CS277027B6 - Process for preparing beta-lactam derivatives - Google Patents

Abstract

4-Acylcephem sulphones and 3-acylpenam sulphones of formula (Ia) and (Ib) resp. and their salts are new: A = H; 1-12C straight or branched alkyl; 2-10C alkenyl; 6-10C aryl; 3-8C cycloalkyl; 5-8C cycloalkenyl; aralkyl, aralkenyl, aralkynyl or (cycloalkyl)alkyl in which the aryl cycloalkyl, alkyl, alkenyl and alkynyl gps. are as defined above; etc.R1 = (1) Cl, F, Br or I; (2) A as defined above; (3) O-A; (4) S(O)nA; (5) OC(O)A; (6) OSO2A; or (7) NHC(O)A or NH2; R1 and R11 each = 1-7C straight or branched alkyl, phenyl or benzyl; t = 0-3; R111 = 1-7C straight or branched alkyl, phenyl, benzyl, CH2CH2CO2H or CH2CH2CH2CO2H; Z = mono-, di- or tri-peptide composed of D- or L-alpha-aminoacids, namely Ala, Gly, Val, He, Leu, Phe or Pro, with the terminal amino gp. either free, or acylated by a gp. C(O)R111 or C(O)OR111; H, 1-4C alkyl, 1-4C alkanoyloxy or Cl, Br or F; R3 = H, 1-4C alkyl, 1-4C alkoxy, benzyl, halo or =CH2 or CHR1111; R1111 = 1-4C alkyl, phenyl, COOH or 1-4C alkoxycarbonyl; R1 = (1) A; (2) Cl or F; (3) O-A; (4) S(O)nA; (5) C(O)A, C(O) OA or CO2H; (6) CH2-O-A; (7) CH2S(O)nA; (8) CH2OC(O)A or CH2-O-Z; (9) CH2SC(O)A; (10) CH2-N(A)A1; (11) -CH2N(+)(A)(A1)(A11); or (12) -CH2NH-C(O)A or CH2-NH-Z; A1 = same or different A gp.; or NAA1 = heterocyclic ring; A11 = as for A1; or NA1A11 = heterocyclic ring; or NAA1A11 = aromatic heterocyclic ring.

Description

The invention relates to 4-acylcephemsulfones and 3-acylpenamsulfones. and pharmaceutical and veterinary compositions containing these compounds and their preparations.

Accordingly, the invention provides 4-acylcephemsulfones of formula Ia and 3-acylpenamsulfones of formula Ib

in which

A represents a hydrogen atom or an organic radical selected from the group consisting of straight or branched alkyl groups having 1 to 12 carbon atoms, alkenyl groups having 2 to 10 carbon atoms, alkynyl groups having 2 to 10 carbon atoms, aryl groups having 6 to 10 carbon atoms, C 3 -C 8 cycloalkyl, C 5 -C 8 cycloalkenyl, aralkyl, aralkenyl, aralkynyl and cycloalkylalkyl groups in which the aryl, cycloalkyl, alkyl, alkenyl and alkynyl moieties are as hereinbefore defined, five- or six-membered, saturated or unsaturated heterocyclic rings containing at least one heteroatom selected from oxygen, sulfur and nitrogen, optionally coupled to a second 5- or 6-membered heterocyclic group or to a C 3 -C 8 cycloalkyl group, and further to heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkinyl groups , v wherein the heterocyclic, alkyl, alkenyl and alkynyl moieties are as defined above, wherein all of the above organic radicals may be unsubstituted or substituted by one or more atoms or groups selected from halogen atoms,.

hydroxyl, nitro, azido, diazo, amino -NH ₂ , -NHR 'or -NR'R'', where R' and R '' are the same or different and in each case represent a straight or branched alkyl group having 1 to 7 carbon atoms , phenyl or benzyl, formyl -CHO, mercapto-SH or -SR ', where R' is as defined above, cyano, carboxy (alkyl) - (CH ₂ ) -t.CO ₂ H or - (CH ₂₎ ) CO ₂ R ', wherein R' is as defined above and is 0, 1, 2 or 3, the sulfo group -SOgH, the acyl group -C (O) R ', wherein R' is as defined above, or the trifluoroacetyl group - C (O) CF ₃ , carbamoyl group -CONH ₂ , N-methylcarbamoyl group -CONHCH ₃ or N- (carboxymethyl) carbamoyl group

-conh-ch ₂ co ₂ h, carbamoyloxy -OCONH ₂ , acyloxy -OC (O) R ', wherein R' is as defined above, and formyloxy -OC (O) H, alkoxycarbonyl or benzyloxycarbonyl -C (O) OR ' wherein R 'is as defined above, alkoxycarbonyloxy or benzyloxycarbonyloxy-OC (O) R', wherein R 'is as defined above, alkoxy, phenoxy or benzyloxy-O-R', wherein R 'is as defined above, alkylthio - phenylthio- or benzylthio -S-R ', wherein R' is as defined above, alkylsulfinyl, phenylsulfinyl or benzylsulfinyl -S (O) R ', wherein R' is as defined above, alkylsulfonyl, phenylsulfonyl or benzylsulfonyl -S (O) ₂ R ', where R' is as defined above, an acylamino group -NHC (O) R '''or -NHC (O) OR''', wherein R '''represents a straight or branched alkyl group having 1 to 2 7 carbon atoms, phenyl, benzyl, CH ₂ CH ₂ CO ₂ H or CH ₂ CH ₂ CH ₂ CO ₂ H, sulfonamido -NH-SO ₂ R ', where R 1 is as defined above, guanidino -NHC (= NH) NH ₂ , C 1 -C 4 alkyl, C 2 -C 4 alkenyl or alkynyl, C 3 -C 6 cycloalkyl, and substituted methyl selected from groups including chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, aminomethyl, azidomethyl, cyanomethyl, carboxymethyl, carbamoylmethyl, carbamoyloxymethyl, hydroxymethyl, C 3 -C 4 alkoxycarbonyl and guanidinomethyl.

R ¹ is (1) a chlorine, fluorine, bromine or iodine atom, (2) a radical A as defined above, (3) an ether radical -OA, wherein A is as defined above, (4) a thioether, sulfoxide or sulfone radical -S ( O) _n A wherein n is 0, 1 or 2 and A is as defined above; (5) acyloxy -OC (O) A wherein A is as defined above; (6) sulfonyloxy -O-SOoA wherein A or (7) an acylamino group -NHC (O) A, wherein A is as defined above, or an acylamino group -NH-Z, wherein Z is a mono-, di- or tripeptide consisting of D- or La-amino acids selected from groups including Ala, Gly, Val, Leu, Ile, Phe, and Pro, wherein the terminal amino group is either free or acylated with -C (O) R '''or -C (O) OR''', wherein R '''is as defined above,

R ² is either hydrogen or (1) C 1 -C 4 alkyl, (2) C 1 -C 4 alkanoyloxy, or (3) chloro, bromo or fluoro,

R ³ represents either a hydrogen atom or (1) a C 1 -C 4 alkyl group, (2) a C 1 -C 4 alkoxy group, (3) a benzyl group, (4) a halogen atom or (5) a methylene group = CH ₂ or = CHR ^IV , wherein R ^IV is C 1 -C 4 alkyl, phenyl, carboxy or C 1 -C 4 alkoxycarbonyl

R ⁴ represents (1) a radical A as defined above, (2) a chlorine or fluorine atom, (3) an ether group -OA, wherein A is as defined above, (4) a sulfenyl, sulfinyl or sulfonyl group -S (O) _n A wherein A is as defined above, (5) an acyl group -C (O) A, -C (O) OA or -CO ₂ H, wherein A is as defined above, (6) an oxymethyl group -CH ₂ -OA wherein A is as defined above, (7) a thiomethyl group or a derivative thereof of the formula -CH ₂ S (O) _n A, wherein A is as defined above, (8) an acyloxymethyl group -CH ₂ OC (O) A or - CH ₂ -OZ, wherein Z and A are as defined above, (9) an acylthiomethyl group -CH ₂ SC (O) A, wherein A is as defined above, (10) aminomethyl group -CH ₂ -N (A) A ' wherein A is as defined above and A 'is either the same as A, wherein the radicals A and A' may be the same or different, or A and A 'together with the nitrogen atom to which they are attached form five- or a six-membered heteroc an alkyl ring containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, (11) an amoniomethyl group -CH ₂ N ⁺

wherein A and A 'are as defined above and A''has the same meaning as A, being the same or different from A, or A is an alkyl group and A' and A '' together with the nitrogen atom to which they are attached form a five- or six-membered heterocyclic ring containing at least one heteroatom selected from oxygen, sulfur and nitrogen, or A, A 'and A''together with the nitrogen atom to which they are attached form a five- or six-membered aromatic heterocyclic ring containing at least one a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, or (12) an acylaminomethyl group -CH ₂ NH-C (O) A or -CH ₂ NH-Z, wherein A and Z are as defined above, and pharmaceutically and veterinarily useful salts.

The invention includes salts of those compounds of formulas Ia and Ib which contain salt-forming groups, in particular salts of such compounds containing a carboxyl group, a basic group (for example, an amino group or a guanidino group) or a quaternary ammonium group. Salts are in particular physiologically tolerable salts, for example alkali metal and alkaline earth metal salts (for example sodium, potassium, lithium, calcium and magnesium salts), ammonium salts and salts with suitable organic amines or amino acids (for example salts with arginine or procaine) and addition salts formed ^- with suitable organic or inorganic acids such as hydrochloric acid, sulfuric acid, organic carboxylic and sulfonic acids (e.g. acetic acid, trifluoroacetic acid or p-toluenesulfonic acid). Certain compounds of formula Ia or 1b which contain a carboxyl and ammonium groups may exist in the form of zwitterions. Such salts are also within the scope of the invention.

