H, d, J = 8.6Hz), 7.41-7.52 (4H, m), 8.15-
8.24 (4H, m). (7) Trifluoromethanesulfonic acid was added to a mixed solution of the compound (866 mg) obtained in (6) and anisole (1.3 ml) and trifluoroacetic acid (13 ml) with stirring under ice-cooling. (0.42 ml), and the mixture was stirred at the same temperature for 30 minutes. The trifluoroacetic acid was concentrated under reduced pressure, the residue was washed with hexane and ether, dried under reduced pressure, saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate, and washed with saturated saline.
The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (721 mg) as a powder.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1711, 1647, 1607, 1521, 1441, 1405, 1346. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ pp
m: 1.43-2.36 (8H, m), 2.65-2.78 (1H, m), 2.82-3.03 (1
H, m), 3.11-4.22 (7H, m), 4.40-4.53 (1H, m), 4.80-4.
95 (1H, m), 4.98-5.35 (4H, m), 7.42-7.55 (4H, m), 8.2
2 (4H, d, J = 8.6Hz). Reference Example 2 (2S, 4S) -4-mercapto-2-[(3S) -3
-[2- [N-methyl-N- (4-nitrobenzyloxycarbonyl) amino] ethyl] pyrrolidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) -pyrrolidine (3R) -3- [ Reference Example 1- (6), (7) using 2- [N-methyl-N- (4-nitrobenzyloxycarbonyl) amino] ethyl] pyrrolidine hydrochloride (99 mg).
The title compound (176 mg) was obtained as a powder in the same manner as in the above.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1706, 1652, 1607, 1521,1439, 1404, 1346, 1
321. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ pp
m: 1.40-2.33 (8H, m), 2.57-2.80 (1H, m), 2.95 (3H, br
s), 3.08-3.98 (8H, m), 4.35-4.54 (1H, m), 4.97-5.38
(4H, m), 7.49-7.53 (4H, m), 8.22-8.24 (4H, m). Reference Example 3 (2S, 4S) -2-[(3S) -3- [2- [2,3
-Bis (4-nitrobenzyloxycarbonyl) guanidino] ethyl] pyrrolidin-1-ylcarbonyl] -4
-Mercapto-1- (4-nitrobenzyloxycarbonyl) pyrrolidine (3S) -3- [2- [2,3-bis (4-nitrobenzyloxycarbonyl) guanidino]
Ethyl] pyrrolidine hydrochloride (4.5 g) was used to obtain the title compound (5.5 g) as a powder in the same manner as in Reference Examples 1- (6) and (7).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1731, 1711, 1643, 1609,1574, 1522, 1596, 1
437, 1412, 1380, 1347, 1323. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ pp
m: 1.47-2.37 (8H, m), 2.68-2.75 (1H, m), 2.88-3.06 (1
H, m), 3.10-4.15 (9H, m), 4.91-4.03 (1H, m), 4.97-5.
35 (6H, m), 7.41-7.59 (6H, m), 8.15-8.33 (6H, m). Reference Example 4 (2S, 4S) -2-[(3S) -3- [2- [2,3
-Bis (4-nitrobenzyloxycarbonyl) guanidino] ethyl] pyrrolidin-1-ylcarbonyl] -4
-Mercapto-1-methylpyrrolidine (1) (2S, 4S) -4- (4-methoxybenzylthio) -1-methyl-2-pyrrolidinecarboxylic acid (346
triethylamine (0.19 ml) and pivaloyl chloride (0.16 ml) were added to a solution of (mg)) in tetrahydrofuran (7 ml) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. This reaction solution was added to (3S) -3- [2- [2,3-bis (4-nitrobenzyloxycarbonyl) guanidino]
Ethyl] pyrrolidine (690 mg) and N, N-diisopropylethylamine (1.29 ml) were added, and the mixture was stirred at 0 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with water, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 10/1) to obtain powdery (2S, 4S) -2-[(3S)-
3- [2- [2,3-bis (4-nitrobenzyloxycarbonyl) guanidino] ethyl] pyrrolidin-1-ylcarbonyl] -4- (4-methoxybenzylthio)-
1-Methylpyrrolidine (710 mg) was obtained.

