DD216240A5 - PROCESS FOR THE PREPARATION OF 2-NAPHTHYLGLYCYLAMIDOCEPHALOSPORINES - Google Patents

Abstract

A process is described for the preparation of novel 2-2-Naphthylglycylamidocephalosporins with the formula (I), wherein R is high 1 for one of the three resulting from the formula sheet bicyclic radicals, wherein R is high 7 and R is high 8 hydrogen, halogen , Hydroxy, C deep 1-C deep 4-alkyl, C deep 1-C deep 4-alkoxy, nitro, amino, C deep 1-C deep 4-alkanoylamino, C deep 1-C deep 4-alkylsulfonylamino or together are methylenedioxy , A and B are hydrogen or a double bond. R 2 is hydrogen, an amino protecting group, hydroxy or methoxy, R 3 is hydrogen, R 4 is hydrogen, methoxy or methylthio, R 5 is hydrogen, methoxy, methyl, halogen or methoxymethyl, and R 6 is hydrogen or a carboxy-protecting group, and pharmaceutically-acceptable salts thereof by known per se. Known o. known per se starting materials, Preferred Verbindg. of this type are sodium D-7- (2-naphthylglycylamido) -3-chloro-3-cephem-4-carboxylate, 7- (6-chloronaphth-2-ylglycylamido) -3-methyl-3-cephem-4-carboxylic acid or D-7- (2-naphthylglycylamido) -3-methyl-3-cephem-4-carboxylic acid.

Description

Process for the preparation of 2-Naphthylglycylamidocephalosporins

15. ^!

Application area of the invention :

The invention relates to a process for the preparation of novel 2-Naphthylglycylamidocephalosporine, which is a new class of cephalosporins which are orally active and. have advantageous pharmacokinetic properties.

Characteristic of the known technical solutions:

The cephalosporin antibiotics have been extensively studied and several members of this class are routinely used to combat bacterial diseases caused by a wide range of gram positive and gram negative microorganisms. The

Most of these compounds are not effective orally, so 30

das.er administered intramuscularly or intravenously, which requires the help of medically trained personnel. Furthermore, these compounds are effective against a broad spectrum of microorganisms, and therefore they are generally not used selectively.

Aim of the invention:,. , · '

According to the above, there is still a need

Cephalosporin antibiotics which are orally active and have a degree of specificity towards one or more groups of microorganisms. The aim of the invention is therefore to provide a new connection group that meets this need.

Presentation of Wes ens the invention Fiction: ·

The above object is now achieved according to the invention by 2-naphthylglycylarnidocephalosporins of the formula (I)

Jyl!

ul

(I

BRAT"

20 1

where R is for

R '

R ^c

 χ / χ. /

1 Γ

Χ / χ /

R '

θ *

/ Χ / χ

or

9 st c

x / \ y

7 8. wherein R and R are independently hydrogen, halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, nitro, amino, C ₁ -C ₄ alkanoylamino or C ₁ -C 8 alkylsulfonylamino, or

7 R R and R taken together form methylenedioxy, A and B are each hydrogen or are themselves zusarnmengenom-

complement a double bond,

2 ''

R is hydrogen, an amino protecting group, hydroxy or methane

oxy is and

R is hydrogen or

2 3

R and R together for "

where M and L are independently C 1 -C 4 alkyl,

4. *?

R is hydrogen, methoxy or methylthio,

R is hydrogen, methoxy, methyl, halogen or methoxymethyl,. '' - '. , ". ν \ -

R is hydrogen or a carboxy-protecting group, with the proviso that R is hydroxy or methoxy only when A and B are complementary to a double bond, and that A and B are both hydrogen when R is other than hydrogen _A and pharmaceutically acceptable Salts thereof. ., '.,. These compounds are orally effective antibiotics and intermediates for this.

Preferred compounds according to the invention include the compounds of the formula (I) in which R represents

/ VV 1 f

f , wherein R and R ^{8 are} as defined above. Particularly preferred compounds within this group are those in which R is hydrogen, an amino-protecting group, hydroxy or methoxy and R is hydrogen or a carboxy-protecting group.

Another preferred group includes ¹ the

in which R is for

1 fi

wherein R and R are as defined above. Especially

  /.

Preferred within this group are the compounds wherein A, B, R, R, R and R are all hydrogen.

A particularly preferred group includes the compounds of the following formula ^:

iooR ⁶

wherein R, R 'and R are as defined above. Most preferred are the compounds wherein R is hydrogen, halogen, hydroxy or methoxy, R is methyl or chloro and R is hydrogen, or the pharmaceutically acceptable salts thereof, such as the sodium or potassium salts.

The invention also includes pharmaceutical formulations of a naphthylglycylamidocephalosporin derivative of the formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutical carrier, diluent or excipient therefor. Preference is given here to oral administration suitable formulations. 35 ·. '· ... .... : -, ... ,. ,

Another embodiment of the invention is directed to a method of treating bacterial infections in

c

A method of administering to the subject comprises administering to the subject an effective amount of an antibacterial compound of formula (I) or a pharmaceutically acceptable salt thereof A preferred method of this type consists of administering orally administering such a naphthylglycylamidocephalosporin derivative for the treatment of diseases that are caused by gram-positive bacteria.

, The invention furthermore relates to a process for the preparation of a compound of the formula (I) which is characterized in that (A) a compound of the formula (II)

20. -.

with an acylating agent of the formula (III)

BR ²

R ¹ - C - C - OH (III)

I Il

A 0

or an activated derivative thereof, wherein Λ, B, R, R, R, R and R are as defined above, acylated and optionally present any amino

or carboxy-protecting group, (B) a protected acid of the formula (I) wherein R is a carboxy-protecting group deblocked and so on

a compound is hydrogen,

an Aminosch

Formula (I) removes and so a compound of formula

forming a compound of formula (I) wherein R represents

2 (C) an amino protecting group R of a compound of the

(I) wherein R is hydrogen,

'. , - ''

(D) if one wishes to prepare a compound wherein R

and R together form a group of the formula

·; \: - .. ' ^{/ x} '. ''

⁷ · '' 2

form a compound of the formula (I) in which R and R are each hydrogen, with a ketone of the formula

mel

M-C (O) -L,

wherein M and L are as defined above,

15 .., 'or

(E) a compound of formula (I) wherein A and B together

     . ' "2

form a double bond and R is hydroxy or methoxy, thus reducing a compound of formula (I)

2 -

wherein a, B and R are hydrogen, and

(F) if desired, salting a compound of formula (I), or

(G); if desired, a salt of a compound of the formula

(I) into the free amine or acid.

In the above formulas, R represents a 2-naphthyl or 2-tetrahydronaphthyl group. These naphthyl and tetrahydronaphthyl groups may be unsubstituted, for example

7 8 "

when R and R are each hydrogen, in which:

, Positions 1, 3, 4, 5, 6, 7 or 8 monosubstituted, ^ O, for example, when R is hydrogen and R has a meaning other than hydrogen, or disubstituted

7 8 if R and R are each other than hydrogen

are. To the groups by which the naphthyl and Tetrahydronaphthylringe may be substituted, hydroxy, ß-5 C, -C.-alkyl, C.-C alkoxy, halogen, nitro, amino, _C-4 0. -Alkanoylarnino and C''-C alkylsulfonylamino ..

The term C, -C.-alkyl is known to include both straight chain and branched chain lower alkyl groups such as methyl, ethyl, isopropyl, n -propyl, isobutyl]. 'and t-butyl. Similarly, C 1 -C ₄ alkoxy refers to lower alkyl groups attached to the naphthyl or tetrahydronaphthyl ring via an oxygen atom. Examples of C 1 -C ₄ alkoxy groups include methoxy, ethoxy, n-propoxy, n-butoxy and isobutoxy. The term halogen refers to fluorine, chlorine, bromine and iodine. A preferred halogen group is chlorine. C, -C.-Alkanoylamino is understood to mean an acyl radical of a lower alkanecarboxylic acid which is bonded to the naphthyl or tetrahydronaphthyl ring via a nitrogen atom. Such groups include formylamino, acetylamino and butyrylamino. To C ₁ -C alkylsulfonylamino-14

groups include methylsulfonylamino, ethylsulfonylamino

and n-butylsulfonyl, inino.

R represents a substituent on the glycyl nitrogen atom, such as hydrogen or an amino-protecting group.

The term amino-protecting group refers to any known substituent which may be on an amino-nitrogen atom and which may be readily cleaved, if desired. Such protecting groups are often used during the preparation of the compounds of this invention and serve to reduce the likelihood of undesirable side reactions which result from the presence of a free amino group. The connections,

where R is a protecting group are biologically active overall, but the compounds are believed to have the most favorable biological activity

2 '' ι 2

where R is hydrogen. The compounds wherein R is an amino protecting group are therefore primarily useful as intermediates for the synthesis of the more preferred free ones

Amino compounds. '

The exact nature of the amino protecting group is according to the invention

not critical, and all known protecting groups can be used. Typical amino protecting groups are described by J.W. Barton in "Protective Groups in Organic Chemistry", J-.P. McOmie, Ed., Plenum Press, New York, N.Y. 1973, Chapter 2 and by Greene in Protective Groups in Organic Synthesis, John Wiley & Sons, New York, N.Y., 1981, Chapter 7. Both references are hereby incorporated in connection with amino protecting groups useful in this invention. -.

The most commonly used amino-protecting groups include C 1 -C 4 alkanoyl groups and halo C 1 -C 4 alkanoyl groups such as forrriyl, acetyl, chloroacetyl, dichloroacetyl, propionyl, hexanoyl, 3,3-diethylhexanoyl or J '-Chlorbut-

'

yryl, C 1 -C 4, "-alkoxycarbonyl groups and C 1 -C 4" -alkenyloxycarbonyl groups, such as methoxycarbonyl, t-butoxycarbonyl and allyloxycarbonyl, CC, C 1 -C 4 -aryloxycarbonyl groups and C 1 -C 8 -aryl-alkenyloxy.carbonyl groups, such as benzyloxycarbonyl, A- nitrobenzyloxycarbonyl and cinnamoyloxycarbonyl, halogenated

20 '' '

C, -C, "alkoxycarbonyl groups, such as 2,2,2-trichloroethoxycarbonyl, and C, -C, C, arylalkyl groups and alkenyl groups, such as benzyl ,. Phenytyl, trityl or allyl.

Other commonly used amino protecting groups include enamines prepared by reacting the free amino compound with a β-ketoester, such as methyl or ethyl acetoacetate.

2 " '.''. ·

R in the above formulas may be used in addition to the meaning

^^ fabric or amino protecting group together with R form a ring system, which compounds of the formula

. ' \ ' ^L

OOR ⁶

* wherein R, R, R, R, ^M and L are as defined above. Typical such compounds are the Acetoni.de, wherein M and L are each methyl. Such compounds are prepared by reacting a glycylamidocephalosporin, wherein R and R are each hydrogen, with a ketone, such as acetone. These cyclic compounds are particularly useful as antibacterial agents with long-lasting efficacy. _; , ,

R in the above formula is hydrogen, an addition salt cation, such as ammonium, or an alkali metal cation, such as lithium, sodium or potassium, or a carboxy-protecting group. The term carboxy-protecting group refers to the known groups which are commonly used to block or protect the carboxylic acid function of a cephalosporin during chemical reactions at other functional sites in the molecule and which are readily precipitated by the use of conventional techniques such as hydrolysis or hydrogenolysis to let. Typical carboxy-protecting groups include the groups described by E. Haslam in Protective Groups in Organic Chemistry, J.F. McOmie Ed. Plenum Press, New York, N.Y. 1973, Chapter 5 / and by Green in Protective Groups in Organic Synthesis, John Wiley & Sons, New York, N.Y. 1981, Chapter 5, and these references are hereby incorporated by reference. Examples of commonly used carboxy-protecting groups include C, -C, "alkyl groups such as methyl, t-butyl or decyl, haloC, -C," -alkyl such as 2, 2,2-trichloroethyl or 2-iodoethyl, C -C, arylalkyl such as benzyl, 4-methoxybenzyl, 4-nitrobenzyl, diphenylmethyl

; or triphenylmethyl, C, -C, "alkanoyloxymethyl, such as acetoxymethyl or propionoxyrnethyl, and other groups, such as phenacyl, 4-halophenacyl, allyl, dimethylallyl or tri (C, -C.-alkylsilyl, such as trimethylsilyl and thus

turned groups. ,

The naphthylglycyl and tetrahydronaph-

thylglycylcephalosporins can be removed by several methods. getting produced. One of these practitioners is a. (II)

ner clutch of a 7-Aminocephalosporinkerns the formula

HSN

(II)

10-, <

: 00R ^s

4 5 6 '

wherein R _{t is} R and R is as qben defined sihd, naphthylglycine of the formula (III) or an activated derivative thereof -

¹⁰ '- AO

: '' - · R ¹ - C - C - OH (III)

, / '- ·.''' Ι -ν - R ² ;. · ^:

wherein A-B, R,... R, R, R and R are as defined above. "Examples of cephalosporin cores which can be used in the synthesis of the compounds according to the invention include the compound which has meanings.

include the compounds wherein R, R and R are the following

R "

H -CH ₃ H   H -CH ₃ . t-butyl. CH ₃ O- -CH ₃ p-Nitrobenzyl H -CH ₃ 2, 2, 2-trichloroethyl H- -Cl H ' H -egg t-butyl H -Cl ¹ phenacyl CII ₃ p ^v -Cl Methyl ^X Λ CH ₃ O H H H H p-Nitrobenzyl CII ₃ p -CH ₂ OCH ₃ diphenylmethyl H. -CH ₂ OCH ₃ t-butyl H H trimethylsilyl H -ei * Trityl. CH ₃ O- -CH ₃ t-butyl H -Br, H H -F methyl H -OCH ₃ H . H -CH p-Nitrobenzyl CH ₃ S- -CH ₃ t-butyl H -Cl , Allyl II Br 2,2,2-trichloroethyl H -ι methyl

The 7-aminocephalosporin cores which are used for the synthesis of the compounds according to the invention are known and readily preparable by known methods. The 3-halocephalosporin cores can be prepared, for example, using the methods described in US Pat. No. 3,925,372. The 3-methylcephalosporin cores can be prepared by ring enlargement of penicilli sulfoxides and subsequent cleavage of the side chain or by hydrogenation of 3-acetoxymethyl derivatives.