The C 3 -C 8 cycloalkyl groups referred to herein include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

C 5 -C 8 cycloalkenyl groups include cyclopentenyl and cyclohexenyl.

Examples of heterocyclic rings include thiazolyl, triazolyl, thiadiazolyl, tetrazolyl, triazinyl, pyrrolyl, imidazolyl, furyl, thienyl, morpholinyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and thiopyranyl.

The invention encompasses all possible stereoisomers as well as racemic or optically active mixtures thereof. However, the configurations represented by formulas Ia 'and 1b' are particularly preferred.

in which

A represents a straight or branched C 1 -C 10 alkyl, alkenyl or alkynyl, dimethylphenyl, diphenylmethyl, phenyl or benzyl group, wherein the alkyl, phenyl and benzyl groups are either unsubstituted or substituted by fluorine, chlorine, carboxyl, alkoxycarbonyl C 1 -C 4 alkoxy, carbamoyl, carbamoyloxy, methylsulfonyl, diazo, hydroxyl, methoxy, athoxy, tert-butoxy, benzyloxy, acetoxy, pivaloyloxy, phenyloxy, benzoxyloxy

R ¹ is (1 ') chloro, fluoro or bromo, (2') C 1 -C 4 alkyl, 1-hydroxyethyl, 1-benzyloxyethyl, 1- (benzyloxycarbonyloxy) ethyl 1-phenylacetoxyethyl, 2 -fluoro-1-hydroxyethyl, isopropyl, phenyl or benzyl, (3 ') methoxy, ethoxy, isopropoxy, phenoxy or benzyloxy, (4') methylthio, (5 ') formyloxy, acetoxy (f) or acetoxy (f); ) mesyloxy or tosyloxy, (7 ') formamido, acetoamido, fluoroacetamido, trifluoroacetamido or chloroacetamido, (8') the radical R ⁱⁿ -Ala-1 H, where R ^v is acetyl, t-butoxycarbonyl, benzoxycarbonyl or benzoxycarbonyl (9 ') the radical R ⁱⁿ -Val-NH, wherein R ^v is as defined above, or (10') the radical Val-Pro-NH, Lys-NH, Ala-Ala-Pro-NH, wherein the terminal amino group of the residue Val, Lys or Ala, or -amino group of Lys is either free or acylated R radical as defined above ^in,

R ² is hydrogen, chlorine or fluorine,

R ³ represents hydrogen, methyl, benzyl or bromine and

R ⁴ is either hydrogen or (1 ') methyl, chloromethyl, bromomethyl or benzyl, (2') chlorine, (3 ') methoxy or benzyloxy, (4') methylthio, (5 ') formyl, acetyl , benzoyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, (6 ') methoxymethyl, ethoxymethyl, isopropoxymethyl, benzyloxymethyl, phenoxymethyl, phenyl or 3-pyridyloxy, and 3-pyridyloxy and 3-pyridyloxy; the rings are either unsubstituted or substituted by one or two of the same or different substituents selected from the group consisting of hydroxyl, carboxyl, amino and C 1 -C 4 alkoxycarbonyl, (7 ') methylthiomethyl, phenylthiomethyl, methylsulfonylmethyl with couplings, phenylsulfinylmethyl, phenylsulfonylmethyl or -CH ₂ -S-CH ₂ -CH (NH ₂ ) CO ₂ H wherein the amino group is either free or protected with tert-butoxycarbonyl, benzoxycarbonyl or acetyl and the carboxyl group is either free or protected in the form of ethyl ester, tert-butyl ester, benzyl ester, methyl ester or diphenylmethyl ester, (8 ') -CH ₂ -S-Het residue, wherein Het represents a heterocyclic ring, preferably selected from the group consisting of residues

CH-

ch ₂ every ₂ h

CH ₂ CH ₂ CH ₂ CC ~ h (9 ') acetoxymethyl, benzoxymethylovou group ·, fenylacetoxymethylovou group or an alkanoyloxymethyl group having from 3 to 10 carbon atoms in the alkanoyl part, wherein the above groups are either unsubstituted or substituted by one or two identical or different substituents selected from the group consisting of carboxyl, hydroxyl, and amino, wherein the amino may be either free or acylated with an acyl group (Ac), a benzoxycarbonyl group (Cbz), a tert-butoxycarbonyl group (Boc), a succinyl group HOOCCH ₂ CH ₂ CO- or a glutaryl group of hooc-ch ₂ -ch ₂ -ch ₂ -co-, (10 ') a Z-OCH ₂ - residue, wherein Z is Val-Pro,

Ac-Val-Pro, Cbz-Val-Pro or Boc-Val-Pro, (11 ') acetylthiomethyl, (12') aminomethyl or C 1 -C 4 alkylaminomethyl, the alkyl moiety being either unsubstituted or substituted with a carboxyl group, in particular a -CH ₂ -Ala, -CH ₂ -Gly group or

_-CH2 -Val, (13 ') trialkylamoniomethylovou group in which the alkyl is selected from methyl, ethyl, propyl or butyl, optionally substituted with carboxyl, alkyl (cycloalkyl) amoniomethylovou group selected from the group consisting of radicals of the formula

wherein A is as defined above, pyridinomethyl

-ch _{2 -} k

 where A is as defined above,

A 4-carbamoylpyridiniomethyl group or a quinuclidiniomethyl group optionally substituted with a carbamoyl group or a residue as defined above, or (14 ') acetylaminomethyl group, benzoylaminomethyl group, Ala-NH-CH ₂ -, Gly-NH-CH ₂ -, Val-NH-CH ₂ - NH-CH ₂ -, Phe-NH-CH ₂ - in which the terminal amino residue of Ala, Gly, Val, Pro, Phe is either free or acylated with a radical selected from the group consisting of Ac, Cbz, Boc, succinyl and a glutaryl group, or a Z ₂ NH-CH ₂ - residue, wherein Z is Val-Pro, Ala-Aia or Ala-Pro, and the terminal amino group of Val and Ala is either free or acylated with a radical selected from the group consisting of Ac, Cbz, Boc, succinyl and glutaryl groups, and pharmaceutically and veterinarily acceptable salts thereof.

Even more preferably, the compounds correspond to the general formulas Ia and Ib

in which

A represents hydrogen, methyl, ethyl, tert-butyl, neopentyl, phenyl, benzyl, 1-phenylethyl, dimethylphenyl, diphenylmethyl, propenyl, phenylethynyl, cyclopentyl, 1-carboxycyclopentyl a diazomethyl group, a chloromethyl group, a hydroxymethyl group, a methoxymethyl group, an acetoxymethyl group or a pivaloyloxymethyl group,

· R ³ represents a chlorine, bromine or fluorine atom, methoxy, formamido, acetamido, trifluoroacetamido, methyl, ethyl, 1-hydroxyethyl, l- (benzyloxycarbonyloxy) ethyl, 1-benzoyloxyethyl group, l- (phenylacetoxy) ethyl or Ala-NH, Ac-Ala-NH, Succinyl-Val-NH, L-Val-L-Pro-NH, Succinyl-Lys-NH, Ala-Ala-Pro-NH or Ac-Ala-Ala-Pro- NH,

R ² is hydrogen,

R ³ is hydrogen, methyl or bromine,

R ⁴ represents methyl, bromomethyl, acetoxymethyl, hydroxymethyl, carbamoyloxymethyl, methoxymethyl, carboxyl, phenoxymethyl, aminomethyl, pyridinomethyl or a radical selected from the group consisting of radicals

1) -ch ₂ oconh-ch ₂ every ₂ h,

2) -CH ₂ OCONH-CH (R ^vi ) CO ₂ H, wherein R ^VI represents a phenyl group or a straight or branched alkyl group having 1 to 7 carbon atoms,

3) -ch ₂ oc (o) ch ₂ ch ₂ every ₂ h,

5) -CH ₂ OC-CH ₂ NH ₂ or Ν-Ac-, N-Boc- or its

N-Cbz derivative,

6) -CH 2 OC-CH-CH 3 or Ν-Ac-, N-Boc- or its

O nh ₂

N-Cbz-derivative, - ---------- 7) -CH ₉₀ O-CH-CH (CH ₇ ) ₉ or its Ν-Ac-, N-BocII I

NH 3 or N-Cbz derivative,

8) -CH ₂ OCOCH CH-NH-C- (CH _{2) 3} -CO ₂ H,

N-CO-CH-CH (CH3) ₂ or N-Ac-,

NH.

N-Boc- or N-Cbz-derivative,

10) -CH ₂ -OCH ₂ -Ph or -CH ₂ O

11) -CH ₂ -OC-Ph or

-CH ₂ OC-CH ₂ Ph,

12) —CH ₂ SO ₂ CH ₃ or

-CH ₂ -S (O) Ph,

ch ₂ co ₂

-ch ₂ nh every ₂ h,

15) -CH ₂ NH-C-CH-CH (CH ₃ ) ₂ and nh ₂

16) -CH ₂ SHet, wherein Het represents a heterocyclic ring preferably selected from the group consisting of radicals

ch ₂ ch ₂ ch ₂ co ₂ h

'and and p / N-

N

SCH ₂ CO ₂ H and their pharmaceutically and veterinarily acceptable salts.

