DE2338389A1 - NEW PENICILLINS AND THE METHOD OF MANUFACTURING THEM - Google Patents

Description

LAWYERS DR-JUR-DIPL-CHEM-WALTERBEIi J7 fitli 107 * 3 ALFREDHOEPPENER 4Λ JUIL 13/3 DR. JUR. PfPL-CHEM. H.-J. Wolf" DR. JUR. HANS CHR. AX

«23 FRANKFURT AM MAIN-HOCHSf

Our lobster 18 794

Pfizer Inc., Hew York, N.Y., V.St.Α.-

New penicillins and methods of making them

The invention "relates to a number of penicillins and in particular to 6- [2-aryl-2- (amidino- and imidoylaminoalkanoylamino) acetamidojpenicillanic acids and their pharmaceutically acceptable basic salts, which have a high antibacterial effect, especially against gram-negative microorganisms.

The compounds in the group belonging to the penicillin family belong, differ from one another in the nature of their H-substituent and correspond to the general formula

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23383B9

R-C-NH ^ 6

¹ APS *
ι

in which the Aeylrest on the 6-aminopenicillanic acid of a carboxylic acid or a functional derivative thereof, e.g., an acyl halide or anhydride.

The pharmacodynamic properties and the antibiotic The profile of a given penicillin depends to a large extent on the nature of the R group. The most widely used so far Penicillins are those in which the H group is a benzyl, Is phenoxymethyl or α-phenoxyethyl group. These well-known Analogs are highly effective antagonists of gram-positive Microorganisms; however, they have only a very limited gram-negative effect. Compounds or remedies, ία it

fight the spread of gram-negative infections let, 2.B. by E. coli, Pseudomonas or Klebsieila therefore of great value to medicine.

Recent efforts to improve the circulatory profile in the penicillin family have resulted in the synthesis of several new gowns. It is reported in Ij, JL-j patent specification 3,142,673 that a-carboxybenzylnenicilliri, a broad-spectrum antibiotic, has a greater effect on gram-negative bacteria in parenteral · \ ^r ^, - v; .breici'iunp; heated, but only a limited effect when administered orally.

* In the following, this part of the formula to the right of the dotted line will be referred to as - \ for the sake of simplicity.

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BATH ORIGINAL

a-Arainoarylmethylpenicillins and their derivatives are from the USA patents 2,985,648, 3 UO 282, 3 373 156, 3 308 023 and 3 342 677 are known, but their spectrum of activity against certain gram-negative microorganisms is limited. The 6-ureidopenicillanic acid derivatives are said to have both a gram-negative and a gram-positive effect which are described in U.S. Patents 3,180,863, 3,120,512, and 3,118,877, as well as U.S. Patents 3,180,863, 3,120,512, and 3,118,877 ct-ureidopenicillins, which are described in U.S. Patent 3,352,851 are described. An effect against gram-negative bacteria, in particular against those of the genus Pseudomonas, should also the a-CarbamylureidopenicJiiie (US Patent 3 483 118) and the cx-alkoxycarbonylureidopenicillins (U.S. Patent 3 481 9 ^ 2) own. Recently it has been reported that α-guanylureidopenicillins (UoA Patent 3,579,501) and α-imidoylureidopenicillins (UiiA Patent 3 634 405) as an agent against infectious diseases, especially those that caused by Pseudomonas are useful.

It has now been found that a new family of. Penicillins including the pharmaceutically acceptable basic courtship of the same are highly effective against gram-negatives Iuiirroorganisnen is. These new penicillins correspond to the general formulas

7-CHG Οι

υπ

C = O

-APt)

and

Ar-CHCO-

NH

C = O MR ₁ ι ·

C = I-E,

-ZiP 3

II

^ 4

In the formulas:, .r denotes phenyl, 4-hydroxypienyl, 2-thienyl oaer 3-thienyl; ..1 1,4-Pheiiyl? N, Allcylen with 1 to 3 carbon

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BATH ORIGINAL

mm 4 -

atoms or alkylidene having 2 to 3 carbon atoms; R. and Rp taken by themselves are hydrogen or alkyl having 1 Ms 3 carbon atoms; R, and R. each for itself thienyl, furyl, pyridyl, naphthyl, pyrryl, phenyl, benzyl or substituted phenyl or benzyl with a chloro, fluorine, bromine, methyl, methoxy, trifluoromethyl, 3,4- Dichloro or 3,5-dichloro substituents; R ₁ and Rp together are alkylene of 2 to 6 carbon atoms; Rp and R, together with alkylene. 2 to 4 carbon atoms; Rp and R. together are alkylene with 3 to 5 carbon atoms.

In a preferred group of descendants of the invention Compounds of the formula I are Ar phenyl, A alkylene having 1 to 3 carbon atoms, R-hydrogen and Rp and R, if Considered individually - hydrogen or - when considered together - alkylene with 2 to 5 carbon atoms.

A second class of preferred compounds according to the present invention Invention are those of the formula II in which Ar is phenyl, A is alkylene having 1 to 3 carbon atoms, R and R are hydrogen and R. hydrogen or alkyl of 1 to 3 carbon atoms mean.

A third class of preferred compounds according to the invention includes those of the formula II in which Ar is phenyl, A is methylene, R and R _{2 is} hydrogen and R. is euryl, thienyl, phenyl or by fluorine, chlorine, bromine, 3, 4-dichloro or 3,5-dichloro-substituted phenyl.