The indication activated derivative refers to a derivative

vat, which renders the carboxy unsubstituted of the acylating agent of formula (III) reactive with a primary amino group coupling to form the amide bond which binds the acyl side chain to the nucleus.

Suitable activated derivatives, processes for their preparation and their use as acylating agent for a primary min are known to those skilled in the art. Preferred activated derivatives s "ind (a) acid halides, such as chlorides or bromides, or (b) Alkanoyloxyderivate as formyloxy or Acetoxymischanhydride (where, for example Y is in der'folgenden grid for HCIIO or _OCOCH3). Other. ' Methods for activating the carboxyfunction include reacting the carboxylic acid with a carbodiimide such as N, N'-dicyclohexylcarbodiimide or N, N'-diisopropylcarbodiimide to form a reactive intermediate which reacts with the 7-amino group in the reaction mixture This reaction will be described in more detail later. '' - '

  Similarly, the naphthylglycyl and tetrahydronaphthylglycylreaktanten according to the above formula (III) are known compounds which can be prepared using known Methöden. Typical Naphthylglycyl- and Tetrahydronaphthylglycylderivate that can be used for the preparation of the compounds according to the invention, can have the above-mentioned For following meanings may have.

2 7 8 have the formula given above, wherein R> R and R

toCJ!

to O

cn

H H H Cl (hydrochloric acid H     H , chloroacetyl OH H 5-OCH ₃ Allyloxycarbonyl. , OH H 5-OCH ₃ t-butoxycarbonyl Cl H 7-OCH ₃ B enyl br H 8-OCH ₂ CH ₃ Tr imethylsilyl OCHO 1-Cl 5-OCH ₃ p-Nitrobenzyl OCOCH ₃ 3-Cl 7-Cl H Br (hydrobromide) 3-Cl H Benzyloxycarbonyl. , br 4-OCH ₃ t-butoxycarbonyl Cl H 7-NO ₂ Methylacetoacetate enamine OH. · · 3-NO ₂ 8-1 2,2,2-trichloroethoxycarbonyl Cl 7-CH ₂ CH ₂ D -Uli -.- allyloxycarbonyl OH H 6-CH ₃ formyl Cl H 7-CH ₂ CH ₃ acetyl OH 1-OH 8-CH ₉ CH ₂ CH ₃ :. benzoyl HCHO

'. \ ./.,. '

The coupling of a naphthylglycine or tetrahydronaphthylglycine derivative with a 7-aminocepha-losporin core can be achieved using conventional acylation techniques. For example, a naphthylglycyl

5 "''"'·'

acylating agent, especially an acid chloride or acid bromide, or an alkanoyloxy derivative, such as a formyloxy or acetoxyanhydride, with a cephalosporin nucleus using conventional acylation conditions. During such acylation reactions, it is generally preferred that R is an amino-protecting group and R is a carboxy-protecting group. These protective groups are intended to minimize undesirable side reactions and to increase the solubility properties of the respective reactants.

be improved. _x '

For carrying out the acylating reaction, generally about equimolar amounts of a naphthylglycyl or tetrahydronaphthylglycyl acylating agent of the formula (III) (for example, an acid halide or mixed acid anhydride) are combined with the 7-aminocephalosporin core. The Acyliorungsreaktion is usually carried out in a mutual solvent such as benzene, chloroform, dichloromethane, toluene, N, N-dimethylformamide or acetonitrile and is generally complete in about 1 to about 12 hours when nian at a temperature of about -20 ⁰ C until about 60 ⁰ C works. If desired, in this reaction as an acid scavenger an approximately equimolar amount of. Base, such as pyridine, triethylamine, aniline or sodium carbonate, use. The product may be isolated from the reaction mixture by removal of the solvent, for example by evaporation under reduced pressure, and further, if necessary, using conventional techniques such as chromatography, crystallization, solvent extraction or other related methods

35 are cleaned. '

Another and preferred method for coupling a

Naphthylglycyl- or tetrahydronaphthylglycylderivan L to a 7-aminocephalosporin nucleus to form compounds of the invention makes use of a coupling reagent, as is common in peptide syntheses. To see typi ^ used coupling reagents include carbodiimides such as N, N ¹ -Diethylcarbodiimid, Ν, Ν-Diisopropylcarbodi- ^λ imide and NFN-dicyclohexylcarbodiimide (DCC), C'arbonylkupplungsreagenzien, such as carbonyldiimidazole, isoxazolinium, such as N-ethyl-5 'phenylisoxazolinium-3'-sulfonate, and quinoline compounds such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ).

To couple a 7-aminocephalosporihkerns with a Naphthylglycyl- or Tetrahydronaphthylglycylderivat using a Peptidkupplungsreagens are generally combined about equimolar amounts of ein.em 7-Aminpceph-3-em-4-carboxylic acid derivative, a Naphthylglycinderivat Λ

and a peptide coupling reagent according to the following reaction

., '·'

schema with each other:. ·

R ¹ -CH-C-OH R "TFT _ Peptide Couplings

I ₂ + Jm -PL. "- R medium

EAR ² / \ y

CH-C-N MH "4

COOR ⁶ .

Herein R, R, R, R and R are as defined above. currency

For such coupling reactions, R is preferably an amino-protecting group and R is preferably hydrogen or a carboxy-protecting group. The protective groups that may be present can then be removed by conventional methods.

*, Which leads to the respective antibiotic active ingredient according to the invention. , '. '. , ,

The coupling reaction is usually carried out in a mutual solvent, such as dichloromethane, acetone, water, acetonitrile, N, N-dimethylformamide or chloroform, and is usually completed within about 10 to about 90 minutes, when at a temperature of about -20 ⁰ C to about 60 ⁰ C works. Longer reaction times do not separate the product and may be used if desired. _; The product, a Naphthylglycylöder Tetrahydronaphthylglycyicephalosporin, can be isolated readily by ¹ removal of the reaction solvent, for example by its Verdampfuhg under reduced pressure. The product may be purified by other common methods, such as acid-base extraction, chromatography, salt formation, and the like.

Another process for the preparation of the compounds according to the invention makes use of a naphthyloxime of the formula

, R ¹ · C - C - OH;

25 N

, R ²

or an activated derivative thereof, wherein R is as above

'2 2

is defined and R is hydroxy or methoxy. Is R

30. for hydroxy, then this substituent is generally protected by trimethylsilyl or a similar hydroxy protecting group during the coupling reaction. Such naphthyloxime derivatives can be coupled to a cephalosporin nucleus by all methods described above to give a compound of the following formula:

^r4 "TT I -

H (or OCH ₃ ) Jk-k , - fT

00R ^e

wherein R, R, R and R are as defined above. These compounds are useful as intermediates because they can be reduced by conventional methods readily to form the preferred Naphthylglycylamidoverbindungen invention. In addition, the oximes are of the above formula, in which R is a valuable antibiotic.

of the above formula, wherein R is dihydrogen, or the SaI

Compounds which carry a nitro group on the naphthylglycyl or the tetrahydronaphthylglycyl side chain can be converted by modification into other compounds according to the invention. Thus, for example, the

on ·

Nitrosubstituent by conventional reduction or hydrogenation process in the corresponding amino-substituted Naphthylglycylcephalosporinderivat result, from which, if desired, by acylation of the amino group with a C, -C ^ alkanoyl halide or anhydride or a

^ΔΌ nem C, -C.-Alkylsulfonylhalogenid the corresponding alkanoylarnino- or Alkylsulfonylaminonaphthylglycylamido- and tetrahydronaphthylglycylamidocephalosporine according to the invention can be produced.

j _n-like "manner Verbindun- the invention can

2 3, wherein R and R together form the group

 V

35 / \

can be prepared by adding a ketone of the formula

\. - 18 -:. -. ^! , ''.

M-C-L. ,

ι: , -'· "2 3

with a compound according to the invention, in which R and R ν '. , .

are each hydrogen, generally in the presence of an acid such Methansulfonsäu-, - re or the like, is reacted. The cyclic compounds thus prepared, for example the preferred acetonitrile

^: d; e, wherein M and L are each methyl, are especially

10-

valuable oral antibiotics as they overshadow their effectiveness

maintain a long period of time. .

Other compounds according to the invention, of. who are expected to be particularly susceptible to antibiotics.

2

efficacy are the compounds wherein R is a Alkanoylaininosehutzgruppe i ^x st, such as formyl or acetyl. are Such compounds are conveniently prepared simply by reacting a naphthylglycylamidocephsilosporin,

wherein R "is hydrogen, with a C, -C-," -Alkanoylacylie-

or, for example, formyl chloride or acetic anhydride. These iJ-acylated products should not only be effective directly as antibiotics but also as so-called precursors, since in the animal system they can be used as the parent naphthylglycyl- or -tetrahydronaphthylglycyl-

OK ' -' '

  hydrolyzed derivative.

The inventive. Cephalosporins contain in their Naphthylglycyl- and Tetrahydfonaphthylglycyl side chains an asymmetric carbon atom, if A is hydrogen, so that. these compounds occur in the form of optical isomers, namely the D and L isomers. The compounds of the invention may be used as a D, L mixture for the treatment of bacterial infections in animals. Or, if desired, the isomers may be separated and used alone. Although both isomers are effective antibacterial agents, one isomer may be more potent than the other, namely the D-isomer,

which is therefore preferred according to the invention.

Separation or dissolution of the optical isomers

can be determined by applying conventional methods either on 5

cephalosporin product according to the invention or on as.

Starting material used naphthylglycine or tetrahydronaphthylglycine side chain reach. The optical isomers can generally be separated by high-performance chromatography, enzymatic separation or chemical analysis.

mixed crystallization or racemization. A special

the preferred method of forming D -naphthylglycine is to react the D, L mixture with benzaldehyde. hyd and optically active tartaric acid according to the in US-PS

3,976,680. ι

15

Preferred compounds of the invention are, as already

mentioned / the compounds in which R in the above formula is hydrogen. These compounds are primary amines and therefore have a basic character such that they

readily form salts by reaction with acids. The pharmaceutically acceptable salts are preferred salt forms for the treatment of bacterial infections. Under pharrna. zeut: ica acceptable salts are meant those salts which warmblü- to the chemotherapeutic treatment - can be used term animals. Typical acids commonly used to form salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, and organic acids such as acetic acid, trifluoroacetic acid, ³ ^ succinic acid, methanesulfonic acid, oxalic acid or p-toluenesulfonic acid. The compounds according to the invention in which

2 fi

both R and R is hydrogen, readily form an internal acid addition salt, namely a zwitterion.

The compounds of this invention are generally crystalline solids derived from conventional solvents such as ethanol, water, N, N-dimethylformamide, acetone

ι, '. ''. ,

and the like, crystallize. The compounds wherein _x R. Hydrogen is the 4-carboxylic acids. Such compounds are acidic and readily form salts with organic and inorganic bases. Pharmaceutically acceptable salts are therefore also understood to mean these base addition salts. ".

The compounds of the invention often crystallize; 'as sol vat' or hydrate and can be used in this form. The invention therefore also includes, for example, a crystalline composition,. which is 7 ~ (D-2-Na-pl-l-glycyl amido) -3-i-thio 1-3-cephem-4-car bon acid tetrahydrate. ' The crystals are big, dense and stable / and they can be easily mixed and ground,

to make a pharmaceutical formulation from it,

, in particular a solid dosage form, as-filled capsules and the like. The tetrahydrate according to the invention is prepared by isolating 7 - (D-2-naphthylglycylamido) -3-methyl-3-cephem-4-carboxylic acid.