Nuclear magnetic resonance spectrum (400 MHz, CD
Cl ₃ ) δ ppm: 1.42-1.90 (8H, m), 2.01-2.62 (3H, m),
2.29, 2.31 (3H, sx2), 3.03-3.17 (4H, m), 3.37-3.94 (3
H, m), 3.69, 3.71 (2H, sx2), 3.79, 3.80 (3H, sx2),
5.22 (2H, s), 5.28 (2H, s), 6.80-6.90 (2H, m), 7.17-7.
24 (2H, m), 7.51-7.58 (4H, m), 8.18-8.27 (4H, m). (2) Anisole (1.2 ml) of the compound (709 mg) obtained in (1), trifluoroacetic acid (5.86m
To the mixed solution of 1), trifluoromethanesulfonic acid (0.38 ml) was added with stirring under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The trifluoroacetic acid was concentrated under reduced pressure, the residue was washed with hexane and ether, dried under reduced pressure, saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate, and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (764 mg) as a powder.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1737, 1644, 1610, 1575,1523, 1450, 1379, 1
348, 1323. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ pp
m: 1.51-2.42 (8H, m), 2.75-3.98 (10H, m), 3.11, 3.13
(3H, sx2), 4.70-4.75 (1H, m), 5.23, 5.24 (2H, sx2),
5.29 (2H, s), 7.53-7.57 (4H, m), 8.19-8.25 (4H, m),
8.35-8.03 (1H, m). Reference Example 5 (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- [3
-(4-Nitrobenzyloxycarbonyl) aminopropyl] pyrrolidin-1-ylcarbonyl] pyrrolidine Reference Example 1 using (3S) -3- (4-nitrobenzyloxycarbonylaminoethyl) pyrrolidine hydrochloride (544 mg) A powdery title compound (663 mg) was obtained in the same manner as in (6) and (7).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1711, 1646, 1607, 1521, 1441, 1405, 1346. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ pp
m: 1.30-2.32 (9H, m), 2.64-2.96 (2H, m), 3.10-4.20 (8
H, m), 4.48-4.53 (1H, m), 4.80-4.93 (1H, m), 5.14-5.
38 (4H, m), 7.41-7.55 (4H, m), 8.18-8.23 (4H, m). Reference Example 6 (2S, 4S) -4-mercapto-2-[(3S) -3
-[3-N-methyl-N- (4-nitrobenzyloxycarbonyl) aminopropyl] pyrrolidin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine (3S) -3- [3- N-methyl-N
Reference Example 1 using-(4-nitrobenzyloxycarbonyl) aminoethyl] pyrrolidine hydrochloride (743 mg).
-The title compound (1.15 g) as a powder was obtained in the same manner as in (6) and (7).

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1705, 1651, 1607, 1521, 1439, 1403, 1346, 1
320. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ pp
m: 1.33-2.32 (9H, m), 2.65-2.75 (1H, m), 2.80-4.15 (1
0H, m), 2.95 (3H, s), 4.41-4.53 (1H, m), 4.97-5.38 (4
H, m), 7.42-7.53 (4H, m), 8.16-8.23 (4H, m). Reference Example 7 (2S, 4S) -2-[(3S) -3- [3- [2,3
-Bis (4-nitrobenzyloxycarbonyl) guanidino] propyl] pyrrolidin-1-ylcarbonyl]-
Reference Example 1- (6) using 4-mercaptopyrrolidine (3S) -3- [3- [2,3-bis (4-nitrobenzyloxycarbonyl) guanidino] propyl] pyrrolidine hydrochloride (1.04 g),
In the same manner as in (7), the title compound (1.03
g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1712, 1643, 1608, 1574,1521, 1496, 1438, 1
407, 1379, 1346, 1323. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ pp
m: 1.30-2.36 (10H, m), 2.64-2.75 (1H, m), 2.82-4.15
(10H, m), 4.42-4.53 (1H, m), 4.97-5.35 (6H, m), 7.43
-7.57 (6H, m), 8.16-8.34 (6H, m). Reference Example 8 (2S, 4S) -2-[(3S) -3- [3- [2,3
-Bis (4-nitrobenzyloxycarbonyl) guanidino] propyl] -4-mercapto-1-methylpyrrolidin-1-ylcarbonyl] pyrrolidine (3S) -3- [3- [2,3-bis (4-nitrobenzyl) Reference Example 4- (1) using (oxycarbonyl) guanidino] propyl] pyrrolidine hydrochloride (1.04 g),
In the same manner as in (2), the title compound (1.03
g) was obtained.