It is readily apparent to those skilled in the art that the a-carbon atom the penicillin side chain to which the amidino or imidoylaminoacylamino radical is linked asymmetric carbon atom indicating the existence of two optically active isomers i.e. D- and L-diastereoisomers as well des Racemates, DL form, allows. In accordance with previous Findings Affecting the Activity of Penicillins

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Asymmetric α-carbon atoms relate to the compounds according to the invention, which have a D-configuration, more active than the compounds which have a! -configuration on iron; the former are therefore preferred, although the L and DL forms of the compounds of the invention are natural can also be used and fall within the scope of the present connection.

The compounds according to the invention in which A is an alkylidene which is derived from an α-amino acid have an asymmetric carbon atom, which allows the formation of D, L and DL norms. Although the natural form of the as Starting material used amino acid, i.e. the L-3 form, is preferred the DL and D forms should also be considered according to the invention.

In addition to the definitions already given above for the various substituents, those derivatives of the compounds of the formulas are also intended. I and II fall within the scope of the present invention in which the various substituents have the following meanings: Ar 1,4-cyclohexadien-iyl; A 1,3-phenylene, divalent heteroyclic ring, cycloalkylene, cycloalkylidene, arylene, aralkylene, alkylene aralkylene or alkylene arylene; A in formula II can together with the nitrogen atom to which it is attached form a heterocyclic ring; R ₁ and R ₂ can stand alone aroyl, cycloalkyl, acyl, alkyl and aryl sulfonyl or halogen or amino-substituted aryl or alkyl; R ~ and R- are both heterocyclic, phenyl, substituted-by dimethylamine · ', acyl, carboxy, carbamoyl, Ή- and Ν, Ν-alkyl-substituted carbamoyl, acylamino or carboalkoxy or phenyl (disubstituted by two organic radicals); R, carboalkoxy, carboxy or alkyl substituted by halogen, alkoxy, carboalkoxy, carboxy, sulfamyl or carbamoyl; R .. and Rp together with the nitrogen atom to which they are attached can form a heterocyclic ring which is of a heteroatom

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-6- 233838S

interrupted like oxygen, sulfur or nitrogen can, where the nitrogen atom is optionally substituted by alkyl, substituted alkyl, aryl, acyl or sulfonyl Also included are alkyl and 1-acyloxyalkyl esters the described and claimed penicillins.

Also fall within the scope of the present invention Compounds of the formulas III and IY,

Ar-CH CO APS Ar-CH CO APS

t ι

MH HH

ι t

<T ° III and? = ° R ₂ IV

AN \ ...

R ₅ N NR ₁ NHCON-CR ₄

^R 2 R ₁

in which Ar, A, R ₁ , R ₂ , R * and R, have the meaning already given.

The penicillins according to the invention can be divided into two different ways Build ways. The first way can be explained by the following formula:

C-A-COCl - HCl

ArCH CO APS · TÄA

R ₂ -N

Lj) -A-C (X ;! • HCl

APS: see footnote on p. 2.: Triethylamine

> II

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- π. -

In practice, the required a-aminoarylmethylpenicillin triethylamine (iDÄA) salt and the acid chloride hydrochloride, where Ar, A, R ^, Rg, R * and R. have the meaning given above, in an inert aprotic Solvent in the presence of a hydrogen halide absorbing agent, for example a tertiary amine, reacted ^{at -30 to O 0 O.} In general, it is favorable to use the acid chloride in an excess of 100-200 fo . Under these conditions it is necessary to add a sufficient amount of tertiary amine, preferably triethylamine, in order to neutralize both the hydrogen chloride of the acid chloride and the hydrogen chloride which is formed during the reaction of the acid chloride with the α-amino group of the penicillin in question .

The solvent, which is inert under the reaction conditions, which forms the liquid phase of the reaction mixture, should be a solvent which neither with the reactants nor with the product of the reaction is intrinsically worthwhile Extent responds. Favorable solvents for this purpose are anhydrous, aprotic, polar solvents such as Dimethylformamide or hexamethylphosphoramide.

The implementation of the reactants is at the beginning of the reaction performed at ice bath temperature to prevent the formation of Reduce by-products; however, it is generally advantageous to leave the reaction mixture a few minutes after mixing To allow room temperature until the reaction has expired completely or almost completely. The reaction time, which depends on the temperature, the The concentration and reactivity of the reactants changes is generally about 0.5 to 12 hours.

After completion of the reaction described above, insoluble material is filtered off and the product is precipitated by adding the filtrate to a large amount of diethyl ether or any other solvent in which the product is insoluble.

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The crude product is filtered off with suction and dried. 3ine suspension of the crude product in methylene chloride is replaced by all traces of the α-aminoarylmethy! penicillin used as starting material freed by adding a small amount of! which the penicillin used in that in methylene chloride

converts soluble Iriäthylaminalz. The pure product becomes then filtered off and dried.

