JPS63203685A - Bicyclic beta-lactam carboxylic acid and its production - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] [Summary of the invention] This invention is based on the following formula (I): H.

(wherein R1 is lower alkyl substituted by hydroxy or protected hydroxy; R2 is carboxy or 4!1 functionally modified carboxy;
R1 is hydrogen, amino, mono- or di-substituted amino,
carbamoyl, hydroxy, protected hydroxy, carbamoyloxy, lower alkoxy, halogen, lower alkanoyl, sulfamoyl, or heteroarylthio; each of R4 and R2 is, independently of one another, hydrogen, lower alkyl, hydroxy, protected represents hydroxy, lower alkoxy, halogen, amino, protected amino, lower alkanoylamino, or carbamoyl; or R4 and R3 together represent methylenedioxy; Y is of the formula -〇-1-S-1 or -NR,-
represents a group, R& is hydrogen or lower alkyl; A
l represents a lower alkylene group or an unsubstituted or substituted phenylene group; and At is a direct bond or a lower alkylene group), a salt of a compound of formula (1) having a salt-forming group; It relates to medicaments containing the compounds and to the use of these compounds for the manufacture of medicaments or as active ingredients of medicaments.

[Specific Description] Within the scope of this invention, the definitions used in this specification have the following meanings.

The functionally modified carboxy R2 is in particular an esterified carboxy which can be cleaved under physiological conditions, or a protected carboxy group A'.

can be cleaved (i.e. metabolized) under physiological conditions
Esterified carboxy R8 is in particular an acyloxymethoxycarbonyl group or, alternatively, an acylaminomethoxycarbonyl group, where acyl is, for example, a group of an organic carboxylic acid, in particular an unsubstituted or, for example, amino-substituted lower alkane carbonyl group. Acids or arene carboxylic acids, such as the benzoic acid Φ group, or acyloxymethyl constitute the lactone group. Such groups are, for example, lower alkanoyloxymethoxycarbonyl, amino-lower alkanoyloxymethoxycarbonyl, especially α-amino-lower alkanoyloxymethoxycarbonyl, and lower alkanoylaminomethoxycarbonyl.

Other esterified carboxy groups R2 that can be cleaved under physiological conditions are, for example, 3-phthalidyloxycarbonyl,
1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, l-lower alkoxy-lower alkoxycarbonyl, or 2- substituted by lower alkyl or phenyl at the 5-position of the dioxolene ring
Oxo-1,3-dioxolen-4-ylmethoxycarbonyl.

Mono- or di-substituted amino R1 is, for example, lower alkyl, hydroxy-lower alkyl, carbamoyl-lower alkyl, amino-lower alkyl which may be N-lower alkylated, e.g. amino- lower alkyl, lower alkylamino-lower alkyl or di-lower alkylamino-lower alkyl, heteroaryl, heteroaryl-lower alkyl and/or N-
Azaheterocyclyl - amino mono- or di-substituted by lower alkyl, or aminomethyleneamino, guanidino, N-azaheterocyclylamino or protected amino.

Heteroaryl in heteroaryl-lower alkyl or in heteroarylthio R1 as a substituent of the amine group R3 in particular has 1 to 4 ring nitrogen atoms and is bonded by a ring carbon atom. monocyclic 5- or 6-membered heteroaryl groups, e.g. pyrrolyl, e.g. 2- or 3
-pyrrolyl, imidazolyl, e.g. 2- or 4-imidazolyl, pyrazolyl, e.g. 3- or 4-pyrazolyl, triazolyl, e.g. IH-1,3,4-triazol-2-yl or l)[-1,2°4 -triazol-3-yl, tetrazolyl, such as IH- or 2H-tetrazol-5-yl, pyridyl, such as 2-13- or 4-pyridyl, or pyrimidyl, such as 2-14- or 5-pyrimidyl.

N-Azaheterocyclyl as substituent R1 or in amino R3 substituted by N-azaheterocyclyl-lower alkyl has, for example, 1 to 4 ring nitrogen atoms and is bonded by an uncharged ring nitrogen atom. Monocyclic 5-
membered heteroaryl groups, such as l-pyrrolyl, l-imidazolyl, 1-pyrazolyl, IH-1,2,4-1-riazol-1-yl, 1lI-1,3,4-)riazol-1-yl, I H-tetrazol-1-yl, or 2
II-tetrazol-2-yl21 Monocyclic partially saturated 6-membered heteroaryl groups having from 1 to 3 ring nitrogen atoms and bonded by uncharged ring nitrogen atoms, such as 1,4-dihydropyrido -1-yl; or a monocyclic saturated ring having from 1 to 3 ring nitrogen atoms and optionally additional ring heteroatoms selected from the group consisting of sulfur and oxygen, and bonded by an uncharged ring nitrogen atom; 5- or 6-membered azaheterocyclyl groups, such as pyrrolidin-1-yl,
piperidin-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl, and derivatives thereof, such as 1,3-dihydro-isoindol-2-yl or 1.2.3. 4-tetrahydro-inquinolin-2-yl.

The heteroaryl and N-azaheterocyclyl groups mentioned above can be unsubstituted or substituted, for example with the following substituents: hydroxy, lower alkoxy,
Halogen, lower alkylthio, phenylthio, lower alkyl, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, carbamoyloxy-lower alkyl, halo-lower alkyl, N-lower alkylated optionally amino-lower alkyl, such as amino-lower alkyl, lower alkylamino-lower alkyl or di-lower alkylamino-lower alkyl, lower alkanoylamino-lower alkyl, sulfo-lower alkyl,
lower alkanoyl, optionally substituted amino,
For example amino, lower alkylamino, di-lower alkylamino or lower alkanoylamino, carboxy or sulfo which may be functionally modified, for example carboxy, lower alkoxycarbonyl, carbamoyl, cyano, sulfo or sulfamoyl, pyridyl, for example 2 −
7- or di-substituted by 13- or 4-pyridyl, and/or phenyl, or phenyl, which is substituted by lower alkyl, lower alkoxy and/or halogen, and can be di-substituted N-azaheterocyclyl moieties having ring carbon atoms may also be substituted by oxo. The substituents are preferably attached to a ring carbon atom and, in the case of a saturated azaheterocyclyl group, also to a second ring nitrogen atom. The lower alkyl in the heteroaryl-lower alkyl and N-azaheterocyclyl-lower alkyl groups has 1 to 4, especially 1 or 2 carbon atoms.

Phenylene A, is l, 2-11,3- or especially 1,4-
Phenylene, which is unsubstituted or substituted, for example by lower alkyl, hydroxy, lower alkoxy, amino or halogen.

In this specification, the term "lower" used in connection with the definition of a group or compound means that the group or compound described has 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise specified. means containing atoms.

Lower alkyl RI substituted by hydroxy is especially
lower alkyl substituted by hydroxy in the α-position with respect to the benem ring structure, and for example ■-hydroxyprop! -yl, 2-hydroxyprop-2
-yl, l-hydroxybr-1-yl, and especially hydroxymethyl or 1-hydroxyethyl, while hydroxy-lower alkyl as a substituent of the group R8 is, for example, 1-hydroxyethyl or especially 2-hydroxyethyl. and hydroxymethyl as a further substituent on the heteroaryl or azaheterocyclyl group.

Lower alkanoyloxymethoxycarbonyl is, for example,
Acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl. α-Amino-lower alkanoyloxymethoxycarbonyl is, for example, glycyloxymethoxycarbonyl, L-valyloxymethoxycarbonyl or L-leucyloxymethoxycarbonyl. Lower alkanoylaminomethoxycarbonyl is, for example, acetaminomethoxycarbonyl. l-Lower alkoxycarbonyloxy-lower alkoxycarbonyl is, for example, ethoxycarbonyloxymethoxycarbonyl or l-ethoxycarbonyloxyethoxycarbonyl. 1-Lower alkoxylower alkoxycarbonyl is, for example, methoxymethoxycarbonyl or 1-methoxyethoxycarbonyl. A 2-oxo-1,3-dioxolen-4-ylmethoxy group which is unsubstituted or substituted in the 5-position of the dioxolene ring by lower alkyl or phenyl is especially 5-phenyl- and especially 5-methoxy-2 -oxo-1,3-dioxolen-4-ylmethoxy group.

Lower alkyl as the radical Ra, Rs or Rs or as a substituent of the phenylene radical A, or of the radical R3, is, for example, ethyl, n-propyl, isopropyl or n
-butyl, but especially methyl.

Carbamoyl-lower alkyl is, for example, carbamoylmethyl or 2-carbamoylethyl.

Amino-lower alkyl is, for example, aminomethyl or 2-aminoethyl, while lower alkylamino-lower alkyl is, for example, methylaminomethyl, ethylaminomethyl, 2-methylaminoethyl or 2-ethylaminoethyl; -lower alkylamino-lower alkyl is, for example, dimethylaminomethyl, 2-dimethylaminoethyl or 2-diethylaminoethyl; and lower alkanoylamino-lower alkyl is, for example, acetoxymethyl, 2-acetoxyethyl or formylaminomethyl. .

Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.

Halogens are, for example, chlorine, bromine and especially fluorine.

Lower alkylthio is, for example, methylthio, ethylthio or n-propylthio.

Lower alkanoyloxy-lower alkyl is, for example, acetoxymethyl or 2-acetoxyethyl.

Carboxy-lower alkyl is, for example, carboxymethyl, or l-carboxy-12-carboxy- or 1
．． 2-dicarboxy-ethyl.

Carbamoyloxy-lower alkyl is, for example, carbamoyloxymethyl or 2-carbamoyloxyethyl.

Halo lower alkyl is, for example, chloromethyl, bromomethyl, 2-chloroethyl or 2,2-dichloroethyl.

Sulfo-lower alkyl is, for example, sulfomethyl or 2-
It is sulfoethyl.

Lower alkylamino is for example methylamino, ethylamino, n-propylamino, isopropylamine or n-
butylamino, while di-lower alkylamino is, for example, dimethylamino, diethylamino, di-n-propylamine or diisopropylamino, and lower alkanoylamino is, for example, formylamino, acetylamino or propionylamino.

Lower alkoxycarbonyl is, for example, methoxycarbonyl or ethoxycarbonyl.

Lower alkanoyl is, for example, formyl or acetyl.

Lower alkylene A and A2 are in particular straight-chain lower alkylene radicals having 1 to 5 carbon atoms, such as methylene, ethylene, 1,3-propylene or 1,4-butylene radicals, but in addition also 2-5 carbon atoms. It may also be a branched lower alkylene radical having 5 carbon atoms, for example methylene, ethylene or l, each substituted by methyl.
, 3-propylene group, or ethylene group substituted with ethyl. Such branched lower alkylene groups are, for example, ethylidene, 1,2-propylene, 1,2-butylene, 1,3-butylene or 2-methyl-1,3-butylene groups.

