DE2311346A1 - PENICILLIN AND METHOD FOR MANUFACTURING THEREOF - Google Patents

Description

Dr. Hans-Heinrich Willrath

Dr. Dieter Weber Dipl.-Phys. Klaus Seiffert

PATENT LAWYERS

D-62 WIESBADEN March 7, 1973 P.O. Box 1327 _ . ,

Cusuv-Frcytag-Stns / iS - 9 (06121) 372710 TclefMmaadramt WILLPATENT

LA 338-1

Astra Läkemedel Aktiebolag

Kvarnbergagatan 16, S-151 85 Södertälje, Sweden

Penicillins and processes for their manufacture

Priority : dated March 13, 1972 in

Great Britain,
Registration no. 11 687/72

The invention relates to new penicillins and methods for their Manufacture and pharmaceutical agents containing these penicillins. The invention also relates to new intermediates, which are useful in the manufacture of penicillins. In particular, the invention is Esters of penicillins of the general formula

R ¹

CH-

-CO-NH-CH-CH

i I

CO - N-

CH,

CH ₃

CH - COOR '

309843/119 4

and their therapeutically acceptable salts. In the formula mean

R is an alkyl or alkenyl group with 1 to 10 carbon atoms, aryl group such as phenyl and naphthyl, aryloxy group, aralkyl group, such as benzyl and naphthylmethyl or a heterocyclic group such as furyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, Oxazolyl ^, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, Tetrazolyl or sydnony! Group, where the alkyl, alkenyl, Aryl, aryloxy, aralkyl or heterocyclic groups are unsubstituted or with at least one substituent, such as an amino group, Alkyl group with 1 to 4 carbon atoms, alkoxy group with 1 to 4 carbon atoms, hydroxyl group, halogen, nitro group, Nitrile group, azido group, alkylthio group having 1 to 4 carbon atoms, carboxy group, carboxymethyl group, substituted or unsubstituted mononuclear aryl group or substituted or unsubstituted mononuclear heterocyclic group, can be substituted,

R ² CH ³ CH _c R ³

i I ^{2 5} t

I 4 · '4 ^Or ' 1 4

-CH - 0 - CO - R, -CE - 0 - CO - R -CH - X- COOR

-.- / orin X denotes an -NH group or oxygen, R denotes hydrogen, -CK ₃ or "CK ₅ , R denotes an alkyl group with 1 to 8 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms. Aryl, aralkyl or heterocyclic Group means, where the alkyl, cycloalkyl, aryl, aralkyl or heterocyclic group unsubstituted or with at least one azido group, amino group, substituted amino group, such as methylamino, diethylamino or acetamido group, Ha-

309 ^ 3/1194

logen, nitro or alkoxy group with 1 to 4 carbon atoms can be substituted,

X is hydrogen, azido, hydroxyl, carbalkoxy group with 1 to 4 carbon atoms, alkyl group with 1 to 4 carbon atoms, Alkoxy group having 1 to 4 carbon atoms or guanidino group means and η = 0 or 1,

with the proviso that X is a hydroxyl, carbalkoxy, alkyl, alkoxy or guanidino group when η = 1, R ² '-,

CH, R ³

I I

-Ch-O-CO-R ¹⁰ , -CH-O-COO-R ¹⁰ or -CH ₂ -NH-COO-R ¹ ? where R is an unsubstituted alkyl group and R is an alkyl, thienyl, Fury1, phenyl or hydroxyl substituted phenyl group.

Examples for the explanation of residues which are covered by the above definitions are:

Alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,

Kexyl, heptyl, octyl, 2-ethylhexyl Cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Cycloheptyl
Alkoxy: Hethoxy, ethoxy, propyloxy, isopropyloxy, butoxy, isobutoxy

Halogen: F, Cl, Br
Alkenyl: allyl, propenyl
Aryl: phenyl, naphthylmethyl
/ \ ralkyl: benzyl, naphthylmethyl
Alkylthio: methylthio, rthylthio, butylthio

309843/1194

heterocyclic groups:

The above examples of radicals illustrate, where applicable, all of the radicals mentioned above to the extent that is given for each radical is and within the limits of the number of carbon atoms that may be prescribed for each radical.

The compounds of the invention are useful in treatment of infectious diseases in humans or animals caused by bacterial organisms. You can be isolated and can be used as such, but they can also be used depending on the presence of basic or acidic groups in the molecule in the form of salts with pharmaceutically acceptable organic or inorganic acids or bases. Examples suitable acids are hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid and fumaric acid. Examples of suitable bases are Sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, ammonium hydroxide, non-toxic amines, such as TriaIky! Amine, including triethylamine, procaine, dibenzylamine, N-benzylö-phenethylamine, 1-ephsnamine, N, M -dibenzylethylenediamine, dehydroabietylamine, N, M -bis-dehydroabietylethylenediamine, N-lower-

3 0 9 ^ 3/1194

alky! piperidine, ζ. B. N-ethyl-piperidine and other bases that have been used to make salts with penicillins.

The side chain of the penicillin structure in formula I can contain an asymmetric center. Depending on the configuration At this center the compound will appear in two different diastereoisomeric forms, both of which are biologically active. The ester groups can also contain asymmetric atoms, which give rise to various diastereoisomeric forms of AnIaS, which are also all biologically active. It should be emphasized that the invention covers the pure diastereoisomers as well their mixtures.

It is known that penicillins of the general formula

CH X

CO-NH-CH-CH
CO - Ν—

.CH, • CH,

CH - COOH

or their salts, in which n, R and X have the above meanings, have good antibacterial activity against gram-positive and gram-negative bacteria, and various such compounds have found extensive clinical use.

In combating infectious diseases, it is desirable to have antibacterial agents which, with good oral intake, permit the infection to be treated easily, conveniently and safely. Penicillins of Formula II are generally not completely absorbed from the gastrointestinal tract, and many are

309843/1 194

these compounds are even very poorly absorbed, so that they v.-egen represent instability against gastric juice and related Properties need to be injected. It is an object of the invention to provide penicillin esters according to formula I, which absorbs well orally and then within the body delivering blood and organ levels of the compounds of the general formula II are hydrolyzed so that they are appropriate for the treatment of infectious diseases, caused by bacteria that act against the penicillins of the general formula II are sensitive. To achieve the full antibacterial activity of the penicillins it is necessary to to choose those ester groups that rapidly fall under in vivo Release of penicillins to be hydrolyzed. It is an essential feature of the invention to provide such ester groups, which are rapidly hydrolyzed in the body after oral administration.

Such compounds according to formula I are well tolerated, they give a low frequency of side effects and can be used comfortably pharmaceutical agents are used either as such or in the form of their ■ salts, they can also be used with solid carrier yarn and / or mix auxiliaries. In such preparations, the relationship between the therapeutic substance and the carrier and aids vary between 1 and 95%. The preparation can either be processed into tablets, pills or coated tablets, for example or filled into medicament containers such as capsules. As far as it is a question of mixtures, you can also use Bottles are filled.

309843/1194

It can be pharmaceutically acceptable organic or inorganic solid or liquid carriers suitable for oral or enteral administration or for topical application can be used are. Gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, vegetable gum and polyalkylene glycol as well as other known carriers for medicaments are all suitable for the manufacture of preparations of these compounds. In addition, the preparation can contain other pharmaceutically active ingredients which are combined with the compounds can be administered according to the invention in a suitable manner when treating infectious diseases such. B. other suitable Antibiotics, such as gentamicin and polymyxin.

Be used in the treatment of bacterial infections in humans the compounds according to the invention in amounts corresponding 5 to 200 mg / kg / day, preferably in the range of 10 to 100 mg / kg / day in divided doses, e.g. B. 2, 3 or 4 times a day, given. They are administered in dosage units which, for. E. 175, 350, 500 or 1000 mg of the compounds.

Preferred classes of compounds according to the invention are such according to formula I, wherein at the same time η = 1, R from γ -methylbutyl, 5-methylpentyl, n-hexyl, phenyl, 2- or 3-thienyl, 2- or 3-furyl, oxazolyl, thiazolyl, 2-phenyl-thiazolyl-2, 3-pyridyl, m-fluorophenyl, p-hydroxypheny1, p-aminophenyl, phenoxy, n-Keptyl, 1-butenyl, X from hydroxyl, carbalkoxy or

2
Guanidino and d from Niederalkoxycarbonyloxymethyl, 1'-Niederalko>: ycarbor.ylo>: y-ethyl, 1 '-Loweralkoxycarbonyloxypropyl, Nie-

309843/1194

deralkoxycarbonylaminomethyl, 1 '-Loweralkoxycarbonylarrdno-ethyl, 1 '-iiiederalkoxycarbonylaitiino-propy 1, 1 * -Niederacyloxy-äthy1, I'-iiiederacyloxypropyl, phenoxycarbonyloxymethyl, 5-indanyloxycarbonyloxymethy1, 1'-phenoxycarbonyloxy-ethyl, 1 '- (5-indanyloxy) -carbonyloxy ethyl, 1'-benzoyloxy-ethyl, 1'-benzoyloxy-propyl exist.