The starting materials with which the products of the present invention are made can be readily made by known methods. The oc-aminoarylmethylpenicillins are known Te ^ bonds that are described in U.S. Patents 2,985,648 and 3,342,677 and by Long, et al. in J.öhem.Soc. 1920 (1971); the acid chloride hydrochlorides can easily be prepared from the corresponding acids using shionyl chloride or phosphorus pentachloride. The corresponding acids can in turn be prepared again by methods that are known to every pachmann. In this context, reference is made to the following work: Ried et al., Ann., 661 , 76 (1963), Ried et al., Chem. Ber., 95. » 728 (1962), McElvain et al., J. Am. Chem. Soc., 7J_, 40 (1949), Bauer et al., J. Org.Ohem., 27, 4382 (1962) and Oardellini et al., Ann.Ohim. (Rome), 58, 183, 1199 (1958).

The further way for the production of the invention. Compounds in which Ar, A, R ₁ , R ₂ , R- and R. have the meaning given can be represented by the following formula:

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R ₂ -N

GA-CO ₉ H

DCC + E-

ArCHCO APS

R ₉ -N

^C I!

R ₄ -CN (R ₁ ) -A-CO ₂ H
DCC + 2-

According to the synthesis certificate shown above are equimolecular amounts of the required alkanecarboxylic acid hydrochloride, p-nitrophenol and dicyclohexylcarbodiimide (DCC) in an inert solvent (of the type already indicated in the first process route) at ambient temperatures implemented. After 1 to 3 hours, the intermediate p-nitrophenyl ester formed in situ becomes with the equimolecular Amount - or better a smaller amount - of a suitable α-aminoarylmethy! Penicillin, preferably in the form of a basic tertiary amine salt. The reaction time can be 1 to 6 depending on the temperature, the concentration and the reactivity of the reactants used Hours.

The product is isolated by first adding the reaction mixture filtered and the filtrate mixed with a large volume of diethyl ether. The product can be cleaned if necessary in which one with triethylamine in the first procedure described type treated.

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It is readily apparent to the skilled person that the amidino and imidoylamino groups according to the invention "claimed Compounds can exist in several different tautomeric forms, all within the scope of the present Invention fall.

It is one of the characteristic properties of those according to the invention acidic compounds that they have the ability "to form basic salts". Acid derivatives according to The present invention can by reacting the acid with a suitable base in an aqueous or non-aqueous Medium can be converted into basic salts. Basic reagents which are suitable for the preparation of the salts mentioned, can be of any type; Suitable are, for example, bases such as organic amines, ammonia, alkali metal hydroxicl ^ carbonates, -bicarbonates, -hydrides and -alkoxides as well as ercialkali metal hydroxides, hydrides, alkoxides and carbonates. Typical representatives of such bases are ammonia, primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-Toluidine ■, ethylamine and octylamine, secondary amines like dicyclohexylamine and tertiary amines like diet hy! aniline, ΪΓ-methylpyrrolidine, H-methylmorpholine and 1,5-diazabicyclo- (4,3,0) -5-n.onea; Sodium hydroxide, potassium hydroxide, ammonium hydroxide, Ifodium ethoxide, potassium methoxide, magnesium hydroxide, Calcium hydride and barium hydroxide.

Bs is easily recognizable to the person skilled in the art that the invention Compounds due to the amidino and imidoylamino groups are sufficiently basic to form acid addition salts form; these salts, particularly the pharmaceutically acceptable acid addition salts, also fall within the scope of the present invention.

Because the compounds according to the invention, the basic salts are of interest because of their chemotherapeutic effect, pharmaceutically acceptable ones are preferably used Salts.

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Insolubility in water, high toxicity, or a lack of Crystallinity can make some salts unsuitable or at least unsuitable for pharmaceutical * see application are; however, the water-insoluble or toxic salts can decompose in the "described Manner converted into the corresponding acids and into "any desired pharmaceutically acceptable basic salts being transformed. The preferred pharmaceutically acceptable salts include the sodium, aluminum, potassium, Calcium, magnesium, ammonium and substituted ammonium salts, e.g. procaine, dibenzylamine, ϊΓ, Η-bis-cäehydroabietyl) ethylenediamine, 1-ephenamine, IT-ethylpiperid in, N-benzyl-ßphenäthylamine, H ^ N'-dibenzylethylenediamine »triethylamine as well as the salts with other amines which have already been used to form salts with benzylpenicillin.

The new penicillins according to the invention are notable in vitro by activity against a wide range of microorganisms including gram positive and gram negative bacteria. Their beneficial effect can be demonstrated in corresponding in vitro tests on various organisms in a brain-heart infusion medium can be shown using the usual two-fold serial dilution method. The in vitro activity of the compounds according to the invention makes them suitable for a local Use in the form of ointments, creams, etc. "or for sterilization purposes, e.g. suitable for cleaning objects in hospital rooms.

The new penicillins are also effective antibacterial agents in vivo, i.e. in animals and humans, and not just in parenteral administration, but also when administered orally.

The dose in which the compounds according to the invention are to be administered must be determined by the doctor; it is directed

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according to the individual. Person as well as their age, weight and reaction and of course also according to the type and extent of the symptoms, the type of "bacterial infection, which is to be treated and the pharmacodynamic properties of a particular agent which is being administered shall be. It will often be found that a compound, when administered orally in larger amounts, is - based on the active ingredient - must be given, while smaller amounts will suffice for parenteral administration.