In compounds of formula (1) in which R1 and R2 together represent methylenedioxy, the twice-bonded WtA group methylenedioxy is formed between two adjacent carbon atoms of the phenyl ring,
In particular, it is bonded to carbon atoms 3 and 4.

Examples of heteroaryl in heteroaryl-lower alkyl or in heteroarylthio R3 as a substituent of the amino group R4, as a substituent of the amino group R3 are unsubstituted pyridyl or pyridyl substituted by carbamoyl. , for example 2-13- or 4-pyridyl, or unsubstituted IH-tetrazol-5-yl, or LH-tetrazol-5-yl (lower alkyl, carboxy-lower alkyl, sulfo-lower alkyl, N-lower alkylated or carbamoyl-lower alkyl). N-azaheterocyclyl as radical R1 or in amino R1 substituted by N-azaheterocyclyl-lower alkyl is, for example, unsubstituted l-imidazolyl, or l-imidazolyl substituted by lower alkyl, unsubstituted lH-tetrazole- IH-tetrazol-1-yl substituted by 1-yl or lower alkyl, unsubstituted 1
．． 4-dihydropyrid-1-yl, or 1,4-dihydropyrid-1-yl (substituted by lower alkyl, hydroxy, oxo and/or carbamoyl), pyrrolidin-1-yl, unsubstituted piperidin-I-yl, or piperidin-1-yl (substituted by lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, hydroxy or carbamoyl), morpholine-4
-yl, thiomorpholin-4-yl, or piperazin-I-yl, which is unsubstituted or substituted by lower alkyl, carbamoyl-lower alkyl, carbamoyl, lower alkanoyl or pyridyl.

As radical R+, hydroxymethyl and especially l-hydroxyethyl are preferred. Preferred esterified carboxy groups R2 which can be cleaved under physiological conditions are, for example, lower alkanoyloxymethoxycarbonyl, such as acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, and l-lower alkoxycarbonyloxy-
Lower alkoxycarbonyl, such as 1-ethoxycarbonyloxyethoxycarbonyl. R3 is preferably carbamoyl, carbamoyloxy, amino, methylamino, dimethylamino, (2-hydroxyethyl)-
Amino, bis-(2-hydroxyethyl)-amino, (
4-pyridyl)-amino, (3-pyridyl)-amino,
Morpholin-4-yl, piperazin-1-yl, 4-carbamoylpiperazin-1-yl, 3-hydroxy-4
-oxo-1,4-dihydropyridin-1-yl, IH
-tetrazol-1-yl, pyridin-4-ylthio or 1-methyl-I H-tetrazol-5-ylthio. A preferred meaning of radicals R4 and R3 is hydrogen.

Y is preferably a 10-group.

In preferred compounds of formula (1), A1 is lower alkylene having 1 or 2 carbon atoms, and Az
is a direct bond or a lower alkylene group having 1 or 2 carbon atoms, the group At-R5 being arranged in the 0-1m- or especially p-position relative to the group Y.

Functional groups present in the compounds of formula (1), such as hydroxy, carboxy or amine groups, are optionally protected by conventional protecting groups used in penem, penicillin, cephalosporin and peptide chemistry. Such protecting groups protect the functional group in question from undesired condensation reactions, substitution reactions, etc. during the synthesis of the compound of formula (I) from its precursors. Such protecting groups can be easily removed, ie, without undesired side reactions resulting from, for example, solvolysis or reduction.

Protective groups of this type and their introduction and removal methods are described, for example, in J, F, W, McO+sie, "Protecti
ve Groups inOrganic Chea+
1stry”, Plenum Presss London, New York, 1973; TJ, Greene,
”Protective Groups in Org
"Anic 5 Synthesis", WiteyS New York, 1981; "The Peptides",
Vol I, 5 chroeder and l, uebke
, Academic Press, London, New York, 1965 i and l1ouben-Weyl+
”Methoden der Organlschen
Chemie”, Vol, 15/1. Georg
ThiemeVerlags Stuttgart, 197
4, is described.

In the compounds of formula (I), the hydroxyl group can be protected, for example by an acyl group. Suitable acyl groups are, for example, lower alkoxycarbonyl which is unsubstituted or substituted by halogen, such as 2-bromoethoxycarbonyl or 2,2.2-1-lichloroethoxycarbonyl, lower alkenyloxycarbonyl, such as allyl. Oxycarbonyl, lower alkenyloxyoxalyl, such as allyloxyoxalyl, or unsubstituted or nitro-substituted phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl. Other suitable hydroxy protecting groups are, for example, tri-substituted silyls, such as tri-lower alkylsilyls, such as trimethylsilyl, dimethyl-(2,3-dimethylbra 2
-yl)-silyl, or tert-butyl-dimethyl-silyl. Tri-lower alkylsilyl, lower alkenyloxyoxalyl and lower alkenyloxycarbonyl are preferred as hydroxy protecting groups.

Carboxy groups are usually protected in esterified form, which ester groups can be protected under mild conditions, e.g. It can be easily cleaved under neutral or neutral hydrolytic conditions.

Such esterified carboxy groups contain as esterifying group, in particular, a lower alkyl group which is branched in the 1-position or suitably substituted in the 1- or 2-position. Suitable carboxy groups in esterified form are in particular benzyloxycarbonyl, unsubstituted or substituted by nitro or by lower alkoxy such as methoxy, such as 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, lower alkanoylmethoxycarbonyl, e.g. acetonyloxycarbonyl, halo lower alkoxycarbonyl, e.g. 2-halo lower alkoxycarbonyl, e.g. 2.2.2-)lichloroethoxycarbonyl or 2
-bromoethoxycarbonyl, lower alkenyloxycarbonyl, such as allyloxycarbonyl, or 2
Ethoxycarbonyl substituted in the -position by tri-lower alkylsilyl, such as 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl. Preferred protected carboxy groups are 4-nitrobenzyloxycarbonyl and lower alkenyloxycarbonyl, especially the allyloxycarbonyl group, and by tri-lower alkylsilyl in the 2-position, for example trimethylsilyl or ';-n-butyl-methyl-silyl. is an ethoxycarbonyl group substituted with

A protected amino group can be, for example, in the form of an acylamino group, a nitro group, or an azido group, which can be easily cleaved. In the corresponding acylamino groups, the acyl group is, for example, an acyl group of a lower alkanecarboxylic acid which is unsubstituted or substituted, for example by halogen or phenyl, or in particular an acyl group of a carbonic acid half ester. Such acyl groups include, for example, lower alkenyloxycarbonyl, such as allyloxycarbonyl, unsubstituted or substituted benzyloxycarbonyl,
For example, 4-nitrobenzyloxycarbonyl, 2-halo lower alkoxycarbonyl, e.g. 2.2.2-)
Lichloroethoxycarbonyl or 2-bromoethoxycarbonyl, or 2-(trisubstituted silyl)-ethoxycarbonyl, such as 2-tri-lower alkylsilylethoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl -silyl)-ethoxycarbonyl. Preferred protected amino groups are, for example, azide, nitro, lower alkenyloxycarbonylamino, such as allyloxycarbonylamino, and unsubstituted or nitro
IA is benzyloxycarbonylamino.

Salts of the compounds of this invention are particularly pharmaceutically acceptable non-toxic salts of compounds of formula (1). Such a salt has the formula (1
) and in particular metal or ammonium salts, such as alkali metal salts and alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts, and ammonia or suitable salts with organic amines such as lower alkyl amines such as triethylamine, hydroxy-lower alkyl amines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine, carvone, Basic aliphatic esters of acids, such as 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkylene amines, such as l-ethylpiperidine, cycloalkylamines, such as dicyclohexylamine, or benzyl amines, such as N,N'-dibenzyl. It is a salt of ethylenediamine, dibenzylamine or N-benzyl-β-phenethylamine. Compounds of the formula (RI) having a basic group, such as an amino group R3, can form acid addition salts,
For example, inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or suitable organic carboxylic or sulfonic acids such as acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, citric acid, benzoic acid, mandelic acid, malic acid, Acid addition salts can be formed with ascorbic acid, methanesulfonic acid or 4-toluenesulfonic acid.

Compounds of formula (I) having acidic and basic groups are in the form of internal moieties, i.e. zsyitter ions (zsyitter ions).
ion).

For isolation or purification purposes, it is also possible to use salts that are not suitable as pharmaceuticals. Only pharmaceutically acceptable non-toxic salts can be used therapeutically and are therefore preferred.

Penem compounds of formula (1) can have additional chiral centers in formula R2. For example, 1- as 5 R1
Hydroxyethyl can be present in the R-1S-1 or racemic R,S-configuration.

In preferred penem compounds of formula (1), the group R1 having an asymmetric carbon atom, especially l-hydroxyethyl, is R-
Has an arrangement. The invention therefore relates to pure diastereomers and diastereomeric mixtures of compounds of formula (1) having additional chiral centers in the radical R4.

The compounds of formula (1) have valuable pharmacological properties or can be used as intermediates for the preparation of such compounds having valuable pharmacological properties. Compounds of formula (r) in which the functional group is in the unprotected form, and pharmaceutically acceptable salts of such compounds having salt-forming groups, have antibacterial activity. For example, they have been tested in vitro against Gram-positive and Gram-negative cocci, including methicillin-resistant Staphylococci, such as Staphylococcus aureus.
reus) S. Staphylococcus evidermizois (Harikokuho■92 Machirikisuibio 1 school, Stre. tococcus 5. pyogenes), Streptococcus pneumoniae (SLre.
tococcus[r! Streptococcus faecalis and Streptococcus faecalis
), and Haemophilus influenzae), less than 0.1~
At a minimum concentration of about 8 μ/ml, and Enterobacteriaceae s such as N. coli μ! 5cherichia c
oli) and Talebscilla pneumonia (Klebs
Pseudomonas aeruginosa), Pseudomonas aeruginosa (Nasa), as well as anaerobes such as Bacteroides sp, (Bact
eroides sp,) in vivo, such as Staphylococcus aureus and Nigelisha
For mice systemically infected with Escherichia coli, after subcutaneous or oral administration of the compounds of this invention, the E.
D. value is obtained.

The novel compounds of this invention can be used as antibacterial antibiotics for the treatment of infections, for example in the form of corresponding pharmaceutical preparations, administered orally or parenterally.

Compounds of formula (r) in which at least one functional group present is in protected form can be used as intermediates for the preparation of the abovementioned pharmacologically active compounds of formula (1). .

This invention particularly provides that R and R1 have the above meanings, R
1 is hydroxy, protected hydroxy, carbamoyloxy, halogen or heteroarylthio, R4
and R3 are each independently hydrogen, lower alkyl, halogen, carbamoyl, hydroxy, protected hydroxy, lower alkoxy, amino, protected amino, or lower alkanoylamino, and A and R
each of 1 represents methylene, and Y is of the formula -〇-
or -S-, pure optical isomers of the above compounds of formula (I) and mixtures of these optical isomers, as well as compounds of formula (1) having a salt-forming group. Regarding salt.