·

lent, a preferred product according to the invention, from a

hem aqueous medium.

This crystalline compound gives the following typical X-ray diffraction spectrum by measurement with a Debye-Scherrer 114.6 mm camera containing nickel-filtered copper radiation of 1.5405 Å:

Interplanar distance d Relative intensities I / I ,.

30 13,29 '' 0,44

10.53 0.22

7:14, '. 0.4 4 .-).

6,58 1,00

6.09. , 0.22; '/ _ ..'

35. 5.64 0.33

5, _# 36, 0.8 8

5/14 0, 28

_ 21 -

Interplanarabsfand, d Relative intensities I / I,

4.8 6 0.17

4, G6 0.11

4,44 '0,33'

4,12 0,28.

3.92 0.17

3.75 0.22

3.65 0.94

₁₀ 3.51 0.38

3.3 4 0.72 2.94 0.39

2.78 0.17

2.6 9 0.14

₁₅ , 2.58 '0.11

2.4 6 0.17 _t . , 2.42 0.17

2.32 .11

2.2 5 0.0 3

20 ^{2 '18} "°' ¹⁴

2.10 0.06

2.0 4 0.06

This compound can be prepared in particular by reacting an acid addition salt of 7- (D-2-Naphthylglycylamido) -3-methyl-3-cephem-4-carboxylic acid with a base such as sodium hydroxide or triethylamine, to form the decision j speaking zwitterion and this zwitterion crystallized from water. For this purpose, for example, a .Salt, such as the Trifluoressxgsauresalz or the hydrochloric acid salt, in water or a mixture. ι from water and an organic solvent such as acetone or acetonitrile, solve. To adjust the pH to about 3 to about 5, a base such as aqueous ammonium hydroxide is added. The precipitate which forms is the tetrahydrate according to the invention and can easily be recrystallised from water.

-. 22 -

10

15

20

25

Optionally, the compound of the invention can also be prepared by isolating the product of the acylation of 7-amino-3'- ^T- methyl-3-cephem-4-carboxylic acid (7-ADCA) from an aqueous solvent. For example, 7-ADCA may be conventionally acylated as a silylated derivative, as described above, with an N-protected D-2-naphthylglycylic acid halide or a mixed anhydride thereof. The acylation may generally be carried out in an organic solvent such as acetonitrile. After completion of the acylation, the protecting groups can be removed by conventional procedures and the solution of 7- (D-2-Naphthylglycylamido) -3 "inethyl-3- _Ä cephem-4-carboxylic acid so diluted with water that they are about 10 to 50 VoI. % Water, and adjust the pH of the solution to about 3: to about 5. Thus, 7- (D-2-naphthylglycylamido) -3-methyl-3-cephem-4-carboxylic acid tetrahydrate is obtained as a crystalline product .. ...;

This crystal form is very stable over a long period of time, but is still very well absorbed after oral administration. This is somewhat surprising since the compound is only minimally soluble in water. For example, the compound forms a saturated solution in water of 37 ° C. according to the following table.

Solubility, mg / ml

30

35

1.2 2.0 3.0

5,0 6,0 7,0 '7,5 8,0 8,5

8.6 1.7 0.2 0.2 0.2 0.3 0.8 1.2 4.1 '7.5

-. ' - 23 - .. ·

Another example of a hydrated form of a compound of the invention is 7- (D-2-naphthylglycylamido) 3-methyl-S-cephem-1-carboxylic acid hydrochloride monohydfate.

The crystals of this compound are large, dense and stable, and they are readily mixed and ground to produce a pharmaceutical formulation, particularly a solid dosage form such as filled capsules and the like. The hydrochloride megohydrate is prepared by crystallizing 7- (D-2-naphthylglycylamido) -S-methyl ^ -cephem * carboxylic acid from an aqueous hydrogen chloride acid medium.

This crystalline hydrochloride monohydrate gives the following typical X-ray diffraction spectrum by measurement with a Debye-Scherrer 114.6 mm camera containing 1.5405 Å nickel-filtered copper radiation:

Interplanar distance d

15.64 7.90 6.61 6.22

5.74

5.54 5.11 4.75 4.47 4.23

4.10 3.93 3.85 3.71 3.49

3.35 3.27 3.15 3.08 3.03

2,93 2,78 2,69 2,61 2, 5 3

Relative intensities I / I.

1.00 0.57 0.24 0.05 0.24

0.12 0.2 9 0.10 0.14 0.19

0.17 0.71 0, l'2 0.33 0.0 7

0.12 0.14 0.10 0.07 0.07

0.10 0.10 0.12 0.02 0.10

Interplanar distance, d

Relative intensities I / I

2.4 7 2.37 2.30 2 7-24

2.17

0/10 0.10 0.02 0.02 • 0.05

The hydrochloride monohydrate according to the invention can be prepared by reacting 7- {D-2-naphthylglycylamido) -3-methyl-3-cephem-4-carboxylic acid, generally in the form of the solvate or crystalline tetrahydrate described above, with hydrochloric acid in water or a solution of water and an organic solvent such as acetone or acetonitrile. So much hydrochloric acid is used that the pH of the solution remains below about 2.0, and generally between about 0.1 and about 0.8. The reaction is usually complete after about 1 to about 3 hours when operating at a temperature from about ⁰ ° C to about 60 ^° C. The precipitate formed is the hydrochloride monohydrate and can readily be isolated by conventional methods.

Alternatively, this compound can also be prepared by isolating the product of the acylation of 7-amino-, 3-methyl-3-cephem-4-carboxylic acid (7-ADCA) from a solvent containing aqueous hydrochloric acid. For example, 7-ADCA can usually be acylated as a silylated derivative as described above with an N-protected D-2-naphthylglycylic acid halide or a mixed anhydride thereof. The acylation may generally be carried out in an organic solvent such as acetonitrile. After completion of the acylation, the protective groups can be removed by conventional methods and the solution of 7- (D ^ -2-Na'phthylglycylamido) -S-methyl-O-cephein-4-carboxylic acid so diluted with water that they are about 10 to 50 Vol .-% water, and the pH of the. Adjust the solution to about 0.1 to about 0.8 by adding hydrochloric acid. In this way, 7- (D-2-Naphthylglycylamido) ^ -methyl-S-cephem ^ -carboxylic acid hydro-

- 2 5 chloride monohydrate as, crystalline product.

Examples of typical classes of naphthylglycyl

and tetrahydronaphthylglycylcephalosporins and also spe-

The compounds according to the invention include the following:

A. The preferred compounds of the formula:

₇ ψ γ d9 -CH-HÜ'NH S

^R ό. β i filHa H "^

R 5 4

R = hydrogen or a salt cation,

"7 fi

a) R and R = each hydrogen

IaI. R ⁵ = Methyl Ia2. R ⁵ = Chlorine Ia3. R ⁵ = Bromine Ia4. R ⁵ = Fluorine IAs. R ⁵ = Iodine Ia6. R ⁵ = Hydrogen Ia7. R ⁵ v = Methoxy

Ia8. R ⁵ = methoxymethyl.

b) R ⁷ = hydrogen and R ⁸ = 6-methoxy IbI. R ⁵ = methyl

Ib2. R ⁵ = chlorine

Ib3. R ⁵ = methoxy

Ib4. R = methoxymethyl

7 R

c) R = hydrogen and R = 7-fluoro

IcI. R ⁵ = methyl

I c2. R ⁵ = chlorine

C3. R ⁵ = fluorine

Ic4. R = methoxy

Ic5. R = methoxymethyl

- 26 -

7

d) R = hydrogen and R = 6-hydroxy

^x IdI. R 1 = methyl 1 (32 R ⁵ = chlorine Id 3 R ⁵ = methoxy

⁵ . _v ''"Id4. R ⁵ = bromo

e) R 1 = '4-methyl and R ⁸ = 6-chloro

IeI. R ^ = methyl. ₍ .

Ie 2. R = methoxy. '· ¹⁰ . _; ',' Ie3. R ⁵ = chlorine

or the pharmaceutically acceptable salts thereof.

2. The compounds of the formula

R ¹ -CH - C-NH

-R ⁵

20 '. 'COOR ⁶

where R is for

R and R is hydrogen or a salt cation.

7 8

a) R and R = each hydrogen

2a1. R ⁵ = methyl

2a2. R ⁵ = chlorine

2a3. R ⁵ = methoxy

35 "2a4. R ⁵ = hydrogen

\

"7 ft ⁽

b) R = hydrogen and R = 7-hydroxy

2b1. R ⁵ = methyl.

2b2. R ⁵ = fluorine

2b3. R ⁵ = iodine

2b4. R ⁵ = methoxy

2b5. R = hydrogen

7 8

c) R = 1-methoxy and R =. 8-t-butyl

2 cl. R ⁵ = methyl.

'2c2. R ⁵ = methoxy

2c3. R ⁵ = chlorine

2c4. R = methoxymethyl

1 ft

d) R = 3-chloro and R = 7-isopropoxy 2dl. R ⁵ = hydrogen

2d2. R ⁵ = methoxymethyl

2d3. R ⁵ = methoxy

2d4. R ⁵ = methyl

2d5. R ⁵ = ^ chlorine and the pharmaceutically acceptable salts,

B. The compounds of the formula

/ VVt JU

R "S

OOR ⁶ -

1. R ⁴ = hydrogen and R ⁵ = methyl

a) R and R = each hydrogen, R = t-butoxycarbonyl IaI. R = p-nitrobenzyl

i a2. R ⁶ = 2,2,2-trichloroethyl

Ia3. R ⁶ = trimethylsilyl • Ia4. R ⁶ = phenacyl

' '''.'' - 28 -. '-

¹ b) R ⁷ and R ⁸ = each hydrogen and R ⁶ = t-butyl

2 IbI.'R = t-butoxycarbonyl

Ib2. R ² = acetyl

Ib3. R .- = p-nitrobenzyloxycarbony1 Ib4. R ² = chloroacetyl

7 V, ₈ c) R = hydrogen, R = 7-methoxy and

R = 2, 2, 2 ~ trichloroethoxycarbonyl

IcI. R = p-nitrobenzyl Ic2. R ⁶ = Natriumkat'iön

C3. R ⁶ = methyl ',

2, R ⁴ / = methoxy and R ⁵ = chlorine

a) R and R = each hydrogen and R ² . = Formyl _t

2al. R ⁶ = 2,2,2-trichloroethyl 2a2. R ⁶ = hydrogen 2a3. R = sodium cation

7 8

3. R = methylthio and R and R = each hydrogen

a) R ^J = methyl

3al. R = t-butoxycarbonyl 3a2. R p-nitrobenzyl

b) R ⁵ = · 'bromine

3bl. R == t-bivitoxycarbonyl

3b2. 'R ⁶ = trimethylsilyl

c) R = methoxymethyl 3cl i R ² = hydrogen

'.''.' , ° 3c2. R = trimethylsilyl 3c3. R ⁶ = allyl

- 29 4. R ⁴ = methylthio, R ⁷ = hydrogen and R ⁸ = 6-methoxy

a) R ⁵ = methoxy

2

4al. R = t-butoxycarbonyl

ö 4a2. R ⁶ = methyl

b) R ⁵ = chlorine

4bl. R ² = hydrogen 4b2. R ² = phenacyl 4b3. R ⁶ = 't-butyl

C. The compounds of the formula

15 30

R'-C _-ΐΟΝΗ S

"•• V / N

OH (or OCH ₃ ) / · ~ Λ. / * ~ ^

where R is for

R ⁷ - \ -4- R ⁷

R ⁸ R ⁸ R ⁸

stands. ·. '.

8th '

1. R and R = each hydrogen

a) R ⁵ = methyl

IaI. R = p-nitrobenzyl Ia2. R ⁶ = .t-butyl Ia3. R = hydrogen Ia4. R = trimethylsilyl

b) R ⁵ = · fluorine

Ibi. ' R ⁶ = methyl

c) R = methoxymethyl 5

rl

Examples :

The invention will be further elucidated by the following non-limiting examples

 ,

Manufacture 1 '

Preparation of 2-naphthylglycine (also referred to as a-amino-CX- (2-naphthyl) acetic acid)

A solution of 15.6 g (0.1 mol) of 2-naphthaldehyde in 700 ml of a 50% mixture of ethanol and water containing 14.7 g (0.3 mol) of sodium cyanide and 38, 4 g (0.4 mol) of ammonium carbonate is heated to 50 ⁰ C for 20 hours. The -Reaktionsgemisch is cooled and concentrated by Ver ^v attenuation under reduced pressure to about 400 ml, whereupon the solution is acidified by addition of concentrated hydrochloric acid to pH 2.0. The resulting solid precipitate is collected by filtration, washed with dilute hydrochloric acid and then dried to give 22.1 g of A- (2-naphthyl) -2,4-imidazolidinedione.