Specific examples of preferred compounds of the invention are set forth in the following reviews

Compound No. AR ¹

R '

1 2 tC ₄ H ₉ 1? Cl lt 3 ’ lt lt 4 ti lt 5 tt II 6 tt tt 7 tt lt 8 VI IV 9 tt tt

H CH ₃ '· CH ₂ Br

CH ₂ OCOCH ₃

CH ₂ OH ch ₂ oconh ₂ ch ₂ and ₃

CH ₂ O-Ph

CH ₂ NH ₂

10 tt II 11 th tt 12 tt 11

ch ₂ oconh-ch ₂ co ₂ h ch ₂ ococh ₂ ch ₂ co ₂ h

CH ₂ OCOPh

CH ₂ OCO ·

Compound No. AR ¹

R ³ R ⁴ t C ₄ H _g Cl

H CH ₂ OCOCH ₂ -Ph CH ₂ S-Ph

ch ₂ occh ₂ nh ₂

O

CHnOCCHoNH-C-Ot-C.Hn ² || ³ Feb ⁴⁹ oo

CH ₉₀ ° C-CH-CH ² II I nh ₂

ch ₃ ch ₃

CH21

CH, OC-CH-CH ² II

About NH

CHCOOt-C ₄ Hg

Compound No. AR ¹ CH ₃ Cl ₄ H _g Cl

H CH ₉₀ O-CH ² II o

NHC-Ot-C ₄ H _Q ^{4 4} o

CH ₉ OC-CH-CH ₉ CO ₉ H 2 11 I 2 2

About NH.

CH ₉₀ O-CH-CH ₉ ² 11 I ³

O NH-J- (CH ₂ ) ₃ -CO ₂ H o

CH ₉ 0C Z II

CH27

N-C-CH-CH II

\

CHCHC-CH-CH

About NH CH.

AND

COO-tC ₄ H _g ch ₂ with ₂ ch ₃

O

II

CH ₂ S-Ph t C ₄ H _g Cl H

II fl II

II II II ^C 2 ^H 5 II II fl II II CH ₂ Ph II II II II II CH ₂ -tC ₄ H _g II II Ph II II H II II ch ₂ eyes ₃ II II ch ₂ and ₃ II II CH _(CH3) Ph II II ch ₂ ci II II ch ₂ n ₂ II II ch ₃ ll II ch ₂ i II II ch ₂ oh II II CH ₂ OPh II 11 t C ₄ H _g och ₃ Η II II 11 II II 1 «

CH ₂ NH-C-CH (NH ₂ ) CH (CH ₃ ) ₂ O ch ₃ ch ₂ oc ₃ ch ₂ oc ₃ ch ₂ oconhch ₂ co ₂ h ch ₂ oc ₃ ch ₃

CH ₂ Br ch ₂ ococh ₃ Compound No. AR ¹

R-

52 tC ₄ Hg och ₃ H ch ₂ oh 53 II II II ch ₂ oconh ₂ 54 11 11 -11 ch ₂ and ₃ 55 II 11 11 CH ₂ O-Ph 56 II II II ^CH 2 ^NH 2

ch ₂ oconh-ch ₂ co ₂ h ch ₂ ococh ₂ ch ₂ co ₂ h

CH ₂ OCOPh

CH ₂ OCOCH ₂ Ph

CH ₂ S-Ph ch ₂ with ₂ ch ₃

O

II

CH ₂ S-Ph

-CH ₂ N ⁺

CH Compound No. AR ¹

R ³ R ⁴ C ₄ H _g OCH ₃

ch ₂ eyes ₂ nh ₂

CH ₂ OCOCH ₂ NHCOO-tC ₄ H _g

, CH72 ch ₂ oc-ch-ch <5

NH.

CHr

CH73 ch ₂ oc-ch-ch

NH 2 OH-CHC

KTW \

CHC-Q- _t -C ₄ H ₉ ch ₃

CH, OC-CH ² II o

nh ₂ Compound No. AR ¹

R ³ R ⁴ : h.

tC ₄ H _g OCH ₃ ch ₂ oc-ch

NHC-OtC ₄ H ₉

CH ₉ OC-CH-CH ₉ CO ₉ H 2 II I ²² o nh ₂

II

CHoOC-CH-CH-, ² II | ^J o n-c- (ch ₂ ) ₃ -co ₂ h

II

CH _{(CH3) 2}

NHCO ₂ -tC ₄ H ₉ fl

CO ₂ CHPh ₂

NHCO ₂ -tC ₄ H ₉

CH ₂ SCH ₂ CH (CO ₂ H) NHCO ₂ -tC ₄ H ₉ ch ₂ sch ₂ ch (co ₂ h) nh ₂ CH ₂ NH- <j: -CH (NH ₂ ) CH (CH ₃ ) ₂

O

CS. 277027 B6 Compound No. AR ¹

R ³ R ⁴

84 85 86 87 88 89 ^C 2 ^H 5 t ₁ CH ₂ Ph tt CH ₂ -t C ₄ H _g Ph och ₃ tt tt tt H tf lt tf th tt CH ₂ SOPh CH ₂ OCOCH ₃ CH ₂ SOPh CH ₂ OCOCH ₃ tt tt 90 H tt 91 ch ₃ tt ff 92 ch ₂ and ₃ tt tf 93 CH ₂ OPh tt lt tt 94 CH ₂ C1 lt lt tt 95 tC ₄ H ₉ F th tt ‘96 lt NHCH II 0 tt tt 97 tt NHCCH II 0 3 lt tf 98 lt NHCCF II 0 3 lt ff 99 lt ch ₃ tt tf 100 ALIGN! t C ₄ H _g ^C 2 ^H 5 ^ OH lt lt 101 th CH -ch ₃ ff tt 102 lt CH 2 OCH, Ph II ² 0 tt lt

ch ₃

103

nhcooh ₂ lt tt ch ₃

CS 277027 Ββ Compound no.

104

105

106

107

108

109

110

111

AR ¹ tC ₄ H ₉

NH-C-CH

II o

NH-C-CH II o

R ³ R ⁴

-NH-CH _{(CH3) 2}

NHC (CH) _o CO ₉ H II ^zz o

tC ₄ H _g NH-C-CH- (CH ₂ ) ₄ -NH ₂ o ₂ h ₂ ch ₂ co ₂ h ch ₂ oc ₃

It II

NHCOCHCH ₃

NHCOCH j-tC ₄ H ₉ Cl Cl CH ₂ CH ₃ CH ₃ OCOCH ₃

Compound II

R ³ R ⁴

^T_C 112 9 ^H 4 ^0CH 3

113 CH ₂ F ch ₃ ch ₂ oc ₃

II M

Compound No. AR ¹

114 CH ₂ Ph 115 ch ₃ 116 ^C 2 ^H 5 117 tC ₄ H ₉ 118 H 119 Ph 120 ch ₂ n ₂ 121 ch ₂ ci 122 CH ₂ Ph 123 ch ₃ 124 c ₂ h ₅ 125 tC ₄ H ₉ 126 H 127 Ph 128 CH ₂ OPh 129 ch ₂ ci 130 tC 'H _o

Cl and ₃ Compound No. A

131

132

133

NHCH

II o

NHCCHII 'o

NHCCF134

135 ch ₃ ^C 2 ^H 5

OH

136

CH

CHOC-O-CH ₂ Ph

137

CH

138

CH-

-NHCOCH <

139

NH-C-CH II o

CHNH140

NH-C-CH

II 'o

CHCS 277027 B6 Compound No. AR ^3,

141

NH-C- (CH) ₉ CO ₉ H II ^{2 2}

142

NH-G

II

N-CO-CH

CH

NH ₂

143

NH-C-CH- (CH-) _δ -ΝΗα 1 | I ²⁴ 2

O NHCO-CH ₂ CH ₂ CO ₂ H

144

CH nk ₂

145 Compound No. AR ¹

146 C ₂ H ₅ ........... Br

Compound No. AR ^x R ^J R ⁴

147 ^C 2 ^H 5 och ₃ H ch ₃ 148 Ph Cl H ch ₃ 149 -ch = ch-ch ₃ Cl H ch ₂ eyes ₃ ft lt 150 tC ₄ H ₉ Cl H ch ₂ -s - 1

CH

151 and ₃ h

152

Cl

CHV ^CH

CH ₂ -F ₁₀ Compound No. AR ¹ R ^J R ⁴

153 OCH ₃

N

154 ° C ₄ H _g OCH ₃

Br, CH ₂ -S

CH155 and ₃

156 and ₃

N

H

157 and ₃

H

II

N

158 and ₃ h every ₂ h

CH ₂ CH ₂ CH ₂ CO ₂ H Compound No. A

R ³ R ⁴

160

CH

161 every ₂ h

162

163 CMe ₃ Ph ch ₂ eyes ₃

161 CMe ₂ Ph

N

CH Compound No. AR ¹ R ³ R ⁴

166 C-C-Ph

167 ·· mt

co ₂ h

168 ch ₂ -s

The process for the preparation of the compounds according to the invention is characterized in that, in any order, the carboxyl group -CO ₂ H is converted in the 4-position of the cephem core or in the 3-position of the penam core of the compound of formula IIa and IIb.

R ¹

co ₂ h

(IId) y in which:

R ¹ , R ² , R ^3, and R ⁴ are as defined above, to the carbonyl group -CA, where A is as defined above, and the sulfur atom at the 1 position 11 o

The cephem or penam core is oxidized to give the desired sulfone, whereupon optionally the resulting compound of formula Ia or 1b is converted to a pharmaceutically or veterinarily usable salt.

