NO752419L - - Google Patents

Description

"Antimicrobial azetidione derivatives and process for their preparation". 2. INVENTORS : (All of them are chemists, our research workers and citizens of Japan)

1) Reach : Takashi Kamiya

Address : No. 1-11-6, Furuedai, Suita-shi, Japan

2) Name : Yoshihisa Saito

Address : No. 16-11, Matsugaoka, Hanayashiki,

Takarazuka-shi, Japan

3) Name : Masashi Hashimoto

Address : No. 3-16-39, Kumano-cho, Toyonaka-shi, ♦

Japan

. 4) Name : Tsutomu Teraji

Address : Rose villa 212, Minamisenri, No. 4-20-18,

Kamishinden, Toyonaka-shi, Japan ,5) Name : Takao Takaya

Address : No. 5-1-10, Mikunigaoka-cho, Sakai-shi,

Japan

6) Name : Tadaaki Komori

Address No. 506-42, Higashiamagawa-cho,

Takatsuki-shi; Japan

7) Name : Osamu Nakaguti

Address : Nagaikohpo 603, No. 5-157, Nagaicho Higashi,

Sum: "oshi-ku, Osaka-shi, Japan

8) Name : Tcruo Oku

Address : No. 5-14-3, Hirose, Shimamoto-cho,

Mishima-gun, Osaka-fu, Japan 9) Name : Youichi Shiokawa

Address : Tondadanchi 18-502,

No. 1319, Makita-cho, Takatsuki-shi, Japan 10) Name : Keiji Hemmi

Address : Otokoyamadanchi B-17-402,

No. 180, Koaza-kanaf uri , Oaza-Yawatasou, ...

Yawata-cho, Tsuzuki-gun, Kyoto-fu, Japan 11) Name : Hisashi Takasugi

Address : No. 3-27, Nishino-cho, Kohama,

Sumiyoshi-ku, Osaka-shi, Japan

Every applicant of the above mentioned basic Japanese application is Fujisawa Pharmaceutical Co., Ltd.

The present invention is based on the result of the identification of the chemical structure of FR-1923. FR-1923 is a known antibiotic, which is isolated from the culture fluid of a strain of the genus Nocardia, which is deposited with the American Type Culture Collection under ATCC No. 21806, which is more carefully described e.g. in German Patent Description No. 2,242,699.

In the aforementioned literature, FR-1923 is defined by means of

of various physico-chemical properties without any indication whatsoever of the chemical structure thereof.

As a result of extensive research, the inventors of the present invention have succeeded in determining the chemical structure of FR-1923, and the product in question is attributed the following chemical structure and name"

FR-1923

1-(o-carboxy-4-hydroxybenzyl)-3-(2-[4-(3-amino-3-carboxypropoxy)-phenyl]-2-hydroxyiminoacetamido)-2-azetidinone.

The above stated recognition gave the inventors of the present invention the opportunity to investigate for the first time some chemical modifications of FR-1923. On the basis of such findings, the inventors have investigated the aforementioned modifications, and succeeded in synthesizing a large number of hitherto unknown and unique modified compounds which are

derived from FR-1923 and similar compounds.

To illustrate the known technique, known compounds derived from penicillins, and the corresponding literature

The present invention relates to azetidinone derivatives. In more detail, the invention relates to a method for the production of hitherto unknown azetidinone derivatives with antimicrobial activity.

The azetidinone derivatives described here have a new and hitherto unknown chemical structure which has never been foreseen by the person skilled in the art.

The azetidinone derivatives described here can be represented by the general formula I

where R<*> denotes amino or acylamino, and A denotes hydrogen, a saturated or unsaturated normal aliphatic hydrocarbon group,

which is substituted with at least Sn substituent selected from carboxy or derivatives thereof, cyano, hydroxy and amino, a saturated branched aliphatic hydrocarbon group, which is substituted

with at least Sn substituent selected from the group consisting of carboxy or derivatives thereof, cyano, hydroxy and amino, an unsaturated branched aliphatic hydrocarbon group, which is substituted with at least one substituent selected from the group consisting of carboxy or

derivatives thereof, cyano, hydroxy and amino, or an aliphatic hydrocarbon group, which is substituted with aryl, which ring may be substituted with Sn or more substituents selected from the group consisting of hydroxy, amino, nitro, alkyl, alkoxy, aryl alkoxy, alkylthio, halogen and sulfo, with the caveat,

that when R<1> denotes 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido, A denotes hydrogen, a saturated or unsaturated normal aliphatic hydrocarbon group which is substituted with at least a Sn substituent selected from the group consisting of of carboxy or derivatives thereof, cyano, hydroxy and amino, a saturated branched aliphatic hydrocarbon group, which is substituted with at least

Sn substituent selected from the group consisting of carboxy or

derivatives thereof, cyano, hydroxy and amino, an unsaturated branched aliphatic hydrocarbon group which is substituted with at least one substituent selected from the group consisting of carboxy or derivatives thereof, cyano, hydroxy and amino, or an aliphatic hydrocarbon group, which is substituted with aryl, which ring may be substituted with one or more substituents selected from

the group consisting of amino, nitro, alkyl, alkoxy, arylalkylthio, alkylthio, halogen and sulfo, when R<*> denotes acetamido, benzoylamino or phenylacetamido, A denotes hydrogen, a saturated or unsaturated normal aliphatic hydrocarbon group which is substituted with at least Sn substituent selected from the group consisting of carboxy

or derivatives thereof, cyano, hydroxy and amino, an unsaturated branched aliphatic hydrocarbon group, which is substituted with at least one substituent selected from the group consisting of carboxy or derivatives thereof, cyano, hydroxy and amino, or an aliphatic hydrocarbon group which is substituted with aryl, which ring may be substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, alkyl, alkyl, aryl alkoxy, alkylthio, halogen and sulfo, and when R<1> denotes 2-(2-nitrophenoxy)acetamido or 2- (2-nitrophenoxy)-2-methyl-propionamido, A denotes a saturated or unsaturated normal aliphatic hydrocarbon group which is substituted with at least one substituent selected from the group consisting of carboxy or derivatives thereof, cyano, hydroxy and amino, a saturated branched aliphatic hydrocarbon group which is substituted with at least one substituent selected from the group consisting of carboxy or derivatives thereof, cyano, hydroxy and amino, an unsaturated branched aliphatic hydrocarbon gr above, which is substituted with at least one substituent selected from the group consisting of carboxy or derivatives thereof, cyano, hydroxy and amino, or an aliphatic hydrocarbon group, which is substituted with aryl, which ring may be substituted with one or more "'substituents selected from the group consisting of hydroxy, amino, nitro, alkyl, alkoxy, aryl alkoxy, alkylthio, halogen and sulfo.

The method according to the present invention for the production of azetidinone derivatives with the general formula Z appears from the following reaction schemes:

With regard to the above-mentioned reaction schemes

it should be noted that method variant 1) and method variant 2) are fundamental method variants, and the remaining method variants are alternative.

The definitions of the symbols used in the formulas stated above appear from the following:

R<1> has the meaning given above,

A has the above meaning,

A<*> has the same meaning as the symbol A, with the proviso that

it does not denote hydrogen,

R<*3*> denotes aoylamino,

Y denotes alkyl, whose first carbon atom is substituted with protected amino, protected hydroxy, oxalo or esterified oxalo, o

R denotes amino or acylamlno,

R 3 denotes amino or aoylamino,

R 4 denotes oxo or hydroxyimino,

5

R denotes amino or hydroxy,

6 7 6 R and R together denote oxo or hydroxyimino, or R

denotes hydrogen, and R 7 denotes amino or hydroxy,

8 R denotes aoylamino,

R<9> and R<10> together denote oxo or hydroxyimino, or R<9> denotes hydrogen, and R<10> denotes amino, hydroxy, aoylamino or acyloxy,

X* denotes an acid residue,

A<1> denotes a divalent aliphatic hydrocarbon group,

R<1*>denotes a residue of a nucleophilic connection,

12

R denotes aoyl with one or more protected amino, protected hydroxy or protected carboxy groups,

R' 12 denotes aoyl with Sn or several amino, hydroxy or carboxyl groups,

13

R denotes hydrogen or alkyl,

X<2> denotes hydrogen or halogen,

R*^ denotes aoyl,

X 3 denotes hydrogen or halogen,

4

X denotes halogen,

R^ denotes hydrogen, alkyl, aryl, arylalkyl, aryloxy, a heterocyclic group or heterocyclic alkyl,

16'

R denotes amino or a hydrocarbon group with amino,

R 17 denotes acylamlno or acylamino-substituted hydrocarbon group, 18

R denotes hydrogen or aryl,

19

R denotes alkyl, N-arylcarbamoylalkyl or aryl,

R<20> denotes amino or aoylamino,

R 21 denotes aryl, which is substituted with at least one substituent selected from the group consisting of nitro and esterified carboxy, R 22 denotes arylamino, which aryl ring is substituted with at least one substituent selected from the group consisting of nitro and esterified carboxy, 23

R denotes mono- or dialkylamino,

24

R denotes nitroaryl,

25

R denotes aminoaryl,

26

R denotes hydrogen or aryl,

5

X denotes hydrogen or halogen,

A 2 denotes a divalent aliphatic hydrocarbon group,

27

R denotes hydroxy, alkoxy or alkanoylamino,

■' 28

R denotes acylamlno,

29

R denotes acylamlno,

R<3>0 and R3<1> together denote oxo or hydroxyimino, or R30

31

denotes hydrogen, and R denotes hydroxy,

32 33

R and R denote hydrogen or alkyl,

34

R denotes acylamlno,

R and R together denote oxo or hydroxyiminope or R

36

denotes hydrogen, and R denotes acylamlno or hydroxy, R 37 and R 38 together denote oxo, hydroxyimino, alkoxyimino or substituted alkoxyimino, or R 37 denotes hydrogen, and R 38 denotes acylamlno, hydroxy, alkoxy or substituted alkoxy,

39

R denotes alkyl or substituted alkyl,

40

R denotes hydrogen, alkyl or substituted alkyl,

R<41> denotes alkyl or substituted alkyl,

42

R denotes alkyl, aryl or arylalkyl,

3

A denotes the alkylene,

A 4 denotes a divalent aliphatic hydrocarbon group, R 43 denotes aryl, which is substituted with at least one substituent selected from nitro and esterified carboxy, or an aromatic heterocyclic group, 44 • R denotes arylalkyl,

45

R denotes alkyl,

46

R denotes hydrogen or alkyl,

47

R denotes carboxy or a derivative thereof,

48

R denotes protected amino,

49' R denotes aoylamino with carboxy or a reactive derivative thereof,

50

R denotes aoylamino with carbazoyl, N-(hydroxyalkyl)carbamoyl or N-arylalkylcarbamoyl,

51

R denotes aoylamino with amino,

52

R denotes aoylamino with esterified carboxyalkylamino,

• 53 ■

R denotes acylamino with alkenoylamino, which is substituted with esterified carboxy,

54

R denotes acylamlno with nitro or azido,

R 55 denotes aoylamino with one group selected from the group consisting of formyl, alkanoyl and aroyl,

R<56> denotes acylamlno with hydroxyalkyl or hydroxyarylalkyl,

R5^ denotes arylalkylamino,

X** denotes halogen,

58 59 60

R , R , and R each represent alkyl, and

61'

R denotes arylalkanoylamino.

In the following, examples of the definitions of those are given

above indicated symbols.

With regard to compounds with the general formulas

I, I", IIIr IV, XXXIII and XXXXIV note the following"

An acyl part in acylamlno (R3*) includes aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl, where the aliphatic part is substituted with an aromatic group or a heterocyclic group. Examples of such acyl groups are given in the following: An aliphatic part in the aforementioned aliphatic acyl group if includes saturated or unsaturated, acyclic or cyclic hydrocarbon groups, where the acyclic hydrocarbon group may be branched and partially cyclized. Suitable examples of such acyclic or alicyclic hydrocarbon groups (hereinafter referred to as aliphatic hydrocarbon groups) are indicated in the following: alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, pentyl, neopentyl, octyl, undecyl, tridecyl, pentadecyl, cyclohexylmethyl, /cyclohexylethyl or bornanyl), alkenyl (e.g. vinyl, propenyl, isopropenyl, 3-methylbutenyl, butenyl, 2-methylpropehyl, pentenyl,

octadecenyl or 3-cyclohexenylmethyl), alkynyl (e.g. ethynyl

or 2-propynyl), cycloalkyl (e.g.* cyclopropyl, cyclopentyl, cyclohexyl, indanyl, bornyl or adamantyl) and cycloalkenyl (e.g. 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclohexene -1- yl or bornenyl).

A suitable aromatic group in the mentioned aromatic acyl group includes e.g. aryl such as phenyl, tolyl and naphthyl.

A heterocyclic group in the said heterocyclic acyl group comprises e.g. a monocyclic or polycyclic heterocyclic group containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen. Suitable examples of such heterocyclic groups are given below: A 3- to 8-membered monocyclic heterocyclic group containing at least one sulfur atom (e.g. thienyl or dihydrothio-pyranyl),

a 3-8 membered monocyclic heterocyclic group containing at least one oxygen atom (e.g. oxyranyl, furyl, dihydrofuryl, pyranyl, dihydropyrany1, tetrahytiropyranyl or dioxanyl),

a 3- - 8-membered monocyclic heterocyclic group containing at least one nitrogen atom (e.g. aziridinyl, azetidlnyl, pyrrolyl, 2- or 3H-pyrrolyl, 2- or 3-pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyridyl, pyrimidyl , pyrazinyl, piperidinyl, pyridazinyl or tetrazolyl),

a 3- to 8-membered monocyclic heterocyclic group containing at least one oxygen atom and at least one nitrogen atom (e.g. oxazolyl, isoxazolyl, oxadiazolyl or sydnonyl),

a 3- to 8-membered monocyclic heterocyclic group containing at least one sulfur atom and at least one nitrogen atom (e.g. thiazolyl,

isothiazolyl or thiadiazolyl),

a polycyclic heterocyclic group containing at least one sulfur atom (e.g. a benzene-fused heterocyclic group such as benzothienyl or benzothiopyranyl),

a polycyclic heterocyclic group containing at least one nitrogen atom (e.g. indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoclnolyl, dlhydroisoquinolyl, quinazolyl, 1- or 2H-indazolyl, 1- or 2H-benzotriazolyl, purinyl and carbazolyl),

a polycyclic heterocyclic group containing at least one oxygen atom and at least one nitrogen atom (eg benzoxazolyl and benzoxadiazolyl),

and a polycyclic heterocyclic group containing at least one sulfur atom and at least one nitrogen atom (eg, benzothiazolyl or benzothiazolyl).

The aliphatic part in the said aliphatic acyl group, whose aliphatic part is substituted with an aromatic group or a heterocyclic group, has the same meaning as in the above explanation of the aliphatic part in the aliphatic acyl group, and includes the same suitable examples thereof, as indicated above. Similarly, both the aromatic group and the heterocyclic group have the same meaning, as indicated above in connection with the aromatic group in the aromatic acyl group and a heterocyclic group in a heterocyclic acyl group, and include the same suitable examples thereof, which are indicated above.

The possible carbon atom in the above-mentioned aliphatic acyl group can be replaced and/or interrupted by one or more radicals selected from the group consisting of a divalent aromatic radical, a divalent heterocyclic radical,

-0-, -N», -S-, -SO-, -SO2~ and -NH-, where the hydrogen atom may be replaced by alkyl or aryl. Any aliphatic part, aromatic group and heterocyclic group in the aliphatic acylamino group, the aromatic acylamino group, the heterocyclic acylamino group and the aliphatic acylamino group, where the aliphatic part is substituted with an aromatic group or a heterocyclic group in the above manner, can optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, amino, carboxy, esterified carboxy, hydroxy, -Nj-, -CN, -NHNH2, =0, »NH, =>S, sulfo and «= N0H, where the hydrogen atom can be replaced by alkyl or arylalkyl, and the heterocyclic group in the above-mentioned acylamino groups can optionally be substituted with alkyl and/or an aromatic group.

As particularly suitable examples of those indicated above

acylamino groups R<1> can be designated as follows:

Alkanoylamino, alkenoylamino, arpylamino, heterocyclic carbonylamino, alkanoylamino, which is substituted with aryl or a heterocyclic group, alkanoylamino, which is substituted with

aryl or a heterocyclic group, alkanoyl or alkenoylamino, where the carbon chain or chains, if any, are interrupted by

a divalent aromatic radical and/or divalent heterocyclic radical, alkanoyl- or alkenoylamino which is substituted with aryl and/or a heterocyclic group, where the possible carbon chain(s) in the acyclic hydrocarbon part is interrupted by a divalent aromatic radical and/or divalent heterocyclic radical . -, -S-, -S0o- and -NH-, where hydrogen-

the atom may be substituted with alkyl or aryl, alkanoyl or alkenoylamino which is substituted with aryl and/or a heterocyclic group, where the possible carbon chain(s) in the acyclic hydrocarbon part is interrupted by an aromatic radical and/or divalent heterocyclic radical and is further interrupted by one or more radicals selected from the group consisting of

of -0-, -N«, -S-, -S-, -SO,- and -NH-, where the hydrogen atom can

in

be replaced by alkyl or aryl, alkanoyl- or alkenoylamino, where the possible carbon chain is interrupted by one or more radicals selected from the group consisting of -0-, -N=, -S-, -S-,

0 -SO2_ and -NH-, where the hydrogen atom can be replaced by alkyl or aryl, alkanoyl- or alkenoylamino, where the possible carbon chain is interrupted by a divalent aromatic radical and/or divalent heterocyclic radical and is further interrupted by one or more radicals chosen from the group consisting of -0-, -N«,

-S-, -S-, -S0-- and -NH, where the hydrogen atom can be replaced

0

with alkyl or aryl, aroylamino or heterocyclylcarbonylamino, where the bond between the ring and the carbonyl group is interrupted by one or more radicals selected from the group consisting of -0-,

-N«=, -S-, • -S å-, -S02- and -NH-, where the hydrogen atom can be out-

substituted with alkyl or aryl, alkanoyl or alkenoylamino which is substituted with cycloalkyl, aryl and/or a heterocyclic group, where the bond between the ring and the acyclic hydrocarbon part is interrupted by one or more radicals selected from the group

consisting of -O-, -N=„ -S-, -S-, -SO,- and -NH-, where hydrogen-

the atom may be replaced by alkyl or aryl, alkanoyl or

alkenoylamino, which is substituted with cycloalkyl, aryl and/or a heterocyclic group, where each of the bonds between the ring and the acyclic hydrocarbon part and any carbon chain in the acyclic hydrocarbon part is interrupted by a divalent aromatic radical and/or divalent heterocyclic radical and/or one or more radicals selected from the group consisting of -0-, -ND-, -S-, -0-, -SO2- and -NH-, where the hydrogen atom may be replaced

with alkyl or aryl, aroylamino or heterocycl&Scarbonylamino, where the bond between the ring and the carbonyl group is interrupted by

one or more divalent aromatic radicals and/or divalent gé

heterocyclic radicals, alkanoyl- or alkenoylamino, which are substituted with aryl and/or a heterocyclic group, where the bond between the ring and the acyclic hydrocarbon part is interrupted by a divalent aromatic radical and/or divalent heterocyclic radical and one or more radicals selected from the group consisting of -0-, -N», -S-, -S-, -SO,- and -NH-, where

é hydrogen atom can be replaced by alkyl or aryl, and alkanoyl- or alkenoylamino, which is substituted by aryl and/or a heterocyclic group, where the bond between the ring and the acyclic hydrocarbon part is interrupted by one or more divalent aromatic radicals and/or divalent heterocyclic radicals.

An optional carbon atom in the above-mentioned acylamino group can be substituted with Sn or several substituents selected from the group consisting of halogen, nitro, amino, carboxy, esterified carboxy, hydroxy -N3, -CN, -NKNH2, «0» «NH, «S , sulfo and "NOH, where the hydrogen atom can be replaced by alkyl or arylalkyl, and the heterocyclic group in the above-mentioned acylamino group can optionally be substituted by alkyl.

Some particularly suitable examples of acylamlno R*" are given in the following: Alkanoylamino, where any carbon chain is interrupted of the phenyl, and further optional carbon atoms are substituted with halogen and oxo, phenylalkanoylamino, where an optional carbon atom may be substituted with Sn substituent selected from the group consisting of amino, carboxy, esterified carboxy, hydroxy, halogen, nitro, sulfo, oxo, hydroxyimino and benzyloxyimino, naphthylalkanoylamino, dihydropyranylalkanoylamino,

where an optional carbon atom is substituted by hydroxy,

morpholinoalkanoylamino, thienylalkanoylamino, where an optional

carbon atom can be substituted with a substituent selected from the group consisting of amino, hydroxy, oxo and hydroxyimino, furylalkanoylamino, tetrazolyalkanoylamino, indolylalkanoylamino, where any carbon atom is substituted with amino, diphenylalkanoylamino, alkanoylamino, which is substituted with phenyl and thienyl, 3 -alkyl-1,2,5-oc3adiazol-4-yl-alkanoylamino, phenylalkenoylamino, phenylalkanoylamino, where a possible carbon chain in the alkane part is interrupted by phenylene, phenylalkanoylamino, where a possible carbon chain in the alkane part is interrupted by one or two

divalent radicals selected from the group consisting of -0-f-N»,~S-, -NH-, -N- and -S-, and a further eight or more optional

Carb atoms in the aforementioned group can be substituted with 1-4 substituents selected from the group of amino, carboxy, esterified carboxy, halogen, oxo and ^ IHE, thienylalkanoylamino, where Sn or more possible carbon chains in the alkane part are interrupted by one or two divalent radicals selected from the group . consisting of -0-, -s- and -NH-, and one or more possible carbon atoms in the said group are substituted with 1-4 substituents selected from the group consisting of amino, carboxy, halogen<p>g oxo, dihydropyranylalkanoylamino, where any

carbon chain in the alkane part is interrupted by -NH-, and any carbon atom in the mentioned group is substituted with halogen,

diphenylalkanoylamino, where Sn or several possible carbon chains in the alkane part are interrupted by 1-3 divalent radicals selected from the group consisting of -0-, -N«= and -NH-, and one or more possible carbon atoms in the said group may be substituted with Sn or two substituents selected from the group consisting of carboxy, hydroxy and oxo, alkanoylamino, which is substituted with phenyl and thienyl, where Sn or several possible carbon chains in the alkane part are interrupted by one or two divalent radicals selected from the group consisting of -0-, ^N«° and -NH-, and a further one or more possible carbon atoms in the aforementioned

group can be substituted with 1-5 substituents selected from the group consisting of amino, halogen, oxo and thioxo, alkanoylamino, which is substituted with phenyl and indolyl, where one or more possible carbon chains in the alkane part are interrupted by -0-

and -NH-, and a further possible carbon atom in the aforementioned group is substituted with oxo, alkanoylamino which is substituted with phenyl and benzo[d]isoxazolyl, where one or more possible carbon chains in the alkane part are interrupted by -0- and -NH- , and a further possible carbon atom in the said group is substituted with oxo, phenylalkanoylamino, where one or more possible carbon chains in the alkane part are interrupted by et or two divalent radicals selected from the group consisting of phenylene, 2-oxazetidine-1,3-diyl, l ,3,4-thiadiazole-1,5-diyl and 1,3-oxazolidine-3,4-diyl and 1-4 divalent radicals selected from the group consisting of -O-, -N=, -S-,

-NH- and -N-, and one or more optional atoms i

<CH>3

the said group can be substituted with 1-6 substituents selected from the group consisting of amino, halogen, hydroxy, esterified carboxy, oxo, hydroxyimino, benzyloxyimino and hydrazino, thienylalkanoylamino, where one or more possible carbon chains in the alkane part are interrupted by the phenyl and two divalent radicals selected from the group consisting of -0- and -NH-, and one or more possible carbon atoms in the said group are substituted with carboxy, oxo and hydroxyimino, benzo[c]-pyrrolidinylalkanoylamino, where a possible carbon chain in the alkane part of interrupted by phenylene and -0-, and any further carbon atoms in the aforementioned group are substituted with four substituents selected from the group consisting of amino, carboxy, hydroxy, esterified carboxy, oxo, hydroxyimino and methoxyimino, diphenylalkanoylamino, where any carbon atoms in the alkane part are interrupted by the phenyl , -0- and -NH-, and one or more possible carbon atoms in the said group are substituted with 2-4 substituents selected from the group consisting of amino, halogen, nitro, oxo and hydroxyimino, alkanoylamino, which are substituted with phenyl and furyl, where any carbon chains in the alkane part are interrupted by phenylene, -NH- and -0-, and a further or more optional carbon atoms in the aforementioned group are substituted with three substituents selected from the group consisting of halogen and oxo, alkanoylamino, where one or more optional

carbon chains are interrupted by one or two divalent radicals chosen

from the group consisting of -O-, -S-, -NH-, -SO2~ and

and a further one or more optional carbon atoms in the said group may be substituted with one or two substituents selected from the group consisting of amino, azido, carboxy, hydroxy, oxo, thioxo and »NH, alkenoylamino, where the optional carbon chain is interrupted by -S -, alkanoylamino, where one or more optional carbon chains are interrupted by one or two phenylene groups and 1-5 divalent radicals selected from the group consisting of -0-, -N», -S-, -NH- and and one or more optional carbon atoms in the aforementioned group can be substituted with 1-7 substituents selected from the group consisting of amino, carboxy, hydroxy, halogen, azido, sulfo, esterified carboxy, oxo, thioxo, hydroxyimino and methoxyimino, alkanoylamino, where any carbon chain is interrupted by 1,3,4-thiadiazole-2,5-diyl and one or two divalent radicals selected from the group consisting of -S- and -NH-, and one or more optional carbon atoms in said group are substituted with 1-6 substituents v selected from the group consisting of amino, hydroxy and oxo, alkenoylamino, where a possible carbon chain is interrupted by phenylene and one or two divalent radicals selected from the group consisting of -0- and -NH-, and one or more possible carbon atoms in the said group is substituted with 1-3 substituents selected from the group consisting of carboxy, esterified carboxy, nitro, oxo and hydroxyimino, 1,2-oxazolidinylcarbonylamino, where the bond between 1,2-oxazolidinyl and the carbonyl group is interrupted by -NH-, and a further optionally carbon atom 1 of said group is substituted with oxo, bicyclo[2,2,1]heptylalkanoylamino, where

the bond between bicyclo[2,2,2]heptyl and the alkane moiety is interrupted by -0-, and one or more possible carbon atoms

in the bicyclo[2,2,1]heptane ring is substituted with 3 alkyl groups,

phenylalkanoylamino, where the bond between the phenyl and the alkane part is interrupted by one or two divalent radicals selected from the group consisting of -O-, -S-, -NH- and -SO2-, and a further possible carbon atom in the said group can be substituted with a substituent selected from the group consisting of halogen and nitro,

naphthylalkanoylamino, where the bond between the naphthyl and the alkane moiety is interrupted by a divalent radical selected from the group consisting of -0- and -NH-, pyridylalkanoylamino, where the bond between the pyridyl and the alkane moiety is interrupted by -0-, 1,3,4-thiadiazolyl- alkanoylamino, where the bond between 1,3,4-thiadiazolyl and the alkane moiety is interrupted by -S-, 1H-1,2,3-benzotriazolylalkanoyl-amino, where the bond between 1H-1,2,3-benzotriazolyl and the alkane moiety is interrupted by -0-, pyridyl-l-oxyalkanoylamino, where the bond between pyridyl-l-ftoxyd and the alkane moiety is interrupted by -S-, diphenylalkanoylamino, where the bond between one or two phenyl groups and the alkane moiety is interrupted by one or two divalent radicals selected from the group consisting of of -O-, -S-, -NH- and -SO2~, and one or more optional carbon atoms in the said group are substituted with one or two substituents selected from the group consisting of nitro, carboxy, halogen, hydroxy and oxo, alkanoylamino, which is substituted with phenyl and naphthyl, where bindin gene between the naphthyl and the alkane part is interrupted by -0-, alkanoylamino, which is substituted with phenyl and pyrimidinyl, where the bond between the pyrimidinyl and the alkane part is interrupted by -S-, and one or more possible carbon atoms in the aforementioned group are

substituted with amino and hydroxy, alkanoylamino, which is substituted with bicyclo[2,2,1]heptyl and phenyl, where the bond between bicyclo[2,2,1]heptyl and the alkane moiety is interrupted by -0-, and a possible carbon chain in the alkane part is interrupted by -NH-, and a further possible carbon atom in the alkane part is substituted with oxo, and any carbon atoms in the bicyclo[2,2,1]heptane ring are substituted with 3 alkyl groups, diphenylalkanoylamino, where the bond between one of the diphenyl groups and the alkane part is interrupted by one or two divalent radicals selected from the group consisting of

of -0-, -NH-, -S-,

SO2" and

and one possible carbon chain

carbon chain in the alkane part is interrupted by one or two divalent radicals selected from the group consisting of -NH- and -S-, and one or more possible carbon atoms in the said group are substituted with 1-3 substituents selected from the group consisting of carboxy, esterified carboxy, halogen, nitro and oxo, alkanoylamino which is substituted with 9H-purinyl and phenyl, where the bond between 9H-purinyl and the alkane moiety is interrupted by -S-, and a

possible carbon chain. in the alkane part is interrupted by -NH-, and . a further possible carbon atom in the said group is

substituted with oxo, alkanoylamino which is substituted with phenyl and thienyl, where the bond between the phenyl and the alkane moiety is interrupted by a divalent radical selected from the group consisting of -0- and -NH-, and any carbon chain in the alkane moiety is interrupted by -NH- , and any further carbon atoms in the said © group are substituted with three substituents selected from the group consisting of,

of esterified carboxy, halogen, nitro and oxo, alkanoylamino,

which is substituted with phenyl and pyridyl-1-oxide, where the bond between pyridyl-1-oxide and the alkane moiety is interrupted by -S-, and a possible carbon chain in the alkane moiety is interrupted by -NH-, and a further possible carbon atom in the aforementioned group is substituted with oxo, alkanoylamino which is substituted with naphthyl

and phenyl, where the bond between the naphthyl and the alkane moiety is interrupted by a divalent radical selected from the group consisting of -O- and -NH-,

and any carbon chain in the alkane part is interrupted by one or two divalent radicals selected from the group consisting of -0-, -S-,

-NH- and

and a further possible carbon atom in the aforementioned

group is substituted with oxo, alkanoylamino, which is substituted with phenyl and pyrimidinyl, where the bond between pyrimidinyl and the alkane part is interrupted by -S-, and any carbon chain in the alkane part is interrupted by -NH-, and further possible carbon atoms in the said group is substituted with amino, hydroxy. and oxo, triphenylalkanoylamino, where the bond between Sn or two

feryl groups and the alkane part are interrupted by one or two divalent radicals selected from the group consisting of -0- and -NH-, and a possible carbon chain in the alkane part is interrupted by -NH-, and one or more possible carbon atoms in the mentioned group are substituted with Sn or two substituents selected from the group consisting of halogen and oxo, alkanoylamino, which is substituted with naphthyl and diphenyl, where the bond between the naphthyl and the alkane part is interrupted by -0-, and any carbon chain in the alkane part is interrupted by -NH-, and a further possible carbon atom in the mentioned group is substituted with oxo, alkanoylamino, which is substituted with dinaphthyl and phenyl, where the bond between the two riaphthyl groups and the alkane part is interrupted by -0-, and a possible carbon chain in the alkane part is interrupted by -NH -, and

a further possible carbon atom in the aforementioned group is substituted with oxo, phenylalkanoylamino, where the bond between the phenyl and the alkane part is interrupted by a divalent radical selected from the group consisting of -0-, -NH- and -S-, and any carbon chains in the alkane part - is interrupted by phenylene and 1-3 divalent © radicals selected from the group consisting of -0- and -NH-, and one or more possible carbon atoms in the said group are substituted with 1-5 substituents selected from the group consisting of carboxy, esterified carboxy, halogen, nitro, oxo, thioxo and hydroxyimino, naphthylalkanoylamino, where the bond between naphthyl and the alkane part is interrupted by -NH-, and any carbon chains in the alkane part are interrupted by phenylene and three bivalent radicals selected from the group consisting of -0- and -NH-, and any additional carbon atoms in the aforementioned group are substituted with carboxy, oxo and thioxo, alkanoylamino, which is substituted with pyridyl and phenyl, where the bond between the pyridyl and the alkane part is interrupted by -S-, and the possible carbon chains in the alkane part are interrupted by two phenylene groups and three divalent radicals selected from the group consisting of -0- and -NH-, and further possible carbon atoms in the said group are substituted with four substituents selected from the group consisting of halogen and oxo, alkanoylamino, which is substituted with phenyl and benzo[c]pyrrolidinyl, where the bond between the phenyl and the alkane part is broken by -NH-, and one or more possible carbon chains in the alkane part are broken by the phenyl and -0- - NH-, and one or more possible carbon chains in the alkane part are interrupted by phenylene and 1-3 divalent radicals selected from the group consisting of -0- and

-NH-, and one or more possible carbon atoms in the said group are substituted with 1-5 substituents selected from the group consisting of carboxy, nitro, esterified carboxy, oxo and thioxo, dinaphthylalkanoylamino, where the bond between the two naphthyl groups and the alkane part is interrupted by -NH-, and any carbon chains in the alkane part are interrupted by phenylene and trivalent radicals selected from the group consisting of -0- and -NH-, and further possible carbon atoms in the said group are

substituted with three substituents selected from the group consisting of carboxy and thioxo, alkanoylamino which is substituted with phenyl and thienyl, where the bond between the thienyl and the alkane moiety is interrupted by tetrazole-1,5-diyl, and a possible carbon chain in the alkane moiety is interrupted by -NH -, and a further possible carbon atom in the aforementioned groups substituted with oxo, phenylalkanoylamino, where the bond between the phenyl and the alkane part is interrupted by rO-, and a possible carbon chain in the alkane part is interrupted by -NH-, and further the possible carbon atoms in the said group is substituted with halogen, nitro and oxo, diphenylalkanoylamino, where the bond between phenyl and the alkane part is broken by phenyl and -0-, and a possible carbon chain in the alkane part is broken by -NH-, and a further possible carbon atom in the said group is substituted with oxo, diphenylalkanoylamino, where the bond between the phenyl and the alkane part is broken by isoxazo1-3,4-diyl, which is substituted with alkyl, and a possible carbon chain those in the alkane part are interrupted by -NH-, and a further possible carbon atom in the aforementioned group is substituted with oxo, benzamido, where the bond between phenyl and carbonyl is interrupted by isoxazole-3,4-diyl, which is substituted with alkyl, and one further possible carbon atom in the aforementioned group is substituted with halogen, phenylalkanoylamino, where the bond between the phenyl and the alkane moiety is interrupted by a divalent radical selected from the group consisting of phenylene and 1,3,5-oxadiazole-2,4-diyl and one or two divalent radicals selected from the group consisting of -0-, -NH- and -SO2~, and further the possible carbon atom in the said group can be substituted with carboxy and hydroxy, phenylalkanoylamine, where the bond between the phenyl and the alkane part is interrupted by 4, 5-dihydro-1,2,4-okeadiazole-3,4-diyl, and any carbon atom in the aforementioned group is substituted with oxo, and thienylalkanoylamino, where the bond between the thienyl and the alkane moiety is interrupted by -1H-tetrazole-1, 5-diyl.

With respect to compounds of the general formula I,

I', II, XXXXV, XXXXVI, XXXXVTI, XXXXXVIII, XXXXIX, XXXXXII,

XXXXXXIII and XXXXXIV note the following i

Suitable examples of saturated or unsaturated normal (or branched) aliphatic hydrocarbon in the definition for A may include alkyl, which may be branched (eg methyl, ethyl, propyl, butyl, pentyl, isopropyl, i-methylpropyl, isobutyl, tert. butyl, methylbutyl, methylpentyl, ethylpropyl, ethylbutyl, neopentyl or dimethylbutyl), and alkenyl, which may be branched (e.g. 1-propenyl, allyl, l~butenyl, 1-pentenyl, isopropenyl, methylpropenyl, methylbutenyl, methylpentenyl, ethylpropenyl , ethylbutenyl, dimethylpropenyl or dimethylbutenyl).

The aliphatic hydrocarbon portion of the aliphatic hydrocarbon group, which is substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, alkyl, alkoxy, aryl alkoxy, alkylthio, halogen and sulfo, in the definition for A may be substituted with at least one substituent selected from the group consisting of carboxy, derivatives thereof,

cyano, hydroxy and amino.

Suitable examples of derivatives of carboxy in the saturated or unsaturated normal (or branched) aliphatic hydrocarbon part, which are substituted with at least one substituent selected from the group consisting of carboxy, derivatives of carboxy, cyano, hydroxy and amino, include esters, acid amides and salts,

which is exemplified in the following:

a) Esters:

Esters are conventional esters, including silyl esters,

aliphatic esters and esters containing an aromatic or a heterocyclic ring.

Suitable silyl esters can e.g. be tri-lower alkyl silyl esters (e.g. trimethylsilyl or triethylsilyl esters).

Suitable aliphatic esters include e.g. saturated or unsaturated acyclic or cyclic aliphatic esters, which may be branched, or which may contain a cyclic ring,

such as aliphatic esters, e.g. alkyl esters (e.g. methyl,

ethyl, propyl, isopropyl, 1-cyclopropylethyl, butyl, tert.butyl, octyl, nonyl or undecyl esters), alkenyl esters (e.g. vinyl, 1-propenyl, allyl or 3- butenyl esters), alkynyl esters (e.g. 3-butynyl or 4-pentynyl esters) and cycloalkyl esters (e.g. cyclopentyl, cyclohexyl or cycloheptyl esters), and aliphatic esters containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen, e.g. lower alkoxyalkyl esters (e.g. methoxymethyl, ethoxyethyl or methoxyethyl esters), lower alkanoyloxyalkyl esters (e.g. acetoxymethyl, propionyloxymethyl or pivaloyloxymethyl esters), alkylthioalkyl esters (e.g. methylthiomethyl, ethylthioethyl

or methylthiopropyl esters), dialkylamino esters (e.g. dimethylamino, diethylamino or dipropylamino esters), alkylidene amino esters (e.g. ethylideneamino, propylideneamino or isopropylideneamino esters) or lower alkylsulfinyl-lower alkyl esters (e.g. methylsulfinylmethyl or ethylsulfinylmethyl esters .