With the foregoing in mind, it can be said that an effective daily dose of the present invention Compounds when administered orally to humans is about 10 to 100 mg per kilogram per day, the preferred amount is about 50 to 75 mg per kilogram per day; the amount can be taken as a single dose or in several divided doses administered. In the case of parenteral administration, the daily dose is 25 to 100 mg per kilogram, preferably about 20 to 75 mg per kilogram. The values mentioned are only examples; in individual cases they can go up or can be changed downwards.

As stated earlier, the penicillins according to the invention are broad spectrum antibiotics that are different than most penicillin analogues, highly effective antagonists of gram-negative microorganisms, especially E. coli, Pseudomonas and Klebsiella are. Moreover, they appear to be more resistant to destruction by penicillinase to be than most penicillins; penicillinase is an enzyme that is produced by certain bacteria and which breaks down penicillin into inactive penicillanic acid.

Preferred compounds according to the invention include the following: 6- (2-Phenyl-2 ~ (amidinoacetamido) acetamido) penicillan-

acid and the following 6- (2-phenyl-2- () acetamido) peni-

cillanic acids, where successively the following meaning

may have:

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3-amidinopropionamido

2-imidazoliny / acetamido

2- (2-imidazolinyl) propionamidο

formimidoylaminoa c etamid ο

acetimidoylaminoacetamido

prop ionimid oylaminoac etamid ο

butyrimidoylaminoaeetamido

iso-butyrimidoylaminoacetamido

benzimidoylaminoaeetamido

p -chlorobenzimidoylaminoacetamido

p-fluorine enzimide oylaminoa c e tami d ο

p-Bromobenzimidoylaminoacetamido

2-furoimidoylaminoacetamido

2-thenoimiaoylaminoacetamido

3,4-dichlorobenzimidoylaminoacetamido

3,5-dichlorobenzeneoylaminoacetamido.

+ will

Within this group of the preferred, particularly outstanding compounds ⁺ the diastereoisomers with D configuration are particularly preferred.

The antimicrobial activity spectra of a number of compounds according to the invention are given in the following tables. In Table I is the in vitro profile of 6- (D-2-phenyl-2- (amidinopropionamido) acetamido) penicillanic acid (PAP) compared to those of ampicillin (AMP) and carbenicillin (OAR). The experiments were carried out under standard conditions in a liquid broth containing various concentrations of the test material contained. The broths were each inoculated with a specific organism, whereupon the minimum concentration (MIC) was determined at which no further growth of the organism occurred.

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Facts

In vitro comparative data for PAP, AMP and GAR

(MIG; mcg / ml)

organism

PAP

AIlP

AT ALL

E. coil 51A266 E. CoIi 51A002 Ps. Aeruginosa 52A490 Ps. Aeruginosa 52A104 Ps. Aeruginosa 52A173 Kleb, pneumoniae 53AOO9 Kleb, pneumoniae 53AO15 A. aerogenes 55AOO2 A. aerogenes 55AOO4 Ser »marcescens 63A001 P. mirabilis 570015 P. vulgaris 57A059 S. aureus

1.56 3.12 3.12 200 200 200 1.56 0.78 0.6 12.5 200 50 0.78 38 75 25th 100 200 > 200 250 > 200 100 100 25th 6.25 5 50 3.12 200 25th 6.25 1.56 1.25 1.56 6th 12.5 - 0.09 1.56

In Table II are the in vivo comparative data for the three Compounds contained in Table I versus various experimental infections in mice.

The values (fo survivors) were obtained under standard conditions known to the person skilled in the art. For the E. coli organism, the test compound was administered to the infected mice on a multiple dose schedule, the first dose being given 0.5 hours after vaccination and the subsequent doses being given 4 hours and 24 hours later, respectively.

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Table II

organism

Protection +

Route * Dose (mg / kg) PAP

AMP

CAR

E. coli 51A266

E. coli 51A266

200 50

200 50

30th
20th

80
80

90 80

90 80

70 10

90 90

* P0 = oral administration; SC = subcutaneous administration + = ° fa survivors

In Table III are further in vitro data for the invention Compounds contain related compounds.

Table III

0-GHC (t

HH

C = O »

GH ₉ ι * -

NH HN = O-O-X

APS

APo
0 = : see footnote on
Phenyl Page 2 X = H X MIC (mcg / ml) X = Br organism O
25th
12th , 78
, 5 O,
12
3, = j? X = Cl O
25th
6th , 39
, 25 S.
Pg c
Ps. aureus 01AÜ05
aeruginosa 52A104
aeruginosa 52A49O 39
5
12th 0.39
25th
12.5

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Table III - continued

Klee, pneumoniae 53AOO9 100 5 25th , 12 12.5 12.5 Λ. aerogenes 25th 5 25th , 25 3.12 3.12 P. mirabilis 570015 12, 5 3 , 56 3.12 3.12 Ser. marcescens 63AOO1 12, 6th 6.25 6.25 Ε. coli 51A266 12, 1 0.78 0.39

In Table IY, the in vivo comparative data for the four in Table III contains compounds against E. coli infections included in mice.

The values, reported as $ survivors, were among those skilled in the art. known standard conditions. The test compound was administered to the infected mice according to a multiple dose schedule, the first dose given 0.5 hours after infection and the further doses 4 hours and 24 hours later, respectively became.