The conversion described above is typically carried out by activating the carboxyl group in the form of an acid halide, anhydride, mixed anhydride, thioester or ester, and then reacting with the synthetic equivalent of anion A ', where A is as defined above. Suitable synthetic equivalents A 'are the following organometallic derivatives containing residue A:

A-MgX (Grignard reagents),

A-Li (organolithium reagents, for example phenyllithium),

A ₂ CuLi (lithium dialkyl copper reagents),

A (PhS) CuLi (lithium-phenylsulfenyl (alkyl) cupric reagents),

A-Cu (copper reagents such as copper acetylides),

A ₂ Cd (organocadmium reagents),

AZnBr (organo-zinc reagents),

ARh (CO ₃ ) (Ph ₃ P) ₂ (bis (triphenylphosphine) carbonylalkyl reagents) and

(Organotin reagents wherein X is C 1 -C 12 alkyl, chlorine or phenyl; and n can be 0, 1, 2, 3 or 4).

When A is a hydrogen atom, suitable synthetic equivalents are mixed hydrides, in particular organoboronous, organoaluminium or organotin hydrides, for example copper (II) boron (III) borohydride, tert-butoxyaluminium hydride or tributyltin hydride.

When A is CHN ₂ , the synthetic equivalent of A is diazomethane. The compounds obtained in which A represents a CHN ₂ group can be further converted to the corresponding compounds in which A represents a CH ₂ Cl group (by reaction with hydrogen chloride in an inert organic solvent, for example dichloromethane, ether or acetone), a CH ₂ I group ( by reaction with molecular iodine), CH ₂ OH (by reaction with sulfuric acid in dioxane / water), CH ₂ OCH ₃ (by reaction with boron trifluoride etherate in methanol), CH ₂ OCOR ', where R' is as defined above (reaction with a compound of formula R'CO ₂ H), a CH ₂ OSO ₂ R 'group (by reaction with a compound of formula R'SO ₃ H), or a group CH ₃ (reaction with an excess of 47% hydrogen iodide).

The conditions of the above reactions are described or discussed in basic textbooks (see, inter alia, J. March, Advanced Organic Chemistry, McGraw-Hill) and may vary within wide limits depending upon the particular substrate and the nature of the Group A.

In the oxidation step, the respective compounds are oxidized to the corresponding sulfones. Preferred oxidizing agents are peracids in an inert organic solvent or a mixture of water and an organic solvent. Suitable peracids are, for example, peracetic acid, m-chloroperoxybenzoic acid, monoperphthalic acid, and suitable solvents are chloroform, dichloromethane, tetrahydrofuran and ethanol. Another oxidizing agent used preferably for the penam type substrates is potassium permanganate in a mixture of water and acetic acid.

It will be understood that in the process described above, any functional or functional groups which may be required or desirable can be conveniently protected and then optionally deprotected upon completion of the reaction. It should also be noted that at the end of the process described above, or at any stage thereof, the R ⁴ group can be conveniently converted to another R ⁴ group within the above process.

31.

CS 277027 B6 - 'definition of the meaning of this group. Such conversion or deprotection are well known in the art of the cephemed derivatives of formula (IIa) and their sulfones.

Compounds of formulas IIa and IIb are known or can be prepared from known compounds by known methods.

The potential of protease inhibitor therapy in the treatment of conditions resulting from the destruction of connective tissues has recently attracted considerable attention. Considerable efforts have been devoted to the search for inhibitors of human leukocyte elastase (HLE), which is the primary destructive agent in pulmonary emphysema and is likely to be involved in rheumatoid arthritis (JC Power, Am. Rev. Resp. Diseases 127, 54-58, 1983; CH; Hassal et al., FEBS Letters, 183, No. 2, 201, 1985; G. Weinbaum and VV Damiano, TIPS, 8, 6, 1987; M. Velvart, Rheumatol. Int. 1, 121, 1981). Low molecular weight inhibitors appear to have a number of advantages over natural high molecular weight protease inhibitors obtained either from plant or animal sources;

(1) may be obtained in larger quantities;

2) their structure can be rationally determined or optimized,

(3) are not antigenic; and

4) can be administered orally or in aerosols.

Many of the low molecular weight elastase inhibitors found hitherto contain reactive functional groups (chloromethyl ketones, isocyanates, etc.). Thus, these substances may react with the functional groups of the proteins and therefore the compounds may be very toxic. In this regard, β-lactam derivatives are of particular interest because, although they react with proteases, they are, as is well known, non-toxic at very high concentrations.

The compounds of the invention are characterized by their high HLE inhibitory activity. In in vitro tests, these compounds have advantages over previously known β-lactam inhibitors. In addition, the compounds are unexpectedly well stable at physiological pH, suggesting their further advantages under in vivo conditions. For example, Compound No. 51 (Example 4) compares favorably with the corresponding cephalosporanic acid ester (comparator) in terms of (t1 / 2), higher complexing rate, better chemical stability with HLE (K _on ), lower dissociation rate ( K _O f _f ) and better efficiency (lower apparent dissociation constant of HLE - inhibitor at steady state,

K _± ^ss ). The results of this comparison are summarized below.

XtC.H _o

9 substance chemical stability ( ^and kinetic parameters of HLE ^(b) inhibition t 1/2 (h) ^K on ^K off (10 ⁴ M ^-1 s ^-1 ) (10 ^_3 s ^_1 )

K ^ ³ (nM) Compound No. 51 19.3 (X = binding) Comparative 3.2 (X = -O-)

2.0 2.6 11

0.9 3.5 18.4

Legend:

chemical stability at 37 ° C in 0.05 M phosphate buffer pH 7.4 (5% dimethylsulfoxide as solubilizing vehicle) was determined by monitoring the time course of starting material loss (fairly rapid kinetics; initial concentration 10 mM) using a high resolution liquid chromatography (stationary phase Whatman Partisphere 5 C18, column 110x4.7 mm (internal diameter), mobile phase A: 0.1M phosphate buffer pH 2.5, mobile phase B: a 60:40 mixture of phase A and acetonitrile, detection UV radiation at λ = 254 nm) kinetic parameters of HLE inhibition (Calbiochem. Lot 702738) are determined at 37 ° C in 0.027M phosphate buffer pH 7.4 with 1% dimethylsulfoxide, 1% acetonitrile and NaCl (I = 0.15) ) by monitoring the release of 7-amino-4-methylcoumarin (fluorescence detection) from N-methoxysuccinyl-alanyl-prolyl-valyl-7-amido 4-methylcoumarin as a substrate, according to the following equations:

(Vz-Vs) [P] = _Vt + (1-e kt), ^K = ^K off κ _οη · EU + -, + CS]! ^ + [SJ / Kjh i + [sj / Kjh + [υ] / κ ^ where [P3, [I] [S] = concentration of product, inhibitor and substrate 'V _s = steady state velocity V _z = velocity at time O

V _Q = speed at [I] - O

- Michaelis constant for enzyme-substrate pair (independently determined under the same experimental conditions)

Because of their high elastase inhibitory activity and very low toxicity, the compounds of the invention can be used in the treatment of inflammatory and degenerative diseases caused by proteolytic enzymes in mammals, including humans. The disclosed compounds can be used in the manufacture of medicaments useful for preventing or arresting the progression of diseases caused by proteolytic degradation of lung and connective tissues, to reduce or suppress inflammation and fever, and to relieve pain. The above-mentioned diseases include emphysema, acute respiratory insufficiency, bronchitis, rheumatoid arthritis, osteoarthritis, infectious arthritis, rheumatic fever, spondylitis, gout, lupus, psoriasis and the like.

Accordingly, the invention provides pharmaceutical and veterinary compositions comprising a suitable carrier and / or diluent and, as active ingredient, 4-acylcephemsulfone of formula Ia or 3-acylpenamsulfone of formula 1b, or a pharmaceutically or veterinarily acceptable salt thereof. Pharmaceutical or veterinary compositions containing a compound of formula (Ia) or (1b) or a salt thereof may be prepared in conventional manner using conventional, non-toxic pharmaceutical carriers or diluents in a wide variety of dosage forms for various modes of administration. In particular, the compounds of formula Ia or 1b can be administered

(a) orally, for example in the form of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.

Formulations for oral administration may be prepared by any of the methods known in the art for the manufacture of pharmaceutical compositions. These compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to give the resulting composition a good appearance and acceptable taste.

Tablets contain the active ingredient in admixture with non-toxic farmed vehicles and excipients suitable for the manufacture of tablets.

These may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binders such as starch, gelatin or acacia, and glidants such as magnesium stearate, stearic acid or talc.

The tablets may be uncoated or may be coated by known techniques to slow their disintegration and absorption in the gastrointestinal tract and thereby prolong the effect. Materials such as glyceryl monostearate or glyceryl distearate may be used for this purpose.

Oral formulations may also be in the form of hard gelatin capsules containing the active ingredient in admixture with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia. As the dispersing or wetting agents, natural phosphatides, for example lecithin, or condensation products of alkylene oxides with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadeca-ethyleneoxycethanol, or ethylene oxide condensation products with partial esters derived acids and hexitol, such as polyoxyethylene sorbitol monooleate, or ethylene oxide condensation products with partial esters derived from fatty acids and hexitol anhydride, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, or one or more coloring agents, or one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain thickeners, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those mentioned above and flavoring agents may be added to produce palatable dosage forms for oral administration. These compositions may be preserved by the addition of antioxidants such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water contain the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those already mentioned above. Said preparations may also contain other excipients, for example sweetening, flavoring and coloring agents.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or a mixture of these oils. Suitable emulsifiers may be natural gums such as gum arabic or tragacanth, natural phosphatides such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monoate . These emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be prepared using sweetening agents, for example glycerol, sorbitol or sucrose. The compositions may also contain a demulcent, a preservative, a sweetener and a colorant.

(b) parenterally, either subcutaneously, intravenously, intramuscularly or intrasternally, or by infusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions.

Thus, the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. These suspensions may be prepared in a manner known per se using the abovementioned suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Suitable usable vehicles and solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a suitable solvent or suspending medium, and non-fixed oils of any kind may be employed, including synthetic mono- and diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of these injectables.