Suitable esters containing an aromatic ring include e.g. aryl esters (e.g. phenyl, xylyl, tblyl, naphthyl, indanyl or dihydroanthryl esters), aralkyl esters (e.g. benzyl or phenethyl esters), aryloxyalkyl esters (e.g. phenoxymethyl, phenoxyethyl or phenoxypropyl esters) , arylthio alkyl esters (e.g. phenylthiomethyl, phenylthioethyl or phenylthiopropyl esters), arylsulfinyl alkyl esters (e.g. phenylsulfinyl methyl or phenylsulfinyl ethyl esters), aryloxyalkyl esters (e.g. benzoylmethyl or toluoyl esters) or arylamino esters ( eg faalimido esters).

Suitable esters containing a heterocyclic ring include e.g. heterocyclic esters and heterocyclylalkyl esters, where the suitable heterocyclic ester e.g. can be a saturated or unsaturated, condensed or uncondensed 3- - 8-membered heterocyclic group containing 1-4 heteroatoms such as oxygen, sulfur and nitrogen (e.g. pyridyl-, piperidinoy, 2-pyridon-l-yl-, tetrahydropyrany1- , quinolyl or pyrazolyl esters), and the suitable heterocyclyl alkyl esters include e.g. saturated very unsaturated, condensed or uncondensed 3- - 8-membered heterocyclyl containing 1-4 heteroatoms such as oxygen, sulfur and nitrogen (e.g. pyridyl, piperidino, 2-pyridon-1-yl, tetrahydropyranyl, quinolyl or pyrazolyl) substituted alkyl - (e.g. methyl, ethyl or propyl) esters.

The above-mentioned silyl esters, aliphatic esters and esters containing an aromatic or heterocyclic ring can have 1-10 relevant substituents such as lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl or tert.butyl), lower cycloalkyl (e.g. e.g. cyclopropyl or cyclohexyl), lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert.butoxy), lower alkylthio (e.g. methylthio, ethylthio or propylthio), lower alkylsulfinyl (e.g. methylsulfinyl, ethylsulfinyl or propylsulfinyl), lower alkanesulfonyl (e.g. methanesulfonyl or ethanesulfonyl), phenylazo, halogen (e.g. chlorine, bromine or fluorine), cyano or nitro, and examples of such can be mentioned mono ( or di- or tri-)halo-lower alkyl esters (e.g. chloromethyl-, bromoethyl-, dichloromethyl-, 2,2,2-trichloroethyl- or 2,2,2-tribromomethyl esters), cyano-lower alkyl esters (e.g. e.g. cyanomethyl or cyanoethyl ester), mono-(or di- or tri- or tetra- or penta-) halophenyl esters (e.g. 4-chlorophenyl 1-, 3,5-dibromophenyl-, 2,4,5-trichlorophenyl-, 2,4,6-trichlorophenyl- or pentachlorophenyl esters), lower alkanesulfonylphenyl esters (e.g. 4-methanesulfonylphenyl or 2-ethanesulfonylphenyl esters), 2-(or 3- or 4-)phenylazophenyl esters, mono-(or di- or tri-)nitrophenyl esters (e.g. 4-nitrophenyl -, 2,4-dinitrophenyl or 3,4,5-trinitrophenyl esters), mono-(or di- or tri- or tetra- or penta-)halophenyl lower alkyl esters (e.g. 2-chlorobenayl-r-, 2,4-dibromobenzyl-, 3,4,5-trichlorobenzyl- or pentachlorobenzyl esters), mono-(or di- or tri-)nitrophenyl-lower alkyl esters (e.g. 2-nitrobenzyl-, K2,4-dinitrobenzyl- or 3,4,5-trinitrobenzyl esters), mono-(or dl- or tri-)-lower alkoxyphenyl-lower alkyl esters (e.g. 2-methoxybenæyl-, 3,4-dimethoxybenzyl- or 3,4j,5-trimethoxy<y> benzyl esters) and hydroxy- and di-lower alkylphenyl-lower alkyl esters (e.g. 3,5-dimethyl-4-hydroxybenzyl or 3,5-di-tert.butyl-4-hydroxybenzyl esters. b) Acid amides;

Suitable acids include e.g. N-unsubstituted©

acid amides, N-lower alkyl acid amides (e.g. W-methyl acid amides

or N-ethyl acid amides), N,N-di-lower alkyl acid amides (e.g.

N,N-dimethyl acid amides, N,N-diethyl acid amides or N-methyl-N-ethyl acid amides), N-phenyl acid amides or acid amides with pyrazole, imidazole or 4-lower alkylimidazoles (e.g. 4-methylimidazole or 4-ethylimidazole).

c) Salts.

Suitable salts include salts with inorganic bases

(e.g. sodium salts, potassium salts, magnesium salts or

ammonium salts) and organic bases (e.g. dicyclohexylamine salts, pyridine salts or ethanolamine salts).

With regard to compounds of the general formula IV, the following is noted

Suitable examples of alkyl in the definition for Y include

those mentioned above in connection with alkyl groups, which may be branched.

Suitable examples of protected groups in a protected amino group or a protected hydroxy group in the definition for Y include conventional acyl groups such as conventional alkanoyl groups (e.g. formyl or acotyl), conventional haloalkanoyl groups (e.g. dichloroacetyl or trifluoroacetyl), conventional aroyl groups (e.g. e.g. benzoyl), conventional alkoxycarbonyl groups (e.g. ethoxycarbonyl, tert-butoxycarbonyl or adamantyloxycarbonyl), conventional halogeno-alkoxycarbonyl groups (e.g. trichloroethoxycarbonyl) and conventional substituted or unsubstituted aryl alkoxycarbonyl groups (e.g. benzyloxycarbonyl or p -nitro-benzyloxycarbonyl).

The above-mentioned protecting groups refer to a group attached to the terminal amino or hydroxy group of the acylamino group in the definition for R1, and for the sake of completeness, it should be noted for the explanation of the present invention that the term "protected group" also - with the same meaning as indicated above - refers to a group attached to the other terminal functional group, ie* the carboxy group mentioned below.

With regard to compounds of the general formula I<*>, the following is noted: Suitable examples of acyl in acylamlno in the definition of R<*1> include the same examples given in connection with acyl in the definition of R^".

With regard to compounds of the general formula I", the following is noted: Suitable examples of the groups indicated by the symbol A<*> include the same examples indicated in connection with the group i definition for A, with the exception of hydrogen.

With regard to compounds of the general formula V, VI, VII, VIII, X, XXI, XXIX, XXX, XXXIII and XXXIV, the following is noted:

A suitable acyl moiety in the acylamino group in the definition for

2 '3 „8 «10 «20 «22 «28 «29 «34 «36 «38 ^ _

R , R , R , R , R , R'*, R , R , R , R and R include

the same aliphatic acyl groups, aromatic acyl groups, heterocyclic acyl groups and aliphatic acyl groups, where the aliphatic part is substituted with an aromatic group or a heterocyclic group which is indicated in connection with acyl in acylamlno in the definition for R i.

Suitable examples of the above-mentioned acyl groups can e.g. be alkanoyl or cycloalkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl and cyclohexanecarbonyl), arylalkanoyl (e.g. phenylacetyl, phenylpropionyl and naphthyl-acetyl), heterocyclic alkanoyl (e.g. thienylacetyl, tetra- zolylacetyl, furylacetyl, thiadiazolylacetyl, thiazolylacetyl, morpholinoacetyl, piperazinoacetyl, benzothiazolylacetyl and thienylpropionyl), aroyl (eg* benzoyl, toluoyl, xyloyl, naphthoyl and phthaloyl), heterocyclic carbonyl (eg thenoyl, furoyl, propyl, nicotinoyl, isonicotinoyl and benzodioxanecarbonyl) or cycloalkylalkanoyl (eg cyclopentylacetyl or cyclohexylacetyl). In the examples given above, the possible bond in the alkylene part, the bond between the carbonyl and the aliphatic, aromatic or heterocyclic group, and/or the bond between the alkylene and the cycloalkyl group, the aryl group or the heterocyclic group can be interrupted by a divalent radical selected from the group consisting of - 0-, -S- or -NH-. Suitable examples of such acyl groups are e.g. alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or tert-butoxycarbonyl), cycloalkyloxycarbonyl (e.g. cyclopropoxycarbonyl, cyclohexyloxycarbonyl, bornyloxycarbonyl or adamantyloxycarbonyl), arylalcokecarbonyl (e.g. benzyloxycarbonyl or phanethyloxycarbonyl), heterocyclic alkoxy carbonyl (e.g. furfuryloxycarbonyl, pyrrolidinylmethoxycarbonyl or pyridylmethoxycarbonyl), aryloxycarbonyl (e.g. phenoxycarbonyl or naphthoxycarbonyl), alkoxythiocarbonyl (e.g. methoxythiocarbonyl, ethoxythiocarbonyl or propoxythiocarbonyl), alkoxyalkanoyl (e.g. methoxyacetyl or ethoxy -propionyl), cycloalkoxyalkanoyl (e.g. cyclohexyloxyacetyl, bornyloxyacetyl or adamantyloxyacetyl), alkylthioalkanoyl (e.g. methylthioacetyl, ethylthioacetyl, isopropylthioacetyl or butylthioacetyl), arylthioalkanoyl (e.g. exo phenylthioacetyl), heterocyclylthioalkanoyl (e.g. thienylthioacetyl, thienylthiopropionyl, thiazolylthioacetyl, thiadiazolylthioacetyl, ox aaolylthioacetyl,, oxadiazolylthioacetyl, triazolylthioacetyl, tetrazolylthioacetyl or benzothiazolylthioacetyl), N-alkylcarbamoyl (e.g.» N-methyl-carbaroyl or N-ethylcarbamoyl), N-arylcarbamoyl (e.g. N-phenylcarbamoyl or N-naphthylcarbamoyl), N-alkylthiocarbamoyl (eg N-methylthiocarbamoyl or N-ethylthiocarbamoyl), N-arylthiocarbamoyl (eg* N-phenylthiocarbamoyl).

The possible carbon atom in the acyl group can be substituted with Sn or several suitable substituents such as halogen (e.g. chlorine or bromine) nitro or formyl.

With regard to compounds of the general formula XI, the following is noted: Suitable examples of an acid residue in the definition for X* include, for example, an acid residue of an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid) or an organic acid such as an organic sulfonic acid (e.g. methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid) or an organic carbamic acid (e.g. dimethylcarbamic acid or diethylcarbamic acid). Suitable examples of a divalent aliphatic hydrocarbon radical in the definition for A include, for example, alkylene or alkylidene (e.g. methylene, ethylene, trimethylene, propylene, pentylidene or hexamethylene), where the possible carbon atom may be replaced by at least one radical selected from the group consisting of -NH-, -0- and

and further may be substituted with oxo,

aryl such as phenyl or naphthyl or a heterocyclic group such as thienyl.

With respect to compounds of the general formula XII

the following is noted:

Suitable examples of a residue of a nucleophilic compound 11

1 the definition for R includes e.g. substituted or

unsubstituted alkylthio (e.g. methylthio, ethylthio, propylthio or isopropylthio), alkenylthio (e.g. vinylthio, propenylthio,

isopropenylthio or butenylthio), alkynylthio (e.g. 2-propynylthio) or arylthio (e.g. phenylthio or naphthylthio), substituted or unsubstituted arylalkylthio (e.g. benzylthio, phenethylthio, phenylpropylthio or phenylbutylthio), where the carbon atom in the alkyl part may be replaced by at least one radical chosen

from the group consisting of -0- and -NH- and may further be substituted with oxo, substituted or unsubstituted hetero-cyclylthio (e.g. morpholinylthio, thiadlazolylthio, oxadiazolylthio, triazolylthio, pyrimidinylthio, oxazolylthio, tetrazolylthio, purinylthio, pyridine-l- oxyd-2-ylthio, 5-methyl-1,3,4-thiadiazolylthio, 5-ethyl-1,3,4-thiadazolylthio, 1-methyltetrazolylthio, 2-aminothiazolylthio or 1-methyltriazolylthio), substituted or unsubstituted

aryloxy (e.g. phenoxy, tolyloxy, chlorophenoxy, biphenylyloxy,

naphthoxy, methoxyphenoxy, phenoxyphenoxy, vinylphenoxy, propenylphenoxy, acetylphenoxy, benzoylphenyloxy or beneoylnaphthoxy), substituted or unsubstituted arylamino (e.g. anilino, N-methylanilino or naphthylamino) and substituted and unsubstituted arylalkylamino (e.g. benzylamino, N- methylbenzylamino, phenethylamino or naphthylamino).

The above-mentioned residues of nucleophilic compounds may be substituted with min3t Sn substituent selected from the group consisting of carboxy, esterified carboxy (e.g. methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl), halogen

(eg bromine or chlorine), nitro, formyl, amino; hydroxy, protected amino or protected hydroxy)•

With respect to compounds of the general formula XIII

and XIV the following is noted'

Suitable examples of the acyl part in the acyl group with protected amino, protected hydroxy and/or protected carboxy in the definition for R 12 can include the same examples that are indicated in connection with acyl in acylamlno in the definition for R<*>.

Suitable examples for the acyl part in acyl with amino, hydroxy or carboxy in the definition for R' 12 may include the

same examples as those indicated 1 connection with acyl in acylamlno in the definition for r\

13

Suitable examples for alkyl in the definition for R include e.g. methyl, ethyl and prppyl.

Suitable halogen in the definition for X includes e.g. bromine and chlorine.

With regard to compounds of the general formula XV and XVI, the following is noted'

Suitable examples for acyl 1 the definition for R may include the same examples that are given in connection with acyl 1

in acylamlno in the definition for R , more specifically aroyl (e.g. benzoyl or naphthoyl), arylalkanoyl (e.g. phenylacetyl or phenylpropionyl), heterocyclic alkanoyl such as thienylalkanoyl (e.g. thienylacetyl, thienylpropionyl or thienylbutyryl) and alkoxyarylalkanoyl, where the possible carbon atom is substituted with at least an Sn substituent selected from the group consisting of hydroxyimino, carboxy, amino and protected amino, and; examples of such are the following"

2-[4-(3-carboxy-3-acetaraidopropoxy)phenyl]-2-hydroxyimino-acetyl,

2-(4-[3-carboxy-3-(3-phenylureido)propoxy]phenyl)-2-hydroxy= iminoacetyl

2-(4-C 3-(2,2,2-trifluoroacetamido)-3-carboxypropoxy]phenyl)-2-hydroxyaminoacetyl 0

Suitable examples of halogen in the definition for X 3 and X<4> can be the same/as stated in the context of halogen

2

in the definition for X .

With regard to compounds of the general formula XVII and XVIII, the following is noted;

15

Suitable examples for the definition of R are the following: Aryl (eg phenyl or naphthyl), alkyl (eg methyl, ethyl or propyl), arylalkyl (eg benzyl or phenylpropyl), aryloxy (eg phenoxy or naphthoxy) , a heterocyclic group (e.g. thienyl, pyranyl, 5,6-dihydro-2H-pyranyl, isophenezofuranyl or indolyl) and heterocyclylalkyl (e.g. thienylmethyl, tlenylpropyl, furylmethyl, furylethyl, furylpropyl, indolylethyl, thiadiazolylmethyl, thiadiazolylethyl or oxazolyl- methyl).

Suitable examples of a hydrocarbon residue with amino in the definition for R<*6> include e.g. aminoalkyl (eg aminomethyl, aminoethyl or aminopropyl) and aminoaryl (eg aminophenyl or aminonaphthyl).

17

Suitable examples for the definition for R are the following: The hydrocarbon group in the acylamino-substituted hydrocarbon group in the definition for R includes e.g. alkyl (e.g. methyl,

ethyl, propyl, butyl, pentyl or hexyl), alkenyl (eg vinyl, propenyl or isopropenyl), aryl (eg phenyl or naphthyl)

or arylalkyl (e.g. benzyl, phenethyl?phenylpropyl or

phenylbutyl), and the possible carbon atom in the hydrocarbon group may be substituted with at least one substituent selected from the group

consisting of halogen (e.g. bromine or chlorine), hydroxy or carboxy, and the possible carbon atom in the hydrocarbon group

may further be substituted with at least one divalent radical selected from the group consisting of oxygen, nitrogen, sulfur, imino, carbonyl, thiocarbonyl and carbamoyl.

Suitable examples of acyl in acylamlno and acylamineb-17 substituted hydrocarbon residue in the definition for R are the same as those indicated in connection with acyl in acylamlno in the definition for R<1>.

With respect to compounds of the general formula XIX and. XX, the following is noted in

■:. Suitable examples of aryl in the definition for R18 may be the same as those set out above <>

Suitable examples of alkyl and aryl in the definition for 19

R can be the same as indicated above0

Suitable examples of N-arylcarbamoylalkyl in the definition for R include e.g. N-phenylcarbamoylmethyl, N-phenylcarbamoylethyl, N-aphthylcarbamoylmethyl and N-naphthylcarbamoylethyl.

With. consideration of compounds of the general formula XXII

the following is noted

Suitable examples of aryl, which is substituted with at least one substituent selected from the group consisting of nitro and esterified carboxy in the definition for R 21 include e.g. p-nitrophenyl, 2,4-dinitrophenyl or 2-nitro-4~m®toxycarbonylphenyl„ and suitable examples of substituted aryl in arylamino, where the aryl ring is substituted with at least one substituent selected from the group consisting of nitro and esterified carboxy, in the definition of 22

R can be the same as indicated in connection with

21

the definition for R .

With respect to compounds of the general formula XXIV

the following is noted

Suitable examples of mono- or dialkylamino in the definition for R 23 include e.g. monoalkylamino such as methylamino, ethylamino, propylamino, isopropylamino or butylamino, and dialkylamino such as dimethylamino or diethylamino, and the possible carbon atom in the mono- or dialkylamino group can be

substituted with esterified carboxy such as alkoxycarbonyl (eg, methoxycarbonyl or ethoxycarbonyl).

With regard to compounds of the general formula XXV, the following is noted

Suitable examples of nitroaryl in the definition for R include e.g. mono- or dinitrophenyl or mono- or di-nitronaphthyl.

With regard to compounds of the general formula XXVI, the following is noted

Suitable examples of aminoaryl in the definition for R<25>include1 e.g. mono- or diaminophenyl or mono- or diamino-

naphthyl.

With respect to compounds of the general formula XXVII and XXVIII, the following is noted. Suitable examples of aryl in the definition for R 26 include e.g. phenyl and. naphthyl»

Suitable examples of alkylene in the definition for A 2 are the same as those given in connection with the definition for Å^„ Suitable examples of halogen atoms in the definition for

5

X includes f»eies. bromine and chlorine.

Suitable examples of alkoxy in the definition ddBr R<27> include e.g. methoxy, ethoxy or propoxy, where the alkyl part may be substituted with suitable substituents such as carboxy,

esterified carboxy and the like, e.g. carboxymethoxy or methoxycarbonylmethoxy

Suitable specimen on alkanovlamino in the definition for 27

R includes, for example, formamido, acetamido and propionamido, where the alkyl part may be substituted with ammonium radicals (e.g. N,N,N-trimethylammonio, N,NjN-tritylammonium or pyridinio)

bearing an anion such as chlorine, bromine, iodine, sulfoxy, methylsulfoxy, ethylsulfoxy, formyloxy or p-toluenesulfonyloxy"

With regard to compounds of the general formula XXXII, the following is noted

Suitable examples of alkyl in the definition for R■" ^2 and R<33> are the same as those given in connection with alkyl in the definition 13

for R .......

With regard to compounds of the general formula XXXIXI and XXXIV, the following is noted

39 40 Suitable examples of alkyl in the definition for R<39>, R<40> and R 41 and the alkyl part in alkoxy and acyloxyalkyl in the definition

38

for R are the same as indicated in connection with alkyl i

13

the definition for R .

Suitable examples of the acyl part of the acyloxyalkyloxy in the definition for R : are conventional alkanoyl groups (e.g. acetyl, propionyl, butyryl, isobutyryl or pivaloyl), which are indicated in connection with the protecting group Y.

Suitable examples of substituted alkyl in the definition

for R 39 and R 4" 1 includes, for example, acyloxyalkyl such as alkanoyloxyalkyl (e.g. acetoxymethyl, acetoxyethyl, acetoxypropyl, propionyloxymethyl, propionyloxyethyl, butyryloxymethyl or

pivaloyloxymethyl) and haloalkyl such as monohaloalkyl (e.g. fluoromethyl, chloromethyl, bromomethyl, chloroethyl, bromomethyl, chloropropyl or bromopropyl), dihaloalkyl (e.g. dichloroethyl or 2,3-dlchloropropyl) and trihaloalkyl (e.g. trichloromethyl ).

With regard to compounds of the general formula XXXV and XXXVI, the following is noted

Suitable examples of aryl in the definition for R 42om-

understands e.g. aryl which may be substituted with selected substituents such as carboxy, and examples of such groups may include phenyl, carboxyphenyl, tolyl or naphthyl.

3

Suitable examples of the alkylene in the definition for A include e.g. methylene, ethylene and propylene.

!With regard to compounds of the general formula

XXXIX and XXXX note the following:

Suitable examples of aryl, which are substituted with at least

Sn substituent selected from nitro and esterified carboxy, in the definition for R<43> are the same as indicated in connection with 21

the group indicated by the symbol R.

Suitable examples of an aromatic heterocyclic group

43

in the definition for R may include the same as those mentioned in connection with the heterocyclic group in the definition for R<1>

in compounds of the general formula I, more specifically pyridyl, pyridyl-1-oxide, pyrimidinyl and oxadiazolyl, which may be substituted with aryl such as phenyl, tolyl or naphthyl.

With respect to compounds of the general formula

XXXXI and XXXXII note the following:

Suitable examples of arylalkyl in the definition for R<44>

15

are the same as those indicated in connection with R .

45 46 Suitable examples of alkyl in the definition for R and R

13

are the same as those indicated in conjunction with R ♦

With respect to compounds of the general formula

XXXIII and XXXXIV note the following:

Suitable examples of carboxy or derivatives thereof in the definition for R 47 are the same as those given in connection with the definition for A, i.e. in connection with carboxy or derivatives thereof.

Suitable examples of the protection group in the protected 48

amino group in the definition for R may include the same ones as stated in conjunction with the definition for Y.

With respect to compounds of the general formula

XXXXV, XXXXVI, XXXXVII,XXXVIII, XXXXIX, XXXXXII, XXXXXXIII and

XXXXXZV notes the following:

Suitable examples of the acyl part of the acylamino group in the definition for R49, R50, R<5>1, R<52>, R<53>, R54, R55 and R56 can include the same as indicated in connection with an acyl moiety in acylamlno in the definition for R1.

Suitable examples of carboxy or reactive derivatives thereof in the definition for R 49 are the same as those given in

in connection with the explanation of the symbol A, i.e. in connection with carboxy or derivatives thereof.

Suitable examples of N-(hydroxyalkyl)carbamoyl in the definition for R SO include e.g. N-(hydroxymethyl)carbamoyl, N-(hydroxyethyl)carbamoyl and N-(hydroxypropyl)carbamoyl. Suitable examples of N-arylalkylcarbamoyl in the definition for R SO include e.g. N-benzylcarbamoyl, N-phenethylcarbamoyl, where the aryl moiety may be substituted with one or more suitable substituents.

Suitable examples of esters in esterified carboxyalkyl-52

the amino part in the definition for R includes the same ones that are indicated in connection with the explanation of the symbol A, i.e. in connection with the ester, more specifically indicated e.g. methoxyethylamino, ethoxyethylamino and propoxymethylamino. Suitable examples of alkenoylamino, which is substituted 53

with esterified carboxy in the definition for R , includes e.g.

alkoxycarbonylalkenoylamino such as methoxycarbonylvinylamino, methoxycarbonylpropenylamino, ethoxycarbonylvinylamino, methoxycarbonyl-li-methylvinylamino and ethoxycarbonyl-2-, propenylamino, and examples of the ester in "esterified carboxy" include the same as those indicated in connection with the explanation of the symbol A, i.e. in connection with esters .

Suitable examples of alkanoyl in the definition for R 55 ■' may include the same ones that are indicated in connection with the acyl part of acylamlno in the definition for R<1>.

55 Suitable examples of aroyl in the definition for R may include the same ones that are indicated in connection with the acyl part in acylamlno in the definition, for R<1>.

Suitable examples of the alkyl part in the definition for R are the same as those indicated in connection with R.

Suitable examples of α-hydroxyarylalkyl in the definition for R<56> include e.g. α-hydroxybenzyl and 1-hydroxy-1-(1-naphthy1)methyl.

With regard to compounds of the general formula XXXXXVT, the following is noted: Suitable examples of the arylalkyl moiety in arylalkylamino in 57

the definition for R may include the same ones as stated in connection with R 15•

With regard to compounds of the general formula XXXXXVI and XXXXXvTX, the following is noted: Suitable examples of halogen in the definition for X<6> may include the same as those given in connection with the definition of x<2>.58 59 Suitable examples of alkyl in the definition for R , R and R60 are the same as indicated in connection with R^3.

With regard to compounds of the general formula XXXXXI, the following is noted: Suitable examples of the arylalkanoyl moiety in arylalkanoylamino in the definition for R<61> may include the same as those indicated in connection with the acyl moiety in acylamlno in the definition for R1.

The method according to the invention is explained in detail

in the following:

In the method described here, FR-1923 and 1-substituted 3-amino-2-azetidinone with the formula a which can be derived from FR-1923 and 1-substituted 3-amino-2-azetidinone with the general formula b are used as basic starting compounds and 3-amino-2-acetidinone of the formula c from which it can be derived 3-acylamino-2-acetidinone.

The aforementioned output connections can e.g. is prepared using the methods used in the following reaction schemes: where X denotes one acid residue, and A' has the above meaning.

Method variant 1)t

In this process variant, the desired compound with the general formula I is prepared by reacting a compound with the general formula II or a reactive derivative thereof at the amino group with an acylating agent.

As examples of acylating agents which can be used for the reaction described here, an organic carboxylic acid, an organic sulphonic acid and the corresponding thio- and imido acids can be specified, more specifically an aliphatic acid and an aromatic or heterocyclic carboxylic acid and the corresponding sulphonic acids, carbamic acids, carboxylic acids and thio acids and reactive derivatives thereof.

Examples of reactive derivatives include acid hydrides, activated amides, activated esters, isocyanates and isothiocyanates.

Examples of such reactive derivatives can be an acid azide, a mixed acid anhydride with an acid such as a dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphoric acid, sulfuric acid, thiosulphuric acid, hydrogen halide acids (e.g. hydrochloric acid or hydrobromic acid) , sulfuric acid, monoalkylcarboxylic acid, aliphatic carboxylic acid (e.g. acetic acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid) or aromatic carboxylic acid (e.g. benzoic acid), a symmetrical acid anhydride, an acid amide with pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole and an ester

(e.g. cyanomethyl ester, methoxymethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester , piperidyl ester, 8-chnolylthioester or esters with

N,N-dimethylhydroxylamine, l-hydroxy-2-(lH)-pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide).

The reactive derivatives specified above are chosen taking into account the nature of the acid to be used. When a free acid is used for the reaction as acylating agent, the reaction can preferably be carried out in the presence of a condensing agent such as N^-dicyclohexylcarbodiimide, N-cyclohexyl-N<*->morpholinoethylcarbodiimide, N-cyclohexyl-N*-(4-diethylaminocyclohexyl )carbodiimide, N,N'-diethylcarbodiimide,N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, N,N'-carbonyldi-(2-methylimidazole), pentamethyleneketen-N- cyclohexylimide, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkyl-l-chloroethylene, trialkylphosphite,. ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine,. 2-ethyl-7-hydroxybenz-isoxazolium salt, 2-ethyl-1-5-(m-sulfophenyl)isoxazolium hydroxide (chloromethylene)dimethylammonium chloride, 2,2,4,4,6,6-hexachloro-2,2,4,4,6 ,6-hexahydro-1,3,5,2,4,6-triazatriphosphorine, or a

mixed codenizer such as triphenylphosphine and a carbon tetrahalide (eg carbon tetrachloride or carbon tetrabromide).

As examples of an acyl group that can be introduced on the amino group 1 one compound with the general formula I below

use of the above-mentioned acylating agent can e.g. a dehydroxylated group of an aliphatic, aromatic and heterocyclic carboxylic acid and the corresponding sulphonic acid, carboxylic acid, carbamic acid and thioacid are indicated in more detail the acyl group can be the same acyl group, which is indicated in connection with the acyl group in the acylamino group in the definition for R^.

As examples of reactive derivatives of amino in the 3-position in compounds of the general formula II, Schiff's bases, salts with acid (e.g. hydrochloric acid) and conventional reactive derivatives can be given.

The acylation according to the method variant described here is carried out in a manner known per se, e.g. analogous to the acylation of 6-aminopenicillanic acid or 7-cephalosporanic acid to produce the corresponding 6-acylaminopenicillin and 7-acylaminocephalosporin compounds.

The reaction described here is therefore carried out by reacting a compound with the general formula II or a reactive derivative thereof on the amino group with an acylating agent, usually in a solvent, which does not have an undesirable influence on the reaction, e.g. water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, dichloroethane, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide or pyridine, the above-mentioned hydrophilic solvents can be used in mixture with water.

The reaction described here can also be carried out in the presence of a base such as an inorganic base (e.g. an alkali metal hydrogen carbonate) and an organic base such as trialkylamine (e.g. trimethylamine, triethylamine or tributylamine), N-methylmorpholine,

N-methylpiperidine, N,N^dialkylaniline (e.g., N,N-dimethylaniline or N,N-diethylaniline), N,N-dialkylbenzylamine (e.g., N,N-diethylbenzylamine), pyridine, picoline, lutidine, 1 ,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undecene-7.

In the reaction described here, a liquid base or a liquid condensation agent can also be used as a solvent.

The reaction temperature used in the reaction is not limited, and the reaction described here can preferably be carried out under cooling or at room temperature.

Method variant 2):

In this process variant, the desired compounds of the general formula I" can be prepared by reacting

a compound of the general formula III with a reagent of the general formula A<*->X, where A' has the meaning given above, and X denotes an acid residue.

With respect to reagents of the general formula A'-x, examples of the definition for A* are the same as those given in connection with the definition for A with the exception of hydrogen. Examples of the acid residue in the definition for X can be an acid residue of one inorganic acid (e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid) and the acid residue of an organic acid such as an organic sulfate (e.g. methyl sulfate or ethyl sulfate) , one organic sulfonic acid (eg methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid) and one organic carbamic acid (eg dimethylcarbamic acid or diethylcarbamic acid).

The reaction is usually carried out in a solvent.

Suitable examples of solvents are water, acetone, dioxane, acetonitrile, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, ethyl acetate, N,N-dlmethylformamide and pyridine, among which the hydrophilic solvents can be used in mixture with water. Any other solvent can also be used, which does not have an undesirable effect on turnover.

The reaction temperature is not limited, and the turnover

usually carried out at room temperature or under cooling.

If the connection created in this way with

the general formula I" has a derivative of carboxy or protected carboxy as a substituent, the compound with the general formula I" can be subjected to an elimination reaction, in which the derivative of the carboxy group or the protected group is converted into a corresponding carboxy group, and the present invention also encompasses this reaction.

The elimination reaction is carried out in a conventional manner, i.e. essentially the same methods as are explained with regard to the elimination reaction for the subsequent method variant 3), e.g. solvolysis or reduction.

Method variant 3):

In this process variant, the desired compound with the general formula II can be prepared by conventionally eliminating the acyl group in a compound with

the general formula I*.

A suitable embodiment of the elimination reaction of the acyl moiety in acylamlno may include solvolysis such as hydrolysis using an acid or a base, hydrazinolysis and reduction such as chemical reduction or catalytic reduction and combined methods including iminohalogenation, iminophoresis and solvolysis.

Suitable examples of reagents that can be used for the above-mentioned reaction are the following

For solvolysis:

The solvolysis is carried out in the presence of an acid or a base. Suitable acids are an inorganic acid (e.g. hydrochloric or sulfuric acid), an organic acid (e.g. formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid or p-toluenesulfonic acid) and an acidic ion exchange resin.

Suitable bases are an inorganic base such as a hydroxide, carbonate or bicarbonate of an alkali metal (eg sodium or potassium) or an alkaline earth metal (eg magnesium or calcium), an organic base such as an alkoxide of one of the above metals, a tertiary amine such as trialkylamine (e.g. trimethylamine or triethylamine), a disubstituted aryl amine (e.g. N,N-dimethylamine) or a heterocyclic amine (e.g. N-methylmorpholine, N-methylpiperidine, N,N-Dimethylpiperazine

or pyridine) or a basic ion exchange resin.

For reduction

The reduction is carried out using conventional chemical reducing agents or by conventional catalytic reduction.

Suitable reducing agents are a metal (e.g. tin, zinc, or iron) or a combination of one metallic compound (e.g. chromic chloride or chromic acetate) and an organic or an inorganic acid (e.g. acetic, propionic or hydrochloric acid) ).

Suitable catalysts which can be used for catalytic reduction are conventional catalysts such as platinum catalysts (e.g. platinum plates, porous platinum, platinum aort, colloidal platinum, platinum oxide or platinum wire), palladium catalysts (e.g. porous palladium, palladium black, palladium oxide, palladium on charcoal, colloidal palladium,

palladium on barium sulfate or palladium on barium carbonate),

nickel1 catalysts (e.g. reduced nickel, nickel oxide or Raney nickel), cobalt catalysts (e.g. reduced cobalt or Raney cobalt) in iron catalysts (e.g. reduced iron or Raney iron), copper catalysts (e.g. eg reduced copper, Raney copper or Ullraan copper), or other conventional catalysts.

For the combined method: The iminohalogenation, the iminophoretination and the solvolysis are carried out, with a conventional iminohalogenation agent and a conventional iminophoretination agent and then by conventional solvolysis: Suitable iminohalogenation agents are a phosphorus compound such as phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychlorold and reaction equivalents

hence such as thionyl chloride or phosgene.

Suitable iminophoretic agents that can be used for re-. the statement with the resulting product from the above-mentioned iminohalogen ring of an acylamino compound with the general

formula I', is one alcohol such as an alkanol (e.g. methanol, ethanol, propanol, isopropanol, butanol or tert.butanol), or the corresponding alkanols, which on the alkyl part thereof are substituted with

one or more alkoxy groups (e.g. methoxy, ©toxy, propoxy, isopropoxy or butoxy), and an alkoxide of one of the above

specified metals (eg sodium alkoxide, potassium alkoxide, calcium alkoxide or barium alkoxide) each derived from the alcohol.

The resulting reaction product is then solvolysed, if necessary, in a conventional manner.

The elimination reactions, i.e. the solvolysis, the hydrazinolysis, the reduction and the combined method comprising the iminohalogenation, the iminophoresis and the solvolysis, are conventional methods used for the elimination of an acyl group in an acylamino group in penicillin and cephalosporin compounds, and the reactions can be carried out under conditions such as are analogous to those used in elimination reactions in connection with penicillins and cephalosporins.

E.g. the iminohalogenation and the iminophoresis are carried out preferably at room temperature or under cooling, and the solvolysis is carried out simply by pouring the reaction mixture into water or a mixture of a hydrophilic solvent such as an alcohol (e.g. methanol or ethanol) and water, if necessary with the addition of an acid or base, as exemplified above.

Compounds of the general formula II which are prepared by the above-mentioned elimination reaction are also used as intermediates for the preparation of compounds of the general formula I. That is. by the introduction of an acyl group which is different from that found in compounds of the general formula I<*>, in a 1-substituted 3-amino--2T-azetidinone of the general formula II, a hitherto unknown 1-substituted 3- !-acylamino-2-azetldinone of the general formula I, which has an antimicrobial spectrum of activity different from the spectrum of activity of compounds of the general formula I*.

Method variant 4) t

The desired compounds of general formula III can be prepared by subjecting compounds of general formula IV to a degradation elimination reaction.

Suitable methods which can be used for the elimination reaction are conventional solvolysis such as hydrolysis (e.g. an acid or basic hydrolysis) and a reduction (e.g. chemical or catalytic reduction), which may optionally be selected depending on the nature of the starting compound with the general formula IV.

Solvolysis such as hydrolysis is preferably carried out in a conventional manner in the presence of an acid or a base, and which

examples of such are referred to the explanation in connection with method variant 3).

Suitable examples of reducing agents for chemical reduction and catalysts for catalytic reduction are the same as those indicated in connection with method variant 3).

The degradation reduction is usually carried out by conventionally reducing a compound of the general formula IV with a reducing agent. The reaction conditions,

e.g. the solvent to be used and the reduction temperature are chosen in accordance with the reduction method used and/or the nature of the compound of the general formula IV and/or III. In the catalytic reduction, it is usually preferred to use a solvent such as methanol, ethanol, propanol, isopropanol or ethyl acetate. In the method using a combination of a metallic compound and an acid, the acid is usually used as a solvent, but if necessary, a solvent such as water or acetone can be used.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature or at an elevated temperature.

The compound with the general formula III produced by using the method variant described above can . is also used as an intermediate for the preparation of compounds with the general formula I<*>.

Method variant 5):

In this process variant, the desired compound with the general formula VI is prepared by hydrolysis of a for bond of the general formula V or a derivative of carboxy. Examples of derivatives of carboxy of the starting compound are the same as those given in connection with the definition for A in compounds of the general formula I.

The hydrolysis is carried out in a conventional manner.

That is, a suitable method that can be used for it

hydrolysis described here, is to carry out the reaction in the presence of an acid or base, and as examples of such can be given the same ones that are stated in connection with the hydrolysis in connection with method variant 3).

Although the reaction temperature is not limited, it can be suitably chosen in accordance with the hydrolysis conditions to be used in the reaction, and the reaction is preferably carried out at room temperature or at an elevated temperature in accordance with the nature of the solvent used or other reagents used.

Method variant 6):

In this process variant, the desired compounds of the general formula VIII are prepared by reducing a compound of the general formula VII or a derivative thereof to carboxy.

Examples of derivatives of carboxy in starting compounds with the general formula VII are the same as those given in connection with the definition for A in compounds with the general formula I.

In the reduction described here, the reaction is carried out in a conventional manner such as catalytic reduction, reduction using a combination of a metal such as iron, tin or zinc and an acid such as an inorganic acid (e.g. hydrochloric or sulfuric acid) or an organic acid ( eg acetic acid), a combination of an alloy (eg sodium amalgam or aluminum amalgam), a metal (eg zinc, tin or iron)

or a salt thereof (e.g. zinc chloride, stannous chloride or ferric or ferric chloride) and water, an alkaline solution of an alcohol (e.g. methanol, ethanol, propahol or butanol ), a hydrazine compound (e.g. phenylhydrazine or hydrazine),

a combination of titanium chloride and hydrochloric acid, an alkali metal borohydride such as sodium borohydride and potassium borohydride, diborane or an electrolytic reduction.

