DE2450048A1 - 4-OXO-1-PYRIDINYL-PENICILLIN- AND -CEPHALOSPORIN-DERIVATES AND THE METHOD FOR THEIR PRODUCTION - Google Patents

Description

f oi? iW. WAUER nisfo 21. OHI. 1974

Wfo κ ·? ¹ ■■ '-! ■; · :? «? Λ ζ η Ω Λ

DS. JUk. i..l · 1. ·. ·! ' -. 'A ii-J. WOSiv Z H 0 U ϋ · 4 Ο

OR. JIi * :. ii .- .. ij «:»: ■ ·· t '-' li · F R A N K F Li :: ϊ Λ / Λ MtM H - HOCffrti

Our Mr. 19 521

Richarcteon-Florrell Inc. Mw York, M.Y. V.St.A.

i-Oxo-l-pyridlxnj-l-fonicillin and cophalosporin derivatives as well as the procedure for your acquisition

do invention relates to new derivatives of substitnierfcea (4-03co-l-pyridin3'l) -acetylamino-penicillineft Hind cephalosporins and processes for their production. The inventionsGCTTtißen Terbindwnc ^ n öer -penicillin- and Cephalosporin-Klrscon oind breakable "as anti-bacterial Active ingredients. These compounds boritson a high degree at. Effectiveness on a large number of microorganisms. The cephaloporin derivatives according to the invention are particularly useful against penicillin producers microorganismsn. The compounds according to the invention are antibacterial ·? nittel at the Behaiidluns of infectious diseases caused by gram-positive and ßraraiaesafeiYQ Bakfcox'ion in poultry ^ l and animals, including Human beings. Furthermore are the invention compounds as an additive see below Animal feed unä nlr, active ingredient in r;? Rnibiden preparations,

509820/1167

which is used as a surface disinfectant become usable.

The cleavage of penicillins to 6-aminopnicillanic acid in 1959 and the chemical cleavage of cephalosporin made the corresponding 7-aminocephalosporanic acid Synthesis of new synthetic penicillins and cephalosporins possible, which previously by fermentation process were not accessible. The acylation of the amino group led to derivatives which are in the 6-position Side chain contained a heterocyclic ring, as in the case of the penicillin series, or, as in the case of the Cephalosporin series is the case in the corresponding 7-position side chain. Among such heterocycles fall the ThiophenrinG »see for example US-PSn 3,218,318; 3 M9 338 and 3 '498 979 (cephaloridin and Cephalothin); the picoline (US-PS 3,553,203) and hydantoin ring (US-PS 3,227,712) and various others, Nitrogen-containing heterocycles including pyrolidine and nicotinic acid (U.S. Patent 3,308,120).

In all cases the heterocyclic radical is over one of the ring carbon atoms to a side chain in which Usually that of an acetyl radical, bonded. The l4-Ojto-l-pyridinyl derivatives according to the invention are through the hetero atom linked directly to the acetyl radical. One of those Linkage is known per se, and in this Respect is U.S. Patent No. 3,516,997 which exemplifies a Tetraaolring there (Ce.f azolin) and the US-PS 3,652 5 ^ 7, vielhe certain quinazolinyl derivatives of Penieillanic acid disclosed, most relevant prior art.

509820/1167

-Ii

In favor of the invention are substituted (iJ-Oxol-pyridinyD-accfcylamino-penicillin- and -cephalosporin-

deri ^ ate of allsomoinon Poraol I

! [I Jl

R ₅ 0 ^ MR

(ι)

wherein

Rj, Rp, R, and R _J} hydrogen or halogen atom,

Hydroxyl, lower alkyl, trifluoromethyl, nitro, amino, cyano, Carbojty-, Carbomothoity- or Carbäthoxygruppsn daroteile or R ^ and R ₂ toaamnsn one of the two cyclinchen Rocto -CH ^ CHgCHpCHp- or -CH = CH- CH = CH-

represent;

R _{5 is} a Waoseratoffatom, a Hethy! -, Carboxy-, Carboraethoxy-

or carbethoxy group; Rg one of the leftovers

CH ₃ or ι

T ^H X-CH ₂ X

COOR ₇ - γ

COOR ₇

509820/1187

2A500A8

X © in WncmeratoffrAora, olno Il ^ aroisy-, acetoxy-, H-

, Sn.ofciij'l-1 ₉ 3, ^f 5 ~ thiaöias; ol-2-ylthio or oth3rl-1 s2 ρ 3 s' s-fcotrnrsol-S- ^ lthio group;

oin UnonorntoiTrAc ^ B olno Alkanoyloityraothyl-, Alkanoyloj ^ 'c ^ .r ^ on ^ l ^^ inoraotJUyloöer one psjrli5rwppo _I , in eier ßie Allconoyl- odor 1 to 5 Koblon ^ toffatomG includes, and

represent a Waooojrofcoffatom or Oino Methoiqrgruppe; dio pharasisGUtir.ch excellent Salae of the same.

The inventions in-ou can be achieved Condensation oinor G-aninoponicillanic acid cdor one T-Aroi.nocGphaloaporanny.tAre raifc of a substituted * 5-oxo-l-pyridinyl oaic acid according to the following reaction getting produced:

H ₂ O

CH-C-OH

(IO

H ₂ N

Jl

NR ₆

(Ml)

□ TJL *

(D

509820/1167

, if ^Γ > -

All compounds according to the invention contain a ΐΙ-Οχό-1-pyridinyl group or an iJ-pyridone radical in the terminal position of the Aeefcjflsirdno side chain, as can be seen from the general formula I. In the case of the penicillin series, the acetylamino side chain is referred to as being in the 6-position, whereas in the case of compounds with the cephalonporin series, the position is numbered 7. The terms of reference for both herons and compounds are illustrated below with the aid of the intermediate products 6-aminopenicillanic acid (IV) and 7 "" te? -Nocophalosporansuro (V):

CH ₃

0 COOH

(IV) '(V)

The Ί-pypidonrestj attached to the acetylamino side chain bound iot, can be aubotitwiert or unsubötituiert. This © SubDtituonton dissolve either in the 2-, 3-, 5- or 6-position before the Pyriäinkorno and include the following Residues: halogen, hydroxyl, lower alkyl, trifluoroethyl, Nitro, amino, cyano, carboxyl and the methyl and xthyl esters of the carboxyl radical. The term halogen includes this Fluorine, chlorine, brorine and iodine atoms * The term "lower alkyl groups" includes gorad- and branched-chain ones aliphatic hydrocarbon residues with 1 b s.l »carbon

509820/1167

to understand material atoms, such as the methyl, ethyl, Propyl, isopropyl, butyl, isobutyl and the tert-butyl group.

In addition to the various substituents described above, the 4-pyridonreate can be regarded as being substituted with an adjacent, saturated or unsaturated 6-membered ring. Thus, the substituent R ₁ together with the adjacent substituent Rp can be viewed as forming a 6-cyclic3 alicyclic or aromatic derivative which is bonded to the 2,3-position of the pyridine ring. These derivatives are more useful than 2-C substitute. (*! - 0xo-l-tetrahydro-quinolinyl) 3 acetylamino- and 2-C-substitute. (^ - Οκο-1-quinolinyl)] -acetylamino derivatives of penicillins and cephaloaporins. Due to the symmetry of the pyridine molecule, only one pair of the neighboring substituents needs to be so defined. The tricyclic, heterocyclic dibenzopyridine or acridine rincsysteines are not intended to be included in the present invention.

In addition to the obligatory substitution of the 2-methyl group of the acetylamino or acetamido part of the molecule with the ty-oxo-l-pyridinyl group, the 2-methyl group can also be substituted by a methyl group or a carboxyl group, as shown by the substituent R ₅ . If R 1 is a methyl group, the compounds are more appropriately referred to as propionyl derivatives of 6-aminopenicillanic acid or 7-aminocephalosporanic acid. However, in the present they are for reasons

509820/1167

a uniform nomenclature called 2- (substitut.) acetylamino derivatives. For example, in the case of a derivative of cephalosporanic acid, where d "> m R- is a methyl group and the *! - pyridone radical is unsubstituted, the compound is cephaloaporanic acid as Z-Cz-C ^ -oxo-1-pyridyl ^ -methylacetylam In addition to the carboxyl group at R ₅ , the methyl and ethyl esters or the carbo.nethoxy and carbethoxy groups are also included in the present Er-Jt.

The invention is primarily concerned with the preparation and description of 2- (4-oxo-l-pyridinyl) ~ acetylaroinoj Side chain derivatives of ß-lactam antibiotics. These

; Derivatives are condensed with the easily accessible

j borrowed 6-aminopenicillanic acid or one of the available ones

j Prepared 7-aminocephalosporin intermediates. Accordingly

j is when R _{g is} the remainder

/ CH ₃

CH
00R ₇

represents to the penicillin series, while it is when Rg the rest

CH ₂

C-CH ₂ X
- U

COOR ₇

509820/1 167

This is about the CophnJLoaporinrcihe.

Dar ß-XrriPftrr ^ cra knsm Wnaubatituiorfc odor RiIt dinar Kothoxy .gruppo OüA σ tit id ort oein, as by the substitute tone R. aiMPßcaftolli; wefl. Eino äorortigo Substitution Vorlüuft at dor 6-3i: o3LlW7iG dor Vorüinöwncon egg Poniciliinroiho or © si dos · 7 ~ SfeollwnG dar Yori> lnclunQon dor Cephalooporlnroihe.

oils 3-Stollunc dor Yorb: solutions of the Picnicilllnreiho © Ic. nisisli, Clio S-fifcoüLlunc; dor Yorüindwngon the Copiinlonporin series ir.t substituted by a carbon ^ Huro or a carboxylic acid ester, as represented by the Toi! structure- COOR ₇ R- a W ao aero to ff atom, the dl® ent-FcnicillancLluron o-clor Cephalosporanöuron er

halton. ϊίοτ Subotituont E ^, Izann fernor foljpndo remnants befleistons Air.tanoyloxjrottiyl-, Alkanoylaminomothyl-, Alkoxy-

This © Eoftor t ^r orleihcn Cora r: olol-ttl horvorrasenös Aboorptionseigensctaaftcn and oio c are cloicha-sided phj ^ siolosisch unstable.

become diooo entor from the ßastro-intootinal 'slightly ßbsorbiort and r, w the corresponding Ponicillan or CephaloDpornnsüu.Fen / hj'arois.siert, which makes an excellent oral effectiveness is conditioned.

o booondero Abucichuncon roped through the subotituonts X within the cphcilosporin series of cordon. Thus, in the case of the compounds where X is a waooeretoffate, it is a question of dcoacotoj ^ -cöphalosporan acid, and where the sibotite ent 3t means a hydro: ^ rl group, it is deacetyl-cscpEialojspornnosuron. If the substituent X represents an Ac © t © J5S7root, the ß-lactate nucleus eats dorjonig® of the cephalocporanoic acid. Further sub-substituents in the 3-position of the