Table IV

fo protection

organism

path

Dose (mg / kg) X = HX = FX = Cl X = Br

E. coli 51A266

Ξ. coli 51A266

PO

SG

10
0
0

90
70
10

90
70
50

0 0 0

70 60 50

10

90 60 50

The new products according to the invention are valuable antibacterial ones Agents that are eminently effective in treating a number of infections caused by susceptible gram-negative

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and gram-positive bacteria in poultry and animals and humans. The pure ones are used for treatment Materials or mixtures with other active biotics. The agents can be used alone or in combination with a pharmaceutical Carrier material administered v / ground, the latter according to Art the administration is selected in the usual way. For example, the agents can be administered orally in the form of tablets be used as an extender starch, lactose, certain types of clay and so on, or in capsules alone or in admixture with the same or similar excipients. she can also be administered orally in the form of elixirs or oral suspensions, the flavorings or coloring agents contain; finally, the agents can be injected parenterally, i.e. intramuscularly or subcutaneously. For the parenteral For administration, they are best used in the form of sterile aqueous solutions, which are either aqueous

Solutions like Y / ater, isotonic saline, isotonic dextrose or Ringer's solution; one can also use non-aqueous ones Solvents such as fatty oils of vegetable origin (cottonseed oil, Peanut oil, corn oil, sesame oil) and other non-aqueous vehicles that increase the therapeutic efficacy of the Do not affect preparations and which are non-toxic in the amount and in the proportions in which they are used (Glycerine, propylene glycol, sorbitol). In addition, you can Manufacture preparations that are suitable for the ex tempore preparation of solutions immediately before use »Such Preparations include liquid diluents, e.g. propylene glycol, Diethyl carbonate, glycerine, sorbitol, etc., buffering agents, as well as local anesthetics and inorganic salts to achieve certain pharmacological properties.

The following examples serve to further illustrate the invention. The examples show frequently recurring Designations and terms Abbreviations are used, namely the following:

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MC = methylene chloride

DMF = dimethylformamide

TIiA = triethylamine

Ä = diethyl ether

IR peaks = peaks in the infrared spectrum

NMR peaks = peaks in nuclear magnetic resonance

bspectrum

Rt = room - bDW. Ambient temperature

example 1

6- [D-2-phenyl-2- (amidinoacetamido) acetamido jpenicillanic acid (I: Ar = Ο ₆ Ήή A = -CH ₂ -; K ₁ , R ₂ and IU = H)

To 10 ml of dry DMP were at room temperature under a. Nitrogen atmosphere 810 mg (6 mmol) p-ITitrophenol, 1.24 g (6 mmol) dicyclohexylcarbodiimide and 830 mg (6 nmol) amidinoacetic acid hydrochloride given; the mixture was left with stirring for 2 hours. After that it became D-oc-aminobenzylpenicillin TaA salt (1.8 g, 4 mmol) was added to the yellow suspension, whereupon the mixture was turned off overnight while stirring at Rt “The solid matter was then filtered off and the filtrate became clear poured into 200 ml of Ä. The precipitated yellow substance was filtered off and dispensed in 100 ml MG, to which 2 ml TAA was added had been. After stirring for one hour, the purified product was filtered off and dried in vacuo; 910 mg (52.5 S & ige Yield).

IR peaks (microns; ICBr): 3.0 (b), 3.4, 5.6, 6.0, 6.25, 6.6, 6.85, 7.15, 7.4, 8.1 and 8.85.

NMR peaks (PPM; DMSO-D ₆ ): 1.48 (d, 6H), 3.95 (s, 2H), 4.04 (1H), 5.2-5.8 (c, 3H), 7.36 (7H) and 8-9 (b, 3H).

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Example 2

6-LD-2-phenyl-2- (3-amidinopropionamido) acetamido-penicillanic acid (I: Ar = C ₆ H ₅ ; Λ = - (CHg) ₂ -; R ₁ , R ₂ and R ₅ = H)

To a suspension of 1.35 g (3 mmol) of da-aminobenzylpenicillin TÄA salt in 15 ml of dry DMF, which was kept under nitrogen, was added 0.63 ml (4.5 mmol) of TÄA. The solution was cooled to temperature in an ice bath, 3-amidinopropionyl chloride hydrochloride (770 mg, 4.5 mmol) was added to the mixture, which was then stirred for 15 minutes and placed at room temperature for a further hour. The mixture was then cooled again to 0 C and a further 237 mg (1.5 mmol) of the acid chloride hydrochloride and 0.21 ml (1.5 mmol) of TAE were added. The reaction mixture was stirred at rt for one hour. Thereafter, the solid substance was filtered off and the filtrate was added dropwise to 200 ml of A with stirring. The crude dried product, 1.2 g, was suspended in 200 ml MG and treated with 1 ml TÄA. After stirring for 30 minutes, the purified product was filtered off and dried under reduced pressure; 640 mg (47.4% yield) _o

IR peaks (microns; KBr): 3, o (b), 3.35, 5.6, 6.0, 6.2, 6.6, 6.85, 7.15, 7.65, 8.0, 8.15 and 8.85.

lH7R-i ^J ec.ks (PPM; DIISO-D ₆ ): 1.5 (d, 6H), 2.55 (b, 4H), 4.0 (s, 1H), 5.24-5.85 (c, 34 7.4 (7H) and 9.0 (b, 3H) _o

Example 3

6- [DL-2- (2-thienyl] -2- (IT-methylamidinoacetamido) penicillanic acid (I: Ar = C ₄ H ₅ S; A = -CHg-; R-, = CH ₅ ; R ₃ and R ₅ = H)