(c) by inhalation, in the form of aerosols or solutions for inhalers.

d) rectally, in the form of suppositories prepared by mixing the active ingredient with a suitable non-irritating carrier which is solid at normal temperature but liquid at the rectal temperature, so that when applied in the rectum it melts and the active ingredient is released therefrom. Such materials are cocoa butter and polyethylene glycols.

(e) topically, in the form of creams, ointments, jellies, solutions or suspensions.

The invention also provides a method of preventing and treating inflammation and degenerative diseases by administering a therapeutically effective amount of one or more of the active ingredients of the invention to a human or mammal in need of such treatment.

The daily doses range from about 0.5 to 100 mg of active ingredient per kg body weight of the patient, depending on the efficacy of the particular compound used, the age, body weight and condition of the patient being treated, the type and severity of the disease, the frequency administration and administration route. The daily doses in human medicine are preferably from 50 mg to 2 g.

The amount of active agent that can be combined with the carriers to produce a single dosage form varies depending on the patient being treated and the particular route of administration.

For example, a composition intended for oral administration in human medicine may contain from 5 mg to 2 g of active ingredient which is mixed with a suitable amount of carrier material which may be about 5 to 95% of the total weight of the composition. Unit dosage forms generally contain about 25-500 mg of active ingredient.

The invention is illustrated by the following non-limiting examples.

Example 1 (7a) -chloro-4-ethylcarbonyl-3-methyl-3-cephem-1,1-dioxide (Compound No. 33)

A solution of (7α) -chloro-3-methyl-3-cephem-4-carboxylic acid (515 mg) in dry benzene (30 mL) was stirred with oxalyl chloride (0.38 mL) at 7 ° C for 1 min. Evaporation of the volatiles in vacuo afforded crude (7α) -chloro-4-chlorocarbonyl-3-methyl-3-cephem.

IR (KBr): 9 _max 1780 (broad band), 1750 cm ^-1 .

This material was taken up in dry ether, and 195 mg of aluminum chloride and 1.5 ml of 2M ethereal ethyl magnesium bromide were added to the solution under nitrogen at -70 ° C. After 5 minutes, the reaction mixture was poured into ice water and washed first with aqueous sodium hydrogen carbonate solution and then with aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated in vacuo to give 210 mg of (7α) -chloro-4-ethoxycarbonyl-3-methylcephene as a mixture of isomers.

This mixture was dissolved in 9 mL of a mixture of 0.05 M phosphate buffer pH 7 and ethyl acetate (1: 2) and 385 mg of m-chloroperoxybenzoic acid was added at 0-5 ° C. The reaction mixture was stirred at room temperature for 1 hour, then poured into ice water and washed successively with aqueous sodium metabisulfite solution, aqueous sodium bicarbonate solution and aqueous sodium chloride solution. After drying over sodium sulfate, the solvent was evaporated and the residue was subjected to silica gel chromatography. 90 mg of pure title compound are obtained in the form of a syrup.

IR (chloroform): max ^1,780 > ^{1,880 cm} ~ ^ ·

Example 2

4-tert-Butylcarbonyl- (7X) -methoxy-3-methyl-3-cephem-1,1-dioxide (Compound No. 49)

To a solution of 1.68 g of (7α) -methoxy-3-methyl-3-cephem-4-carboxylic acid in 100 mL of dry benzene at 7 ° C was added a few drops of dry dimethylformamide and 1.26 mL of oxalyl chloride. The reaction mixture was stirred for 45 minutes and then the volatiles were evaporated in vacuo to give crude 4-chlorocarbonyl- (7a) -methoxy-3-methyl-3-cephem.

This material is taken up in 50 ml of dry tetrahydrofuran and 195 mg of aluminum chloride and 5.13 ml of a 1.43 M ether solution of tert-butyl magnesium chloride are added under nitrogen at -70 ° C. The reaction mixture was stirred at -50 ° C for 15 minutes, then poured into ice water, washed sequentially with aqueous sodium bicarbonate solution and brine, and evaporated to dryness. Crude 4-tert-butylcarbonyl- (7a) -methoxy-3-methylcephene is obtained.

A portion of this material (300 mg) was dissolved in 70 mL of ethyl acetate and 570 mg of m-chloroperoxybenzoic acid was added at room temperature. After 1.5 hours, the reaction mixture was washed successively with aqueous sodium bisulfite, aqueous sodium bicarbonate, and aqueous sodium chloride. After drying over sodium sulfate, evaporation of the solvent and chromatography of the residue on silica gel, 114 mg of pure title compound is obtained in the form of a white powder, melting at 128 ° C.

IR '(chloroform):? _Max ^1785, 1685 cm' ^1.

NMR (200 MHz, CDCl3, δ ppm):

1.26 (9H, s), 1.70 (3H, s), 3.51 and 3.93 (2H, d each, J = 18 Hz), 3.56 (3H, s), 4.66 and 5.16 (1H each, d, J = 1.6 Hz).

Mass spectrum (FD): 301 m / z (M ^& lt ^{; +} & gt ^; ).

Example 3

3-Bromomethyl-4-tert-butylcarbonyl- (7a) -methoxy-3-cefem-1,1-dicxide (Compound No. 50)

A solution of 130 mg of 4-tert-butylcarbonyl- (7a) -methoxy-3-methyl-3-cephem-1,1-dioxide (see Example 2), N-bromosuccinimide (100 mg) and 5 mg of α, α'-azoisobutyronitrile in 20 ml of carbon tetrachloride and 15 ml of dichloromethane are heated under reflux for 2 hours. Evaporation of the solvent and chromatography of the residue on silica gel gave 130 mg of the title compound as a white powder.

IR (chloroform): _max 1790, 1690 cm ^-1 .

NMR (200 MHz, CDCl3, δ ppm):

1.31 (9H, s), 3.56 (3H, s), 3.58 (1H, d, J = 14.6 Hz), 3.79 and 3.91 (2H, each d, J = 11 4 Hz), 4.28 (1H, dd, J = 14.6 and 1.4 Hz), 4.76 (1H, dd, J = 1.9 and 1.4 Hz), 5.20 (1H , d, J = 1.9Hz).

Mass spectrum (FD): 379 m / z (M ^& lt ^{; +} & gt ^; ).

Example 4

3-Acetoxymethyl-4-tert-butylcarbonyl- (7a) -methoxy-3-cephem-1,1-dioxide (Compound No. 51)

A solution of 93 mg of 3-bromomethyl-4-tert-butylcarbonyl- (7a) -methoxy-3-cephem-1,1-dioxide (see Example 3) in 5 ml of dry acetonitrile is treated with 0.15 ml of acetic acid and 118 mg. silver acetate was stirred at room temperature for 1 hour. The reaction mixture was taken up in ethyl acetate and washed successively with aqueous sodium bicarbonate solution and brine. Drying over sodium sulfate, evaporation of the solvent and chromatography of the residue on silica gel gave 45 mg of the title compound as a white powder, m.p. 134 ° C.

IR (KBr): ν _max 1,780, 1,732, 1,687 cm ^-1 .

NMR (200 MHz, CDCl3, δ ppm):

1.28 (9H, s), 2.08 (3H, s), 3.57 (3H, s), 3.83 (1H, d,

J = 18.5 Hz), 4.00 (1H, dd, J = 18.5 and 1.5 Hz), 4.43 (2H,

ABq, J = 1.9 Hz), 4.73 (1H, dd, J = 1.9 and 1.5 Hz), 5.20 (1H, dd, J = 1.9 Hz).

Mass spectrum (FD): 359 m / z (M ^& lt ^{; +} & gt ^; ).

Example 5

4-tert-butylcarbonyl- (7a) -chloro-3-methyl-3-cephem-1,1-dioxide (Compound No. 1)

To a solution of 2.32 g of (7α) -chloro-4-chlorocarbonyl-3-methyl-3-cephem (see Example 1) in 80 mL of dry tetrahydrofuran at -70 ° C under nitrogen atmosphere was gradually added 2.076 g of copper iodide and 4.95 ml of a 2M ethereal solution of tert-butyl magnesium chloride.

The reaction mixture was allowed to warm to -50 ° C and poured into ice water. After stirring for 10 minutes, the mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium bicarbonate solution, dried over sodium sulfate and the solvent was evaporated to give crude 4-tert-butylcarbonyl- (7α) -chloro-3-methylcephene.

This material was purified on a short silica gel column and then treated with 2.5 g of m-chloroperoxybenzoic acid in ethyl acetate overnight at 10 ° C. The reaction mixture was diluted with ethyl acetate, washed successively with aqueous sodium bisulfite solution, aqueous sodium hydrogencarbonate solution and aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography to give 550 mg of the title compound as a white powder, melting at 218 ° C.

IR (KBr): 9 _max 1773, 1687 cm ^-1 .

NMR (200 MHz, CDCl3, δ ppm):

1.26 (9H, s), 1.72 (3H, s), 3.60 (1H, d, J = 18.1 Hz), 3.96 (1H, dd, J = 18.1 and 1), 3 Hz), 4.76 (1H, dd, J = 1.3 and 1.7 Hz), 5.32. (LH, d, J = 1.7Hz).

Example 6

3-Bromomethyl-4-tert-butylcarbonyl- (7a) -chloro-3-cephem-1,1-dioxide (Compound No. 2)

A solution of 150 mg of 4-tert-butylcarbonyl- (7a) -chloro-3-methyl-3-cephem-1,1-dioxide (see Example 5) in 40 ml of carbon tetrachloride in the presence of 114 mg of N-bromosuccinimide and 2 mg of α, The α'-azoisobutyronitrile was refluxed for 4 hours. Evaporation of the solvent and chromatography of the residue gave 112 mg of the title compound as a white powder, m.p. 155 ° C. 40 mg of starting material are also obtained in this chromatography.