509820/116 V

2A50043

nncSlwrOj, ro 1 before also under the

Erfimilv.rr; fn.JLlcn wnd o by the substituents X

been cdnü the p-Pyridii.ium-, 5-Methyll "V" -fchio £! lr.! 3ol-2-ylthio and 1-PTsthy 1-1,2,3 »4-tetrazole

Di © pfarjrraascv.ticeh brr.uchbarnn salts of the compounds of Ponsol I include the non-toxic carboxylic acid salts, die rait oinop bolicfeipcn. c; ooi £ notes inorganic or i Bo.cc RcMlöofe t.-crden. Examples of such

Alfeiin? ₍ ctnllnalr, e _s such as sodium »and ίπο; Salso \ -on Ercialfcaliir ^ tallen, such as tmü Πηβη ^ αΐΜη, of light metals of the group IHa oeicJitfion Ssrmftcra, t; io sB aluminum; and salts toor primJ'.ror, cokuinciSror or tertiary amines, tdto SB Trlnlkyiamlne, wio triethyrlamine, procaine, dibenzyl-RPiiii l-thoncimine ₈ N, ri »-dibcnayläthylenendiainln, dihydro-

orain, WD-ioörlc-Alk-lpiporldin and other amines, are used to form non-toxic salts with benzylpenicillin. These salts can be horcpstollt by herfc orasalichen method, for example by bringing in and neutralizing a solution of the carboxylic acid in polar solvent with a stoichiometric amount of a base. '

Under dio pharmazeutioch useful Saei reanlagerungssalze the non-toxiachen, organic or inorganic SäureenlftseninsBoalBo fall dor baoiochen compounds of formula I. Examples of WIOR _S anioch © acids which form suitable salts include SalBoSwro, hydrobromic, sulfuric and PhODphoroaure and the acidic Metal salts such as sodium monohydrosonorthophosphate and potassium hydrogen sulfate.

509820/116 7

- 10 -

Examples of organic acids ₉ polygamy suitable S se constitute al, ednrä Ποηο-, di- and Triearbonaäuren as Eanig-'säure, glycolic _s lactic acid, "T-consuming ens ä acid, malic acid, succinic acid, glutaric acid, fumaric acid, malonic acid *, tartaric acid , Citric acid, ascorbic acid, maleic acid »HydrojtjnBaleinnäure ₉ Benzoic acid, p-HyaroxybenscooSuro,

ZiratsSuro, Salicylic Acid, SS-

] acid sonics sulfonic acids such as s.B. MothansulfonoSure and

e. Dcrartigo Salae can either in a hydrated or singular pralt table tir, soerfrcien Form vorlioQ; on.

In addition to non-toxic carboxylic acids and non-toxic acid addition in the basic compounds, the term "pharmaceutically usable salts" also includes inner salts of zwitterions of those compounds of the formula I which are amphoteric. Compounds such as 7C2- ( ⁱ {-03to-l-pyridinium) -acetylamino-cephalosporanate, 7-t2- (4-Ojio-l-pyridinium) -acetylamino] -3-L (5-m®thyl-l, 3 » ¹ * - thiadiazol-2-ylthio) methy] 3-decephalosporanate or 7-t2- (U-oxo-l-pyridinyl) -acetylamino] - |) yridiniummethyl) -decephalosporanate as dipolar ion, especially when they are in solution are available.

Examples of specific basic compounds that fall under the formula I are:

o-CS-iM-Oxo-l-pyridinyD-acetylaminol-penicillanic acid, 6-L2- (2-Hydroxy ~ H-oxo-l-pyridin.y l) -acetylamino3-penicillanic acid,

6-C2- (3-trifluoromethyl- ¹ 4-oxo-l-pyridinyl) -2-methylacetylnminoj-penieillanic acid,

5098 2 0/1167

2Α50048

6rC2 - (?! p3p5-Tr3.ch3.or-? J-ono-l-pyriäinyl) -acotylßnliio3! -

penlcdMraniUnrctj,.

6- £ 2- (3 "β ^ ~ '! ~ ®κβ ~ ^" ΡΓ ^ · * · ^ ^{: ϊ} · ^ Γ ^ 6-t2-C2-2lfchrl-5-r- ^

6-r.2-C3
I der (n ~? Lt; hOTTcarTjonyl "n - r.'3tI '?;" L) -Er! Iinoir'2thyloofeoiP üov

; 7 £ 2i

o 1 · ™ copiin.looporo.no riwr ^; 7-t2- (2-chloro-3-hydrochloric: qr- ⁱ ! ~ Acetylamine © 3 "cephalo! 3-porno acid;

arainoS-cephalooporcic acid;

7-C2- (2,5-dicarbäthoity- ^f ! -Oso-l-pyridinyl) -2-carbethoxy-

acetylamino3-cophalosporanoic acid;

the pivaloyloxymethyleator represents 7-t2- (U-oxo-l-pyridinyl) -

acetylamino3-cephalonporic acid;

derip-Aestyloxybenzylooter öer 7C2- (3 »5 ~ Dicyan- ⁱ l-oxo-'l-

pyridinyl) acetylamine © 3-cphalosporanic acid;

the (N-propionyl-N-mathyD-aminomethyl ester of 7-C2 ~ (3-amino- '»- oxo-1-pyridinyl) -2-carbethoxyacetylamino-3-cephalosporanic acid;

7-t2- (3 »f ^; -dimc3thyl-'l-uXo-pyridinyl) -2-methylacetylamino3-desacetoxycephalosporic acid;

509820/1167

" ¹² K WW

2A50048

(2 _s 6 "-P: * ^^ flrQ-r ™" ^ -o--

the p-Propionsrloxybonßi / 'Ji.octoE »ßor 7- £ 2- (3> 5-Dichlop- ^? } -ojso

7-t2- (Js-Qjto- 1-totrohydro chiriollnyl) -acety lamino 3 "

decephalooporannt; 7-C2- (2-hydroxy-3,5 3 ~ (pyridiniM! CTethyl) -docopiinlo! 3poronate;

Sl (pyridiniuinmethyD-decephnlooporanat;

7- £ 2- (2-Carbomethoitjf- ^< io ^ ol-pyridinyl) -2-carbethoxy ^j

509820/1167

3-E (3-rot ^ r 3.-1 "3 * ^f 3-tbi r.di iir, Q ^ -2 ~ 3 * lthio) -no thy 1 3-Ot

aporanonw.ro; 7 ~ £ 2 "( ⁱ 5-Oj: o-'i

thieictiasol-2-ylthio) -i! iothsrl3-clecephalosporanic acid-pivaloyloxy "

msthjleoter;

dsr 7-t2-

3-t (5-irr'3i; hyl-l, 3, ¹ i-thiaäia! Sol-2-ylthio) -methyX3-deeephalo-

the (H-Aeefcyl ~ M-H3thyl) -aniinomothy! ester of the 7-t2- (3-cyano- * »- oxo-l-pyriclirijfl) -nc © tylr, raino3-3-L (5-niethyl-l, 3, ^l * -thiadiazole-

tetrasol-5-ylthio) -mothyl3 ~ decophalosporanic acid; ί 7-C2- (5-rfethyl-2- "propy It ¹ J-OKO-l-pyridinyl) -2-methylacetyl-

j I arain © 3-3-C (l-m3thyl-l, 2,3, ^| i-tetrazol-5-ylthio) -m®thyl3-

I decephalooporanoic acid;

509820/1 167

T. 7- ί
\ ■ t ( ί sp I. 7- Ά 153 'i C5 & 1 7t ! © P 7- 3 tc ί mi at 3 s: \ 7th i L. I. S. I. 7th i S. 7th i IT ε

7-L2- (3-Trifl wherein ethyl-M-OJtO-I ~ p3 "ridinyl) -acetylain © 3-3-C (! -methyl-1,2,3, M-I

acid;

7C2- (2-chloro-5j6-aifluoro-i | -oxo-1-pyriclinyl) -acetylamino3-3 t (1-methly-1,2,3, ^I »-tetrazol-5-ylthio) -methyl3-decephalosporanic acid;

tetrazol-5-ylthio) -msthyl3-decephalosporanic acid-acetoKymethylesterj

the (N-methoxycarbonyl-N-methyD-aminomethyl ester of 7-C2 (2 "6-Dihydro" y-M-oxo-1-pyridinyl) -2-carbä.thoxyacetylamino3 3 - [(l-raethy1-1,2,3, ^ - tetrasol-5-ylthio) -methyl3-decephalosproanaic acid;

7-C2- (5-rTE »ifluorrasthyl-U-oxo-l-quinolinyl) -acetylsmin © 3-3 - [(l-methyl ^{-1,2,3» 1} t-tetrazol-5-ylthio) -methyl3- decephalosporanic acid p-pivaloyloxybenzyl ester; 7-lethoxy-7- [2- (II-oxo-1-pyrid5: nyl) -acetylaraino3 "cephalosporanic acid;

7-methoxy-7-C2- (M-OXO-1-pyridinyl) * • acetylamine Q J-3-1 (δ-methyl-1,3, M-thiadiazol-2-ylthio) -methyl-3-decephalosporanic acid;

6-methoxy-6-C2- (M-oxo-1-pyridinyl) -acetylarainQ3 ~ penicillanic acid;

7-methoxy-7-C2- (M-oxo-1-pyridinyl5-acetylamine <O ~ decephalosporanic acid;

6-methoxy-6- £ 2- (3,5-dicyano-M-oxo-1-pyridinyl) -acetylamino3-peni ei 11anoic acid;
6-methoxy-6-C2- (5-nit ro - »» - oxo-1-quinolinyl) -2-carbethoxyacetylamine © 3 ~ penicillanic acidG »

509820/1167

\ V. "■

6-Metho3jy-6- £ 2- (^ s-ORO-l-

yD-ocetylaioino 3-penicilian-

sporansSure-acefcoisj'rrs thy lector;

raethylester;

cephalosporansSwro;
7THethoxy-7- £ 2 ~ (5-trifluoron: suhyl - ')' - oxo-l-ehinolinyl) -2-ethylacety larain © 3-öesacoto:!:; Rcophalo3por £ n3i ^! .ur0Tp-acetoxybenzyl ester;

ps7y33 (5th

methyl-l ₉ 3 ₉ 4-thiadiasol-2-ylthio) -> inothyl3- ^> deeephalooporanoic acid aeefcojtyroethy lector;

the (N-Xthonyeartjonyl-np.othyD-c.niinoiizathylestor the 7-Mth C £ l »2,3» ¹ l7tetrasol-5-ylfciiio) -ri othyl3-öGcephalosporansSure!; and 7-methoxy-7- £ 2- (4-oxo-l -pyridinyl) -acetylamino3-3- £ (l-

- t> 4 yμ, «

The compounds of the invention are made by one ß-lactamioche 6-aminopenicillanic acid or 7-aminocephalosporanic acid or a derivative thereof of the general formula

HsN

J: ⁰

LJ ΐ

/ -NR ₀
(III)

with e shape

in d «zuvo:

The verb

can hydr

The Bi Id Vol.