A solution of 5.0 g (22 mmol) of the 4- (2-naphthyl) -2, A- imidazolidinedione in 100 ml of 16% (v / v) aqueous sodium hydroxide is heated to reflux for 2.5 hours. The reaction mixture is then filtered, cooled and washed with ethyl acetate. The aqueous solution is then diluted to pH 5.1 with 6N hydrochloric acid and filtered to give 2-naphthylglycine. To form larger amounts of product, the reaction is repeated several times.

A sample of 10.0 g of 2-naphthylglycine is dissolved in 125 ml of methanol containing 3.9 ml of acetyl chloride for purification. The reaction mixture is filtered and the filtrate is then diluted with 5 ml of aniline. The precipitated product is collected by filtration and dried, yielding 7.0 g of 2-naphthylglycine, which melts at 219-221 ° C. '

Production 2 ¹⁰ ·

Separation of 2-naphthylglycine ^v

A mixture of D- and L-2-naphthylglycine is reacted with optically pure cx ~ aminoethylbenzene in the presence of N, N'-dicyclo-

· * ^ Hexylcarbodiimide to give N- (1-phenylethyl) -t-amino-O - (2-naphthyl) acetamide. Separation of the diastereomers by chromatography on silica gel gives, after acid hydrolysis, D-2-naphthylglycine (OD = -190 ° + 3 °) and L-2-naphthylglycine (OD =

20 + 190 ° + 3 °). ,

Preparation of 6-methoxynaphth-2-ylglycine 25

Mam converts 2-bromo-6-methoxynaphthalene into the 2-lithium derivative by reaction with n-butyllithium. Diethyloxalate is then reacted with 2-lithium-6-methoxynaphthalene to give ethyl CX-keto-G-methoxynaphth ^ -yl-acetate. This compound is converted by reaction with hydroxylamine hydrochloride and sodium acetate in ethyl-OHiys-, droxyiminp-6-methoxynaphth-2-yl acetate. A solution of 17.55 g of this oxime in 600 ml of methanol containing 5.3 g of zinc dust and 135 ml of 50% (v / v) aqueous formic acid is stirred for 3 hours at 0 ⁰ C. After filtration of the reaction mixture, the solvent is removed by evaporation, yielding 10.3 g of ethyl acetate.

^: '.' ·. -. '* - 32 ¹ CX-amino-Ct (6-methoxynaphth-2-yl) acetate reached.

NMR spectrum (CDCl ₃ ): 6 = 1.20 (t, 3H), 2.15 (s, 2H), 3.89

(s, 3H), 4.15 (m, IH), 4.72 (s, IH), 6.08 to 6.75 (m, 6H).

Hydrolysis of the ester thus formed by reaction with In sodium hydroxide gives 6-methoxynaphth-2-ylglycine.

¹ ^ Manufacturing 4 -: ^

Preparation of N-t-butoxycarbonyl-2-naphthylglycine

A solution of 10 g (50 mmol) of 2-naphthylglycine (from Preparation 1) in 100 ml of sodium hydroxide is added with stirring first 50 ml of tetrahydrofuran and then with 30 g (140 mmol) of di-t-butyl carbonate. The reaction mixture is stirred for 4 hours at 24 ° C. The product is isolated by first washing the reaction mixture three times with 50 ml of diethyl ether each time, and then acidifying the mixture to pH 2.0 by adding concentrated hydrochloric acid. The aqueous mixture is extracted several times with ethyl acetate and the extracts are combined, washed with water, dried and the solvent is removed by evaporation under reduced pressure to give 12.8 g (yield = 85%) of Nt-butoxycarbonyl-2 -naphthylglycine. '

NMR spectrum (DMSO-d ,,): 8 = 2.5 (s, 9H), 6.85 (s, IH),

30 7.28 to 7.9 (m, 7H).

Following the general procedures given above in Preparations 1 to 4, the following further compounds are prepared:

- 33 - N-t-Butoxycarbonyl- (6-methoxy-2-naphthyl) glycine ·. <·

NMR spectrum. (GDCl ₃ ): C = 1.2 and 1.4 (two broad Singulotts, 9H), 5.4 (broad singlet, 1H), 6.7 (broad singlet, IH), 7.03 to 7.8 ( m, 6H).

N-t-butoxycarbonyl (6-hydrpxy-2-naphthyl) glycine

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 5 = 1.2 to 1.4 (broad singlet, .91-1)., 5.3 to 5.9 (two broad singlets, IH), 6.9 to 8.5 (m, 711).

N - t -butoxycarbonyl- (6-chloro-2-naphthyl) glycine

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 8 = 1.15 (s, 9H), 5.3 to 5.7 (m, IU), 7.3 to 8.3 (m, 8H).

Preparation 5 α-Amino-α- (2-naphthyl-octyl chloride hydrochloride

In a cold (0 ⁰ C) solution of 5.0 g (2.5 mmol) of 2-naphthylglycine in 150 ml of dichloromethane is introduced for 20 minutes hydrogen chloride. The reaction mixture is added with Kühren at once with 7.6 g (38 mmol) of phosphorus pentachloride and then stirred for two hours at 0 ⁰ C to 10 ^{v p} C. The solution is filtered, dried and freed from the solvent by evaporation under reduced pressure, yielding 5.2 g (yield = 81%) of CX-Arn i no-Ck- (2).

30 naphthylJacetylchlorid hydrochloride.

IR spectrum (mull) = 1795 cm ^-1

Analysis for C ₁₂ H ₁₁ Cl ₃

35 Calculated: Cl 27,68 Found: Cl 27,69

. ' I: ·. . '"'- ³⁴ "

'ι' ': ·' * ·.:: Manufacturing 6. '

Enzymatic separation of D, L-2-naphthylglycine

Following the general procedure of U.S. Patent 3,386,888, 19.8 g of D, L-N-chloroacetyl-2-haphthylglycine are reacted with 4 g of N-acyl-L-amino acid amidohydrolazine in 1250 ml of a 0.1 molar potassium hydrogen phosphate buffer

-. , '-4'

of pH 7.0, containing 5 x 10 moles of cobalt chloride hexahydrate. The reaction mixture is shaken for 2 hours at 37 ° C. The precipitated L-2-naphthylglycine is removed by filtration. The filtrate is added by addition of In. Hydrochloric acid acidified to pH 2, and the mixture is extracted twice with 500 ml of ethyl acetate. The extracts are combined, dried and evaporated from the solvent by evaporation under reduced pressure to give 9.065 g of D-N-chloroacetyl-2-naphthylglycine (Yield = 91.5%).

20 Analysis for C, 'H.' NO Cl

Calculated: C 60.55 H 4.36 N 5.04 Found: C 60.62 H 4,3 4 N 4,7 6 £ * qI? ⁼ -t212,0 °

The L-2-naphthylglycine collected by filtration is washed first with a buffer of pH 7.0, then with water and finally with hexane and then air-dried) to give 6.82 g (yield = 95%). L-2-naphthylglycine passes. .

30 .- '. '"·

; Analysis for ^c ₁₂ ^H n ^NO 2

Calculated: C, 71.63, H, 5.55, N, 6.96, Found: C, 69.85, H, 5.62, N, 6.51

/ E]? = +195,2 '35

ι Ο

* Manufacturing 7

8-nitro-2-naphthoic acid 5-nitro-2-naphthoic acid

A solution of 400 ml of concentrated nitric acid is added at 60 ° C with stirring in portions with 18 g (0.11 mol) of 2-naphthoic acid. The reaction mixture is heated to 70 ⁰ C for 2 hours, cooled and added to 200 g of ice.

The precipitate is collected by filtration and dried, yielding 18.8 g (Yield = 77%) of a _N mixture of 5- and 8-nitro-2-naphthoic acid. The

Mixture is reacted with ethanol for conversion to the ethyl ester in the presence of sulfuric acid. By crystallization of 5 g of the mixture of ethyl esters of 20 ml of ethyl acetate leads to 800 mg of ethyl 8-nitro-2 ~ naphthöat (melting point 120 ⁰ C) and 1.9 g of ethyl 5-nitro-2-naphthoate.

Production 8,

Ethy1-8-amino-2-naphthylformiat

A solution of 11.2 g of ethyl 8-nitro-2-naphthoate (prepared as in Preparation 7) in 100 ml of ethanol is hydrogenated in the presence of 5% palladium on carbon.

The reaction mixture is filtered and the solvent is removed from the filtrate, yielding ethyl 8-amino-2-naph-

thyIformiat. 30

Production 9

Ethyl 8 ~ hydroxy-2-naphthylformiat

A cold (0 ⁰ C) solution of 9.5 g (44 mmol) of ethyl 8-amino-2-naphthylformiat in 150 ml of 6N sulfuric acid is added dropwise during 10 minutes with a solution

of 3.1 g (45 mmol) of sodium nitrite in 25 ml of water. The reaction mixture is stirred for 50 minutes and then added to a hot solution (90 ^° C.) of 90 ml of water in 10 ml of concentrated sulfuric acid. The reaction mixture is stirred for 10 minutes at 90 ⁰ C, whereupon it is cooled and extracted with dichloromethane. The extracts are combined, washed with brine, dried and freed of solvent to give, after chromatographic purification, 1.7 g of ethyl 8-hydroxy-2-naphthylformate

which melts at 136 to 137 ⁰ C.

Following the same general procedure are employed 14.9 g of ethyl 8-amino-2-naphthylformiat with t-butyl nitrite and "Copper (II) chloride in order to obtain 11.5 g of ethyl ¹ · ^ 8-chloro ~ 2-Naphthylformiat receives.

Preparation 10 Ethyl 8-methoxy-2-naphthylformate

A solution of 216 mg of ethyl 8-hydroxy-2-naphthyl orrniate (from Preparation 9) in 15 ml of acetone containing 6 drops of dimethyl sulfate and 150 mg of potassium carbonate is stirred for 24 hours at 25 ° C. The reaction solvent is removed and the product is dissolved in ethyl acetate and the solution is washed with 5% hydrochloric acid and brine, dried and concentrated to give 200 mg of ethyl 8-methoxy-2-naphthylformate.

30 H generates 11 oi ~ methoxyimino ~ 0 - (8-chloro-2-naphthyl) acetic acid

A suspension of 9.2 g of sodium hydride in 50 ml of N, N-dimethylformamide is added all at once with stirring to a solution of 5.6 g (24 mmol) of ethyl 8-chloro-2-naphthylformnate and 4.4 g (36 mmol ) Methylmethylthiomethylsulfoxide in 10 ml

Ν, Ν-Dimethyiformamid given. The reaction mixture was stirred for a further 4 hours at 25 ^° C. and then concentrated to dryness. The product is dissolved in 250 ml of ethyl acetate, and

the solution is seeded with 5% hydrochloric acid, 5

washed sodium bicarbonate and saline. The solution is dried and the solvent removed by evaporation, yielding 4.7 g (yield = 63%) of 1-oxo-1- (8-chloro-2-naphthyl) -2-methylthio-2-methylsulfinylethane. A solution of 3.12 g (10 mmol) of the product in 150 ml of formic acid and 12 ml of acetic anhydride is stirred for 30 minutes at 65 ° C. The reaction mixture is treated with 8 56 mg (4 mmol) of sodium periodate and stirred for a further 15 minutes. The reaction mixture is cooled and concentrated to dryness, the product is dissolved in ethyl acetate, the solution is washed with sodium bicarbonate and brine, and the solvent is removed. In this way one reaches 1.2 g (yield = -46%) of methylthio-α ~ οκο-σ- (8-chloro-2-naphthyl) acetate.

* ^W A solution of 220 mg of the above product in 15 ml of methanol and .15 ml of water containing 0.83 ml of sodium hydroxide and 70 mg of methoxyamine hydrochloride lh 16 hours at 25 ⁰ C stirred. The reaction mixture is acidified by addition of hydrochloric acid to pH 2 in hydrochloric acid.

^ΔΌ The acid solution is extracted with ethyl acetate, the drying and concentration of which gives 170 mg of CC-methoxyimino-CC- (8-chloro-2-naphthyl) acetic acid.

Following the same general procedure, the following further compounds are prepared:

# -Methoxyiniino-0- (8-nitro-2-naphthyl) acetic acid, Ct-methoxyimino-Oi-t 8-amino-2-naphthyl 1) acetic acid, CX-methpxyimino-ui- (8-hydroxy-2-naphthyl) acetic acid and α-methoxyimino-0C- (8-methoxy-2-naphthyl) acetic acid. '

- 38 ¹ Production 12.

Preparation of 7-amino-3-chloro-3-cephem-4-carboxylic acid

° The synthesis of 7-phenylglycylamido-3-chloro-3-cephem-4-. carboxylic acid, which is now commonly known as cefaclor, is described in U.S. Patent 3,925,372. By reacting cefaclor with phosphorus pentachloride, methanol and water under conditions known for cleavage of cephalosporin side chains, 7-amino-3-chloro-3-cephem-4-carboxylic acid is obtained.