This invention particularly provides that R3 is lower alkyl substituted by hydroxy in the α-position; Rt is carboxy;
or esterified carboxy which can be cleaved under physiological conditions and iRs is hydrogen, amino, or amino (which is
lower alkyl, hydroxy-lower alkyl, carbamoyl-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, or heteroaryl, heteroaryl-lower alkyl and/or N-azaheterocyclyl - mono- or di-substituted by lower alkyl groups); or sulfamoyl, aminomethyleneamino, guanidino, carbamoyl, hydroxy, lower alkoxy, halogen, carbamoyloxy, lower alkanoyl,
N-azaheterocyclyl or heteroarylthio, where heteroaryl is a monocyclic 5- or 6-membered heteroaryl group having 1 to 4 ring nitrogen atoms and bonded by ring carbon atoms; and N-azaheterocyclyl is a monocyclic 5-shell heteroaryl group having 1 to 4 ring nitrogen atoms and bonded by an uncharged ring nitrogen atom, having 1 to 3 ring nitrogen atoms and a monocyclic partially saturated 6- bonded by an uncharged ring nitrogen atom
membered heteroaryl group, or having 1 to 3 ring nitrogen atoms and optionally an additional ring heteroatom selected from the group consisting of sulfur and oxygen and bonded by an uncharged ring nitrogen atom; monocyclic saturated 5- or 6-membered azaheterocyclyl groups, or their benzo derivatives, and these heteroaryl groups and N-azaheterocyclyl groups are unsubstituted or with the following substituents, i.e. Hydroxy, lower alkoxy, halogen, lower alkylthio, phenylthio, lower alkyl, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, carbamoyloxy-lower alkyl,
Halo lower alkyl, optionally N-lower alkylated amino-lower alkyl, such as amino-lower alkyl, lower alkylamino-lower alkyl, di-
lower alkylamino-lower alkyl, lower alkanoylamino-lower alkyl, sulfo-lower alkyl, lower alkanoyl, unsubstituted or substituted amino, such as amino, lower alkylamino, di-lower alkylamino,
lower alkanoylamino, optionally functionally modified carboxy or sulfo, e.g. carboxy,
substituted by lower alkoxycarbonyl, carbamoyl, cyano, sulfo, sulfamoyl, pyridyl, such as 2-13- or 4-pyridyl, and/or tunyl, or phenyl (substituted by lower alkyl, lower alkoxy and/or halogen) and the N-azaheterocyclyl group having a disubstituted ring carbon atom r may also be substituted by oxo; R4 and R2
each independently of one another represents hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen, amino, lower alkanoylamino, or carbamoyl; or R4 and R3 together represent methylenedioxy; Y is a group -0-1-8- or -NR,-, R
6 is hydrogen or lower alkyl; Al is a lower alkylene group, an unsubstituted phenylene group, or a phenylene group (which is substituted by lower alkyl, hydroxy, lower alkoxy, amino or halogen); and 82
is a direct bond or a lower alkylene group, a compound of formula (1
) and mixtures of these optical isomers, as well as salts of the compounds of formula (1) with salt-forming groups.

This invention particularly provides that R+ is hydroxymethyl or 1-hydroxyethyl; R2 is carboxy or esterified carboxy that can be cleaved under physiological conditions; R3
is amino, methylamino, dimethylamino, (2-hydroxyethyl)-amino, bis-(2-hydroxyethyl)-amino, (4-pyridyl)-amino, (3-pyridyl)-amino, morpholin-4-yl , piperazine-
1-yl, 4-carbamoylpiperazin-1-yl, 3
-hydroxy-4-oxo-1,4-dihydropyridin-1-yl, 1lI-tetrazol-1-yl, pyridin-4-ylthio, l-methyl-IH--tetrazol-5-ylthio, carbamoyl, or carbamoyloxy Yes; R4 and R2 represent hydrogen; Y is a group -0-
A1 represents lower alkylene having 1 or 2 carbon atoms; and R2 represents a direct bond or a lower alkylene group having 1 or 2 carbon atoms, 2(1) and mixtures of these optical isomers, as well as salts of said compounds of formula (I) with salt-forming groups.

This invention particularly provides that R, is l-hydroxyethyl;
R2 is carboxy, R1 is amino, methylamino or dimethylamino, each of R4 and R1 is hydrogen, Y represents a group -0-, A is a methylene group, and A2 is a methylene group or an ethylene group, pure optical isomers of said compounds of formula (1), mixtures of these optical isomers, and salts thereof.

The invention particularly relates to the compounds described in the Examples and their pharmaceutically acceptable salts.

The compounds of the invention can be produced by methods known per se.

The novel compounds of this invention can be prepared, for example, by a) the following formula (II): W.

(wherein R+, Rz and At have the meanings described in formula (1), and Y' is the following formula): [wherein Y, At, R3, R4 and R3 are in formula (r) or b) the following formula (■): li2・ [wherein, R+, R3, R-, Rs, At,
or C) the following formula (■): [wherein R+, R3 , Ra , Rs , At
, Ax and Y have the meanings described in formula (1), Z is oxygen or sulfur, and R, / is a protected carboxy group] by an organic compound of trivalent phosphorus. and optionally or necessary converting a protected functional group in the resulting compound of formula (1) to a free functional group and/or optionally converting a protected functional group in the resulting compound of formula (I) into a free functional group; carboxy MR, into an esterified carboxy group that can be cleaved under physiological conditions and/or optionally in the resulting compound of formula (1) the group R1
into a different group R1 and/or optionally the formula (
Separating the resulting mixture of isomeric compounds of 1) into individual isomers and/or optionally converting the resulting compounds with salt-forming groups into salts or converting the resulting salts into free compounds or different Convert to salt.

In the starting compounds of formulas (II) to (IV), a functional group,
For example, free hydroxy groups and free amino groups, for example in the radical R1, are preferably protected by customary protecting groups, such as those mentioned above.

a) The group Y' which can be converted into a group represented by the following formula (Ila): S is, for example,
Hydroxy, or a group that can be exchanged by a nucleophilic reaction.

That is, the compound of formula (summer) where Y is a group -〇- is Y
′ is hydroxy and the compound of formula (■) and the following formula (Va
) : +<.

The phenol represented by is an organic compound of trivalent phosphorus,
For example, in the presence of a tri-lower alkyl phosphine, such as a tri-lower alkyl phosphine, a tri-lower alkyl phosphite, such as triethyl phosphite, or triphenylphosphine, and an azo-dicarboxylic acid diester, such as the corresponding tri-lower alkyl ester, such as azo dicarbonate. in the presence of an acid diethyl ester in an inert aprotic solvent such as a cyclic ether such as tetrahydrofuran or dioxane at room temperature or at a reduced or slightly elevated temperature, e.g. from about -70°C to about 40°C. °C, preferably about 20 °C to about 20 °C
It can be produced by reaction at a temperature in the range of °C.

Compounds of formula (1) in which Y is formula -8- or -NH4- are compounds of formula (II) in which Y' is a group that can be exchanged by a nucleophilic reaction.
) can be produced from the compound.

Such groups Y' which can be exchanged by nucleophilic reactions are in particular esterified hydroxy groups, such as hydrohalides, lower alkyl sulfates, di-lower alkyl phosphates or diaryl phosphates, unsubstituted or By lower alkanecarboxylic acids substituted by oxo or halogen, lower alkanesulfonic acids unsubstituted or substituted by halogen, or benzenesulfonic acids unsubstituted or substituted by halogen or lower alkyl. It is an esterified hydroxy. Such groups Y' can be, for example, halogens, such as chlorine, bromine or iodine, lower alkyl sulfates, such as methyl sulfate or ethyl sulfate, di-lower alkylphosphoryloxy or diarylphosphoryloxy, such as dimethylphosphoryloxy, diethylphosphoryloxy or diphenylphosphoryl. oxy, lower alkanoyloxy unsubstituted or substituted by halogen or oxo, such as formyloxy, acetoxy or acetoacetoxy, lower alkanesulfonyloxy, unsubstituted or substituted by halogen, such as methanesulfonyloxy or trifluoromethanesulfonyloxy, or benzenesulfonyloxy optionally substituted by halcogen or lower alkyl, such as benzenesulfonyloxy, 4-chlorobenzenesulfonyloxy, 4-bromobenzenesulfonyloxy or 4-methylbenzenesulfonyloxy be.

2 ([
I) and, for example, the following formula (Vb):S [wherein the amino group that may be present in the radical R1 is in protected form and Y"
&)-] at least equimolar amounts of a basic condensing agent, such as an alkali metal lower alkoxide, such as sodium methoxide or potassium Lert-butoxide, or an alkali metal hydride or amide, such as sodium in the presence of a hydride or sodium amide, an inert solvent such as an ether, such as dioxane or tetrahydrofuran,
or amides, such as formamide or dimethylbormamide, and, if alkali metal lower alkoxides are used, also in the corresponding lower alkanol, or in a mixture of inert solvents, at room temperature or at reduced or slightly elevated temperatures. at a temperature, for example from about -60°C to about +40°C, especially from about -20°C to about +30°C.
If necessary, the step is carried out in an inert gas atmosphere, for example, in a nitrogen atmosphere.

b) The group XΦ in the starting material of the formula (I [
ittig) one of the phosphonio groups or phosphono groups commonly used in condensation reactions, in particular triarylphosphonio groups, such as triphenylphosphonio groups, or tri-lower alkylphosphonio groups, such as tri-n-butylphosphonio groups, or a phosphono group di-esterified with a lower alkyl, for example ethyl, symbol in the case of a phosphono group) (e can also be a strong basic cation, in particular a suitable metal ion, for example an alkali metal ion, for example lithium, sodium or Envelops potassium ions.

As radical XO, preference is given on the one hand to the triphenylphosphonio group and, on the other hand, to the diethylphosphono group together with an alkali metal ion, for example a sodium ion.

Cyclization can occur spontaneously, i.e. during the preparation of the starting materials, or can be carried out, for example, by heating at a temperature range of about 30°C to 160°C, preferably about 0°C to about 130°C. . The reaction is preferably carried out in a suitable inert solvent, such as an aliphatic, cycloaliphatic, or aromatic hydrocarbon,
For example, it is carried out in cyclohexane, benzene or toluene and, if necessary, in an inert gas atmosphere, for example in a nitrogen atmosphere.

C) The organic compound of trivalent phosphorus to the process (■) is derived from, for example, phosphorous acid,
and especially lower alkanols, such as methanol or ethanol, and/or their esters with unsubstituted or substituted aromatic hydroxy compounds, such as phenol or pyrocatechol, or of the formula:
The amide ester thereof is represented by P (OR-) J (Rh) z, in which each of R1 and R2, independently of one another, is lower alkyl, such as methyl, or aryl, such as phenyl. Preferred compounds of trivalent phosphorus are tri-lower alkyl phosphites, such as trimethyl phosphite or triethyl phosphite.