Who.n is also η = 1, R is chosen from

Ύ-Iiethyibutyl, 5-methyl-pentyl, n-hexyl, phenyl, 2- or 3-thienyl, 2- or 3-furyl, oxazolyl, thiazolyl / 2-phenyl-thiazolyl- 2, 3-pyridyl, m-fluorophenyl, p-hydroxyphenyl, p-aminophenyl, phenoxy, n-heptyl, 1-butenyl, X under hydrogen, azido, hydroxyl,

2
Carbalkoxy and guanidino, R under Miederalkoxycarbonyloxymethyl, 1'-lower alkoxycarbonyloxy-ethyl, 1'-Niederalkoxycarbonyloxypropyl, Niederalkoxycarbonylaminomethyl, 1'-lower alkoxycarbonylamino-ethyl, 1'-lower alkoxycarbonylamino-propyl, 1'-Niederacyloxypropyl, 1'-Niederacyloxyäthyl, Phenoxycarbonyloxymethyl, 5 -Indanyloxycarbonyloxy, 1'-phenoxycarbonyloxy-ethyl, 1 '- (5-indanyloxy) -carbonyloxy-ethyl, 1'-benzoyloxy-ethyl, 1-benzoyloxypropyl, whereby the acyloxy-, alkoxycarbonyyloxy-, acyloycarbonxycarbony-, acyloxy-, alkyloxy-, alkyloxy-, alkyloxy-, alkyloxy-, alkyloxy- or acyloxycarbonyl

amino group in R with amino, lower alkylamino or di-lower alkylamino groups are substituted.

Further classes of preferred compounds are obtained if, if

1 2

at the same time η = O, R from n-butyl, / S ^ -pentenyl, alkylthiomethyl, phenyl, 2,6-dimethoxyphenyl, 2-methoxy-6-chlorophenyl, 2-biphenyl, 2-ethoxynaphthyl, 3- (2-chlorophenyl ) -5-methylisoxazotyl-4, 3- {2,6-dichlorophenyl) -5-methylisoxazolyl-4, 3- (2-chloro-6-

309843/1194

2 fluorophenyl) -5-methylisoxazolyl-4 and R from lower alkoxycarbonyl:

oxymethyl, 1'-lower alkoxycarbonyloxy-ethy1, 1'-lower alkoxycarbonyloxy-propyl, Lower alkoxycarbonylaminomethyl, l'-lower alkoxycarbonylamino-ethyl, 1'-lower alkoxycarbonylamino-propyl, 1'-lower acyloxy-ethy1, 1'-lower acyloxy-propyl, phenoxycarbonyI ^ oxymethyl, 5-indanyloxycarbonyloxymethyl, 1'-phenoxycarbonyloxyethy 1, 1 '- (5-indanyloxy) -carbonyloxy-ethy1, 1'-benzoyloxy-ethy1, l'-Benzoyloxy-propyl, with the acyloxy, alkoxycarbonyloxy, Acyloxycarbonyloxy, alkyloxycarbonylamino, alkyloxycarbo

nyloxy or acyloxycarbonylamino groups in R with amino, lower alkylamino or di-lower alkylamino groups can.

Examples of preferred compounds according to the invention are compiled in the table below.

Table 1 Preferred compounds according to the invention

R ¹

CH-

I I

CO-NH-CxH - CH

n.

CO - N

, CH, CH,

CH - COOR

(CH ₃ ) ₂ CH-CH ₂ -CH ₂ -

H ₅ ) ₂ -CH- (CH ₂ ^

0 0 0

Ch ₂ OCOOCH ₂ CH ₂ NH ₂

CH ₂ OCOOCH ₂ CH ₂ -NH-Ch ₅

-CH ₉ -COOCH ₉ CH ₉ N-

30984

194

X η R,

231 1 3 A 6

CH ^ -CH ₂ -CK = CH-CH ₂ -KOOC-CH- (CH ₂ ) ₅ -

-CH ₂ OCOOC ₆ H ₅

-CH ₂ OCOOC ₂ H ₅

^C 6 ^H 5 "

2,6- (Ii-OCH ₃ -C ₆ H ₃ -2,6- (U-OCH ₃ -C ₆ H ₅ -2,6- (U-OCH ₃ -C ₆ H ₅ -

2,6-CU-OCH ₃ -C ₆ H ₃ -

-CHpOCOOC ₂ H ₅

-CH ₂ OCOOC ₂ H ₅

CH-OCOOC ₂ H ₅

-CH ₂ -OCOOCH ₂ CH ₂ Nh ₂ -

CH-OCOCH ₂ -MH ₂

2-Xthoxy-naphty1-2-ethoxy-r.aphty 1-2-ethoxy-naphthyl- 2-ethoxy-naphthyl-

2-biphenyl

2-biphenyi-

2-biphenyl-2-biphenyl-

> - (2-C iilor -phenyl) - ^ - methyl - ^ - isoxazolyl-

-CHpOCOOCH,

CH ₂ -OCOOC ₂ H ₅

CH ₂ -OCOOC ₄ H ₉

-CH ₂ -O-COOCH ₂ CH ₂ Nh ₂

CH ₂ -OCOOC ₂ H ₅

-CH ₂ NH-COOC ₂ H ₅

-CH-OCOCH ₂ -NH ₂

j -CH-OCOOC ₀ Hr

-CH ₂ OCOOC ₂ H ₅

309843/1 194

Il _

3- (2,6-dichloro ₇ phenyl) - "

-5-n: ethyl-4-isoxazolyl- 0 -CH ₂ UCUuL ₂ H ₅

_r μ ru 0 -Ch ₀ OCOOCH ₀ CH ₀ NH ₀

^C 6 ^ri 5 2 ² 2 2 2

0 '-CH ₂ OCOOCH ₂ Ch ₂ NH-CH ₅

0 -CH ₂ OCpOCH ₂ CH ₂ -N (C ₂ H ₅ ) J 0 -CH ₂ OCOOC ₆ H ₅ ,

"_ '0 -CH ₂ OCOO

. 0. -CH ₂ OCOOCH ₂ O • I 3
-CH-OCOCH ₂ NH ₂ 0 f3 ■ ■. T -
·. -CH-OCOOCh ₂ CH ₂ NH ₂ CH ₅
-CHOCOCh ₂ CH ₂ MH ₂ 0 CH ₅
-CH-OCOoY
CH, - CH ₃
-CH-OCOCH-C ^ H ^
1 6 ϊ
TiTt-T 0 INrIp
C ₂ H ₅ 0 -CH-OCOCH ₂ IiH, 0 0
309843/119 A

ο ·

-CH ₂ -OCOOC ₂ H, CH ₃ -

-CH-OCOOCoH ₁ -CH _x

I ³

-CH-OOOCR-

-CH ₂ OCOOCH ₂ Ch ₂ NH ₂

Kl

tr_

0 -CH ₂ OCOOC ₂ H ₅

Il _

N-N

^C 6 ^H 5

M-

H 1 -CH ₂ OCOOC ₂ H ₅ H 1 -CH ₂ OCOOCH ₂ Ch ₂ NH H -, 1 fs:
-CH-O-COCH ₂ NH ₂ - - 1 CH ₅
- -Ch-OCOCH ₂ CH ₂ NH ₂ H 1 -CH ₂ OCOOC ₂ H ₅ H 1 -CH-OCOCH ₂ NH ₂ H 1 -CH ₂ OCOOC ₂ H ₅ CH ₃ - H 1 -CH-OCOOC ₂ H ₅

309843/1 194

rr_

it

1
1 1 23113 46 H
H 1 1 -CH ₂ -OCOOCH ₂ CH ₂ Nh ₂
CH,
I ³
-CH-OCOCH ₅ H 1
1 -CH ₂ -OCOOC ₂ H ₅ H
H 1 -CH ₂ OCOOCH ₂ Ch ₂ NH ₂
f 3
-CH-OCOOC ₂ H ₅ H -CH ₂ OCOOC ₆ H ₁₅ CH, \
-CH-O-COCH ₅ fs
-CH-OCOCH ₀ NH ₀

H_

-CH ₂ OCOOC ₆ H ₁₂

-CH ₂ OCOOCH ₂ CH ₂ N;

.C ₂ H ₅

N ₅ 1 -CH ₂ OCOO- ^ V

\\ - 0CH,

0 9 3 A 3/1 1 9 4

-CHo-NH-COO - // V ^ -

-S ⁿ 5 "

■ 2.

ψ
-CH-O-COOC ₆ H ₅

N,

ι 3

-CH-O-COC ₆ H ₅

CK- o ρ

N,

CH ₃ -CH-OCO -J / Vy- OCH

-CH ₂ -KH-COOC ₆ H ₅

-CH ₂ OCOOCH ₂ -I ^

- ^C 2 ^H 5 X ₂ H ₅

It _

-CH ₂ -OCOOC ₆ H ₅

-CH ₀ OCOO

-OCH-

-CH ₂ OCOO-

CH

3.