IR (KBr): 1795, 1690 cm ^-1 .

Mass spectrum (FD): 383 m / z (M ^& lt ^{; +} & gt ^; ).

NMR (200 MHz, CDCl3, δ ppm):

1.31 (9H, s), 3.65 (1H, d, J = 18.1 Hz), 3.85 (2H, ABq,

J = 11.4 Hz), 4.32 (1H, dd, J = 11.4 and 1.3 Hz), 4.88 (1H, dd, J = 1.8 and 1.3 Hz), 37 (1 H, d, J = 1.8 Hz).

Example 7

3-Acetoxymethyl-4-tert-butylcarbonyl- (7a) -chloro-3-cephem-1,1-dioxide (Compound No. 3)

A solution of (7α) -chlorcephalosporanic acid (50 g) in dichloromethane (450 ml) and ethanol (150 ml) was treated with m-chloroperoxybenzoic acid (80 g) at room temperature overnight and at room temperature for 4 hours. The reaction mixture was washed with aqueous sodium bisulfite solution, the layers were separated and the solvent was evaporated from the organic layer in vacuo. The residue was dissolved in 400 ml of ether and left to crystallize in a refrigerator overnight. 28 g of (7α) -chlorcephalosporanic acid 1,1-dioxide are obtained in the form of a white powder.

IR (KBr): _max 3400 (broad band), 1800, 1740 to 1700

715 cm ¹ .

NMR (90 MHz, CDCl3, δ ppm):

2.08 (3H, s), 3.90 (2H, ABq, J = 18Hz), 4.85 (1H, d,

J = 1.5 Hz), 4.93 (2H, ABq, J = 13.5 Hz), 5.28 (1H, d,

J = 1.5 Hz), 9.73 (1H, bs, exchangeable with D ₂ O).

732 mg of the above product are reacted with 0.15 ml of oxalyl chloride in the presence of a few drops of dimethylformamide in 20 ml of dry tetrahydrofuran under nitrogen at 7 ° C. The reaction mixture was allowed to warm to room temperature, cooled to -70 ° C for 1.5 hours and treated with 453 mg of copper (I) iodide under nitrogen. After stirring for 15 minutes, 2.5 mL of a 2M tert-butylmagnesium chloride ether solution was added. The temperature was allowed to rise to -10 ° C and the reaction mixture was poured into ice-water. After filtration, the solution was shaken between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried, evaporated and the residue subjected to silica gel chromatography. 250 mg of the title compound is obtained as a white powder, melting at 168 ° C.

IR (KBr): 9 _max 1788, 1732, 1690 cm ^-1 .

NMR (200 MHz, CDCl3, δ ppm):

1.28 (9H, s), 2.09 (3H, s), 3.74 (1H, d, J = 18.1 Hz), 4.02 (1H, dd, J = 18.1 and 1), 0 Hz), 4.45 (2H, ABq, J = 13.4 Hz),

4.84 (1H, dd, J = 1.8 and 1.5 Hz), 5.36 (1H, d, J = 1.8 Hz). Mass spectrum (FD): 363 m / z (M ^& lt ^{; +} & gt ^; ).

Example 8

3-Acetoxymethyl-4-benzylcarbonyl- (7a) -chloro-3-cephem-1,1-dioxide (Compound No. 35)

In analogy to Example 10, 0.364 ml of oxalyl chloride, 620 mg of copper (I) iodide and 1.6 ml of 2M benzylmagnesium chloride in 20 ml of dry tetrahydrofuran are successively added to a solution of 1 g of (7α) -chlorcephalosporanic acid 1,1-dioxide (see Example 10) in 20 ml of dry tetrahydrofuran. tetrahydrofuran. Workup and chromatography gave 150 mg of the title compound as a white powder, m.p. 147 ° C.

IR (KBr): 9 _max 1,795, 1,735, 1,705 cm ^-1 .

¹ H-NMR (200 MHz, CDCl 3 δ in ppm):

2.07 (3H, s), 3.79 (2H, ABq, J = 18.1 Hz), 4.07 (2H, s),

4.17 (1H, d, J = 1.7 Hz), 4.53 and 5.00 (2H, each d,

J = 14.4 Hz), 5.30 (1H, d, J = 1.7 Hz), 7.17-7.38 (5H, m).

¹³ C-NMR (50 MHz, CDCl3, δ ppm):

20.49 _(OCOCH3), 48.70 and 51.25 _(COCH2 Ph and _C2), 56.17 _(C?)

61.29 (CH ₂ OCOCH ₃ ), 70.65 (C 8), 125.52 (C ₃ ), 127.72 (C ₄ phenyl), 129.10 and 129.40 (C ₂ , C ₃ , C ₅ and Cg phenyl), 131.20 and 132.44 (C ₄ and C _1-4 phenyl), 158.85 (β-lactam), 170.02 (CH ₂ OCOCH ₃ ), 193.01 (CH ₂ Ph).

Mass spectrum (FD): 397 m / z (M ^& lt ^{; +} & gt ^; ).

Example 9

3-Acetoxymethyl- (7a) -chloro-4-ethylcarbonyl-3-cephem-1,1-dioxide (Compound No. 34)

41.

By analogy to Example 7, 85 mg of the title compound is obtained from 53.8 mg of (7α) -chlorcephalosporanic acid, 0.20 ml of oxalyl chloride, a few drops of dimethylformamide, 333 mg of copper iodide and 0.8 ml of a 2M ethereal solution of ethylmagnesium bromide. as a white powder, m.p. 168 ° C.

IR (KBr): ν _max 1,810, 1,730, 1,705 cm ^-1 .

NMR (200 MHz, CDCl3, δ ppm):

1.17 (3H, t, J = 7.1 Hz), 2.08 (3H, s), 2.75 and 2.88 (2H, each q, J = 7.1 Hz), 3.74 and 4.02 (2H, each d, J = 18.4 Hz), 4.52 and 4.98 (2H, each d, J = 14.3 Hz), 4.86 and 5.36 (each

1H, d, J = 1.7Hz).

Example 10

3-Acetoxymethyl- (7a) -chloro-4-formyl-3-cephem-1,1-dioxide (Compound No. 39)

To a solution of 323 mg of (7α) -chlorcephalosporanic acid 1,1-dioxide (see Example 7) in 8 mL of dry tetrahydrofuran at -20 ° C was added 1 drop of dimethylformamide and 0.172 mL of oxalyl chloride. The reaction mixture is allowed to warm to room temperature, after one hour the volatiles are evaporated, the residue is taken up in a mixture of 2 ml of dichloromethane and 6 ml of benzene and 0.269 ml of tributyltin hydride is added to the solution. The resulting mixture was stirred at room temperature for 30 minutes, then concentrated and the residue was partitioned between acetonitrile and n-hexane. The lower layer was separated and evaporated. The residue was purified by silica gel chromatography to give 200 mg of the title compound as a syrup.

IR (chloroform): _max 2800, 1810, 1740 (broad band) cm ^-1 .

NMR (90 MHz, deuterochloroform, δ in ppm):

2.10 (3H, s), 4.10 (2H, ABq, J = 18Hz), 4.90 (1H, d,

J = 2 Hz), 5.05 (2H, s), 5.40 (1H, d, J = 2 Hz), 10.00 (1H, s).

Mass spectrum (FD): 307 m / z (M ^& lt ^{; +} & gt ^; ).

Example 11 (6a) -Bromo-3-ethylcarbonylpenam-1,1-dioxide (Compound No. 146) *

To a solution of 7.18 g of 6,6-dibrompenicillanic acid in dichloromethane at -20 ° C was added 4.41 g of 2-pyridyldisulfide and 5.24 g of triphenylphosphine. The reaction mixture was allowed to warm to room temperature, the solvent was evaporated in vacuo and the residue (consisting of crude 2-pyridylthioester starting material) was stirred at room temperature.

-75 ° C in 110 mL of tetrahydrofuran was treated with 15.5 mL of 2M ethereal ethyl magnesium bromide. After 35 minutes, the reaction was quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate: isopropyl ether (1: 2). The organic extracts were washed twice with water, dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel to give 1.3 g of (6a) -bromo-3-ethylcarbonylpenam as a white solid, m.p. 68-69 ° C.

IR (chloroform): 9max ^1780, 1710 cm ^"1; NMR (90 MHz, CDCl₃ δ ppm):

1.10 (3H, t, J = 7.5 Hz), 1.37 and 1.70 (each 3H, s), 2.62 and 2.67 (2H, each q, J = 7.5 Hz) 4.40 (1H, s), 4.85 and 5.41 (each 1H, d, J = 2 Hz).

100 mg of this material was stirred at 25 ° C in 5 ml of dichloromethane for 5 hours in the presence of 293 mg of m-chloroperoxybenzoic acid. The reaction mixture was washed successively with aqueous sodium bisulfite solution and aqueous sodium hydrogencarbonate solution, the solvent was evaporated in vacuo and the residue was subjected to flash chromatography. 80 mg of the title compound is obtained as a yellowish powder, m.p. 117-118 ° C.

IR (KBr technology): *) max ^1,793 ' ^1,712 c ³¹¹ ” ¹ ·

NMR (90 MHz, CDCl3, δ ppm):

1.10 (3H, t, J = 7.5 Hz), 1.38 and 1.62 (each 3H, s), 2.70 (2H, q, J = 7.5 Hz), 4.20 ( 1H, s), 4.70 and 5.21 (each 1H, d,

J = 1.7Hz).