The reaction is preferably carried out in an inert solvent, e.g. an aromatic hydrocarbon,
for example in benzene or toluene, ethers such as dioxane or tetrahydrofuran, or halogenated hydrocarbons such as methylene chloride or chloroform, from about 20°C to 140°C, preferably from about 0°C to about 1
Performed at a temperature of 10°C, 1 molar equivalent of formula (I'/)
reacts with 2 molar equivalents of a phosphorus compound. Preferably, the compound of formula (TV) is placed in an inert solvent and the phosphorus compound, preferably dissolved in the same inert solvent, is added for example over a period of 2 to 4 hours.

In a preferred form of this process, a starting material of formula (rV) is prepared as described below and is reacted with a compound of trivalent phosphorus without isolation from the reaction mixture to produce the final product of formula (1). Manufacture things.

The starting materials of formulas (n) to (V) used are preferably those which lead to the compounds mentioned at the outset as being particularly preferred.

In the resulting compounds of the formula (1) in which one or more functional groups are protected, these, for example the protected carboxy, hydroxy and/or amino groups, can optionally be added stepwise or simultaneously to the compounds known per se. In a process, it can be liberated by solvolysis, in particular by hydrolysis, alcoholysis or acidolysis, or by reduction, in particular by hydrogenolysis or chemical reduction.

In the compounds of formula (1) obtained by the process of the invention, in which R2 is a protected carboxy, the protected carboxy can be liberated in a manner known per se. For example, an ethoxycarbonyl substituted in the 2-position by a trisubstituted silyl group can be prepared by treatment with a carboxylic acid, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol or anisole. Can be converted to free carboxy. Unsubstituted or substituted benzyloxycarbonyl can be cleaved, for example, by hydrogenolysis, ie, by treatment with hydrogen in the presence of a metal hydrogenation catalyst, such as a palladium catalyst. Furthermore, suitably substituted benzyloxycarbonyl, e.g. 4-
Nitrobenzyloxycarbonyl is produced by chemical reduction.
For example, by treatment with an alkali metal dithionite, such as sodium dithionite, or with a reducing metal, such as tin, usually a hydrogen generating agent, such as a suitable carboxylic acid, which is capable of producing nascent hydrogen together with said metal; e.g. lower alkane carboxylic acids (unsubstituted or substituted e.g. by hydroxy)
, for example in the presence of acetic acid, or an alcohol or thiol (preferably with addition of water) to the free carboxy. Removal of the allyl protecting group can be carried out, for example, by reaction with a palladium compound, such as tetrakis-(triphenylphosphine)-palladium, optionally in the presence of tosphenylphosphine, to an allyl group acceptor, such as a carboxylic acid, e.g.
- It can be carried out with the addition of ethylhexanoic acid or its salts, or dimedone or tributyltin hydride.

2-halo-lower alkoxycarbonyl (optionally after converting the 2-bromo-lower alkoxycarbonyl group to the corresponding 2-iodo-lower alkoxycarbonyl group) to carboxy by treatment with the reducing metal or metal salt described above. It can also be converted. Substituted 2-silylethoxycarbonyl can be further substituted with a salt of hydrofluoric acid, e.g. sodium fluoride, in the presence of a chemical polyether (crown ether), producing fluoride ions, or with a fluoride of an organic quaternary base. , for example by treatment with a tetra-lower alkylammonium fluoride, such as tetrabutylammonium fluoride, to the free carboxy.

On the other hand, in addition, compounds of formula (1) in which R2 is carboxy can be converted to compounds of formula (1) in which R2 is an esterified carboxy that can be cleaved under physiological conditions. That is, free carboxy groups can be esterified, for example, by reaction with the corresponding alcohol, in the presence of an esterifying agent, such as a carbodiimide, such as dicyclohexylcarbodiimide, or carbonyldiimidazole. Such esters can also be combined with salts of acids (which salts may then be formed) and with the corresponding reactive esters of alcohols and strong mineral acids, such as sulfuric acid, or strong mineral sulfonic acids, such as 4-toluene. It can be produced by reaction with sulfonic acid.

In the compound of formula (1) obtained by the process of the present invention, in which 5R, contains a protected hydroxy group as a substituent, the protected hydroxy group can be converted into a free carboxy group by methods known per se. can. For example, a hydroxy group protected by a suitable acyl group or by an organosilyl group can be liberated in the same manner as a correspondingly protected amino group (see below), and a tri-lower alkylsilyl group can be, for example, further Can be removed using butylammonium fluoride and acetic acid (
Under these conditions, the carboxy group protected by trisubstituted silylethoxy is not cleaved).

In the compounds of formula (1) obtained according to the invention which have a protected amino group, this group can be liberated by methods known per se, for example, preferably by solvolysis or reduction, depending on the type of protecting group. Can be converted to an amino group. For example, 2-halo lower alkoxycarbonylamino (in some cases, 2-but[one moly lower alkoxycarbonylamino group has been converted into a 2-iodo-lower alkoxycarbonylamino group) or 4-nitrobenzyloxycarbonylamino group] a suitable chemical reducing agent in the presence of an acid, such as aqueous acetic acid,
Cleavage can be achieved, for example, by treatment with zinc or by catalytic reaction using hydrogen in the presence of a palladium catalyst. 4-Nitrobenzyloxycarbonylamino can also be cleaved by treatment with an alkali metal dithionite, such as sodium dithionite. Allyloxycarbonylamino can be prepared by reaction with a palladium compound, such as tetrakis-(triphenylphosphine)-palladium, optionally in the presence of triphenylphosphine, and with an allyl group acceptor, such as a carboxylic acid, such as 2-ethoxyhexane. It can be cleaved in the presence of an acid or its salt, or dimedone or tributyltin hydride. Amino groups protected by 2-substituted silylethoxycarbonyl groups can be treated with a salt of hydrofluoric acid, e.g. sodium fluoride, in the presence of a chemical polyether (crown ether) to generate a fluorine anion. or by treatment with a fluoride of an organic quaternary base, such as a tetra-lower alkylammonium fluoride, such as tetraethylammonium fluoride.

Amino groups protected in the form of nitro or azido groups can be prepared, for example, by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum or palladium oxide, or in the presence of an acid such as acetic acid. can be converted to the free amino by treatment with zinc.

Furthermore, in the compounds of formula (I) obtained according to the process of the invention, the group R3 can be converted into other groups R3.

For example, in compounds of formula (1) where At is lower alkylene and R1 is halogen, the halogen compound ([) is dissolved in an inert solvent at room temperature or at a reduced temperature, e.g. from about -20°C to about 30°C. Halogens can be exchanged for unsubstituted or substituted amino or heteroarylthio by reaction with ammonia, the corresponding amine or heteroaryl mercaptan in the temperature range of To scavenge the hydrohydric acid, at least equimolar amounts of inorganic bases, such as alkali metal hydroxides, bicarbonates or carbonates, or organic bases, such as tertiary amines such as triethylamine, N,N-dimethylaniline or Add pyridine.

In compounds of formula (1) where R1 is hydroxy, this hydroxy group can be converted to a carbamoyl group. For this conversion, the hydroxy compound (1), in which the other functional groups, such as in particular the hydroxy group in the group R1, are present in protected form is prepared from the carbamoyl compound (1) in an inert solvent, such as a lower alkyl ether or methylene chloride, at room temperature. React with chloride or trichloroacetyl isocyanate.

The N-1-lichloroacetylsocyanate initially formed when using trichloroacetyl isocyanate is targeted by solvolysis with a lower alkanol, e.g. methanol, at room temperature, optionally in the presence of silica gel. Converted to carbamoyloxy compound.

Compounds of formula (1) where R1 is amino can be converted to other compounds of formula (1) where R3 is aminomethyleneamino or guanidino. This conversion can be carried out, for example, by one of the methods described in German patent publication Th 2652679.
You can follow according to one.

For example, a compound of formula (I) in which R2 is amino can be prepared by reaction with ethylformimidate or
, Y, ) C=NH, where Yl is lower alkylthio, e.g. ethylthio, can be converted to compounds of formula (1) in which R1 is aminomethyleneamino or guanidino, respectively. can.

In compounds of formula (RI) where R3 is amino, this amino group can also be converted to a dimethylamino group by reaction with formalin and lithium hydride or a polyhydride, such as sodium cyanoborohydride.

Salts of compounds of formula (I) having salt-forming groups can be prepared by methods known per se.

For example, a salt of a compound of the formula (RI) having a free carboxy group may be, for example, a salt of a metal compound, such as an inorganic alkali metal salt or an alkaline earth metal salt, such as sodium bicarbonate;
Acid addition salts of compounds of formula (I), which may alternatively be formed by treatment with ammonia or a suitable organic amine, preferably using a stoichiometric amount or a slight excess of the salt-forming agent, can be prepared by conventional methods. For example, by treatment with a suitable acid or a suitable ion exchanger.

Internal salts of compounds of formula (1) can be prepared, for example, by neutralizing a salt, e.g. an acid addition salt, to its isoelectric point with a weak base.
Alternatively, it can be formed by treatment with an ion exchanger.

Salts can be converted into the free compounds according to conventional methods, metal salts and ammonium salts, for example by treatment with a suitable acid, and acid addition salts, for example by treatment with a suitable basic agent, to the MR compound. Can be converted.

The resulting mixture of isomeric compounds can be separated into the individual isomers according to methods known per se. for example,
The resulting racemate can be reacted with an optically active auxiliary agent, the resulting mixture of two diastereomeric compounds separated by suitable physicochemical methods (e.g. fractional crystallization, adsorption chromatography), and the individual diastereomeric compounds Stereomeric compounds can be cleaved into optically active compounds.

In all subsequent transformations of the resulting compounds of formula (1), it is preferred to carry out the reactions under mildly alkaline conditions or especially under neutral conditions.

The process of the invention also includes variants in which the compound produced as an intermediate is used as a starting material and used to carry out the remaining reaction steps, or in which the process is stopped at any stage. The starting materials can be used in the form of their derivatives or optionally formed in situ under the reaction conditions.

Starting compounds of formulas (III) and (rV) can be prepared according to the following reaction scheme (1).

Margin below Anti-lord no Jji-ni top victory',·.

In the compounds of formulas (III'), (■) and (■), W' is a group represented by the following formula: or triphenylmethylthio or lower alkanoylthio.

LL W is a group easily exchangeable by a nucleophilic reaction, such as an alkanoyloxy, such as acetoxy, or a sulfonyloxy Ro 5ot-, in which Ro is, for example, unsubstituted or substituted by hydroxy. lower alkyl, such as methyl, ter
Formula (Vl
Suitable starting materials for
4,055, and German application publication fish 3.013,997
or can be produced by methods similar to these.