The following cores, which are required for the synthesis of compounds according to the invention, are prepared in a similar manner:

7-amino-7-methoxy-3-bromo-3-cephem-4-carboxylic acid _/ 7-amino-3-cephem-4-carboxylic acid,

7-Amino-S-methoxymethyl-S-cephein-4-carboxylic acid, 7-amino-7-methylthio-3-methyl-3-cephem-4-carboxylic acid.

Production 1 3 · '

7- (D-2-Naphthylglycylamido) -4-methyl-S-cephem ^ -carboxylic acid N, N-dimethyifpramide monohydrate

A cold (-20 ⁰ C to -30 ⁰ C) suspension of 51.0 g of D / N- (1-methoxycarbonyl) -2-prppenyl _L / -2-naphthylglycinnatriumsalz prepared by reacting methyl acetoacetate with D-2- Naphthylglycine in 500 ml of acetonitrile containing 250 ml of N, N-dimethylformamide is added with stirring in sequence with 0.44 ml of methanesulfonic acid, 0.45 ml of N, N-dimethylbenzylamine and 12.35 ml of methyl chloroformate. After completion of the addition, the reaction mixture is stirred for 2 hours at 20 ^ ⁰ C to -30 ⁰ C. The reaction mixture is prepared by adding a cold (0 ⁰ C) solution of 34.24 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 230 ml of acetonitrile containing 59.4 nil N-Methylmonotri-

methylsilyl trifluoroacetamide diluted. The Reaktionsgem.i.sch is stirred for 2 hours at -20 ⁰ C to -30 ⁰ C and then warmed to 0 ⁰ C. The reaction mixture is acidified by the addition of IGO ml of acid In hydrochloric acid, and the sciure mixture is added with stirring at once with 1.85 g semicarbazide hydrochloride. The pH of the reaction mixture is adjusted to 3.0 and maintained by the addition of triethylamine. The mixture is filtered after heating to 25 ° C through a filter aid (Hyflo). The filtrate is diluted to pH 6.2 by the addition of triethylamine, cooled to 0 ^° C. for ¹ 45 minutes and then filtered. The filter cake is washed four times mi.t per 50 ml of acetonitrile and dried for 7 hours under reduced pressure at 35 ° C, which is 66.8 g of 7- (D-2-Naphthylglycylami- do) - 3-me thy 1- 3 -cephem-4-carboxylic acid N, N-dimethyl formamide monohydrate. Yield = 86%. Water analysis according to Karl Fisher: 4.69%.

NMR spectrum (TFA): signals at 8 = 2.1 (S, 3H), 3.2 (S, 311), 3.3 (ABq, 211), 3.4 (S, 3H), 5.2 (d, IH), 5.8 (dd, HI), 5.8 (S, IH), 7.3 to 8.2 (m, 7H), 8.3 (S, IH).

Example 1-

7- (2-Naphthylglycylamido) -3-methyl-3-cephem-4-carboxylic acid trifluoroacetate salt. ·

A suspension of 1.0 g (4.7 mmol) of cephem-4-carboxylic acid (7-ADCA) in 25 ml of acetonitrile is combined with stirring 3.7 ml (14.0 mmol) of bis (trimethylsilyl) trifluoroacetamide all at once , The reaction mixture is stirred at room temperature until all the solids have dissolved, indicating completion of the formation of the trimethylsilyl ester of 7-ADCA.

In a separate flask, a solution of 1.35 g (4.5 mmol) of N-t-butoxycarbonyl-2-naphthylglycine is stirred

(from Preparation 4) in 20 ml of acetonitrile, containing 1.1 g (4.5 mmol) of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) for 15 minutes at room temperature. The

Solution is then added all at once to the cold ( ⁰ C) solution of 5 "

Acetonitrile containing the above trimethylsilyl ester of 7-ADCA. The reaction mixture wir.d one hour at 0 ⁰ C stirred and then warmed to room temperature; The solvent is removed by evaporation under reduced pressure, then the resulting oil is dissolved in ethyl acetate, the solution is washed twice with hydrochloric acid, dried and freed from solvent by evaporation to give 7- (Nt-butoxycarbonyl-2-naphthylglycylamido). 3-ethyl-3-cephem-4-carboxylic acid in the form of a foam.

The N-protected Naphthylglycylcephalosporin thus formed is dissolved in 5 ml of trifluoroacetic acid, after which the trifluoroacetic acid is removed by evaporation under reduced pressure to give, after precipitation from diethyl ether, 5.7 g of 7- (2-naphthylglycylamido) -3-methyl-3 cephem-4-carboric acid trifluoroacetate salt.

B e i s ρ i e 1 2,

* ° 7- (2-Naphthylglycylamido) -3-methyl-3-cephem-4-carboxylic acid tetrahydrate

A mixture of 5.7 g of the trifluoroacetic acid addition salt of Example 1 in 55 ml of a mixture of 10% water and acetonitrile (v / v) is heated to about 50 ^° C. and then filtered to remove the undissolved solids. The filtrate is washed with -1.8 molar ammonium hydroxide diluted to pH 4.5. The precipitate formed is collected by filtration and dried, yielding 3.15 g (yield = 72%) of 7- (2-naphthylglycylamido) -3-me- '. Thyl-3-cephem-4-carboxylic acid tetrahydrate passes.

- 41 - "Example 3

7- (D-2-Naphthylglycylamido) -3-methyl-3-cephem-4-carboxylic "

retetrahydrat

The procedure of Example 1 is repeated using 5.0 g of optically active DNt-butoxycarbonyl-2-naphthylglycine and 5.6 g of 7-ADCA to give, after removal of the N-protecting group, 6.8 g (yield = 80 %) D-7- (2-naphthylglycylamido) -3-methyl-3-cephem-4-carboxylic acid trifluoroacetic acid salt. The salt thus formed is dissolved in 90 ml of acetonitrile and 10 ml of water containing 5 ml of triethylamine. The. Reaction mixture is stirred at 25 ° C. for 20 minutes and filtered. The filtrate is concentrated to dryness einge- ¹ ^ and the product crystallized from water to give 2.9 g of 7- (D-2-Naphthylglycylamido) obtained -3-methyl-3-cephem-4-carbonsäuretetrahydrat that at 171 to 1.80 ⁰ C melts with decomposition.

Analysis for C 51 7 ^N 3 ⁽ ) gS 5, 80 N 8th 95 S 6 , 93 Calculated: C 52 16 H 5, 47 N έ , 73 S 6 , 83 Found: 52 H

NMR spectrum (DMSO-d _c) 6 = 1.9 (s, 3H), 4.8 (s, III), .4,9

, D

25 (dd, IH), 5.6 (dd, IH), 7.49 to 7.99 (m, 7H). Example 4

7- (D-2-Naphthylglycylamido) -S-methyl-S-cephem - ^ - _{carbonsäuretetrahydrat.}

D-2-> naphthylglycine sodium salt is protected as an enamine by reaction with methyl acetoacetate. A suspension of 102 g (317.7 mmol) of the protected D-2-Naphthylglycinnatriumsalzes in 1000 ml of acetonitrile and 500 ml of N, N-dimethylformamide is cooled to -30 ⁰ C and stirring ^! 0.88 ml of methanesulfonic acid were added at once, whereupon

•. , ·. - 42 - '',; -

Add 0.90 ml of Ν, Ν-dimethylbenzylamine and 24.7 ml of methyl chloroformate. The reaction mixture is stirred for 2 hours at -3O ⁰ C and then by dropwise addition of a solution of 68.5 g (302.8 mmol) of 7-amino-3-methyl-3-cephem-, 4-carboxylic acid in 460 ml of acetonitrile, ^ containing 118.8 ml of hexamethyldisilazane, diluted. After completion of the addition, the reaction mixture is stirred for about 2 hours at '-3.0' ⁰ C and then, heated to 0 ⁰ C. The reaction mixture is diluted by addition of 320 ml of hydrochloric acid, after which 35.7 g Semxcarbazidhydrochlorid added. To adjust and maintain a pH of 3.0, ammonium hydroxide is added while allowing the mixture to reach 22 ° C. The reaction mixture is further diluted by addition of 4 ml of water and then added to the

¹ ^ staining for 15 minutes with 10.0 g of activated charcoal. The reaction mixture through a filter aid (Hyflo) and the filtrate is heated to 40 ⁰ C. The pH is adjusted to 4.0 by the addition of ammonium hydroxide, followed by crystallization. The crystallization ι takes about 30 minutes, whereupon the pH is raised to 5.2 by addition of In Ammoniumhydx'oxid. The mixture is cooled to 20 ° C and stirred for one hour, after which it is filtered. The filter cake is washed twice with 50 ml of water and dried in air to give

25 to 110.8 g of 7- (D-2-Naphthylglycylamido) -S-4-carboxylic acid tetrahydrate passes.

Analysis for ^C 2o ^H l9 ^N 3 ° 4 ^S ' ^4H 2 ° 30

Water analysis according to Karl Fisher: Calculated: 15.3%

Found: 13.73%

Nuclear Magnetic Resonance Spectrum (TFA): δ = 2.2 (s, 3H), 3.21 (q, 2H), 5.08 (d, IH), 5.68 (m, 2H), 7.4 up to 8.3 (m, 7H), 10.5 (s, 12H)

IR Spectrum (KBr): 1766, 1751, .1696 cm ^-1

Calculated: C 51 16 H 5, 80 .N 8th 97 S 6 , 83 Found: C 50, 31 H 5, 62 N 8th , 87 S 6 , 89

1 UV spectrum (CH-.OH): λ = 227,

= 78,000

λ = 265, e = 12000: ^v max

Titration (66% Ν, Ν-dimethylformamide / water), pKa values = 5.5, 7, 5, 11, 2. ,

· · '

B e i s ρ i e 1 5_

7 ~ (D-2-Naphthylglycylamido) ^ - methyl-S-cephem ^ -carboxylic acid hydrochloride monohydrate,

A solution of 200 ml of water containing 10 ml of 12N hydrochloric acid is added with stirring at once to 20 g of 7- {D-2-naphthylglycylamido) -3-methyl-3-cephem-4-carboxylic acid NiN-dimethylformamide solvate (ex the preparation 13). The reaction mixture is adjusted to pH 0.60 by addition of 12N hydrochloric acid and then stirred for 4 5 minutes at 25 ⁰ C. The precipitated solid is collected by filtration and washed once with 50 ml water ^Scir. The crystalline material is dried for 16 hours at 35 to 40 ⁰ C, whereby one gets 17.69 g (92%) of 7- (D-2-Naphthylglycylamido) -3-methyl-3-cephem-4-carboxylic acid ehydrochl or idmonohydrat ,

25 Analysis for C ₂₀ H ₂₂ ClN ₃ OS

Calculated: C 53.15 H 4.91 N 9.30 S 7.09 0 17.70

Cl 7.85 Found: C 52.75 H 4.85 N 9.85 S 7.03 O 17.07

Cl 7,60

Water analysis according to Karl Fisher: Calculated 4.29%

Found 4.62% Chloride Analysis (Titration): Calculated 7.85

Found 8:16 and 8:02

IR spectrum (KBr): 3040, 2940, 1768, 1707, 1533, 1232 cm ^-1 UV spectrum (EtOH): ^ _max - 225, £. = 100,000

Titration (66% N, N-dimethylformamide / water, v / v): 5.5, 7.3

  ". ' ': - 44. -

Be i s ρ i e 1 6 -

7 ~ (D-2 ~ Naphthylglycylamido) -S-säurehydrochloridrnonohydrat

^& '. '' · '''^

A solution of 5 g (10.6 mmol) of 7- (D-2-Naphthylglycylamido) -3-metnyl-3-cephem-4-carbQnsäuretetrahydrat .If (from Example 3) in 50 ml of acetone heated to 40 ⁰ C and then acidified by the addition of 1 ml of 12N hydrochloric acid. The mixture is stirred and diluted to pH 3.3 by addition of 5 ml of water and 6N ammonium hydroxide. The pH is lowered to 0.20 by the dropwise addition of 12N hydrochloric acid, after which the reaction mixture is stirred for 2 hours at 25 ° C. De: r precipitated solid material is collected by filtration, washed twice with 10 ml of water and 2 Stunden.bei 25 ⁰ C dried under vacuum to give 1.929 g (yield = .40,5%) of crystalline 7- (D 2-Naphthylglycylamido) -3-methyl-3-cephem-

4-carbonic acid hydrochloride monohydrate. 20

Chloride analysis: Calculated 7.85%

Found 7,96%

Example 7

7- (b-2 ~ _i hthylglycylamido Nap) -3-methyl-3-cephem-4-carbonsäurehydrochloridmonohydrat

A warm (40 ⁰ C) solution of 1 ml of 12N hydrochloric acid in 25 ml of water and 25 ml of acetone is added with stirring at once with 5 g of 7- (D-2-Naphthylglycylamido) -3-methyl-3-ce-. phem-4-carboxylic acid tetrahydrate (from Example 3). The reaction mixture is adjusted to pH 0.15 by addition of further 12N hydrochloric acid, whereupon the mixture is cooled to 25 ° C and stirred for 2 hours. The precipitated solid is collected by filtration, washed three times with 10 ml of water and 4 hours at 25 ° C.