Suitable examples of catalysts for the catalytic reduction are the same as those indicated in connection with catalysts in process variant 3).

The reaction conditions for the reduction described here, e.g. the solvent to be used, and the reaction temperature, can possibly be chosen in accordance with the reduction method to be used. It is usually preferred to use a solvent such as water, one of the above-mentioned alcohols, dioxane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide or pyridine, and Sn of the above-mentioned acids can also be used as a solvent.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature or at an elevated temperature.

Method variant 7)t

In this process variant, compounds with the general formula X are prepared by reacting a compound with the general formula IX or a derivative thereof on carboxy with an acylating agent.

As examples of derivatives on the carboxy of the starting compound, the same as those given in connection with the definition for A in compounds of the general formula I can be given.

As examples of acylating agents for the reaction described here, the same ones that are indicated in connection with acylating agents in connection with process variant 1) can be given.

The reaction conditions, e.g. the solvent to be used, and the reaction temperature, are essential

the same as those indicated in connection with the acylation in connection with method variant 1). The acylation described here also includes those cases where the starting compound of the general formula IX has one or more free hydroxy and hydroxyimino groups, which are also occasionally acylated.

Method variant 8)t

In this process variant, the desired compounds of the general formula XII can be prepared by reacting a compound of the general formula XI or a reactive derivative

hence on carboxy with a nucleophilic compound of the general formula R^-H, where R<*>^ denotes the residue of a nucleophilic compound, or a salt thereof.

The nucleophilic compound of the general formula R₂-H, where R₂ has the above meaning, which is used as a reagent, may comprise an amine such as a primary or secondary amine, a thiol compound and a hydroxy compound.

As examples of the residue of a nucleophilic compound, aliphatic hydrocarbonamino (e.g. alkylamine or alkenylamino), di-aliphatic hydrocarbonamino (e.g. dialkylamino), aromatic-amino (e.g. phenylamino, tolylamino or naphthylamino), heterocyclylamino (e.g. thienylamino, thiadlazolylthio or triazolthio), aliphatic hydrocarbon substituted with an aromatic or heterocyclic group, aliphatic hydrocarbon-thio(or -oxy), aromatic-thio(or-oxy), heterocyclyl-thio-(or - oxy) and aliphatic hydrocarbon thio(or -oxy), which is substituted with an aromatic or heterocyclic group, where the aliphatic hydrocarbon moiety may be saturated or unsaturated and branched or partially cyclic, and the aliphatic hydrocarbon moiety, aromatic ring and heterocyclic ring may be substituted with at least one possible substituent.

Suitable examples of an aliphatic hydrocarbon residue, an aromatic group, a heterocyclic group and an aliphatic hydrocarbon residue, which is substituted with an aromatic or heterocyclic group; may include the same ones as stated in the context of the definition éf>r R1.

More suitable examples of the residue of a nucleophilic compound are given in connection with compounds with the general

formula XII.

For the reaction described here, the above-mentioned nucleophilic compound can be used in the form of a salt such as an alkali metal salt (e.g. sodium or potassium salt) or an alkaline earth metal salt (e.g. magnesium salt or calcium salt)

in

of the above-mentioned thiol or phenolic hydroxy compounds. In those cases where the thiol compound as a substituent has a free amino group, the amino-substituted thiol compound can be used in the form of a salt of amino with an acid such as an inorganic acid (e.g. hydrochloric acid or hydrobromic acid) and an organic acid (e.g. formic acid or p-toluenesulfonic acid).

The reaction is usually carried out in a solvent.

Suitable examples of solvents include any solvent which does not adversely affect

the turnover, and as examples of such can be stated water, acetone, methanol, ethanol, tetrahydrofuran, dioxane, N,N-dimethylformamide,

methyene chloride, chloroform or carbon tetrachloride, as a hydrophilic solvent can be used in mixture with water.

The reaction described here is preferably carried out in the presence of a base such as an alkali metal hydroxide (e.g. sodium hydroxide or potassium hydroxide), an alkaline earth metal hydroxide (e.g. magnesium hydroxide or calcium hydroxide), an alkali metal carbonate (e.g. sodium carbonate), an alkaline earth metal carbonate (e.g. calcium carbonate), an alkali metal alkoxide (e.g. sodium alkoxide or potassium alkoxide), an alkaline earth metal alkoxide

(eg calcium alkoxide or barlum alkoxide), an organic amine (eg trimethylamine) or a basic ion exchange resin.

The reaction temperature used in the reaction is

not limited, and the reaction is usually carried out under cooling, at room temperature or at an elevated temperature.

Method variant 9):

In this process variant, the desired compounds of the general formula XIV can be prepared by removing the protective group on the terminal amino, hydroxy and/or carboxy group in the acylamino group in the 3-position 1 a compound of the general formula XIII or a derivative thereof on carboxy.

As examples of protecting groups on the terminal amino, hydroxy and carboxyl group, the same can be given as those given in connection with a protecting group for compounds

with the general formula IV, including the examples of esters

of the carboxy group (ie esterified carboxy), which is indicated in the context of the definition of derivatives of carboxy in the context of compounds of the general formula I.

Suitable methods that can be used for the reaction described here are conventional methods, including conventional solvolysis, conventional reduction and a conventional method using a heavy metal, which is chosen depending on the nature of the starting compound with the general formula XIII.

The solvolysis and the reduction can be carried out in essentially the same way as stated in connection with the decomposition-elimination reaction in connection with method variant 4).

Suitable examples of heavy metals for the method using a heavy metal are copper and zinc.

There are no particular limitations with regard to the reaction temperature, and the preferred temperature is chosen depending on the nature of the protecting group to be removed, and the method used, the reaction being usually carried out under cooling, at room temperature or at elevated temperature.

In the reaction described here, the protective group on the terminal amino, hydroxy and/or carboxy group in the acylamino group in the 3-position in the starting compound with the general formula XIII is removed to produce the corresponding free amino, hydroxy and/or carboxy group, and when the carboxy derivative in the substituent 1 1 position in the starting compound with the general formula XIII is an ester, the ester is also converted to the corresponding free carboxy group, and the present invention also encompasses this conversion.

Method variant 10)p

In this process variant, the desired compounds of the general formula XVI can be prepared by reacting a compound of the general formula XV or a derivative thereof on carboxy with a halogenating agent.

As examples of derivatives of carboxy of the starting compound with the general formula XV, the same as those indicated in connection with compounds of the general formula II can be indicated.

Suitable examples of halogenating agents include e.g. halogen such as chlorine or bromine, halogen hypoacid or alkyl esters thereof such as chlorine hypochlorite or tert.butyl hypochlorite, N-halogenamides such as N-bromoacetamide, N-iodoacetamide, N-bromosuccinamide, N-chlorosuocinimide or N-chlorophthalimide, a copper(I) halide such as copper (I) chloride or copper (I) bromide, pyridinium hydrobromide, perbromide or dioxane dibromide.

The reaction is usually carried out in an inert solvent medium. A suitable solvent that can be used for the reaction described here includes e.g. any solvent, which does not have an undesirable effect on turnover, e.g. water, methanol, ethanol, acetic acid, chloroform, methylene chloride, carbon tetrachloride, dioxane, acetonitrile, tetrahydrofuran or N,N-dimethylformamide.

The reaction temperature used in the reaction is not limited, and the reaction is usually carried out under cooling,

at room temperature or at elevated temperature.

Method variant 11):

In this process variant, the desired compounds of the general formula XVIII can be prepared by reacting a compound of the general formula XVII or one derivative thereof on carboxy with an acylating agent. As examples of derivatives of the carboxy of starting compounds with the general formula XVII, the same can be given, which are indicated in connection with compounds with the general formula I.

The acylating agents used in the reaction described here include the same ones that are indicated in connection with acylating agents in connection with method variant 1).

The acylation described here is carried out in a conventional manner, and the reaction conditions, e.g. the solvent to be used, and the reaction temperature, are essentially the same as those stated in connection with the acylation in connection with process variant 1).

Method variant 12)h

In this process variant, the desired compounds with the general formula XX can be prepared by oxidizing a compound with the general formula XIX or a derivative thereof

on carboxy.

As examples of derivatives of the carboxy of starting compounds of the general formula XIX, the same as those indicated in connection with compounds of the general formula I can be stated.

The oxidation described here is carried out in a conventional manner with a conventional oxidation medium, which is able to

oxidize a group with the formula -S- to a group with the formula

Suitable examples of oxidizing agents are inorganic peracids and salts thereof (e.g. periodic acid, persulfuric acid or sodium or potassium salts thereof), an organic peracid or salts thereof (e.g. perbenzoic acid, m-chloroperbenzoic acid, permauric acid, peracetic acid, chloroperacetic acid, trifluoroperacetic acid or sodium or potassium salts thereof), ozone, hydrogen peroxide or urea-hydrogen peroxide.

The reaction described here is preferably carried out in the presence of a compound containing a metal from group Vb or VIb in the periodic table, e.g. tungstic acid, molybdic acid, vanadic acid or salts thereof with an alkali metal (eg sodium or potassium), an alkaline earth metal (eg calcium or magnesium) or ammonium or vanadium pentoxide.

The oxidation described herein is usually carried out in a solvent such as water, acetic acid, chloroform, methylene chloride, alcohols (e.g. methanol or ethanol), tetrahydrofuran, dioxane, N,N-dimethylformamide or any other solvent which does not have unwanted impact on the turnover described here.

The reaction temperature is not particularly limited, and the reaction referred to here is usually carried out at room temperature or under cooling.

Method variant 13) t

In this process variant, the desired compounds of the general formula XXII can be prepared by reacting a compound of the general formula XXI or a derivative thereof on carboxy with an aryl halide of the general formula R<*->X', where R' denotes aryl, which is substituted with at least one substituent selected from the group consisting of nitro and esterified carboxy, and X* denotes halogen.

As examples of derivatives of the carboxy of starting compounds of the general formula XXI, the same as those indicated in connection with compounds of the general formula I can be stated.

Suitable examples of the aryl group in aryl, which is substituted by at least one substituent selected from the group consisting of nitro and esterified carboxy, in the definition for R' are the same as those given in connection with the definition of R and R 22 in connection with compounds with the general formula XXII, and suitable examples of halogen are chlorine and bromine. Examples of the ester in the esterified carboxy may include the same ones indicated in connection with the ester in the definition for A in compounds of the general formula I.

The reaction described herein is usually carried out in a solvent such as water, methanol, ethanol, propanol, tetrahydrofuran, dioxane, acetone, N,N-dimethylformamide, methylene chloride, chloroform, carbon tetrachloride and any other solvent which does not have an undesirable effect on the described turnover.

The turnover described here is preferably carried out in one

base such as an inorganic or organic base, e.g. an alkali metal hydroxide (e.g. sodium hydroxide or potassium hydroxide), an alkaline earth metal hydroxide (e.g. magnesium hydroxide or calcium hydroxide), an alkali metal carbonate (e.g. sodium carbonate), an alkaline earth metal carbonate (e.g. calcium carbonate), an alkali metal alkoxide (e.g. .eg sodium alkoxide or potassium alkoxide),

an alkali metal alkoxide (eg calcium alkoxide or barium alkoxide), an organic amine (eg trimethylamine) or a basic ion exchange resin.

The reaction temperature is not particularly limited, and the reaction described here is usually carried out under cooling, at room temperature or at an elevated temperature.

Method variant 14)h

In this process variant, the desired compounds of the general formula XXIV can be prepared by reacting a compound of the general formula XXIII or a

derivative thereof on carboxy with a carbonyl compound of the general formula

where R"' and R',<n> are the same or different and each represents hydrogen, alkyl or arylalkyl, or acetals or ketals thereof and then reducing the resulting product.

As examples of derivatives of carboxy of starting compounds with the general formula XXIII, the same ones that are indicated in connection with derivatives of carboxy in the definition for A in compounds of the general formula I can be stated.

Examples of alkyl in the carbonyl compound include methyl, ethyl, propyl, butyl, isobutyl or pentyl, which may be substituted with at least one substituent selected from the group consisting of carboxy, alkoxycarbonyl and halogen (e.g. chlorine or bromine), and examples on arylalkyl is benzyl, phenethyl, phenylpropyl and naphthylmethyl, where the aryl part may be substituted with at least one of the above-mentioned substituents. Suitable examples of the carbonyl compound may include an aldehyde such as an alkanealdehyde (e.g. formaldehyde, acetaldehyde, propionaldehyde, butylaldehyde, isobutylaldehyde or valeraldehyde), an arylalkanealdehyde (e.g. benzaldehyde) or a ketone (e.g. acetone, methyl ethyl ketone, diethyl ketone, methyl propyl ketone, methyl phenyl ketone or methyl tolyl ketone).

The resulting product formed by reacting the compound of general formula XXIII or a derivative thereof on carboxy with the carbonyl compound may, with or without isolation thereof, be subjected to the subsequent reduction.

In the subsequent reaction, the reduction is carried out in a conventional manner, including essentially the same methods and reaction conditions (e.g. solvent volume and temperature) as stated in connection with the reduction according to process variant 6).

The first step in the said reaction is usually carried out in an inert solvent which does not have an undesirable effect on the reaction such as water, dioxane, methanol, ethanol or N,N-dimethylformamide. The carbonyl compound can also be used as a solvent in liquid form.

There are no particular limitations with regard to the reaction temperature which is chosen depending on the nature of the carbonyl compound to be used and the reducing agent to be used, and the reaction is usually carried out under cooling, at room temperature or at elevated temperature.

In the reaction described here, during the course of the reaction or during post-treatment, the carboxy derivative can be converted into the corresponding carboxy group, the group with

the formula

can by reduction be converted into the group with the formula

and the substituent halogen can by dehalogenation

is replaced by hydrogen. The present invention also covers the cases indicated above.

Method variant 15): In this method variant, compounds of the general formula XXVI can be prepared by reducing eh compound of the general formula XXV or a derivative thereof. carboxy. Examples of derivatives of carboxy in starting compounds of the general formula XXV are the same as those indicated in context, with compounds of the general formula I.

In the conversion described here, the reduction is carried out in a conventional manner, and examples of reducing agents and reduction conditions are essentially the same as those stated in connection with the reduction according to method variant 6)*

Process variant 16)j In this process variant, compounds with the general formula XXVIII can be prepared by reacting compounds with the general formula XXVII or derivatives thereof on carboxy

27 with an amine compound of the general formula R -NH,,, where

27

R has the above meaning.

As examples of derivatives of the carboxy of starting compounds of the general formula XXVII, the same as those indicated in connection with compounds of the general formula I can be stated.

Examples of the alkoxy group and the alkanoyl moiety in alkanoyl-27

the amino group in the definition for R in the amine compound are the same as stated above in connection with compounds of the general formula XXVII.

During the reaction, the amine compound with the general 27

formula R -NHj is used in the form of a salt thereof with an acid such as an inorganic acid (e.g. hydrochloric or sulfuric acid) or an organic acid (e.g. formic or acetic acid), and in these cases the reaction can preferably be carried out under alkaline conditions, e.g. in the presence of an alkali metal hydroxide (eg sodium hydroxide or potassium hydroxide) or an alkaline earth metal hydroxide (eg calcium hydroxide).

The reaction is usually carried out in an inert solvent medium. Suitable examples of the solvent are water and a hydrophilic solvent such as methanol, ethanol, propanol, N,N-dimethylformamide and any other solvent which does not have an undesirable effect on the reaction described here.

There are no particular restrictions with regard to the reaction temperature, and the reaction described here is usually carried out under cooling, at room temperature or at an elevated temperature.

Method variant 17):

In this process variant, the desired compounds of the general formula XXX can be prepared by acylating a compound of the general formula XXIX or a derivative thereof on carboxy with an acylating agent.

Examples of derivatives of carboxy in the starting compound can be given the same as those given in connection with compounds of the general formula I.

As examples of acylating agent and acyl group i

29 the acylamino group in the definition for R can be specified the same as specified in connection with method variant 1).

The conditions for the acylation reaction described here, e.g. The solvent and reaction temperature are also the same.

The method is carried out in a conventional manner and can essentially be carried out under the same conditions (e.g. solvent volume and reaction temperature) as stated in connection with method variant 1).

Method variant 18) t

In this process variant, the desired compounds with the general formula XXXII can be prepared by reacting a compound with the general formula XXXI or a derivative thereof on carboxy with a hydroxyalkanesulfonic acid with

the general formula

32 33

where R and R each have it

meaning given above, or a salt thereof.

As examples of derivatives of carboxy of the starting compound with the general formula XXXI, the same can be given as those indicated in connection with compounds with the general formula I. 32 33 As examples of alkyl in the definition for R and R in the above-mentioned reagent, hydroxyalkanesulphonic acid, can be indicated those indicated in connection with compounds of the general formula XXXII. As examples of salts of hydroxyalkanesulfonic acids, a salt with a metal such as an alkali metal (eg sodium or potassium) or an alkaline earth metal (eg calcium or magnesium) can be mentioned. The hydroxyalkanesulphonic acid used as a reagent can be prepared by reacting a carbonyl compound with it general formula

32 33

where R and R each have the above

stated meaning, with sulfuric acid or a salt thereof (eg an alkali or alkaline earth metal). The desired compounds of the general formula XXXII can also be prepared by reacting

a compound of the general formula XXXI with the above-mentioned carbonyl compound and then reacting with sulfuric acid or a salt thereof, and the present invention also covers such cases.

The reaction is usually carried out in a solvent.

Examples of suitable solvents include water and hydrophilic solvents such as methanol, ethanol, propanol, tetrahydrofuran, dioxane, N,N-dimethylformamide, mixtures thereof and any other solvent which does not have

unwanted impact on the turnover described here.

There are no particular restrictions with regard to the reaction temperature, and the reaction described here is usually carried out under cooling, at room temperature or at an elevated temperature.

During the reaction, the amino group in the compound of the general formula XXXI can react with hydroxyalkanesulfonic acid, whereby it is converted into the corresponding disubstituted

amino group

32 33

where R and R each have the above

stated meaning, or salts thereof], and the present invention also covers such cases.

When the hydroxyalkanesulfonic acid is used as reagent, the reaction is preferably carried out in the presence of an alkali or alkaline earth metal.

Method variant 19)j

In this method variant, compounds with

39 the general formula XXXIV which has esterified carboxy (-COOR

41 39 41

and -COOR, where R and R are groups derived from an esterification agent), are prepared by reacting a compound of general formula XXXIII with a conventional esterification agent.

As examples of esterified carboxy of the compounds in question, the same can be stated as stated in connection with esters in connection with derivatives of carboxy in compounds of the general formula I, including silyl esters, aliphatic esters and esters containing an aromatic or heterocyclic ring.

The esterifying agent may comprise any conventional agent capable of esterifying a carboxy group to produce an esterified carboxy group.

Suitable esterifying agents may include a halide such as an alkyl halide (eg methyl iodide, ethyl bromide, ethyl iodide or propyl bromide), an alkenyl or alkynyl halide (eg allyl bromide, methallyl bromide or propynyl bromide), a substituted alkyl halide such as an alkanoyloxyalkyl halide (eg . acetoxymethyl chloride, acetoxyethyl chloride or acetoxypropyl bromide), aroylalkyl halide (e.g. phenacyl bromide) or an arylalkyl halide (e.g. benzyl chloride or phenethyl chloride), a dialkyl sulfate (e.g. dimethyl sulfate, diethyl sulfate or dipropyl sulfate), an alkyl sulfonate (e.g. eg methylbenzenesulfonate,

methyl p-toluenesulfonate or ethyl 4-bromobenzenesulfonate, et

haloformate such as an alkylhaloformate (eg methyl chloroformate, ethyl chloroformate or propylchloroformate), an alkenyl or alkynyl haloformate (eg allyl chloroformate or propynyl chloroformate), a diazoalkane (eg diazomethane or diazoetari) and one hydroxy compound such as an alcohol , e.g.

an alkanol (e.g. methanol, ethanol, propanol, 2-chloroethanol, '2,2,2-trichloroethariol, butanol or 1-cyclopropyletanol), a cycloalkanol (e.g. cycloprpanol, cyclopentanol, cyclohexanol, borneol or adamantanol) or an arylalkanol (eg benzyl alcohol, diphenylmethanol or phenethyl alcohol).

If a hydroxy compound is used as esterification agent in the process variant described here, the reaction can preferably be carried out in the presence of a condensation agent, such as one of the kp-condensation agents specified in connection with process variant i). During the reaction described here, the hydrogen atom in the hydroxy group in the starting compound with the general formula XXXIII can be replaced with a group derived from an esterification agent, i.e. the hydroxy group can e.g. be alkylated or . arylalkylated. The present invention also covers such transformations.

The reaction is usually carried out in a solvent such as water, dioxane, acetone, pyridine, N,N-dimethylformamide or ether.

There are no particular limitations with regard to the reaction temperature, and the reaction is usually carried out under cooling, at room temperature or at an elevated temperature.

Method variant 20):

With this process variant, the desired compounds with the then general formula XXXVI can be prepared, by oxidation of a compound with the general formula XXXV or a carboxy derivative.

As examples of derivatives of the carboxy of the starting compound with the general formula XXXV, the same as those indicated in connection with compounds with the general formula I can be given.

The oxidation described here is carried out in a conventional manner.

The same can be given as examples of oxidizing agents

which is stated in connection with oxidizing agents in method variant 12) o

The reaction described here can also be carried out under essentially the same conditions (e.g. solvent volume and reaction temperature) as stated in connection with process variant 12),

Method variant 21)p

In this process variant, the desired compounds of the general formula XXXVIII can be prepared by reacting a compound of the general formula XXXVII or a derivative thereof on carboxy with a diazotizing agent and then solvolyzing the resulting diazonium salt.

As examples of derivatives of carboxy of the starting compound with the general formula XXXVII can be stated the same as those indicated in connection with derivatives of carboxy in the definition for A with regard to compounds of the general formula I.

Suitable examples of diazotizing agents which can be used for the reaction may include nitrous oxide, nitric acid or derivatives thereof such as alkyl esters (e.g. methyl nitrite, ethyl nitrite or amyl nitrite), alkali metal salts (e.g. sodium nitrite or potassium nitrite) and mixed anhydrides (e.g. nitrosyl chloride, nitrosyl bromide, nitrosyl sulfuric acid or nitrosyl acetic acid).

The diazotization is usually carried out in a solvent such as water, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide or any other solvent which does not have an undesirable effect on the reaction.

The resulting diazonium salt obtained by reacting a compound of the general formula XXXVII or a carboxy derivative thereof with a diazotizing agent is solvolyzed by treating the reaction mixture per se or the isolated diazonium salt under acidic conditions in the presence of an acid such as an inorganic acid (f .eg hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid) and an organic acid (eg formic acid, acetic acid, propionic acid, butyric acid or p-toluenesulfonic acid).

There are no restrictions on the reaction temperature, and the reaction is usually carried out under cooling, at room temperature or at elevated temperature

In the reaction described here, the amino group in a starting compound with the general formula XXXVII is first diazotized, and then the resulting diazonium salt is solvolysed to produce the corresponding hydroxy group. It is thus, depending on the nature of the diazotizing agent used, possible to prepare the desired compound of the general formula XXXVIII or a derivative thereof on carboxy in one step by diazotizing a compound of the general formula XXXVII or a derivative thereof on carboxy under acidic conditions, i.e. in an acidic solvent selected from the liquid inorganic and organic acids specified above and a mixture of an inorganic and organic acid and one of the solvents specified above, whereby the desired compounds of the general formula XXXVIII are obtained without specific solvolysis .

Method variant 22):

In this process variant, the desired compounds of the general formula XXXX can be prepared by reacting a compound of the general formula XXXIX or a derivative thereof on carboxy with an aryl halide of the general formula R"X<5>, where R" denotes aryl, which may be substituted with at least one substituent selected from the group consisting of nitro, esterified carboxy and a heterocyclic group, and X' denotes halogen"

As examples of derivatives of carboxy of starting compounds of the general formula XXXIX, the same as those indicated in connection with compounds of the general formula I can be stated.

Suitable examples of the aryl group in aryl, which may be substituted with at least one substituent selected from the group consisting of nitro, esterified carboxy and a heterocyclic group,

43

in the definition for R are the same as those given in connection with process variant 13) (reference is made to the explanation of compounds of the general formula XXII).

Examples of the ester in the esterified carboxylic acid include

the same as those indicated in connection with esters in the definition for A in compounds of the general formula I,

Examples of the heterocyclic group are given in connection with compounds of the general formula XXXIX.

The reaction is carried out under essentially the same conditions (e.g. solvent ratio and reaction temperature) as those stated in connection with process variant 13).

Method variant 23)p

In this process variant, the desired compounds of the general formula XXXXII can be prepared by reacting a compound of the general formula XXXXI with an alkylating agent.

Suitable alkylating agents include e.g. alkanols (e.g. methanol, ethanol, propanol, isopropyl alcohol and butanol), diazoalkanes (e.g. diazomethane or diazoethane), dialkyl sulphates (e.g. dimethyl sulphate, diethyl sulphate or dipropyl sulphate) and alkyl tosylates (e.g. methyl tosylate or ethyl tosylate ).

The reaction described here is usually carried out in a solvent such as methanol, ethanol, acetone, ether, N,N-dimethylformamide and any other solvent which does not have an undesirable effect on the reaction.

If diazoalkanes, dialkyl sulfates or alkyl tosylates are used as alkylating agents in the reaction in question here, both carboxy and hydroxy groups are usually alkylated in compounds with the general formula XXXXI, but if an alkanol is used as the alkylating agent, the carboxy group in compounds with the general formula XXXXI is alkylated selectively .

When dialkyl sulfates or alkyl tosylates are used as alkylating agent in the reaction described here, the reaction can preferably be carried out in the presence of a base such as an inorganic base (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate) and an organic base ( e.g. trimethylamine, triethylamine, pyridine or picoline), and when an alkanol is used as alkylating agent in the reaction described here, the reaction is preferably carried out in the presence of a conventional condensation agent such as 1-(4-chloro-benzenesulfonyloxy)-6 -chloro-1H-benzotriazole.

There are no particular limitations with regard to the reaction temperature, and it can be appropriately selected in accordance with the nature of compounds of the general formula XXXXI and the alkylating agent used. When the turnover described here e.g. diazoalkaner is used, the reaction can be carried out under cooling or at room temperature.

Method variant 24)i

. In this process variant, the desired compounds with the general formula XXXXIV can be prepared by

subjecting a compound of the general formula XXXIII to an amino protecting group elimination reaction.

The elimination reaction described here is carried out in a conventional manner, i.e. under essentially the same conditions as stated in connection with the elimination reaction for

the protecting group for amino in compounds with the general formula XIII in connection with process variant 9).

Examples of the protecting group may include those indicated in connection with compounds of the general formula IV.

If the starting compound with the general formula XXXIII in the reaction referred to here has another protected amino, protected hydroxy and/or protected carboxy group, such a protecting group can be eliminated during the reaction, whereby the corresponding amino, hydroxy and/or carboxy group is obtained, and the present invention also covers such cases.

Method variant 25):

In this process variant, the desired compounds of the general formula XXXXVI can be prepared by reacting a compound of the general formula XXXXV with a reagent selected from the group consisting of hydrazld, hydroxyalkylamine and arylalkylamine and salts thereof.

Suitable examples of hydroxyalkylamines include e.g. hydroxyethylamine and hydroxypropylamine, and suitable examples of arylalkylamines include e.g. benzylamine and phenethylamine. Suitable examples of salts of hydrazld, hydroxyalkylamines and arylalkylamines may include an organic acid salt (eg acetate, maleate, tartrate, benzene sulphonate or toluene sulphonate) and an inorganic acid salt (eg hydrochloride, sulphate or phosphate).

Pen reaction described here can be carried out under essentially the same conditions as stated in connection with the acylation of compounds with the general formula II in connection; with process variant 1).

Method variant 26):

In this process variant, the desired compounds of the general formula XXXVIII can be prepared by reacting a compound of the general formula XXXXVII with an esterified alkene carboxylic acid.

Examples of the alkene moiety in the esterified alkene carboxylic acid may include alkenyl, which may be branched such as alkyl, 1-propeny1, 1-buteny1, 1-pentenyl, isopropeny1, methylpropenyl, methylbutenyl, methylpehtenyl, ethylpropenyl and ethylbutenyl, and examples of the ester moiety may include a non -reactlv ester in an ester which is indicated in connection with compounds of the general formula I, I' and II.

The reaction described here is usually carried out in a solvent that does not have an undesirable effect on the reaction, such as water, methanol, ethanol, acetone, chloroform or N,N-dimethylformamide •

The reaction described here can preferably be carried out in the presence of a base such as an inorganic base (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate) and an organic base (e.g. trimethylamine, triethylamine, pyridine or picoline) .

There are no particular restrictions with regard to the reaction temperature, and the reaction can be carried out during cooling or during heating.

Method variant 27):

The desired compounds of the general formula XXXXIX can be prepared by reacting a compound of the general formula XXXXVII or a salt thereof with an esterified aliphatic hydrocarbon carbonyl acetic acid or a salt thereof.

As examples of the aliphatic hydrocarbon de1 in the esterified aliphatic hydrocarbon-carbonylacetic acid, the same can be stated as indicated in connection with acyl with regard to compounds of the general formula I. Suitable examples of esterified aliphatic hydrocarbon-carbonyl acetic acids are esterified alkanoyl acetic acids such as esterified acetyl-, propionyl or butyroylacetic acid.

Examples of the ester moiety in esterified aliphatic hydrocarbon carbonyl dioxygens may include a non-reactive ester in an ester which is indicated in the context of the ester with respect to compounds of the general formula I, I<*> and II.

Suitable salts sv compounds of the general formula XXXXVII may comprise one organic acid salt (eg acetate, maleate, tartrate, benzene sulphonate or toluene sulphonate) and one inorganic acid salt (eg hydrochloride, sulphate or phosphate), and suitable salts of alkanoylacetic acid esters includes a salt with an inorganic base (eg sodium salt, potassium salt, calcium salt or magnesium salt).

The reaction described here can be carried out with or without a solvent. Suitable solvents may include methanol, ethanol, propanol, ether, acetone, benzene, toluene and any

preferably another solvent which does not have an undesirable effect on turnover. The reaction described here can preferably be carried out in the presence of a base such as an inorganic base (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carborate, sodium hydrogen carbonate or potassium hydrogen carbonate) or an organic base (e.g. trimethylamine, triethylamine, pyridine or picoiin)..

There are no particular restrictions with regard to the reaction temperature, and the reaction described here is usually carried out under heating.

The resulting compounds of the general formula XXXXIX may include isomers of compounds of the general formula

formula XXXXIX, where the group indicated by the symbol R 53 is replaced by acylamino with alkylideneamino, which is substituted by esterified carboxyl.

Process variant 28): In this process variant, the desired compounds of the general formula XXXXVII can be prepared by reduction of compounds of the general formula XXXXXII.

The reduction is carried out in a conventional manner, whereby the nitro and azido group can be reduced to an araino group, including the reduction method indicated in connection with the reduction according to process variant 15).

Suitable reduction methods that can be used for the conversion include chemical reduction using a metal (e.g.

tin, zinc or iron) and an acid (e.g. acetic or hydrochloric acid) or catalytic reduction in the presence of a metallic

catalyst such as palladium/charcoal, Raney-nickel platinum oxide and other conventional catalysts.

The reaction is carried out in a solvent such as methanol, ethanol or propanol.

There are no particular restrictions on the reaction temperature, and it can be appropriately selected in accordance with the nature of the compound of the general formula XXXXXII and the reduction method.

Procedure variant 29a) p

In this process variant, the desired compounds of the general formula XXXXXIV can be prepared by reduction of a compound of the general formula XXXXXXIII.

The reduction is carried out in a conventional way. Suitable reduction that can be applied to the turnover described here can e.g. be reduction using an alkali metal borohydride (eg sodium borohydride or lithium borohydride).

The reaction described here is usually carried out in a solvent which does not have an undesirable effect on the reaction, such as water, methanol, ethanol, chloroform, benzene or toluene.

There are no particular restrictions on the reaction temperature, and it can be appropriately selected in accordance with the nature of compounds of the general formula XXXXXXIII and the reduction method.

Method variant 29b):

In this process variant, the desired compounds with the general formula XXXXXVT can be prepared by

react with a compound of the general formula XXXXXV or

a derivative thereof on carboxy with an arylalkylamine under reductive conditions.

Suitable examples of arylalkylamines are e.g. benzylamine and phenethylamine, where the benzene ring may be substituted with at least one suitable substituent.

Examples of derivatives of carboxy of the starting compound of the general formula XXXXXV are the same as those indicated in connection with derivatives of carboxy in the definition for A in connection with compounds of the general formula I.

The reaction described here is carried out under reductive conditions, i.e. by reacting the starting compound of the general formula XXXXXV with an arylalkylamine in the presence of a

conventional reducing agent or by reacting the starting compound of the general formula XXXXXV with one arylalkylamine and then reducing the resulting product with a conventional reducing agent.

Suitable examples of reducing agents are alkali metal borohydrides (e.g. sodium borohydride or potassium borohydride), and other conventional reducing agents and methods are indicated in connection with process variant 6).

If the reaction is carried out by reacting a compound of the general formula XXXXXV with an arylalkylamine and then reducing the resulting product, the reaction of a compound of the general formula XXXXXV with an arylalkylamine can preferably be carried out in the presence of a base such as an inorganic base (f .eg sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate) or an organic base (eg trimethylamine, triethylamine, pyridine or picocholine).

The reaction described here is usually carried out in a solvent which does not have an undesirable effect on the reaction, such as methanol, ethanol, chloroform, benzene or toluene.

There are no particular restrictions on the reaction temperature, and it can be appropriately selected in accordance with the nature of the compound of the general formula XXXXXV, the arylalkylamine, and the reduction conditions or reduction method.

Method variant 30):

With this method variant, the desired for compounds of the general formula XXXXXVIII are prepared by reacting a compound of the general formula XXXXXVII or a carboxy derivative thereof with a trialkylamine.

Examples of derivatives of carboxy are the same as those

which is indicated in the context of derivatives of carboxy i

the definition for A with respect to compounds of the general formula I.

Suitable trialkylamines include e.g. trimethylamine,

triethylamine or tripropylamine.

The reaction described here is usually carried out in a solvent which does not have an undesirable effect on the reaction, such as methanol, ethanol, acetone, ether or N,N-dimethylformamide.

There are no particular restrictions with regard to the reaction temperature, and the reaction is usually carried out at room temperature or by heating•

Process variant 31)s In this process variant, the desired compounds of the general formula XXXXXI can be prepared by reacting a compound of the general formula XXXXX or a derivative thereof on carboxy with an acylating agent.

The derivative of carboxy of starting compounds of the general formula XXXXX are the same as those indicated in connection with derivatives of carboxy in the definition for A with respect to compounds of the general formula I.

The acylation is carried out in a conventional manner, and the reaction is carried out under essentially the same conditions (e.g. solvent volume and reaction temperature) as stated in connection with the acylation according to process variant 1).

Examples of acylating agents may include the same ones as stated in connection with the acylating agent According to method variant 1).

Depending on the nature of the reactions used in the above-mentioned process variants, the carboxy group can be converted into a corresponding derivative of carboxy, and/or a derivative of carboxy can be converted into the corresponding free carboxy group during the reaction of the starting compounds or during post-treatment of the reaction mixture or the relevant compounds .

In a similar way, one or more protecting groups for protected carboxy, protected amino and/or protected hydroxy can be converted into the corresponding carboxy, amino and/or hydroxy group(s). The present invention also includes the above-mentioned turnovers.

The compounds of the general formula I described here have antimicrobial activity against several pathogenic microorganisms and may be useful in the treatment of diseases

which are caused by such microorganisms in animals, including humans.

With respect to the representative compounds described herein, their antimicrobial activity against pathogenic micro-organisms is hereinafter indicated as MIC values (minimum inhibitory concentrations), which are determined in a conventional manner. The MlO values are given in the following as micrograms per ml.

The compound produced by the method according to example 39: Pseudomonas aeruginosa (3), the compound produced by the method according to example 51: Bacillus subtilis (12.5), the compound produced according to example 112: Escherichia coil (60), Proteus vulgaris (<3 ), Staphylococcus aureus (60), the compound prepared by the method according to example 157: Bacillus subtilis (7.5), Staphylococcus aureus (7.5), the compound prepared by the method according to example 158: Bacillus subtilis (80), Staphylococcus aureus (80), the compound produced by the method according to example 161: Escherichia coil (16), Proteus vulgaris (8), Staphylococcus aureus (8), the compound produced by the method according to example 291: Escherichia coil (1.6), Proteus vulgaris (25), the one by the method according to example 300

compound produced: Pseudomonas aeruginosa (15),

Escherichia coli (60), that by the method according to example 400

compound produced: Pseudomonas aeruginosa (32, Escherichia coli (16), the compound produced by the method according to example 409: Escherichia coli (60), Proteus vulgaris (<3),

Staphylococcus aureus (60), the compound produced by the method according to example 469: Bacillus subtilis (60), Escherichia coil (4), Staphylococcus aureus (4), the compound produced by the method according to example 489: Pseudomonas aeruginosa (15), Escherichia coli (3.9), Proteus vulgaris (60), the compound prepared by the method according to example 507: Pseudomonas aeruginosa (6.3), Proteus vulgaris (25), the compound prepared by the method according to example 508: Pseudomonas aeruginosa (6.3 ), Proteus vulgaris (25), the compound produced by the method according to example 508: Pseudomonas aeruginosa (6.3), Proteus vulgaris (25), Staphylococcus aureus (1.6), the compound produced by the method according to example 5111: Bacillus subtilis ( 6), Escherichia coli (30), Staphylococcus aureus (60).