-CH-OCOC ₆ H ₅

CH ₂ -OCOOCH ₂ Ch ₂ NH ₂

CH ₅

CH-O-COCH ₂ -NH ₂

309843/1194

NH

^ S ^ N, 1 -CH ₀ OCOOCH ₉ CH ₉ N ^

CH (CH ₅ ) ₂ CH-CH ₂ - N ₅ 1 -CH ₂ OCOOCH ₂ CH ₂ N ^ ²

OH · 1 -CH ₂ -OCOOC ₂ H ₅

OH 'I' -CH ₂ OCOOCH ₂ CH ₂ Nh ₂

• OH 1 -CH ₂ OCOOCh ₂ CH ₂ -NHCH ₅

"- OH 1 -CH ₂ -OCOOC ₆ H ₅

■> _. OH 1 -CH ₂ -OCOO

OH 1 -CH ₂ -OCOOC ₅ H ₁₁

- CH ₅ OH 1 -CH-OCOOC ₂ H ₅

OH 1 -CH-OCOOC ₅ H ₇

OH 1 -CH ₂ -NH-COOC ₂ H ₅

OH · 1 -CH ₂ NH-COOC ₆ H ₅

CH,

t ³

OH 1 -CH-O-COCH ₀ NH ₀

A 3/1194 ' ^{ά z}

C, -K- 6 D OH

CH-

OH 1 -CH-O-COCH ₂ NH ₂

Cl

OH

-CH ₂ OCOOC ₂ H,

OCOCH ₃ 1 -CH ₂ OCOOC ₂ H ₅

ιι_

-CH ₂ OCOOCH ₂ Ch ₂ NH ₂

CHj

-CH-OCOCH ₂ -NH ₂

OCH-

-CH ₂ OCOOC ₂ H ₅

Il _ OCH,

-CH ₂ OCOOCh ₂ CH ₂ MH ₂

CH,

still,

-CH-OCOOC ₂ H ₅

Il _ OCH, 1

-CH ₂ -OCOOC ₆ H ₅

Il _ OCH,

CH,

-CH-OCOCHpNH ₉

HN-C = NH 1
NH ₂

0 * 9 843/1194

-CH ₂ OCOOC ₂ H ₅

Il _ n_

1 -CH ₂ OCOOC ₆ H ₁₃

1 -CH ₂ -OCOOC ₆ H ₅

I '

-CH ₂ -OCOOCH ₂ CH ₂ Nh ₂

CH ₃ -CH-OCOOC ₂ H ₅

II- CH-OCOOC ₅ H ₇

Il _

1 -CH ₂ -NH-COOC ₂ H ₅

Il _ ! I -

Il _

Il _: . 1 1 -CH ₂ NH-COOC ₆ H ₅ HN-C = NH
I. 1 CH ₃
-CH-O-COCH ₃ NH ₂
I - 1 <f2 ^H 5
-CH-OCOCH ₅ Il - CH _x
-CH-COCH ₂ NH ₂

C ₆ H ₅ O

. 1 '-CH ₂ -OCOOC ₂ H ₅

It _

1 . -CH ₂ OCOOCH ₂ Ch ₂ NH ₂

CH,

• H 1 -CH-OCOCH ₂ -NH ₂

309843/1

-CH-OCOCH-CH ₀ r Thu

NH «. .

The compounds according to the invention can be prepared by various methods:

Method a

R ¹ ^ -I-CH-

I I

J III

CO - Z + H ₂ N - CH - CH

CO - N-

XH,

CH,

CH - COOR

2.

IV

R ¹ ^ -t CHr-r CO - NH - CH - CH

in

CO

.CH,

CH - COOR '

R ¹ -

- CO - NH - CH - CH

CO - K

^CH 3
CH- COQR ²

According to this method, an activated carboxylic acid derivative III,

1 '1 1

where R corresponds to the above definition of R or, if R contains an amino, carboxy or hydroxyl group, is a protected derivative of R and X "either corresponds to the above definition of X or, if X is an amino or hydroxyl group

309843/1194

contains, a protected derivative of X and -CO-Z means a reactive group capable of reacting with a Amino group with formation of an amide residue, e.g. B. an acid chloride or its functional equivalent, with a

Esters of 6-aminopenicillanic acid (IV) wherein R is defined above is brought to implementation with the formation of a penicillan ester V.

I ¹ I

If R = R and X ¹ = X, then the product is a compound

ι ·
manure according to the invention. If R or X ^{1 contains} amino, carboxy or hydroxyl groups which are protected, the protective group is removed in a manner known per se in at least one additional stage in order to obtain the compounds of the general formula I. Protective groups for the amino and hydroxyl groups that can be used are those which can be removed without destroying the penicillin ring system. Such known protecting groups are, for. B. the benzyloxy · carbonyl, o-nitrophenylsulfenyl, 2-p-tolylsulfonyl-ethoxycarbonyl, ß-chloroethoxycarbonyl and the 1-methoxycarbonylpropan-2-yl group as a protective group for the amino group, z. B. the benzyl group as a protective group for the hydroxyl group and the benzyl, ß-trichloroethyl, 2,6-dichlorobenzyl and the 2-p-tolylsulfonylethyl group as a protective group for the carboxy group. .

The implementation between the compounds of formulas III and IV represents an acylation of an ester of 6-aminopenicillanic acid and can be used for the acylation of other esters of 6-aminopenicillanic acid VJeise described (e.g. according to French patent specification 1 576 027) carried out. The acylation

309843 / 119A

group -CO-S in the compound III can be an acid chloride group or a group acting in the same way, e.g. B. an acid bureau, an acid azide, an anhydride, a mixed anhydride, formed with an inorganic acid or an organic acid, especially with alkoxy formic acid.

The compound III can also be a derivative which may be produced by reaction between a compound of the formula

R ¹

I Γ "/ - · ΤΤ i

CH-i COOH

wherein π R and X ^{1 have} the meanings given above, and a carbodiimide or other compounds which act in the same way as N, N -carbonyldiimidazole, N-ethyl-5-phenylisoxazoliuia-3 * -sulfonate or N-tert-butyl -5-methylisoxalolium perchlorate is obtained.

The reaction can be carried out in organic solvents such as diethyl ether, Tetrahydrofuran, acetone, ethyl acetate, chloroform, methylene chloride, Dimethylformamide, dimethyl sulfoxide or hexamethylphosphorainide, in water or in aqueous organic solvents in the presence of organic or inorganic bases, such as triethylamine, Quinoline, pyridine, N-methylmorpholine, sodium hydroxide, Sodium bicarbonate or potassium carbonate.

The compound according to the general formula V can be obtained by extraction from the reaction mixture, optionally after dilution with water

309843/1194

Ground water and neutralization in isolation.

The esters of 6-aminopenicillanic acid with the general structure IV can be prepared by treating salts of 6-aminopenicillanic acid

2 1 2

acid with compounds R -Y, in which R has the same meaning as above, and Y is selected from halogen or a functionally equivalent Group which is capable of reacting with a carboxy group to form an ester linkage, such as a organic sulfonic acid residue. The reaction is preferably carried out in organic solvents such as dimethylformamide, Dimethyl sulfoxide or hexamethyl phosphoramide carried out.

Instead: you can also use salts of 6-acylaminopenicillanic acid with acyl groups that do not destroy the penicillin ring system.

2 1

can be removed, treated with R -Y to form esters from which the acyl groups are then removed to give the esters of 6-aminopenicillanic acid of formula IV. A preferred method is to use a salt such as a sodium, potassium or tetraalkylammonium salt of benzylpenicillin with R -Y in an organic solvent such as acetone, Dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, diethylethy ketone, chloroform, methylene chloride or a mixture an organic solvent and water, e.g. B. aqueous acetone or dioxane with the formation of the corresponding Reacts benzyl penicillin ester. The phenylacetyl side chain is then carried out according to the method described in the Dutch patent publication 6 401 421 or South African Patent Publication 67/2927 by treatment with phosphorus pentachloride in the presence

309843/1194

a tertiary organic base reacted under supply of imino chloride which is the influence of alcohol with an alcohol is reacted to form the corresponding iminoether, such as propanol, which is hydrolyzed by addition of water or by the addition of alcohol, in order to obtain the ester III. Instead , the phenylacetyl side chain can also be removed by enzymatic hydrolysis using E. Coli acylase according to the method described in French patent 1,576,027.

Another method is to use nitrogen protection

2 1

6-aminopenicillanic acids reacted with R -Y to form the corresponding ester, from which the protective group! are removed in order to obtain the compounds of the general formula IV. Examples of protective groups that can be used are the benzyloxycarbonyl groups, which are removed by catalytic hydrogenation, the o-nitrophenylsulfeny! Group, which can be removed by treatment with nucleophilic agents at acidic pH according to Japanese patent 505 176, and the trityl group which can be removed by mild acidic hydrolysis.

Method B.

A natural penicillin of the formula

R-CONH-CH-CH C ^

- N CH - COOM

309843/1194

-.orin RCO the acyl group in the side chain of natural gasoline and M denotes hydrogen or an alkali atom such as sodium, potassium or calcium, is by reaction with a compound of the formula VII

2 1

esterified. Here, R and Y have the meanings given above. Thereupon the ester of the formula thus formed is

R-COKH-CH - CH

co

-CH - COOR '

with a phosphorus halide in an inert solvent and expediently in the presence of a tertiary amine to form an iminohalide compound implemented, which is implemented with a lower alcohol to deliver an imino ether derivative, which then with a compound of the formula

1 "Γ

CH

^c0 - ^Z

in

1 ι
is implemented. Here, R, X 'and Z have the above meanings.

The reaction product yields on treatment with water or a Alcohol is a compound of the formula

3090 A3 / 1

Li-J

CO - IiH - CH - CH

I I

CO - N-

CH

CH

CH - COOR '

This compound is then converted into a compound of the formula I.
converted according to the information described under A. In this method, the intermediate imino ether compound is acylated directly without isolation of any intermediate products.