509820/1 167

'2450043

©! Nor ft-Oxo-l-pyridinylsodigic acid der generaloinen

R:

in <Sbr

Swtootituenton

CM-C-OH

! 0 Rs 0

(M)

R ^. R.

₃ , R ₁₁ , r R _{ß and} d

gonnmito Bodout «nc bcoitcon. implements.

the

Ploß-LnctGra-Auoeancovorbinäuncen (III) are known. the fs ö-Andnopcnicillanoßure der Forrasl

LI

CH ₃

^ CH ₃ COOH

using biological methods or by Hydrolysis τοη verochiedenen penicillins (see US-PS 3 ^ 99 909)

, made north.

Di® Hyärolyoo des Antibiotikwma Cephalosporin C leads to Image of T-aminocophaloopopanic acid (cf. Biochem. J. BdL 79 »S. iK> 8 - * Ι1β (1961)), enough the formula

509820/1167

2A500A8

having. _ (V) ■ I

The compound T-AoinodoDacoto ^ -ccphalosporanoäur © der; f,

general formula, ίι

■ ' ^b

COOH (Vl)

is produced by catalytic eho reduction of cephalosporin C and subsequent hjdroljticcho removal of the 5-aminoadipoyl side oxette (ν ^ Ι. US-PS 3,129 22 ').

Such © Yovfoinaxtngen of ß-Lnctarr-Auagangsmatorials (III), honing at (dor substituent R "means one Hethoxygruppe," have been described in U.S. Patent No. 3,778 '532nd

The treatment of cephalosporin C with an acatylesterase, which is obtained from orange peel (Biochem. J. ^ Vol. 81, p. 591 (1961)) leads to the formation of 3-hydroxyn-ethyl-7-aminodecephalosporanoic acid or 7-aminoesacetyl-cephalosporanic acid the formula

509820/1167

1 ι

Y- N

I COOH

(VM)

! The treatment of cephalosporin C with pyridine and subsequent acid hydrolysis leads to the compound 7-amino-3- (pyriäiniwiP ^ othyl) -öocGphn3i.onporanaaure of the following form. The production of this connection is known and is described, for example, in US Pat. No. 3,117,126 _{and GB Pat. Nos. 932 6Hk 9} 957 570, as well as 959 05 ¹ ».

H ₅ N

(VIIJ)

The 7-aminocephalosporanic acid which is substituted in the 3-position by a thiol group can be obtained by reacting 7-aminocephalosporanic acid with the corresponding thiol (cf. US Pat. No. 3,516,997). Thus, one separating 5-methyl-l, 3, ¹ "-thiadiazol-2-thiol is used, 7-amino-3-L (5-methyl-l, 3, ^l" -thiadiazol-2-ylthio) -methyl3 -decephalosporansSure obtained from the formula below:

H ₂ N-

IJ .... WW

-CH,

COOH

(IX) 509820/1167

N JL,

■ i ■ I

■ I i

■ Ml

! i; I.

: ij!

! ill;

ί ■;

! I j: j

i ί ι ■ I

.1 ■ j

! I.

If the compound i-Hethy 1-1,2,5,4-fcotrasol- jj 5-thiol is used, no vlru die

C (l-Rr5fchyl-l, 2,3 _i ^| »-t; ct; raiiol-5-

ranaöure der nachofcefoanöon Formally obtained:

The ^

^f "on C ^ r Γθγγ ^ Ι II n _n t; clcho either 1- oöor 2«

by condensation an Alisalinotalloalses oinoa jrxy I

pyridino (H) nit Ktiir ^ ronnicc ^ at or einora s ^ ofcifcwierten |

(KII) horc ^ ntollt can be. In the ί;

Usually will dna Kaliwr ^ nlr, olon Kjrdronypyridino swp condensation 1

prevented, and the ester obtained becomes the correct %

4-0xo-1-pyridinsr 1- (aubotitut.) ~ Osoiso8ure öor Poreal II |

with a wäoorisen Βίίσο hjfdrolisiert, as in doia following p

Reaction scheme orlüutort becomes: i; Ü

509820/116 7

ηι

(κι)

(KIi)

Il

CM-COQH

(II)

Cs

α,

O (XIM)

The Esolf \ onwrcn

strong trüoorio by

Γογγ-ϊΙ II can eibor nwf? En <?, wr © ii5 Um-CkilQrcjooiganwro οίο ρ © in® p ÄT- (KI ¥) in GeconnnFi; © israr Βααο cSiroIit Ι?, Ογ ^ οοtollt woröon ₉ nio

will:

(Kl)

HCI

ClCH-COOH

R ₅
(KIV)

IJL

CH-COOH <-Rs

(M)

OH

509820 / 11C7

A bcTiD-rnw ^ feoo © inc · ?? © r ^ raiDoEi

(II) 0 *;?; 3Γΐ? _ρ r ^ i in ci

Ffniiron τ ~> λγ \ Ο £ dia previous Siylation
a) f5 ~ r.-7c "rx -." - p; "rldino 'XI) lsi Gecpnuart
Γ ~ πο., Rl ο nB Tri & th ^r It ¹ FIn _x , r & fc © ims? »

in ΰ.οητη Π. _Γ nin! •!

nwCtrolsoci

Di © (r ^ nfclfcr ''. ^ "^" Ür ^^ i. ^ PrrLV ^ lnjrlcinnlRrinw.rcp. «5.cx ° Γθπγ. ^ Ι II,

.ογ, τ. ^ οαΓρ. ^ οπ t »cöcvi1iot ₈ isDninicsi also horge- ^ rv ^ j, iof; ¹ '- !! π ".γϊ Γ" γοτϊι ofer a ni ^ otiifewiorfcGs Pyron sdfe. Oly ^ iui Io C ^ rn ~ -: ojrt; ei.nor Brno bohanfelt, EoI this nyfcleepiuilcä noai ^ iors rrärcl ύον Pyronring Gpöfftiofe ₉ V? goo © p © 3J.rlctIοrfe ρ viü öor Hins uioöor with dom An & nosfcieltstoff-ROoeblosnoD. » rolchon now ira- Psrridinfing befilob,] Ttlorc tr ~ r.otr, waG? cUn In öor Rogel bei © r ^ Obton EpoJTD.twrcin τ - Γ, ϊ?, γ. ~ εοΙ clnor Xänc ^^ sn Since © do go leads uird, can like folct crüilwtcrt; worion, wobsi 2,6-dintothyl-i | - parron (3tV) πίλΐ? Corr. Division ^ "© n 2,6-Dimethyl-ii-pyriäon-lesaißs & ure (XVI) vor? Onöet; t7lrä:

H ₂ ^ H ₂ COOH

base

H ₂ O

XX

509820/1167

CH ₂ COOH

'■ "Vft

I c i a ■ a ζ T

N h F i

(XVI)

In general, the east-7-aminocephalosporanic acid derivatives or Arranopenicillan- of the invention can be prepared according by condensation of a ^1-oxo-1-J pyridinylessigsäure (II) with an amino-beta-lactam (III) are prepared as described above. This reaction is usually carried out in solution in the presence of a suitable solvent. Examples of suitable solvents are acetone, dioxane, acetonitrile, chloroform, ethyl chloride, tetrahydrofuran or other inert and easily accessible solvents. The reaction is also carried out in öor Rogel in the presence of a base, for example of cinsra alkali metal carbonate or an acidic alkali metal carbonate, of trialkylamine in which the alkyl group has 1 to 5 carbon atoms, or of pyridine. The Rgaktionstemperatur may vary between -20 ° to 10O ⁰ C, with the preferred temperature iot the room temperature or a temperature which is slightly below the same. The reaction time can be between 15 minutes to 36 hours, depending on the temperature of the reaction mixture and the reactivity of the particular reaction mixture used.

; Attendees. A time of 1 to 8 hours is preferred applied. After the condensation, the reaction products are isolated and using conventional methods

\ Extraction and crystallization process won.

f In order to promote condensation, a condensation is used

Funds used. One. Kind of condensation-promoting

?: Acting essentially as a dehydrating agent,

; ■; which favors the acylation and because during the

l; j sedimentation removed. Such drainage

yy | medium are e.g. dicyclohexyl-carbodiimide, N-cyclohexyl-

N-morpholinomethyl-carbodiimide, Pentamethylketon-N-cyclohexylimine, N-ethyl-5-phenyli ⁱ sonazolium-3-sulfonate and Phoaphortrichlorid. The compound dicyclohexyl-carbodiiraid is a preferred dehydrating agent, especially in

^! : | the marriage of the compounds of the cephalosporin series.

I 5 0 9 8 2 0/1167

Eino swoito Klcoijo ron oils condensation forderao.cn

meditate reacts; apparently 'Jon calls different used j

4-Oxo-1-pyriöinrlenciGi3Surcn öornrt, äass öor carboxyl radical j

des Eooisoawrotoilo'dco Holofiüla is activated, uctooi j

© in rofflrtionafßhicciCJ JfrrixcIionprodMltt. ßobilöot nl'rä. This !

E3r »itionofc ^r .! HiEo ^ - j.nc'sc-prc:" ^^ ncyliort nolnorr.oito öao j

Amino-ß-lacfer.n. ImifolG ^^^ "^^^ nind! Followcoö.a YcJr ^ iraöwrsGQn {Suitableoto rcrMtiono £" h ± G ^ ilqwivalcnte ,, wolcho oit success v © rt7ondot north fiöoncn: ijn.Mrohalogonide, SSyron ^ iöo,

mixedfe Silwrono ^^ driclo with Mlttflphoaphorottuvcin odor alkyl- j

kohleno & uren ₈ SSwrnnnicO rat Iraidnsol or cinon 'J-oubotit. ^! '

he and SSurs-p-nifcFopheny! ester. i

The manufacture ac; rorittionofähigen Zwiochonproduktes provides a bovorsiigto AMPffitirungsform deo process for preparing the compounds erfindungogomäßen aear _t

: especially in the manufacture of those previously described

^: Cephalosporin derivative c. Designed to promote condensation

Means are sB carbonyldiiraidazole, alkyl chloroformate, '■' where the allty! Groups 1 bir. Include 5 carbon off at orao.

Thionyl chloride chlorocicotonitrile and BiG-p-nitrophenyl carbonate. The bo'vOrisuGtooto means is carbonyldiiiuidazöl, which in the Hegel leads to a solution of 4-OJto-l-pyridinyleseigoacid at one below room temperature

j "temperature is added. Han lets the re-air ti ons mixture

; 'Calibrate to room temperature en-rärraon, after which a ver

j is subjected to reduced pressure in order to reduce the pressure

ι to remove the formation of the imidasolida formed CO-. the

containing the reactive imidasolid intermediate product

j f solution is cooled again and now with the

II speaking ß-lactam condoned. The condensation will

usually at a temperature of 0 ° to 150 ° C during

Sj 1 bio 12 hours filled out, after which the desired product

is obtained by isolation in a known manner.