Example 12 (6a) -chloro-3-ethylcarbonylpenam-1,1-dioxide (Compound No. 116)

A solution of 543 mg of sodium (6α) -chlorpenam-3-carboxylate in anhydrous tetrahydrofuran was treated with 0.18 ml of oxalyl chloride in the presence of 1 drop of dimethylformamide at -5 ° C for 1 hour. The reaction mixture is evaporated to dryness, the residue is taken up in 10 ml of dry tetrahydrofuran, the solution is cooled to -78 ° C under nitrogen, and 402 mg of cuprous iodide and 1.06 ml of 2M ethereal ethyl magnesium bromide are added. The reaction mixture was stirred for 15 minutes, then poured into ice water and extracted with ether. The extracts were washed with aqueous sodium bicarbonate solution and evaporated to dryness. The residue was chromatographed on silica gel to give 50 mg of (6a) -chloro-3-ethylcarbonylpenam as a syrup.

IR (chloroform): 9 _max 1,778, 1,705 cm ^-1 .

NMR (200 MHz, CDCl3, δ ppm):

1.05 (3H, t, J = 7.1 Hz), 1.41 and 1.62 (each 3H, s), 2.58 and 2.62 (2H, each q, J = 7.1 Hz) 4.36 (1H, s), 4.77 and 5.29 (1H each, d, J = 1.3 Hz).

mg of the above material was dissolved in 1 ml of ethyl acetate and treated with 81 mg of m-chloroperoxybenzoic acid at room temperature for 6 hours. The reaction mixture was washed with 1M aqueous sodium bisulfite solution, saturated aqueous solution

With sodium bicarbonate and brine, the solvent is evaporated and the residue is chromatographed on silica gel. 17 mg of the title compound is obtained as a foam.

IR (chloroform): 9 _max 1 805, 1715 cm ^-1 .

NMR (200 MHz, CDCl3, δ ppm):

1.08 (3H, t, J = 7.1 Hz), 1.39 and 1.62 (each 3H, s), 2.66 and 2.71 (2H, each q, J = 7.1 Hz) 4.19 (1H, s), 4.65 and 5.19 (each 1H, d, J = 1.7 Hz). '

Example 13

4-Ethylcarbonyl- (7a) -methoxy-3-methyl-3-cephem-1,1-dioxide (Compound No. 147)

To a solution of 0.7 g of (7α) -methoxy-3-methyl-3-cephem-4-carbonyl chloride, prepared as described in Example 2, in 20 mL of dry distilled ethyl ether was added at -70 ° C under nitrogen. 54 g of copper iodide.

After stirring for 10 minutes, 2 ml of a 2M ethereal solution of ethylmagnesium bromide was added dropwise, the temperature of the reaction mixture was allowed to rise to -50 ° C and the mixture was poured into ice-water. The aqueous mixture was extracted with ethyl acetate, the extract was washed with aqueous sodium bicarbonate solution and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane and treated with 1.5 g of m-chloroperoxybenzoic acid in cold (0 ° C) ethyl acetate. The reaction mixture was stirred at 10 ° C for 1 hour, and the residue was washed successively with aqueous sodium bisulfite solution, aqueous sodium bicarbonate solution and aqueous sodium chloride solution. Drying over sodium sulfate, evaporation of the solvent and flash chromatography of the residue gave 150 mg of the title compound as a yellowish oil.

IR (chloroform): 9 _max 1780, 1685 cm ^-1 .

NMR (200 MHz, CDCl3, δ ppm):

1.13 (3H, t, J = 7.1 Hz), 1.96 (3H, s), 2.66 and 2.90 (2H, dq each, J = 18 and 7.1 Hz), 3, 59 (3H, s), 3.60 (1H, d, J = 17.6Hz), 3.85 (1H, dt, J = 17.6 and 1.2Hz), 4.65 (1H, dd) J = 1.4 and 1.2 Hz), 5.14 (1H, d, J = 1.4 Hz).

Example 14 (7a) -chloro-3-methyl-4-phenylcarbonyl-3-cefem-1,1-dioxide (Compound No. 148)

To a solution of 1.6 g of (7α) -chloro-3-methyl-3-cephem-4-carboxylic acid 1,1-dioxide in tetrahydrofuran at 5-10 ° C was added 0.52 ml of oxalyl chloride and 2 drops of dimethylformamide.

After one hour, the reaction mixture was cooled to -70 ° C and added

1.14 g of copper (I) iodide are then slowly added dropwise with stirring to 3 ml of a 2M solution of phenylmagnesium bromide in tetrahydrofuran. The mixture was

The reaction mixture was allowed to react at -70 ° C for 0.7 hours, then poured into ice water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, dried over sodium sulfate and the solvent was evaporated. The crude product was purified by flash chromatography to give 150 mg of pure title compound as a white powder, mp 184-186 ° C.

IR (KBr) :; 1 780, 1 677 cm ¹ .

NMR (200 MHz, CDCl3, δ ppm):

1.67 (3H, s), 3.66 (1H, d, J = 18.3 Hz), 4.03 (1H, dt,

J = 18.3 and 1.43 Hz), 4.91 (1H, dd, J = 1.87 and 1.43 Hz),

5.33 (1H, d, J; = 1.87 Hz), 7.48-7.94 (5H, m).

Example 15

3-Acetoxymethyl- (7a) -chloro-4-phenylcarbonyl-3-cephem-1,1-dioxide (Compound No. 38)

Using the procedure described in Example 14, using 500 mg of 3-acetoxymethyl- (7a) -chloro-3-cephem-4-carboxylic acid 1,1-dioxide, 60 mg of the title compound was obtained as a yellowish powder.

IR (chloroform): _max 1790, 1735, 1670 cm ^-1 .

NMR (200 MHz, CDCl3, δ ppm):

1.97 (3H, s), 3.80 (1 H, d, J = 18.4 Hz), 4.11 (1H, dd, J = · 18,4 a 1 Hz), 4.42 (2H, ABq, J) = 13, 5 Hz), 4.96 (1H, dd, J = 2,0 a 1 Hz), 5.37 (1H, d, J = 2 Hz), 7.47 - 7.93 (5H, m).

Example 16

3-Acetoxymethyl- (7a) -chloro-4 - [(E) -1-oxo-2-butenyl] -3-cephem-1,1-dioxide (Compound No. 149)

A solution of 323 mg of (7α) -chlorcephalosporanic acid 1,1-dioxide in tetrahydrofuran was treated with 2 mol equivalents of oxalyl chloride in the presence of a catalytic amount of dimethylformamide at -20 ° C. The volatiles were removed in vacuo, the residue was taken up in 20 ml of a mixture of benzene and dichloromethane and stirred at 0.4C for 10 minutes with 0.4 ml of allyltributyltin. The usual work-up and chromatography gave 110 mg of the title compound as a white solid, m.p. 121-124 ° C.

IR (KBr): ν _max 1,810, 1,735, 1,680, 1,625 cm ^-1 .

NMR (200 MHz, CDCl3, δ ppm):

1.99 (3H, dd, J = 6.8 and 1.7 Hz), 2.06 (3H, s), 3.76 and 4.02 (2H, each d, J = 18.4 Hz), 4.52 and 4.70 (2H, each d,

J = 13.6 Hz), 4.90 (1H, d, J = 1.9 Hz), 5.35 (1H, d,

J = 1.9 Hz), 6.39 (1H, dg, J = 15.5 and 1.7 Hz), 7.07 (1H, dq, J = 15.5 and 6.8 Hz).

Example 17

4-tert-butylcarbonyl- (7a) -chloro-3- (1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl-3-cephem-1,1-dioxide (Compound No. 150)

To a solution of 65 mg of 3-bromomethyl-4-tert-butylcarbonyl- (7α) -chloro-3-cephem-1,1-dioxide (prepared as in Example 6) in 5 mL of dry acetonitrile was added 0.025 mL. triethylamine and 26 mg

5-mercapto-1-methyl-1,2,3,4-tetrazole with immediate reaction (monitoring by thin layer chromatography). The solvent was evaporated in vacuo and the residue was purified by flash chromatography. This gives 35 mg of the title compound as a white powder, m.p. 162-164 ° C.

IR (KBr): _max 1790, 1690 cm ^1st

NMR (200 MHz, CDCl3, δ ppm):

1.26 (9H, s), 3.76 and 4.08 (2H, d each, J = 14.3 Hz), 3.93 (3H, s), 4.01 (1H, d, J = 17) 9 Hz), 4.26 (1H, dd, J = 17.9 and 0.9 Hz), 4.85 (1H, dd, J = 1.7 and 0.9 Hz), 5.33 (1H , d, J = 1.7Hz).

Example 18

4-tert-Butylcarbonyl- (7a) -methoxy-3- (1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl-3-cephem-1,1-dioxide (Compound No. 151)

To a solution of 52 mg of 3-bromomethyl-4-tert-butylcarbonyl- (7a) -methoxy-3-cephem-1,1-dioxide (prepared as described in Example 3) in 1 ml of dimethylformamide is added 36 mg of sodium 1-methyl- 1,2,3,

4-Tetrazolyl-5-mercaptide. After 10 minutes, the reaction mixture was diluted with ethyl acetate, washed with brine and the solvent was evaporated. Flash chromatography gave 30 mg of the title compound as a white powder, mp 60-62 ° C.

IR (KBr): _max 1790, 1690 cm ^1st

NMR (200 MHz, deuterochlorophone, δ in ppm):

1.2 (9H, s), 3.78 and 4.05 (2H, d each, J = 14.2 Hz), 3.56 (3H, s), 3.93 (3H, s), 3, 93 (1H, d, J = 17.8Hz), 4.20 (1H, d, J = 17.8Hz), 4.75 (1H, bs), 5.17 (1H, d, J = 1) 7 Hz).