The group RCO- in the compound of the formula VI is one known in the art organic acyl group containing natural penicillins. For example, the group R can be an alkyl, cycloalkyl, aryl, aralkyl or heterocyclic group or a derivative thereof. Examples suitable groups R are heptyl, phenoxymethyl, 2-thienylmethyl, 2-furylmethyl and benzyl. Examples of suitable phosphorus halides are phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, Phosphorus trichloride, etc. Phosphorus pentachloride is preferred. Examples of suitable alcohols with which the iminohalide are lower alkyl alcohols such as methanol, ethanol and n-propanolr

Method c

R ¹ -fCH- CO - NH - CH - CH *

! I.

CO ~ N-

Li-J

R ¹ --f CH ⁷ } - CO

Li-.L,

CO - K -

309843/1

+ R ² Y ¹

CH - COOH

^ - "- ^CH 3 ^ CH ₃

CII - COOR ²

R ¹ ~ r- CH] —CO - NH -

T J J.

CK
CO

- CH

CH,

CH-

CH - COOR '

Penicillins of the formula IX, in which R and X ¹ and η have the above meanings, are prepared by acylating 6-aminopenicillanic acid by known methods. Treatment of the penicillins of formula IX with a compound of formula

where R has the above meaning and Y is halogen, preferably Is chlorine, bromine or iodine, or means an organic sulfonic acid residue, provides the compounds of the formula V, which after

ungen the information in method A in connection / according to the invention (I) urr. to be changed.

The reaction is preferably carried out with a salt, e.g. a sodium, Potassium, calcium, tetraalkylammonium or a trial ky I ammonium al ζ of the compound IX in an organic solvent, such as acetone, tetrahydrofuran, chloroform, methylene chloride, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoraramide bzv /. in a mixture of water and an organic solvent, e.g. aqueous dioxane or acetone.

V.'ie described above, the starting material can be in the form a salt, e.g. a sodium, potassium, calcium or trialkylaruT'.oniun salt in any of the methods of manufacture

0 -

3/1194

-2P-

of the compounds according to the invention are present. Also can 'j.-_ craalk.ylammonium salts and other analogous salts, e.g. B. Salza can be used, in which the cation has the formula

-1.2. 3-4 .. ®

AAAAN

has, in which A consists of a straight or branched alkyl group with 3 to 6 carbon atoms, substituted or unsubstituted

te.fi aryl, substituted or unsubstituted aralkyl

2 3 4
and in which A, A and A - identical or different -

from straight or branched alkyl groups with 1 to 6 carbon

There are 2 3 material atoms, provided that A, A and A

Are alkyls with 3 to 6 carbon atoms when A consists of alkyl »

12 3 4 Examples of suitable combinations of A, A, A and A in the quaternary Ammonium ion AAAAN ^ are the following:

Table 2

A ¹ A ² A ³ A ⁴

n-propyl n-propyl n-propyl n-propyl

i-propyl i-propyl i-propyl i-propyl

η-butyl n-butyl η-butyl n-butyl

i-eutyl i-butyl i-butyl i-butyl

n-pentyl n-pentyl n-pentyl n-pentyl

n-hexyl n-hexyl n-hexyl n-hexyl

Phenyl methyl methyl ethyl

Phenyl ethyl ethyl ethyl

p-tolyl ethyl ethyl ethyl

p-chlorophenyl ethyl ethyl ethyl

30 ° O / 1194

vif the radicals A to A are all different, contains the resulting Ion has an asymmetric center and can be divided into two enantiomers Forms occur. Epine forms can occur when A, A, A and / or A have at least one asymmetric carbon atom contain.

Examples of quaternary ammonium ions with an asymmetric center can be found in the following table:

Table 3

Benzyl

Benzyl

Eanzyl

n-propyl

n-propyl

n-? ropyl

n-propyl

n-propyl

The above-mentioned use of a quaternary salt form of the starting material for the preparation of the compounds according to the invention has not previously been described in the relevant literature in this field. With this method is the preferred cation is the tetraalkylammonium, in particular that Tetrabutylammonium ion. The preferred solvents are chloroform, i'-ethylene chloride and acetone.

The quaternary ^ ammonium salt form of the above-described

3 0 "- / 1194

A ² A ³ A ⁴ n-propyl i-propyl n-butyl n-propyl i-propyl sec-butyl n-propyl η-butyl. sec-butyl n-propyl n-butyl sec-butyl n-propyl n-propyl sec-butyl n-propyl n-propyl sec-pentyl n-propyl n-propyl sec-hexyl n-propyl n-butyl sec-hexyl

Gang material can be produced by manipulating the relevant Made from .jangsir.eterial with a quaternary Airjttoniurisalz of the formula

12 3 4

wherein A , A, A and A have the meanings given above and B is a suitable anion, such as HSO ₄ ^ Cl ^ or CH-COO, to form a quaternary salt of the starting material.

The salts of the above formula with B as the anion can be used in __ can be produced in a known manner according to the information found, for example, in Belgian patent specification 751 791. The anion B ^ is KSO. ^ in the preferred embodiment.

The following examples serve to further illustrate the invention.

example 1 p-nitro-benzyloxycarbonyloxymethylbenzyl penicillinate

A stirred cold suspension of 7.45 g (0.02 mole) potassium benzylpencillanate in 10 ml of dimethyl sulfoxide is mixed with a solution of 4.9 g (0.02 mol) of p-nitrobenzyl ehlomethyl carbonate in 8 ml Dinethyl sulfoxide added in the course of 30 minutes. After 23 Hours of stirring at room temperature, the mixture is poured into 60 ml of saturated sodium bicarbonate solution and with 40 + 5 + 5 ml Ethyl acetate extracted.

The combined organic extracts were washed with dilute sodium bicarbonate, Kasssr and Saizsole washed, dried and evaporated in vacuo at 3O C to 9.0 g of a reddish heavy oil. The product was purified by column chromatography to give 5.5 g of pale yellow solid. It showed strong IR absorption at 1785 to 1750 cm (ß-lactam and ester). The product showed a purity of 92.0% iodometrically and was in Rapidly hydrolyzed in the presence of human serum.

NMR (nuclear magnetic resonance spectrum) (CDSl ₃ , tetramethylsilane as internal standard) = 1.45 (s), 3.63 (s), 445 (s), 5.35 <s), 5.50 to 5.80 (m ), 5.85 (s), 6.30 to 6.50 (d), 7.35 (s>, 7.50 to 8.40 (m) ppm.

Example 2

p-Nitro-benzyloxycarbonyloxymethyl-o ^ -hydroxybenzyl penicillinate

A stirred, cooled suspension of 3.7 g (0.01 mol) of sodium

oC-hydroxybenzyl penicillinate in 10 ml of dimethyl sulfoxide was with a solution of 2.5 g (0.01 mol) of p-nitrobenzyl chloromethyl carbonate added in 10 ml of dimethyl sulfoxide in the course of 30 minutes. After stirring at room temperature for 20 hours, the Pour mixture into 60 ml of saturated sodium bicarbonate solution and extract with 40 + 5 + 5 ml of ethyl acetate. The united organic Extracts were washed with dilute sodium bicarbonate solution, water and brine, dried and in vacuo 30 ° evaporated to 4.3 g of a reddish oil. The product was Purified by column chromatography and gave the title compound

309843/1194

dung than 1.6 cj schvuchgslben Feststof J. Oas product showed strong IR-Ab ^r; orption at 1735-1750 cm (g-lactam and ester).

Jas's product showed a purity of 96.3% iodometrically and was rapidly hydrolyzed in the presence of human serum.

NMR; (CDCl ₃ , tetramethylsilane as internal standard) = 1.45 (s), 1.60 (s), 4.45 (s), 5.08 (s), 5.35 (s), 5.50 to 5 , 80 (m), 5.90 (s), 7.43 (s), 7.50 to 8.40 (m) ppm ..

Example 3 Ethoxycarbonyloxymethyl phenoxymethyl penicillinate

A stirred, cooled suspension of 11.6 g (0.03 mole) potassium phenoxymethyl penicillinate in 12 ml of dimethyl sulfoxide was with 4.6 g (0.03 mol) of ethyl chloromethyl carbonate in the course of 30 minutes offset. To. Stirring at room temperature for 16 hours, the mixture was poured into 50 ml of saturated sodium bicarbonate solution and extracted three times with 50 ml of ethyl acetate. The combined organic extracts were washed with dilute sodium bicarbonate solution, Water and salt soÜa washed, dried and in the vacuum evaporated at 30 C, washed repeatedly with petroleum ether, dissolved in ethyl acetate and evaporated again at 30 ° C. The title compound was obtained as 4.4 g of a brownish oil. That Product showed strong IR absorption at 1785 to 1750 cm (β-lactam and ester).

The product was rapidly hy-

309.3 / 1194

.irolyzed-

NMR (CDCl ₃ , tetramethylsilane as internal standard) = 1.15 to 1.45 (t), 1.55 (s), 1.60 (s), 4.110 to 4.45 (q), 4.50 6s ), 4.55 (s), 5.5O to 5.80 (m), 5.85 (s), 6.8O to 7.50 (m) ppm.

Oral administration of the compound to mice resulted in peak blood concentration levels of 17.3 Aig / ml phenoxymethylpenicillin after 60 minutes versus a peak blood concentration level of 15.9 Aig / ml 30 minutes after administration of equimolar amounts of potassium phenoxymethylpenicillinate.