It has previously been indicated that the compounds produced by the method according to the present invention are hitherto unknown compounds. The hitherto unknown compounds can in particular be indicated by the following general formula:

where 1) Ra and R<b>each represents hydrogen, 2) Ra represents hydrogen, and R represents hydrocarbonsulfonyl (such as arenesulfonyl), 3) R a and R b together represent a divalent acyl group which is derived from a dicarboxylic acid (e.g. phthalic acid), 4) Ra denotes hydrogen, and R b denotes an acyl group which is indicated in connection with the acyl group in the definition for R1, more specifically an acyl group chosen from among the following groups:

where n denotes an integer from 0 to 4, R' denotes hydrogen, carboxy or a derivative thereof (e.g. a salt or an ester), R" v" denotes hydroxy, halogen, azido, amino, aliphatic radical-amino such as alkylamino, alkenylamino or cycloalkylamino, arylamino, aoylamino such as aliphatic acylamno (e.g. alkanoylamino), aliphatic radical-oxy(thiocarbonyl)amino (e.g. alkoxy-(thiocarbonyl)amino), aryloxy-aliphatic acylamno (e.g. . aryloxyalkanoylamino), aryl-aliphatic acylamno (e.g. ary1-alkanoyiamino), aryloxy-aliphatic acylamno (e.g. aryloxyalkanoylamino), heterocyclyl-aliphatic acylamno (e.g. heterocycly1-alkanoylamino), aroylamino, substituted ureido such as N '-arylureido, substituted thioureido, such as N'-arylthioureido or arylthio, R"' v» denotes hydrogen, hydroxy, amino, arylamino, acylamno such as aliphatic acylamno (e.g. alkanoylamino), aliphatic radical-oxy(thiocarbonyl)amino ( eg, alkoxy-(thiocarbonyl])amXNO), aroylamino, substituted ureido such as N'-aryl- ureido or substituted thioureido such as N'-arythioureido, RM"b denotes hydrogen, or R"* and R"" together denote oxo, hydroxyimino or substituted hydroxyimino such as alkoxyimino, where the aliphatic hydrocarbon moiety is substituted with at least Sn a suitable substituent selected from the group consisting of carboxy, derivatives thereof (e.g. salts or esters), halogen and sulfo, and the aryl ring and the heterocyclic ring may be substituted with

at least one suitable substituent selected from the group consisting of nitro, halogen, carboxy and derivatives thereof (e.g.* salts or esters),

il)

where R"1" denotes oxo, hydroxyimino or substituted hydroxyimino such as aliphatic radical-oxyimino (e.g. alkoxyimino) or aryl-aliphatic radical-oxyimino (e.g. arylalkoxyimino), R""w denotes cyano, an aliphatic radical such as alkyl, aryl, a heterocyclic radical, aliphatic radical-amino such as alkylamino, aryl-aliphatic radical-amino such as arylalkylamino or aliphatic radical-oxy such as alkoxy, where the aliphatic part may be substituted with at least one suitable substituent selected from the group consisting of hydroxy , carboxy and derivatives thereof (e.g. salts or esters), and the aryl ring and the heterocyclic ring may be substituted with at least one suitable substituent selected from the group consisting of hydroxy, aliphatic radical-oxy (e.g. alkoxy or alkenyloxy), which may have carboxy or one derivative thereof, and aryl-aliphatic radical-oxy (e.g. aryl-alkoxy), lii) where R"""• denotes aryl, aryloxy, aryl-aliphatic radical-oxy such as aryl-alkoxy, arylamino, a heterocyclic advice ical, guanidino or substituted guanidino such as acylguaaidino. (e.g. 3-arylalkanoylguanidino), where the aryl radical and the heterocyclic radical may be substituted with at least one suitable substituent selected from the group consisting of nitro, halogen, an aliphatic radical (e.g. alkyl), aliphatic radical-oxy (e.g. .ex. alkoxy) and the like. (iv)

where n2 and n3 each denote an integer from 0 to 4,

RHnniii> denotes hydrogen, an aliphatic radical such as alkyl, aryl, substituted oxy such as aryloxy, a heterocyclic radical or N-substituted carbamoyl such as N-arylcarbamoyl, where the aryl radical and the heterocyclic radical may be substituted by at least one

suitable substituent (e.g. hydroxy), R«»«<»»«b>denotes hydrogen, amino, azido, halogen, hydroxy, carboxy, derivatives thereof (e.g. salts or esters), sulfo, substituted sulfo such as arylsulfo or an aliphatic radical such as alkyl or alkenyl, which may be substituted with at least one suitable substituent selected from the group consisting of amino, protected amino, azido, halogen, hydroxy, carboxy, derivatives thereof (e.g. salts or esters), sulfo , aoyl (e.g. aroyl), N,N-disubstituted amino (e.g. N-alkyl-N-arylaminoalkyl), aryl, substituted aryl, a heterocyclic radical and a substituted heterocyclic radical, and the like,

aryl, which may be substituted with at least one suitable substituent selected from the group consisting of hydroxy, nitro, carboxy, halogen, and substituted sulfonamido (e.g., aromatic ring sulfonamido (e.g., benzenesulfonamide)), which may have at least one substituent (e.g. carboxy or hydroxy), and the like,

a heterocyclic radical, which may be substituted with at least one suitable substituent selected from the group consisting of an aliphatic radical, aryl, a heterocyclic radical, acylamlno and the like (e.g. a heterocyclic radical, alkyl-heterocyclic): radical, aryl-heterocyclic radical, heterocyclyl-heterocyclic radical, heterocyclyl-aliphatic acyl (e.g. heterocyclylalkanoyl), amino-heterocyclic radical, aryl-aliphatic acyl (e.g. arylalkanoyl) or amino-heterocyclic radical, where the ayl ring

and the heterocyclic ring may have at least one suitable substituent (eg oxo or halogen)),

acyl such as aroyl, aliphatic radical-oxo such as alkoxy or cycloalkyloxy, which may be substituted with at least one suitable substituent, aryloxy, where the aryl ring may be substituted with at least one substituent selected from the group consisting of nitro, halogen, acyl (e.g. formyl or alkanoyl), cyanoamino (e.g. alkanoylamino), aryl, aryl-aliphatic radical (e.g. arylalkylamino) and an aliphatic radical (e.g. alkyl or alkenyl), which may be substituted with at least one suitable substituent ( e.g. carboxy, derivatives thereof (e.g. salts or esters), amino, hydroxy, nitro, hydroxyimino, substituted hydroxyimino such as aliphatic radical-oxyimino (e.g. alkoxyimino), which may be substituted with e.g. carboxy, (N-halo-N,N,N-trialiphatic radical-ammonio)aliphatic acylhydrazono (e.g. N-halo-N,N,N-trlalky1-

ammonio)alkanoylhydrazono) or aliphatic radical-thio-aliphatic acylamino (e.g. alkylthioalkanoylamino), where the aliphatic-thiodel may be substituted with at least one suitable substituent (e.g. amino or carboxy)), and the like,

heterocycly1-oxy,

aliphatic radical-thio, which may be substituted with at least one suitable substituent selected from the group consisting of e.g. amino, carboxy, acyl and acylamlno (e.g. alkylthio, alkenylthio, acylamino-aliphatic radical-thio (e.g. aroylalkanoylaminoalkylthio) or acyl-aliphatic radical-thio (e.g. aroylalkylthio or N-arylcarbamoylalkylthio), which may have at least one suitable substituent (e.g. halogen or nitro)),

aliphatic radical-sulfinyl, which may be substituted with at least one suitable substituent selected from the group consisting of substituted carbamoyl and the like (e.g. alkylsulfinyl or N-arylcarbamoyl-alkylsulfinyl),

arylthio, which may be substituted with at least one suitable substituent selected from the group consisting of carboxy and the like,

heterocyclyl-thio, which may be substituted with at least

one suitable substituent selected from the group consisting of e.g. amino, hydroxy, araino-aliphatic radical and acylamino-aliphatic radical (e.g. heterocyclyl-thio, amlnoalkyl-heterocyclyl-thio or alkanoyl-aminoalkyl-heterocyclyl-thio), which may have at least one suitable substituent (e.g. hydroxy ),

arylamino, which may be substituted with at least one suitable

substituent,

heterocycly1-amino, which may be substituted with at least one suitable substituent selected from the group consisting of e.g. oxo and aryl (e.g. oxo-substituted heterocyclyl-amino or aryl-heterocyclyl-amino),

mono- or disubstituted amino such as aliphatic radical-amino (e.g. alkylamino), N-aliphatic radical-N-protected amino (e.g. N-alkyl-N-protected carboxyamino), N-substituted-N-arylamino ( eg N-aliphatic radical-N-arylamino (eg N-alkyl-N-arylamino)), N-acyl-N-arylamino (eg N-alkanoyl-N-arylamino), N- aliphatic radical-N-arylamino (e.g. N-alkyl-N-arylamino), where the aliphatic hydrocarbon moiety may have at least one suitable substituent (e.g. azido or carboxy), or N-substituted sulfonyl-N-arylamino ( eg N-alkanesulfonyl-N-arylamino),

acylamlno selected from the group consisting of:

aliphatic acylamlno (e.g. alkanoylamino), which may be substituted with at least one suitable substituent (e.g. halogen or amino), aliphatic radical-oxy-aliphatic acylamlno (e.g. cycloalkyloxy-alkanoyl), which may be substituted with at least one suitable substituent„ aliphatic radical-tlo-aliphatic acylamlno (e.g. alkylthioalkanoylamino), where the aliphatic hydrocarbon part may be substituted with at least one suitable substituent (e.g. amino, halogen or carboxy), aryl-aliphatic acylamlno, where the aryl ring may be substituted with at least one suitable substituent selected from the group consisting of e.g. aliphatic radical-oxy and aryloxy (e.g. alkoxyarylalkanoylamino or aryloxyarylalkanoylamino), where the aliphatic hydrocarbon part and the aryl ring may be substituted with at least one suitable substituent (e.g. halogen,; arylaliphatic radical-oxyimino (e.g. arylalkoxyimino), arylamino, amino or hydroxy)p aryiamino-aliphatic acylamlno (e.g. ~arylaminoalkanoyl-. amino), where the aryl ring and the aliphatic hydrocarbon part may be substituted with at least one suitable substituent (e.g. halogen, carboxy or amino), aryloxy -aliphatic acylamino, where the aryl ring may be substituted with one substituent selected from the group consisting of e.g. aliphatic radical (eg alkyl), aryl, arylaliphatic radical (f«,eg arylalkyl), a heterocyclic radical, aryl ~ (e.g. aliphatic acyl, substituted aroyl or heterocyclyl-carbonyl) and arylaliphatic radical-amino-aliphatic radical (e.g. arylalkylaminoalkyl) (e.g. aryloxyalkanoylamino, which , may be substituted with at least one suitable substituent (eg -halogen, nitro, carboxy, formyl or carbazoyl)), alkylaryloxyalkanoylamino, which may be substituted with at least one suitable substituent (e.g. hydroxy), arylaryloxy-alkanoylamino,

arylalkylaryloxyalkanoylamino, which may be substituted with at least one suitable substituent (e.g. hydroxyimino or halogen),

formylaryloxyalkanoylamino,

alkanoylaryloxyalkanoylamino,

aroylaryloxyalkanoylamino, which may be substituted

with at least one suitable substituent (eg nitro, amino or halogen), alkylthioalkanoylaminoaroylaryloxyalkanoylamino, which may be substituted with at least one suitable substituent (eg halogen, amino or carboxy), alkylthioalkylaminoaroylaryloxyalkanoylamino, which may be substituted with at least one suitable substituent (e.g. amino or halogen), (N-halo-N,N,N-trialkylammonio)alkanoylaminoaroylaryloxyalkanoylamino, which may be substituted with at least one suitable substituent (e.g. halogen), heterocyclyl-1-carbonylaryloxyalkanoylamino, which may be substituted with at least one suitable substituent (e.g. halogen),

arylalkylaminoalkylaryloxyalkanoylamino, which may be substituted with at least one suitable substituent (e.g. alkebsy, carboxyalkyloxy or carboxy),

heterocyclyl-1-aryloxyalkanoylamino, where the heterocyclic ring may be substituted with at least one suitable substituent (e.g. alkyl, aryl or with e.g. halogen substituted aryl),

and the alkane moiety may be substituted with at least one suitable substituent (e.g. halogen or amino),

daryloxy-aliphatic acylamlno (e.g. diaryloxyalkanoyl-amino), where the aliphatic hydrocarbon part may be substituted with at least one suitable substituent (e.g. halogen or amino),

arylthio-aliphatic acylamino (e.g. arylthioalkanoylamino), which may be substituted with at least one suitable substituent (e.g. carboxy),

heterocyclyl-aliphatic acylamlno, where the heterocyclic radical may have at least one suitable substituent (e.g. an aliphatic radical (e.g. alkyl) or aryl, which may be substituted (e.g. with halogen)), and the aliphatic hydrocarbon moiety may have at least one suitable substituent (e.g. halogen or amino),

heterocyclyl-heterocyclyl-aliphatic acylamino (e.g.

heterocyclyl-heterocyclyl-alkanoyl),

heterocyclyl-thio-aliphatic acylamlno (e.g. heterocyclyl-thio-alkanoylamino), which may be substituted with at least one suitable substituent (e.g. hydroxy, amino or an aliphatic radical (e.g. alkyl), which may be substituted with at least one suitable substituent (eg amino)),

acylamino-aliphatic acylmino(Cf.eg arylaliphatic acylamino-aliphatic acylamlno (eg arylalkanoylaminoalkanoylaminec

where the aliphatic hydrocarbon moiety and/or the aryl ring may be substituted with at least one suitable substituent (e.g. amino,

halogen or carboxy)),

substituted sulfinyl-aliphatic acylamlno (e.g. aryl-sulfinylalkanoylamino), which may be substituted with at least one suitable substituent (e.g. carboxy),

substituted sulfo-aliphatic acylamlno (e.g. aryl-sulfoalkenoylamino),

N,N-disubstituted amino-aliphatic acylamino (e.g.

(N-aryl-N-arylsulfonylamino)alkanoylamino),

substituted glyoxyloylamino (e.g. arylglyoxyloylamino),

substituted oxalylamino (e.g. alkoxyalylamino or

arylalkylamino-oxalylamlno),

N-substituted carbamoyl (e.g. N-arylcarbamoyl),

guanidinocarbonylamino,

substituted sulfonamido (e.g. aromatic ring sulfonamido (e.g. benzenesulfonamido)), aliphatic hydrocarbon sulfonamido (e.g. alkanesulfonamido), which may have at least one suitable substituent (e.g. hydroxy, carboxy or halogen) ,

substituted ureido (e.g. acylureido (e.g. N-aroyl-ureido)),

substituted aminooxy such as acylaminooxy (e.g. aliphatic acylaminooxy, which may be substituted with aryloxy (e.g. aryloxyalkanoylaminooxy)), alkylideneaminooxy, which may be substituted with aryl or a heterocyclic radical (e.g. alkylideneaminooxy, heterocycly1-alkylideneaminooxy or aryl-alkylideneaminooxy), which may be substituted with at least one suitable substituent (e.g. carboxy, derivatives thereof or alkoxy),

wherein the aryl ring and the heterocyclic ring may be further substituted with at least one suitable substituent selected from the group consisting of carboxy, derivatives thereof (e.g. salts or esters), amino, protected amino, hydroxy, protected hydroxy, halogen, nitro, oxo, carbazyl, acyl (e.g., alkanoyl (e.g., formyl or alkanoyl)), an aliphatic radical (e.g., alkyl), aliphatic radical-oxy (e.g., alkoxy), aryl, aryl-aliphatic radical ( e.g. arylalkyl), acylamlno (e.g. alkanoylamino) and the like,

and the aliphatic part or the aliphatic radical may contain 1-8 carbon atoms, preferably 1-4 carbon atoms, and

may be further substituted with at least one suitable substituent

selected from the group consisting of carboxy, derivatives thereof (eg salts or esters), amino, protected amino, azido, nitro, halogen, hydroxy, sulfo and the like.

In the definition given above, the term "heterocyclic radical" denotes in particular a monoaliphatic or -aromatic heterocyclic radical, which can be a 5- to 7-membered heterocyclic radical containing at least 1 heteroatom selected from the group consisting of oxygen, nitrogen and sulphur, or a polyaliphatic or -aromatic heterocyclic radical, e.g. a benzene-fused heterocyclic radical, heterocyclyl-fused aryl radical or heterocyclyl-fused heterocyclic radical, where the heterocyclic group can be 5- to 7-membered and can contain at least 1 heteroatom selected from the group consisting of oxygen, nitrogen and sulphur.

Aa denotes a group with the general

where Aa' denotes hydrogen, Aa" denotes hydrogen, one aliphatic radical (e.g. alkyl, alkenyl or cycloalkyl) or aryl, which may be substituted with at least one suitable substituent selected from the group consisting of hydroxy, protected hydroxy, amino, protected amino, nitro, halogen and an aliphatic radical, aliphatic radical-oxy (e.g. alkoxy) or aliphatic radical-thio (e.g. alkylthio), or Aa<*>and Aa" together denote aliphatic radical-methylene (f .e.g. alkylidene) or cycloalkadienylidene, and Aa'" denotes carboxy, derivatives thereof (e.g. salts, esters

or azido), cyano, amino, protected amino, hydroxy or protected hydroxy.

The compounds of the general formula I described here can be formulated for administration in any

conventional way analogous to the preparation of other antibiotics.

The preparations described here can be used in the form of a pharmaceutical preparation, e.g. in solid form, semi-solid form or liquid form, containing an active compound of the general formula li in admixture with a pharmaceutical organic or inorganic carrier or excipient, which is suitable for external administration, or an inorganic carrier or excipient,

which is suitable for external or parenteral administration.

The active ingredient he e.g. prepared with usual carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, aqueous suspensions and other forms,

which can be appropriately used. As examples of carriers that can be used, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starches keratin, colloidal silicon dioxide, potato starch, urine fcoff and other carriers that are suitable for the production of preparations in solid , semi-solid or liquid form,

and further auxiliaries, stabilizers, thickeners, dyes and perfumes. The preparations described here may also contain preservatives or bacteriostatic agents, whereby the active ingredient in the desired preparations preserves its activity. The active compound of the general formula I is present in the preparations described here in an amount sufficient to achieve the desired therapeutic effect against the bactericidal infection.

Since the dose or the therapeutically effective amount of the compound of the general formula I varies, and also depends on the age and condition of the individual patient, a daily dose of about 0.5-5 g, preferably 1-2 g, of active ingredient for the treatment of diseases against which the compounds of the general formula I described here are applicable.

The method according to the invention is explained in more detail by the following examples:

Example 1

0.94 g of 3-amino-1-(o-carboxy-4-hydroxybenzyl)-2-acetidinone (hereinafter referred to as 3-aminolactacylanic acid) is suspended in 10 ml of water, after which 0.80 g of sodium bicarbonate is added to the suspension. 10 ml of acetone is added to the solution, and then the solution is cooled to a temperature of -7°C, after which 5 ml of acetone containing 0.80 g of 2-phenylacetyl chloride is added to the solution. The reaction mixture is stirred at the same temperature for 2 hours, and then the acetone is distilled off under reduced pressure. The resulting aqueous phase is washed with ether and then adjusted to a pH value of 2 with 10% hydrochloric acid, after which two extractions are carried out with 15 ml of ethyl acetate. The resulting extracts are combined and washed with water

and a saturated aqueous sodium chloride solution, after which they are dried over "other-free magnesium sulphate. The solvent is distilled off from the extract, and the resulting residue is treated with a small amount of a mixture of ethyl acetate and ether,

thereby obtaining 0.53 g of 3-(2-phenylacetamido)lactacylanic acid with a melting point of 134~141°C.

The following compounds are prepared in essentially the same way as described above.

Example 57

492 mg of N-phenylglycyl chloride hydrochloride are suspended in 10 ml of methylene chloride, and the suspension is cooled to a temperature of -15°C. A solution prepared by dissolving 472 mg of 3-aminolactacillanic acid and

2.03 g of N,0-bis(trimethylsilyl)acetamide in 17 ml of methylene chloride. The mixture is stirred for 1 hour, the reaction temperature of the mixture

kept between 0 and -10°C, and then stirred for 1.5 hours after removing the cooling bath. The methylene chloride is distilled off from the reaction mixture, and the reducing residue is dissolved in ethyl acetate. The solution is washed with water and a saturated aqueous sodium chloride solution and dried. The solvent is distilled off from the solution, and a small amount of acetone is added to the residue, whereby 116 mg of crystalline 3-(N-phenyl-glycinamido)lactacylanic acid with a melting point of 194-194.5°C is obtained. The filtrate is left to cool, thereby obtaining 60 mg of the same crystalline compound with a melting point of 193-194.5°C. The total yield is 176 mg.

The following compounds are prepared in essentially the same way as described above.

Example 83

A mixture of 320 mg of N,N-dimethylformamide and 780 mg of thionyl chloride is heated for 30 minutes at a temperature of 40-50°C, excess thionyl chloride is distilled off from the mixture,

and the resulting residue is suspended in 10 ml of methylene chloride.

370 mg of 4-hydroxyphenylglyoxylic acid is added to the suspension while cooling at a temperature of between -15 and -20°C, and the mixture is stirred for 15 minutes. After the reaction temperature of the mixture has risen to a temperature between -5 and -10°C, the mixture is stirred for 10 minutes, whereby a clear solution containing 4-hydroxyphenylglyoxyloyl chloride is obtained. The solution is then cooled to a temperature of between -45 and -50 C, a solution of 440 mg of triethylamine and 2 ml of methylene chloride is added dropwise over the course of 5 minutes, and the reaction mixture is then stirred for 30 minutes. A solution prepared by dissolving 470 mg of 3-aminolactacylanic acid and 1.2 g of N,0-bis-(trimethylsilyl)acetamide in 10 ml of dry methylene chloride at room temperature for 1 hour with stirring is added at once to the solution, the temperature being kept between -45 and -50 C. The reaction mixture is stirred for 30 minutes and then stirred for 1.5 hours, the reaction temperature being slowly increased to room temperature after removal of the cooling bath. The methylene chloride is distilled off from the reaction mixture, and the resulting residue is dissolved in 20 ml of 5% aqueous sodium bicarbonate solution. The solution is washed twice with 10 ml of ethyl acetate, and 50 ml of ethyl acetate is added to the solution, after which the aqueous phase is adjusted with sufficient shaking to a pH value of 1 with 5% hydrochloric acid. The ethyl acetate phase is separated, and the aqueous phase is extracted twice with 20 ml of ethyl acetate. The ethyl acetate fractions are collected, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, whereby 460 mg of crude crystalline 3-(4-hydroxyphenylglyoxyloylamino)lactacylanic acid are obtained. 760 mg of the product prepared in an analogous manner as described above are dissolved in 3 ml of ethyl acetate, and the solution is chromatographed on a column using silica gel. The fractions containing the relevant compound are collected by elution with ethyl acetate. The residue obtained by distilling off the solvent from the eluate is dissolved in acetone, an acetone solution of sodium 2-ethylhexanate is added to the solution to produce a solution of the sodium salt of the compound in question, and then the acetone is distilled off from the solution. The residue is pulverized by adding ether, and the powder is collected by filtration and washed with acetone, thereby obtaining 170 mg of the sodium salt of 3-(4-hydroxyphenylglyoxyloylamino)-lactacylanic acid with a melting point of 220-225°C.

The following compounds are prepared in essentially the same way as described above.

Example 89

0.453 g of sodium bicarbonate is dissolved in 10 ml of water, and the solution is cooled to a temperature of 5°C. 0.427 g of 3-aminolactacylanic acid is added to the solution, and 10 ml of acetone is added to the solution. Add drop by drop to the solution

during 5 minutes 5 ml of an acetone solution of 0.38 g of butyric anhydride. 0.04 g of sodium bicarbonate is added

the reaction mixture, which is then stirred for 1.5 hours at 5°C.

The acetone is distilled off from the reaction mixture, and the aqueous phase is washed with ether and then adjusted to a pH value of 1-2 with 10% hydrochloric acid. The aqueous phase is extracted twice with 30 ml of ethyl acetate. The extracts are combined, washed with 50 ml of water and then with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is concentrated, whereby 112 mg of crystalline 3-butyramido-lactacillanic acid with melting point 178 - 178.5 (decomposition) is obtained.

Example 90

Dissolve 0.350 g of pivaloyl chloride in 15 ml of methylene chloride,

and to the solution is added a solution prepared by

to dissolve 0.520 g of 4-methoxyphenylglyoxylic acid and 0.290 g of triethylamine in 10 ml of methylene chloride. The mixed solution is allowed to react for 1 hour to produce a solution of a mixed anhydride with 4-methoxyphenylglyoxylic acid and pivalic acid.

2.3 g of N,0-fi>is(trimethylsilyl)acetamide are added to a suspension which has been prepared by suspending 0.680 g of 3-aminolactacylanic acid in 10 ml of methylene chloride, and the suspension is stirred for 1 hour at room temperature. To the resulting solution

the previously obtained solution of the mixed acid anhydride is added, and the reaction mixture is allowed to react for 2 hours, the reaction temperature being kept between -10 and -15°C. The methylene chloride is distilled off from the reaction mixture, and the resulting residue is dissolved in ethyl acetate. The solution is washed with 5% hydrochloric acid and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, until the residue is set approx. 30 ml of diisopropyl ether, and then the mixture is stirred for 1 hour. The

resulting precipitated product is collected by filtration, whereby 1.14 g of powder is obtained. The powder is dissolved in 30 ml of ethyl acetate, and the solution is treated with 0.11 g of activated charcoal and filtered.

The filtrate is concentrated to a volume of approx. 2 ml, and by scraping

of the walls of the container containing the solution, crystals are obtained. The crystals are collected by filtration and recrystallized from a small amount of ethyl acetate, whereby 0.16 g of crystalline 3-(4-methoxyphenylglyoxyloylamino)-lactacylanic acid with melting point 178 - 181°C (decomposition) is obtained.

The following compounds are prepared in essentially the same way as described above.

Example 109

0.944 g of 3-aminolactacylanic acid is suspended in 60 ml of dry methylene chloride, and 7.0 g of N,0-bis-(trimethylsilyl)acetamide and 0.7 ml of N,N-dimethylformamide are added to the suspension, after which the mixture is stirred for 2 hours at room temperature.

To 30 ml of a dry methylene chloride solution of 0.523 g of ethyl chloroformate is added dropwise over the course of 7 minutes while cooling at a temperature between -5 and -10°C 30 ml of a

dry methylene chloride solution of 1.40 g of N-behzyloxycarbonyl-2-(2-thienyl)glycine and 0.485 g of triethylamine, and then the mixture is stirred at the same temperature for 20 minutes to prepare a solution of a mixed acid anhydride. The previously obtained solution is added dropwise to the solution over the course of 20 minutes, the reaction mixture is stirred for 3 hours at the same temperature, and the reaction temperature slowly increases,

during 2 hours with stirring, rise to room temperature. The reaction mixture is washed with dilute hydrochloric acid and water and then dried. The solution is concentrated, thereby obtaining 1.40 g of crystalline 3-[2-(2-thienyl)-N-benzyloxycarbonylglycinamido]-lactacylanic acid with IR absorption spectrum v cm"1 (liquid film)s 1730, 1710 and 1650 cm"<1>.

The following compound is prepared in substantially the same manner as described above.

Example 111

500 mg of 2-(4-methoxyphenyl)-2-methoxyiminoacetic acid and

495 mg of N,N'-dicyclohexylcarbodiimide are dissolved in a mixture of 9 ml of chloroform and 3 ml of dioxane, and the solution is stirred for 1.5 hours under ice-cooling* A solution prepared by dissolving 472 mg of 3- aminolactacylanic acid and 1.22 g of N,0-bis(trimethylsilyl)acetamide in 10 ml of chloroform, and then the reaction mixture is stirred for 4 hours at room temperature. The solvent is distilled off from the reaction mixture, and to the residue is added a volume of sodium hydrogen carbonate solution and ethyl acetate. After stirring the mixture, the aqueous phase is separated, it is adjusted to a pH value of

1-2 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water and then dried. The solvent is distilled off from the extract, and ether is added to the residue, whereby crude crystals are obtained. The crystals are collected by filtration and washed with ether, thereby obtaining 150 mg of crystalline 3-[2-(4-methoxyphenyl)-2-methoxyiminoacetamido]lactacylanic acid with melting point 157-161°C (decomposition).

The following compound is prepared in substantially the same manner as described above.

Example 113

0.472 g of 3-arainolactacylanic acid is suspended in 10 ml of methylene chloride, to the suspension is added at room temperature 1.22 g of N,0-bis(trimethylsilyl)acetamide, and then the solution is cooled to a temperature of -15°C. To the solution is added drop by drop over 25 minutes 10 ml of methylene chloride solution

of 935 mg of triethylammonium salt of acid anhydride, which is prepared from 2-phenyl-2-sulfoacetic acid and ethyl chloroformate, and the reaction mixture is stirred for 11 hours at the same temperature and for a further 1.5 hours at room temperature. 50 ml of water is added to the reaction mixture, and then the aqueous phase is separated. The aqueous phase is washed with ethyl acetate and adjusted to a pH value of 5-6 with an aqueous sodium bicarbonate solution, and then the solution is filtered. The filtrate is concentrated, and the resulting residue is adsorbed on a column, which is packed with 20 ml of non-ionic adsorption resin, "Amberlite XAD-4"

(sold by Rohm and Haas Co., Ltd.), which has been previously treated with methanol, and the compound in question is eluted with water. The eluate is concentrated under reduced pressure, and ethanol is added to the eluate, after which the solvent is distilled off from

the eluate under reduced pressure. Ethanol is added to the residue, whereby crystals are obtained. The crystals are collected by filtration, whereby 120 mg of the crystalline disodium salt of 3-(2-phenyl-2-sulfoacetamido)lactacllanoic acid are obtained. The filtrate is concentrated, and the resulting oily product is treated with acetone, whereby 0.45 g of the powdery crystalline disodium salt of 3-(2-phenyl-2-sulfoacetamido)lactacillanic acid with a melting point of 144-152°C is obtained.

The following compounds are prepared in essentially the same way as described above.

Example 116.

652 mg of 2-(benzo[d]isoxazol-3-yl)-N-benzyloxycarbonyl-glycine and 202 mg of triethylamine are dissolved in 8 ml of dry tetrahydrofuran. 690 mg of 6-chloro-1-(4-chlorobenzenesulfonyloxy)benzotriazole are added to the solution while stirring under ice cooling, and the solution is stirred at the same temperature for 3 hours. While the resolution

kept under ice-cooling, a solution prepared by dissolving 472 mg of 3-aminolactacillanic acid and 202 mg of triethylamine in 10 ml of a mixture of acetone and water (1.1) is added to the solution. The reaction mixture is stirred for 1 hour, and then 20 ml of water is added to the resulting residue, after which ethyl acetate is added to the solution, and then the solution is acidified by adding 1N hydrochloric acid dropwise while shaking. The ethyl acetate phase is separated, after which the aqueous phase is extracted with ethyl acetate, and the ethyl acetate extracts are collected. The extract is washed with water and then dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, whereby 1.2 g of residue is obtained. The residue is subjected to column chromatography using silica gel, and the elution is carried out with 500 ml of ethyl acetate containing 10% methanol to recover fractions containing the desired compound. The residue resulting from concentration of the eluate is treated with ether, whereby 180 mg of crystalline 3-[2-(benzo[d]isoxazol-3-yl)-N-behzyloxycarbonylglycinamido]lactacillanic acid with a melting point of 159-168°C is obtained.

The following compound is prepared in substantially the same manner as described above.

Example 118

0.472 g of 3-aminolactacylanic acid is suspended in 20 ml of water, and 0.420 g of sodium bicarbonate is added to the suspension.

20 ml of acetone is added to the solution, and the solution is cooled to 0-5°C. 2 ml of acetone solution containing 0.286 g of phenyl isocyanate is added dropwise to the solution, and the solution is then stirred for 2.5 hours at the same temperature. The acetone is distilled off from the reaction mixture, and then the resulting residue is filtered to remove undissolved constituents.

The resulting aqueous solution is washed with ethyl acetate and then adjusted to a pH value of 1 with 10% hydrochloric acid, after which it is extracted with ethyl acetate. The resulting ethyl acetate phase is washed with water and then dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, whereby a crystalline residue is obtained. The residue is washed with diisopropyl ether and collected by filtration, whereby 0.470 g of crystalline 3-(N<*->phenylureido)lactacylanic acid with melting point 167-172°C is obtained.

Example 119

0.38 g of guanidinocarbohydrazide dihydrochloride is dissolved in

2 ml of water, to the solution is added under cooling at 0-5°C 0.14 g of sodium nitrite, and then the solution is stirred for 15 minutes to prepare a solution of guanidinocarbonyl azide.

0.240 g of 3-aminolactacylanic acid is suspended in 7 ml of water, and 0.170 g of sodium bicarbonate is added to the suspension.

The aqueous solution is cooled to 0-5°C, the previously prepared solution of guanidinocarbonyl azide is added dropwise over 10 minutes to the solution, and the reaction mixture is stirred for 2 hours. The reaction mixture is washed with 10 ml of ethyl acetate and concentrated until the remaining solution becomes transparent, and then the ethyl acetate which is saturated in the aqueous phase is completely distilled off to precipitate crystals. The solution containing crystals is allowed to stand for some time, and the crystals are collected by filtration, whereby 0.15 g of 3-(guanidinocarbonamido)lactacillanic acid with a melting point of 20G-210°C is obtained.

Example 120

A solution containing 1.42 g of 2-phenyl-N-(2,2,2-

trichloroethoxycarbonyl)glycine and 15 ml of thionyl chloride are heated in

1 hour under reflux cooling. Excess thionyl chloride is distilled off from the solution under reduced pressure, and the resulting residue is dissolved in acetone. A solution containing 1.0 g of 3-aminolactacylanic acid, 0.9 g of sodium bicarbonate, 40 ml of water and 40 ml of acetone is added dropwise to the solution while cooling at 0-5°C. The acetone is distilled off

the reaction mixture under reduced pressure, and the resulting solution is washed with ethyl acetate. The resolution is set to

a pH value of 1-2 with 10% hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate phase is separated and dried over anhydrous magnesium sulfate. The solvent is distilled off from the ethyl acetate solution, and the resulting residue (2.1 g) is dissolved in ether. The ether solution is concentrated, whereby a residue is obtained. The residue is washed with diisopropyl ether, whereby 1.69 g of crystalline 3-[2-phenyl-N-(2,2,2-trichloroethoxycarbonyl)-glycinamido]lactacylanic acid with melting point 130-132°C (decomposition) is obtained.

The following compounds are prepared in essentially the same way as described above.

Example 131

700 mg of 3-aminolactacylanic acid are suspended in 15 ml of dry methylene chloride, 3.6 g of N,0-bis(trimethylsilyl)-acetamide are added to the suspension, and the mixture is stirred for 3 hours. The resolution

- is cooled to a temperature between -50 and -40°C, until the solution is added at once 630 mg of 2-(2-pyridyloxy)acetyl chloride hydrochloride, and the reaction mixture is stirred for 20 minutes at the same temperature. The reaction temperature is slowly allowed to rise to -10°C over 40 minutes, and the reaction mixture is stirred for 1 hour at the same temperature and for a further 1 hour under ice cooling. The methylene chloride is distilled off from the reaction mixture, and to the residue is added a solution containing 25 ml of aqueous 5Sig sodium bicarbonate solution and 30 ml of ethyl acetate. The aqueous phase is separated and then washed with ethyl acetate. The aqueous phase is adjusted under ice-cooling to a pH value of 3 with 10% hydrochloric acid, and then extracted

the aqueous solution with ethyl acetate. The ethyl acetate phase is separated, the resulting aqueous phase is adjusted to a pH value of 1-2 with 10% hydrochloric acid, and then the aqueous solution is extracted several times with ethyl acetate. The ethyl acetate cages and the

previously obtained ethyl acetate phase is collected, and the solution is washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off from the ethyl acetate solution, and the resulting residue (330 mg) is pulverized with ether. The powder is washed with acetone, whereby

130 mg of crystalline 3-[2-(2-pyridyloxy)acetamido]lactacillanic acid with melting point 192.5 - 193°C (decomposition) is obtained.

Example 132

A mixture of 292 mg of N,N-dimethylformamide and 710 mg of thionyl chloride is heated for 30 minutes at 50°C. Excess thionyl chloride is distilled off from the mixture, whereby a residue is obtained. The residue is washed with ether. Add 7 ml to the residue

methylene chloride, and the solution is cooled to 0-5°C, after which a solution prepared by dissolving 455 mg of 2-(5,6-dihydro-2H-pyran-3-yl)-glycolic acid in 5 ml is added dropwise to the solution methylene chloride. 5 ml of 1 methylene chloride solution of 600 mg of triethylamine is added dropwise over 10 minutes while cooling at -50°C, and the solution is stirred for 130 minutes at the same temperature.

The solution is added one time to a mixture of 472 mg of 3-aminolactacylanic acid, 1.22 g of N,0-bis(trimethylsilyl)acetamide and 10 ml of methylene chloride which has previously been stirred for 2 hours at room temperature. The reaction mixture is stirred for 2 hours at -50 °C and stirred for a further 2 hours, the reaction temperature being slowly raised to 0°C. The solvent is distilled off from the reaction mixture, and an aqueous solution of sodium bicarbonate and ethyl acetate is added to the resulting solution. The resulting aqueous phase is adjusted to a pH of

1-2 with 10% hydrochloric acid, and then the solution is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate, and then the solvent is distilled off from the extract, thereby obtaining 80 mg of crystalline 3-[2-(5,6-dihydro-2H-pyran-3-yl)glycolamido]lactacylanic acid with an IR absorption spectrum: v cm"<1>(nujol): 1740, 1685 and 1660.

Example 133

To a solution of 10 ml of methylene chloride containing 216 mg of ethyl chloroformate is added dropwise under cooling at -30°C a mixture of 576 mg of 2-(2-bromoacetamido)-2-phenylacetic acid,

200 mg of triethylamine, one drop of N,N-dimethylbenzylamine and 8 ml of methylene chloride, and the reaction mixture is stirred for 30 minutes at the same temperature. A mixture of 472 mg of 3-aminolactacylanic acid, 1.2 g of N,0-bis-(trimethylsilyl)acetamide, 10 ml of methylene chloride and 1 ml of N,N -dimethylformamide, which has been stirred at room temperature and cooled to 0°C. The reaction mixture is stirred for 2 hours at -25°C and then stirred for 1 hour, the reaction temperature being slowly raised to 0°C. The reaction mixture is concentrated, and ethyl acetate and water are added to the resulting residue. : The reaction mixture is then adjusted to a pH value of 1-2 with 10% hydrochloric acid. The ethyl acetate phase is separated, washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue is washed with diisopropyl ether and then pulverized with ethyl acetate, thereby obtaining 400 mg of 3-[2-(2-bromoacetamido)-2-phenylacetamido]lactacylanic acid. A further 188 mg of the same compound is recovered from the mother liquor. The total yield is 588 mg. Melting point 156-161°C.

The following compounds are prepared in essentially the same way as described above.