- 45 - .. '

dried under vacuum. This gives 3.596 g (yield = 75%) of 7- (D-2-naphthylglycylamido) -3r methyl-S-cephem-1-carboxylic acid hydrochloride monohydrate.

Water analysis according to Karl Fisher:

Calculated: 4.29%

Found: 5.95% -

Chloride analysis:.

10 Calculated: 7.85% Found: 8.09%

example

7- (D-2-Naphthylglycylarnido) -3-methyl-3-'Cephem-4-carbonsäurehydrochloridmonohydrat

A solution of 10 g (21.3 mmol) of 7 ~ (D-2-naphthhylglycylamido) -3-methyl-3-cephem-4-carboxylic acid tetrahydrate in 100 ml of water containing 5 ml of 12N hydrochloric acid is added with stirring 40 ° C added dropwise to a pH of 0.6 'with 12n hydrochloric acid. The reaction mixture is cooled to 25 ° C and stirred for one hour at this temperature. The crystalline product is collected by filtration, washed twice with 20 ml of fresh water and dried at 25 ⁰ C under reduced pressure for 3 hours. The dried product is crystallized as 8.16 g (yield = 84.5%) of 7- (D-2-naphthylglycylamido) -methyl-cepheiT ^ -carboxylic acid hydrochloride monohydrate

₃ q identified.

Water analysis according to Karl Fisher:

Calculated: 4.29%

Found: 5.37% -

_{q (} - chloride analysis:

Calculated: 7.85% Found: 7.62%

  , - 46 Example 9. ,

p-nitrobenzyl 7- (N-t-butoxycarbony1-2-naphthylglycylamido) -

3-chloro-3-cephem-4-carboxylate

⁵ ' ^: '''''

A solution of 260 mg EEDQ in 50 ml of acetonitrile containing> 301 mg the N-t-butoxycarbonyl-2-naphthylglycin is at once with stirring to a cold (0 ⁰ C) solution of 682 mg of p-nitrobenzyl 7-amino-3- chloro-3-cephem-4-carboxylate in 50 ml of acetonitrile. The reaction mixture is stirred at 0 ^° C. for 90 minutes and then warmed to room temperature. The reaction solvent is removed by evaporation under reduced pressure to give the product as an oil. The oil is dissolved in ethyl acetate, and the solution is diluted with dilute hydrochloric acid, a

Buffer of pH 7.0 and finally with saline solution. ' see. The organic solution is dried and then freed from the solvent by evaporation, yielding 598 mg (yield = 93%) of p-nitrobenzyl-7 - (Nt-butoxycarbonyl) -1-bony1-2-naphthylglycylamido) -3-chloro-3 cephem-4-carboxylate. , , ,

NMR spectrum (CDCl3); δ = 1.2] (s, 9H), 3.1 to 3.8 (m, .211), 4.9. (two doublets, IH), 5.28 (s, 2H) ,. 5.4 to 6.2 x (m, 3H), 7.2 to 8.21 (m, 12H). ".

Example 10

7- (2 "Naphthylglycylamido) -3-chloro-S-cephors ^ -carboxylic acid trifluoroacetate

A solution of 598 mg of p-nitrobenzyl-7- (Nt-butoxycarbonyl-2-naphthylglycylamido) -S-chloro-cephem ^ -carboxylate (from Example 9) in 50 ml of tetrahydrofuran containing 10 ml of methanol and 5 ml of ethanol. is partially with 1.20 g

5% palladium-on-carbon added. The reaction mixture. is spent one hour in a pair hydrogenation apparatus under a

, -47-. ^:

no initial hydrogen pressure of 4.1 bar shaken.

The reaction mixture is then filtered and the solvent is removed from the filtrate by evaporation under reduced pressure to give an oil. The oil is in 5

dissolved in a buffer of pH 7.0, and the pH is adjusted to 7.75 by adding dilute sodium hydroxide. The aqueous solution is washed with ethyl acetate and diethyl ether and then by addition of hydrochloric acid in. acidified pH 2/3. The acidic solution is extracted with ethyl acetate, the whole is dried and the solvent is removed by evaporation to give 360 mg (yield = 77 %) of 7- (mt-butoxycarbonyl-2-naphthylglycylamido) -S-chloro-S-cephem ^ -carboxylic acid passes.

The acid thus formed is dissolved in 6 ml of trifluoroacetic acid, and the solution is stirred for 5 minutes at 25 ° C. Then Öer pH is increased by addition; of dilute ammonium hydroxide is adjusted to 3.9, after which the solvents are removed by evaporation to give an oil.

20 ··

The 01 is subjected to gradient chromatography over reverse phase silica gel eluting with 0 to 25% acetonitrile, 1% acetic acid and 99 to 74% water (v / v). The appropriate fractions are combined and the solvent is removed by lyophilization to give 49 mg of L- and 49 mg of D-7- (2-naphthylglycylamido) -3-chloro-3-cephem-4-carboxylic acid.

NMR spectrum (TFA-d ^: δ = 3.82 (q, 2H), 5.49 (d, IH),

5.8 to 6.1 (m, 2H), 7.6 to 8.35 (m, 7H). 30

B e i s ρ i e 1 11

, 7- (2-Naphthylglycylamido) -3-methoxy-3-c ephem-4-carboxylic acid ⁱ ,. trifluoroacetate 35

A solution of 1.05 g of D, L-N-t-butoxycarbonyl-2-naphthylglycine in 15 ml of acetonitrile containing 1.06 g of EEDQ

Stirred for 30 minutes at 25 ° C and then added with stirring all at once to a solution of 1.0 g of 7-amino-3-methoxy-3-cephem-4-carboxylic acid in 15 ml of acetonitrile, 1 ml of bis (trimethylsilyl ) trif luoracetainide. The reaction mixture is stirred for 2 hours at 25 ° C and then concentrated by evaporation of the solvent under reduced pressure to dryness, whereby an oil is obtained. The oil is dissolved in 10 ml of trifluoroacetic acid, and the solution is allowed to stand at 0 ^° C. for 5 minutes. The solvent is evaporated and the product is purified by chromatography over silica gel, yielding 89.5 mg of D, L-7- (2-naphthylglycylamido) -S-methoxy-S-cephem-1-carboxylic acid trifluoroacetate. ,

15 IR spectrum (KBr): 1762.10 cm ^-1 (β-lactam)

Nuclear Magnetic Resonance Spectrum ('1'Fh-O ₁ ): δ = 3.2 to 4.25 (m, 5H), 5.2 to 5.9 (, m, 3H), 7.5 to 8.3 ( m, 7H).

20 B e i s ρ i e 1 12

D-7- ("6-Chloro-naphth-2-yl glycyl amido) -S-methyl-S-cephem ^ -carboxylic acid

2-Chloronaphthalene is acylated with ethylchloroxalate to give ethyl (X-keto-CW 6-chloronaphth-2-yl) acetic acid. Reaction of this compound with hydroxylamine, subsequent reduction and hydrolysis gives 6-chloronaphth-2-ylglycine. This compound is then converted to the t-butoxycarbonyl-protected derivative on nitrogen. ·

A cold (0 ⁰ C) solution of 523 mg (1,5'mole) of p-nitrobenzyl-7-amino-3-methyl-3-ce ^) hem-4-carboxylate in 300 ml of acetonitrile is added with stirring to a Solution of 500 mg (1.5 mmol) of Nt-butoxycarbonyl-6-chlororaphth-2-ylglycine in 100 ml of acetonitrile containing 369 mg of EEDQ. The reaction

mixture is stirred for 1 hour at ^{0 0} C, after which it is warmed to room temperature and stirred for a further 48 hours. The reaction solvent is then removed by evaporation under reduced pressure to give the product as O1. The oil is dissolved in 100 ml of ethyl acetate and the solution is washed with hydrochloric acid, aqueous sodium bicarbonate and water and then dried. Removal of the solvent by evaporation gives 770 mg of a white solid (Yield = 77%) of p-nitrobenzyl-7- (Nt-butocycarbonyl-6-chloronaphth-2-yl-glycylamido) -3-methyl-3-cephem -4-carboxylate.

NMR spectrum (CDCl ₃ ): .6 = 1.40 x (s, 9H), 2.12 (two singlets, 3H), 3.40 (q, 2H), 4.68 and 4.90 (two doublets , IH)., 5.30 (broad s, 3H), 5.6 to 6.0 (m, IH), 7.2 to 8.3 (m, 8H).

To remove the p-nitrobenzylcarboxy protecting group, 770 mg of the above compound are hydrogenated with 1.0 g of 5% strength

^AV> palladium on carbon in 50 ml of methanol containing 20 ml of ethanol under an initial hydrogen pressure of about 3.8 bar. The reaction is complete after 55 minutes, after which the reaction mixture is filtered and the solvent is removed from the filtrate to give an oil. The oil is dissolved in 50 ml of ethyl acetate containing a buffer of pH 7, and the aqueous layer is acidified to pH 2.3 with hydrochloric acid . The product is extracted into ethyl acetate and the extract is washed with water, dried and evaporated to dryness. This gives 220 mg (yield = 36%) of 7- (Nt-butoxycarbonyl-6-chloronaphth-2-yl-yl glyyl amido) -3-

methyl-3-cephem-4-carboxylic acid.

NMR spectrum (CDCl ₃ ): δ '= 1.46 (s, 9H), 2.15 (two singlets, 3H), 3.35 (m, 2H), 7.2 to 8.1 (m, 811 ).

The product formed is dissolved in 5 ml of trifluoroacetic acid and the solution is stirred for 5 minutes at room temperature. Evaporation of the solvent and purification of the product by ionic performance liquid chromatography gives D-7- (6-chloronaphth-2-ylglycylamido) -3-methyl-3-cephem-4-carboxylic acid. -

Example 13

 , d-7- (2-Naphthylglycylamido) -S-methoxymethyl-S-cephem ^ carboxylic acid

A solution of 570 mg of diphenylmethyl-7-amino-3-methoxymethyl ^j: -3-cephem-4-carboxylate tosylate in 30 ml of ethyl acetate containing 10 ml of aqueous sodium bicarbonate is stirred for 5 minutes and then evaporated to dryness to give diphenylmethyl ^ -amino-S-methoxymethyl ^ -cephem ^ -carboxylate as a white foam. The foam is dissolved in 20 ml of acetonitrile and the solution is added all at once with stirring to a solution of 301 mg of DNt-butoxycarbonyl-2-naphthylglyein in 20 ml of acetonitrile containing 207 mg of N, N-dicyclohexylcarbodiimide and 135 mg of hydroxybenzotriazole. The reaction mixture is stirred for 4 hours at 25 ° C. The mixture is poured into 100 ml of ethyl acetate and the solution is washed once. Wash 50 ml of aqueous sodium bicarbonate once with 5Q-ml ¹ in hydrochloric acid and once with water, dry and remove the solvent by evaporation under reduced pressure to give diphenylmethyl-D-7- (Nt-butoxycarbonyl-2-naphthylglycylamido) -S -rnethoxymethyl-S-cephem ^ -carboxylate passes as a white foam! The foam is dissolved in 2 ml of triethylsilane and 5 ml of trifluoroacetic acid, and the solution is stirred for 9 minutes at 25 ° C. Removal of the solvent by evaporation under reduced pressure gives 260 mg of D-7- (2-naphthylglycylamide) -4-methoxymethyl-S-cephe- rn-4-carboxylic acid et atl acetate acetate.

The salt formed is dissolved in 5 ml of water and 5 ml of acetonitrile.

tril dissolved, and the pH of the mixture is adjusted to 4.5 with ammonium hydroxide. The solution is lyophilized to give a white solid, which is purified by preparative reverse phase high pressure liquid chromatography to give 20 mg of D-7- (2-naphthyl-glycylamido) -3-methoxymethyl-3-cephem-4-carboxylic acid.

NMR spectrum (DMSO-d,): δ = 3.13 (s, 3H), 3.28 (q, 2H), 4.12 (s, 211), 495 (d, IH), 5.65 ( d, IH), 7.41 to 7.23 (m, 7H).

Example 14,

¹ ^ p-Nitrobenzyl-7- / Nt-butoxycarbonyl- (6-methoxy-2-naphthyl) cyanyl] amide f) / - 3-methyl-3-cephem-4-carboxylate

A solution of 62.7 mg (2 mmol) of Nt-butoxycarbonyl- (6-niethoxy-2-niiphthyl) glycine in 100 ml of acetonitrile containing 500 mg (2 mmol) of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline is added with stirring 770 mg (2.2 mmol) of p-nitrobenzyl ^ -nino-S'-methyl-S-cephem ^ -carboxylate at once. The Reaktionsgernisch is stirred for 16 hours at 2-j ° C and then converted by concentration to dryness in an oil. The oil is dissolved in 50 ml of ethyl acetate and the solution is washed with 25 ml of hydrochloric acid, 25 ml of aqueous sodium bicarbonate and water. The solution is dried and concentrated to dryness, yielding 1.3 g of p-nitrobenzyl-7- / Nt-butoxycarbonyl- (6-methoxy-2-naphthyl) -glycylamido / 3-methyl-3-cephem-4-carboxy at.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 6 = 1.39 (s, 9H), 2.08 and 2.15 '(two singlets, 3H), 3.34 (q, 2H), 3.90 (s, 3H ), 4.9 (m, IH), 5.29 (s, 2H), 5.31 (s, IH), 5.68 (m, IH), 7.08 to 8.25 (m, 12! ).