2in 150 ml flask equipped with a nitrogen inlet tube was, with a suspension of 3.55 g (0.01 IJoI) DL-α-amino-2-thienylmethylpenicillin in 70 ml of dry DMF and 3.06 ml (0.022 hol) TAA loaded. The reaction mixture was on

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^{The mixture was cooled to 0} ° C. and 1.88 g (0.011 mol of IT-methylamidinoacetyl chloride hydrochloride) were added in portions. The suspension was then allowed to accept Rt and kept at this temperature for an otund Liter of γ was added, γ / obei vigorously stirred. The resulting suspension was stirred for a further 30 minutes and then filtered; the solid substance was dried in vacuo. The crude product was suspended in 100 ml of MG, to which 2 ml of TAA had been added Minutes - the purified product was suctioned off and dried under reduced pressure,

Example 4

Starting from the corresponding a-aminoarylmethylpenieillin or its TÄA salt of the specified configuration and the required Amidinoalkanecarboxylic acid or its acid chloride were prepared using the procedures of Example 1 or 2 synthesized the following penicillins:

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R, -N NR ₁

RR ₂

SV * A ^{+ R} i * 2 H- ^R 3 H- Way of working Ar SV D. -CH ₂ - ^CH 3 " C ₂ H ₅ - C ₂ H ₅ - example SV DL -CH ₂ - H- HC ₃ H ₇ - H- 1 SV D. -CH ₂ - CH ₃ - CH ₃ - CH ₃ - 1 SV D. - (CEl ₂ ), - CH ₃ - 1-C ₃ H ₇ - 1-C ₃ H ₇ - 1 SV L. - (CH ₂ ) 2- H- H- H- 2 SV DL - ^(CH 2> 3- H- CH ₃ - CH ₃ - 1 SV D. - ^(CH 2 ⁾ 3 " H- H- H- 2 SV D. - (CH ₂ ) ₂ - C ₂ H ₅ - H- H- 2 ^C 6 ^H 5- PL -CH ₂ - HC ₃ H ₇ - H- H- 2 D J
SV DL CH ₃ OH- CH ₃ - CH ₃ - CH ₃ - 1 SV DL CH ₃ CH- H- H- H- 1 SV DL (CH ₃ ) ₂ C- H- ^C 2 ^H 5- C ₂ H- 1 DL CH CH ₂ CH- H- 1 2

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* A ⁺ - 22 - H- ^R 2 H- 2338389 H- Artificially D. -CH ₂ - CH ₃ - H- H- wel ββ D. -CH ₂ - H- C ₂ H ₅ - C ₂ H ₅ - H «i game - Ar D. -CH ₂ - ^R l HC ₃ H ₇ - H- ^R 3 H- 1 4-HOC ₄ -H _x - DL -CH ₂ - CH ₃ - CH ₃ - CH ₃ - 1 D H
4-H0C, H, - D. - (CH ₂ ) ₂ - C ₂ H ₅ - H- H- 1 4-H0C, H.-
6 4 D. - (CH ₂ ) ₂ - CH ₃ - H- H- 1 4-H0C.H.-
6 4 L. CH ₃ CH- H- C ₂ H ₅ - C ₂ H ₅ - 2 4-HOC ₆ H ₄ - DL CH ₃ CH ₂ CH- H- H- H- 2 4-H0CH - D. (CH ₃ ) ₂ t- H- H- H- 1 4-HOC ₆ H ₄ - L. - (CHj) ₃ - H- H- H- 1 4-KOC ₆ H ₄ - D. - (CHj) ₃ - H- SV C ₂ H ₅ - 1 4-HOC ₆ H ₄ - D. - (CHj) ₃ - H- HC ₃ H ₇ - HC ₃ H ₇ - 2 4-HOC ₆ H ₄ - DL - (CHj) ₃ - H- H- H- 2 4-HOC ₆ H ₄ - D. -CHj- CH ₃ - HC ₃ H ₇ - H- 2 4-HOC ₆ H ₄ - D. - ^ ₂ " H- C ₂ H ₅ - C ₂ H ₅ - 2 4-HOC ₆ H ₄ - DL -CH ₂ - HC ₃ H ₇ - H- H- 1 2-C ₄ H ₃ S- DL -CH ₂ - HC ₃ H ₇ - H- H- 1 2-C ₄ H ₃ S- L. -CH ₂ - CH ₃ - CH ₃ - CH ₃ - 1 2-C ₄ H ₃ S- D. -CH ₂ - H- 1-C ₃ H ₇ - iC ₃ H ₇ - 1 2-C ₄ H ₃ S- D. - (CH ₂ ), - H- H- H- 1 2-C ₄ H ₃ S- D. - (CHjI ₂ - ^C 2 ^H 5- H- H- 1 2-C ₄ H ₃ S- L. - (CH ₂ ), - H- H- H- 2 2-C ₄ H ₃ S- D. - (CH ₂ ) 3- H- CH ₃ - CH ₃ - 2. 2-CJJ ₃ S- DL - (CHj) ₃ - H- C ₂ H ₅ - C ₂ H ₅ - ά 2-C ₄ H ₃ S- L. - (CHj) ₃ - H- HC ₃ H ₇ - HC ₃ H ₇ - Z 2-C ₄ II ₃ S- DL - (CHj) ₃ - CH ₃ -
H-
H- H-
H-
CH ₃ - H-
H-
CH ₃ - 2. 2-C ₄ H ₃ S- D.
D.
DL CH ₃ CH-
CH ₃ CH-
CH ₃ CH- H- . C ₂ H ₅ - C ₂ H ₅ - 2 2-C ₄ H ₃ S- D. CH ₃ CHjCH- H- H- H- 2. 2-C ₄ H ₃ S- DL CH.CH.CH-
I. CH ₃ - H- H- 2.
2.
2 .2-C ₄ H ₃ S-
2-C ₄ H ₃ S-
2-C ₄ H ₃ S- L. CH ₃ CH ₂ CH- H- H- H- 2 ² " ^C 4 ^H 3 ^S - D. .CH ₂ - CH ₃ - K— H- 2
r \ 2-C ₄ H ₃ S- D. -CH ₂ - H- ^C 2 ^H 5 ". C ₂ H ₅ - C.
1 2-C ₄ H ₃ S- DL -CH ₂ - I.
A. 3-C ₄ H ₃ S- I. 3-C ₄ H ₃ S- 1 3-C ₄ H ₃ S-