For example, a compound into which a group represented by the following formula is introduced is represented by the following formula (I
Xa): or in particular a salt thereof, such as an alkali metal salt, such as the sodium or potassium salt thereof. This substitution may be carried out in an organic solvent such as a lower alkanol, lower alkane carboxylic acid amide, cyclic ether, or similar inert solvent at room temperature or at slightly elevated or reduced temperatures, e.g. The introduction of the triphenylmethylthio or lower alkanoylthio group W', carried out at about 40° C., is analogous to the introduction of the triphenylmethylthio or lower alkanoylthio group W′ with an alkali metal salt, e.g. It is carried out by reaction.

The starting compound of formula (IV) is an azetidinone of formula (■) in which W' is of the formula With an acid halide, such as an acid chloride, at a temperature of -50°C to 80°C, preferably -20°C to 0°C, an inert solvent,
For example, to produce a compound of formula (1),
) is carried out in any of the solvents mentioned for the reaction of the compound.

If acid halides are used, this operation is preferably carried out in the presence of acid binders, such as tertiary aliphatic amines, aromatic amines, or in particular alkali metal or alkaline earth metal carbonates or bicarbonates. .

A compound of formula (■) in which W' is triphenylmethylthio or lower alkanoylthio can be converted into a starting compound of formula (■) in which W' is , in the presence of a base such as pyridine or tri-n-butylamine, in a suitable solvent such as diethyl ether or methanol, a salt of formula MA (where M is a transition metal cation, in particular a silver ion,
A is then reacted with a customary anion favoring the dissolution of the salt MA in the chosen solvent, such as nitrate, acetate or fluoride, and a product of the following formula () is formed: The salt can be treated with an acylating agent that introduces a group represented by the following formula: For example, the following formula (
IXb): a reactive functional derivative of an acid of formula (IXb) treated with an acid of formula (IXb) or a reactive derivative thereof, such as an acid halide, such as an acid chloride or bromide, azide or anhydride;
For example, when using acid chlorides, the acylation is carried out in an inert solvent, such as a chlorinated hydrocarbon, or an ether, at room temperature or with heating or cooling, e.g.
It is carried out in a temperature range of about +60°C, especially about -30°C to about +20°C.

Downfall 1 Compounds of formula (■) in which Xo is a reactive esterified hydroxy, especially a halogen, such as chlorine or bromine, are of formula (■)
A glyoxylic acid compound of 2Rz' Cll0 or a suitable derivative thereof, such as a hydrate, hemihydrate (
he+++1 hydrate) or hemiacecur, for example a lower alkanol, such as methanol or ethanol, and converting the hydroxy group into a reactive esterified hydroxy in the resulting compound of formula (■) where Xo is hydroxy. The compound of formula 0 (■) produced usually has two types of isomers [with respect to the group -C1l(R'z)"=Xo]
It is obtained in the form of a mixture of.

The addition of the glyoxylate compound to the nitrogen atom of the lactam ring in the compound of formula (■) is carried out at room temperature or, if necessary, with heating. When using hydrates of glyoxylic acid compounds, water is generated, which water is removed if necessary by distillation, for example by azeotropic distillation or by using a suitable water removal agent. The operation is preferably carried out in the presence of a suitable inert solvent or solvent mixture.

The conversion of the hydroxy group X0 in the compound of formula (■) to a reactive esterified hydroxy group X0 is carried out by treatment with a suitable esterifying agent, such as a thionyl halide, such as thionyl chloride, preferably a basic agent, In particular, it is carried out in the presence of an organic basic agent, such as an aliphatic tertiary amine or a heterocyclic base of the pyridine type. This operation is preferably carried out in the presence of a suitable solvent, such as dioxane or tetrahydrofuran, or a mixture of solvents, for example at about -30<0>C to about 30<0>C, with cooling if necessary.

The starting material for formula (III) is the reaction of a compound of formula (■) with a suitable phosphine compound, such as tri-lower alkyl phosphine, such as tri-n-butylphosphine, or triarylphosphine, such as triphenylphosphine, or treatment with a suitable phosphite compound, such as a tri-lower alkyl phosphite, such as triethyl phosphite, or an alkali metal di-lower alkyl phosphite, such as alkali metal diethyl phosphite, and W' is triphenylmethylthio or lower alkanoylthio. A compound of a certain formula (m') is expressed as W'
is a group represented by the following formula: Formula (I[') (= (III
) can be obtained by converting to the compound of ).

The reaction with the phosphine or phosphite compound is preferably carried out in a suitable inert solvent, such as a hydrocarbon, or an ether, or a solvent mixture. Depending on the reactivity, the reaction is carried out with cooling or at elevated temperature. For example, from -1θ°C to +100°C, preferably from about 20°C to 80°C.
It is carried out at a temperature in the range of °C. The reaction is generally carried out in the presence of a basic agent, such as an organic base, such as an amine, or a polystyrene Hünig base 1, or an inorganic base, such as an alkali metal carbonate, and is : (wherein, X is a phosphono group or the meaning of group X0 [formula (■
The initially formed phosphonium compound, represented by an anion, such as a chloride ion, together with a phosphonio group), is converted into the ylide starting material of formula (III).

The introduction of a group of the following formula into a compound of formula (■') in which W' is lower alkanoylthio or triphenylmethylthio can be carried out in the same manner as described in step 2.

The starting materials of formula (n) are known or can be prepared, for example, by cyclization as described in variant b) of a phosphorane of formula (X): can be synthesized in the same manner as shown in reaction scheme (2).

Penem compounds of this invention, such as formula (Va).

The starting compounds for forming the side chain in the 2-position of (Vb), (IXa) and (IXb) are known or can be prepared by methods analogous to those described in the literature.

The method described in Reaction Scheme I for the preparation of compounds of formula (III), (IV), (■) and (■) and further for the preparation of compounds of formula (II) and final compounds of formula ([). The process described for can also be carried out using optically inactive compounds and, at any stage of the process, the optically active compounds of this invention can be converted from the resulting diastereomeric mixture or racemate into the known It can be isolated by any method.

The invention also provides novel starting materials and novel intermediates obtainable by the process of the invention, such as formula (1), (I
V), and (■), and (■) (wherein W' represents the following group), and methods for producing them.

The starting materials used and the reaction conditions selected are preferably those which lead to compounds of formula (2), which are given above as particularly preferred in this specification.

The pharmaceutically acceptable compounds of this invention can be used, for example, for the manufacture of pharmaceutical preparations, which contain a therapeutically effective amount of the active ingredient in an inorganic or organic solid or liquid form, orally. For administration or parenteral administration, i.e., intramuscular, intravenous, subcutaneous or intraperitoneal administration, it comprises, together with or in admixture with a suitable pharmaceutically acceptable carrier.

For oral administration, tablets or gelatin capsules are used which contain, together with the active ingredient, diluents such as lactose, gykistrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants such as silica, talc, stearic acid or the like. salts such as magnesium or calcium stearate, and/or polyethylene glycols. The tablets may further contain binders such as magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone,
and optionally contains disintegrants such as starch, agar, alginic acid or its salts, such as sodium alginate and/or foaming mixtures or absorbents, colorants, fragrances or 1R flavors.

For parenteral administration, infusion solutions, especially isotonic aqueous solutions or suspensions, are preferred; these are prepared for use, for example, from chilled dry preparations containing the active ingredient alone or together with a carrier such as mannitol. Can be done. These preparations may be sterilized and/or contain auxiliary agents, such as preservatives, stabilizers, wetting agents, and/or emulsifiers,
It may contain solubilizers, osmotic salts and/or buffers.

The pharmaceutical preparations in question, which can optionally contain other pharmacologically valuable substances, are produced by methods known per se, for example by conventional mixing, solvent or lyophilization methods, and contain about 0. 1% to 100%, especially about 1% to about 5
Contains 0% of active ingredient, or up to 100% in the case of lyophilizates.

Depending on the type of infection and the condition of the infected organism, the dosage (oral or parenteral) used for the treatment of bleeding animals with a weight of about 70 kg is from about 100 to about 100 kg.
0■ b, i, d or t, i, d.

The invention will now be explained by way of example. Temperatures are given in °C.

8.4 g of 2-((3S) in 750-g of toluene.

4R)-3-[(1R)--1-allyloxycarbonyloxyethyl)-4-(4-(N-allyloxycarbonylaminomethyl)-phenoxyacetylthio]-2
The solution of -oxo-azetidin-1-yl)-2-triphenylphosphoranylidene acetic acid allyl ester is stirred at reflux temperature for 45 minutes under an argon atmosphere. The solvent is then evaporated off and the crude product is purified by silica gel chromatography.

Rf (solvent toluene/ethyl acetate l:1) = 0.6I
R(CIIzClg): 3440,1793,17
45.1720.1590am-'.

The starting material can be produced as follows.

0.97g of 4-aminomethylphenoxyacetic acid to 15-
of water, and to this was added 2.4-5N Na011? After adding the solution and cooling with water, 0.63a# of chloroformic acid allyl ester is added thereto over a period of 5 minutes. After removing the cooling bath, the reaction mixture is stirred for 20 minutes at room temperature.

The reaction mixture is then washed twice with ethyl acetate and the aqueous phase is adjusted to pH 2 with 4N HCJ and extracted with ethyl acetate. The organic solution is washed with brine and dried over sodium sulfate. After evaporating off the solvent, the title compound is obtained.

TLC (ethyl acetate/acetic acid 95:5) Rt -0
,4゜2- ((3S,4R)-3-[(1R)--1
-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-ylk 2-triphenylphosphoranylidene acetic acid allyl ester silver salt 1
B, 5 g was dissolved in 320 d of methylene chloride and to this was added 4.36 aF of pyridine, 100 μ of 4-dimethylaminopyridine at 0°C, and then 21
A solution of 12 g of 4-(N-allyloxycarbonylaminomethyl)-phenoxyacetyl chloride in 0-methylene chloride is added.

After stirring for 20 minutes at 0° C., the solid material is filtered off on Hyflo and the filtrate is washed with aqueous sodium bicarbonate solution and then with saturated NaCl1 solution. Na
After drying with zSOa, the solvent is distilled off.

Purify the residue by silica gel chromatography (
Eluent = toluene-toluene/ethyl acetate 75:25)
R, = 0.33°IR (CIlzClg): 3440.1760.1
? 20,1695 cs-'.

0.528 g of (5R,63) in 14d of pure THF in portions of 43g of tetrakis-triphenylphosphine-palladium and 1.51g of tributyltin hydride.
-2-(4-(N-allyloxycarbonylaminomethyl)-phenoxymethyl]-6-[(1R)--1-allyloxycarbonyloxyethyl]-2-penem-3
- Add to the solution of carboxylic acid allyl ester. After stirring for 1.5 hours at room temperature, add 0.32N acetic acid to the mixture and add 151N7 hexane to the reaction mixture, which is stirred for an additional 15 minutes. After centrifuging and decanting the liquid, the residue is washed again with water, then triturated with water and filtered off. Approximately 10% of the filtration residue
-Wash 5 times with water. The combined filtrate is concentrated on a rotary evaporator and chromatography on OPT IUPC+z (eluent: water) gives the title compound.