509320/1 167

2,500Λ8

■ parts of a direct condensation of the amino-ß-lactam- T ^ the ontDp ^ chonöo S-aminopenicillanic acid or

^ "Lonpornnnauro nia noutrale" Sal, odor in For, nfcoro konAonoiert rorden. Iced shells are «.D. l ^ oniw ^^ o, boi which the AUtyXOWPe 1 to mtoffreiten uraf ^ t. Boicpiclo for dorartißD salts ορίΓΡΏ, üio ^ * Trit ^ fchyleinin odor Trläthylomin Son! Eoto. C- ,. .ο, _F o ™ ol XIl .iod those, -B OiQ rroic Ca ^ o-lGrvppe des ΑιΛηο-β-lactaine in ir ^ ov roloo rcrootor * rurOe. In Jo.on Failca ro the ^ ifr »« »PO nnöhftlGona ontrora. t, ird ₅ «a flio froie Säare

AP-lton. -earth vorr. _W roioo that Eotor perishes, _TO n Eotorswpiopuns can easily be removed.

«Tor" ΛΛΙΪηΧαηϋΜΒ "llto, D _Efl in _G « n _E on _r ; _r "; n Klnnon. fall the SiIy 1 and Stannylostor. So "" en bolopl.l ~ .i ~ CIo Boter a = r Hy.rolyoe. 8ol ~ l, .. V ^ a "" fcloophllon Λ ", ^". * Uvt ^ orfen "x * m. without ^: ^ l would remain part acc. ttol.Mil »changed viM. Ge

nind, .B. «Ldlrttoi» and Ho

"Oiopl.!" ""! "" A - (trl-n-butrl-c

«Ie

- »»! », A tri-di-iodo-alkyl-.inn

Tri-niodrIr

durcn Be _ha ndl "n = ₈ it a neutral central as W _3, ER ^ rt.mm.rr _0G eneriert" orden. As hydrogen U ^^ ntt.1 «ird vorzussweioo Vta.ner or a lower alkanol,

S09820 / 1167

2450043

Ui ■

νίο π.B. Äfchnnol,

used.

A AltornafcÄv-Vorfp.hrcn r, ixr Horatellung the erfindunga- gcmmon compounds comprising "as in subsequent RooiEfcioacr.cIiert ?. oplßvitort is the Bohardluns of a G ^ nrxloKon & cebrriioO-pcnicillin- or 7- * Halogsnacetamido «cophalosporinöoriiraftc? with a silylated ^ -hydroxypyrldln: OSI (R _e ) s 0

wherein

(KVII)

R ₅ O

ο ¹

(D

R _g ,

Y-CH-C-NH- ■ , Rs y -N ~ R ₆

(XVII I)

ι i

and Rg di. _e previously mentioned

_{g 3} ^ _{5 g} g have meanings; FL represents a lower alk ;; 1 group having 1 to 5 carbon atoms, and Y represents a bromine or chlorine atom.

509820/1167

The a-HalOGonc.cotajiiiäo-ß-lnctam-Ausgsins3verbin «! Limc-n are known (from the left J. Kod. -Chens. Bö. I6 _s page 1413 (1973),

1 'BE-PS 750 5S7 sonio US-PSs 2 9 * 11 995 and 3 516 997). DIo

I Manufacture (Her silylated ^ -Kyöroitypyridine succfc

f with a cocicot SilyliorunG ^ mifctGl, as suvor to © -

1 wrote. Examples of gooiG ^ ka Silylierungonittol nlnd:

I Di-low-Glkyl-chloroilr.n, Tr

1 Di-niearis-alltsfl-broisgilan, υηά

I in which the lower Alkylocuppo 1 to 5 carbon atoms

I includes j, also TotramathyMiniIr ^ nn »HeKsmethyldisilrvsan

ί as well as bis-triia ^ thyloilylacetaraiö.

The condensation is carried out in an in situ solution in the form of chloroform, acetone, ethylene chloride, dimethylformmide, dioitane or acetonitrile. The ReaktionstOEperatur can sxjischen ~ 20 ° C to 100 ⁰ C fluctuate

1 whereby, however, a temperature of 20 ° C is avoided. Qe

! the reaction takes place in an inert atmosphere,

I such as a nitrogen, arson or helium & troosphere,

I instead. The implementation is usually carried out during a period of

From 15 minutes to 36 hours, in ab-

i dependence on the type of Reaktionsteilnehiiiisr and

1 reaction temperature. The implementation is usually within

I half from 1 to 2M hours completely, if one

I selected temperature range is working.

I In general, an equivalent of the silylated one is used

X U-hydroxypyridine derivative with one equivalent of the ft-

⁽ ; Haiogenacetamido-ft-lactam derivatives to. The ß-lactam derivative

J can also be in the form of a salt, such as sodium,

jf} triethylamine, Ν, Ν-diethylaniline or diisopropylethyl

«5 amine salt, can be applied. But the a-lactam can also

are in the form of an ester. The esters include those

509820-1167

which only RoGeimcricrwnG the free Söuro can easily be regenerated under lüildon conditions urad «Si © the rust of the molecule not change. Xnisfooaowdtero v ^ faoson such first the following: tort .-! 3iÄ & $ X- _e TotalityI-cils; 3L- ^Mnö Tr3.nl ^f t; /lrst.K^IoOtOr ₈ at tftonon öio 1 am 5 Koto lonn to ff era at cwiVjoiDtp ßouio BcEi

oil ο toovornwGton Entor vora TriGl! iylsils? lfc3fp are.

Eotor lEÖiTiTücn loicht su the free SfiiMra Is ^ öro- j?

tJGrö ^ n ,, in ^ on nnn you with eincra nowtpaXarajHydrogen I lieforns'.on nitbclj, n: la nD oinora AlkoSiol ₈ b

Eoi allen den swror ^^^^ ntcn Kondeno at ionon wordon alle

ßorf, Yer ^ indunson, welcho roalttlomofnEiiso groups awffTcioon, the <3io Konöornoßfeicn otören! Sonnen »rnitcr Vcn-Tondwnc G ^ öisnster Schiat ^ rüppon gesjcWttnt. So! Tons of Car'ao ~ 2?! Groups, which ran in the Iä-P ^ ridonteil dOD Elolel'-ülD © öer in Ecoigsuröteil the HololtOls, with aflorcn labile Eotcrn, like suvor boGciirietoen, silylated

j odor be voräthejpt. In a similar t-jeino! Tons im * l ~

Pyridonteil TIOA Holofiüla lying amino hydroxyl ST-Jecltnaßioort Toiso-alo be UNU labile Dsrivate. Examples of such derivatives are (Sis Si3LyI -ether, Bonsyinthor and Cr.rbonatester for Hydro3: y! Groups, sct-jio for Arüdnosruppen carbobenzyloxy-, Carbo-tert-butyloxy- and triphonylraothyldorivate.

Another way of producing the cephaloporin derivatives of the formula I, where the substituent X is 5-ftothyl-li 3, ^ - thiadiasol-2-ylthio or l-methyl-l.S ^ .li-tetrGZol-S-ylthio group means, consists in the distance and the | · | ι Replacement of Acetoxyßruppo by the methyl group in the 3-position

I the substituted O-oxo-l-pyridinylacetyD-aminocephalo-

H \ sporanoic acids (XIX), Diea is represented by the following two

; Peaktionsschema clarifies:

509820/1 167

2A50CK8

11

/ φ

rstoff

ies I

(KSK)

N "

(XX!)

COOH

(XIX)

c H ₈ -S

COOH

N M

CH ₃

CH ₃

55K

I I

509820/1

ι j: ί I

; been.

where the sub-ordinates R ^ ₉ Rp "R", Rj., R ₁ - and Rg the Sf

zmror ßonr.nntcn Eo & nMfcuingon bsnitzen. "'

: «At ε

The cephalosporins ^, wren dor Pormol (XIX) are not susaraien '; clca 2-f! arcrpto-5 "ns £ fo: 'll _Ä 3i,' l-thia <HGsol (X] I) odor eieom Hot olio rlr, Coor-olbon in oinora inert LOsiinonmittel go loot ;. YovzvrpvolzQ trlrd an Alkaliniotallsals aar Cephalo- © pOFcnaiUtro (ΧΪΧ) used. The Sals © can bo for example ö.wrch Bohanöluns c?. ^ r Cophalosporan ^ aurs with an Al ^ n-lirotalllaic ^ räon ^ ft horgoatollt worösn Solvent ₉ such as & .B. Wäosricom Acoton, aqueous tetrahydrofuran or t'Sßorigera Dirothylformr-mici, if necessary ßor pH of the Ro olz ion ο mixtures α by adding a

Buffer controlled t-iorden. VIif the free ones

Cephalooporanoic acids ala Auocangsatoffe can be used, ^sta

Umaetsuns in the presence of a base, such as natriumj TFÄr.tla: flr, rf.n oC-τ

The UrasGtsMnr, Izenn inncrlip.lb of a tone? .P © raturb © roiches of

Been 25 to 100 ⁰ C, to 110 ° durchßoführt _β ror ^ w ^ nt Oino 50th ^Cel

OowOnschfccnfnllo can io unaetsung in the presence of a3: ^eil

inert Gaoco »ni © nitrogen or argon made P ^b '

troröon. The noairfcionosoifc can take between 15 minutes and " 2 ^ hours ociinnnlron, but one of 15

Minutes to β hours is preferably used. ^we

In small fillings, the displacement of the acetoxy group causes ^En

from the HothylGruppe in 3-Stcllung the migration of the double bond to the 2-position ^ma de3 ß ~ lactam nucleus. In such

Cases, the position of the double bond -wiederhergestellt ^Di

by adding the ringo-sulfur atom to the sulfoxide with ^Fl * '

509820/1 167

J / 245G048

such oxidizing agents as e.g. hydrogen peroxide, Natriuiranet ^ aperiodat or an organic peroacid oxidized. By subsequent reduction of the sulfoxido means catalytic hydrogenation or sodium dithionite will do that desired cephalosporin derivative, which in the 3-position dea ß-lactam rings unsaturated int.

The new invention compounds are biological active and show how it was found a good antibacterial Effectiveness. As a result, it is considered an antimicrobial © Means, polygamy a broad, spectrum dor antiiniltrobielle.i Efficacy in vitro against standard laboratory microorganisms have, in the case of attempts at disposal to determine the Viirksamkcit against pathogenoa Bacteria used, '"Dao" antibacterial spectrum of typical erfindungsgeraäß Vorbindungen is after an I.