Example 19

4-tert-Butylcarbonyl- (7a) -methoxy-3- (2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl) thiomethyl-3-cephem -1,1-dioxide (Compound No. 153)

To a solution of 230 mg of 3-bromomethyl-4-tert-butylcarbonyl- (7α) -methoxy-3-cephem-1,1-dioxide (prepared as in Example 3) in 50 ml of dry acetonitrile is added 0.1 ml of triethylamine and 2.75 mg of 3-mercapto-2-methyl-5-oxo-6-benzhydryloxy-2,5-dihydro-1,2,4-triazine. After 20 minutes the solvent was evaporated, the protected compound was purified by silica gel chromatography, then dissolved in 2 ml of dichloromethane and 0.025 ml of anisole and 1 ml of trifluoroacetic acid were added. After 15 minutes the trifluoroacetic acid was completely evaporated in vacuo and the residue was taken up in 1 mL of dichloromethane. Addition of isopropyl ether gave 175 mg of the title compound as a white powder, m.p. 148-150 ° C. ’

IR (Kbr-technique): _max 1790, 1690, 1640 (broad band) cm ^-1 .

NMR (200 MHz, CDCl3, δ ppm):

1.28 (9H, s), 3.63 and 4.19 (2H, d each, J = 14.1 Hz), 3.56 (3H, s), 3.74 (3H, s), 3, 83 (1H, d, J = 17.8 Hz), 4.09 (1H, d, J = 17.8 Hz), 4.76 (1H, bs), 4.17 (1H, d, J = 1) 7 Hz).

Claims (3)

PATENT CLAIMS t in which A represents a hydrogen atom or an organic radical selected from the group consisting of straight or branched alkyl groups of 1 to 12 carbon atoms, alkenyl groups of 2 to 10 carbon atoms, alkynyl groups of 2 to 10 carbon atoms, aryl groups of 6 to 10 carbon atoms, (C 3 -C 8) cycloalkyl, (C 5 -C 8) cycloalkenyl, aralkyl, aralkenyl, aralkynyl and cycloalkylalkyl groups in which the aryl, cycloalkyl, alkyl, alkenyl and alkynyl moieties are as hereinbefore defined, 5- or 6-membered, saturated or unsaturated heterocyclic rings containing at least one heteroatom selected from oxygen, sulfur and nitrogen, optionally fused to a second 5- or 6-membered heterocyclic group or to a C 3 -C 8 cycloalkyl group, and further heterocyclylalkyl, heterocyclylalkenyl and heterocyclylalkinyl groups; that you can the rocyclic, alkyl, alkenyl and alkynyl moieties are as defined above, wherein all the above organic radicals may be unsubstituted or substituted by one or more atoms or groups selected from the group consisting of halogen atoms, hydroxyl, nitro, azido, diazo, amino -NH ₂ , -NHR 'or -NR'R'', where R' and R '' are the same or different and in each case represent a straight or branched alkyl group having 1 to 7 carbon atoms, a phenyl or benzyl group, a formyl group -CHO, mercapto-SH or -SR ', wherein R' is as defined above, cyano, carboxy (alkyl) - (CH ₂ ) fCO ₂ H or - (CH ₂ ) fCO ₂ R ', wherein R' is as defined above and t is 0, 1, 2 or 3, sulfo -SO ₃ H, acyl -C (O) R ', wherein R' is as defined above, or trifluoroacetyl -C (O) CF ₃ , carbamoyl -CONH ₂ , N-methylcarbamoyl - COHNCH ₃ or N- (carboxymethyl) carbamoyl -conh-ch ₂ for ₂ h, carbamoyloxy -OCONH ₂ , acyloxy -OC (O) R ', where R' is as defined above, and formyloxy -OC (O) H, alkoxycarbonyl or a benzyloxycarbonyl group -C (O) OR ', wherein R' is as defined above, an alkoxycarbonyloxy group or a benzyloxycarbonyloxy -OC (O) R 'group, wherein R' is as defined above, an alkoxy-, phenoxy- or benzyloxy group -O-R ' wherein R 'is as defined above, alkylthio-, phenylthio- or benzylthio -S-R', wherein R 'is as defined above, alkylsulfinyl, phenylsulfinyl or benzylsulfinyl -S (O) R', wherein R 'is as defined above an alkylsulfonyl, phenylsulfonyl or benzylsulfonyl group -S (O) ₂ R ', wherein R' is as defined above, acylaminos -NHC (O) R '''or -NHC (O) OR''', wherein R '''represents a straight or branched (C 1 -C 7) alkyl group, a phenyl group, a benzyl group, a CH ₂ CH _{2 group} CO ₂ H or CH ₂ CH ₂ CH ₂ CO ₂ H, sulfonamido -NH-SQ ₂ R ', where R' is as defined above, guanidino -NHC (= NH) NH ₂ , C 1 -C 4 alkyl, (C 2 -C 4) alkenyl or alkynyl, C 3 -C 6 cycloalkyl and substituted methyl selected from chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, aminomethyl, azidomethyl, cyanomethyl, carboxymethyl, carbamoylmethyl, carbamoyloxymethyl, hydroxymethyl, alkoxycarbonylmethyl; C 3 -C 4 and guanidinomethyl. R ¹ is (1) a chlorine, fluorine, bromine or iodine atom, (2) a radical A as defined above, (3) an ether radical -OA, wherein A is as defined above, (4) a thioether, sulfoxide or sulfone radical -S (O) _n A wherein n is 0, 1 or 2 and A is as defined above, (5) acyloxy -OC (O) A wherein A is as defined above, (6) sulfonyloxy -O-SO ₂ A, wherein A is as defined above or (7) acylamino -NHC (O) A wherein A is as defined above or acylamino -NH-Z wherein Z is a mono-, di- or tripeptide composed of D or La-amino acids selected from the group consisting of Ala, Gly, Val, Leu, Ile, Phe, and Pro, wherein the terminal amino group is either free or acylated with -C (O) R '''or -C (O) OR''' wherein R '''is as defined above, R ² is either hydrogen or (1) a C 1 -C 4 alkyl group, (2) a C 1 -C 4 alkanoyloxy group, or (3) a chlorine, bromine or fluorine atom, R ³ is either hydrogen or (1) C 1 -C 4 alkyl, (2) C 1 -C 4 alkoxy, (3) benzyl, (4) halogen or (5) methylene = CH ₂ or = CHR ^IV , wherein R ^IV is C 1 -C 4 alkyl, phenyl, carboxy or C 1 -C 4 alkoxycarbonyl; and R ⁴ is (1) a radical A as defined above, (2) a chlorine or fluorine atom, (3) an ether group -OA, wherein A is as defined above, (4) a sulfenyl, sulfinyl or sulfonyl group -S (O) _n A wherein A is as defined above, (5) (6) (7) an acyl group -C (O) A, -C (O) OA or -CO ₂ H, wherein A is as defined above, oxymethyl group - CH ₂ -OA, wherein A is as defined above, a thiomethyl group or a derivative thereof of the formula -CH ₂ S (O) _n A, where A is as defined above, (8) an acyloxymethyl group -CH ₂ OC (O) A or -CH ₂ -OZ, where Z and A are as defined above,. an acylthiomethyl group -CH ₂ SC (O) A wherein A is as defined above, (10) an aminomethyl group -CH ₂ -N (A) A 'wherein A is as defined above and A' has the same meaning as A, wherein the radicals A and A 'may be the same or different, or A and A' together with the nitrogen atom to which they are attached form a five- or six-membered heterocyclic ring containing at least one heteroatom selected from oxygen, sulfur and nitrogen (11) amoniomethyl wherein A and A 'are as defined above and A''has the same meaning as A, being the same or different from A, or A is an alkyl group and A' and A '' together with the nitrogen atom on which are attached to form a five- or six-membered heterocyclic ring containing at least one heteroatom selected from oxygen, sulfur and nitrogen, or A, A 'and A''together with the nitrogen atom to which they are attached form a five- or six-membered aromatic heterocyclic ring containing at least one heteCS 277027 B6 roatom selected from the group consisting of oxygen, sulfur and nitrogen, or (12) acylaminomethyl -CH ₂ NH-C (O) A or _-CH2 NH-Z wherein A and Z are as and the pharmaceutically and veterinarily acceptable salts thereof. 2. A process for preparing β-lactam derivative of the formula Ia and Ib wherein the symbols have the meanings given in claim 1, according to claim 1, characterized in that, in any order, converting the carboxyl group -C 0 -C ₂ H 4-position of the cephem nucleus or at position 3 of the penam nucleus of the compound of formula (IIa) and (IIb) (IIb) / (Hb) / in which R ¹ , R ² , R ³ and R ⁴ are as defined above, by converting to an activated derivative such as a halide, anhydride, mixed anhydride, ester or thioester and reacting it with a corresponding organometallic derivative containing residue A, mixed anhydride or diazomethane to a carbonyl the group -CA, where A is as defined above, and the sulfur atom at the 1-position of the C0- or penam nucleus is oxidized to give the desired sulfone, whereupon optionally the resulting compound of formula Ia or Ib is converted to a pharmaceutically or veterinarily usable salt. A process according to claim 2, characterized in that the corresponding starting materials and reaction conditions are used to give compounds of the above formulas Ia and Ib in which: A is as defined in claim 1 except carboxy (alkyl) - (CH ₂₎ .j.CO ₂ H or - _(CH2) ^. 00 ₂ R ', wherein R' is as defined in claim 1 and t has a value of 1, 2 or 3 R ³ has the meaning as in claim 1 except for the halogen atom and the remaining general symbols have the meaning as in item 1, and their pharmaceutically and veterinarily acceptable salts.