Example 141

A mixture of 537 mg of N-phenylimidinodiacetic acid,

495 mg of N,N'-dicyclohexylcarbodiimide, 9 ml of chloroform and 3 ml of dioxane are stirred for 1.5 hours under ice cooling. The undissolved components are filtered from the solution until the filtrate settles

Once a mixture of 472 mg of 3-aminolactacylanic acid, 10 ml of methylene chloride and 1.2 g of N,0-bis(trimethylsilyl)acetamide, and then the reaction mixture is stirred for 4 hours at room temperature. The solvent is distilled off from the reaction mixture, the residue is dissolved in ethyl acetate and an aqueous sodium bicarbonate solution is added to the solution. The mixture is set

at a pH value of 4.0 with lOSlg hydrochloric acid, and the ethyl acetate phase is separated. The resulting aqueous phase is adjusted to a pH value of 1-3 with 10% hydrochloric acid, and the aqueous solution is extracted with ethyl acetate. The ethyl acetate fractions are combined, washed with water and dried, and then the solvent is distilled off from the solution, thereby obtaining 260 mg of crystalline 3-(N-carboxymethyl-N-phenylglycinamido)-lactacylanic acid with a melting point of 142.5-145°C (decomposition).

Example 142

A solution prepared by dissolving 300 mg of 2-[4-(3-bromopropoxy)phenylacetic acid and 300 mg of thionyl chloride in 2 ml of chloroform is heated for 2 hours under reflux. The solvent and excess thionyl chloride are distilled off from the solution, and the resulting residue is dissolved in 1 ml of dry acetone. The solution is added dropwise with stirring while cooling at 0-5°C to a solution prepared by dissolving 240 mg of 3-aminolactacylanic acid and 210 mg of sodium bicarbonate in a mixture of 10 ml of water and acetone. The reaction mixture is stirred for 45 minutes at the same temperature. The acetone is distilled off from the reaction mixture, and 30 ml of ethyl acetate are added to the resulting aqueous phase. The mixture is adjusted to a pH value of 1 with 10% hydrochloric acid. The ethyl acetate phase is separated, and then the aqueous phase is extracted with 20 ml of ethyl acetate. The ethyl acetate fractions are collected, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, and the resulting residue (510 mg) is washed with ether, thereby obtaining 420 mg of crystalline 3-(2-[4-(3-bromopropoxy)-phenyl)acetamido]lactacylanic acid with a melting point of 120-123°C (fission).

The following compounds are prepared in essentially the same way as described above.

Example 148 A mixture of 472 mg of 3-aminolactacylanic acid, 1.2 g of N,O-bis(trimethylsilyl)acetamide, 10 ml of methylene chloride and 1 ml of N,N-dimethylformamide is stirred for 1 hour at room temperature. The solution is cooled to 0-5°C, and 3 ml of methylene chloride solution containing 548 mg of hexadecanoyl chloride is added dropwise to the solution, after which the reaction mixture is allowed to react for 1.5 hours at the same temperature and for a further 30 minutes at room temperature. The reaction mixture is concentrated, ethyl acetate and water are added to the resulting solution, and then the mixture is adjusted to a pH value of 1-2 with 100% hydrochloric acid. Wash the separated ethyl acetate3 with water and then dry over anhydrous magnesium sulfate. The solution is concentrated, whereby 0.95 g of crude 3-hexadecanoylaminolactacylanic acid is obtained. 600 mg of the product is subjected to further column chromatography using silica gel, and the elution is carried out with ethyl acetate. The solvent is distilled off from the eluate, thereby obtaining 110 mg of the desired purified compound with melting point 157-161 (cleavage). Example 149 To a solution of 400 mg of 2-[W-(2-tenylidene)aminooxy]-2-phenylacetic acid, 155 mg of triethylamine and 10 ml of tetrahydrofuran are added dropwise over the course of 5 minutes while cooling at a temperature between -2 and 0° C a solution prepared by dissolving 184 mg of pivaloyl chloride in 3 ml of tetrahydrofuran, and the mixture is stirred for 30 minutes. The solution is added at once under cooling at -30°C to a solution of 320 mg of 3-aminolactacylanic acid, 825 mg of N,O-bis(trimethylsilyl)acetamide and 10 ml of methylene chloride, and the reaction mixture is allowed to react for 2.5 hours, the reaction temperature slowly raised to 10°C. The solvent is distilled off from the reaction mixture, and an aqueous solution of -sodium bicarbonate and ethyl acetate is added to the resulting solution. The separated aqueous phase is adjusted to a pH value of 1-2 with 1% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water and dried, and then the solvent is distilled off from the solution, whereby 300 mg of residue is obtained. The residue is dissolved in: acetone, and then sodium 2-ethylhexanate is added to the solution, whereby 160 mg of the crystalline sodium salt of 3-(2- :[N-(2-thenylidene)aminooxy3-2-phenylacetamldb)lactacyllanic acid.

IR absorption spectrum v cm<-1>(nujol): 1730/1650 and 1600.

Example 150

355 mg of 3-aminolactacylanic acid, 0.92 g of N,0-bis(trimethylsilyl)acetamide and 0.23 ml of N,N-dimethylformamide are added to 7 ml of methylene chloride, and the solution is stirred for 2 hours at room temperature.

380 mg of 2-(2-nitrophenoxy)-2-phenoxyacetic acid, 132 mg of triethylamine and 2 drops of N,N-dimethylbenzylamine are dissolved in 10 ml of methylene chloride, and the solution is cooled to -30°C. 141 mg ethyl chloroformate is added dropwise to the solution, and the mixture is stirred for 40 minutes at the same temperature. The previously prepared solution is quickly added to the solution, and the reaction mixture is stirred for 5.5 hours at a temperature between -40 and -20°C. The solvent is distilled off from the reaction mixture under reduced pressure, and ethyl acetate and an aqueous sodium bicarbonate solution are added to the residue. The separated aqueous phase is adjusted to a pH value of 1-:2 with 10% hydrochloric acid, and then the mixture is extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium hydrogen-. carbonate solution and dried over anhydrous magnesium sulfate, and then the solvent is distilled off from the solution. The resulting residue (540 mg) is dissolved in a small amount of acetone, and sodium 2-ethylhexanate is added to the solution. Ether is added to the solution, and the precipitated crystals are collected by filtration and washed with a mixture of ether and acetone, thereby obtaining 380 mg of the crystalline sodium salt of 3-[2-(2-nitrophenoxy)-2-phenoxyacetamido]lactacylanic acid with a melting point of 169 -172°C (decomposition)o

The following compounds are prepared in essentially the same way as described above.

Example 175

260 mg of 2-(4-[3-(4-nitrophenylthio)propoxy]phenyl)acetic acid and 300 mg of thionyl chloride are dissolved in 10 ml of chloroform, and the solution is heated for 2 hours under reflux.

Chloroform and excess thionyl chloride are distilled off from the reaction mixture under reduced pressure, and the resulting residue is dissolved in 11 ml of acetone. The acetone solution is added dropwise while cooling at 0-5°C to a solution of 180 mg of 3-aminolactacylanic acid, 160 mg of sodium bicarbonate, 5 ml of water and 5 ml of acetone, and then the reaction mixture is stirred in

45 minutes at the same temperature. The acetone is distilled off

from the reaction mixture under reduced pressure, 40 ml of ethyl acetate are added to the resulting residue, and then the solution is adjusted to a pH value of 1 with 10% hydrochloric acid. The ethyl acetate phase is separated, and the resulting aqueous phase is extracted with 20 ml of ethyl acetate. The ethyl acetate fractions are collected, washed with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, whereby 400 mg of crystalline 3-[2-(4-[3-(4-nitrophenylthio)-propoxy]phenyl)acetamido]lactacylanic acid with melting point 142-146°C (decomposition) is obtained.

Example 176

10 ml of dry tetrahydrofuran solution containing 351 mg of 2-[2-(2-naphthoxy)acetamidooxy]-2-phenylacetic acid and 101 mg of triethylamine are cooled to -10°C, 5 ml of dry tetrahydrofuran solution containing 120 mg of pivaloyl chloride are added dropwise to the solution, and the mixture is stirred for 1 hour at the same temperature. The solution is cooled to -30°C until the solution is applied

Then 5 ml of dry methylene chloride containing 236 mg of 3-aminolactacylanic acid and 600 mg of N,0-bis(trimethylsilyl)acetamide, and the reaction mixture is stirred for 1 hour at -10°C and for 1 hour at 0°C. The solvent is distilled off from the reaction mixture under reduced pressure, and a saturated aqueous sodium bicarbonate solution is added to the residue. The aqueous solution is washed with ethyl acetate, adjusted to a pH value of 1-2 with 10% lg hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, and the resulting residue is pulverized with ether, thereby obtaining 340 mg of crystalline 3-(2-[2-(2-naphthox<y>)-acetamidoox<y>]-2-phen<y>lacetamido )lactac illanic acid with melting point 109-112°C (decomposition).

Example 177

455 mg of 2-[2-oxo-3-(2-phenylacetamido)-1-azetidinyl]-3-methylbutyric acid, 151 mg of triethylamine and 2 drops of N,N-dimethyl-benzylamine are added to 10 ml of methylene chloride, and the solution is cooled to -30°C* 5 ml of methylene chloride solution containing 163 mg of ethyl chloroformate is added dropwise to the solution. The solution is cooled to -40°C, and to the solution is added at once a solution prepared by dissolving 389 mg of 3-aminolactacylanic acid, 1.0 g of N,0-bis(trimethylsilyl)acetamide and 0.25 ml of N,N -dimethylformamide in 10 ml of methylene chloride, and then the solution is stirred for 3 hours at room temperature. The reaction mixture is allowed to react for 1.5 hours with stirring. The solvent is distilled off from the reaction mixture, ethyl acetate and an aqueous sodium bicarbonate solution are added to the residue, and then the aqueous phase is separated. The resulting

aqueous phase is adjusted to a pH value of 1-2 with 1N hydrochloric acid, and it is extracted by adding ethyl acetate to the solution. The ethyl acetate phase is separated, and the resulting aqueous phase is extracted with ethyl acetate. The ethyl acetate phases are combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, and the resulting powder (480 mg) is washed with

ether, whereby 359 mg of crystalline 3-(2-[2-oxo-3-(2-phenylacetamido)-1-azetidinyl]-3-methylbutyramido)lactacylanic acid with melting point 160-164°C (decomposition) is obtained.

The following compounds are prepared in essentially the same way as described above.

Example 188

0.320 g of 2-methyl-5,6-dihydro-1,4-oxathine-3-carboxylic acid is dissolved in 1 10 ml of chloroform. To the solution is added 5 ml of dry methylene chloride solution containing 7 ml of thionyl chloride, and the mixture is heated for 4 hours under reflux and then concentrated, whereby a solution of an acid chloride of a 2-methyl-5,6-dihydro-1,4-oxatiine is obtained -3-carboxylic acid.

0.236 g of 3-aminolactacyllanic acid is suspended in 20 ml

dry methylene chloride, 1.50 g of N,0-bis-(trimethylsilyl)acetamide is added to the suspension, and then the mixture is stirred for 4 hours at room temperature. To the resulting solution

the previously prepared acid chloride solution is added dropwise while cooling at a temperature between -5 and 0°C, and the mixture is stirred for 2 hours at the same temperature and for a further

50 hours at room temperature. The reaction mixture is concentrated

under reduced pressure, whereby a residue is obtained. To the residue

ethyl acetate and an aqueous sodium bicarbonate solution are added, and the mixture is sufficiently stirred, after which the aqueous phase is separated. The aqueous phase is washed with ether and adjusted to a pH value of 1-2 with dilute hydrochloric acid, and then the solution is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, whereby a powder is obtained.

5 ml of hot ethyl acetate is added to the powder, and an undissolved product in the mixture is collected by filtration, whereby

240 mg of crude 3-(2-methyl-5,6-dihydro-1,4-oxathine-3-carbonylamino)-lactacyllanic acid. The product is recrystallized from acetone, thereby obtaining 172 mg of the desired purified compound with melting point 172.5 - 175.0°C (decomposition).

Example 189

0.708 g of 3-aminolactacylanic acid is suspended in 20 ml of dry methylene chloride. 2.0 g of N,0-bis(trimethylsilyl) acetamide is added to the suspension, and the mixture is stirred for some time to dissolve this. 1.212 g of N-[4-(3-benzyloxycarbdnyl-5-oxo-1,3-oxazolidih-4-yl)butyryl]succinimide are dissolved in 15 ml of dioxane, and the solution is cooled to 0-5°C. The previously obtained solution is added dropwise to the solution, and the mixture is stirred in

6 hours at the same temperature. The reaction mixture is concentrated under reduced pressure, whereby a residue is obtained, and 5% aqueous sodium bicarbonate solution and ethyl acetate are added to the residue. The aqueous layer is separated and washed twice with ethyl acetate. The aqueous solution is adjusted to a pH value of 1-2 with dilute hydrochloric acid and then extracted with

ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution and the resulting oily product (0.470 g) is subjected to column chromatography using 10 g of silica gel. The elution is carried out with a mixture of ethyl acetate and methanol (50 volumes in 1 volume), and the fractions containing the desired compound are collected. The factions gather,

and the solvent is distilled off from the solution, whereby 0.100 g of 3-[4-(3-benzyloxycarbonyl-5-oxo-1,3-oxazolidin-4-yl)-butyramido]lactacillanic acid is obtained. IR absorption spectrum v cm 1 (nujol): 1730, 1720, 1700 1680 and 1650.

Example 190

472 mg of 3-aminolactacylanic acid, 458 mg of 2-(2-propionyl-phenoxy)acetic acid and 238 mg of chloroformic acid ethyl ester are treated on

essentially the same way as described in example 109, whereby 40 mg of 3-[2-(2-propionylphenoxy)acetamido]lactacylanic acid with melting point 114-118°C (decomposition) is obtained.

Example 191

0.236 g of 3-aminolactacylanic acid, 0.610 g of 2-(4-[4-chloro-N-(2,2,2-trichloroethoxycarbonyl)anilinomethyl]phenoxy)-2-methyl-propionic acid and 7 ml of thionyl chloride are treated in essentially the same way as described in example 120, whereby 450 mg of 3-[2-(4-[4-chloro-N-(2,2,2-trichloroethoxycarbonyl)anilinomethyl]-phenoxy)-2-methylpropionamido)lactacylanic acid with melting point 76-82 is obtained °C (decomposition).

Example 192

1.0 g of 1-(1-methoxycarbonyl-2-methyl-1-propenyl)-3-phenoxyacetamido-2-azetidinone is dissolved in 40 ml of methylene chloride. 0.55 g of N,N-dimethylaniline is added to the solution, and the solution is cooled to a temperature between -35 and -30°C. To

0.94 g of phosphorus pentachloride is added to the solution at once while stirring, and then the reaction mixture is stirred for 1 1.5 hours at the same temperature. 0.9 g of methanol is added to the reaction mixture, and then the solution is stirred for 1 hour at the

same temperature. As the reaction temperature is raised to 0-5°C, 0.6 ml of water is added to the solution, and the solution is stirred for 1 hour. The reaction mixture is extracted three times with a total of 10 ml of water, and the aqueous extracts are collected and adjusted to a pH value of approx. W with sodium bicarbonate. The aqueous solution is washed with 10 ml of ethyl acetate and 5 ml of ethyl acetate.

The aqueous phase is salted out with sodium chloride and then extracted seven times with 8 ml of chloroform. The chloroform extracts are collected and dried over anhydrous magnesium sulfate, and the solvent is distilled off from the solution, whereby 0.34 g of crystalline 3-amino-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone is obtained. Some of this product is treated in a conventional manner with p-toluenesulfonic acid, whereby the p-toluenesulfonic acid salt of said compound is obtained. Melting point 169-171 C (decomposition).

Example 193

1.52 g of 1-(1-carboxy-2-methylpropyl)-3-phenylacetamido-2-azetidinone and 2.15 g of N,N-dimethylaniline are suspended in 12 ml of methylene chloride, and 0.88 g of trimethylsilyl chloride is added to the suspension . The solution is stirred for 30 minutes at room temperature and cooled to -50°C. 1.1 g of phosphorus pentathioride is added to the solution, and the solution is stirred for 2 hours (the reaction temperature is raised to approx. -30°C during the stirring). The solution is cooled to -50°C, 1.85 g of n-butyl alcohol is added to the solution, and then the solution is stirred for 2 hours (during this time the reaction temperature is raised to approximately -30°C). The solution is cooled to -50°C, and to the solution is added a solution prepared by dissolving 1.3 g of sodium bicarbonate in 15 ml of water (during this time the reaction temperature is raised to approximately -25°C, and the solution has a pH -value of approx. 3). The solution is adjusted to a pH value of 4 with sodium bicarbonate, and then the aqueous phase is separated and washed with ether. The solution is evaporated to dryness under reduced pressure, the temperature of the solution being kept below 25°C. 15 ml of isopropyl alcohol is added to the resulting residue, and the mixture is filtered, whereby an undissolved product and a filtrate are obtained. The filtrate is evaporated to dryness under reduced pressure. The aforementioned treatment is repeated twice, whereby 0.3 g of colorless powder form 3-amino-1-(1-carboxy-

2-methylpropyl)-2-azetidinone. The previously obtained insoluble products in isopropyl alcohol are collected and dissolved in a small amount of water, and the solution is adjusted to a pH value of 2.5 with 1N hydrochloric acid. The aqueous solution is evaporated to dryness under reduced pressure at 25°C, and the resulting residue is treated with isopropyl alcohol in an analogous manner as described above,

whereby 0.13 g of the nth compound is obtained. The total yield is 0.43 g. The product is processed in a conventional manner to prepare its salt of D-camphor-10-sulfonic acid, and

the salt is recrystallized from a mixture of acetone and ether,

whereby the D-camphor-10-sulfonic acid salt of the aforementioned compound is obtained. Melting point 178-183 C.

Example 194

7.2 g of 3-(2-[4-(3-benzamido-3-carboxypropoxy)phenyl]-2-(3-phenylthioureido)acetamido]lactacylanic acid is dissolved in 20 ml of acetic acid, and to the solution is added dropwise while cooling with stirring 2 ml of concentrated hydrochloric acid.The reaction mixture is stirred for 1.5 hours and poured onto a mixture of 50 ml of ice water and 50 ml of ethyl acetate.

The mixture is separated into an ethyl acetate phase and a single-walled phase. The ethyl acetate phase is extracted with 20 ml of ice water. It

aqueous phase and the previously obtained aqueous phase are collected and washed with 20 ml of ethyl acetate. To the aqueous phase is added 60 ml of weakly basic anion exchange resin "Amberlite IR-45" (OH type, trademark, sold by Rohm and Haas Co. Ltd), and the mixture is stirred under ice cooling and then filtered. The resin

washed with 10 ml of ice water, then the washing liquid and the filtrate are collected, and it is concentrated under reduced pressure, whereby a residue is obtained. Methanol is added to the residue, and then collected

the residue by filtration. The residue is washed with acetone, whereby

obtain 0.59 g of 3-amiridlactacylanic acid with a melting point of 203-206°C

(cleavage. IR absorption spectrum v cm"<1>:(nujol)%1763 and

1742'. NMR absorption spectrum 6 ppm (D2O+NaOD): 2.89 (1H, d,d, J=3Hz, 6Hz)

3.79 (1H, t, J»6Hz)

4.22 (1H, d, d, J=3Hz, 6Hz)

5.26 (IQ, p)

6.91 (2H, d, J«=9Hz)

7.23 (2H, d, J»9Hz).

Example 195

3-(2-phenylacetamido)lactacillanoic acid is treated in substantially the same manner as described in Example 193, whereby 3-aminolactacillanoic acid is obtained, which is identified by comparing the compound's IR absorption spectrum, NMR absorption spectrum and melting point with the corresponding constants for an authentic sample .

Example 196

1.44 g of 3-[2-(4-[3-(3-phenylthioureldo)-3-carboxypropoxyl-phenyl)-2-(3-phenylthioureido)acetamido]lactacylanic acid is suspended in 10 ml of water, and to the suspension is added 0, 56 g anhydrous potassium carbonate. The solution (pH value 9) is stirred for 27 hours at 3d°C and then filtered. The filtrate is diluted by adding 50 ml of ethanol, and the solution is allowed to stand under ice-cooling, whereby a precipitate is obtained. The precipitate is filtered off,

and the filtrate is concentrated under reduced pressure, whereby a residue is obtained. The residue is adjusted to a pH value of 2 with 5% hydrochloric acid and then washed with ethyl acetate. The solution is adjusted to a pH of 7.5 with sodium carbonate and then evaporated to dryness under reduced pressure to give 0.75 g

powder. 7 ml of water is added to the powder, and a product not dissolved in water is collected by filtration and washed with water, thereby obtaining 40 mg of 3-aminolactacylanic acid. The filtrate and the washing liquid are collected, and the combined solution is treated with activated charcoal, whereby 123 mg of crude crystalline 3-aminolactacylanic acid is obtained.

The mentioned products are collected and suspended in 30% aqueous methanol solution. The suspension is stirred for 1 hour and then filtered, yielding 133 mg of purified crystalline 3-aminolactacylanic acid, which is identified by comparing the compound's IR absorption spectrum, NMR absorption spectrum and melting point with the corresponding constants of an authentic sample.

Example 197

0.36 g of 3-E2-(4-[3-(3-phenylthioureido)-3-carboxypropoxyl-phenyl)-2-(3-phenylthioureido)acetamido]lactacylanic acid is dissolved in 3 ml of methanol, until the solution is placed under ice-cooling 0, 1 ml

concentrated hydrochloric acid, and then the reaction mixture is stirred for 30 minutes. 0.08 g of sodium bicarbonate is added to the reaction mixture, and the solution is stirred for 10 minutes. 10 ml of ice water is added to the solution, and the solution is filtered

removal of precipitated crystals. The filtrate is washed with 10 ml of ethyl acetate and evaporated to dryness under reduced pressure. Methanol is added to the residue to produce crystals, and the crystals are collected by filtration, whereby 10 mg of 3-aminolactacylanic acid is obtained. The mother liquor is concentrated for recovery

the said compound (80 mg), which is identified by comparing the compound's IR absorption spectrum, NMR absorption spectrum and melting point with the corresponding characteristics of an authentic sample.

Example 198

0.50 g of 3-[2-(4-]3-(3-phenylthioureido)-3-carboxypropoxy]-phenyl)-2-(3-phenylthioureido)acetamido]lactacylanic acid is dissolved in 4 ml of 2,2,2-trifluoroacetic acid , and the solution is stirred for 1 hour

under ice cooling. The reaction mixture is poured for approx. 10 ml of ice water, and the solution is washed twice with 10 ml of ethyl acetate. The aqueous solution is adjusted to a pH value of 4 med

9.5 ml weak basic anion exchange resin, "Amberlite IR-45"

(OH-type, trademark, sold by Rohm and Haas Co. Ltd.), the resin is filtered from the mixture, and the filtrate is concentrated to give a residue. Methanol is added to the residue to produce crystals, which are collected by filtration, whereby 30 mg of 3-aminolactacylanic acid is obtained. The product is identified by comparing the product's IR absorption spectrum, NMR absorption spectrum and melting point with the corresponding characteristics of an authentic sample.

Example 199

0.67 g of 3-(2-[4-(3-acetamido-3-carboxypropoxy)phenylj-2-(3-phenylthioureido)acetamido]lactacillanic acid is dissolved in 6.7 ml of acetic acid, until the solution is placed once under water cooling with stirring 0.15 ml of concentrated hydrochloric acid, and the reaction mixture is stirred for 1 hour The reaction mixture is treated in essentially the same way as described in Example

198, whereby 90 mg of 3-aminolactacylanic acid is obtained, which is identified by comparing the product's IR absorption spectrum and NMR absorption spectrum with the corresponding characteristics of an authentic sample.

Example 200

3-[2-(4-[3-carboxy-3-(N-ethoxy(thiocarbonyl)aminopropoxy]-phenyl)-2-(N-ethoxy^thiocarbonyl)amino)acetamedo]lactacylanic acid

is treated in essentially the same way as described in example 199, whereby 3-aminolactacillanic acid is obtained.

Example 201

Dissolve 2.28 g of 3-(2-[4-[3-(3-phenylthioureido)-3-carboxy]phenyl)-2-(3-phenylthioureido)acetamido]lactacillanic acid in 6 ml of acetic acid, and add dropwise to the solution during 15 minutes under water cooling while stirring a mixture of

0.45 ral of concentrated hydrochloric acid and 6 ml of acetic acid. The reaction mixture is stirred for a further 15 minutes, and 25 ml of ethyl acetate and 25 ml of water are added to the reaction mixture, after which the mixture is stirred. The separated ethyl acetate phase is extracted with 10 ml of water. The extract and the previously obtained aqueous phase

are collected, and the combined aqueous solutions are washed with ethyl acetate and adjusted with 15 ml of weakly basic anion exchange resin, "Amberlite IR-45" (0H type, trademark, sold by Rohm and Haas Co. Ltd.), to a pH value of 3 ,4. The resin is filtered from the mixture, and the filtrate is concentrated under reduced pressure,

whereby a residue is obtained. Methanol is added to the residue, whereby crystals are obtained which are collected by filtration, whereby 0.25 g of 3-aminolactacylanic acid is obtained. The product is identified by comparing the product's IR absorption spectrum, NMR absorption spectrum and melting point with the corresponding characteristics of an authentic sample.

Example 202.

1.54 g of 3-(2-[4-(3-benzamido-3-carboxypropoxy)phenyl]-2-(2-nitro-4-methoxycarbonylanilino)acetamido)lactacillanic acid is dissolved in a mixture of 10 ml of water and 20 ml of methanol , and to

500 mg of 10% palladium Aull is added to the solution as a catalyst. The solution is stirred for 2 hours in a hydrogen atmosphere at elevated pressure using a suitable reducing apparatus at room temperature. After the turnover has ended, it is transferred

the catalyst, and the methanol is distilled off from the filtrate under reduced pressure. The resulting solution is washed with ethyl acetate and cooled. Acetone is added to the solution, whereby crystals are precipitated, which are collected by filtration, whereby 83 mg of 3-aminolactacillanic acid is obtained. The mother liquor is further evaporated to dryness under reduced pressure, and the resulting residue is washed with methanol, whereby crystals are obtained.

The crystals are collected by filtration, whereby 50 mg of the aforementioned compound are obtained. The fcotal yield is 12 3 mg. The product is identified by comparing the product's IR absorption spectrum

and NMR absorption spectrum with the corresponding characteristics

for an authentic sample.

Example 203

3-[2-(4-[3-(2-nltro-4-methoxycarbonylanilino)-3-carboxypropoxy3-phenyl)-2-(2-nitro-4-methoxycarbonylanilino)-acetamido]lactacillanic acid is treated in substantially the same

manner as described in example 202, whereby 3-aminolactacillanic acid is obtained.

Example 204

Dissolve 2.5 g of 3-(2-[4-(3-acetamido-3-carboxypropoxy)phenyl]-2-t3-(1-naphthyl)thioureido]acetamido)lactacyllanic acid in 10 ml of acetic acid, and add to the solution under water cooling while stirring 0.56 ml of concentrated hydrochloric acid. The reaction mixture is stirred for 30 minutes and then poured into a mixture of 10 ml of ice water and 20 ml of ethyl acetate, and the aqueous phase is separated. The resulting ethyl acetate phase is extracted with 10 ml of ice water. The

aqueous phases are collected and washed with 10 ml of ethyl acetate. To the solution is added 15 ml of a weakly basic anion exchange resin, "Amberlite IR-45M (OH type, trademark, sold by Rohm and Haas Co. Ltd.), and the mixture (pH value 3.4) is stirred for 5 minutes . The resin is filtered from the mixture, and it is washed with 5 ml of ice water. The filtrate and the washing liquid are collected and concentrated, thereby obtaining

a residue. The residue is washed with methanol, whereby crystals are obtained. The crystals are collected by filtration, thereby obtaining

149 mg of 3-aminolactacillanic acid. The mother liquor is further concentrated, and the resulting residue is washed with methanol, whereby 80 mg of the aforementioned compound is recovered. The total yield is 229 mg. The product is identified by comparing

of the product, IR absorption spectrum and NMR absorption spectrum with the corresponding characteristics of an authentic sample.

Example 205 2.6 g 3-(2-[4-(3-carboxy-3-E3-(1-naphthyl)thioureido]-propoxy)phenyl J-?2-[3-(1-naphthyl)thioureido]acetamido]lactacylanic acid is reacted in essentially the same way as described in example 204, whereby 190 mg of 3-aminolactacylanic acid is obtained, which is identified by comparing the product's IR absorption spectrum and melting point with the corresponding characteristics of an authentic sample.

Example 206

816 mg of 3-(2-phenylacetamido)-2-azetidinone and 1.22 g of 2-bromo-2-phenylacetic acid benzyl ester are dissolved in 20 ml of N,N-dimethylformamide, until the solution is placed under ice-cooling while stirring in a nitrogen atmosphere 210 mg 50 µg of oily sodium hydride, and then the reaction mixture is stirred for 1 hour at the same temperature. 150 ml of ethyl acetate are added to the reaction mixture, and the solution is washed with water, with a saturated aqueous sodium bicarbonate solution and with water in the order indicated and then dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, whereby 1.7 g of a yellow oily product is obtained. The product is subjected to column chromatography using silica gel (chloroform is developed), whereby two isomers of 1-(c-benzyloxycarbonyl-benzyl)-3-(2-phenyl)acetamido-2-azetidinone are obtained. The yield of isomer A is 26 mg, and the yield of isomer B is 65 mg.

Physical constants for isomer Ai oil, mass spectrum m/e»>428 (M+), IR absorption spectrum v cm""1 (CHCl-j): 1760, 1740 ^shoulder) and

1678.

NMR absorption spectrum 6 ppm (CDCl 3 ) in 3.46 (2H, m), 3.55 (2H, s)

4.96 (1H, m), 5.15 (2H, s), 5.61 (1H, s), 6.37 (1H, d, J » 8Hz), 6.90-7.60 (15H, m).

Physical constants for isomer Bt melting point 96-98°C, mass spectrum, m/e & 428 (M<+>)

-1

IR absorption spectrum v cm (nujol) at 1750, 1732 and 1680. NMR absorption spectrum: 6 ppm (CDCl1): 3.03 (1H, d,d, J=>3Hz, 5Hz),

3.53 (2H, s), 3.85 (1H, d,d, J = BHz, 5Hz), 4.88 (1H, m), 5.17 (2H,s), 5.62 (1H, s), 6.05 (1H,d, J=8Hz), 7.00-7.60 (15H, m).

The following compounds are prepared in essentially the same way as described above.

Example 217

610 mg of 3-(2-phenylacetamido)-2-azetidinone, 900 mg of 2-bromo-2-(3-nitrophenyl)acetic acid methyl ester and 460 mg of anhydrous potassium carbonate are added to 60 ml of ethyl methyl ketone and the solution is heated, for 8 hours under reflux with stirring . The reaction mixture is cooled and then poured into ice water, after which the mixture is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solution is evaporated to dryness, and the resulting oily residue is subjected to column chromatography. The fractions eluted with a mixture of chloroform and methanol (100:1) are subjected to thin-layer chromatography using silica gel (developer: a mixture of chloroform and methanol (40:1)), thereby obtaining 7.5 mg of a mixture of two isomers of 1-(α-methoxycarbonyl-3-nitro-benzyl)-3-(2-phenylacetamido)-2-azetldinone. IR absorption spectrum: v cm"<1>(CHClj): 1765, 1745 and 1680.

Example 218

612 mg of 3-(2-phenylacetamido)-2-azetidinone and 825 mg of 2-bromo-2-(4-methylthiophenyl)acetic acid methyl ester are dissolved in 20 ml of N,N-dimethylformamide. Keeping the temperature of the solution at 20-30°C, 20 ml of a benzene solution of 546 mg of sodium-N,N-bis-(trimethylsilyl)amine is added to the solution over the course of 1 hour in a nitrogen atmosphere, and the reaction mixture is stirred for 15 minutes,

at the same temperature. 150 ml of ethyl acetate are added to the reaction mixture, and the ethyl acetate phase is washed with water, with a saturated aqueous sodium bicarbonate solution and with water in the order indicated and then dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, whereby 1.2 g of an oily residue is obtained. The residue is subjected to column chromatography using silica gel (developer: chloroform), whereby two isomers of 1-(α-methoxycarbonyl-4-methylthiobenzyl)-3-phenylacetamido-2-azetidinone are obtained. The yield of isomer A is 10 mg with a melting point of 115-117°C (decomposition), and the yield of isomer B is 43.5 mg with a melting point of 157-159°C (decomposition).

Example 219

408 mg of 3-(2-phenylacetaraido)-2-azetidinone and 152 mg of 2-chloroacetonitrile are dissolved in 15 ml of K,N-dimethylformamide, to

the solution is stirred at room temperature with 105 mg of 50% oily sodium hydride, after which the reaction mixture is stirred for 1 hour at room temperature, and 100 ml of ethyl acetate is added to the reaction mixture. The ethyl acetate phase is washed with water and dried over anhydrous magnesium sulfate, and then the solvent is distilled off from the solution under reduced pressure. The resulting oily residue (0.25 g) is subjected to column chromatography using silica gel. From fractions eluted with chloroform, 56.3 mg of 1-cyanomethyl-3-(2-phenylacetamido)-2-azetidinone with melting point 108-109°C (decomposition) are obtained.

Example 220

154 mg of 2-(2-phenoxyacetamido)-2-azetidinone is dissolved in 1.75 ml of N,N-dimethylformamide, 174.6 mg of thallium oxide is added at once to the solution, and then the mixture is stirred for 10 minutes at room temperature. A solution prepared by dissolving 232 mg of 2-bromo-2-(4-ethoxycarbonyloxyphenyl)acetic acid ethyl ester in 0.6 ml of N,K-dimethylformamide is added dropwise to the reaction mixture, and then the reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is filtered, whereby an undissolved product and a filtrate are obtained. The undissolved product is washed with ethyl acetate. The filtrate and washing liquid are collected and diluted with ethyl acetate. The solution is washed with water and dried over anhydrous magnesium sulfate. The solution is concentrated under reduced pressure, whereby a yellow oily residue is obtained which is subjected to column chromatography using silica gel. From fractions eluted with benzene, oily 1-(o-ethoxycarbonyl-4-ethoxycarbonyloxybenzyl)-3-(2-phenoxyacetamido)-2-azetidinone is obtained. IR absorption spectrum?

v cm<-1> (waxy film) s 1760, 1740 (shoulder) and 1675.

Example 221

63 mg of Isomer B of 1-(o-benzyloxycarbonylbenzyl)-3-(2-phenylacetamido)-2-azetidinone (prepared according to example 206) is dissolved in 12 ml of isopropyl alcohol, and 10 mg of lOSig palladium/charcoal is added to the solution. The mixture is reacted in 1 atmosphere of hydrogen at normal temperature and pressure, until the absorption of hydrogen gas has ended. The catalyst is filtered; the solvent is distilled off from the filtrate, and then ether is added to the resulting residue, whereby 27 rags of crystalline 1-(ct-carboxybenzyl)-3-(2-phenylacetamido)-2-azetidinone are obtained, which is recrystallized from a mixture of methanol and ether, whereby the aforementioned pure compound with melting point 174-175°C (decomposition) is obtained.

Example 222

1-Carboxymethyl-3-(2-phenylacetamido)-2-azetidinone is prepared by treating 1-benzyloxycarbonylmethyl-3-(2-phenylacetamido)-2-azetidinone in essentially the same manner as described in Example 221. Melting point 144-145 °C.

Example 223

750 mg of 3-(2-phenylacetamido)-2-azetidinone and 1.51 g of 2-bromo-2-(4-benzyloxyphenyl)acetic acid benzyl ester are added to 10 ml of anhydrous N,N-dimethylformamide and dissolved by heating

for some time. The solution is cooled in an ice-water bath, and 178 mg of 50% oily sodium hydride are added to the solution at once with stirring. After removing the cooling bath, the reaction mixture, to which ethyl acetate has been added, is stirred for 30 minutes. The reaction mixture is filtered, and the filtrate is washed

with water, with 2% hydrochloric acid and with water in the specified order and then dried over anhydrous magnesium sulphate. The solution is concentrated under reduced pressure, whereby 1.98 g of oily product is obtained, which is subjected to column chromatography

using 40 g of silica gel. The fractions eluted with a mixture of benzene and chloroform are subjected to thin-layer chromatography using silica gel, developing with a mixture of chloroform and acetone gives two isomers of 1-(o-benzyloxycarbonyl-4-benzyloxybenzyl)-3-(2- phenylacetamido)-2-azetidinone. Isomer A is recrystallized from a mixture of chloroform and ether. The yield is 90 mg with a melting point of 129-130°C (decomposition). Isomer B is an oily product, the yield is 120 mg. The obtained isomer A (90 mg) is dissolved in 7 ml of methanol, and the solution is added. 30 rag loSig palladium/coal. The mixture is reacted in a hydrogen atmosphere at normal temperature and normal pressure, until the absorption of hydrogen gas has ended. The catalyst is filtered from the reaction mixture, and the filtrate is concentrated under reduced pressure. The resulting residue is crystallized from a mixture of ethyl acetate and ether, whereby crystalline 3-(2-phenylacetamido)-lactacillanic acid is obtained. The product is identified by comparison of

the product's IR absorption spectrum, NMR absorption spectrum and melting point with the corresponding characteristics of an authentic sample, which is prepared in a different way from 3-aminolactacylanic acid.

Example 224

300 mg of 3-(2-phenylacetamido)-2-azetidlone and 604 mg of 2-bromo-2-(4-benzyloxyphenyl)acetic acid benzyl ester are dissolved under

heating in 4 ml of anhydrous N,N-dimethylformamide. The solution is cooled in a cooling bath, 71 mg of 50% oily sodium hydride are added at once, and then the reaction mixture is stirred for some time. After removing the cooling bath, the reaction mixture is stirred for 30 minutes, after which ethyl acetate is added. The reaction mixture is filtered, and then the filtrate is washed with water, with 2% hydrochloric acid and with water in the order indicated and then dried over anhydrous magnesium sulfate. The solution is concentrated, whereby 727 mg of an oily residue are obtained,

which is subjected to column chromatography using 15 g of silica gel. The elution is carried out with a mixture of benzene and chloroform, whereby 255 mg of an oily product are obtained. Part of this product (200 mg) is dissolved in 14 ral of methanol, and 60 mg of I0§i palladium/charcoal is added to the solution. The mixture is allowed to react in a hydrogen atmosphere at normal temperature and pressure, until the absorption of hydrogen gas has ended. The catalyst is filtered from the reaction mixture, and the filtrate is concentrated

under reduced pressure. The resulting residue is crystallized from a mixture of ethyl acetate and ether, whereby 3-(2-phenylacetamido)lactacyllanic acid is obtained. IR absorption spectrum v cm"1 (nujol): 1745, 1690 and 1650.

The following compounds are prepared in essentially the same way as described above.