Standard ancestors, namely dor Aßar-Verdünnunss-StreiehplattenimthodG (agar-dilution otrcakplate tochniquo) determined, which usually r, wm testing new antibiotics is applied. "

The presence of the T-Methojxyaubafcitucnten has at dor Cephalosporin series have a beneficial effect in that this an increase in the antimicrobial spectrum of activity compared to causes certain gram-negative microorganisms. In particular, there are compounds with 7-methoxy substitutes effective against certain genetic microorganisms, which compared to those compounds which have the 7-wethoxy substituent not contain, are resistant, such as Enterobacter aerogenes, Enterobnctor cloacae, Serratia marcescens and the indole positive species from Proteus.

The high antibacterial effectiveness in vitro of the invention Compounds makes them useful not only as pharmacological agents per se, but also as additives for

509820/1167

Animal feed, .ort. Additives for substances »oak a BÜtrobioUen destruction are subject as * · ^Β · cutting un _ä KmftntoffOlo. IM ^ * "*""" ^ also ", smokable on your«, tttokfrieU «. Shepherd« «

in soaps, shampoos and in t _w opiscnen * «» for the treatment of wounds and burns.

The following examples explain the invention in more detail.

Beis piel 1

A suspension of 19.0 a (0.2 Hol) ft-22.2 ε (O _ffi 22 mol) Triathja ^ nxn and 300 ml of toluene is allowed to reflux to its reflux temperature HP or: -: ärot, after which 23 S (0.2 mol ) Chlort rlraothjrlsi lan tropiOn'-oiPO zuoßoben tturfcB. The mixture was heated inside the tube at its reflux temperature for 18 hours and filtered. The filtrate was evaporated; wnd the residue was distilled under reduced pressure, with 10 ₉ '! g nilylicrteo ^ - accrued; Kp. = 102 am 10'J ⁰ C / 15

9 g (0.05 ^ mol) of the 'oilyliortsn ^ -Hydroxypyridins t-jurden with 25 iral ethyl bromoacetate i ^r ornu.3elit, and the Geraisch was stirred until the exothermic reaction subsided. The solidified mixture was triturated with ether and filtered. The pesticide was uracrystallized from ioopropyl alcohol, with 8 g of ^ -pyridon-1-oooiGoäureothyleoter as hydrobromide with a melting point of 195 ° C.

509820/1167

/7.450043

111

The hydrobromide of the ester (8 G ₉ 0.03 Hol) was sued to a 1N sodium hydroxide (SO oil) socoben ^ nd dna Geraisch

was stirred for 5 hours, concentrated immediately to 20 ml. The solution was then filtered and filtered, 3.7 g of H-pyridone-1-eaoicciauro being obtained at a Scheol spit of 265-266 ° C.

After in weoonfeliohen equal pre-friiron, wcboi however

instead of ra U-Hrdro3TPrr3Löin 3-ncfthyl-ft-pyridinol, 2.5 "» i «9tliyl-ii-pypiäinol bffl. 3 ^ Tii; rc- ^ p _r ridinol used

"I" 9tliylipypiäinol 3

were, wwrdon jt ^ thyl-O-pyriCijn-a-cnoiGßaure; 2 _s 5 ~ Dx-

methyl-U- nidl

essigaäuro

Example _n 2

20 g (0.2 mol) «j-Hydro3t3TCliinolinH ^ iVx ^? c »'Jn ^a ln 50 years of aqueous potassium! 5» ydPOitidlöouns gelöot, and 20 β (0.2 hol) ChloresoiGsävKO trurdo in proportions. Top Looms obtained t "Pöo on Itiro RüclsflußteKporatur lO hours ERTF & rmt, _S nb okffihlt, onßooauort and filtered to give 7 g of H-Chlnolon-l-enoAeanure oit a Schiwlepunlst 278-279 ° C were obtained.

Following essentially the same procedure, but wokei the H-hydroxyquinoline pihydrate by 3-cyano-2,6-di0ethyl-H-pyridinol; 5-chloro-2-atho «y-il-P7ridinol bw. 3-trifluoro- ■ ethyl- ^ - pyridinol was reddened, 3-cyano-2,6-dimethyl-

Midlsxg

UpyridonlG;

e acid bnr. 3-Trlfluonethyl-n-pyridone -! - acetic acid obtained.

ίίψ

ν «

2,500Α8

movie theater

7Z

7.5 g

ad IO ml

he-

l _7l ^ _rzr ?, on -% - rrrt.cr.Cvxo with e * nem punf: rou 2 ^ J. orSalSon rrrCnn.

".., .. ri <-? R'7- ~ n Tc r drive, but rob ei

Mach Cnn in troacnfcHchon G- ¹ ^ - ¹ - ^ ■ * ■ "■»

1-H-pypon «vrcii 3-r: ^ thoxy-2-ra9

^ n b— a.G-töcnrbäthosy-ft-pyron replaced

(Mat r 3.0β

(0 _e 02 Hol) ft-Pyriöca-l-corlgoaure were in ^ SO ml ECiraJld © i? .Öot, tsnö-dio Waunß was reduced to 0 C.

cool. 3 _S 2 C (0 _# 02 Hol) Car ^ onrl ^ iinidasol -rurden added, and the Gemisfeh rwrtf.cf wnter SfeAc'Mtoff at ^{0 0} C for 30 pinks and then warmed to room temperature. The RsaktionoHolben nwrde 3 John ninwfccn evacuated to the carbon dioxide su remove, and then cooled to -20 ⁰ C. In a separate flask, 7-Awiinoeephalo3poransäure trwrclo by EnfSrmsn a suspension \ ^r on 5 ^ S of this acid (0.02 * mol) and 8 ml of Hcxarcotli ^ läicilasan in 50 ml of chloroform

50982 0/1167

cilylicrt under reflux for 30 minutes. DicoG Lo

rnirde sur removal & aü, f-oiconokstcn Anmoni Trockno elriGsdcicpft. A Lögwp.g ö.oo Rüclfcstandon in 50 ral 'chloroform rjsrt ^ on -SO ⁰ C rt, ^'"«"^^ · ^ ^wn ^ swn Iprlflnr, © !! ^ asußsßcbon. · Ι? Λγ» 'Ror ^ ftionnG ^ R? - "^ wwrör" oino Sfcwnflo stirred at OC "on Rcunrtoisporntur orrriTrnt and üor Uacht co

The Löcswns n ^ röo rat 2 ml ΓΤο ^^ γώοΙ treated j, imü 0io gmss®- precipitated T-AEdraoccphnloßporruT.nnwrQ wuröo © tofiltriert. En became a LOciras of Nntrium-S-öfthrl ^^ Jt ^ noat in n-Bufccmol (10 ml ciKsr 2n - KiO3Wi? .G) s »ro [- ^ cn _c and c1d, d GsnlneSi rrisrdo with ÄtfeGS ^ nw. r a Υσϊ, ΐΏ ^ η τ ^Γ ^ η rrrr.?r,I?.crod oiworn Llfeer rordünnts win dno product only> r, urailon. after filling from methanol with Kfehor was 2 ₉ 2 κ 1-lZ-V ^ oxo-l-pwriulnyl) " acety3.nmin <ti3-cephalooporanr7fluro nln tjoisssr solids rait a snap point of ICO ⁰ C (JSoro.) an iodine titration was ör.D ProdvTct su 72.7 S pure.

According to deni ira weekly on the same Vorfcihron, · trcfeoi jcöoch the 7 ~ Aminoccphaloopor £ nsriurc dwrch e-

7-andno-3-f (l-methyl-l, 2,3, 'J decephalooporanoaure asked ?. 7-Anino-7-E "thojiycophalO3poranaäure ersotst tfurdo that Nntrium ^ than the 6-Cs (J- ¹ was OKo-I-pyridinyl) -ßCGtylamine © 3-pcnicillnnoaurG; 7-C2- (1-oxo-l-pyridinyl) -acetylciminp3-don3acet? L-cophalosporanoauro; 7- [2- (il-Oxo-l-pyridinyl) -ncotylamine3- 3-C (5-methyl-li3 " ¹ " - thiadia2ol-2-ylthio) -mGthyl3-decophalosporanaöur ©; 7-C2 ~ (l | - Oxo-l-py '^ <iAnyl) -acetylainin "> 3-3 -C (l-methyl ^A l _t 2 _f 3t ^| l-tetrazol-5-ylthio) -methyl3-decephaloBporanBaure or 7-Mothojcy-7-f ₂ - (ii-Oxo-l-pyridinyl) -acetylaniine3-cephaloaporaneaure .

50982 0 / Ί 167

in the

Beis gfosl

6 ~ ü l2- ( ^ UTp-t-chJM.olxmriy-D.

A wntsr cinor Stieftntoffc ^ r ^ rphore gewaltcraa of fl, ic (Q "02 Pol) ^" Cixln ^ .c ^ l-oafsiGanuro lsi 50 «t! Hjl formula, d t7wri-5 ü.n £ IQ ⁰ C r, ^ Gc! Tühlt wrad rrsit 3 »2

(0.02 Clol) Garüon; -lö? .Iriönn5> l nv.f once veroofcsfc. after

He «rSrr.iiag öos G ^ rolcchon π ^, Γ Piston 15 ninwfcon Ir.rg; crr ^ ilort, urn öno bei

lidc. cntwicfiolfco Kolioliiliojdd su enfcfcnaoEB. Dio s tn,?. RöG γλίΓ iO ° C r "> G - '". Ss ^ l ^ wnd with cinos »LOnw ^ s ^ ^»' SG (0.02 i: ol) ö-Anincponißillr.noauro wnö 5 β (SO ft überocfewpv) TriStfeylr-In Ιγλ 50 rl chloroform vorr.otr, * ;. RealsfcieoRQ ^ mioe'Ti wwf ^ .oo: Iro "t ^ n ^ at 10 ⁰ C ßorilnJFiä ₉ nwf Raumtcrpcrafcwx · er: tSrrnt ₉ ν.ηύ. cl ^ .a tubes t?« Rde ufitarc; ^ another three StwnO.ors fo

10 ml of a 2n LöouriG of H & tr £ uiR-> 2-IlthylhQX & noat in butanol were added, wnd ώασ Produttt t-iuröo dureSn zuQQbe of 700 parts of ether. The 6-C2> (4-Oxo-l-etiinolinyl) ^a acetylaminoj-ponicillaidoüuro v! Wrclo filtered off, aborracils from K ^ hanol rait Kthor filled out and under Vaitwun cotrockne with 5.0 s oinea treißon PGOtntoffee from the very ^ lspunttt 20M C (Zera.). An iodine titration showed the purity to be 86.M % .