Example 4

; Ai: hoxycarbonyloxymethyl-2,6-dimethoxyphenyl penicillinate

A stirred, cooled suspension of 12.1 g (0.03 mol) of sodium 2,6-dimethoxyphenyl penicillinate in 12 ml of dimethyl sulfoxide, de in the course of 30 minutes with 4.6 g (0.03 mol) of ethyl chloromethyl carbonate offset. After stirring for 16 hours at room temperature, the mixture was dissolved in 50 ml of saturated sodium bicarbonate solution poured and extracted three times with 50 ml of ethyl acetate. The combined organic extracts were washed with dilute sodium carbonate solution, Washed water and brine, dried and evaporated at 30 ° C in vacuo; the title product was obtained as 12.8 g of pale yellow oil that when treated with isopropyl alcohol crystallized. F 97.0 to 98.0 ° C. The product showed strong IR absorption at 1785 to 1750 cm "(β-lactam and lster). Ls hydrolyzed rapidly in opposition to human

309 643/1194

NMR (CDCl ₃ , tetramethylsilane as internal standard) = 1.20 to 1.45 (t), 1.55 (s), 1.65 (s), 3.85 (s), 4, IO to 4.45 (g), 4.5O (s), 6.6O to 6.15 (m), 6.50 to 6.75 (m), 7.20 to 7.50 (m) ppm.

Oral administration of the product to mice led to blood concentration peaks of 5.6 aig / inl of 2,6-dimethoxyphenylpenicillin after 60 minutes, compared to a peak blood concentration of 2.6 / µg / ml 60 minutes after oral administration, more equimolar Amounts of sodium 2,6-diinethoxyphenyl penicillinate.

Example 5

Ethoxycarbonyloxymethyl-S-methyl-S- (2-chlorophenyl) -4-isoxazolyl penicillinate

A stirred, cooled suspension of 13.7 g (0.03 moles) of sodium 5-ynethyl 1-3- (2-chlorophenyl) -4-isoxazolyl penicillinate in 20 ml Dimethyl sulfoxide was added with 4.6 g (0.03 mole) of methyl chloromethyl carbonate added in the course of 30 minutes. After stirring at room temperature for 16 hours, the mixture in 50 ml became saturated Liatriombicarbbnatlösung poured and three times with 50 ml of ethyl acetate extracted. The combined organic extracts were washed with dilute Liatrium bicarbonate solution, water and brine, dried and evaporated at 30 ° C in vacuo; an oil was obtained which was washed repeatedly with petroleum ether in ethyl acetate dissolved and evaporated again in vacuo at 30

3 0 9- ^ 7/1194

wurdo; the title compound was obtained as 11.5 g of brown oil. The product showed strong IR absorption at 1790 to 1750 cm (ß-lactam and ester). It quickly became in the presence of human Hydrolyzed serum.

NMR (CDCl ₃ , tetramethylsilane as internal standard) = 1.20 to 1.50 (t), 1.45 (s), 1.50 (s), 2.80 (s), 4.10 to 4.45 ( q), 4.40 (s), 5.40 to 6.00 (m), 7.55 (m) ppm. ,

Example 6 Athoxycarbonyloxymethyl-S-pyridylpenicillinate hydrochloride

A stirred, cooled suspension of 3.35 g (0.01 mol) 6- (3-pyridylacetamido) penicillanic acid in 5 ml of dimethyl sulfoxide was added dropwise with 1.4 g (0.01 mol) of ethyl chloromethyl carbonate offset. After stirring for 16 hours at room temperature, the mixture was poured into 25 ml of saturated sodium bicarbonate solution and extracted three times with 25 ml of ethyl acetate. The combined organic extracts were washed three times with 25 ml of sodium bicarbonate solution and washed 25 ml of water. The organic solution was then washed twice with 25 ml of water, that with dilute hydrochloric acid acidified to pH 3.0. The combined water extracts were washed with isopropyl ether and freeze-dried in order to To give 1.0 g of the title compound. The product showed strong IR-7 absorption at 1780 to 1750 cm (β-lactam and ester). Ls vmrdü rapidly hydrolyzed in the presence of human serum.

3 0; ■ Λ 3/1 1 9

23113Λ6

• - ■ thox y carbo ^ yloxy ^ thyl-S-oyriavlpenir-illinate hydrochloride

In the same manner as in Example 6, this compound was prepared from 3.35 g (0.01 mol) of 6- (3-pyridylacetamido) -penicillanic acid

and 1.5 g (0.01 mol) of ethyl S-chloroethyl carbonate in 5 ml of dimethyl sulfoxide synthesized. 0.1 g of freeze-dried product showed strong IR absorption at 1780 to 1750 cm (β-lactam and ester). It was made in the presence of human serum rapidly hydrolyzed.

Example 8 Phenoxy carbonyloxyethyl 3-pyridyl penicillinate - hydrochloride

In the same manner as in Example 6, this compound was prepared from 2.2 g (0.007 mol) of 6- (3-pyridylacetamido) penicillanic acid and 1/5 g (0/007 mol) of phenyl chloroethyl carbonate in 5 ml of dimethyl sulfoxide synthesized. 0.2 g freeze-drying product showed strong IR absorption at 1780 to 1750 cm (ß-lactam and ester), It was rapidly hydrolyzed in the presence of human serum.

Example 9 Ethoxycarbohyloxymethyl e-caprylamidopenicillanate

In the same manner as in Example 3, this compound was prepared from 3.6 g (0.01 mol) of sodium 6-caprylamidopenicillanate and 1.5 g (0.01 mol) ethyl chloromethyl carbonate in 5 ml dimethyl sulfoxide synthesized. 1.3 g of product were obtained as a yellow oil. It shows very strong IR absorption at 1780 to 1750 cm (Q-Lactoin

3,99843 / 1194

and liter J. i: s became rapidly in the presence of human serum hydrolyzed-.

Example IQ

Ethoxycarbonyloxyinethyl 6- (3-phenylthiadiazolyl-acetamido) penicillanate

In the same manner as in Example 3, this substance was obtained from 2.3 g (0.05 mol) of 6- (3-phenylthiadiazolylacetamido) penicillanate and 1.5 g (0.1 mol) of ethylchloromethyl carbonate in 5 ml of dimethyl sulfoxide synthesized. The organic extract was washed with acidic water, dried and evaporated in vacuo at 30 ° C, washed repeatedly with petroleum ether, dissolved and evaporated. 1.2 g of the title product were obtained as a brownish gum. The product showed strong IR absorption at 1780 to 1750 cm (ß-lactam and esters).

LiMR (CDCl-, tetramethylsilane as internal standard) = 1.15 to 1.45 (t), 1.5O to 1.6O (d), 4.10 to 4.45 (q), 4.25 (s), 4.50 (s), 5.55 to 5.85 (m), 7.20 to 8.10 (m) ppm.

Example 11

Phanoxycarbonyloxyethyl 6- (3-phenylthiadiazolylacetamido) penicillanate

In the same manner as in Example 3, this substance was obtained from 4.6 g (0.1 mol) of potassium 6- (3-phenylthiadiazolylacetamido) penicillanate and 2.0 g (0.01 mol) phenyl-O-chloroethyl carbonate in Synthesized 10 ml of dimethyl sulfoxide. The reaction mixture was

309 i3 / 1194

Poured ue into bO ml of ice-cold sodium bicarbonate solution and extracted three times with 50 ml of ether. The combined ether extracts were washed with sodium bicarbonate solution / water and brine, dried and evaporated in vacuo at 30 ° C., washed repeatedly with petroleum ether, dissolved and evaporated to give the title compound as 1.2 g of a brownish oil. The product showed strong IR absorption at 1780 to 1750 cm " ¹ (β-lactam and ester).

Example 12

athoxycarbonyloxymethyl 6- (4-phenyl-2,5-thiazolylacetamido) penicillanate

In the same manner as in Example 10, this compound was turned off 4.5 g (0.01 mole) 6- (4-phenyl-2,5-thiazolylacetamido) penicillanate and 2.8 g (0.02 Hol) of ethyl chloromethyl carbonate in 10 ml of diroethyl sulfoxide The product obtained was 2.7 g of brownish solid foam. It showed strong IR absorption at 1780 up to 1750 cm (ß-lactam and ester). The product was rapidly hydrolyzed in the presence of human serum.

I-uiR (CuCl ₃ , tetramethylsilane as internal standard) = 1.10 to 1.70 (m), 3.77 (s), 4.05 to 4.45 (q), 4.40 (s), 5 , 40 to 5.90 (n), 7.10 to 8.10 (ra).

üeisoiel 13

.-. t hoxycarbonyloxyethyl- i>'- hy dr oxy benzyl Den i ei llinat

If the same procedure as in Example 3, this compound was au;

309-43 / 1194

3.7 c (0.01 mol);>; atri- ^{;> y} -hyJroxybenzylpenicillinat and 3.0 g (0.02 Hol) -, ethyl-tV-chloroethyl carbonate in 25 ml of dimethyl sulfoxide synthesized. The product was obtained as 4.2 g of brownish foam and showed strong IR-absorption at 1730 to 175O ^- cm (ß-Lact: on and esters) "The product was rapidly hydrolyzed in the presence of human serum.

NMR (CDCl ₃ tetramethylsilane as internal standard) = 1.10 to 1.45 (t), 1.50 to 1.55 (d), 4.07 to 4.45. (Q), 4.50 (s) ,

5.10 (s), 5.45 to 5.70 (m), 6.65 to 6.95 (q), 7.30 (s).