Example 239

157 mg of a crude product that is not separated and purified, and which is prepared by reacting ethyl 3-(2-phenoxyacetamido)-2-azetidinone with 2-bromo-2-(4-ethoxycarbonyloxyphenyl)acetic acid ethyl ester in an analogous manner as described in example 220, dissolve in 3 ml of ethanol until the solution is cooled in a

ice water bath 1.0 ml IN aqueous sodium hydroxide solution, and then the solution is stirred for 30 minutes after removing the cooling bath. The reaction mixture is concentrated under reduced pressure, and water is added to the resulting residue. The aqueous solution is washed with ethyl acetate, and then the aqueous phase is adjusted to a pH value of 1-2 with IN hydrochloric acid, after which it is extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution under reduced pressure, whereby a residue is obtained which is washed with ether, whereby 3-(2-phenoxyacetamido)lactacillanic acid is obtained. IR absorption spectrum: G cm"1 (nujol): 1745, 1690 and 1660.

By treating the corresponding 3-acylamino-2-azetidinones in essentially the same way as described above, the following compounds are obtained.

By treating the 3-acylamino-2-azetidinones indicated in the following table with the general formula III in essentially the same way as described in example 224, the compounds indicated in the following table with the general formula I are obtained".

By treating the 3-acylamino-2-azetidinones listed in the following table with the general formula III in essentially the same way as described in example 239, the compounds listed in the following table with the general formula I are obtained.

By treating 3-acylamino-2-azetidinones with the general formula III in essentially the same way as described in example 239, the compounds with the general formula I shown in the following table are obtained.

Example 291

1.0 g of 3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido)lactacillanic acid is dissolved in 20 ml of 1.5% aqueous sodium hydrogen carbonate solution, 1.0 g of sodium hydrogen sulphite is added to the solution, and the mixture is heated for 3 hours at 80°C. The reaction mixture is adjusted to a pH value of 3 with 10% hydrochloric acid, the mixture is concentrated to a volume of

about. 10 ml, and the concentrate is adjusted to a pH value of 3 with 10% hydrochloric acid, thereby obtaining 0.57 g of crystalline 3-[4-(3-amino-3-carboxypropoxy)phenylglyoxyloylamino]lactacylanic acid with melting point 216°C (decomposition) .

Example 292

3-(2-[4-(3-acetamido-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido)lactacyllanic acid is treated in essentially the same way as described in example 291, whereby crystalline 3-[4-(3-acetamido) is obtained -3-carboxypropoxy)phenyl-glyoxyloy lamino]lactacylanic acid with melting point 96-102°C (decomposition).

Example 293

4.2 g of 3-(2-[4-(3-carboxy-3-phthalimidopropoxy)phenyl]-2-hydroxyiminoacetamido)lactacylanic acid are dissolved in 40 ml of methanol. A solution prepared by dissolving 4.2 g of sodium hydrogen Bulfite in 80 ml of water is added to the solution, and the reaction mixture is heated for 3.5 hours under reflux. The reaction mixture is then concentrated to a volume of approx. 30 ml, the concentrate is adjusted to a pH value of 2.0 with 10% hydrochloric acid under ice-cooling, and then the solution is extracted with ethyl acetate. The extract is washed with water and dried, and then the solvent is distilled off from the extract, thereby obtaining 2.1 g of 3-[4-(3-carboxy-3-phthalimidopropoxy)phenylglyoxyloyl-amino]lactacylanic acid with a melting point of 115-120°C (decomposition).

Example 294

3-[2-(4-[3-carboxy-3-(3-phenylureido)propoxy]phenyl)-2-hydroxyiminoacetamido]lactacillanic acid is treated in essentially the same way as described in example 293, whereby 3-(4- [3-carboxy-3-(3-phenylureido)propoxy)phenylglyoxyloylamino]-lactacylanic acid with melting point 100-106°C (decomposition).

Example 295

Of 5 g of 3-(2-[4-(3-aminob-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido)lactacylanic acid is suspended in 10 ml of an aqueous solution of 1.93 g of ammonium acetate and 0.3 ml of 28% ammonia water, and 0.435 g of zinc powder is added to the solution, after which the mixture is stirred for 24 hours at room temperature. The reaction mixture is adjusted to a pH value of 4 with 1N hydrochloric acid, hydrogen sulphide gas is passed to the solution, and then the undissolved product is filtered off. The filtrate is concentrated under reduced pressure, whereby a residue is obtained, the residue is dissolved in 10 ml of water, and then 200 ml of ethanol is added to the solution. The formed precipitate is collected by filtration and dried, thereby obtaining 420 mg of 3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]glycine-amido)lactacylanic acid with a melting point of 206-208°C (decomposition).

Example 296

0.5 ml of N,N -dimethylforroamide, 0.5 ml of formic acid and 1.0 g of zinc powder, and the mixture is stirred for 4 hours. The zinc powder is filtered from the reaction mixture, hydrogen sulphide is passed to the filtrate and then the undissolved product is filtered off. The filtrate is concentrated under reduced pressure, whereby a residue is obtained which is pulverized with acetone, whereby 0.68 g of 3-(2-[4-(3-phthalimido-3-carboxypropoxy)phenyl]glycinamido)lactacylanic acid with a melting point of 215-219°C is obtained (fission).

Example 297

To a solution containing 1.85 g of 3-(2-[4-(3-acetamido-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetamido]lactanoic acid, 0.6 g of sodium bicarbonate and 20 ml of water, add 0.6 g 10% palladium/coal. The mixture is subjected to absorption of the calculated volume-amount of hydrogen gas at normal temperature and pressure. The catalyst is filtered from the reaction mixture, bg the filtrate is adjusted to a pH value of 3 with 10% hydrochloric acid under ice cooling and then treated with activated carbon. The resulting aqueous solution is crystallized under ice-cooling from 150 ml of acetone. The crystals are collected by filtration and washed with 10 ml of water and with acetone, whereby 0.38 g of 3-(2-t4-(3-acetamido-3-carboxypropoxy)phenyl]glycinamido)-J lactacyllanic acid is obtained. The previously obtained washing liquid is further crystallized under ice-cooling from 10 ml of acetone, and the crystals are washed with acetone and then collected by filtration, whereby 0.32 g of the aforementioned compound is obtained.

The total yield is 0.70 g. Melting point 198-204°C (decomposition).

Example 298

3 g of 10% palladium/ coal, and the mixture is subjected to kfcaalytic reduction for 15 hours with sufficient shaking at 3 atmospheres at normal temperature. After the reaction, the catalyst is filtered from the reaction mixture, and the filtrate is adjusted to a pH value of 3.0 with 10% hydrochloric acid under ice cooling, thereby obtaining 7.8 g of crystalline 3-(2-[4-(3-benzamido-3-carboxypropoxy) )phenyl]-glycinamido)lactacillanic acid. 0.4 g of the aforementioned compound can be further recovered from the mother liquor. The total yield is 8.2 g. Melting point 171-176°C (decomposition).

Example 299

1.10 g of 3-[4-(3-carboxy-3-phthalimidopropoxy)phenyl-glyoxyloylamino]lactacillanic acid is suspended in 11 ml of water, and 0.40 g of sodium bicarbonate is added to the suspension to dissolve. 0.08 g of sodium borohydride is added to the solution under ice cooling, and the mixture is stirred for 4 hours at the same temperature. The reaction mixture is adjusted to a pH value of 2 with 10% hydrochloric acid, whereby 0.91 g of crystalline 3-(2-[4-(3-carboxy-3-phthalimidopropoxy)phenyl]-2-hydroxyacetamido)lactacillanic acid with a melting point of 160- 163°C (decomposition).

Example 300

20 ml of acetic anhydride is added to a suspension which

is prepared by suspending 10 g of [3-(2-4-O-amino-S-carboxy-propoxy)phenyl-2-hydroxyiminoacetamido)lactacylanic acid in 150 ml of methanol, and the mixture is stirred for 4.5 hours. The reaction mixture is concentrated under reduced pressure, whereby a residue is obtained to which toluene is added. The solution is concentrated under reduced pressure, whereby a residue is obtained which is pulverized by the addition of ethyl acetate, whereby 10.3 g of 3-(2-[4-(3-acetamido-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido)-

lactacyllanic acid with melting point 90-93°C (decomposition).

Example 301

6 ml of acetic anhydride is added under ice-cooling to 60 ml of a methanol suspension of 3.0 g of 3-[4-(3-amino-3-carboxy-propoxy)phenylglyoxyloylamino]lactacylanic acid, and the mixture is stirred for 1 hour at the same temperature and for a further 4 hours at room temperature. The reaction mixture is concentrated

under reduced pressure, and the concentrate is pulverized with ether, thereby obtaining 2.26 g of 3-[4-(3-acetamido-3-carboxypropoxy)phenyl-glyoxyloylamino]lactacllanoic acid with melting point 96-102°C (decomposition).

Example 302

3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]glycinamido)-lactacylanic acid is treated in essentially the same way as described in example 301, whereby 3-(2-[4-(3-acetamido) is obtained -3-carboxypropoxy)phenyl]-N-acetylglycinamido)lactacillanic acid. IR absorption spectrum v cm"<1>(nujol)t 1735 and 1650.

Example 303

0.50 g of 3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido)lactacillanic acid is suspended in 20 ml of dry methylene chloride. 1.50 g of N,0-bis-(trimethylsilyl)acetamide is added to the suspension, and the mixture is stirred for 2 hours at room temperature and then heated for 10 minutes under reflux. The reaction solution is cooled to 0-5°C, 0.12 g of triethylamine and 0.27 g of 2,2,2-trifluoroacetic anhydride are added to the solution, and then the reaction mixture is stirred

the solution for 1 hour. The methylene chloride is distilled off from the reaction mixture, whereby a residue is obtained which is dissolved in 20 ml of ethyl acetate. The solution is washed five times with 2% hydrochloric acid, twice with water and once with one saturated aqueous sodium chloride solution in the order indicated and then dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, and benzene is added to the residue, whereby 0.41 g of powdery crystalline 3-[2-(4-[3-carboxy-3-(2,2,2-trifluoroacetamido)propoxy]phenylJ-2-hydroxyimino is obtained -acetamido)lactacillanic acid with melting point 143-147°C (decomposition).

Example 304

To a suspension prepared by suspending 4.0 g of 3-(4-(3-amino-3-carboxypropoxy)phenylglyoxyloylaminol-lactacylanic acid in 80 ml of dry methylene chloride, add 15 ml of N,0-bis(trimethylsilyl)-acetamide, and the mixture is stirred for 2 hours until the starting material is completely dissolved. 0.88 g of triethylamine is added under ice-cooling to the solution, and then a solution that is prepared is added dropwise over the course of 30 minutes

by dissolving 1.9 g of 2,2,2-trifluoroacetic anhydride in 5 ml of methylene chloride, to the solution. The reaction mixture is stirred for 1.5 hours at the same temperature, and then the methylene chloride is distilled off from the reaction mixture under reduced pressure, after which the residue is poured into a mixture of 50 ml of ice water and 100 ml of ethyl acetate. The ethyl acetate phase, which separates out, is dried over anhydrous magnesium sulfate, and then the solvent is distilled off, thereby obtaining a residue to which benzene is added to produce 3.0 g of powdery crystalline 3-(4-[3-carboxy-3-(2 ,2,2-trifluoroacetamido)propoxy]phenylglyoxyl-oylamino)lactacyllanic acid. IR absorption spectrum v cm 1

(Nujol): 1730 and 1680.

Example 305

20.0 g of 3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido)lactacillanic acid is suspended in a mixture of 200 ml of water and 200 ml of acetone, after which 6.8 g of sodium bicarbonate. 6.7 g of benzoyl chloride are added dropwise under ice cooling to the solution, the pH value of the solution being kept at 8.0. The reaction mixture is stirred for 14 hours, and the acetone is distilled off from the reaction mixture.

The resulting aqueous solution is washed with ethyl acetate, and

add 400 ml of ethyl acetate to the solution. The mixture is adjusted under cooling to a pH value of 2.0 with 10% hydrochloric acid, and the ethyl acetate phase is separated, washed with water and with a saturated aqueous sodium chloride solution in the indicated order and dried. The ethyl acetate is distilled off from the solution, whereby a residue is obtained, and then it is suspended in 200 ml of water.

160 ml of aqueous IN sodium hydroxide solution are added to the suspension, and the solution is stirred for 2 hours. 400 ml of ethyl acetate are added to the solution, and the mixture is adjusted under ice-cooling to a pH value of 2.0 with 10% hydrochloric acid. The ethyl acetate phase is separated, washed with water and dried. The solvent is distilled off from the solution, thereby obtaining 21.6 g of powder which is crystallized from a mixture of acetone and benzene, thereby obtaining 10.4 g of crystalline 3-(2-[4-(3-benzamido-3-carboxypropoxy)phenyl]-2 -hydroxyimino-acetamido)lactacillanic acid with melting point 170-172°C (decomposition).

Example 306

970 mg of 3-[4-(3-amino-3-carboxypropoxy)phenylglyoxyloyl-amino]lactacylanic acid is suspended in 10 ml of water, and the suspension is adjusted under ice-cooling to a pH value of 8-9 with IN aqueous sodium hydroxide solution. 10 ml of an acetone solution of 360 mg of phenyl isocyanate is added dropwise to the solution,

the solution's pH value when added dropwise is kept at 8-9. The solution is stirred for 1 hour, and the diphenylurea formed as a by-product is filtered off. The filtrate is adjusted to a pH value of 1-2 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, after which the solvent is distilled off from the solution, thereby obtaining 1.33 g of crystalline 3-(4-[3-carboxy-3-(3-phenyl-ureido)propoxy]phenylglyoxyloylamino )lactacillanic acid with melting point 100-106°C (decomposition).

Example 307

250 mg of 3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]-glycinamido)lactacylanic acid are suspended in 5 ml of water, and the suspension is adjusted under ice-cooling to dissolve at a pH value of 8 with 1N aqueous sodium hydroxide solution. Add to the solution under ice-cooling 2 ml of a dried

acetone solution of 150 mg of phenyl isocyanate, the solution's pH value during the addition being kept at 8-9. The solution is stirred for 1 hour under ice cooling and then adjusted to a pH value of 2 with 10% hydrochloric acid, whereby a precipitate is obtained. The sediment

collected by filtration, washed with water and then dissolved

in an aqueous sodium bicarbonate solution. An insoluble product is filtered off, and the filtrate is adjusted to a pH value of 1-2 with 10% hydrochloric acid, whereby crystals are obtained, which are collected by filtration, washed with water and then dried over phosphorus pentachloride, whereby 0.35 g of crystalline 3- [2-(4-[3-carboxy-3-(3-phenylureido)propoxy)phenyl)-2-(3-phenylureido)acetamido]-lactacylanic acid with melting point 170-172°C (decomposition).

Example 308

A suspension of 10 g of 3-(2-[4-(3-amino-3-carboxypropoxy)-phenyl]-2-hydroxyiminoacetamido)lactacylanic acid, 100 ml of water and 30 ml of acetone is adjusted under ice-cooling to a pH value of 8- 9 with a 1N aqueous sodium hydroxide solution. To the solution is added dropwise at the same temperature 5 ml of an acetone solution of 2.0 g of phenyl isocyanate, and the mixture is stirred for 11 hours. The acetone is distilled off from the reaction mixture under reduced pressure, and the resulting solution is adjusted to a pH value of 2 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with dilute hydrochloric acid and with water in the order indicated and dried. The ethyl acetate is distilled off from the solution, whereby a residue is obtained which is crystallized from .100 ml of ether, whereby 10.3 g of crystalline 3-[2-(4-3-carboxy-3-(3-phenylureido)-propoxy ]phenyl)-2 is obtained -hydroxyiminoacetamido lactacyllanic acid with melting point 135-139°C (decomposition).

Example 309

5 ml of an acetone solution containing 0.60 g of ethyl phthalimidoformate is added dropwise to a solution containing 0.94 g of 3-(2-[4-(3-amirio-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido)lactacyllanic acid , 20 ml of 10% aqueous dipotassium hydrogen phosphate solution and 10 ml of acetone, and the mixture is stirred for 12 hours, keeping the pH value of the mixture at 8. The acetone

is distilled from the reaction mixture under reduced pressure, and the resulting solution is adjusted to a pH of 2 with dilute hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate. The ethyl acetate is distilled off from the solution, whereby a residue is obtained, which is crystallized from an aqueous ethanol solution, whereby 0.69 g of crystalline 3-(2-[4-(3-carboxy-3-phthalimidopropoxy)phenyl]-2-hydroxyiminoacetamido) is obtained. lactacyllanic acid with a melting point of 160-165°C (decomposition).

Example 310

3-(2-[4-(3-amino-3-carboxypropoxy)phenylglycolamido)-lactacyllanic acid is treated in essentially the same way as

described in example 309, whereby crystalline 3-(2-[4-(3-carboxy-3-phthalimidopropoxy)phenyl]glycolamino]lactacylanic acid with melting point 160-163°C (decomposition) is obtained.

Example 311

3-[4-(3-amino-3-carboxypropoxy)phenylglyoxyloylamino]-lactacillanic acid is treated in essentially the same way as described in example 309, whereby crystalline 3-[4-(3-carboxy-3-phthalimidopropoxy)phenylglyoxyloylamino] is obtained lactacyllanic acid with a melting point of 216°c (decomposition).

Example 312

To 6 ml of an aqueous 50% pyridine solution of 250 mg of 3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]glycinamido)lactacylanic acid is added at 40°C with stirring 320 mg of phenylisothiocyanate.

The mixture is stirred for 1 hour, the pH value of the mixture being maintained at 8-9 using a saturated aqueous sodium bicarbonate solution. The reaction mixture is washed with ether, and the aqueous phase is separated and then adjusted under cooling to a pH value of 1-2 with 10% hydrochloric acid, whereby 250 mg of crystalline 3-12-(4-[3-carboxy-3-(3 -phenylthioureido)propoxy]phenyl)-2-(3-phenylthioureido)acetamido]lactacylanic acid with melting point 190-195°C (decomposition).

Example 313

2.0 g of 3-(2-[4-(3-amino-3-carboxypropoxy)phenyl3-glycine-amido)lactacylanic acid are suspended in 20 ml of aqueous 50% pyridine solution, and the suspension is set to dissolve at a pH value of 8 .6 with IN aqueous sodium hydroxide solution. 1.94 g of 1-naphthyl isothiocyanate is added to the solution, and the mixture

stirred for 4 hours. The reaction mixture is washed with ether and adjusted while cooling to a pH value of 2.0 with 10% hydrochloric acid, whereby a precipitate is obtained. The precipitate is collected by filtration and washed with water. The precipitate is dissolved in a saturated aqueous sodium bicarbonate solution, and 10% hydrochloric acid is added to the solution, thereby obtaining 2.7 g of crystalline 3-(2-[4-(3-carboxy-3-[3-(1-naphthyl)thioureido]propoxy) phenyl]-2-[3-(1-naphthyl)thioureido]acetamido)lactacyllanic acid with melting point 169-173°C (decomposition).

Example 314

480 mg of 3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]-glycinamido)lactacylanic acid are suspended in 10 ml of water, and 5 ml of 1N aqueous potassium hydroxide solution is added to the suspension under ice-cooling with stirring. Add 5 ml of one to the solution

acetone solution of 0.72 g of O-ethyl-S-methyldithiocarbonate, and the mixture is stirred for 15 hours at room temperature. The reaction mixture is washed with ether, and the resulting aqueous phase is separated. The aqueous solution is adjusted to a pH value of 1-2 with 10% hydrochloric acid and extracted with ethyl acetate, and then the extract is washed with water and dried. The solvent is distilled off from the solution, thereby obtaining 230 mg of 3-[2-(4-[3-carboxy-3-ethoxy(thiocarbonyl)amlnoprepoxy]phenyl)-2-ethoxy-(thiocarbonyl)aminoacetamido]lactacylanic acid with a melting point of 112-119°C (fission).

Example 315

1.0 g of 3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyaminoacetamido)lactacylanic acid is dissolved in a mixture of 40 ml of 0.1N aqueous sodium hydroxide solution and 15 ml of acetone. 5 ml of an acetone solution containing 550 mg of 2t(4-chloro-2-nitrophenoxy)acetyl chloride and 40 ml of 0.1N aqueous sodium hydroxide solution are added to the solution dropwise under ice-cooling while stirring. The mixture (pH value 9.2-9.4) is stirred for 40 minutes at the same temperature and for a further 40 minutes at room temperature. The reaction mixture is washed with ethyl acetate, and ethyl acetate is added to the aqueous phase, after which the mixture is adjusted to a pH value of 2 with 10% hydrochloric acid. The ethyl acetate phase is separated, washed with water and dried

anhydrous magnesium sulfate. The solvent is distilled off from the solution, whereby a residue is obtained which is washed several times with ether. The residue is dissolved under heating in ethyl acetate,

an undissolved product is filtered off, and chloroform is added to the solution, whereby a powder is obtained which is collected by filtration, whereby 150 mg of 3-(2-[4-(3-|2-(4-chloro-2-nitrophenoxy)-acetamido) is obtained ]-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido)-lactacyllanic acid. A further 30 mg of the aforementioned compound is obtained from the mother liquor. The total dividend is 180 rag. The product has a melting point of 145-150°C (decomposition).

Example 316

4 ml of an acetone solution containing 352 mg of 2-(2-thienyl)acetyl chloride is added dropwise under ice-cooling with stirring to a solution containing 1.0 g of 3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]- 2-hydroxyiminoacetamido)lactacillanic acid, 504 mg of sodium bicarbonate, 30 ml of water and 10 ml of acetone,

the pH value of the solution is kept at 8. The mixture is stirred for 40 minutes at the same temperature and for a further 30 minutes at room temperature. The reaction mixture is washed with ethyl acetate, then ethyl acetate is added to the solution, after which the mixture is adjusted to a pH value of 2 with 10% hydrochloric acid. The ethyl acetate phase is separated, and the resulting aqueous phase is extracted with ethyl acetate. The ethyl acetate layers are combined, washed with a saturated aqueous sodium chloride solution and then dried

over anhydrous magnesium sulfate. The solvent is distilled off from the solution, and the resulting residue (740 mg) is added to 30 ml of 0.1N aqueous sodium hydroxide solution. The resolution

(pH value 9.4) is stirred for 1 hour at room temperature and washed with ethyl acetate, and ethyl acetate is added to the solution. The mixture is adjusted to a pH value of 2 by adding 10% hydrochloric acid and is then treated in an analogous manner as described above,

whereby 450 mg of residue is obtained. The residue is dissolved in a mixture of acetone and n-hexane, and the solution is treated with activated charcoal followed by filtration. The filtrate is concentrated, whereby a residue is obtained which is washed several times with ether and once with n-hexane, whereby 400 mg of 3-(2-[4-(3-carboxy-3-fi2-(2-thienyl)-acetamido) is obtained propoxy)phenyl3-2-hydroxyiminoacetamido)lactacylanic acid with melting point 145-150°C (decomposition).

Example 317

25 ml of an acetone solution containing 3.1 g of o-ethoxycarbonyloxycarbonyl-a-toluenesulfonic acid triethylamine salt and 10 ml of an aqueous solution of 756 mg of sodium bicarbonate are added dropwise over 15 minutes under ice-cooling to a solution containing 2.0 g of 3-(2- [4-(3-amino-3-carboxypropoacyl)-phenyl]-2-hydroxyiminoacetamido)lactacylanic acid, 756 mg of sodium bicarbonate, 35 ml of water and 15 ml of acetone. The reaction mixture (pH value 7.6) is stirred for 30 minutes at the same temperature and for a further 30 minutes at room temperature.

The acetone is distilled off from the reaction mixture, and the resulting solution is adjusted to a pH value of 3 with 10% hydrochloric acid, after which the solution is washed with ethyl acetate. The ethyl acetate phase is separated, and the resulting aqueous solution is adjusted to a pH value of 1 with 10% hydrochloric acid and extracted with n-butyl alcohol. The resulting extract is washed once with 5% hydrochloric acid and once with a saturated aqueous sodium chloride

solution in the order indicated and dried over anhydrous magnesium sulfate. The extract is adjusted to a pH value of 6 with 21 ml of an acetone solution containing 11 mg of sodium 2-ethylhexanate, whereby a powder is obtained which is collected by filtration. The powder is washed with acetone, whereby 2.3 g of colorless powder is obtained. A portion of the powder (1.0 g) is dissolved in 3 ml of water, the solution is adjusted to a pH value of 3 with 10% hydrochloric acid and then washed with ethyl acetate, after which the solution is subjected to column chromatography using a non-ionic adsorption resin, " Amberlite XAD-2" (trademark, sold by Rohm and Haas Co. Ltd.), and the water-eluted compound is freeze-dried to obtain 350 mg of the sodium salt of 3-[2-(4-[3-carboxy-3-(2 -phenyl-2-sulfoacetamido)propoxy]phenyl)-2-hydroxyiminoacetamido]lactacylanic acid. From fractions eluted with water containing 20% methanol and methanol, a further 480 mg of the aforementioned compound are recovered. A total tube exchange is 830 mg. The product has a melting point of 244-250°C (decomposition).

Example 318

0.127 g of potassium carbonate and 3 ml of water are added to 3 ml of an acetone solution containing 0.200 g of N-methylaniline, and the solution is stirred at a temperature of 25-28°C. A mixture of 4 ml of acetone and water (1.1) containing 0.321 g of 3-(2-bromoacetamido)lactacylanic acid and 0.067 g of sodium bicarbonate is added dropwise to the solution, and the reaction mixture is allowed to react for 17 hours at the same temperature. The acetone is distilled off from the reaction mixture under reduced pressure, and the resulting aqueous phase is washed with ethyl acetate. The aqueous phase is adjusted to a pH value of 3 with dilute hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water, dried and then concentrated. The resulting residue is crystallized from methanol, whereby 0.208 g of crystalline 3-(N-methyl-N-phenylglycinamido)lactacylanic acid with melting point 198-199°C (decomposition) is obtained.

The following compounds are prepared in essentially the same manner as described above*

Example 323

0.262 g of morpholine is dissolved in 5 ml of a mixture of acetone<p>g water (lsl), and 0.180 g is added to the solution

callum carbonate. The solution is cooled to 10°C, and 5 ml of a mixture of acetone and water (lsl) containing 0.464 g of 3-(2-bromoacetamido)lactacillanic acid and 0.110 g of sodium bicarbonate are added dropwise to the solution. The reaction mixture is allowed to react for 15 hours, the reaction temperature being kept at 10-20°C. The acetone is distilled off from the reaction mixture under reduced pressure

pressure, and the resulting aqueous solution is washed with ethyl acetate. The aqueous solution is adjusted to a pH value of 1-2 with dilute hydrochloric acid and washed with ethyl acetate. The aqueous solution is adjusted to a pH value of 4.5-4.8 with sodium bicarbonate, the solution is concentrated under reduced pressure, and then the residue is extracted with methanol. The extract is concentrated, whereby an oily product is obtained, which is dissolved in a small amount of methanol. Acetone is added to the solution which is filtered. The filtrate is concentrated, thereby obtaining 0.38 g of an oily product, which is subjected to column chromatography under

using 35 ml of nonionic adsorption resin, "Amberlite XAD-2" (trademark, sold by Rohm and Haas Co., Ltd.). Isolation and cleaning are carried out. The fractions eluted with water are collected, and the water is distilled off from the eluate, whereby 0.38 g of crystalline 3-(2-morpholinoacetamido)lactacylanic acid with melting point 201-203°C (decomposition) is obtained.

Example 324.

A mixture containing 196 mg of 3-[2-(2-bromoacetamido)-2-phenylacetamido]lactacylanic acid, 62 mg of 2-mercaptobenzoic acid and 12 ml of 0.1N aqueous sodium hydroxide solution is stirred for 1 hour at room temperature. The reaction mixture (pH value 6.8-7.8) is adjusted to a pH value of 3 with 0.4 ml 1N hydrochloric acid, washed with ether and then adjusted to a pH value of 1-2 with 1N hydrochloric acid. The solution is extracted with ethyl acetate, and the extract is washed with water and dried over anhydrous magnesium sulfate. The solution is concentrated under reduced pressure to a volume of approx. 4 ml, whereby crystals are obtained which are washed with ether, whereby 125 mg of crystalline 3-(2-[2-(2-carboxyphenylthio)acetamido]-2-phenylacetamido 3 lactacylanic acid are obtained. From the filtrate, a further 50 mg of the aforementioned compound is recovered. Dot total yield is 175 mg.

The product has a melting point of 143-146°C (decomposition).

The following compounds are prepared in essentially the same way as described above"

Example 340

86 mg of 3-(2-bromo-2-phenylacetamido)lactacylanic acid and 35 mg of cysteine hydrochloride (a hydrate) are suspended in 3 ml of water, and 0.4 ml of IN aqueous sodium hydroxide solution is added to the suspension under ice-cooling with stirring. The solution is allowed to react

for 3 hours, and then the mixture's pH value is set to 8, after which the reaction is allowed to proceed for 2 hours. The reaction mixture is adjusted to a pH value of approx. 2 with IN hydrochloric acid and filtered, then. The filtrate is adjusted to a pH value of 8-9 with an aqueous sodium bicarbonate solution and then concentrated to give a residue which is subjected to column chromatography using 20 ml of a non-ionic

adsorption resin, "Amberlite XAD-2" (trademark, sold by Rohm and Haas Co., Ltd.) prewashed with methanol

and water. The fractions recovered by elution with water are collected, and the eluate is evaporated, thereby obtaining 20 mg of the crystalline disodium salt of the carboxy group in 3-[2-(2-amino-2-carboxyethyl-thio)-2-phenylacetamido]lactacylanic acid with a melting point of 211-216 °C (decomposition).

Example 341

150 mg of 3-(2-bromo-2-phenylacetamido)lactacylanic acid and

35 mg of 2-aminoethanethiol is treated in essentially the same way as described in example 340, whereby 54 mg of the crystalline sodium salt of 3-[2-(2-aminoethylthio)-2-phenylacetamido]-lactacylanic acid is obtained with a melting point of 171-173°C ( cleavage).

Example 342

A mixture of 107 mg of 3-(2-bromoacetamido)lactacillanic acid,

Add 3 ml of water and 0.6 ml of IN aqueous potassium hydroxide solution

dropwise under ice-cooling with stirring to a solution containing 38 mg of cysteine hydrochloride, 3 ml of water and 0.9 ml of IN aqueous potassium hydroxide solution, and then the solution is allowed to react for 1 hour at the same temperature. The reaction mixture is adjusted to a pH value of approx. 4 with 0.9 ml 1N hydrochloric acid and concentrated under reduced pressure, whereby a residue is obtained which dissolves in methanol. The solution is subjected to column chromatography using a nonionic adsorption resin, "Amberlite XAD-2" (trademark, sold by Rohm and Haas Co. Ltd.).

The fractions that are eluted with water are collected and evaporated, thereby obtaining 95 mg of crystalline 3-[2-(2-araino-2-carboxyethylthio)acetamido]-lactacylanic acid with a melting point of 105-110°C (decomposition).

The following compounds are prepared in essentially the same manner as described above.

Example 348

60 mg of sodium uridine-1-oxide-2-thiolate is added under ice-cooling to a mixture of 200 mg of 3-[2-(2-bromoacetamido)-2-phenylacetamido]lactacylanic acid and 4 ml of 0.1N aqueous sodium -hydroxide solution, and the mixture is stirred for 30 minutes. Ethyl acetate is added to the reaction mixture, and the solution is adjusted to a pH value of 1-2 with 10% hydrochloric acid, whereby a precipitate is obtained, which is collected by decantation. The precipitate is dried and washed with acetone, whereby 82 mg of 3-(2-[2-(pyridyl-1-oxide-2-thio)-acetamido]'-2-phenylacetamido)lactacylanic acid is obtained. The acetone wash is further concentrated, whereby a residue is obtained which is washed with diisopropyl ether, whereby 33 mg of the aforementioned compound is obtained. The total yield is 115 mg. The product has a melting point of 160-164°c (decomposition).

Example 349

285 mg of 3-(2-bromoacetamido)lactacylanic acid and 120 mg of sodium pyridine-1-oxide-2-thiolate are treated in essentially the same way as described in example 348, whereby 250 mg of 3-2-(pyridyl-1-oxide- 2-thio)acetamido lactacyllanic acid with melting point 22i-225°C (decomposition).

Example 350

76 mg of 8-mercapto-9H-purine is added under ice-cooling to

a mixture of 285 mg of 3-[2-phenyl-2-(2-phenylsulfoacetamido)-acetamido]lactacylanic acid and 10 ml of 0.1N aqueous sodium hydroxide solution. After the reaction temperature has risen to room temperature, the reaction mixture is stirred for 3 hours. 0.5 ml 1N hydrochloric acid is added to the reaction mixture, whereby a precipitate is obtained which is collected by filtration. The precipitate is washed with water and dried, thereby obtaining 120 mg of 3-(2-phenyl-2-[2-(9H-purin-8-yl-thio)acetamido]acetamido)lactacylanic acid with melting point 192-197°C (decomposition).

Example 351

9.6 mg of 50% oily sodium hydride and 19 mg of phenol are added to 2 ml of anhydrous N,N-dimeth<y>lforamide, and the mixture is stirred for 30 minutes and then cooled with ice. 50 mg of 3-[2-phenyl-2-(2-bromoacetamido)acetamido]-lactacillanoic acid are added at once to the solution, and the reaction mixture is stirred for 1 hour at the same temperature and in a further 1 titanium at room temperature. To . 10 ml of ether is added to the reaction mixture, whereby a precipitate is obtained

.■' y' i which is collected by filtration. The precipitate is dissolved in a small amount of water, and the solution is adjusted to a pH value of 1 with 103 hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate, and then the solvent is distilled off from the solution. The residue is pulverized with ether, collected by filtration and washed with a sufficient amount of ether, whereby 10 mg of 3-[2-phenyl-2-(2-phenoxyacetamido)acetamido)lactacylanic acid is obtained. IR absorption spectrum v cm"<1>(nujol)s 1740, 1720 and 1650. The following compounds are prepared in essentially same way as described above.

Example 362

150 mg of 3-(2-[2-(2-[4-(2-chloroacetamido)benzoyl]-4-chlorophenoxy)acetamido]-2-phenylacetamido)lactacylanic acid and 25 mg of pyridine-2-thiol are treated in essentially the same method as described in example 324, whereby 120 mg of 3-[2-(2-[2- (4-[2-(pyridin-2-ylthio)acetamido]benzoyl)-4-chloro.phenoxy]acetamido)-2 is obtained -phenylacetamido]lactacillanic acid with melting point 109-114°C (decomposition).

The following compounds are prepared in essentially the same way as described above.

Example 365

25 mg of 10% palladium/charcoal is added to 10 ml of a methanol solution of 220 mg of 3-(6-benzyloxycarbonylaminohexanamido)-lactacillanoic acid, and the theoretical volume of hydrogen gas is added to the mixture over the course of 2 hours at normal temperature at normal pressure. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is pulverized with acetone, washed with acetone and filtered, whereby 100 mg of 3-(6-aminohexanamido)lactacylanic acid with melting point 118~122°C (decomposition) is obtained.

The following compounds are prepared in essentially the same way as described above.

Example 383

0.250 g of 3-[2-(2~thienyl)"N-(2,2,2~trichloroethoxycarbonyl)-glycihamido]lactacillance are dissolved in 13 ml of 90% aqueous acetic acid solution, and the solution is cooled to 10° C. To the solution is added little by little over 50 minutes 1.20 g of zinc powder, and the mixture is allowed to react for 1 hour at the same temperature. To the reaction mixture is added over 30 minutes 0.50 g of zinc powder, and then mixtures, react for a further 2 hours.The zinc powder is removed by filtration to the filtrate

hydrogen sulphide gas is introduced, and then the precipitate is removed by filtration. The filtrate is washed with ethyl acetate, and the resulting aqueous phase is concentrated. The residue is crystallized from a mixture of methanol and ether, whereby 35 mg of 3-2-(2-thienyl)-glycinamido lactacyllanic acid is obtained. The ethyl acetate phase is further extracted with water, and the aqueous phase is concentrated, thereby obtaining 15 mg of the same compound. The total yield is 50 mg. The product has a melting point of 184-189 oC (decomposition).

The following compounds are prepared in essentially the same way as described above.

Example 386

0.50 g 1-(α-carboxy-3,5-dibromo-4-hydroxybenzyl)-3-[2-(4-[3-carboxy-3-(2,2,2-trifluoroacetamido)propoxy]phenyl) -2-hydroxyiminoacetamido]-2-azetidinone is suspended in 3 ml of water,

3 ml IN aqueous sodium hydroxide solution is added to the suspension, and then the solution is stirred for 30 minutes. The reaction mixture is adjusted under ice-cooling to a pH value of 3 with 10% hydrochloric acid. The precipitated crystals are collected by filtration, the crystals

is dissolved in a small amount of aqueous sodium bicarbonate solution, and then the solution is treated with activated charcoal. After the treatment, the solution is adjusted under ice-cooling to a pH value of 4 with 10% hydrochloric acid, and the precipitate is collected by filtration, whereby 40 mg of l-[o-carboxy-3,5-dibromo-4-hydroxybenzyl]-3-(2 -[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyirinoacetamido)-2-azetidinone. Additionally, 60 mg of the same compound is recovered from the mother liquor. The cfctal yield is 100 mg. The product has a melting point of 190-194°C (decomposition).

Example 387

To 15 ml of a methanol solution of 230 mg of 3-[2-(4-benzyloxycarbonyloxyphenyl)acetamido]lactacillanic acid is added 25 mg of 10% palladium/charcoal, and to the mixture is added during

2 hours at normal temperature and normal pressure the theoretical

volume of hydrogen gas. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure, and then the residue is crystallized from a mixture of acetone and ethyl acetate. The crystals are collected by filtration and washed with ethyl acetate, thereby obtaining 90 mg of 3-[2-(4-hydroxyphenyl)acetamido]lactacylanic acid with melting point 171-176°C (decomposition).

Example 388

A solution consisting of 213 mg of 3-(2-ethoxycarbonyl-2-phenylacetamido)lactacylanic acid, 5 ml of ethanol and 1.4 ml of IN aqueous sodium hydroxide solution is allowed to react at room temperature for 1.25 hours. The reaction mixture is cooled after the reaction and adjusted to a pH value of 1 by adding 1.4 ml of 1N hydrochloric acid. The mixture is then adjusted to a pH value of 6-7

by adding 1N aqueous sodium hydroxide solution and concentrating. The residue is dissolved in water, and the solution is adjusted to a pH value of 1-2 with IN hydrochloric acid and then washed with ethyl acetate. The resulting aqueous phase is adjusted to a pH value

of 6 with 1N aqueous sodium hydroxide solution and concentrate. For isolation and purification, the residue is subjected to column chromatography using 30 ml of a non-ionic

adsorption resin, "Amberlite XAD-2" (trademark, sold by Rohm and Haas Co., Ltd.), which is previously purified with methanol and water. The fractions eluted with water are collected, and the water is distilled off from the eluate, thereby obtaining 159 mg of the disodium salt of the carboxy group of 3-(2-carboxy-2-phenylacetamido)lactacylanic acid with a melting point of 209-214°C (decomposition).