409809/1181

* A ^{+ R} i ^R 2 * 3 H- Way of working Ar L. -CH ₂ - CH ₃ - HC ₃ H ₇ - H- ExampleJ D. - (CH ₂ ) ₂ - H- H- H- 1. * if ~ * uc DL - (CH ₂ ), - C ₂ H ₅ - H- CH ₃ - CM 3-C ₄ H ₃ S- DL - (CH ₂ J ₂ - CH ₃ - CH ₃ - H- 2 3-C ₄ H ₃ S- D. - (CHj) ₃ - H- H- CH ₃ - 1 3-C ₄ H ₃ S- DL - (CH ₂ ) ₃ - H- CH ₃ - H-
H- CVl 3-C ₄ H ₃ S- L.
D.
D. CH ₃ CH-
CH CH-
CH CH- H-
H-
CH ₃ - H-
H- H- 2 3-C ₄ H ₃ S-
3-C ₄ H ₃ S-
3-C ₄ H ₃ S- DL (CH ₃ ) ₂ C- CH ₃ - H- H- 1
2
a 3-C ₄ H ₃ S- D. (CH ₃ ) ₂ C- H- H- H- 2 3-C ₄ H ₃ S- D. CH ₃ - H- CH ₃ - 1 3-C ₄ H ₃ S- D. (CH ₃ ) J: - H- CH ₃ - 1-C ₃ H ₇ - 1 3-C.H_S-
H 3 DL H- H- 1 3-C.H-S-
H 3 2

In this and in the following tables, the A group representing alkyl enes - »of the alkylidene is shrieked in such a way that the left bond of the group to the group and the right bond of the group to the Carbon atom of the amidino group is drawn.

Example 5

Using the procedure of Example 2, using of the corresponding intermediate products, the following derivatives are produced:

409809/1181

Phenyl-2- (N-phenylflmidinoacetainido) acetamido Jpenicillan-6- [1--2-phenyl-

2- (4- {Np-chlorophenyl-N'-methy! Amidino} butyramido) acetamido] penicillan-6- [DL-2-phenyl-2- (3- {N-methyl-Np-bromophenylainidino} propionaniido) acetaaido] -penicillan-6- [D-2-p-hydroxyphenyl-2- (3- (Np-raethylbenrylaraidino} propior> ·

araido) acetamido] penicill * n- 6- [D-2-p-hydroxyphenyl-2- (2- {N-ethyl-N'-m-

trifluoromethylphenylaraidino} butyramido) acecaQido] penicillan— 6- [DL-2-

p-Hydroxypheny 1-2- (2- {N, N - dimethyl-N '-of luorobenrylainidino} propionainido) acetamido] penicillan-6- [L-2-a-thienyl-2- (3- {N-2- pyrrylamidino} propion-

amido) acetaaido] penicillan- 6- [D-2-a-thienyl-2- (M, N - dimethyl-N-p_-

methoxyphenylanidinoacetainido) acetamido] penicillan-6- [DL-2-ct-thienyl-

2- (N-a-methylpheuylaraidinoacetamido) acetamido] penicillan_ 6- [L-2-3-

Thieny1-2- (K-n-propyl-N-o-chlorobensylamidinoacetaraido) acetamido] penicillan-6- [L-2-ß-thienyl-2- (4- {N - $ - thienylaaidino} butyramido) acetamido] penicillan and 6- [D-2-3- hienyl-2- (N-4-pyridylamidinoacetamido) acetamido] pen-

Il

icillansq, "- '" «" "·

Example 6

6- [O-2-phenyl-2- (p-amidinnbenzamido) acetamidoIpenicillanic acid (I: Ar = C ₆ H ₅ ; A = 1,4-C ₆ H ₄ ; R ₁ , R ₂ and R ₃ = H)

To a suspension of 806 mg (2 mmol) Da-aminobenzylpenicillin trihydrate in 1 ^ ml of dry DMP welchee, 0.56 ml ECO contained, were in a nitrogen atmosphere after cooling to ⁰ ° C in an ice bath was added dropwise 438 mg (2 mmol) of p Amidinobenzoyl chloride hydrochloride in 10 ml of the same solvent. The solution then present was stirred for 10 minutes at ⁰ ° C. and then for a further 50 minutes at rt. The precipitate formed during the reaction was filtered off and the clear piltrate was added dropwise to 400 ml. The educated

_A. BAD ORiGINAL

409809/1181

23383B9

Tan product was purified by pouring it into 30 ml MC suspended in which 0.5 ml TÄA were dissolved. To With stirring for 1.5 hours, the product was filtered off and vacuum dried; 750 mg (75.5 # yield).