Infrared absorption spectrum (KBr) νmax
cm ^-1 : 1735, 1641, 1574, 1522, 1495, 1439, 1379, 1
347, 1323. Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ
ppm: 1.40-2.38 (9H, m), 2.47, 2.50 (3H, sx2), 2.68-
2.82 (1H, m), 2.93-3.96 (12H, m), 5.22 (2H, s), 5.28
(2H, s), 7.53-7.57 (4H, m), 8.19-8.27 (4H, m). Reference Example 9 (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -2- [(3S) -3- [2
-[(4-nitrobenzyloxycarbonyl) acetimidoyl] aminoethyl] pyrrolidin-1-ylcarbonyl] pyrrolidine (3R) -3- [2-[(4-nitrobenzyloxycarbonyl) acetimidoyl] aminoethyl] The target compound can be synthesized using pyrrolidine hydrochloride in the same manner as described in Reference Examples 1- (6) and (7). Reference Example 10 (2S, 4S) -4-mercapto-1-methyl-2-
[(3S) -3- [2-[(4-nitrobenzyloxycarbonyl) acetimidoyl] aminoethyl] pyrrolidin-1-ylcarbonyl] pyrrolidine (3R) -3- [2-[(4-nitrobenzyloxy Using carbonyl) acetimidoyl] aminoethyl] pyrrolidine hydrochloride, the target compound can be synthesized in the same manner as described in Reference Examples 4- (1) and (2). Reference Example 11 (2S, 4S) -4-mercapto-1- (4-nitrobenzyloxycarbonyl) -2-[(3S) -3- [3
-[(4-nitrobenzyloxycarbonyl) acetimidoyl] aminopropyl] pyrrolidin-1-ylcarbonyl] pyrrolidine (3S) -3- [3- [2-[(4-nitrobenzyloxycarbonyl) acetimidoyl] Aminopropyl]
The target compound can be synthesized using pyrrolidine hydrochloride in the same manner as described in Reference Examples 1- (6) and (7). Reference Example 12 (2S, 4S) -2-[(3S) -3- [3-[(4-
Nitrobenzyloxycarbonyl) acetimidoyl]
Aminopropyl] pyrrolidin-1-ylcarbonyl]-
1-methyl-4-mercaptopyrrolidine (3S) -3- [3- [2-[(4-nitrobenzyloxycarbonyl) acetimidoyl] aminopropyl]
The target compound can be synthesized using pyrrolidine hydrochloride in the same manner as described in Reference Examples 4- (1) and (2). Reference Example 13 (2S, 4S) -4-mercapto-1-methyl-2-
[(3S) -3- [2- (4-nitrobenzyloxycarbonyl) aminoethyl] pyrrolidin-1-ylcarbonyl] pyrrolidine (3R) -3- [2- (4-nitrobenzyloxycarbonyl) aminoethyl] pyrrolidine The target compound can be synthesized using the hydrochloride in the same manner as in the method described in Reference Example 4- (1) and (2). Reference Example 14 (2S, 4S) -4-mercapto-1-methyl-2--2-
[(3S) -3- [2-N-methyl-N- (4-nitrobenzyloxycarbonyl) aminoethyl] pyrrolidin-1-ylcarbonyl] pyrrolidine (3R) -3- [2- [N-methyl-N The target compound can be synthesized using-(4-nitrobenzyloxycarbonyl) amino] ethyl] pyrrolidine hydrochloride in the same manner as described in Reference Examples 4- (1) and (2). Reference Example 15 (2S, 4S) -4-mercapto-1-methyl-2-
[(3S) -3- [3- (4-Nitrobenzyloxycarbonyl) aminopropyl] pyrrolidin-1-ylcarbonyl] pyrrolidine Using (3S) -3- (4-nitrobenzyloxycarbonylaminoethyl) pyrrolidine hydrochloride Reference Example 4-
The target compound can be synthesized in the same manner as in the methods described in (1) and (2). Reference Example 16 (2S, 4S) -4-mercapto-1-methyl-2-
[(3S) -3- [3- (4-nitrobenzyloxycarbonyl) aminopropyl] pyrrolidin-1-ylcarbonyl] pyrrolidine (3S) -3- [3-N-methyl-N- (4-nitrobenzyloxy) Using carbonyl) aminoethyl] pyrrolidine hydrochloride, the target compound can be synthesized in the same manner as described in Reference Examples 4- (1) and (2). Test Example 1 Antibacterial activity test The minimum inhibitory concentration (MIC μg / ml) against various pathogenic bacteria was measured for the compound of the present invention. In addition, the closest prior art WO97 / 41123 as a comparative compound
The compound A described in Example 7 was used. Table 2 shows the results. The compound of Example 3 of the present invention showed excellent antibacterial activity as compared with Compound A. The chemical structural formula of compound A is as follows.