The following compounds are prepared in essentially the same way as described above.

Example 391

170 mg of 3-(2-[2-(2-ethoxycarbonylphenyloxy)acetamido]-2-phenylacetamido)lactacylanic acid is dissolved in 0.9 ml IN aqueous sodium hydroxide solution, and the solution is stirred at room temperature for 3.5 hours* To the reaction mixture is added approximately* 10 ml of water. The mixture is adjusted to a pH value of 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed twice with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off from the ethyl acetate solution, and the residue is crystallized from diisopropyl ether, thereby obtaining 120 mg of 3-(2-[2-(2-carboxyphenoxy)acetamido]-2-phenylacetamido)lactacylanic acid with melting point 130-135°C (decomposition).

The following compounds are prepared in essentially the same way as described above.

Example 410

0.19 g 1-(α-methoxycarbonyl-4-methoxybenzyl)-3-[2-(4-[3-methoxycarbonyl-3-(2,2,2-trifluoroacetamido)propoxy]phenyl)-2-methoxyiminoacetamido]- 2-azetidinone is dissolved in 1 2 ml of acetone. At room temperature, 0.9 ml of IN aqueous sodium hydroxide solution is added to the solution, and the mixture is stirred for 5 minutes. The acetone is distilled off from the reaction mixture, and the resulting solution is adjusted to a pH value of 3 with 10% hydrochloric acid. The separated oily product is isolated by decantation, washed with acetone and water and then pulverized with acetonitrile, whereby 0.02 g of 1-(o-carboxy-4-methoxy-benzyl)-3-[2-(4-[3- amino-3-carboxypropoxy]phenyl)-2-methoxy-iminoacetamido]-2-azetidinone with melting point 170-176°C (decomposition).

Example 411

320 mg of 3-[2-(4-[4-chloro-N-(2,2,2-trichloroethoxycarbonyl)anilinomethyl]phenoxy)-2-methylpropionamido]lactacylanic acid is treated in essentially the same way as described in example 365, whereby 110 mg of 3-(2-[4-(4-chloroanilinomethyl)-phenoxy]-2-methylpropionamido)lactacylanic acid with melting point 130-136°C (decomposition) is obtained.

Example 412

15 mg of sodium methylate and 20 ml of absolute methanol are added to 1.1 g of 1-methoxy-3-(2-phenoxyacetamido)-2-azetidinone, and the mixture is heated under reflux for 30 minutes. The solvent is distilled off from the reaction mixture under reduced pressure, the residue is dissolved in acetone, and then the undissolved product is filtered off. The filtrate is concentrated and allowed to cool, and then the precipitated crystals are collected by filtration. The crystals are washed with acetone and dried, thereby obtaining 456 mg of 3-(2-phenoxyacetamido)-2-azetidinone. A further 109 mg of the same compound is recovered from the mother liquor.

The total yield is 565 mg. The product has a melting point of 153-155°C.

Example 413

Dissolve 240 mg of 1-methoxyalyl-3-benzyloxycarbonylamino-2-acetidinone in 10 ml of methanol, add 6 mg of sodium methylate to the solution, and then heat the mixture under

reflux cooling\for 45 minutes. The methanol is distilled off from the reaction mixture, and the residue is washed with ether, whereby 126 mg of crude 3-benzyloxycarbonylamino-2-azetidinone are obtained. The product is recrystallized from acetone, whereby 50 mg of the purified compound is obtained. From the mother liquor, 54 mg of the same compound is recovered in purified form. The total yield is 104 mg. The product has a melting point of 164-165°C.

Example 414

13.8 g of 1-(1-acetoxy-2-methylpropyl)-3-(2-phenylacetamido)-2-azetidinone are dissolved in a solution of 100 ml of methanol and 100 ml of water. 6 g of potassium carbonate and 1.65 g of sodium borohydride are added to the solution under ice cooling, and the mixture is allowed to react at 20°C for 1 hour. The precipitated crystals are collected by filtration, washed with water and dried, thereby obtaining 5.15 g of 3-(2-phenylacetamido)-2-azetidinone. A further 1.35 g of the same compound is recovered from the filtrate. The total yield is 6.5 g. The product has a melting point of 191-193°C.

Example 415

1,13 gl-[1-(2,2,2-trichloroethoxycarbonylamino)-2-methylpropyl]-3-(2-phenylacetamido)-2-azetidinone is dissolved in 20 ml of 90% aqueous acetic acid solution, and the solution is cooled to 5° C. Add drop by drop to the solution over 5 minutes

1.62 g of zinc powder, and the mixture is stirred for 30 minutes. A further 1.62 g of zinc powder is added to the mixture, and the mixture is stirred for 2 days. The reaction mixture is neutralized with an aqueous sodium bicarbonate solution and extracted with methylene chloride. The extract is washed with water and dried over anhydrous magnesium sulfate" and then the solvent is distilled off from the solution. The residue (0.65 g) is subjected to preparative thin-layer chromatography using silica gel (the developing solvent is a mixed solution of ethyl acetate, ethyl methyl ketone, water and formic acid (volume ratio 5:3.1.1)), isolated and purified, thereby obtaining 0, 3 g of 3-(2-phenylacetamido)-2-azetidinone with melting point 190-192°C.

Example 416

£.18 g of 1-(c-methoxycarbonyl-4-hydroxybenzyl)-3-[2-(2-thienyl)acetamido]-2-azetidinone is dissolved in a solution consisting of 3 ml of sodium borate buffer with a pH value of 7.8 ,

5 ml of methanol and 3 ml of acetone, and the solution is cooled to -5°C.

0.5 ml of a methanol solution containing 0.10 g of tert-butyl hypochlorite is added 3 times every 15 minutes to the solution, and the mixture is stirred for 30 minutes. The solvent is distilled off from the reaction mixture, and the resulting solution is adjusted to a pH value of 2 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is separated, washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off from the ethyl acetate solution, and the residue (0.22 g) is subjected to column chromatography using 10 g of silica gel. The fractions eluted with chloroform are collected, and

the chloroform is distilled off from the eluate, whereby 50 mg of 1-(o-methoxycarbonyl-3,5-dichloro-4-hydroxybenzyl)-3-[2-(2-thienyl)-acetamido]-2-azetidinone are obtained. IR absorption spectrum v cm 1 (wee box-shaped film): 3270, 1760, 1755 and 1665.

Example 417

To a solution of 184 mg of 1-(α-methoxycarbonyl-4-hydroxybenzyl)-3-(2-phenylacetamido)-2-azetidinone in 2 ml of dioxane is added 1.5 ml of chloroform, and to the mixture is added dropwise over the course of 5 minutes under ice-cooling 0.5 ml of a chloroform solution containing 184 mg of bromine. After adding 80 ml of ethyl acetate to the reaction mixture, the ethyl acetate phase is separated,

which is washed with water and dried over anhydrous magnesium sulfate. The solution is concentrated, and the residue is dissolved in a small amount of acetone. The solution is subjected to preparative thin-layer chromatography using silica gel (developing solvent: a mixture of chloroform and methanol (5:0.3))

for isolation and purification. The resulting product is recrystallized from a mixture of ethyl acetate and acetone, whereby 18 mg of 1-(o-methoxycarbonyl-3-bromo-4-hydroxybenzyl)-3-(2-phenylacetamido)-2-azetidinone with melting point 151-153°C are obtained (fission).

Example 418

1 ml of a methanol solution of 352 mg of bromine is rapidly added dropwise with stirring under ice cooling to 5 ml of a solution of 354 mg of 3-(2-phenylacetamidoO)lactacylanic acid and 246 mg of sodium acetate in absolute methanol. The methanol is distilled off from the reaction mixture under reduced pressure. After adding a mixture of ethyl acetate and water to the residue, the ethyl acetate phase is separated, which is washed with water and dried over anhydrous

magnesium sulfate. The solvent is distilled off from the solution, the residue (590 mg of yellow-orange oily product) is dissolved in a small amount of ethyl acetate, and the solution is subjected to column chromatography using 7 g of silica gel. The fraction eluted with a mixture of ethyl acetate and acetone is collected, and the solvent is distilled off from the eluate. The resulting residue is subjected to preparative thin layer chromatography using silica gel for isolation and purification. The fractions eluted with a mixture of ethyl acetate and acetic acid (5:1) are collected, the solvent is distilled off from the eluate, and then the residue is pulverized with chloroform. The powder is recrystallized from a mixture of chloroform and acetone, whereby 157 mg of 1-(o-carboxy-3,5-dibromo-4-hydroxybenzyl)-3-(2-phenylacetamido)-2-azetidinone are obtained. A further 26 mg of the same compound is recovered from the mother liquor. The total dividend

is 183 mg. The product has a melting point of 161-162°C (decomposition).

Example 419

1.77 g of 3-[2-(4-[3-carboxy-3-(2,2,2-trifluoroacotamido)-propoxy]phenyl)-2-hydroxyiminoacetamido]lactacillanic acid are dissolved in 20 ml of methanol. After adding 1.03 g of sodium acetate to the solution, the mixture is cooled to -5°C, and 5 ml of a methanol solution of 1.06 g of bromine is added dropwise over 15 minutes. The reaction mixture is allowed to react for 15 minutes, the methanol is distilled off from the reaction mixture, and then the residue is added to a mixture of 20 ml of ethyl acetate and 20 ml of water. After setting the mixture's pH value to 2 with 2% hydrochloric acid, the ethyl acetate phase is separated, which is washed with an aqueous sodium thiosulfate solution, with water and with a saturated aqueous sodium chloride solution in the specified order, and which is then dried over anhydrous magnesium sulfate. The ethyl acetate solution is concentrated, and the resulting residue (2.56 g) is triturated twice with a mixture of benzene and acetone to give 1.16 g of 1-(α-carboxy-3,5-dibromo-4-hydroxybenzyl)-3 -[2-(4-[3-carboxy-3-(2,2,2-trifluoroacetamido)propoxy]phenyl)-2-hydroxylaminoacetamido]-2-azetidinone. IR absorption spectrum v cm"1 (liquid film): 1720 (broad) and 1650.

Example 420

100 mg of 3-glycinamidolactacylanic acid, which is suspended in 5 ml of water, is dissolved by the addition of 70 mg of sodium bicarbonate. The solution is cooled to 0-5°c, and a solution of 100 mg of 2-(4-chloro-2-nitrophenoxy)-acetyl chloride in 5 ml of acetone is added dropwise. The mixture is allowed to react at the same temperature for 2 hours. The acetone is distilled off from the reaction mixture under reduced pressure, and the resulting solution is adjusted to a pH value of 1-2 by adding dilute hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water and dried, and the solvent is distilled off. The oily residue is washed with ether and dissolved in a small amount of methanol, and then ether is added to the solution. The precipitated powder is collected by filtration and dried, thereby obtaining 82 mg of 3-(2-[2-(4-chloro-2--nitroenoxy)-acetamido]acetamido)lactacillanic acid with a melting point of 149-153 C

The following compounds are prepared in essentially the same way as described above.

Example 469

3-(2-phenylglycinaldo)lactacylanic acid as starting material and 2-[4-chloro-2~(α-aaethoxyiminobenzyl)phenoxy]acetyl chloride as acylating agent are treated in essentially the same way as described in example 420, whereby 3-[2- (2-[4-chloro-2-(o-hydroxyiminobenzyl)phenoxy]acetamido)-2-phenylacetamido]-lactacylanic acid, where the protecting group (ie acetyl) on the hydroxyimino group in the starting compound has been removed. The product has a melting point of 171-176°C (decomposition).

Example 470

A suspension of 200 mg of 3-(2-phenylglycinaldo)lactacylanic acid in a solution consisting of 10 ml of methylene chloride, 1 ml of N,N-dimethylformamide and 1 ml of N,0-bis(trimethylsilyl)acetamide is stirred at room temperature for 1 hour* To the reaction mixture 140 mg of 2-anilino-2-phenylacetyl chloride hydrochloride are placed under ice-cooling, and the mixture is stirred at the same temperature until dissolved for 1 hour. The reaction mixture is stirred for a further 1 hour at room temperature and then concentrated under reduced pressure. After adding ethyl acetate and water to the residue, the ethyl acetate phase is separated, which is extracted with an aqueous sodium bicarbonate solution. After adjusting the then aqueous phase's pH value to 1-2 with 1N hydrochloric acid, the phase is extracted with ethyl acetate, and the resulting extract is washed with water and drained over anhydrous magnesium sulfate. After distilling off the solvent, ether is added to the resulting residue, and then the mixture is stirred for 1 hour. The separated powder is collected by filtration, whereby 89 mg of 3-[2-phenyl-2-(2-anilino-2-phenylacetamido)acetamido]lactacillanic acid with melting point 158-161°C (decomposition) is obtained.

Example 471

A mixture of 50 mg of N,N-dimethylformamide and 200 mg of thionyl chloride is stirred at 40-50°C for 30 minutes. After distilling off excess thionyl chloride, the residue is dissolved in 5 ml of methylene chloride, and the solution is cooled to a temperature between -10 and -5°C. 114 mg of 2-[5-(2-thienyl)tetrazol-1-yl]-acetic acid is added at once to the solution, which is dissolved by the addition of 2 drops of N,N-dimethylformamide, and the mixture is then stirred for 15 minutes. The solution is cooled at a temperature between -60 and -50°C, 2 ml of a methylene chloride solution of 65 mg of triethylamine is added, and then the mixture is stirred at the same temperature for 30 minutes. To the solution, which has been cooled to a temperature between -60 and -50°C, is added at once a solution prepared in advance by stirring a suspension consisting of 200 mg of 3-(2-phenylglycinaldo)-lactacillanic acid, 430 mg N,0-bis(trimethylsilyl)acetamide, 10 ml methylene chloride and 1 ml N,N-dimethylformamide at the same temperature for 1 hour. The reaction mixture is stirred for 30 minutes at the same temperature, for 1 hour at a temperature between -20 and -iO°C and 1 further 1 hour at a temperature between -LO and 0°C. The solvent is distilled off from the reaction mixture, whereby a residue is obtained to which ethyl acetate is added and a

aqueous sodium bicarbonate solution. The aqueous phase is separated, adjusted to a pH value of 4 with 10% hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate phase is separated, washed with water and dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The resulting residue (70 mg) is washed with ether, whereby 60 mg of crude 3-[2-phenyl-2-(2-[5-(2-thienyl)tetrazol-1-yl]acetamido)acetamido]-lactacylanic acid are obtained. The product is dissolved in 1 ethyl acetate, and ether is added to the solution, whereby crystals separate out. The crystals are collected by filtration, which gives 30 mg of pure product with a melting point of 170-174°C (decomposition).

Example 472

2-phenylglycolic acid is treated instead of 2-[5-(2-thienyl)-tetrazol-1-yl]acetic acid in essentially the same way as

described in example 471, whereby 3-[2-(2-hydroxy-2-phenylacetamido)-2-phenylacetamido]lactacylanic acid with melting point 90-93°C (decomposition) is obtained.

Example 473

5 ml of acetone is added to 5 ml of an aqueous solution of 0.358 g of 3-[2-(2-thienyl)glycnamido]lactacylanic acid and 0.185 g of sodium bicarbonate, and the solution is cooled to 0-5°C. 5 ml of a dry acetone solution of 0.230 g of 2-(4-chloro-2-nitrophenoxy)acetyl chloride are added dropwise to the solution, and the mixture is allowed to react at the same temperature for 2 hours. The resulting aqueous phase is washed, after the acetone has been distilled off from the reaction mixture under reduced pressure, with ethyl acetate, adjusted to a pH value of 1-2 with dilute hydrochloric acid and

then extracted with ethyl acetate. The extract is washed with water and dried, and the solvent is distilled off, whereby 0.34 g of residue is obtained. The residue is dissolved in 2 ml of methanol, and

to the solution, 1 ml of an acetone solution of 0.88 g of sodium 2-ethylhexanate and then 15 ml of ether are added. The precipitated powder is collected and washed three times with ether, thereby obtaining 0.140 g of the sodium salt of 3-(2-[2-(4-chloro-2-nitrophenoxy)acetamido]-2-(2-thienyl)-acetamido)lactacylanic acid with a melting point 187-190 C (decomposition).

The following compounds are prepared in essentially the same way as described above.

Example 481

140 mg of sodium nitrite is added little by little under cooling at 0-5°C to a solution of 380 mg of guanidinocarbohydrazide dihydrochloride in 3 ml of water, and the mixture is stirred for 10 minutes, whereby a solution of guanidinocarbonylazide is obtained.

220 mg of 3-(2-phenylglycinaldo)lactacylanic acid and 150 mg of sodium bicarbonate are dissolved in a mixture of 8 ml of water and 4 ml of acetone, and the solution is stirred at o-5°C for 15 minutes.

After removing the undissolved product by filtration from the solution, the previously prepared solution is added dropwise over the course of 5 minutes to the filtrate, and then the mixture is stirred at 0-5°C for 2 hours, while the pH value of the reaction mixture is kept at 7.5-8 .0 by adding 5% aqueous sodium bicarbonate solution. The crystals precipitated in the reaction mixture are collected by filtration, whereby 20 mg of 3-(2-guanidinocarbonylamino-2-phenylacetamido)lactacylanic acid is obtained.

The filtrate is concentrated to a volume of approx. 5 ml, whereby crystals are precipitated which are collected by filtration, whereby 60 mg of the same compound are obtained. The total yield is 80 mg. The product has a melting point of 198-202°C (decomposition).

Example 482

375 mg of 3-[2-(2-thienyl)glycnamido]lactacylanic acid, which is suspended in 5 ml of water, is dissolved by the addition of 104 mg of potassium carbonate (the solution has a pH value of approx. 9). 10 ml of a solution of acetone and water (lii) is added to the solution, and then 5 ml of a dry acetone solution of 163 mg of benzoyl isothiocyanate is added dropwise while stirring at room temperature.

The mixture is stirred for 3 hours (during this time the reaction mixture's pH value is kept at 8.5 by adding a solution of

104 mg of potassium carbonate in 7 ml of water). The acetone is distilled off from the reaction mixture. The aqueous residue is washed with ethyl acetate,

adjusted to a pH value of 1-2 with dilute hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and dried, and the solvent is distilled off. The oily residue (469 mg) is chromatographed on 7 g of silica gel and eluted with a mixture of ethyl acetate and methanol, whereby 97 mg of 3-[2-(3-benzoylthioureido)-2-(2-thienyl)acetamido]lactacylanic acid with a melting point of 124 -129°C (decomposition).

Example 483

50 mg of 85% 3-chloroperbenzoic acid is added under ice cooling to a solution of 100 mg of 3-(2-methylthio-2-phenylacetamido)-lactacylanic acid which is dissolved in 5 ml of methanol, and the mixture is allowed to react with stirring at the same temperature for 1 hour . The reaction mixture is concentrated under reduced pressure, and

the residue is washed with chloroform, whereby 86 mg of 3-(2-methyl-sulfinyl-2-phenylacetamido)lactacylanic acid are obtained. IR absorption spectrum v cm"*1 (nujol) s 1740, 1720, 1665 and 1020.

Example 484

61 mg of 85% chloroperbenzoic acid is added under ice cooling to a solution of 171 mg of 3-(2-[N-(2-naphthyl)carbamoylmethylthio]-2-phenylacetamido]lactacylanic acid, which is dissolved in 7 ml of acetone, and the mixture is allowed to react while stirring at the same temperature for 1 hour.The reaction mixture is concentrated, and the residue

is crystallized from chloroform, whereby 134 mg of 3-(2-[N-(2-naphthyl)carbamoylmethylsulfinyl]-2-phenylacetamido)lactacylanic acid with melting point 151-155°C (decomposition) is obtained.

Example 485

1.00 g of 3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]-glycinamido)lactacylanic acid is dissolved in 20 ml of an aqueous solution of 0.66 g of sodium bicarbonate, and 10 ml of acetone is added . After ice-cooling the solution is added

dropwise with stirring 5 ml of an acetone solution of 0.75 g of 2,4-dinitro~l-fluorobenzene, and the mixture is stirred at the same temperature for 30 minutes o for a further 5 hours at room temperature. The reaction mixture is washed with ethyl acetate, adjusted to a pH value of 2 with 10% hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate phase is separated, and the solvent is distilled off under reduced pressure. The residue is pulverized with ether, whereby 1.50 g of 3-f2-(4-[3-carboxy-3-(2,4-dinitroanilino)propoxy]phenyl)-2-(2,4-dinitroanilino)-acetamido]lactacylanic acid is obtained . IR absorption spectrum v cm"<1>(nujol)s 1735, 1700 (shoulder), 1520 and 1340.

Example 486

0.49 g of 3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]-glycinamido]lactacylanic acid and 0.49 g of sodium bicarbonate are dissolved in 10 ml of water, and 5 ml of methanol is added to the solution.

7 ml of one is added dropwise to the solution; methanol

solution of 0.80 g of methyl-4-fluoro-3-nitrobenzoate, and the mixture is allowed to react at room temperature for 17 hours and for a further

4 hours at 50°C. After cooling the reaction mixture for some time, the precipitate is removed by filtration. The methanol is distilled off

from the filtrate under reduced pressure, and the aqueous residue

washed with ether, adjusted to a pH value of 3 with IN hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is separated and

dry over. anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is pulverized with benzene, whereby 0.86 g of 3-[2-(4-[3-carboxy-3-(4-methoxycarbonyl-2-nitroanillno)propoxy]phenyl)-2-(4-methoxycarbonyl-2- nitréanilino)acetamido]lactacillanic acid with melting point 150-155°C (decomposition).

Example 487

8.9 g of 3-(2-[4~(3-benzamido-3-carboxypropoxy)phenylJ-glycinamido)lactacyllanic acid and 5.4 g of sodium bicarbonate are dissolved in 100 ml of water and 100 ml of methanol and 4.5 g of 4- fluoro-3-nitrbbenzoic acid methyl ester. The mixture is allowed to react with stirring at 40-50°C for 4 hours. The methanol is distilled off from the reaction mixture under reduced pressure, and the residue is washed with ethyl acetate, adjusted to a pK value of 2 with 100% hydrochloric acid and extracted with ethyl acetate. The extract is washed with dilute hydrochloric acid and water and dried. The solvent is distilled off from the ethyl acetate phase under reduced pressure, and the residue is pulverized. with ether and collected by filtration, whereby 9.23 g of 3-(2-[4-(3-benzamido-3-carboxypropoxy)phenyl 1-2-(4-methoxycarbonyl-2-nitroanilino)acetamido)lactacylanic acid are obtained. IR absorption spectrum, v cm"*1 (nujol): 1730, 1620, 1528 and 1352.

Example 488

0.68 g of 3-(2-[4-(3-carboxy-3-phthalimidopropoxy)phenyl]-glycinamido)lactacylanic acid is dissolved in 10 ml of an aqueous solution of 0.40 g of sodium bicarbonate. To the resolution

10 ml of methanol and then 0.30 g of 4-fluoro^-3-nitrobenzoic acid methyl ester are added, and the mixture is allowed to react at 50°C with stirring

for 3 hours. The methanol is distilled off from the reaction mixture, and

the aqueous residue is washed with ethyl acetate, adjusted to pH value

of 2 with 10% hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate phase is separated and dried over anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure from the ethyl acetate phase, and the residue is pulverized with ether, thereby obtaining 0.53 g of 3-(2-[4~(3-carboxy-3-phthalimidoproposky)phenylJ-2-(4-methoxycarbonyl-2-nitroanilino) acetamido)lactacillanic acid with a melting point of 155-160°C (decomposition).

Example 489

0.50 g of sodium salt of 3-(2-[4-(3-amino-3-carboxy-propoxy) phenyl-2-hydroxyiminoacetamido) lactacillanic acid is dissolved in 10 ml of water. 2 ml of acetone is added to the solution, after stirring the solution for some time, 0.30 g of sodium borohydride is added little by little, and then the mixture is stirred for 3 hours. 2 ml of acetone is added to the reaction mixture, and the solution is adjusted to a pH value of 3 with 10% hydrochloric acid. The precipitated crystals are collected by filtration, whereby 0.05 g of 3-[2-(4-13-carboxy-3-(N-isopropylamino)propoxy]phenyl)-2-hydroxy-iminoacetamido]lactacylanic acid is obtained. The mother liquor is concentrated to approximately half the original volume, and the precipitated crystals are collected by filtration, whereby 0.17 g of the same product is obtained. The total yield is 0.22 g. The product has a melting point of 193-194°C (decomposition).

Example 490

3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxy-iminoacetamido)lactacylanic acid as starting compound and 2-formylacetic acid methyl ester as carbonyl compound are treated on

essentially the same way as described in example 489, whereby 3-(2-[4-(3-carboxy-3-[N-(2-methoxycarbonylethyl)amino]-propoxy)phenyl]-2-hydroxyminoacetamido)lactacylanic acid is obtained with melting point 175-179°C (decomposition).

Example 491

0.50 g of the sodium salt of 3-(2-[4-(3-amino-3-carboxy-propoxy) phenyl]-2-hydroxyiminoacetamido) lactacillanic acid is dissolved in 10 ml of water, and it is added under ice cooling to 1 ml of 30% aqueous formaldehyde solution. The mixture is stirred for some time, and 0.15 g of sodium borohydride is added little by little. After stirring the mixture for 30 minutes, the pH value is set under ice-cooling to 3 with 10% hydrochloric acid. The precipitated crystals are collected by filtration, washed with water and acetone and dried at 40QC under reduced pressure, thereby obtaining 0.28 g of 3-[2-(4-[3-carboxy-3-(N,N-dimethylamino)propoxy] phenyl)-2-hydroxyiminoacetamido]-

lactacyllanic acid with melting point 193-194°C (decomposition).

Example 492

Dissolve 235 mg of 3-(4-nitrobenzamido)lactacillanic acid in

20 ml methanol, and 40 mg palladium/- is added as a catalyst

coal. The mixture is shaken in a stream of hydrogen at room temperature under normal pressure, the calculated volume of hydrogen (44 ml) being absorbed during approx. 1 hour. The catalyst is removed by filtration from the reaction mixture, and the filtrate is evaporated to dryness under reduced pressure. The residue is treated with ether and collected by filtration, whereby 200 mg of 3-(4-amino-benzamido)lactacylanic acid with a melting point of 190-194°C (decomposition) is obtained.

Example 493

210 mg of 3-(3,5-dinitrobenzamido)lactacillanic acid are dissolved in 20 ml of methanol, and 40 mg of palladium/charcoal is added as a catalyst. The mixture is shaken at room temperature at normal pressure 1 a stream of hydrogen, and the calculated volume of hydrogen (70 ml) is absorbed within 2 hours. The catalyst is removed by filtration from the reaction mixture, and the filtrate is evaporated to dryness under reduced pressure. The residue is washed with ether and dissolved in acetone. After filtering the acetone solution, ethyl acetate is added to the filtrate, and then the solution is concentrated. The concentrate is filtered, and the filtrate is evaporated to dryness under reduced pressure. The residue is treated with ether and collected by filtration, whereby 60 mg of 3-(3,5-diaminobenzamido)-lactacylanic acid with a melting point of 116-121°C (decomposition) is obtained.

Example 494

200 mg of 3-[2-(4-formylphenoxy)acetamido]-lactacillanic acid is added to a solution of 70 mg of hydroxylamine hydrochloride,

which is dissolved in 1 ml of water and 1.5 ml of 1N aqueous sodium hydroxide solution, and the mixture is stirred at room temperature for 30 minutes. Ethyl acetate is added to the reaction mixture, and it is added

1.5 ml IN hydrochloric acid. The mixture is shaken, and the ethyl acetate phase is separated. The phase is washed with water and dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The residue (190 mg) is allowed to crystallize. A mixture of ethyl acetate and chloroform (1:1) is added to the residue, whereby crystals are precipitated, and the solution is stirred at room temperature for 1 hour. The crystals are collected by filtration, whereby 130 mg of 3-[2-(4-hydroxyiminomethylphenoxy)acetamido]lactacylanic acid are obtained with

melting point 150-155°C (decomposition).

Example 495

200 mg of 3-[2-(4-formylphenoxy)acetamido]lactacylanic acid are added to a solution consisting of 66 mg of 2-aminooxyacetic acid (0.5 hydrochloride) and 1.5 ml IN aqueous sodium hydroxide solution, and the mixture is stirred at room temperature for 12 hours . The reaction mixture is adjusted to a pH value of 2 with 1N hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate phase is separated, washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent from the extract, ether is added to the residue, and then the mixture is stirred at room temperature for 2 hours. The precipitated crystals are collected by filtration, bg the crystals (150 mg) are washed with ethyl acetate, whereby 110 mg of 3-[2-(4-carboxylic acid ethoxyairinoraethylphenoxy)-acetamido]lactacylanic acid with melting point 144-147°C (decomposition) is obtained.

Example 496

237 mg of 3-[2-(4-formylphenoxy)-2-phenylacetamidoJ-lactacylanic acid is added to a solution consisting of 106 mg of 2-aminooxyacetic acid (0.5 hydrochloride) in 1.8 ml of IN aqueous sodium hydroxide solution, and the mixture is stirred at room temperature in 2 hours. The reaction mixture is adjusted to a pH value of 1-2 with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is separated, washed with water and dried over anhydrous magnesium sulfate. The residue is washed after distilling off the solvent from the extract with diisopropyl ether and collected by filtration, thereby obtaining 190 mg of 3-[2-(4-carboxy-methoxy-irainomethylphenoxy)-2-phenylacetamido]lactacylanic acid with melting point 117-121°c (decomposition).

Example 497

200 mg of 3-[2-(4-formylphenoxy)acetamido]lactacylanic acid is added to a solution of 5 ml of IN aqueous sodium hydroxide solution<p>g 90 mg of N-(carbazolylmethyl)-N,N,N-trimet<y>larammonium -chloride, and the mixture is stirred at room temperature for 2 hours. A further 90 mg of N-(carbazoylmethyl)-N,N,N-rximethylammonium chloride is added to the solution, and the mixture is allowed to stand overnight. 0.5 ml 1N hydrochloric acid and 100 mg acetic acid are added to the reaction mixture, and then the solution is washed with ethyl acetate and ether. The aqueous phase is separated, and the saturated organic solvent present in the phase is completely distilled off under

reduced pressure. The residue is chromatographed on 50 ml of nonionic adsorption resin, "Amberlite XAD-2" (trademark, sold by Rohm and Haas Co., Ltd.). The elution is carried out with water and then with methanol, and the fractions containing the desired compound, 3om can eluted with methanol, collected.

The combined fractions are concentrated. The residue is washed with ethanol

and collected by filtration, thereby obtaining 188 mg of W-(3-[4-(N-[1-(cs-carboxy-4-hydroxybenzyl)-2-oxo-3-acetidinyl]carbamoylmethoxy)7 benzylidene]carbazoylraethyl)-N ,N,N-trimethylammonium chloride with melting point 199-205°C (decomposition).

Example 498

A solution of 35 mg of hydroxylamine hydrochloride in water is added to 5 ml of 0.1N aqueous sodium hydroxide solution of 160 mg of 3-(2-[2-(2-benzoyl-4-chlorophenoxy)acetamido]-2-phenylacetamido)-lactacylanic acid. The solution is adjusted to a pH value of 6.0-6.2 by adding a small amount of hydroxylamine hydrochloride and stirred for 10 minutes. 5 ml of methanol is added to the mixture, and after stirring at room temperature for 3 hours, the reaction solution is allowed to stand overnight in a refrigerator. The precipitated crystals are collected by filtration, thereby obtaining 100 mg of 3-[2-(2-[4-chloro-2-(o-hydroxyimlnobenzyl)phenoxy]acetamido)-2-phenylacetamido]lactacylanic acid with melting point 171-176°C (decomposition ).

Example 499

1.3 g of 3-(2-[4-(3-acetamido-3-carboxypropoxy)phenylj-glycinamido)lactacyllanic acid is dissolved in 26 ml of 50% aqueous pyridine solution, and the solution is adjusted to a pH value of 8.4 with IN aqueous sodium hydroxide solution. 0.40 g of phenylisothiocyanate is added to the solution under ice-cooling, and the mixture is stirred for 4.5 hours. The reaction mixture is washed with ether, and the separated aqueous phase is adjusted to a pH value of 2 with 10% hydrochloric acid, whereby a precipitate is obtained, which is collected by filtration. The precipitate is dissolved in an aqueous sodium bicarbonate solution, and the solution is adjusted to a pH value of 2 with 10% hydrochloric acid. The precipitated crystals are collected by filtration, whereby 0.92 g of 3-(2-t4-(3-acetamido-3-carboxypropoxy)phenyl]-2-(3-phenyl-thioureido)acetamido)lactacylanic acid with melting point 150-156 C is obtained (fission)•

Example 500

2.0 g of 3-(2-[4-(3-acetamido~3-carboxypropoxy)phenyl3-glycinamido)lactacillanoic acid are dissolved in 20 ml of 503 ig aqueous pyridine solution, and the solution is adjusted under ice-cooling to a pH value of 8.6 with 1W aqueous sodium hydroxide solution. At the same temperature, 0.74 g of 1-naphthy1-isothiocyanate is added to the solution, and the mixture is stirred at room temperature for 4 hours. The reaction mixture is washed with ether, and the separated aqueous phase is adjusted under ice-cooling to a pH value of 2 with 10% phosphoric acid. The precipitated solid is collected by filtration, washed with water and then dissolved in a saturated aqueous sodium bicarbonate solution. The solution is adjusted to a pH value of 2 with 10% phosphoric acid, and then the precipitated crystals are collected by filtration, whereby 2.5 g of 3-(2-[4-(3-acetamido-3-carboxypropoxy)phenyl]- 2-[3-(1-Naphthyl)-thioureido3-acetamido)lactacillanoic acid with melting point 142-147°C (decomposition).

Example 501

3-(2-[4-(3-acetamido-3-carboxypropoaby)phenyl3glycinamido)-lactacillanic acid as starting material and acetyl chloride as acylating agent are treated in essentially the same way as described in example 500, whereby 3-(2-[4- (3-acetamido-3~carboxypropoxy)phenyl3-2-acetamidoacetamido)lactacylanic acid with IR absorption spectrum, v cm"<1>(nujol): 1735 and 1650.

Example 502

7.8 g of 3-(2-[4-(3-benzamido-3-carboxypropoxy)phenyl3-glycinamido)lactacylanic acid are dissolved in 160 ml of a 50% aqueous pyridine solution, and the solution is adjusted to a pH value of 8.6 by adding of IN aqueous sodium hydroxide solution. At the same temperature, 2.64 g of phenylisothiocyanate are added to the solution, and the mixture is stirred for 3 hours. The reaction mixture is washed with ether, and the separated aqueous phase is adjusted with cooling to a pH value of 2 with 100% phosphoric acid. The precipitated oily product is collected and dissolved in a saturated aqueous sodium bicarbonate solution. The resolution is set to

a pH value of 2 with 10% phosphoric acid, and the precipitated crystals are collected by filtration, whereby 9.6 g of 3-(2-[4-(3-benzamido-3^-carboxypropoxy)phenyl]-2- ( 3-phenylthioureido) acetamido) - lactacyllanic acid with melting point 133-138°C (decomposition).

The following compounds are prepared in essentially the same manner as described in Example 502.

Example 507

2.0 g of .3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido)lactacillanic acid, which is suspended in 20 ml of water, is dissolved by the addition of 4.5 ml of IN aqueous sodium -hydroxide solution, and then 0.66 g of sodium hydroxymethanesulfonate (1 hydrate) is added to the solution. The mixture is stirred at room temperature for 2.5 hours. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to a volume of

about. 2/3 of the original volume. 40 ml of acetone is added to the residue, and the precipitated powder is collected by filtration, whereby 1.85 g of the disodium salt of 3- 2-(4-[3-carboxy-3-(N-sulfomethyl-amino)propoxy]phenyl)-2 is obtained -hydroxyiminoacetamido lactacyllanic acid. IR absorption spectrum ten cm"<1>(nujol): 1730, 1600 and 1240.

Example 508

0.50 g of 3-[4-(3-amino-3-carboxypropoxy)phenylglyoxyloyl-amino]lactacylanic acid, which is suspended in 10 ml of water, is dissolved by the addition of 1.1 ml of IN aqueous sodium hydroxide solution. 0.152 g of sodium hydroxymethanesulfonate (1 hydrate) is added to the solution, and the mixture is stirred at room temperature for 4 hours. The water is distilled off from the reaction mixture under reduced pressure, and the residue is pulverized with acetone. The powder (0.49 g) is dissolved in a small amount of water, and acetone is added little by little to the solution. The precipitated crystals are collected by filtration, thereby obtaining 63 mg of the disodium salt of 3-(4-[3-carboxy-3-(N-sulfomethylamino)propoxy]phenylglyoxyloylamino)lactacylanic acid with an IR absorption spectrum v cm""<1>(nujol): 1720, 1650 and 1260.

Example 509

A mixture of 500 mg of 3-(2-[4-(3-amino-3-carboxypropoxy)-phenyl]-2-hydroxyiminoacetamido)lactacylanic acid in 6 ml of water is dissolved while cooling by adding 1.2 ml of IN aqueous sodium -hydrogen carbonate solution. A solution of 220 mg of acetaldehyde and 520 mg of sodium hydrogen sulphite, which is dissolved in 5 ml of water, is added to the solution, and the mixture is stirred at room temperature for 3 hours and for a further 1 hour at 45°C. The reaction mixture is concentrated under reduced pressure to a volume of approximately 1/3 of the original volume. To the residue is added

10 ml of ethanol, and the precipitated crystals are collected by filtration, whereby 0.3 g of the disodium salt of 3-(2-[4-(3-carboxy-3-

[N-(1-sulfoethyl)amino]propoxy)phenyl]-2-hydoxyiminoacetamido)-lactacylanic acid with melting point 224.5-229°C (decomposition).

Example 510

169 mg of 3-(2-[2-(2-carboxyphenylthio)acetamido]-2-phenylacetamido)lactacylanic acid is dissolved in 6 ml of acetone, until the solution is placed under ice-cooling 61 mg of 85% 3-chloroperbenzoic acid, and then the mixture is stirred at the same temperature for 1 hour. After concentration of the reaction mixture under reduced pressure, approx. 3 ml of ethyl acetate to the residue, and then the solution is stirred for 2 hours. The precipitated crystals are collected by filtration, washed with ethyl acetate and dried, thereby obtaining 120 mg of 3-(2-[2-(2-carboxyphenylsulfinyl)acetamido]-2-phenylacetamido)-lactacylanic acid with melting point 175-181°C (decomposition).