If essentially the same procedure is repeated, but ti-quinolone-1-caaicsigure by 2,5-dimethyl- ¹ · -pyridon-1-anetic acid; 3-Mtro-15-pyridon-1-essiic acid; 3-Hydroxy-i »-pyridon-l-essiEoaurG or 3,5-diiodo-li-pyridon-lessetic acid was replaced, the sodium ala were the

6-C2- (2 5 *

ponicAlJ.awJrt in c * ton TorfaSirone & Useftnt

7 ^^

3 6 β (O 02 MoX) 2,6-Dii ™ * hy * -1-pyrfdon-l-oeeißeaure were An ^ O Bl'DiBathylfonarxdd ßolOot ^ and the solution was cooled to 5c. Now t ₇ "röon 3.2 ₆ (0.02 Hol) carbonyldiimidazole was added and the Gemioch tfunte under nitrogen at 0 C for 50 minutes and then reaches to room temperature, allowed to warm Dor Reaktionekolben vmrde 30 minutes sur Enfc-

509820 / ".167

C r * {. "'Ki ''I

I \

-, c- - y.rrrv-

rl ^ r '. rvrJi iirrk. The ^ '- W ^ Xt vaü rife 50 nl

"ι

f ■ -. j ~~ -, -;. ic " cin ^ f ^ vndc

r - *. *: "^ l red; hr> n.ol rorncijn

'Ti nr - ^^^ cn ,, ir ^ .- i pit Γα It rl ort t:

nit

ν ?:

C er * / "ΤΛ

Mn.ci »f '^ n in

from

Torfnhrcn, ^ c ¹ O c by J-

However

; 5 »6 * 7» G-

cr-ot-nt;

bsw. 3-

were dio

.r5 from ? - £ 2- (3-

; 7-t2- (5> 6.7, C-totrriiydro-iJ-ono-l-

; 7-t2- (5-

sporanoQnre; 7-K.2-C 3-triflworrothyl- »5-oxo-l-pyridinyl) -

bnvr. 7-t2- (3-Hydroity- ¹ »-

obtain·

509820/1

If you trim3thylsilyl-6-amino-6-m3thoxy-penicillanic acid instead of trimethylsilyl ^ -amino-cephalosporanic acid are used, the

Sodium salts of
6-C2- (2,6 ~ Diemthyl-4-oxo-l-pyridinyl) -acetylamino3-6-insthoxy-

peniei uric acid;
6-C2- (3-methyl-i | -oxo-l-pyridinyl) -acetylaniinö3-6-methoxy-

peni ei Hansaure;

6-Γ2- (5,6,7,8-tetrahydro-U-oxo-1-quinolinyl) acetylamino} -

6-methoxy penicillanic acid;
6-C2- (5-chloro-2-ethoxy-i »-oxo-l-pyridinyl) -acetylamine3-6-

methoxy penicillanic acid;

6-C2- (3-Trif luoxTnethy 1-2-oxo-1-pyridinyl) -acetylamino 3-6-

methoxy penicillanic acid; respectively.
6-C2- (3-H.ydroxy-i4-oxo-l-pyridinyl) -acetylamino3-6-n »ethoxy-

get penicillanic acid.

Example 7

7-t2- (i »-oxo-1-pyridinyl) -acetylamino-3- (pyridiniummethyl) -decephalosporanic acid

The sodium salt of 7- £ 2- (U-oxo-l-pyridnVl) -acetylamin © 3-cephalosporanic vxird dissolved in VJasser and for 6 hours with pyridine in the presence of potassium thiocyanate at 6O ⁰ C. The work-up is carried out according to J. Org. Chem. Vol. 32, page 500 (1967) and leads to the preparation of the 7-t2- (1-oxo-pyridinyl) -acetylamine3-3- (pyridiniuinmethyl) -decephalo8poran-

acid as a hybrid ion.

509820/1167

At game 8

7-Γ2- (iS-Oro-l-pyridinyl J-acetylandnoa-desacetyl-cephalo-

sporic acid.

7-C2-C * -Oico-l-pyridinyl) -ocetylaralneJ-cephalosporaneaure is used as sodium with one of OrcE3S®nshells according to &Biochen;. J. Vol. 8I ₉ Scito 591 (3L96l) icolierte. Acetylesteraae treated.

Example 9

* l -TrI nsefc hy Is i Iy 1 ο xy py ri di η

500 g of crude 4-Hydroj: ypyridin were treated with 5f5 l of toluene. The mixture was heated with stirring and about 700 ml of toluene was distilled to remove any water present. The RoaittionsEondsch was maintained .if your Rttckflußteiaperatur, and 5 * "3 S Trinrathylsilylchlorid were langoan swgoG ^ ⁰¹¹ · ^ ^aa neaktionsgemisch was erwflnnt under reflux for about 3 hours, cooled and filtered. The piltrate was evaporated under reduced pressure in order to remove the toluene and the residue distilled at 18-20% Hg. 620 g of 4-trimethylsilyloxypyridine with a boiling point of 95 to 96 ^° C. were obtained.

Example 10

7- £ 2- (i} -Oj: o-l-pyridinyl) -acetylamino-3-cephal03poranic acid (Sodium salt)

509820/1167

- 'JO-

"50048

ί ■. ■■. ■ ■ ■.

f M ^ f- θ Λ ml

20.0 s 7 ~ (2-Bromoacetamido) -cephalosporanaäur &, herge-. · ■■; ' ■ prepared according üer US-PS 3 6h7 7 89j were washed with 135 al of chloroform and 20 Hl ■■ M, O-bis (triE'sthsTlail ^ l) -acetsiaiid

This mixture was given in an hour by v »ntor @ in © r - '.) Stickst off ateospfoiE ® gerlJhrt _B !

'.D-iis / Realttionsgemisch wiarde wntop stirring mif 80 ml Mot! Sy 1-alcohol · Tersetst until üov © oaaraiaö.anfänglich © sbilöet ©''·. ! liederschlag awf © 3löst wap. D .o mixture w ^ ra © .winter in about 1 1 "^ r asserf © IOEN Hthor '(xoc; o53scn _i that ^.disrch: entferntj Delsisintierung and dor sticky precipitate" welcher.surttckblieb _s uurd® in / other MOO ral fethjlalkohol, g © 19st.Sna ÜQF the solution containing the colöstcn üioö ^ roehlag were 65 al. Of a solution of 2n'Hntriura-2-ethylh © sanoate / ^: in n-butanol © 2geb © n ₉ wiü clao obtained mixture'- aura® nit / ■■ ... b © te, cycling nnü dwrch a bed of DiQtonieonord _©::. '.'Das''Piltrat'tJiÄFde long sara 900 ral Isopropjl- / ^ alcohol T © rs © tst Dax ". gobildefco precipitation has been declining.

.filtriertj, wash ether and dry under vacuum, whereby 17 "2 g of the -neitrium as the 7- [2 - ('4-0 ^ o-l-pyridinyl) -' äcetyiamin®3-cephalic acid was obtained.

When replacing the 7 ~ (2-ßi? Oiiaac'etamido) -cephalosporQiisSttrQ 'by' .7-t2-Chloröc © tamiäo3-7-iii3tho «yc © phalo3poran0Svir © '5': f-C2-Chlor-2'- iB © thyläcetamiä © 3-desacetyl-cephalo3por.ansSure ⁱ ;

acid; ; 6-C2-chloro-2-msthylacetas! Dd © 3-penicillanic acid; δ-

and 6-C2- respectively after

obtained the following acids using the procedure described above?

SQ9820 / 1ΊΒ7

2450IK3

l-Ö «o-i-pyridinyl) -2-iratliylaeetylainino3-deeacetyl--

Sä «F © 5

β above process 2,6-dimethyl- ^ trf.iethyleilylpxy-

LiH bsw. ^ 6 »Bis-Ccnrbotri ^ thylsilyloxy) - ^ - fcrimsthyl-

^ sracm the corresponding

: -. ^: ^ _r - / :. 2- <2> 6-Diot © t ^ l - ^ - oso-l-pyridinyl); 2- (2,6-DicaPb6 ^^^

!. ^{·: /;,} ■ ί - '.'";: i-pyr £ dinyl); brau 2- (3 ~ chlorine - ^ - oxo-: _.

Cephaloeporan- and

Beiop igl__il ^: .. '■ ■ ■ ■. ; . ■ · '■ ■'

C 7-Aaidno-3-C '(5-nE3thy 1-1.3 »* l-thiadiaEo3.-2-ylthio) -

dseop! h © losp © ranDäwFC ₉ no lohe according to the in the US-PS 3 _: 51β 997 'b © schri © b & n © n Verfstorsn and the oraish stirred in © iiaora of 25 nil water and 25 ml acetone -bn enthai'beK uar ₈ HMrclcabit 3 g matriunibi carbonate versetsfc. The mixture was cooled to −10 ° C., 2.2 β bromine - acetyibrp! Aid in one ml acetone were slowly added to the stirred mixture over a period of 10 minutes. Daa became Qeraish

109820/1187

^: '2A 5.0.04

stirred for another hour at -10 ° C 'and then on ' ■. Room temperature '.enffSirEEOn left. Dao Roaktionageraioch was made with itihylscetat ejctr ^ iortj, vsma oils © rgmnise! A ©

^: "Phase" became ".. y ^ irti or fen. The aqueous phase was l © .rait 100 lsi

: 'Kt hy Iac © tat besehi © hfcet _s ■ «ind di @ ■ HSosri.se Phas © wwrd a HO $ 1 g © n PhosphoFsäiai ⁵ © ataf © iBoira pHrHert ■ from ^: 2: SteXlt. .THE ORGANIC Fh) Mi © Tfwrflo .ei ^ / rptrennt,. sulfate: getroetoefc wra «ä discolored with HolsnKolalG.

rwur> de ■ filtered ₉ einiseöas ^ ft ^ unö ßep residue itrurdle rait ether betrrietoen. · 'ilaeli TroclfenQh ■ öso liÄo ^ otanöQs im ¥ ®! si5wa

were O ₉ T S 7 ^m (^ "BFOHacetyla !! drao> - 3" -C (5-iisthyl-i. ₁₎ ^ s ^! J ··:

i) 33 obtained.

After essentially the same ancestors were at

Replacement of the 7 * ⁱ -Aniino-3-t (5-in3thyl- "i _J> 3si | -thiadiasol-2-ylthio) -. Methyli-decephalosporanic acid by T-

oporanic acid ©; ■ 7-

TOthylJ-decephalosporcmsäure bsw. ■ 7 ~ Amino-7-icetho3qf "3-L ( i-msthyl-l ^

eporietns & urs "'" contain the following acids *:

7- (a-Broiraace ty lamino) -T ^ methosy- 3-1 (5-nrathy 1-1,3, ^ -

7- (ft * -Bromacetylaraino) -3-C (l-niethyl-i, 2 _t '3 ^ 1-tetrazol-5-ylthio) iisethyl3-d © cephaloaporans £ lure - "bsw ... ■ ·

7- (a-Bromoacety lamino) -: 7-Ei3tho? Qr-3-C (1-methyl-1,2,3 »Ί-tetrazol-5-ylthio) -methy ^ 3-decephalospora? I3 acid.