Oral administration of the product to mice resulted in peak blood concentration levels of 16.3 / ag / ml C ^ -hydroxybenzyl penicillinate after 45 minutes against a blood concentration peak level of 9.6 / tig / ml 120 minutes after administration of equimolar amounts of ^ atrium - ^ - hydroxybenzyl penicillinate.

Example 14

2-ethylhexoxycarbonyloxymethyl- oC hydroxybenzyl penicillinate

In the same manner as in Example 3, this compound was synthesized from 3/7 g (0.01 mol) of sodium c / L> -hydroxybenzyl penicillinate and 2.2 g (0.01; iol) of 2-ethylhexylchloromethyl carbonate in 10 ml of dimethyl sulfoxide. 3.7 g of yellowish oil were obtained. The product showed strong IR absorption at 1780 to 1750 cm (β-lactam and ester). It was rapidly hydrolyzed in opposition to human serum.

3 0 9.: A 3/1 1 9 U

■ 33-

... iii (CDCI ₃ , tetramethylsilane as internal standard) = 0.30 to L, 70 (; λ), 4.00 to 4.10 (in), 4.45 (s), 5.505 (s), 5 , 50 to 5.90 (η), 7.30 to 7.45 (s).

Example 15 Acetoxyethyl - ^ - hydroxybenzyl penicillinate

In the same manner as in Example 3, this was turned off 3/7 g (0.01 mole) sodium - ^ - hydroxybenzyl penicillinate and 1.3 g (0.01 mol) of C ^ -Chloräthyletat synthesized in 20 ml of dimethyl sulfoxide. 1.1 g of dark oil were obtained. The product showed strong IR absorption at 1770 to 1750 cm (β-lactam and ester).

Example 16 p-nitrophenoxycarbonyloxy-methyl-benzyl penicillinate

In the same manner as in Example 3, this substance was obtained from 7.45 g (0.02 mol) of potassium benzyl penicillinate and 4.6 g (0.02 mol) p-Nitrophenylchloromethyl carbonate synthesized in 20 ml of dirr. ethyl sulfoxide. 4.2 g of brown heavy oil were obtained. The product showed strong IR absorption at 1730 to 1750 cm (ß-lactam and esters). The product was rapidly hydrolyzed in the presence of human serum.

Example 17 p-IIIitroathoxycarbonyloxymethyl-m-F - ^ - azidobenzyl penicillinate

In the same manner as in Example 1, this substance was made from

3 0 9 «43/119 4

δ, 3 g (0.02 iiol) of sodium nF- c * -> azidobensyl penicillinate and 2/5 g (0.013 mol) of p-nitroethylchloromethyl carbonate in 25 ml of diirethyl sulfoxide synthesized. O _r 4 g of light brown oil were obtained. It showed strong IR absorption at 2130 cm (azido groups) and at 1780 to 1750 cm (ß-lactam and ester). The product was rapidly hydrolyzed in the presence of human serum.

Example 18 Phenoxycarbonyloxymethyl-m-F-O ^ -azidobenzyl penicillinate

Line an ice-cold, stirred solution of 6.8 g (0.02 mol) of tetrabutylainmoniuiriiydrogensulfat in 20 ml (0.02 mol) of IM sodium hydroxide solution was mixed with 20 ml of methylene chloride and 8.3 g (0.02 mol) of sodium mFo ^ azidobenzyl penicillinate added. The mixture was shaken and the layers were separated. 3.72 g (0.02 mol) of phenylchloromethyl carbonate were added to the organic solution, and the solution was stirred ^{at 40 ° C. overnight.} The solution was poured into 10 ml of ice water and extracted with SO + 40 ml of ether. The combined organic extracts were washed with sodium bicarbonate solution, water and brine, dried and evaporated at 33 ° in vacuo to give 6.7 g of green oil. The product was washed repeatedly with petroleum ether to remove phenylchloromethylorvst, dissolved in toluene and placed in vacuo

Evaporated at 30 ° C. The title compound was obtained as 6.0 g of green heavy oil. It showed strong IR absorption at 2130 cm (/■ zicloc group) and at 1790 to 1750 cm (ß-lactam and ester). 'JSi3 product was rapidly hy ei ro Iy 3 ie r t in the presence of human serum.

309? 43 / 119A

1H-IR (CDCI ₃ , tetramethylsilane as internal standard) = 1.45 to 1, Gi (α), 4.50 (s), 5.05 (s), 5.50 to 5.90 (m), 6.80 to 7.30 (ri) ppm.

Example 19 Phenoxycarbonyloxymethylbenzyl penicillinate

An ice-cold suspension of 2.7 g (0.007 mole) potassium benzyl penicillinate in 7 ml of dimethylformamide was mixed with 1.34 g (0.007 mol) of phenylchloromethyl carbonate in 3.5 ml of dimethylformamide Staggered course of 15 minutes. The suspension was stirred for 17 minutes at room temperature, then in 70 ml of ice-cold sodium bicarbonate solution poured and extracted twice with 50 ml of ether. The combined organic extracts were washed with water and brine, dried and evaporated in vacuo at 30 ° C. The oil obtained was washed repeatedly with petroleum ether, dissolved in toluene and evaporated to give 2.2 g of the title product as a yellowish gum.

The product showed strong IR absorption at 1790-1750 cm (ß-Lactaiu and Ester). It was made in the presence of human serum rapidly hydrolyzed.

NMR (CDCl ₃ , tetramethylsilane as internal standard) = 1.48 (s), 3.60 (s), 4.42 (s), 5.40 to 5.90 (m), 6.15 to 6.35 (d), 7.00 to 7.50 (m) ppm.

309843/1

2Y

Cyclopentoxycarbonyloxyethyl-δ- (4-phenyl-2,5-thiazolylacetamido) penicillanate

In the same manner as in Example 18v, this compound was obtained from 1.0 g (0.0022 mol) of 6- (4-phenyl-2,5-thiazolylacetamido) penicillanate and 0.42 g (0.022 mole). ^ L-chloroethyl cyclopentyl carbonate synthesized. 250 rag of yellow heavy oil were obtained. The IR

• -1

Spectrum showed strong absorption at 1780 to 1740 cm (ß-lactam and esters).

Example 21 β-Azidoethoxycarbonyloxymethyl-i ^ C-hydroxy-benzyl penicillinate

In the same way as in Example 3, this substance was synthesized from 3.7 g (0.1 μl hol) sodium t> -hydroxybenzyl penicillinate and 1.8 g (0.01: Iol) β-azidoethyl chloromethyl carbonate. 2.51 g of yellowish oil were obtained. The IR spectrum showed strong absorption at 2130 cm " ¹ (azido group) and at 1790 to 1750 cm" ¹ (β-liactane and ester).

Example 22 B-Aninoathoxycarbonyloxyraethyl p ^ -hydroxybenzyl penicillinate

1.4 g (0.0028 Hol) ß-Azidoäthoxycarbonyloxymethyl- C ^ -hydroxy benzylpenicillinate was hydrogenated under normal pressure at normal temperature for 2 hours with 2 g of prehydrogenated carbon catalyst iuit -y'ö palladium and with 50 ml of ethyl acetate as solvent. The mixture was filtered and the filtrate washed with Na

3 0 9 R U 3/1 1 9 U

triun bicarbonate solution, water and brine, dried and evaporated in vacuo to give the title product as 0.7 g of a yellowish oil.

IR spectrum showed no band at 210 cm due to hydrogenation of the azido group, but strong absorption at 1790 to 1750 cm (ß-lactam and ester).

Example 23

1'-p-methoxyphenoxycarbonyloxymethyl-e- (D- ^ -azido-m-fluoro pheny! Acetamido) penicillanate

A stirred, ice-cold suspension of 3.0 g (0.007 mol) sodium 6- (-O'-azido-m-fluoro-phenylacetamidoj-penicillinate in 10 ml of dimethylformamide was mixed with a solution of 2 g of chloromethyl p-methoxyphenyl carbonate in 5 ml of dimethylformamide, after 15 hours of stirring at room temperature, the mixture became poured into saturated sodium bicarbonate solution. The inorganic solid was filtered off and washed with ether. The filtrate was extracted with ether. The ether extract v / urde washed with water and brine, dried and in vacuo at Evaporated 30 ° and gave 2.3 g of 1 '-p-ilethoxyphenoxycarbonyloxymethyl-6- (D-o \ - azido-m-f luor phenylace tamido) penicillinate as a dark reddish oil. The product showed strong absorption 2120 cm (azido group) and at 1785 to 1750 cm (ß-lactam and esters). Cs was rapidly hydrolyzed to 6-D-o ^ -azido-m-fluoro-phenylacetamido) -penicillanic acid in the presence of human serum.

icl 24

• --choxycarbonyloxyethyl-G-aminopenicillanate

A. 9.45 g (0.021 mol) of ethoxycarbonyloxyethylbenzyl penicillanate was dissolved in 75 ml of methylene chloride under an argon atmosphere. 5.44 ml (0.047 mol) of quinoline was added and the stirred solution was cooled to -15 ° C. 5.00 g (0.024 mole) of phosphorus pentachloride was added over 2 minutes. Stirring was continued for 65 minutes at -10 ° C. before 15.7 g (0.21 mol) of n-propyl alcohol were added over the course of 5 minutes at -25 ° C. The mixture was stirred for 30 minutes at -10.degree. C. and 7.5 g of sodium chloride, dissolved in 33 ml of water, were added. The temperature rose to 0 ⁰ C. for 30 minutes further stirred at ⁰ C O. 2 η sodium hydroxide was added over 1/2 hour at 0 C in order to adjust to pH 7.0. The layers were separated and the water solution extracted with two 40 ml portions of methylene chloride. The combined organic extracts were washed with sodium bicarbonate solution, water and brine, dried and evaporated in vacuo to give 7.9 g of ethoxycarbonyloxyethyl-6-aminopenicillanate as a yellow gum. The product showed strong IR absorption at 1790 to 1750 cm (β-lactam and ester), but no IR absorption at 1670 cm due to hydrolysis of the amide group of the original benzylpenicillin.