Example 511

0.59 g of 3-[2-(4-[3-carboxy-3-(2,2,2-trifluoroacetamido)-propoxy]phenyl)-2-hydroxyiminoacetamido]lactacillanic acid is dissolved in a solution of 10 ml acetone and 10 ml water, 0.34 g of sodium bicarbonate and 0.15 g of sodium iodide are added to the solution, and then the mixture is allowed to stand for some time. 0.60 g of chloromethylpivalate is added to the solution, and the mixture is heated under reflux for 4 hours. The acetone is distilled off from the reaction mixture under reduced pressure, and the residue is added to a mixture of 20 ml of ethyl acetate and 20 ml of water. The separated ethyl acetate phase is washed

with an aqueous sodium bicarbonate solution, with water and then with a saturated aqueous sodium chloride solution in the order indicated and dried over anhydrous magnesium sulfate. The solvent is distilled off from the ethyl acetate solution under reduced pressure, and the residue is triturated with benzene. The powder obtained (0.19 g) is chromatographed on 10 g of silica gel. The elution is carried out with a mixture of chloroform and methanol (99:1), the fractions containing the desired compound are collected, and then the solvent mixture is distilled off from the fractions. The residue is recrystallized from a mixture of ether and diisopropyl ether, whereby 0.12 g of 1-(α-pivaloyloxymethoxycarbonyl-4-hydroxybenzyl)-3-[2-(4-[3-pivaloyloxymethoxycarbonyl-3-(2,2,2 -trifluoroacetamido)propoxy]phenyl)-2-hydroxyiminoacetamido]-2-azetidinone with melting point 135-140°C (decomposition).

Example 512

1/0 g of triethylamine and 6/4 g of pyridine are added to a solution of 3.04 g of 3-2-(4-[3-carboxy-3-(3-phenylthioureido)-propoxy phenyl)-2-(3 -phenylthioureido)acetamido 3-lactacillanic acid,

which is dissolved in 30 ml of dry acetone* After stirring for some time, the mixture is cooled to a temperature between -20 and -15°C, a solution of 2.1 g of 2,2,2-trichloroethyl chloroformate is added dropwise over 15 minutes which is dissolved in 20 ml of dry acetone, and then the mixture is stirred at the same temperature for 2 hours* The acetone is distilled off from the reaction mixture under reduced pressure, and the residue is added to a mixture of 200 ml of water and 200 ml of ethyl acetate. The ethyl acetate phase is separated, washed with an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off from the ethyl acetate phase, and the residue is pulverized with ether. The resulting powder (1.2 g) is chromatographed on 50 g of silica gel. The elution is carried out with a mixture of chloroform and methanol (99:1). The fractions containing the desired compound are collected and the solvent distilled off, whereby 0.16 g of 1-[ot-(2,2,2-trichloroethoxycarbonyl)-4-hydroxybenzyl]-3-[2-(4-[ 3-(3-phenylthioureido)-3-(2,2,2-trichloroethoxycarbonyl)propoxy]phenyl)-2-(3-phenylthioureido)-acetamido]-2-acetidinone. IR absorption spectrum v cm<1>(nujol): 1750, 1680 and 1220.

Example 513

An ether solution of diazomethane is added dropwise to a solution of 5.5 g of 3-(2-[4-(3-acetamido-3-carboxypropoxy)-phenyl]-2-hydroxyiminoacetamido)lactacylanic acid in 150 ml of methanol, until the color of the diazomethane does not disappears in the last specified resolution. The reaction mixture is allowed to stand overnight in a refrigerator, and the solvent is distilled off. The residue is chromatographed on silica gel. The elution is carried out with a mixture of chloroform and methanol (98:2), and the fractions containing the desired compound are collected. The solvent is distilled off, whereby 3.50 g of 1-(a-methoxycarbonyl-4-methoxy-benzyl)-3-(2-[4-(3-acetamido-3-methoxycarbonylpropoxy)phenyl]-2-methoxyiminoacetamido)-2- azetidinone. NMR absorption spectrum ppm (CDCl 3 ): 1.95 (3H, s), 2.25 (2H, m), 3.15 (1H, d,d,

J 3Hz, 6Hz), 3.70 (3H, s), 3.74 (3H, s), 3.78 (3H, s), 3.89 (3H,a), 3.96 (2H, t, Ja6H2), 4.70 (1H, g, J=8Hz), 4.92 (1H, m), 5.52

(1H, s), 6.75 (2H, d, J«9Hz), 6.86 (2H, d, J»9Hz), 7.20 (2H, d, J«9Hz), 7.45 (2H , d, J»9Hz).

Example 514

2.0 g of 3-[2-(4-[3-carboxy-3~(2,2,2-trifluoroacetamido)-propoxy]phenyl)-2-hydroxyiminoacetamido]lactacillanic acid are dissolved in a mixture of 20 ml of ether and 15 ml methanol, and the solution is ls-cooled. An ether solution of diazomethane is added dropwise to the next solution, until the color of diazomethane does not disappear in the last solution. The reaction mixture is stirred at the same temperature for 4 hours and for a further 2 hours at room temperature. The solvent is distilled off

the reaction mixture, the residue (2.10 g) is chromatographed on 50 g of silica gel, and then elution is carried out with chloroform. The. fractions containing the desired compound are collected, and the chloroform is distilled off, whereby 1.29 g of 1-(α-methoxycarbonyl-4-methoxybenzyl)-3-12-(4-[3-methoxycarbonyl-3-(2,2,2- trifluoroacetamido)propoxy]phenyl)-2-methoxyiminoacetamido]-2-azetidinone. IR absorption spectrum, v cm"1 (liquid film): 1730, 1700 and 1650.

Example 515

3.50 g of 3-(2-[4-(3-carboxy-3-phthalimidopropoxy)phenyl]-2-hydroxyiminoacetamido)-2-azetidinone are dissolved in 30 ml of methanol, and the solution is ice-cooled. An ether solution of diazomethane is added dropwise to the aforementioned solution, until

the color of diazomethane does not disappear in the last solution indicated. The mixture is stirred for 5 hours and then allowed to stand for 1 day in a refrigerator. The solvent is distilled off from the reaction mixture, and the residue is chromatographed on 80 g of silica gel. The elution is carried out with chloroform and then with a mixture of

chloroform and methanol (98s2). The fractions eluted with a mixture of chloroform and methanol are collected, and the solvent is distilled off, thereby obtaining 1.20 g of 1-(o-methoxycarbonyl-4-methoxybenzyl)-3-(2-[4-(3-phthalimido-3-methoxycarbonylpropoxy) )-phenyl]-2-ethoxyaminoacetamido)-2-azetidinone. NMR absorption spectrum, 6 ppm (CDCl 3 ) in 2.70 (2H, s), 3.15 (1H, d, d, J»3Hz, 6Hz), 3.70 (1H, ra), 3.75 (6H , s), 3.78 (3H, s), 3.88 (3H, s), 3.94 (2H, m), 5.05 (1H, m), 5.16 (1H, t, J= 6Hz), 5.56 (1H, s), 6.62 (2H, d, J=9Hz), 6.84 (2H, d, J«9Hz), 7.20 (2H, J«9Hz), 7 .38 (2H, d, J«9Hz), 7.74 (4H, m).

Example 516

An ether solution of diazomethane is added dropwise to a solution of 0.70 g of 3-(2-[4-(3-acetamido-3-carboxypropoxy)-phenyl]-2-acetamidoacetamldo)lactacylanic acid, which is dissolved in 20 ml of methanol, until the color of diazomethane does not disappear in it

last nagitte resolution. The mixture is then allowed to stand overnight in a refrigerator. The solvent is distilled off from the reaction mixture, and the residue is chromatographed on 25 g of silica gel. The elution is carried out with chloroform and then with three portions of chloroform and methanol, namely (99:1), (98:2) and (97:3). The fractions containing the desired compound are collected, and then the solvent is distilled off, whereby 0.30 g of 1-(α-methoxycarbonyl-4-methoxybenzyl)-3-(2-[4-(3-acetamido-3-methoxycarbonylpropoxy)phenyl) is obtained ]-2-acetamidoacetamido)-2-azetidinone. IR absorption spectrum, v (CHCl 2 ): 1745, 1667 and 1195.

Example 517

Dissolve 2.50 g of 3-[4-(3^amino-3-carboxypropoxy)phenylglyoxyloyl-amino]lactacylanic acid in 17.5 ml of dimethylsulfoxide, add 12.5 ml of acetic acid and 12.5 ml of water to the solution under ice-cooling, and then the mixture is stirred for some time. An aqueous solution of 0.50 g of sodium nitrite in 2 ml of water is added to the solution, and the mixture is stirred at room temperature for 12 hours. The reaction mixture is added to 50 ml of ice water, and the solution is extracted three times with 50 ml of ethyl acetate. The ethyl acetate phase is separated, washed twice with 20 ml of water and once with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off, and the residue is crystallized

from a mixture of ethyl acetate and ether, whereby 0.49 g of 3-»[4-(3-carboxy-3-hydroxypropoxy)phenylglyoxyloylamino]-lactacylanic acid is obtained. A further 0.21 g is recovered from the mother liquor

of the same connection. The total yield is 0.70 g. The product has a melting point of 196-201°C (decomposition).

Example 518

3-(2-[4-(3-carboxy-3-phthalimidopropoxy)phenyl]glycinamido)-lactacylanic acid as starting material is treated in an analogous manner as described in example 517, whereby 3-[2-[4-(3-carboxy- 3-r(thalimidopropoxy)phenyl]-2-hydroxyacetamido]lactacylanic acid with melting point 160-163°C (decomposition).

Example 519

300 mg of 3-[2-glycinamido-2-(2-thienyl)acetamido]-lactacillanic acid is dissolved in 5 ml of an aqueous solution of 168 mg of sodium bicarbonate. 5 ml of methanol are added to the solution and then 80 mg of methyl-4-fluoro-3-nitrobenzoate and the mixture is stirred at 50°C for 3 hours. The methanol is distilled off from the reaction mixture under reduced pressure, and the aqueous residue is washed with ethyl acetate. The aqueous solution is adjusted while cooling to a pH value of 2-3 with 10% hydrochloric acid and extracted twice with ethyl acetate. The extracts are collected, washed with water, dried over anhydrous magnesium sulfate and then evaporated to dryness under reduced pressure. The residue

(90 mg) is crystallized from ether, whereby 70 mg of crude 3-(2-[N-(4-methoxycarbonyl-2-nitrophenyl)glycinamido]-2-(2-thienyl)-acetamido)lactacylanic acid are obtained. The product is chromatographed on 2 g of silica gel, the fractions eluted with ethyl acetate are collected, and the solvent is distilled off from the eluate, thereby obtaining 11 mg of the same compound in pure form. The product has a melting point of 160-164°C (decomposition).

Example 520

369 mg of 3-(2-phenylglycinaldo)lactacylanic acid are dissolved in a solution of 572 mg of sodium carbonate (10 hydrate) in 8 ml of water. A solution of 180 mg of 5-chloro-3-phenyl-1,2,4-oxadiazole in 7 ml of acetone is added to the solution, and the mixture is allowed to react at room temperature for 5 hours. The reaction mixture is adjusted to a pH value of 7.0 with sodium bicarbonate and washed with ethyl acetate. The resulting aqueous solution is adjusted to a pH value of approx. 3 with dilute hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate phase is separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off. The oily residue (270 mg) is chromatographed on 7 g of silica gel. The fractions eluted with a mixture of ethyl acetate and methanol (97%) are collected, and the solvent is distilled off, whereby 95 mg of powdered 3-[2-phenyl-N- is obtained.

(3-Phenyl-1,2,4-oxadiazol-5-yl)glycinamido]lactacillanic acid.. IR absorption spectrum, v cm 1 (nujol) t 1738, 1680 and 1618.

Example 521

0.19 g of 3-(2-phenylacetamido)lactacylanic acid is suspended in 5 ml of methanol, and to the suspension is added under ice-cooling a

ether solution containing diazomethane. as the addition continues, until the color of diazomethane in the reaction mixture does not disappear. The reaction mixture is stirred for 2 hours at the same temperature, and then the reaction mixture is concentrated under reduced pressure. The resulting residue is dissolved in chloroform, and the solution is washed with an aqueous sodium triurea hydrogen carbonate solution, with water and with a saturated aqueous sodium chloride solution in the order indicated and then dried over anhydrous magnesium sulfate. The chloroform is distilled off from the solution under reduced pressure, whereby a residue is obtained which is pulverized with ether. The powder is collected by filtration, whereby 0.12 g of 1-(α-methoxycarbonyl-4-methoxybenzyl)-3-(2-phenylacetamido)lactacylanic acid is obtained, which is recrystallized from ether, whereby 0.06 g of the aforementioned compound is obtained in pure form . The product has a melting point of 145-146°C (decomposition).

Example 522

3.0 g of 3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido)lactacylanic acid are dissolved in 60 ml of a methanol solution containing 480 mg of sodium hydroxide. 20 ml of a methanol solution containing 835 mg of methyl acetoacetate is added to the solution, and the mixture is heated for 6 hours with stirring at 74°C. The methanol is distilled off from the reaction mixture, and the resulting residue is suspended in 300 ml of ethanol. The suspension is stirred for 1 hour at room temperature. The undissolved product is collected by filtration and washed with ether, thereby obtaining 1.2 g of the disodium salt of 3-[2-(4-[3-carboxy-3-(2-methoxycarbonyl-1-methylvinylamino)propoxy]phenyl)-2- hydroxyimino-acetamido] lactacyllanic acid. On concentration of the mother liquor, a residue is obtained, ether is added to the residue, and then the powder is collected by filtration, whereby 2.4 g of the aforementioned compound are obtained. The total yield is 3.6 g. NMR absorption spectrum, 6 ppm (D 2 O). 1.8 (3H, s), 2.2 (2H, m), 3.1 (1H, m), 3.8 (2H, m),

3.56 (3H, s), 4.1 (2H, wide s), 5.0 (1H, m), 5.3 (1H, s), 6.7-7.5 (8H, m).

Example 523

200 mg of 3-[4-(3-benzyloxycarbonyl-5-oxo-1,3-oxazol-4-yl)-butyramido]lactacylanic acid is dissolved in 15 ml of methanol, and 50 mg of 10% palladium is added to the solution as a catalyst /coal. The mixture is allowed to react in a hydrogen atmosphere at normal pressure. The

theoretical volumes of hydrogen gas are introduced into the mixture over the course of 4 hours. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The resulting residue

is pulverized with acetone, and the powder is collected by filtration, whereby 97 mg of 3-(S-amino-S-carboxyvalerylamino)lactacillanic acid is obtained. NMR absorption spectrum, 6 ppm (D 2 O + NaHCO 3 ). 1.64-1.90 (4H, m), 2.24 (2H, t, J=4Hz), 2.90, 2.94 (1H, d, d, J=2Hz, 6Hz), 3.67 (1H, t, J=6Hz), 5.19 (1H, s), 6.79 (2H, d, J=8Hz), 7.12 (2H, d, J»8Hz).

Example 524

103 mg of 3-[2-(2-[4-chloro-2-(4-nitrobenzoyl)phenoxy]acetamido)-2-phanylacetamido]lactacylanic acid are dissolved in 15 ml of methanol. 45 rags of 10% palladium/coal are added as a catalyst to the solution,

and the mixture is stirred in a hydrogen atmosphere. The calculated volume of hydrogen is absorbed in the mixture within 2.5 hours. The methanol

is distilled off from the reaction mixture, and the resulting residue (80 mg) is washed with ether, thereby obtaining 70 mg of 3-[2-(2-[2-(4-aminobenzoyl)-4-chlorophenoxy]acetamido)-2-phenylacetamido]-lactacylanic acid with melting point 150-153°C (decomposition).

Example 525

190 mg of 3-(2-[2-(2-phenoxycarbonylphenoxy)acetamido]-2-phenylacetamido]lactacylanic acid and 60 mg of an 80% aqueous hydrazine hydrate solution are dissolved in 6 ml of methanol, and the solution is stirred for 13 hours at room temperature. The methanol is distilled off from

the reaction mixture, whereby a residue is obtained which is pulverized with . ether. A small amount of ethanol is added to the powder (180 mg), and the mixture is stirred for 1 hour, whereby the undissolved product is collected by filtration, whereby 100 mg of 3-(2-[2-(2-hydrazino-carbonylphenoxy)acetamido]-2 is obtained -phenylacetamido)lactacillanic acid hydrazine salt with melting point 178-182°C (decomposition).

Example 526

Dissolve 52 mg of 3-(2-[4-(3-azidopropoxy)phenyl]acetamido)-lactacyllanic acid in 10 ml of methanol, add 10% palladium/charcoal as catalyst to the solution, and stir the mixture in a hydrogen atmosphere. The calculated volume of hydrogen is absorbed in the mixture within 1.5 hours. The catalyst from raf is removed from the reaction mixture, and the methanol is distilled off from the filtrate. The resulting residue is treated with acetone, whereby 38 mg are obtained

3-(2-[4-(3-Aminopropoxy)phenyl]acetamido)lactacylanic acid.

IR absorption spectrum, v cm"<1>(nujol)s 1730, 1660 pg 1610.

Example 527

200 mg of 3-(2-ethoxalylamino-2-phenylacetamido)lactacylanic acid is dissolved in 4 ml of ethanol, 3.5 ml of an ethanol solution containing 136 mg of benzylamine is added to the solution, and the mixture is then stirred for 6.5 hours at room temperature. The reaction mixture is concentrated, whereby a residue is obtained which is added to a mixture of water and ethyl acetate. 1 ml 1N hydrochloric acid is added to the mixture, and then the ethyl acetate phase is separated, which is washed with 1% hydrochloric acid and with water in the order indicated. The ethyl acetate phase is dried over anhydrous magnesium sulphate, after which the solvent is distilled off from the solution, whereby a residue is obtained which is washed with diisopropyl ether, whereby 160 mg of crystals are obtained. The crystals are recrystallized from an extraction of acetone and ethyl acetate, whereby 70 mg of crystalline 3-[2-(N-benzyloxamoyl)amino-2-phenylacetamido]lactacylanic acid with a melting point of 149-154°C (decomposition) is obtained.

Example 528

2 ml of an acetone solution containing 240 mg of 2-phenylacetyl chloride is added dropwise at a temperature of 0-5°C to a

mixture of 160 mg of 3-guanidinocarbonylaminolactacylanic acid,

10 ml of 0.1N aqueous potassium hydroxide solution, 130 mg of sodium bicarbonate, 5 ml of water and 10 ml of acetone, and the mixture is stirred for 1 3.5 hours at the same temperature, thereby obtaining 120 mg of crystalline 3-[3-(2-phenylacetyl)guanidinocarbonylamino ]-lactacillanic acid with melting point 159-161°C (decomposition).

Example 529

200 mg of 3-[2-(4-formylphenoxy)acetamido]lactacylanic acid are dissolved under ice-cooling in 0.1N aqueous sodium hydroxide solution.

20 mg of sodium borohydride is added to the solution, and the mixture is stirred for 50 minutes. 0.5 ml of acetone and 10 ml of ethyl acetate are added to the reaction mixture, and then the mixture is adjusted to a pH value of 1-2 with 1N hydrochloric acid. The ethyl acetate phase is separated, washed with water and with an aqueous sodium chloride solution in the order indicated and then dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, and the resulting residue is crystallized from ethyl acetate, thereby obtaining 110 mg of 3-[2-(4-hydroxymethylphenoxy)acetamido]-

lactacyllanic acid with melting point 182-185°C (decomposition).

Example 530

200 mg of 3-(2-[2-(2-formylphenoxy)acetamido]-2-phenylacetamido)lactacylanic acid is treated in essentially the same way as described in example 529, whereby 130 mg of 3-(2-[2-(2 -hydroxymethylphenoxy)acetamido]-2-phenylacetamido)-lactacylanic acid with melting point 95-101°C (decomposition).

Example 531

170 mg of 3-(2-phenyl-2-phenylglyoxyloylaminoacetamido)-lactacylanic acid is dissolved in 3.5 ml of 0.1N aqueous sodium hydroxide solution, 1 ml of an aqueous solution containing 13 mg of sodium borohydride is added dropwise to the solution, and the mixture is then stirred for 40 minutes. 30 ml of ethyl acetate is added to the reaction mixture, and the mixture is adjusted to a pH value of 1 with 10% hydrochloric acid. The ethyl acetate phase is separated, and the resulting aqueous solution is extracted with 20 ml of ethyl acetate. The extracts are combined, washed with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, and the resulting residue is pulverized with ether, whereby 140 mg of 3-[2-(2-phenylglycol-amido)-2-phenylacetamido]lactacylanic acid with a melting point of 90-93°C (decomposition) is obtained.

Example 532

40 mg of sodium borohydride is added under ice-cooling to a mixture of 200 mg of 3-[2-(4-formylphenoxy)acetamido]lactacylanic acid,

5 ml of 0.1N aqueous sodium hydroxide solution, 106 mg of benzylamine and

2 ml of ethanol, and the reaction mixture is stirred for 30 minutes at the same temperature. The reaction mixture is washed twice with ether and adjusted to a pH value of approx. 4 with 10% hydrochloric acid, whereby an oily product is separated and separated by decantation. The oily product is pulverized with acetone, and the powder is collected by filtration and washed with acetone, thereby obtaining 105 mg of 3-[2-(4-benzylaminomethylphenoxy)acetamido]-lactacylanic acid with melting point 172-177°C (decomposition).

Example 533

200 mg of 3-(2-[4-(1-benzyloxycarbonylamino-1-methoxy-carbonylmethyl)phenoxy]acetamido)lactacyllanic acid are dissolved in 15 ml of methanol. Add 35 mg 10% as catalyst to the solution

palladium/coal, and the mixture is allowed to react for 2 hours in a hydrogen atmosphere at normal temperature and normal pressure. After absorbing the calculated volume of hydrogen, the catalyst is filtered off from the reaction mixture, and the filtrate is concentrated under reduced pressure. The resulting residue is pulverized with acetone and treated with acetone, thereby obtaining 90 mg of 3-(2-[4-(1-amino-1-methoxycarbonylmethyl)phenoxy]acetamido lactacylanic acid with melting point 190-194°C (decomposition).

Example 534

1.35 g of 3-(2-[4-(2-benzyloxycarbonylamino-2-methoxycarbonylethyl)phenoxy]acetamido)lactacylanic acid is dissolved in 6.7 ml of 1N aqueous sodium hydroxide solution, and the solution is stirred for 1 hour at room temperature. A small amount of water is added to the reaction mixture, and then the solution is washed with ethyl acetate, after which the aqueous solution is adjusted to a pH value of 1 with IN hydrochloric acid. The solution is extracted with ethyl acetate, and the ethyl acetate phase is separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, and the residue is crystallized from chloroform, thereby obtaining 1.07 g of crystalline 3-(2-[4-(2-benzyloxycarbonylamino-2-carboxyethyl)phenoxy]acetamido)lactacylanic acid with a melting point of 125-130°C (decomposition) .

Example 535

118 mg of 3-(2-[4-(1-benzyloxycarbonylamino-1-methoxy-carbonylmethyl)phenoxy]acetamido)lactacylanic acid are dissolved in 4 ml of 0.1N aqueous sodium hydroxide solution, and the solution is stirred for 2 hours at room temperature. Then 4 ml of 0.1N hydrochloric acid is added to the reaction mixture, and the solution is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, and the residue is crystallized from a small amount of acetone. The crystals are treated with ethyl acetate, whereby 30 mg of crystalline 3-(2-[4-(1-benzyloxycarbonylamino-1-carboxymethylj-phenoxy]acetamido)lactacyllanic acid with melting point 134-138°C (decomposition) is obtained.

Example 536

0.382 g of 2-(4-benzyloxyphenyl)-2-(2£-dichloroacetoxyimino)-acetic acid is suspended in 7 ml of benzene, and the suspension is cooled to 0-5°C. To the suspension, add 0.250 g of phosphorus

pentachloride, and the mixture is stirred for 1 hour at the same temperature. The benzene is distilled off from the mixture under reduced pressure under water cooling. 7 ml of benzene are added to the residue, the benzene is distilled off from the solution under reduced pressure, and the aforementioned treatment is repeated three times. The resulting residue is dissolved in 10 ml of dry methylene chloride.

0.236 g of 3-aminolactacylanic acid is suspended in 20 ml of dry methylene chloride, 0.87 g of N,0-bis(trimethylsilyl) acetamide is added to the suspension, and the mixture is stirred for some time at room temperature. The solution is added to the previously prepared methylene chloride solution under cooling at 0-5°C during 30 minutes, and the reaction mixture is stirred for 1 hour at the same temperature. The reaction mixture is washed with water and concentrated under reduced pressure, whereby a residue is obtained.

Ethyl acetate and 5% aqueous sodium hydrogen carbonate solution are added to the residue, and the mixture is sufficiently stirred. The aqueous phase is separated, adjusted to a pH value of 1-2 and then extracted with ethyl acetate. The ethyl acetate phase is separated and dried over anhydrous magnesium sulfate. The solvent is distilled off from the resulting phase under reduced pressure, whereby an oily residue is obtained, which is washed with ether and pulverized with chloroform. The resulting powder (£108 mg) is dissolved in 2 ml of acetone, and to the solution is added 1.2 ml of an aqueous solution containing 612 mg of sodium 2-ethylhexanate. 3 ml of ether is added to the mixture, whereby a powder is obtained which is collected by filtration. The powder is washed with ether and dissolved in water. The aqueous solution is adjusted to a pH value of 1-2 with dilute hydrochloric acid and then the solution is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off from the solution, and the residue is crystallized from chloroform, whereby 95 mg of crystalline 3-[2-(4-benzyloxyphenyl)-2-hydroxyimino-3-lactacylanic acid with a melting point of 137-140°C (decomposition) is obtained.

The following compounds are prepared in essentially the same way as described above.

Example 540

14 mg of 3-(2-phenylacetamido)-1-(a-methoxycarbonyl-3-benzyloxycarbonylaminobenzyl)-2-azetidinone is dissolved in 4 ml of isopropyl alcohol, and 10 mg of 10% palladium/charcoal is added to the solution as a catalyst* The reaction mixture is allowed to react in a hydrogen stream at 50°C under normal pressure. The calculated volume of hydrogen gas is absorbed in the reaction mixture within 1 hour. The catalyst is removed by filtration, and the filtrate is concentrated, whereby 7 mg of oily 3-(2-phenylacetamido)-1-(α-methoxycarbonyl-3-aminobenzyl)-2-azetidinone are obtained. IR absorption spectrum, v cm"<1>(CHCl 3 ): 3425, 1755, 1745, 1675 and 1620.

Example 541

Dissolve 150 mg of 3-(2-[2-(4-chloro-2-[4-(2-chloroacetamido)benzoyl]-phenoxy)acetamido]-2-phenylacetamido)lactacylanic acid and 160 mg of 30% aqueous trimethylamine solution in 4 ml of methanol , and the solution is stirred at 50°C for 1.5 hours. Add 160 mg of 30% aqueous trimethylamine solution to the solution 4 times at 1-hour intervals. The solvent is distilled off from the reaction mixture, and the residue is washed with acetone, after which 5 ml of water is added to the residue (150 mg) and the mixture is stirred for 30 minutes. The undissolved product is collected by filtration,

and 10 ml of acetone is added to the product. The mixture is stirred for 30 minutes, and the undissolved product is collected by filtration, whereby 120 mg of crystalline N-[N-(4-[3-chloro-2-(N-[l-(N-[l-(a-carboxy) -4-hydroxybenzyl)-2-oxo-2-azetidinyl]carbamoyl)-1-phenylmethyl]carbamoylmethoxy)benzoyl]phenyl)carbamoylmethyl]-N,N,N-trimethylammonium chloride with melting point 214-220°C (decomposition).

Example 542

1.0 g of 3-(2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido)lactacylanic acid is dissolved in a mixture of 4 ml of IN aqueous sodium hydroxide solution and 20 ml of water. 4 ml of a methanol solution containing 0.34 g of methyl acrylate is added little by little to the solution, and the mixture is stirred for 5.5 hours under ice cooling. The reaction mixture is adjusted to a pH value of 3 with 10% hydrochloric acid, and then the precipitated crystals are collected by filtration. The crystals are collected in a small amount of aqueous sodium bicarbonate solution, after which the solution is adjusted to a pH value of 3 with 10% hydrochloric acid. The crystals precipitated in the aqueous solution are collected by

filtration, whereby 0.57 g of crystalline 3-[2-(4-[3-carboxy-3-(2-methoxycarbonylethylamino)propoxy]phenyl)-2-hydroxyimino-acetamido ] lactacyllanic acid with melting point 175-179°C (decomposition ).

Example 543

3-(2-[2-oxo-3-(2-phenylacetamido)-1-azetidinyl]-3-ethyl-butyramido)-2-azetidinone and 2-bromo-2-(p-benzyloxyphenyl)-acetic acid benzyl ester are treated in essentially the same way as described in example 224, whereby 3-(2-[2-oxo-3-(2-phenylacetamido)-1-azetidinyl]-3-methylbutyramido)lactacylanic acid with melting point 160-164°C (decomposition) is obtained .

Claims (7)

1. Method for producing compounds with the general formula I where R1 denotes amino or acylamlno, and A denotes hydrogen, a saturated or unsaturated normal aliphatic hydrocarbon group which is substituted with at least Sn substituent selected from the group consisting of carboxy, derivatives thereof, cyano, hydroxy and amino, a saturated branched aliphatic hydrocarbon group which is substituted with at least one Sn substituent selected from the group consisting of carboxy, derivatives thereof, cyano, hydroxy and amino, an unsaturated branched aliphatic hydrocarbon group, which is substituted with at least one Sn substituent selected from the group consisting of carboxy, derivatives thereof, cyano, hydroxy and amino, or an aliphatic hydrocarbon group which is substituted with aryl, whose ring may be substituted with Sn or more substituents selected from the group consisting of hydroxy, amino, nitro, alkyl, alkoxy, arylalkyloxy, alkylthio, halogen and sulfo, characterized in that a compound with the general formula II where A has the above meaning, is reacted with an acylating agent. 2. Procedure for making compounds with the general formula I where R1 denotes amino or acylamlno, and A denotes hydrogen, a saturated or unsaturated normal aliphatic hydrocarbon group which is substituted with at least Sn substituent selected from the group consisting of carboxy, derivatives thereof, cyano, hydroxy and amino, a saturated branched aliphatic hydrocarbon group which is substituted with at least one substituent selected from the group consisting of carboxy, derivatives thereof, cyano, hydroxy and amino, an unsaturated branched aliphatic hydrocarbon group which is substituted with at least one substituent selected from the group consisting of carboxy, , cyano, hydroxy and amino, or an aliphatic hydrocarbon group which is substituted with aryl, which ring may be substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, alkyl, alkoxy, aryl alkoxy, alkylthio, halogen and sulfo, with the proviso that when R<1> denotes 2 -[4-(3-amino-3-carboxypropoxy)phenyl]-2-hydroxyiminoacetamido, A denotes hydrogen, a saturated or unsaturated normal aliphatic k hydrocarbon group which is substituted with at least one substituent selected from the group consisting of carboxy, cyano, hydroxy and amino, a saturated branched aliphatic hydrocarbon group which is substituted with at least one substituent selected from the group consisting of of carboxy, cyano, hydroxy and amino, an unsaturated branched aliphatic hydrocarbon group which is substituted with at least one substituent selected from the group consisting of carboxy, cyano, hydroxy and amino, or an aliphatic hydrocarbon group which is substituted with aryl, which ring may be substituted with one or more substituents selected from the group consisting of ay amino, nitro, alkyl, alkoxy, arylalkoxy, alkylthio, halogen and sulfo, when R1 represents acetamido, benzoylamino or phenylacetamido, A represents hydrogen, a saturated or unsaturated normal aliphatic hydrocarbon group which is substituted with at least one substituent selected from the group consisting of carboxy, cyano, hydroxy and amino, a saturated branched aliphatic hydrocarbon group substituted with at least one substituent selected from the group consisting of carboxy, cyano, hydroxy and amino, or an aliphatic hydrocarbon group substituted with aryl, which ring may be substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, alkyl, alkoxy, arylalkoxy, alkylthio, halogen and sulfo, and when R <1> denotes 2-(2-nitrophenoxy)acetamido or 2-(2-nitrophenoxy)-2-methyl- propionamido, A denotes a saturated or unsaturated normal aliphatic hydrocarbon group which is substituted with at least one substituent selected from the group consisting of carboxy, cyano, hydroxy and amino, a saturated branched aliphatic hydrocarbon group, which is substituted with at least one substituent selected from the group consisting of carboxy, cyano, hydroxy and amino, an unsaturated branched aliphatic unsaturated hydrocarbon group which is substituted with at least one substituent selected from the group consisting of carboxy, cyano, hydroxy and amino, or an aliphatic hydrocarbon group which is substituted with aryl, which ring may be substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, alkyl, alkoxy, arylalkoxy, alkylthio, halogen and sulfo, or salts thereof. 3. Method according to claim 2, characterized in that R <1> denotes amino, aliphatic acylamno, aroylamino, heterocyclylcarbonylamino or aliphatic acylamno, where the aliphatic part is substituted with aryl or a heterocyclic group, and A has the meaning stated in claim 2. 4. Method according to claim 2, characterized in that R<1> denotes aliphatic acylamlno, where the possible carbon atom may be replaced by one or more radicals selected from the group consisting of a divalent aromatic radical, a divalent heterocyclic radical, -O-, -N«=, -S-, -SO-, -S02 -f -NHS02 - and -NH-, where the hydrogen atom may be replaced by alkyl or aryl, and A has the meaning stated in claim 2. 5. Method according to claim 2, characterized in that R <1> denotes amino, alkanoylamino, heterocyclylcarbonylamino, aroylamino, arylsulfonylamino, phthalimido, alkanoyl- or alkenoylamino, which is substituted by aryl and/or a heterocyclic group, alkanoyl- or alkenoylamino, where the carbon chain or chains, if any, are interrupted of a divalent aromatic radical bg/or divalent heterocyclic radical, alkanoyl- or alkenoylamino, which is substituted with aryl and/or a heterocyclic group, where the possible carbon chain(s) in the acyclic hydrocarbon part is interrupted by a divalent aromatic radical and/or divalent heterocyclic radical, alkanoyl- or alkenoylamino, which is substituted with aryl and/or a heterocyclic group where the possible carbon chain(s) in the acyclic hydrocarbon part may be interrupted w one or more radicals selected from the group consisting of -0-, -N=, -S-, -SOj - and -NH-, where hydrogen- the atom may be replaced by alkyl or aryl, alkanoyl or alkenoylamino, which is substituted by aryl and/or a heterocyclic group, where the possible carbon chain(s) in the acyclic hydrocarbon part is interrupted by a divalent aromatic radical and/or divalent heterocyclic radical and further is interrupted by one or more radicals selected from the group consisting of -0-, -N», -S-, -SO2 - and -NH-, where the hydrogen atom can be replaced by alkyl or aryl, alkanoyl or alkenoylamino, where the possible carbon chain is interrupted by one or more radicals selected from the group consisting of -0-,-N», -S-, -S02~ and -NH-, where the hydrogen atom may be substituted with alkyl or aryl, alkanoyl or alkenoylamino, where the possible carbon chain is interrupted by a divalent aromatic radical and/or divalent heterocyclic radical and is further interrupted by one or more radicals selected from the group consisting of -0-, -N=», -S-, -SO2 - and -NH-, where the hydrogen atom may be replaced by alkyl or aryl, aroylamino or heterocyclylcarbonylamino, where the bond between the ring and the carbonyl group is interrupted by one or more radicals selected from the group consisting of -O-, -N», -S-, -SO2~ and -NH-, where the hydrogen atom may be replaced by alkyl or aryl, alkanoyl or alkenoylamino, which is substituted by cycloalkyl, aryl and/or a heterocyclic group, where the bond between the ring and the acyclic hydrocarbon moiety is interrupted by one or more radicals selected from the group consisting of -O-, -N", -S-, -SO2 - and -NH-, where the hydrogen atom may be replaced by alkyl or aryl, alkanoyl- or alkenoylamino, which is substituted by cycloalkyl, aryl and/or a heterocyclic group, where each of the bonds between the ring and the acyclic hydrocarbon part and one or several possible carbon chains in the acyclic hydrocarbon part are interrupted by a divalent aromatic radical and/or divalent heterocyclic radical and/or one or more radicals chosen from the group consisting of -0-, -N=>, -S-, -SO2 - and -NH-, where the hydrogen atom can be replaced by alkyl or aryl, aroylamino or heterocyclylcarbonylamino, where the bond between the ring and the carbonyl group is interrupted by one or more divalent aromatic radicals and/or divalent heterocyclic radicals, alkanoyl- or alkenoylamino which is substituted with aryl and/or a heterocyclic group, where the bond between the ring and the acyclic hydrocarbon part is interrupted by a divalent aromatic radical and/or divalent heterocyclic radical and a further one or more radicals selected from the group consisting of -O-, -N" ,-s-, -S02 - and -NH-, where the hydrogen atom may be replaced with alkyl or aryl, and alkanoyl- or alkenoylamino, which is substituted with aryl and/or a heterocyclic group, where the bond between the ring and the acyclic hydrocarbon part is interrupted by one or more divalent aromatic radicals and/or divalent heterocyclic radicals, and one or several positions in the acyl group indicated above may be substituted with one or more substituents selected from the group consisting of halogen, nitro, amino, carboxy, esterified carboxy, hydroxy, -N3 , -CN, -NHNHj , «*0, =NH, =S, sulfo and »N0H , where the hydrogen atom can be replaced by alkyl or arylalkyl, and cycloalkyl, aryl and the heterocyclic group in the above-mentioned acylamino group can optionally be substituted with alkyl, and A has the meaning given in claim 2. 6. Procedure for the preparation of compounds with the general formula I" where R 1 denotes amino or acylamino, and A' has the same meaning as the symbol A specified in claim 1 with the exception of hydrogen, characterized in that a compound with the general formula III where R<1> has the above meaning, is reacted with an alkylating agent of the general formula where A' has the above meaning, and X denotes a acid residue. 7. Procedure for making compounds with the general formula II where A has the meaning stated in claim 1, characterized in that a compound with the general formula I <*> where R <*1> denotes acylamlno, and A has the above meaning, the acylamino group is subjected to a cleavage reaction.