Example 15 - '

D-7- (6 ~ methoxy-2-naphthyl) glycylamido-S-methyl ^ -cephem-

4-carboxylic acid 5.

A suspension of 1.4 g of 5% palladium on carbon in 50 ml of ethanol is added all at once while stirring with 1.3 g of p-nitrobenzyl-V-ZlKHt-butoxycarbonyl- (6-methoxy-2-naphthyl). glycylarnido / 3-methyl-3-cephem-4-carboxylate. The reaction mixture is stirred for 3 hours at 25 ° C under a hydrogen pressure of about 3.8 bar. The reaction mixture is then filtered and the filter cake is washed with fresh ethanol. The filtrate is concentrated to dryness by evaporation under reduced pressure, which gives 1.1 g of 7- / Nt-butoxycarbonyl- (6-methoxy-2-naphthyl) -glycylamido / 3-methyl-3-cephem-4-carboxylic acid arrives.

The acid formed fjo is dissolved in 5 ml of trifluoroacetic acid and the solution is stirred for 5 minutes at 25 ° C. The reaction mixture is added to 20 ml of water and the aqueous solution is lyophilized for 12 hours to give D, L-7- (6-methpxy-2-naphthylglycylamido) -3-methyl-3-cephem-4-carboxylic acid trifluoroacetate , The salt thus formed is redissolved in fresh water and purified by high performance liquid chromatography to give D-7- (6-methoxy-2-naphthylglycylamido) -S-. 4-carboxylic acid receives.

NMR spectrum (TFA-dj ^): 6 = 2.42 (s, 3H), 3.50 (q, 2H),

4.30 (s, 3H), 5.39 (d, IH), 5.8 to 6.1 (m, 2H), 7.4 to 8.30 (m, 6H).

Example 16 35

Following the general procedure of Examples 14 and 15, p-nitrobenzyl-7-amino-3-methyl-3-ce is added.

phem-4-carboxylate with D, LNt-butoxycarbonyl {6-hydroxy-2-naphthyl) glycine in the presence of EEDQ to give p-nitrobenzyl-D, L-7- / Nt-butoxycarbonyl- (6-hydroxy -2-naphthyl) glycylamido / -3-methyl-3-cephem-4-carboxylate.

NMR spectrum (CDCl ₃ ): 6 = 1.41, (s, 9H), 2.0 2 and 2.10 (two singlets, 3H), 2.3 to 3.5 (m, 2H), 4, 9 (m, IH), 5.23 (s, 2H), 535 (rn, IH), 5.6 to 6.0 (m, 2H), 6.72 to 8.21 (m, 12H). , .

The compound thus prepared is reacted with hydrogen and 5% palladium on carbon to give D, L-7- / N-t-butoxycarbonyl- (6-hydoxy-2-naphthyl) glycylamido.

3-methyl-3-cephem-4-carboxylic acid. 15:

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 6 = 1.15 (s, 9H), 1.8 2 and 1.8 9 (, two singlets, 3H), 4.65 (two doublets, III), 5.23 ( in, 1H), * 6, O (m, IH), 6.7 to 7.9 (m, 7H), 8.5 (m, 2H).

The above compound is then converted to D, L-7- (6-hydroxy-2-naphthylglycylamido) 3-methyl-3-cephem-4-carboxylic acid by reaction with trifluoroacetic acid. The isomers are separated by high performance liquid chromatography to give D-7- (6-hydroxy-2-naphthylglycylamido) -3-methyl-3-cephem-4-carboxylic acid.

Example 17

D-7- (2-Naphthylglycylamido) -3-cephem-4-carboxylic acid

A suspension of 2.0 g (10 mmol) of 7-amino-3-cephem-4-carboxylic acid in 15 ml of acetonitrile is added all at once with 8 ml (30 mmol) of bis (trimethylsilyl) trifluoroacetamide with stirring. The mixture is stirred for 30 minutes at 25 ° C, after which it is cooled to ⁰ ° C and all of a sudden with stirring to a solution of 2.0 g (6.6 mmol) of DjL-Nt-butoxycarbonyl-2-naphthylglycine in 15 ml acetonitrile, which is 1.73 g

(7.0 mmol) EEDQ contains. The reaction mixture is stirred for one hour at 25 ⁰ C and then concentrated to dryness to form an oil. The oil is dissolved in 100 ml of ethyl acetate, and the solution is washed four times with each 25 m \ In

Hydrochloric acid and washed twice with brine and dried. The solvent is removed by evaporation under reduced pressure to give a white foam. The foam is dissolved in 25 ml of trifluoroacetic acid, and the solution is sonicated for 5 minutes at 25 ° C. The reaction mixture is evaporated to dryness and the residue is treated with diethyl ether to give 1.8 g (yield = 55%) of D, L-7- (2-naphthylglycylamido) -3-cephern-4-. carboxylic acid trifluoroacetate passes. The product thus prepared is converted via reverse phase C,

Chromatographed dioxide gel, eluting with 8 liters of a solution of 1% acetic acid and a gradient of 95 1 water and 5 % acetonitrile up to 85% water and 15% acetonitrile (v / v). The appropriate fractions are combined and lyophilized to remove the solvent to give 157 mg of D-7- (2-naphthylglycylamido) -3-cephem-4-carboxylic acid.

IR Spectrum (KBr): 1771, 75 cm ' ¹ (ß-Lactam)'

Nuclear Magnetic Resonance Spectrum (TFA-d ^: δ = 3.55 (q, 2H), 4.08 (s, IH), 5.6 to 6.0 (m, 2H), 7.5 to 8.1 ( m, 7H)

Example · 18

7-AX-Methoxyimino-C "- (8-chloro-2-naphthyl) acetamido / 3-methyl-3-cephem-4-carboxylic acid

420 mg of α-methoxyimino- (X- (8-chloro-2-naphthyl) acetic acid are converted into the acid chloride by reaction with excess of chlorine and 500 mg of triphenyl phosphite in 20 ml of dichloromethane of 350 mg of 7-amino-3-methyl-3-ce

 -55.- -. ' ,

phem-4-carboxylic acid in 5 ml of dichloromethane containing 2 ml of bis (tri-.methylsilyl) trifluoroacetamide. The reaction mixture is stirred for 6 hours at 25 ⁰ C and then

diluted by adding 20 ml of methanol. The solution becomes 5

Evaporated by evaporation under reduced pressure to give 7- / ö-methoxyimino-CX- (8-chloro-2-naphthyl) acetamido / 3-methyl-3-cephem-4-carboxylic acid. The product so formed is dissolved in formic acid containing zinc dust to give 7- (8-chloro-2-naphthyl) glycylamido-3-methyl-3-cephem-4-carboxylic acid after isolation and purification.

Similarly, the following compounds are prepared:

, 7- (8-nitro-2-naphthyl) glycylamido-3-chloro-3-cephem-4-carboxylic acid,

7- (8-hydroxy-2-naphthyl) glycylamido-3-methoxymethyl-3 ^ ^ cephein -4-carboxylic acid,

 7- (8-amino-2-naphthyl) glycylamido-3-methyl-3-cephem-4-carboxylic acid and

7- (8-methoxy-2-naphzhyl) glycylamido-3-methyl-3-cephem-4-carboxylic acid.

nc

The naphthylglycylcephalosporins according to the invention are valuable antibiotic substances or intermediates for this purpose. Although the compounds are effective against a broad spectrum of gram-positive and gram-negative bacilli, they are particularly effective against a wide variety of gram-positive bacilli. The antibiotic compounds are particularly useful for treating infections in animals caused by Gram-positive microorganisms. The compounds are particularly effective for the treatment of upper respiratory tract infections and related diseases described by H.H. influenza, S. aureus, S. pyogenes and the like. Furthermore, the links

are also effective in the treatment of diseases caused by anaerobic cocci such as Peptostreptdcoccus anaerobius, Peptostreptococcus intermedius, Pepto-

streptococcus productus, Peptococcus saccharolyticus, Pep-5

tococcus prevotii, Peptococcus anaerobius, Propionibacterium aenes, Fusobacterium necrophorum and the like.

A typical and preferred compound of the invention is 7- (2-naphthylglycylamido) -3-methyl-3-cephem-4-carboxylic acid, namely the compound of Example 3. The antibacterial activity of this compound and several other compounds of the invention is conventional in vitro Agar dilution experiments against a number of Gram-positive microorganisms have been determined. The following • 15 "tables show typical minimum inhibitory concentrations (MICs) in μg / ml for these compounds versus the indicated microorganisms, for comparison also the MIC values for several known compounds.

20 ',

ω ο

TABLE I "

MIC values obtained by agar dilution (pg / ral)

organism tribe Ampi cillin Cepha lexin 3 ν «10A ^a 2rbindi 10B ^b before 11 Beisj 12 piel * 15 16 17 Staph. aureus Xl. 1 V41 X400 S13E 0.25 32 128 64 4 128 128 128 0.5 8 64 8 0.25 16 128 16 8> 128> 128> 128 1 32 128 32 0.25 8 64 8 0.25 16 64 16 0.5 8 32 8 4 64 128 64 Staph. epi EPI 222 8 0.25 32 8 1 0.5 2 0.25 32 4 NJ OO 4 0,5 4 1 4 1 32 4 Strep. A C 20 3 0.03 0.5 0.5 0,125 4 0,125 0.06 0,125 0,125 0.5 Strep. PN PARK 0.03 2 0.5 0,125 4 > 128 0.25 0,125 0.25 1 H. influ. BRUN 251 0.5 16 8 8 8 2 4 2 > 128 16 > 12 8 32 32 2 16 4 8 4 64 16 Klebsiella X26 16 4 2 2 64 8th 8th 4 4 16

D-shape ^ L-shape

co O

to O

CJI

TABLE II

MIC values (pg / ml) versus an extended spectrum of organisms

Connection of example

organism Tribe ' 3 8th 12 - 13 15 16 5 Staph. epi EPIL 4 8th 4 4 4 270 0.5 4 2 4 4 219 2 0 0.5 5 O, 269. 2 4 2 2 2 5 285 1 2 1 2 2 5 286 0.5 1 0.5 0.5 1 Staph. aureus S224 .- 0.5 0.5 0.5 0.5 O, 5 S225 1 0.5 0.5 0.5 O, 5 S226 1 1 1 1 1 S227 0.5 , 0.5 0.5 1 5 S228 1 0.5 0.5 0.5 O, 5 S229 0.5 1 1 1 1 S23C 0.5 0.5 0.5 0.5 O. S231 1 0.25 0.5 0.25 O, S234 1 1 1 1 1 S237 1 0.5 0.5 1 1 S238 1 1 1 1 1 S239 1 1 1 1

TABLE II (continued)

Connection of example

Organism strain 3 12 13 15

H. influ. CL. 8 32 8

76 2 16 8

HESS 8 32 8

STEL 8> 64> 64

312 8 8 8

R465 8 32 16

1930 8 16 16

4842 4 8 8

1683 2 2 4

M366 8> 64> 64

M370 4 8 4

M371 4 8 4

105 4 8 8

158 4 4 8

164 4 4 8

171 4 8 8

169 4 8 8

8th 4 4 2 8th 4 16 > 64 4 4 16 16 8th 4 4 4 2 2 16 > 64 4 4 4 2 4 4 4 2 4 2 4 4 4 4

- 60 TABLE III

MIC values (μg / ml) versus an extended spectrum

organisms

tribe Cephalexin Cefaclor connection of 25 [" I organism 8725 2 2 Example 3 25 S. aureus 8787 1 1 O, 5 9050 2 2 O, 0 9290 4 8th O, 0 9767 4 2 1. 25 8438 1 1 1, 25 9136 2 2 O, 10817 16 64 O, B, fragile 180-821 16 64 2 10695 64 32 2 107268 16 16 4 107266 32 16 .8th 10750 64 > 64 16 10774 > 64 > 64 16 10837 16 > 64 16 10683 > 64 16 16 , 10668 > 64 64 32 "101 8th 2 32 H. influenza 102 16 16 4 103 16 2 32 104 16 1 4 105 4 1 1 106 8th 2 2 107 8th 2 1 108 8th 1 4 109 16 2 4 110 8th 1 4 111 16 1 4 1

35,

- 61 TABLE IV

Susceptibility of anaerobic cocci isolates in the form of MIC values obtained by agar dilution after 24 hours

Anaerobic cocci cefoxitin 0.25 Compound V Example 3 * Peptococcus asaccharolyticus 1344 8th <0.125 Peptococcus constellatus 1468 Second 0.25 P. magnus 1401 0.5 0.25 P. magnus 1477 1.0 0.5 P. prevotii 1293 0.25 0.5 Peptostreptococcus anaerobius 8th 2 <O, 125 Il 52 1 0.25 ti 1477 1.0 <O, 125 Peptostreptococcus intermedius 1264 4.0 1.0 Il 1524 4.0 1.0 Il 1624 16 1/0 Bacteroides fragilis 3625 8th 16 7371A 8th 16 200 16 32 206 16 16 19671 32 > 64 19681 2 16 Propionibacterium acnes 44 8th 4 79 4 8th . 101 4 8th 104 2 8th 105 ί0,06 4 5191 2 0.25 5227 4 0.25 5228 2 8th 5229 4 8th 5246 8th

The data contained in the above tables make it clear that the compounds of the invention have a strong antibacterial activity.