TLC (OPTI UPC, □; water) Rr=0.5゜I
R(DMSO-di): 3445,2970.17
? 4.1613.1583 cm-'.

υV (Wed): λ, □” 307n Mon.

In the same manner as in Example 1, 1.2 g of 2-((33°4R)-
3-[(1R)--1-allyloxycarbonyloxyethyl)-4-(4-fluorophenoxyacetylthio)-2-oxo-azetidin-1-yl)-2-triphenylphosphoranylidene acetic acid allyl ester 750-
to give the title compound.

IR(CIIgClg): 1795,1747,1
705.1650,1580cs*-'.

The starting material is produced as follows.

2-((3S,4R)-3-[(1R)--1-allyloxycarbonyloxyethyl]-4-mercapto-
Silver salt of 2-oxo-azetidin-1-ylcu-2-triphenylphosphoranylidene acetic acid allyl ester 1.74
g in 30Ia1 of methylene chloride, 0.41@1 pyridine, 20μ 4-dimethylaminopyridine and 0.
．． React with 7 g of 4-fluorophenoxyacetyl chloride. After processing in the same manner as in Example 1, 2− ((
3S, 4R) -3-[(1R)--1-allyloxycarbonyloxyethyl)-4-(4-fluorophenoxyacetylthio)-2-oxo-azetidin-1-ylcu-2-triphenylphosphoranylideneacetic acid Obtain allyl ester.

IR(ClhCh): 1755.1690 all
-'.

Anal 5R, 6S) -2-(4-Fluorophe 204
1.3-Dimethylbarbic acid and 36.4 cm of tetrakis-triphenylphosphine-palladium were dissolved in 11-tetrahydrofuran at room temperature.
3)-2-(4-fluorophenoxymethyl)-6-
Add to [(1R)--1-allyloxycarbonyloxyethyl]-2-penem-3-carboxylic acid allyl ester.

After stirring for 25 minutes at room temperature, the reaction mixture is concentrated under high vacuum and then taken up in ethyl acetate/water. The aqueous phase was previously adjusted to pH 7.0 with sodium bicarbonate; after the organic phase had been separated and washed again with ethyl acetate, the aqueous phase was concentrated on a rotary evaporator and this was followed by a column on OPTIUPC+t. The pure title substance is isolated by chromatography (solvent: water).

TLC (OPTI UPC+g; water)/acetonitrile 4; 1) R, = 0.39°IR (DMSO-di): 17?1.1618.1
587cm-'.

UV (Wed): λva*x = 3071111° (5
1S, 6S)-2-(4-fluorophenoxymethyl)
-6-[(IR)-1-hydroxyethyl]-2-penem-3-carboxylic acid sodium salt 90μ
Dissolve in MF and cool the solution to 0° C. and add iodomethyl pivalate of 61d. 4 at 0℃
After stirring for 5 minutes, the reaction mixture was diluted with ethyl acetate and
Washed three times with a saturated aqueous solution of sulfur and lithium chloride, and
, SO,. After filtration and concentration, the crude product was chromatographed on silica gel (solvent=toluene-
Purify with toluene/ethyl acetate 85:15).

IR(CIIzCh): 1795.1750.17
30.1585 am-'.

UV (ethanol): λvamx -328nse As in Example 1, 1.15 g of 2-((3S).

4R)-3-[(1R)--1-allyloxycarbonyloxyethyl)-4-(4-allyloxycarbonylaminophenoxyacetylthio)-2-oxo-azetidin-1-yl)-2-)liphenyl Phosphoranilidene acetate allyl ester is reacted in 150-g of toluene to give the title compound.

IR(CIIxClg): 3420.1792.1
735.1710.1645 cm-'.

The starting material can be obtained as follows.

0.9 g of 4-aminophenoxyacetic acid is suspended in 15-mL water and 2.4 af of 5N NaOH f'a solution is added. After cooling on ice, 0.63 μl of chloroformic acid allyl ester is added over 5 minutes. After removing the cooling bath, the reaction mixture is stirred at room temperature for 20 minutes.

The reaction mixture is then washed twice with ethyl acetate and the aqueous phase is adjusted to pH 2 with 4N HCffi. The organic solution is washed with brine and dried over sodium sulfate.

After distilling off the solvent, the title compound is obtained.

TLC (ethyl acetate/acetic acid 95:5) Rr = 0
．． 4゜Ig 4-(allyloxycarbonylamino)-
Phenoxyacetic acid was suspended in 2ta1 CIl□CI,
and 0.6-1-chloro-1-dimethylamino-2
-Methylprop-1-ene is added thereto. The mixture was stirred for 75 minutes and then 2-((3S,4R)-3-[(1R)--1
-Allyloxycarbonyloxyethyl)-4-mercapto-2-oxo-azetidin-1-yl)-2-triphenylphosphoranylidene acetic acid allyl ester silver salt 1
．． 74g, 50mg dimethylaminopyridine and 0
．． After treatment with a solution of 41 in pyridine for 5 minutes as in Example 1, the title compound is obtained.

IR (CHzCh): 3420,1?55,173
0.1690 ell-'.

530■ (5R,6S)-2-(4-allyloxycarbonylaminophenoxymethyl)-6-[(1R)-
-1-allyloxycarbonyloxyethyl]-2-penem-3-carboxylic acid allyl ester of pure T
Dissolve in HF and add 40 mg of tetrakis-triphenylphosphine-palladium and 1.1 mm of tributyltin hydride one after another with stirring. After 30 minutes, add an additional 20 μ of tetrakis-triphenylphosphine-
Palladium and 0.32-tributyltin hydride are added and the whole is stirred for a further 1.5 hours. 0.3
After 15 minutes of addition of 1- of acetic acid, the reaction mixture is concentrated by vacuum evaporation and partitioned between water/ethyl acetate.

The pH value is adjusted to 7.7 with sodium bicarbonate.

After washing twice with ethyl acetate, the aqueous phase was vacuum t! Shrink.

Column chromatography on OMI UPCtz (eluent: water) gives the pure title compound.

IR (DMSO-dl,): 1771, 1616.
1587.1511 country - 1°UV (Wed) ' λv
aax -302ns.

2 g of 2-((3S,4R)-3-
[(1R)--1-allyloxycarbonyloxyethyl) -4--<4- (2-allyloxycarbonylaminoethyl)-phenoxyacetylthio)-2-oxo-azetidin-1-yl]-2- Triphenylphosphoranylidene acetic acid allyl ester is converted to the title compound in 400% pure toluene.

IR (CHzCl g): 3430,1790,1
740,1710.1640C1l-'.

The starting compound can be produced as follows.

Analogously to Example 6, 3.9 g of 4-(2-aminoethyl)-phenoxyacetic acid are converted to the title compound.

TLC (ethyl acetate/acetic acid 95:5) R,=0.
With a margin of 4° or less, 2-3S 4R-3-(IR-1- In the same manner as in Example 6, 2.25 g of 4-(2-allyloxycarbonylaminoethyl)-phenoxyacetic acid was added to 2-((
3S,4R)-3-[(1R)--1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl)-2-)Silver of liphenylphosphoranylidene acetic acid allyl ester Converted to the title compound together with 3.48 g of salt.

IR(CIIzClg): 3430,1750.1
715.1690 all-'.

Below is the margin 9. 5RS---2-Ani 0.97 g of (5R,6S)-2-
(4-(2-allyloxycarbonylaminoethyl)-
phenoxymethyl)-6-[(1R)--1-allyloxycarbonyloxyethyl]-2-penem-3-carboxylic acid allyl ester was converted to the title compound using tributyltin hydride and tetrakis-triphenylphosphine-palladium. Convert.

IR (DMSO-dJ: 1774, 1613, 15
85,1512 cs-'.

UV (water) λsam-307nllll * 1.8 g of 2-((3S) as in Example 1.

4R)-3-[(1R)--1-allyloxycarbonyloxyethyl]-4-phenoxyacetylthio-2-
Oxo-azetidin-1-yl]-2-triphenylphosphoranylidene acetic acid allyl ester is converted to the title compound in 350 td of toluene.

IR (CIhC12): 1795.1750.1?
10,1650.1600.1590C11-'.

The starting material can be produced as follows.

In the same manner as in Example 1, 912■ phenoxyacetic acid and 2
- ((3S,4R)-3-[(1R)--1-allyloxycarbonyloxyethyl]-4-mercapto-2
-oxo-azetidin-1-yl]-2-triphenylphosphoranylidene acetic acid allyl ester silver salt 2.61
g to 2- ((3S,4R)-3-[(1R)--1-
Allyloxycarbonyloxyethyl]-4-phenoxyacetylthio-2-oxo-azetidin-1-yl)
- Converted to 2-triphenylphosphoranylidene acetic acid allyl ester.

Skin, (5R,6S)-2-phenoxymethyl - Same as Example 4, 654 ■ (5R,6S)-2-phenoxymethyl-6-[(1R)--1-allyloxycarbonyloxyethyl] -2-penem-3-carboxylic acid allyl ester was converted into 230 µ of 1,3-dimethylbarbital acid and 41 q of tetrakis-triphenylphosphine-
Conversion to the title compound in 12-THF using palladium.

IR (DMSO-di,): 17?1.1618,
1597,1492 cm-'.

UV (Wed): λIIIIIIX -307nlle Example 5
Similarly, 105■ of sodium (5R96S)-
2-phenoxymethyl-6-[(1R)--1-hydroxyethyl]-2-penem-3-carboxylate
With iodomethyl pivalate of 0Ii, 2.2 af
of pure DMF to give the title compound.

IR(CH,CI,): 3600.1790.1
750.1?25.1597.1587 pieces - 1°UV
(-Lri) -)L'> λ@IIX = 327n
s.

In the same manner as in Example 1, 3 g of 2-((3S,4R)-3
-[(1R)--1-allyloxycarbonyloxyethyl)-4-(N-(4-allyloxycarbonylaminophenyl)-N-(allyloxycarbonyl)-glycylthio]-2-oxo-azetidine-1- il)-2
-Triphenylphosphoranylidene acetic acid allyl ester is converted to the title compound in 500 aZ of toluene.

IR(CIIzClg): 3415.1790.1
730.1705.1635.1595°1580.1
520 cm-'.

The starting compound can be produced as follows.

Analogously to Example 6, 3.1 g of N-(4-aminophenyl)-glycine are converted to the title compound using 4.97-chloroformic acid allyl ester and sodium hydroxide solution.

TLC (ethyl acetate/acetic acid 95:5) Rf -0
, 5° In the same manner as in Example 1, 2.67 g of N-(4-allyloxycarbonylaminophenyl)-N-(allyloxycarbonyl)-glycine was added to
)-3-[(1R)--1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxoazitidin-1-yl]-2=silver salt of triphenylphosphoranylidene acetic acid allyl ester3. Converted together with 5 g to the title compound.

IR(CIItClg): 3415,1750,1
740.1705.1690, 1520Cs-'.