Example 12 · :. -. ·; ^ '. . '/': '■

7-C2- (i | -oxo-1-pyridinyl) -acetylamino3-3-n (5-niethyl-1,3 » ¹ * -thiadiazöl-2-ylthio) -methyl3-decophalosporanic acid

509820 / 11S7

- "3" Ζ

■ \

1.65 ■■ g "t- (

, received na «5Si

Example Ilj, -Wiarflenl ^ O ml 'chloroform and 5' ml K, 0-1 ■ (irirafch'y lolly t) -Q © Gfcariid TOracfcsfc, Das Qi .unter SfcictafcoffafcnosphCiFG jpjräihrfc, to © ine klaff®

tmvC ^ g \ mü 'no, QlY JSincabe -of 1.6 g ^ -Ti wShroßa 13 S ^ ünsiiösn under! , Sodarie tfOToil it. 5 rai nsfcla ^ lciltiöhol vers © tst ₈ vmü ü®r fixed "NieaerseSilaOj, r -ύον DCIS üiMote Λ νιτύ® The Niederschlag'wurd © he ÄOO ral methyl alcohol with 5 ml einer'2n RI _':?.? atriv ₁ ra -'2-Et; hylheKanoafelBswng in PI ■ uiiä '© bdasBia sit 200 oil Hther-voroetst. Per blow'Wisrde. Filtered off and' dried under vacuum, ■ .the'l ^ fitrlMraals der'7-t2- ( ^? l-0: io-l-pyriöin 3-t (5 ~ fetil5yl-l ₈ 3 ₁ , ^| J-thiaöiasol-2-srlthio) -msthyl3 ™ fe © ephalo- ^: ■ ^: ' ^: p. sporansüiÄr® ■ was obtained ■ · .. · ■ y - _'^; ■■....

'■ NacWäem ira essential', same ancestors, but tjobei ^; , the 7- (© -Broraaco-tylamino ') -3 ~ C (5-IR3chy 1- ■!

by 7- (al Ll ^^ - thiai ßüsthy iS'äecephalosporanoäure; ■ 7- ( ^| a- ^M Broinacetylaraino) -3-

sporansilure or 7- <® -Bs? omacetylamino) -7-mstho ^ -3 "C (l-". 'methyl-1,2,3, i} -tetrasol-5-y itthio) -möthyl3-decephalosporanic acid replaced the sodium salt of the following acids was obtained:
7-Methosy-7-C2- ( ¹ »-OKO-1-pjrritiinyl) -acetylamine © 3-3-C (5- * methyl *" l _> 3, i »-thiadiazol-2-ylthio) -mothyl3 ~ decephalosporanic acid ; 7-L2- ( ^| i-Oxo-l-pyridinyl) -acetylainino3-3-C (l-methyl- ^{1,2,3 »11} " tetrasol-2-ylthio) -i! Iethy3L3 "^ ⁽ 2cephalo3poran3äur © j bsw.

7th
l _i 2,3, ^| i-tetrazol-2-ylthio) -iti3thyl3-decephalo3poranic acid.

50 982 0/1167

(10

7-C ^s * ° n5FC !!? A (5oi!; S7l © raisÄo) - "3" - £ (5-ßist "h ^ l

Da ^ ia would also include

_: from 'Ssi ■■ Ha ⁱ & rivira " ^B '2-.Q'fei2ylt3G ^ nsi» oafc Ίη Bwfcönol wwälö SMgos .to - .. ^ fSCiteo cinoo Elols ^ ciii Tolwr ^ ns iltlioi ^!> wmfös fep gs Mieders ; fies ⁸ «; imü wiber 'Valtuttia © sfereekmot, where

Watriuras.as received

example

methyl-1,2,3, ^| 5-t @ trasol-5-jflthio) ^-methyl3-> decephalo3poransäure _{^{'(Natriumsalss'):'.}} '■ .... V''■.'

A mixture of the Sodium salsea of 7-M © thoxy-7-C-2- (i | -oxo-l ~ quinolinyl> -'- ' acetylamir> © 3-cephalooporanoic acid (3.5 s3.2.5 g sodium bicarbonate, 2.6 g l-Methsrl-S-mercapto-l ^^^ - tetrassol and

509820/1167

- «ir · -

60 ral Mr- ΏΏΟΕ ⁵ wülirooa ft ^ ργ, ^ ώ ^ aiaf © fc *? & 7Q ° C erwfirafc. '■' ■ '. · Ί

? M f £ ltrl © pt _e with S © © ipr®p- ^ aJfiÄol τογγ-ο ^ π ^ ₀ 't? © S? Si © icli

: · 4οή; te

1-eophalosp © rs »[3 & wyö ■ ' i ^ tibj'l-'i-OÄO-A-pyridisiyD-acötyl-

■ ^ '· ■ ■ - ■' - ■■■■■ ■ - · - - - ^: - - - ■ - ₇ . _ζ2 - ■

nQfeltn ^ lj- ^ oecipiinXosporansaMre test ?. 7-

Q © rimlfcen _e

ί · .. 'ί ι' ^"1:.: ■■]: '..'■" ■

-3-t (5-methy 1-1.3, * -

'Eine ι Lös'wras ^ o? I 5 S d © o H ^ fepiumsalaee' ö © r 7-C2- (4-Oxo-lpyridinyl) -: © e © tylaraino3 ™ c © ptialo3poreinaure in 500 ml Was'ser " would with O ₉ 95 S sodium carbonate and 2.96 g of 2-mer c © pfcp-5- ^ ®thyl-1,3 » ^| i-thindlias; ol voraetst. The mixture was

509820/1 167

245 /

ify Vf ** ο

Stickotoffatmosphäre heated for 3 hours at 7O ⁰ C and evaporated under reduced pressure. The residue was dissolved in 50 ml of methanol and treated with an excess of acetonitrile. The white precipitate formed was filtered off, washed with acetonitrile and dried under vacuum, whereby 1.3 g of 7-L2- (M-oxo-1-pyridinyä-acetylamine © 3-3-t (5-methyl-i, 3 ₉ ¹ i-thiadiazol-2-ylthio) -m®thyl3-decephalosporanic acid was obtained as sodium salt.

According to essentially the same procedure, but tsoboi the sodium salts of t-methoxy-T-t2- (1-exo-l-quinolines7l) -acetylamine © 3-cephalo3poranic acid; 7-methoxy-7-Γ2- (Μ-οπο-Ι-pyridinyl) -acetylamino3-cephalosporanic acid or 7- £ 2-methyl-2- (2,6-dimethyl-II-oxo-1-pyridinyl) -acetylamine-3-cephalosporanic acid used vjurde ^, vjurden the following acids as

get their sodium salts:

7- ^w Ietho3 ^ -7-i2- (t | -oxo ~ l-quinolinyl) -acetylainin © 3-3-C (5-

methyl-l, 3, ¹ "-thiadiazol-2-ylthio) -inethyl3-decephalooporan-

acid; ■ '_. "■' ■: ■ ·. '■ ν ·, - ■' ■ '" ■■■. /. ■ '. ^: "'^; . ^; .'..-' ■ ■ ·. ■

7-Methojcy-7-C2- ( ⁱ J-OKo-i-pyridinyl) -acetylamine <? 3-3-C (5-

methyl-l, 3, ¹ "-thiadiazol-2-ylthio) -methyl3-decephalosporan-

8 acid; batr. _: . ./ '. .-. ■■ - ■ / '. "■ ■ .. '' ■■, · '

7-t2-methyl-2- (2,6-dimsthyl-M-oxo-l-pyridinyl) -acetylamine <i3-

3-C (5-ni®thyl-1,3, M-thiadiasol-2-ylthio) -methyl3-decephalo- ^

'sporanic acid.

Example 16

Pivaloylcxymethyl ester of 7-C2- (1-oxo-1-pyridinyl) -acetylamineQ3 ~ ^ce phalosporanic acid

One

_o from Ί, 5β

-acetylaminej-cephalosporanaäure in ^b 0 ml which was ^{cooled to 0 0} C, was with 2.6 g

5 0 9 8 2 0/1167

«*« Tt * ljodid vroet. t. «Nd the solution

ears for about 25 minutes. There, GoBi.eh was

Xtbjlaootat diluted, well «** ^ sor and aodonn with one

denied Katrlwobicartonafelöoune ßwaachan. Dio org ^ iixschs

Phase was gofcroclmet via uaooorfroiom MatrHimoulfat,

filtered and _8U r dryness oinsoda ^ ft, ^ if the gotfOnehte pivaloyloxyraothyleoter was obtained.

After essentially the same procedure, with .jedoch since ₃ previously used PHralorlo ^ KsthylJodid by Aeetosqnwthyljodid, M-Chlornathyl-H-iwthylwethan bsw. p-Acetoi ^ benzylbromid was ersetst, the following esters were obtained: T-CP-CÜ-ORo-l-pyridinyD-acotylaminei-cephalosporanic acid-

acetoKyy;

7-t2- (H-Oxo-J-pyridinyD-acetylai ^ ne 3-eophaloeporaneäure-

N-ethoxycarbonyl-N-iBsthylaminoi ^^ a.eater; bew. 7- [2- (1-oxo-l-pyridinyl) -quotylamine © 3-cephaloeporan3aure-

p-acetylojtybenzyl ester.

If the sodium salts of the 7-Mefchosy-7- £ 2- ( ^| J-oxo-l-

ylthio) -raethyl3-d © cepnalosporanic acid; 6-MetliO3ty-6- [2- (3-cyano-iJ-oKO-l-pyFidinyD-acetylaminoS-penicillanic acid or 6-t2- (ii-O2io-l-quinolinyl) -2-isethylacetylarain03-P © nicillan: acid, the following esters are obtained: 7-M®thoxy-7-C2- (i} -oxo-l-pyridinyl) -acetylamine (! »3-3-C (liRethyl-1,2,3, ⁱ l- tetrazol-5-ylthio) -inethyl3-decephalosporane acid pivaloyloxymethyleater;

6-MethO3ty-6- £ 2- (3-cyano- ¹ I-OXO-1-pyridinyl) -acetylandno3-penicillanic acid pivaloyloxymethyl ester; or 6- [2- (i »-oxo-1-quinolinyl) -2-methyl-acetylamine © 3 ~ penicillan

t acid pivaloyloxymethyl ester.