- thoxycarbonyloxyethyl-S-methyl ^ - (2-chlorophenyl) -4-isoxazolyl- • ienicillinate

_. 2.3 g (0.007 mol) of ethoxycarbonyloxyethyl-5-arr.inopenicirinate • ..urue dissolved in 35 ml of methyl isobutyl ketone and 70 ml of water.

3 0 9 ) 3/1 1 9 U '

1.8 g (0.007 ilol) S-methyl-S-U-chlorophenylW-isoxazolyl chloride, dissolved in 50 ml of methylene chloride was added in the course of 15 minutes, by automatic titration was adjusted to pH 3.0 held. The mixture was stirred for a further 20 minutes while monitoring the pH. Then it was separated, the aqueous layer was washed with twice extracted with 10 ml of methyl isobutyl ketone. The combined organic extracts were washed with water, sodium bicarbonate solution, Washed water and brine, dried and evaporated in vacuo to give 3.7 g of the title product as a brownish heavy oil. It showed strong IR absorption at 1790 to 1750 cm "(ß-lactam and esters).

Example 25

Ethoxycarbonyloxyethyl ^ hydroxybenzyl penicillinate

In the same manner as in Example 24, this substance was obtained from ethoxycarbonyloxyethylbenzyl penicillinate by way of 2.3 g (0.007 mol) ethoxycarbonyloxyethyl-6-aminopenicillanate and 2.0 g (0.007 mol) ίΤ ^ -dichloroacetoxyphenylacetyl chloride synthesized. The consumption of sodium hydroxide showed almost immediate hydrolysis of the dichloroacetyl protecting group. Ethoxycarbonyloxyethyl- £ ^ / - hydroxybenzylpenicillinate was obtained as 2.9 g of yellowish heavy oil. It showed the same IR absorption as the product of the example 13th

Example 26 Jkthoxycarbonyloxyäthyl-6- (d -phenoxybutyranido) -penlcillanat

In the same way as in Eeispial 24, this substance was made out

309843/1194

Athoxycarbonyloxyethylbenzylpenicillinate was synthesized by way of 2.3 g (0.007 ilol) ethoxycarbonyloxyethyl-e-aninopenicillanate and 1.4 g (0.007 ΐίοΐ) ^ -phenoxybutyryl chloride. 3.3 g of ethoxycarbonyloxyethyl 6- {oi> -phenoxybutyraxaido) penicillanate were obtained as a yellowish oil. It showed strong IR absorption at 179o to 1750 cm (ß-lactam and ester).

Example 27

(Diethylamino) -athoxycarbonyloxymethyl-o- {Ώ-Φ -azidophenylacetamido) penicillanate hydrochloride

Line stirred, ice-cold suspension of 10.3 g (0.025 mol) of potassium do ^ azidobenzyl penicillanate in 30 ml of dimethylformamide was treated with chloromethyl diethylaminoethyl carbonate hydrochloride in the course of 30 minutes. After stirring for 15 hours at room temperature, the mixture was poured into 250 ml of saturated sodium bicarbonate solution and 100 ml of ether. The inorganic solid was filtered off and washed with ether. The aqueous layer was extracted with ether. The combined ether extracts were washed with water, sodium bicarbonate solution and brine. Then the Ätharlösung was extracted with 150 + 100 ml of water at pH 2.8. The combined water extracts were freeze-dried and gave 0.5 g of (diethylamino) ethoxycarbonyloxymethyl-δ- (D- cL -azidophenylacetamido) penicillanate hydrochloride as a yellow amorphous solid. It showed strong IR absorption at 2130 cm (azido group) and at 1790 to 1750 cm "" ¹ (β-lactam and ester). The product was rapidly hydrolyzed in the presence of human serum.

309843/1194

Example 28

(Diächy! Amino) ethoxycarbonyloxy methyl benzyl penicillinate

In the same manner as in Example 18, this substance was turned off 3.7 g (0.01 mol) of potassium benzyl penicillinate and 2.5 g (0.01 mol) of (diethylaminoJ-ethylchloromethyl carbonate, fresh from its Hydrochloride was synthesized, but extraction was carried out with ethyl acetate instead of ether. The title compound was obtained as 1 | 3 9 yellowish gum. It showed strong IR absorption at 1780 to 1730 cm (ß-lactam and ester). The product was rapidly hydrolyzed in the presence of human serum.

Example 29

(Diethylamino) -äthoxycarbonyloxy-methy l -. ^ - hydroxybenzylpenicilli-

nat _{i t}

In the same manner as in Example 28, this substance was obtained from 3.7 g (0.01 mol) of sodium 0 ^ -hydroxybenzyl penicillinate and (diethylamino) ethylchloromethyl carbonate synthesized. 0.6 g of yellow solid foam was obtained. It showed strong IR absorption at 1780 to 1740 cm (ß-lactam and ester).

Example 30

1'-phenoxycarbonyloxymethyl 1-benzyl penicillanate

A stirred, ice-cold suspension of 26.3 g (0.07 mol) of potassium benzyl penicillinate in 70 ml of dimethylformamide was mixed with a solution of 13.4 g of (O ₇ O7 Hol) chloromethylphenyl carbonate in 35 ml

3 0 9 8 4 3/1194

Dine thy 1 formamide was added over the course of 30 minutes. After stirring at room temperature for 17 hours, the mixture was poured into 0.5 l of saturated sodium bicarbonate solution. Ether and water were added to the mixture until no solid material remained in the aqueous phase, which would then be extracted with more ether. The combined organic extracts were washed with water and brine, dried and evaporated at 30 ° C. in vacuo. The oily residue was washed repeatedly by decanting with petroleum ether in order to remove unreacted chloromethylethyl carbonate. The oil obtained was dissolved in toluene and evaporated to give 22.1 g of Roteia Gununi. The product showed strong Iβ absorption at 1785-1750 cm (β-lactam and esters) and was rapidly hydrolyzed in the presence of human serum.

Example 31

(Diethylamino) ethoxycarbonyloxymethyl-e- (D - ^ - azido-phenylacetamido ) -penicillanate .

A stirred, ice-cold suspension of 4.1 g (0.01 mol) of potassium D - ^ - azidobenzyl penicillanate in 10 ml of dimethylformamide was treated with 2.5 g of chloromethyl diethylaminoethyl carbonate hydrochloride in the course of 30 minutes. After stirring at room temperature for 15 hours, the mixture was poured into 31% saturated potassium carbonate solution. The inorganic solid was filtered off and washed with ether, the filtrate was extracted with ether. The ether extract was washed with water and sodium bicarbonate and SeIzsole, dried and evaporated in vacuo at 30 C and gave 3.7 g of diethylaraino-ethoxycarbonyloxymethyl-6- (D- OC -

309843 / 119A

azidophenylacetamido) penicillanate as a reddish gum. The product showed strong ΙΓ.-absorption Lei 2120 cm (azido group) and at 1785 to 1750 cm (ß-lactain and ester) and was rapidly hydrolyzed to 6- (D- ^ C -Azibphenylacetamido) -penicillanic acid by human serum. ...... ^ .

309843/1194

Example 32 Pharmaceutical preparations

The following compositions were used to make tablets prepared:

a) ß-Aminoethoxycarbonyloxymethyl-e-phenylacetamidopenicilanate

strength
Magnesium stearate

b) Ethoxy car bony loxymethy 1-6- (2-phenyl-4.-thiazolylacetamido) penicillanate

strength
Magnesium stearate

c) Ethoxycarbonyloxymethyl-6- (3-pyridylacetamido) -penicillanate hydrochloride Calcium carbonate

Magnesium stearate

d) Kthoxycarbonyloxymethyl-e-phenoxyacetamidopenicillanate hydrochloride

Lactose
Magnesium stearate

e) Phenoxycarbonyloxymethyl 6- (2-phenyl-5-thiadiazolylacetamido) penicillanate Microcrystalline cellulose (Avicel®) magnesium stearate

f) 1'-Äthoxycarbonyloxyäthyl-e- (D - ^ - hydroxyphenylacetamido) penicillanate 338 mg

300 rag 1OO mg IO mg 35O rag 1OO mg IO mg 350 mg 1OO mg IO mg 4OO mg 1OO mg 10 mg 37O mg 100 mg 10 mg

3 0 9 ■:. 3 I 1 1 9

" ⁵⁰ " 231) 346

Calcium carbonate 100 mg

Lactose. 100 mg

Magnesia stearate 10 mg

The following approaches were made for filling into capsules:

g) Ethoxycarbonyloxymethyl 6- (2,6-dimethoxybenzamido) penicillanate
Magnesium stearate

h) 1'-Xthoxycarbonyloxyethyl-6- (Dd, -hydroxyphenylacetamido) -penicillanate hydrochloride
Lactose