According to Example 2, 315* (5R,6S)-2-(N-
(allyloxycarbonylaminophenyl)-N-(allyloxycarbonyl)-aminomethyl)-6-[(1
R)--1-allyloxycarbonyloxyethyl]-
2-penem-3-carboxylic acid allyl ester is converted to the title compound using tributyltin hydride and tetrakis-triphenylphosphine-palladium.

IR (DMSO-di): 1767.1612,1
585-1517 cm-'.

UV (water) λass = 302ns.

As in Example 1, 2.4 g of 2-((3S).

4n)-3-[(1R)--1-allyloxycarbonyloxyethyl)-4-(4-(allyloxycarbonylaminomethyl)-2-methoxyphenoxyacetylthio]-2-oxo-azetidin-1-yl )-2-) Riphenylphosphoranylidene acetic acid allyl ester at 350
- The title compound is converted in toluene.

IR(CIItClg): 3440.1792.1
745.1720.1647.15B0゜1510cs
l-'.

The starting compound can be prepared as follows.
Below margin 1.2-2-
Mexi-4-cyanophenoxy) 0.75 g of vanillic acid nitrile, 0.94 g of chloroacetic acid and 0.6
Heat at reflux temperature in 3-g of water with 3-g of sodium hydroxide. After 20 minutes, the reaction mixture was diluted with 2-hydrochloride, and after a further hour it was diluted with 3-hydrochloride in water.
．． Add 2g of sodium hydroxide. After a total reaction time of 5 hours, the reaction mixture is cooled and filtered. The filter residue is suspended twice in ethyl acetate and filtered.

Then put the solid material into water and adjust the pH to 4N NC1
Adjust to 2 by After filtration, the title compound is obtained and is worked up without purification.

TI, C (ethyl acetate 15% acetic acid) Rf=0.2°3.
3 g of 2-(2-methoxy-4-cyanophenoxy)-
Acetic acid was mixed with methanol and 25% aqueous ammonia in 2=1
(Volume) Mixture 9 Hydrogenate in the presence of 1.6 g of Raney nickel at room temperature and normal pressure for 5 hours. After filtering the catalyst, it is washed with methanol and water, and then the filtrate is concentrated to dryness. The resulting solid material is triturated with a small amount of water, filtered and dried in a dryer at P20. Dry on top.

Analogously to Example 6, 3.3 g of 2-(4-aminomethyl-2-methoxyphenoxy)-acetic acid are converted to the title compound.

T, LC (ethyl acetate/acetic acid 95:5) Re =
0.4° In the same manner as in Example 1, 2.36 g of 2- (4-
(allyloxycarbonylaminomethyl)-2-methoxyphenoxy]-acetic acid, 2-((33,4R)-3-
[(1R)--1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidine-1-
yl]-2-triphenylphosphoranylidene acetic acid allyl ester together with 3.5 g of the silver salt of allyl]-2-triphenylphosphoranylidene acetate.

IR (CHzClz): 3440.1755.17
20.1690 cm-'.

Similarly to Example 2, 910■ (5R,6S)-2-(
4-(allyloxycarbonylaminomethyl)-2-methoxyphenoxymethyl]-6-[(1R)--1-allyloxycarbonyloxyethyl]-2-penem-3
-The carboxylic acid allyl ester is converted to the title compound using tributyltin hydride and tetrakis-triphenylphosphine-palladium.

IR (mouth MSO-d,): 1773,1G14,1
592,1585,1517C11-'.

UV (water): λsex -307nm.

As in Example 1, 0.87 g of 2-((3S).

4R)-3-[(1R)--1-allyloxycarbonyloxyethyl)-4-(4-formylphenoxyacetylthio)-2-oxo-azetidin-1-yl)-2
-) Riphenylphosphoranylidene acetic acid allyl ester is converted to the title compound in 170-g of toluene.

IR (C1hCh): 1797, 1750, 170
0,1650,16.05.1582 cm −'.

The starting compound can be produced as follows.

In the same manner as in Example 6, 4-formylphenoxyacetic acid of Ig was converted to 2-((3S,4R)-3-[(1R)--1-
Silver salt of allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl)-2-) liphenylphosphoranylidene acetic acid allyl ester2.
Along with 58 g, 2- ((3S, 411)-3-[(1
R)--1-allyloxycarbonyloxyethyl)-
Convert to 4-(4-formylphenoxyacetylthio)-2-oxo-azetidin-1-yl)-2-triphenylphosphoranylidene acetic acid allyl ester.

IR (CHzClz): 1760,1692 cl
I-'.

Similarly to Example 2, 270■ (5R,6S)-2-(
4-Formylphenoxymethyl)-6-(, (IR)-
1-allyloxycarbonyloxyethyl]-2-penem-3-carboxylic acid allyl ester was dissolved in 2 ml of pure TH using 0.6 aZ of tributyltin hydride and 13 μ of tetrakis-triphenylphosphine-palladium.
Converted to the title compound in F.

IR (DMSO-da): 1773.16B4.1
599.1509 cm-'.

UV (Wed): λIIIK = 283nllei
11.2 g of 2-((3S.

4R)-3-[(1R)--1-allyloxycarbonyloxyethyl)-4-(4-chloromethylphenoxyacetylthio)-2-oxo-azetidin-1-yl)
-2-1-Riphenylphosphoranylidene acetic acid allyl ester solution is stirred at reflux temperature under an argon atmosphere for 45 minutes. The solvent is then distilled off and the crude product is purified by silica gel chromatography.

IR(CH,Ch): 1795.1745.171
0.1650.1610.1590 value -1° The starting material can be prepared as follows.

Below the margin 2-((3S,4R)-3-(IR-1-A) In the same manner as in Example 1, 10.8 g of 4-chloromethylphenoxyacetic acid and 2-((3S,4R) -3- [(1R)-
-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-
10.8 g of the silver salt of triphenylphosphoranylidene acetic acid allyl ester are converted to the title compound.

IR (C112CI2): 1755,1690.1
620cm-'.

400 ■ (5R, 6S) -2 in pure DMF of 2 fire 2ral
-(4-chloromethylphenoxymethyl)-6-((I
n)-1-allyloxycarbonyloxyethyl]-2
- A solution of penem-3-carboxylic acid allyl ester at 0°C.
and to this are successively added 0.64 g of powdered potassium iodide and a solution of 132 μl of sodium l-methyltetrazole-5-thiolate in 0.8 fli DMF. The reaction mixture was placed at 0°C for 15 minutes,
Then, leave it at room temperature for 30 minutes. The DMF is then removed under high vacuum and the residue is partitioned between water-ethyl acetate.

The organic phase is separated and washed with brine, dried over sodium sulfate and concentrated. Silica gel chromatography (eluent = toluene/ethyl acetate 92.5:7
．． After purification according to 5), the pure title compound is obtained.

rR(C1lzClz): 1795,1750.
1710.1650, 1610.1590CIm-'
.

Below is the margin penalty, (5r? 6S -2-4-(450mg0 in the same way as 1-methyl example 2) (5R, 6S) -
2-(4-(1-methyltetrazol-5-ylthiomethyl)-phenoxymethyl]-6-[(1R)--1-
Allyloxycarbonyloxyethyl]-2-penem-
The 3-carboxylic acid allyl ester is converted to the title compound in 7fa1 of pure THF with 22 hours of tetrakis-triphenylphosphine-palladium and 122 hours of 1,3-dimethylbarbylic acid.

IR (DMSO-da): 1772.1617.1
585,1512 on-'.

LIV (IlzO) :λam* = 307nff
Margin capacity below la, (5R63-2-4-(4-morpho) In the same manner as Example 20, 0.5 g of (5R,6S)-2-(4-chloromethylphenoxymethyl)-6-[(1R) −−１−
Allyloxycarbonyloxyethyl]-2-penem-
The 3-carboxylic acid allyl ester is converted to the title compound in 10fa1 of pure DMF with 3.3g of potassium iodide and 105I of morpholine.

IR (CHzClz): 1790.1750.1
705.1650, 1610.1590cm −'.

Similarly to Example 2, 455■ (5R,6S)-2-(
4-(4-morpholinomethyl)-phenoxymethyl)-
6-[(1R)--1-allyloxycarbonyloxyethyl]-2-penem-3-carboxylic acid allyl ester was converted to 24μ of tetrakis-triphenylphosphine-
The title compound is converted to the title compound with palladium and 131 g of 1,3-dimethylbarbisolic acid in 9 g of THF.

IR (DMSO-d,): 1775,1612.1
585.1510 CM-'.

UV (water): λII@X = 307 nm.

Separate button.

The following compounds are prepared analogously to those described in the preceding examples.

(5R,6S)-2-(3-(aminomethyl)-phenoxymethyl)-6-[(1R)--1-hydroxyethyl)-2-penem-3-carboxylic acid IR (DMSO-d
a): 3435.2968.17?4.1616.
1587cm-'; UV (water): λmaw = 3
08nll*(5R,6S)-2-(2-(aminomethyl)-phenoxymethyl)-6-[(1R)--1-hydroxyethyl]-2-penem-3-carboxylic acid IR(
DMSO-dJ: 3436.2968,1776.
1617.1585cm-'; UV (water):
Oh-, = 307 nm.

(5R,63)-2-(4-(aminomethyl)-phenylaminomethyl)-6-[(1R)--1-human[lxyethyl]-2-penem-3-carboxylic acid UV (water): λsag = 308nm
*(5R,6S)-2-(4-(aminomethyl)-phenoxythiomethyl)-6-[(1R)--1-hydroxyethyl)-2-penem-3-carboxylic acid UV (water); λ , □ = 306 nm.

(5R,6S)-2-(2-aminophenoxymethyl)
-6-[(1R)--1-hydroxyethyl]-2-penem-3-carboxylic acid UV (water): λ11111+ = 306in+.

(5I?, 6S)-2-(4-(4-aminophenoxy)-phenyl)-6-[(1R)--1-hydroxyethyl-2-penem-3-carboxylic acid UV (water):
λsag = 322011@(5R,6S)-2-(
4-(4-aminomethylphenoxy)-phenyl)-6
-[(1R)--■-Hydroxyethyl]-2-penem-3-carboxylic acid UV (water): λ□, = 321 nm.

(5R,6S) -2-(4-carbamoylphenoxymethyl)-6-[(1R)- -1-hydroxyethyl]-2-penem-3-carboxylic acid UV (water): λa
mx = 300rv.

(5R,6S)-2-(2-carbamoylphenoxymethyl)-6-((lR)-1-hydroxyethyl]-2
-penem-3-carboxylic acid ■V (water) = λwax = 2
99nll; IR (mouth MSO-da): 34
53,1773.1666.1620.1595cm-
'.

(5rl, 6S)-2-(4-(aminomethyleneaminomethyl)-phenoxymethyl]-6-[(1R)--1
-hydroxyethyl)-2-penem-3-carboxylic acid UV (water): λ1m111+ = 307 nm.

■Profit.

The following compounds are prepared analogously to those described in the preceding examples. In the table below, for method A see example 1; for method B see example 20.