§0982-0 / 1167

■ 24 ^ 48

Example 17
N-ethoxycarbonyl-N-methylamino-7-C2 - (* - oxo-l-pyridinyl) -

. • "• A held at a temperature of 0 ° C up bio 5 '■ <} ■ slurry of the sodium salt of 7-L2- (4-oxo-l ~ pyridinyl) -' / '■''ί acetsrlamin © 3-3-L (5 ~ m3thyl-l _s 3, ¹ ? -Thiadiazol-2-ylthio) -methyl3- ·, ·. ''";'· Decephalocporanic acid (O ₉ ol mol) in 20 ml of dimethylformamide ' ■■ ■■ / was added to a solution of O ₉ Ol mol N-chloromethyl-N-methyl- ^: - ^: -. ''".'.' ■ · , wrethane in 5 ml of dimethylformamide. The mixture. ■ '■ ■.' ■ was stirred for about 1 hour and then poured into water. : ■ "'■' * / 'Dar bodice blow formed was dissolved in Rthylacetat, ■■ ··; i with water and then a dilute solution of ^{sodium; -j!.'} Washed '' bicarSsonat and dried over magnesium sulfate. ··· '·' ■ '1 The LQsvins was evaporated under reduced pressure, whereby

! the modified N-Xthoxycarbonyl-N-methylaitunc? r-L2- ( ¹ * - ^J oxo-l-ps? ridinyl) -acetylandn © 3-3 ~ C (5-methyl-l, 3, ¹ »-thiadiazole-, / 2-ylthio) -raothyl3-eecephalo3poranat was obtained.

Il | ΐ Spesielle, plates coated with agar-agar as a nutrient medium '/ ■ [

I;] J; were completely with the various test organisms;

Ij. inoculated. Pi1teraj were placed on the surface of the agar Iipapierscheiben and placed with 0.1 ml of a solution, which || I; 10, 100 and 1,000 micrograirans of the compound to be tested ft contained, moistened. The antibalttorial effectiveness of the P): ti connections to be tested against the various

!; al? used test organisms was determined based on the inhibition zones of the \

fili'ficroben growth determined. The following table contains j

ΐΐ ■■ '■ ·: -the results regarding the in vitro effectiveness ^ n

50 9820/1 167

1 4 b UU '♦ 8

acid as Watriwmsals (3); T-t ^ Ca.e-Din.ethyl-Vo.o-a

oephalosporanic acid as the sodium salt (1);

Sodium salt (5) i and 6-C2- (1-0 _X oa-quinolinyl) - _a = et _y iamino> peni = allanoic acid as

Sodium Eel (6).

5 0 9820/1167 1

Minimum inhibitory concentration (mcg / ml)

cn link Staphylococcus ο (D aureus ^ (O (2) 10 00
K) (5) I ₀ OOO *> »
_ι % 10 CO (6) 10 (* t) 10 /I.COO

SaJ ^ onsJla

100

> 1 ₃ OOO
100
100
100

Streptococcus pyoqenes

1,000

1,000

> l "000

100

1,000

> sf. ΰο o

(Penicillinase S & orproducer). Resistance ^L " SfäphyTöcbccus ^ - aureus 1,000> l _e 000> l _e 000 I _- OOO 1,000

//, coo

yes yes yes yes yes

Claims (1)

Patent claims : 1. II-oxo-l-pyridinyl penicillin and cephalosporin derivatives the general formula wherein R- »Rp» R3 and R _{11 are} hydrogen or halogen atoms, hydroxyl, lower alkyl, tri fluorine thy I, nitro, amino, cyano, carboxy, carbomethoxy or carbethoxy groups, or R ₁ and R - together represent one of the two cyclic radicals -CHgCHgCHgCHg- or -CH = CH-CHsCH-; R- is a hydrogen atom or a methyl, carboxy, Carbomethoxy or carbethoxy group; Rg one of the groups or -CH COORy CH ₂ C-CH ₈ X COOR ₇ 509820/1167 χ a hydrogen atom, a hydroxy, acetoxy, N-pyridinium, S-methyl-l ^^ - thiadiazol-a-ylthio or l-methyl- ^{1,2,3, I} »-tetrazol-5-ylthio group; R _{7 is} a hydrogen atom, an alkanoyloxymethyl, alkanoylaminomethyl, alkoxycarbonylaminomethyl or p- (alkanoyl · ■■ i / oxy '') - benzy! Group in which the alkanoyl or alkoxy group äilP "- ■ comprises 1 'to · 5 carbon atoms'; and ^; WW ¹ M Rq denote a hydrogen atom or a methoxy group, Ι # ^ · ν .. ■ · ■ and. . ·. , -, ■. ■ - ■. ^: , ■ ■ · ■.: ■ .. ^ ΐ | #: 1ν. the pharmaceutically acceptable salts thereof. · C * -oxo-l-pyridinyl) -acetylamin0l · " penicillin derivatives according to claim 1, in which Rg the group ^ mm ^: i ^: - ·· ■■■■■■■■ ■ ■ ■ - I iiiife .. ^ ■. ■ /. . ■■ ■ ■ ■■■■ Si | I \ .. and Rn mean a hydrogen atom. . . ■ ^ 8 | fr ^: 3. 6-Lsubstitute. (Ii-0xo-l-pyridinyl) -acetylamino3- oeriicillin derivatives according to claim 1, in which Rg the -Rest. . ■ ·. '. v ■:: ■■ '■ I ^X CH ₃ Ψ & and Ro mean a methoxa group. ^{iJfvifc: '.--:.} ■,. · ■ ■: ■ 509820/1 "" "" '"2450043 . 7-Csubstitute. (4-Oxo-1-pyridinyl) acetylamine »3-cephalosporin derivatives according to claim 1, in which !
'R /. the rest CH ₂ / C-CH ₂ X COOH and Rg represent a hydrogen atom. 5. 7-E substitute. (J | -0xo-l-pyridinyl) -aeetylamine <O-cephalosporin derivatives according to claim 1, in which Rg the remainder CH ₂ X-CH.X COOH and Rg represent a methoxy group. 6. Compounds according to claim 3, characterized in that that X is an acetoxy group. 7. Compounds according to claim 3 »characterized in that R _{5 is} a hydrogen atom. 8. 7-L2- ( ¹ I-OxO- 1-pyridinyl) -acetylaminoB-cephalospcranic acid, a compound according to claim 1, and its pharmaceutically acceptable salts. 509820/1167 Mpii ^ Mi ^^ M ^ M'tr ^^ " ■■ '■] ■■ "■,; lir ^ "* -— ■ " - ■ - ■ Ι ^{'ν' Λ -:} - ^'·:; ■ · '■ ■■' ■ ■ ■ ■ ■ '■ ■ # "■■' ■ ■■■■■ - '** ■' 1 24500A8 a compound of claim 1 and compatible salts. Connection according to claim!, And their ph sluggish Salse. ^{; ί} ■■■■ · ■■■ ^^ ■ ■ «.τ '-» _ ηι-ΠτΓθ-1-ΌΥΓΐαΑ "ί ->-''^" _J-de <1- < ο χ ii-fcetrazoi-5-yJ · ^ "" '"---". Pharmaceutical compatible salts the general formula acid _and an amino- _ß- la = tam , he general formula NH ₂ - O' 509820/1 167 dissolves in an inert solvent; ' (B) at a temperature of -2O ⁰ C to 100 ° C for 15 minutes to 36 hours, the pyridinyl acetic acid and the ß-lactam in the presence of dicyclohexyl-. λ, ./^f | carbodiimide, M-cyclohexyl-N'-morpholinoii ^ ethylcarbodiimide, pentamethylketone-N-cyclohexyiimine, N-; Ifchyl-S-phenylisoxazolium ^ sulfonate or phosphorus trichloride condensed with dehydration; and (c) isolating the desired product from the reaction mixture. 13. The method according to claim 12, characterized in that one assumes a connection in which R * does the rest ·. ■■■■■■■. ■ ■ '■ · ■.' ■■ ¹ ^ ο ■ ■ CH ₂ I COOR ₇ 11 ». Method according to claim 13, characterized in that " that the condensing agent used is dicyclohexylcarbodiimide used. 15. A method for producing a connection according to claim 1, characterized in that one 509820/1 167 öaoJäSiä / U , bV i! L. s ». Rr> * r tionoffihlo »« «U- · ^Ch T ^ceto ' f Torah oratura toi. -20 ° C bio 100 ° C aas _B e «an _O chto Product . Orwpp © CH ₂ 509820 / 11S7 17. Method goi ?? 3ß claim 16 ₈ characterized by gplser ^ dlaß ratal bot formation of an iHOxo-l-pyridir ^ Lacetylindäsisolid-Zwiachonprodwictes the ίΐ-Οπο-1-pyridinylmifc carbon ^ lcUimidazol implements. 18. Vsrfohrsn sus * Her ^ tellMnj; a Vorbindimg according to claim 1, thereby G ^^ e ^ nscichniot; «that one (©) a ii-Hi "ilro3 ^ rpypidin of the general formal OM s «r formation of a ^ -Hydroxypyridinsilyläthera with Di-lower-alkylchlorosilane, tri-lower-alkylchlorosilane, Di-nisdrig-alkylbrorasilim, tri-lower alkyl-bromoilane, where the lower alkyl group Contains 1-5 carbon at onis, tetramothyl- dioilasan, Hsxannttayldisilazan or bis-trimethylsilyl-acetaraid uraootafc; (b) the Silyläfcher with a ci-haloacetamido-ßlactatn the allgerossinon formula 509 820/1167 2A50ÖA8 wherein Y is a chlorine, bromine or JodatomA condensed at a temperature of -20 ° to 100 ⁰ C for 15 minutes to 36 hours in solution and (c) the desired product is isolated. 19. The method according to claim 18, characterized in, that one uses a compound in which Rg the group X-CH ₂ XC COOR ₇ means. 20. The method according to claim 19, characterized in that that one uses a compound in which Y is a bromine atom is, and as a control agent trimethylchloride used. 21. A method for the preparation of a compound according to claim 1, in Rg the group X-CH ₂ X COOH and X is the s-methyl-l.S.t-thiadiasol-a-ylthio group characterized in that one I 509820/1167 24500A8 (a) an H-oxo-1-pyridinyl-ß-lactam of the general formula CH-C-NH I !! Rs 0 CH ₂ -OC-CH ₃ COOH and 2-mercapto-5-ni3thyl-1,3, ^| i-thiadiazole dissolves in water or an aqueous solution of acetone, tetrahydrofuran or dimethylformamide; (b) the solution at a temperature of 25 to 150 ⁰ C for 15 minutes bio 2Ί hours umeetst, and (c) isolating the desired product. 22. A method for the preparation of a compound according to claim 1, wherein Rg is the group COOH and X represent the l-methyl-l ^^^ - tetrazol-S-ylthio group, characterized in that one 509820/1167 (a) an iJ-Oxo-l-pyridinyl-ß-lactam of the general and '5-Mercapto-1-iEsthy1-1,2,3, «J-tetrasol in water or an aqueous solution of acetone, tetrahydrofuran or dircrathylforraairaid as an aqueous solvent . ■ -: 'dissolves; ■ ■. . '.'.- ■. ■; (b) the solution is set at a temperature of 25-150 ° C. for 15 minutes to 2½ hours ; and (c) isolate the desired profile. For: Richardson-fferell Inc. New York, NY, V.St.A. (Dr. H.J. Wolff) Lawyer 509820/1167