B '' <·

In addition to this strong antibacterial activity against a wide variety of microorganisms, especially Gram positive organisms and anaerobic bacteria, the compounds of the invention have also been found to be very beneficial pharmacokinetics in animals / For example, if 7- (2-naphthylglycerol) is administered.

, cy4.au; ^l -'0--3 "methyl-3-cephem-4-carboxylic acid in rats at an intravenous dose of 20 mg / kg, then the plasma concentration after 1 hour is 18.6 μg / ml, after 4 hours at 14.1 ^ g / ml and after 24 hours still at

¹ ^ 1.96 μg / ml. The compound is effectively absorbed by rodents orally and has higher and longer blood levels than cefaclor and cephalexin.

The compounds according to the invention also have good stability towards β-lactamases. Table V below shows the results of comparative studies of several cephalosporins (lower numbers indicate greater stability to the indicated β-lactamase)

 25

TABLE V

¹ ρ. Stability to β-lactamases

265A Organism PSl85 TEM 2'3 1082E 1313G Cefaclor 138 71 1 65 4605 Cephalexin 72 37 3 6 254 7- (2-Nap'hthylgly- 50 25 26 256

cylamido) -3-methyl-3-cephem-4-carboxylic acid

The favorable pharmacokinetic behavior of the compounds of the invention in conjunction with their excellent oral antibacterial activity and stability towards β-lactamases makes these compounds too special

interesting agents for the treatment of a number of diseases of bacterial origin. The compounds are particularly useful for treating ambulatory patients, and especially those patients who suffer from weak upper respiratory tract infections caused by gram positive microorganisms.

The invention therefore also includes an agent for the treatment of animals suffering from bacterial diseases

, where there is a risk of developing a bacterial

len infection suspected. To carry out this method of controlling bacteria, an animal in need of such treatment is administered an antibacterially effective amount of a naphthylglycyl cephalosporin antibiotic. The method may be therapeutic or prophylactic.

^UKJ table be applied. The amount of antibiotic agent to be administered depends on the particular compound selected for the application, the severity of the disease to be treated or protected, the particular patient being treated, and related factors commonly associated with such treatment has to do. However, normally the compounds will be administered at a dose of about 0.5 to about 50 mg / kg body weight of the animal, and preferably in an amount of about 1 to about 10 mg / kg. Such amounts may be administered once daily or more often as required to treat the particular disease or patient in need of treatment. A typical daily dose for a mid-adult human is about 200 to about 500 mg per day.

The antibiotically active compounds according to the invention are active in both oral and parenteral administration.

 .: ': - 64 -

Therefore, they can be formulated in any manner desired for such a route of administration.

Alloys contain from about 0.1% to about 95% by weight of a naphthylglycyl cephalosporin antibiotic of the present invention as an active ingredient in admixture with a pharmaceutically acceptable carrier, diluent or excipients therefor. Typical formulations contain from about 10% to about 60% by weight of active ingredient, and more preferably from about 20% to about 50% by weight of active ingredient.

To form orally administrable dosage forms, the compounds may be mixed with any diluent, excipient and carrier conventionally used for oral formulations and formed into tablets, pills or dragees, or encapsulated in gelatin capsules. Typical conventionally used carriers, diluents and excipients include potato starch, corn starch, sucrose, dextrose, microcrystalline cellulose, dicalcium phosphate, alginic acid or acacia, lubricants such as magnesium stearate, binders such as tragacanth or gelatin, and flavorings such as peppermint oil, cherry or raspberry flavor. Wintergreen oil, and the like. The compounds may also be formulated as syrups or elixirs using conventional diluents such as fatty oils, methylparaben or propylparaben, suitable colorants and flavorings. Further, the compounds may also be formulated into a buccal, loop or other form suitable for sustained, controlled release of the active ingredient over an extended period of time ".

The antibiotics of the invention may also be formulated to be administered parenterally, such as intravenously, intramuscularly or subcutaneously, or transdermally. Such compositions contain norma

Usually about 0.1 to about 20.0 wt .-% of active ingredient. Typical excipients, diluents and carriers for parenteral formulations include, for example, isotonic saline, dilute aqueous dextrose or aliphatic polyhydric alcohols and mixtures thereof, such as, glycerol, propylene glycol or polyethylene glycol. Parenteral solutions also contain preservatives such as phenethyl alcohol, methylparaben, propylparaben or thimerosal. If necessary, one may also use about 0.05 to about 0.20% by weight of an antioxidant, such as sodium metabisulfite or sodium bisulfite. For intravenous administration, formulations are preferably used having an initial concentration of only about 0.05 and up to about Q, 25 mg of active ingredient per ml.

^{v is} preferably used for intramuscular injection with an active ingredient concentration of about 0.25 to about 0.50 mg per ml.

Typical suitable formulations are evident from the following examples.

Example 19

Formulation for an oral suspension 25

Ingredients Quantity

Sodium D-7- (2-naphthylglycylamido) -3-chloro-3-cephem-4-carboxylate 500 mg

Sorbitol solution (70% N.F.) 40 ml

30 sodium beratoate 150 mg

Saccharin, 10 mg

Cherry flavor 50 mg

Distilled water to - 100 ml

Add the sorbitol solution to 40 ml of distilled water and suspend the sodium glycylcephalosporin in it. Then, saccharin, sodium benzoate and flavor are added

: - 66 -

and solved. The volume is adjusted to 100 ml with distilled water. Each ml of this syrup contains 5 mg of the naphthylglycyl cephalosporin antibiotic. This oral formulation is especially suitable for pediatric use

, ' Application.

Example 20

Preparation of a 250 mg capsule .

Ingredients Quantity i

250 mg 150 mg 100 mg 500 mg

7- (6-chloronaphth-2-ylglycylamido) -3-methyl-3-cephem-4-carbonsMure

Lactose cornstarch

The ingredients are uniformly mixed together and enclosed in gelatin capsules. Such capsules las _sen to orally administered, for example, once or twice daily.

B e i s ρ i e 1 21

It

Preparation of a parenterally administrable solution

In a solution of 700 ml of propylene glycol and 200 ml of distilled water for injection is dissolved 20.0 g of D-7- (2-Naphthylglycylamido) ^ -methyl-S-cephem ^ -carbonsäurehydrochlorid. The pH of the solution is adjusted to 5.5 with hydrochloric acid and its volume brought to 1000 ml with distilled water. The formulation is sterilized, filled into 5.0 ml ampoules each containing 2.0 ml of formulation (corresponding to 40 mg of active ingredient content) and sealed under nitrogen.

Formula Sheet Formula (I)

- B-

X-6283M

4ΛΛ

R ⁴ '"> Ψ

QT \

R ¹

^ ^ y

Claims (17)

1 claims: 1. Process for the preparation of a compound of the formula (I) : O0R ⁶ where R is for AA- AA-- I · ^R7 -f-t I ^or 20 .'- VV _R a XA / 7 8 where R and R are independently hydrogen, halogen, Hydroxy, C 1 -C 4 -alkyl, C 1 -C -alkoxy, nitro, amino, C 1 -C 4 -alkanoylamino or C 1 -C -alkylsulfonylamino or R and R taken together form methylenedioxy, , A and B are each hydrogen or taken together to form a double bond, R is hydrogen, an amino protecting group, hydroxy or methoxy oxy is and 35 R is hydrogen or 2 3 R and R together for ML where M. and L are independently C ₁ -C -alkyl, 4 14 R is hydrogen, methoxy or methylthio, R is hydrogen, methoxy, methyl, halogen or methoxymethyl, ',. R is hydrogen or a carboxy-protecting group, with the proviso that R is hydroxy or methoxy only when A and B are complementary to a double bond, and that A and B are both hydrogen when R is other than hydrogen, and pharmaceutically acceptable salts thereof, characterized in that (A) is a compound of formula (II) 0OR ⁶ with an acylating agent of the formula (III) BR ² R ¹ - C - C - OH (III) I Il , A 0 or an activated derivative thereof, wherein A, B, R, R, R, R and R are as defined above, acylating and optionally eliminating any amino or carboxy protecting groups present, (B) a protected acid of formula (I) wherein R is H is a carboxy-protecting group deblocked to form a compound of formula (I) wherein R is hydrogen, 2
(C) an amino protecting group R of a compound of ι formula (I) and thus removes a compound of the formula (I) wherein R is hydrogen, (D) if one wishes to prepare a compound wherein R 5 and R together form a "group of formula ML V / \ 2 , a compound of formula (I) wherein R and R are each hydrogen, with a ketone of formula M-C (O) -L, wherein M and L are as defined above, or (E.) a compound of the formula (I) in which A and B are 2 men form a double bond and * R is hydroxy or methoxy, and thus reduces a compound of the formula 2
(I) wherein A, B and R are hydrogen, and (F) if desired, salting a compound of formula (I), or (G) if desired, converting a salt of a compound of formula (I) into the free amine or acid. ^l , 2. The method according to claim 1, characterized in that a compound of Fonrel 2 '3
(I) wherein R and R taken together are the group 30 ML or a pharmaceutically acceptable salt thereof.
35 3. Method according to claim 1, characterized in that a connection is made between the mel (I), in which A and B taken together form a double pectin and R is methoxy, or a pharmaceutically acceptable salt thereof. 4. The method according to any one of claims 1 to 3, d a by gekenn ζ e ichnet, that one obtains a compound of formula (I), wherein R is R ^a _y or a pharmaceutically acceptable salt thereof. , 5. The method according to any one of claims 1 to 3, characterized in that a A compound of formula (I) wherein R is for R ⁷ - or a pharmaceutically acceptable salt thereof. , 6. The method according to one of der.Ansprüche 1 to 3 ,. characterized in that a compound of formula (I) wherein R is R ⁷ - or a pharmaceutically acceptable salt thereof. , 7. The method according to any one of claims 4 to 6, d a - characterized in that a 7 8 A compound of the formula (I) in which R or R is independently hydrogen, halogen, hydroxy, C 1 -C 4 alkoxy, nitro or amino, or a pharmaceutically acceptable salt thereof. 8. The method according to claim 7, characterized in that one produces a compound of formula (I) wherein R or R is independently hydrogen, halogen, methoxy or hydroxy, or a pharmaceutically acceptable salt thereof. 9. The method according to claim 7 or 8, characterized in that j is a compound of 7 8
Formula (I) wherein R and R are each hydrogen or a pharmaceutically acceptable salt thereof. 10. The method according to any one of claims 1 to 9, d a by characterized in that one produces a compound of formula (I) wherein R is methyl, chlorine, hydrogen, methoxymethyl or methoxy, or a pharmaceutically acceptable salt thereof. 11. The method according to claim 10, characterized in that one produces a compound of formula (I) wherein R is methyl or chlorine, or a pharmaceutically acceptable salt thereof. 12. Ver'fahren according to any one of claims 1 to 11, d a by characterized in that one produces a compound of formula (D, wherein R is hydrogen, or a pharmaceutically acceptable salt thereof. 13. The method according to any one of claims 1 to 12, characterized in that a compound of formula (I) wherein R is hydrogen, or f ι a pharmaceutically acceptable salt thereof. 1.4. ; Process according to claim 1, characterized in that 7- / D- (2-naphthylglycylamido) - / - 3-methyl-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof is prepared. 15. The method according to claim 1, characterized g e - used to mark, that 7- / D- (2-Naphthylglycyl-, amido2 produces / -3-methyl-3-cepheIn-4-carbonsäuretetrahydrat. 16. The method according to claim 1, characterized in that one prepares 7- / D- (2-Naphthylglycyl- amidojy-B-methyl-B-cephem - ^ - carboxylic acid hydrochloride monohydrate. 17. The method according to claim 1, characterized in that one prepares 7- / D- (2-NaphthylglycylamidoJ _ / - 3-chloro, 3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof. A process according to claim 1, characterized in that 7- / D- (2-naphthylglycylamido) - / - 3-methoxy-3-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof is prepared. 19. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, characterized in that it has been prepared by a process according to any one of claims 1 to 18. For this 1 page formulas