Below margin 4-CIhNIICOz 306
3435.2%ll, 1773.1615. +58
6 A3-CIIJIICllz
305
A2-CIhN1lCl+3
:106
A4-C1hNIICIIzCIhO1l
307
A3-C11, N11CI+, CI+
,011 306
A2, CIIfNIICII□C
Il□O1l 306
A4-ClllN1lCI
IzClhNIIt 307
A3-Cl12
NIICII□C111NIh 305 82, C11
, N11CI1. CII□Nll□ 3(
Xi A
4CIItNIIC11gCIIJ(CHs)z
306
A4-CIhN (CIls) Cl1zCON
th 306
B・輔 groan - middle school 4cu,) i qu 3os
a\,-
0 7°-1 t, cll, N, N-Cll0 305 34
34.2966.17?4.1616.1587
R4t:lbN 11CI+3 3
06 R7
'-3 4-f: II□Shiba NC+1NIIt 30
6 RRa, R2・1
4-OC1+□-0(At R'l・H) 31+
4.011 (I+, -3fl11.Rs=H) 311
A4, OH317A 4-011 (R, = 3.0II, Its = 5-011)
328
^4-OCI+,
312 3308, 2240, 1772.16+8
．． 1587.1508 ^-・ 4-C11□-N-CII□CI+□011
305 84-C
IIJ (CIItelltOH) t 3
05 BCl
l, -ωNl+.

Margin below Unless otherwise specified, R4 and Rs are hydrogen.

70■(5R,6S)-2-(4-aminomethyl)
-phenoxymethyl)-6-[(1R)--1-hydroxyethyl]-2-penem-3-carboxylic acid is dissolved in 7-aqueous tetrahydrofuran. After adjusting the p)l of the solution to 6.81 by IN Ill, add 50 p
! 37% formaldehyde aqueous solution is added and the whole is stirred for 10 minutes at room temperature under nitrogen (pH approximately 5.9).
). 12.5 g in 1.5 l11 buffer (pH 7)
After adding a mixture consisting of 13.75* of sodium cinanoborohydride and 13.75* of zinc chloride, the pH of the reaction mixture is adjusted to 7.1 with sodium bicarbonate. After stirring for 45 minutes at room temperature, the reaction mixture is concentrated in a vacuum bottom-talley evaporator and the yellow residue is applied to a chromatography column in water (OPTI IJPC
+z: water, then water/acetonitrile 9:1),
In this way, the desired title compound is obtained.

(OPTI UPC+z: water/acetonitrile 4:
1) Re=0.29; UV (water) λmam = 307ns.

Rainbow・ Each contains 0.5g of (5R16S) as active ingredient.
(4-(aminomethyl)-phenoxymethyl)-6-[
(1R)--1-hydroxyethyl]-2-penem-3
- A dry ampoule or vial containing the carboxylic acid is prepared as follows.

(Ampoules are vials 111, 0.5 g of active ingredient, 0.5 g of mannitol) A sterile aqueous solution of the active ingredient and mannitol is lyophilized under sterile conditions in a 5 ta 1 ampoule or a 5 ml vial, and the ampoule or vial is sealed and inspect.

Instead of the active ingredients mentioned above, the same amounts of other ingredients mentioned in the examples above can also be used as active ingredients.

Claims (1)

[Claims] 1. The following formula (I): ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (wherein R_1 is lower alkyl substituted by hydroxy or protected hydroxy; R_2 is carboxy or functionally modified carboxy;
R_3 is hydrogen, amino, mono- or di-substituted amino, carbamoyl, hydroxy, protected hydroxy,
carbamoyloxy, lower alkoxy, halogen, lower alkanoyl, sulfamoyl, or heteroarylthio; each of R_4 and R_5 is independently hydrogen, lower alkyl, hydroxy, protected hydroxy, lower alkoxy, halogen, amino , protected amino, lower alkanoylamino, or carbamoyl; or R_4 and R_5 together represent methylenedioxy; Y represents a group of the formula -O-, -S-, or -NR_6-; R_6 is hydrogen or lower alkyl; A_1 represents a lower alkylene group or an unsubstituted or substituted phenylene group; and A_
2 is a direct bond or a lower alkylene group), pure optical isomers of the above compounds of formula (I), mixtures of these optical isomers, and salts thereof. 2. R_1 is lower alkyl substituted by hydroxy in the α-position; R_2 is carboxy or esterified carboxy that can be cleaved under physiological conditions;
R_3 is hydrogen, amino, or amino (which is lower alkyl, hydroxy-lower alkyl, carbamoyl-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, or heteroaryl; heteroaryl (mono- or di-substituted by lower alkyl and/or N-azaheterocyclyl-lower alkyl groups); or sulfamoyl, aminomethyleneamino, guanidino, carbamoyl, hydroxy, lower alkoxy, halogen, carbamoyloxy , lower alkanoyl, N-azaheterocyclyl or heteroarylthio, where heteroaryl is a monocyclic 5- or 6-membered ring having 1 to 4 ring nitrogen atoms and bonded by ring carbon atoms. heteroaryl group, and N-azaheterocyclyl is a monocyclic 5-membered heteroaryl group having 1 to 4 ring nitrogen atoms and bonded by an uncharged ring nitrogen atom, 1
a monocyclic partially saturated 6-membered heteroaryl group having ~3 ring nitrogen atoms and bonded by an uncharged ring nitrogen atom, or having from 1 to 3 ring nitrogen atoms and a monocyclic saturated 5- or 6-membered azaheterocyclyl group optionally having an additional ring heteroatom selected from the group consisting of sulfur and oxygen and bonded by an uncharged ring nitrogen atom; benzo derivatives, these heteroaryl and N-azaheterocyclyl groups are unsubstituted or with the following substituents: hydroxy, lower alkoxy, halogen, lower alkylthio, phenylthio, lower alkyl, hydroxy-lower alkyl , lower alkanoyloxy-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, carbamoyloxy-lower alkyl, halo-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, Lower alkanoylamino-lower alkyl, sulfo-lower alkyl, lower alkanoyl, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, cyano, sulfo, sulfamoyl, pyridyl, phenyl and/ or phenyl (substituted by lower alkyl, alkoxy and/or halogen), N-azaheterocyclyl groups with disubstituted ring carbon atoms may also be substituted by oxo ;R_4 and R_5 are each
independently of one another represent hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen, amino, lower alkanoylamino, or carbamoyl; or R_4 and R
_5 together represent methylenedioxy; Y represents a group -O-, -S- or -NR_6-, R_6 is hydrogen or lower alkyl; A_1 is a lower alkylene group, an unsubstituted phenylene group, or A compound of formula (I) according to claim 1, which is a phenylene group (which is substituted by lower alkyl, hydroxy, lower alkoxy, amino or halogen); and A_2 is a direct bond or a lower alkylene group, Pure optical isomers and mixtures of these optical isomers of said compounds of formula (I), as well as salts of said compounds of formula (I) with salt-forming groups. 3. R_1 is hydroxymethyl or 1-hydroxyethyl; R_2 is carboxy or esterified carboxy that can be cleaved under physiological conditions; R_3 is amino, methylamino, dimethylamino, (2-hydroxyethyl)- Amino, bis-(2-hydroxyethyl)-
Amino, (4-pyridyl)-amino, (3-pyridyl)
-amino, morpholin-4-yl, piperazin-1-yl, 4-carbamoylpiperazin-1-yl, 3-hydroxy-4-oxo-1,4-dihydropyridine-1-
yl, 1H-tetrazol-1-yl, pyridine-4-
ylthio, 1-methyl-1H-tetrazol-5-ylthio, carbamoyl, or carbamoyloxy;
R_4 and R_5 represent hydrogen; Y represents a group -O-; A_1 represents lower alkylene having 1 or 2 carbon atoms; and R_2 represents a direct bond or lower alkylene having 1 or 2 carbon atoms; Compounds of formula (I) according to claim 1, representing groups of formula (I), pure optical isomers of said compounds of formula (I) and mixtures of these optical isomers, as well as compounds of formula (I) having salt-forming groups. Salts of said compounds. 4, R_1 is 1-hydroxyethyl, R_2 is carboxy, R_3 is amino, methylamino or dimethylamino, each of R_4 and R_5 is hydrogen, Y represents a group -O-, and A_1 is A compound of formula (I) according to claim 1, which is a methylene group and A_2 is a methylene group or an ethylene group, pure optical isomers of said compound of formula (I) and mixtures of these optical isomers. , as well as these salts. 5. (5R,6S)-2-[4-(aminomethyl)-phenoxymethyl]-6-[(1R)- according to claim 1
1-Hydroxyethyl]-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof. 6. (5R, 6S)-2-[4-aminophenoxymethyl]-6-[(1R)-1-hydroxyethyl]-2-penem-3-carboxylic acid according to claim 1, and its medicament Acceptable salt. 7. (5R,6S)-2-[4-(4
-morpholinomethyl)-phenoxymethyl]-6-[(
1R)-1-hydroxyethyl]-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof. 8, (5R,6S)-2-[4-(dimethylaminomethyl)-phenoxymethyl]-6-[(
1R)-1-hydroxyethyl]-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof. 9, (5R,6S)-2-[4-(2
-aminoethyl)-phenoxymethyl]-6-[(1R
)-1-hydroxyethyl]-2-penem-3-carboxylic acid, and pharmaceutically acceptable salts thereof. 10. A medicament comprising a compound of formula (I) according to claim 1. 11. A method of treating a bacterial infection in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1. 12. A method for producing the compound according to claim 1, comprising: a) the following formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (wherein R_1, R_2 and A_1 are the formula ( I), and Y' is the following formula (IIa): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IIa) [In the formula, Y, A_2, R_3, R_4 and R_5 are the formula (
In the compound represented by (representing a group that can be converted into a group having the meaning described in I)), the above group Y' is replaced with the group (IIa): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ( IIa); or b) the following formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, R_1, R_3, R_4, R_5, A_1, A
_2 and Y have the meanings described in formula (I),
Z represents oxygen or sulfur, R_2' represents a protected carboxy group, and X represents either a tri-substituted phosphonio group or, together with the cation, a di-esterified phosphono group] or c) the following formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) [In the formula, R_1, R_3, R_4, R_5, A_1, A
_2 and Y have the meanings described in formula (I),
Z is oxygen or sulfur and R_2' is a protected carboxy group] is treated with an organic compound of trivalent phosphorus; and optionally or necessary, the resulting compound of formula (I) converting the protected functional group in the compound into a free functional group and/or optionally converting the free carboxy group R_2 in the resulting compound of formula (I) into an esterified carboxy group that can be cleaved under physiological conditions and/or optionally converting the group R_3 into a different group R_3 in the resulting compound of formula (I) and/or optionally converting the resulting mixture of isomeric compounds of formula (I) individually. isomers and/or optionally converting the resulting compounds with salt-forming groups into salts or the salts obtained into free compounds or different salts.