[0157]

Embedded image [Table 2] ―――――――――――――――――――――――――――――――――――― Minimum growth inhibitory concentration (MIC μg / ml) Species Compound of Example 3 Compound A ―――――――――――――――――――――――――――――――――― Staphylococcus aureus 209P ≦ 0.012 ≦ 0.012 Enterococcus faecalis 681 0.20 0.39 Escherichia coli NIHJ ≤0.012 ≤0.012 Escherichia coli 609 ≤0.012 0.02 Enterobacter cloacae 963 0.05 0.10 Proteus vulgalis 1420 0.10 0.20 Morganella morganii 1510 0.05 0.10 Pseudomonas aeruginosa 1001 0.025 0.05-Pseudomonas aeruginosa 1001 0.025 0.05 ―――――――――――――――――――――――――――――― Formulation Example 1. (Injection) 500 mg of the compound of Example 1 is dissolved in 5 ml of distilled water for injection, passed through a filter for sterilization, and lyophilized to prepare a lyophilized preparation for injection. Formulation Example 2. (Capsule) Compound of Example 1 50 mg Lactose 128 mg Maize starch 70 mg Magnesium stearate 2 mg 250 mg The powder of the above formulation was mixed and passed through a 60-mesh sieve. Agent. Formulation Example 3. (Tablets) Compound of Example 1 50 mg Lactose 126 mg Corn starch 23 mg Magnesium stearate 1 mg 200 mg The powder of the above formulation was mixed, wet granulated using corn starch paste, dried, and then tableted with a tablet machine. 1
Tablets 200 mg tablets. The tablets can be sugar-coated as needed.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/541 A61K 31/541 A61P 31/04 A61P 31/04 (72) Inventor Katsuya Ishikawa Shinagawa-ku, Tokyo 1-58 Hiromachi, Sankyo Co., Ltd. (72) Inventor Katsuhiko Kojima 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 1-58 Sankyo Co., Ltd. 1-2-58 Sankyo Co., Ltd.

Claims (9)

[Claims] 1. A compound of the general formula (I) [In the formula, n represents 2, 3 or 4, R ¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R ² is the same or different among n repeating units,
R ³ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R ⁴ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; An alkyl group having 1 to 4 carbon atoms having a group (the substituent is a hydroxyl group, a halogen atom, a carbamoyl group, a carbamoyl group substituted with an alkyl group having 1 to 4 carbon atoms, a carbamoyloxy group, A carbamoyloxy group substituted with an alkyl group, an alkoxy group having 1 to 4 carbon atoms, an amino group or an amino group substituted with an alkyl group having 1 to 4 carbon atoms), a cycloalkyl group or a formula -C (= NH) group (wherein, R ⁵ is a hydrogen atom, a 1 to 4 carbon alkyl group or an amino group carbon atoms) represented by R ⁵ indicates, or, R ³ and R ⁴ are bonded to each other Group Or an alkylene group having 2 to 6 carbon atoms which may be interposed through one oxygen atom, nitrogen atom or sulfur atom (the nitrogen atom may be substituted by an alkyl group having 1 to 4 carbon atoms) Good)
Is shown. Or a pharmacologically acceptable salt or derivative thereof. 2. The compound according to claim 1, wherein n is 2. 3. The compound according to claim 1, wherein R ¹ is a hydrogen atom or a methyl group. 4. The compound according to claim 1, wherein R ² is a hydrogen atom. 5. The compound according to claim 1, wherein R ³ is a hydrogen atom. 6. The method according to claim 1, wherein R ⁴ is a group represented by the formula -C (=
NH) A compound represented by R ⁵ (wherein R ⁶ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an amino group). 7. The compound according to claim 1, wherein R ⁴ is a formimidyl group, an acetimidoyl group or an amidino group. 8. The compound according to claim 1, wherein R ⁴ is an amidino group. 9. A medicament comprising the compound according to claim 1 as an active ingredient.