Magnesium stearate The following preparations were made for suspensions to be administered orally:

i) Äthoxycarbonyloxymethyl-6- (3-pyridylacetami-

do) penicillanate hydrochloride 36 g

Sodium Benzoate O, 48 g

Sodium chloride. 0.75 g

Flavors 4.7 g

Aerosil® 0/3 g

Antifoam® O, O375 g

Alkali salts of polysaccharide sulfates 4.0 g

Sodium saccharinate 0.4 g

Sorbitol to 100 g

350 rag 5 mg 350 mg 4O mg 5 ing

309 i ^: '43 / 1194

Claims (12)

Claims and their therapeutically acceptable salts, in which R, an Al, Jcyl or alkenyl group having 1 to 10 carbon atoms, aryl group such as phenyl and naphthyl, aryloxy group, aralkyl group such as benzyl and naphthylmethyl or a heterocyclic group such as furyl, thienyl, pyrrolyl -, pyridyl, pyrimidinyl, oxazo-IyI, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl or sydnonyl groups, the alkyl, alkenyl, aryl, aryloxy, aralkyl or heterocyclic groups being unsubstituted or having at least one substituent such as amino group, alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, hydroxyl group, halogen, nitro group, nitrile group, azido group, alkylthio group having 1 to 4 carbon atoms, carboxy group, carboxymethyl group, substituted or unsubstituted mononuclear aryl group or substituted or unsubstituted mononuclear heterocyclic group, R ² CH ₃ C ₂ H ₅ R ³ -CH-O-CO-R ⁴ , -CH-O-CO-R ⁴ or -CH-X ¹ COOR ⁴ where X is an -NH- group or oxygen, R is water- 4th
substance, -CH ₃ or -C ₃ H ₅ , R is an alkyl group with 1 to 3 0 S ■; i 3/1 1 9 -52- 231 13A6 3 carbon atoms, cycloalkyl group with 3 to 7 carbon atoms, Aryl, aralkyl or heterocyclic group, where the alkyl, cycloalkyl, aryl, aralkyl or heterocyclic Group unsubstituted or with at least one azido group, amino group, substituted amino group, such as methylamino, Diethylamino or acetamido, halogen, nitro or Alkoxy group with 1 to 4 carbon atoms can be substituted, X hydrogen, azido, hydroxyl, carbalkoxy group with 1 up to 4 carbon atoms, alkyl group with 1 to 4 carbon atoms, Denotes an alkoxy group with 1 to 4 carbon atoms or a guanidino group and η = 0 or 1, provided that that X is a hydroxyl, carbalkoxy, alkyl, alkoxy or guanidino group when η = 1, R CH ₃ R ³
-CH-O-CO-R ¹⁰ , -CH-O-COO-R ¹⁰ or -CH ₂ -NH-COO-R ¹⁰ , where R is an unsubstituted alkyl group and R is an alkyl, thienyl, furyl, phenyl - or hydroxyl-substituted phenyl group. 2. A compound according to claim 1 having at least one asymmetric center in the form of a pure stereoisomer. 3. A compound according to claim 1 of the formula -CH, -CONH-CH-CH "^ C
Il. I ^CH 3 S CO-N CH-COOCh ₂ -OC-OCH ₂ CH ₂ NH ₂ or their therapeutically acceptable salt. 4. A compound according to claim 1 of the formula 3 0 S ί ■ -, 3/1 1 9 U S CH N C-CH ₂ CONH-CH-CH ' ^ C ' ³ AJ CO-N CH-COOCH ₂ OCOC ₂ H ₅ or their therapeutically acceptable salt 5. A compound according to claim 1 of the formula -CH ₂ CONH-CH-CH III ^CH 3 CO-N CH-COOCH ₂ OCOC ₂ H ₅ or their therapeutically acceptable salt. 6. A compound according to claim 1 of the formula / ^S \ / ^CH 3 O-CH ₂ CONH-CH-CH ' C CO-N CH-COOCH ₂ OCOC ₂ H ₅ or their therapeutically acceptable salt. 7. A compound according to claim 1 of the formula NN _{Q r} " I II / \ / ^CH 3 ₀ JJ-CH ₀ CONh-CH-CH ^ c. III ^CH 3 Il I ^J Λ CO-N CH-COOCH ₂ OCO- < ^/ or their therapeutically acceptable salt. 8. A compound according to claim 1 of the formula -CHCONH-CH-CH C
I ι ι ι ^ch 3 OH CO-N CH-COOCH-OCOC ₀ H ₅ or their therapeutically acceptable salt. 309843/1194 9. A compound according to claim 1 of the formula -OCH ₃ I CH-, O OCH &quot; I 3 3 CO-N- CH-COOCH ₀ OCOC ₀ H _n <i 2 b or their therapeutically acceptable salt. 10. A pharmaceutical composition containing at least one compound according to claim 1 or 2 as an active ingredient in association with a pharmaceutically acceptable carrier. 11. Process for the preparation of compounds of the formula R ¹ I-CH- CO-NH-CH-CH ^ C CH ₃ II f ^ ^CH 3 CO-N CH-COOR and their therapeutically acceptable salts, in which R is an alkyl or alkenyl group with 1 to 10 carbon atoms, aryl group such as phenyl and naphthyl, aryloxy group, aralkyl group such as benzyl and naphthymethyl or a heterocyclic group such as furyl, Thienyl, pyrrolyl, pyridyl, pyrimidinyl, oxazo IyI, isoxyzolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl or sydnonyl, the alkyl, alkenyl, aryl, aryloxy, aralkyl or heterocyclic groups unsubstituted or with at least one substituent, such as an amino group, alkyl group with 1 to 4 carbon atoms, alkoxy group with 1 to 4 carbon atoms, hydroxyl group, halogen, micro group, nitrile group, azido group, alkylthio group with 1 to 4 carbon atoms, carboxy group, carboxymethyl group, substituted or unsubstituted mononuclear aryl group or sub- 3 0 3 · ■ '· = - 3/1 1 9 substituted or unsubstituted mononuclear heterocyclic groups 2
pe may be substituted, R CH ₃ C ₃ H ₅ R ³ -CH-O-CO-R ⁴ , -CH-O-CO-R ⁴ or -CH-X ¹ COOR ⁴ where X is an -NH group or oxygen, R is hydrogen, "CH ^ or -C-Hc means, R is an alkyl group with 1 to 8 carbon atoms, cycloalkyl group with 3 to 7 carbon atoms, aryl, aralkyl or heterocyclic group, where the alkyl, cycloalkyl, ARyI, aralkyl or heterocyclic Unsubstituted group or with at least one azido group, amino group, substituted amino group, such as methylamino, Diethylamino or acetamido group, halogen, nitro or alkoxy group can be substituted with 1 to 4 carbon atoms can, X hydrogen, azido, hydroxyl, carbalkoxy group with 1 up to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a guanidino group and η = 0 or 1, with the proviso that X is a hydroxyl, carbalkoxy, alkyl, alkoxy or guani- 2; dino group means, when η = 1, R CH ₃ R ³
-CH-O-CO-R ¹⁰ , -CH-O-COO-R ¹⁰ or -CH ₀ -NH-COO-R ¹⁰ , wherein R ^{10 is} an unsubstituted alkyl group and R ^{1 is} an alkyl, thienyl, furyl, phenyl or hydroxyl-substituted phenyl group, characterized in that
a) one is a compound of the formula R ¹ fcHT-CO-7 III . ^X 'Jn 30Si 43/1 1 '1 ■ v / orin η is 0 or 1, R has the above meaning of R or, if R contains an amino, carboxy or hydroxyl group, a protected amino, carboxy or hydroxyl group R is, and X * has the above meaning of X or when X is an amino or Contains hydroxyl group, is a protected amino or hydroxyl group X, and wherein -CO-Z is an acid chloride or functional equivalent group capable of reacting with an amino group to form an amide radical, with a compound the formula S ^ .CH H ₀ -N-CH-CH ^ C ^ -IV III ^CH 3
CO-N CH-COOR ² converts, in which R has the meaning given above, whereupon amino, carboxy and hydroxyl protective groups are known per se Way to be removed, b) an ester of a natural penicillin of the formula R-CO-NH-CH-CH ^ C VI III ₂ CO-N CH-COOR wherein R-CO- is an acyl group in the side chain of natural penicillin, with a phosphorus halide in an inert th solvent reacts, the imino halide compound thus formed with a lower alcohol and the imino ether thus formed with a compound of the formula α ¹ X ¹ -CHtCO-Z III 0: 43/1194 wherein R, X ¹ and Z have the meanings given above, reacts, whereupon the protective groups in the compound of the formula χ · CO-N- I I -CH-COOR be split off , or c) a compound of the formula -CHfCO-NH-CH-CH- I I CO-N- CH-COOH 1' where η = 0 or 1 and R and X ^{1 have} the meanings given above under a), with a compound of the formula Y ² -R ² VII in which R has the meaning given above and Y is selected from halogen or a functionally equivalent, for reaction with the compound IV is capable of forming an ester linkage group, reacts, whereupon the compound of formula I thus obtained if desired, converted into a therapeutically acceptable salt will. 12. The method according to claim 11, characterized in that a connection of the formula I is separated into their optical antipodes with at least one asymmetrical center. 309843/1 194