Example 7

The procedure of Example 6 was followed using additional oc-Aminoarr / lmethylpenicilline and acid chloride ο rld-Hyd ro chlorides repeated, obtaining the following analogues:

Ar-CHCONH I.

Ar

^c * v

4-HOC.H, - • β · »

4-H0C, H.-o 4

4-HOC ₆ H ₄ -4-HOC ₆ H ₄ -4-HOC ₆ H ₄ -4-HOC ₆ H ₄ -

D. CH ₃ - DL D. H- L. ic ₃ L. H- D. CH ₃ DL H- D. H- D. C ₂ H ₅ DL H- DL H- D. CH ₃ - L. H-

H-

C ₂ H ₅ -

H-

H-

H-H- H-H- H-H-

JI

H-H-

^C 2 H-

H-H- '

0-ClC ₆ H ₄ -P-ClC ₆ H ₄ -

2-C _A H, N-4

409809/1181

2-C ₄ H ₃ S

2-C ₄ H ₃ S 3-C ₄ H ₃ S

3-C ₄ H ₃ S-

L. CH ₃ - CH ₃ - CH ₃ - L. H- M- H- L. CH ₃ - H- H- L. H- C ₂ H ₅ - C ₂ H ₅ - L. CH ₃ -. H- 2.-CF ₃ C ₆ H ₄ - D. CH ₃ - K- 3,4-Cl ₂ C ₆ H D. HC ₃ H ₇ - - 3.5-Cl ₂ C ₆ H ₃ L. CM ₃ - « ₃ - CH ₃ - M- C ₆ H ₅ CH ₂ - L. M- M- H- O H- H- 2-C ₄ H ₃ O- L. H- H- 2-C ₄ H ₃ O- L. CH ₃ - CH ₃ - CH ₃ - L. H- H- 0-C ₁₀ H ₇ - L. 1-C ₃ H ₇ - H- H- L. H- H- Q-C1C, H.- D. CH ₃ - H- D. CH ₃ - H- 3,5-Cl ₂ C ₆ H ₃ -

Example 8

6- [D-2-phenyl-2- (2-imidazolinylacetamido) acetamidojpenicillanic acid

(I: Ar = CgHc? A = CHp; R ₁ = H, R ₂ and R, together

-CH ₂ CH ₂ -).

In the manner described in Example 1, 825 mg (5mT! Nl) 2-ImidePzolinylesRigsäure-Hydrochloride, 1.04 x g (5 niKnl ^ bicyclohexyl CBTli οdiimid, 695 mg (5 mmol) p-Nitr ^ phenol and?, 25 g (5 mmol) Da-amine ^ lDenzylpenicillin-ECO salt reacted in 20 ml of dry DMP to give 1.2 g (4-9 ^ yield) received TUs purified product.

4098Q9 / 1181 ^BAD

IR Peak B (microns; KBr): 3.0 (b), 3.35, 5.6, 6.0, 6.2, 6.5, 6.85, 7.15, 7.5, 7.7, 8.0 and 8.85.

NMR peaks (PH !; DMSO-Dg): 1.48 (d, 6H), 3.72 (6H), 3.93 (1H), 5.2-5.8 (c, 3H), 7.3 (7H) and 8.9 (1H).

Example 9

6- [D-2-phenyl-2- (3- [2-imidazolinyl] propidnamido) acetamido] penicillanic acid

(I: Ar = CgHc; A = - (CH ,,) ,, -; Ri = H; Rp and R, together = -CH ₂ CH ₂ -)

In the manner described in Example 2, 1.3 g (4 mmol) of da-aminobenzylpenicillin TAA salt, 1.97 g (10 mmol) of 3- (2-imidazolinyl) propionyl chloride hydrochloride and 1.4 ml (10 mmol ) TÄA reacted in 25 ml of dry DMI ¹ , 1.55 g (77% yield) of the purified product being obtained after work-up.

III peaks (microns; KBr): 3.0 (b), 3.4, 5.62, 6.0, 6.2, 6.6, 6.95, 7.15, 7.55, 7.75, 8.0, 8.3 and 8.8.

LMWH peaks (PPM; DI.ISO-Dg): 1.5 (6H), 2.55 (b, 4H), 3.75 (s, 4H), 4.05 (s, 1H), 5.24-5.6 (c, 3H), 7.36 (5H), 7.8 (b, 2H) and 8.4 (1H).

Example 10

6- [DL-2-phenyl-2- (K, H -pentamethyleneamidinoacetamido) acetamido] penicillanic acid

(I: Ar = CgHf-; A = -CH ₂ -j R .. and R ₂ together = - (CH ₂ ) ₅ -5 R ₃ = H)

Dicyclohexylcarbodiimide (1.04 g, 5 mmol) was added with stirring to a solution of 695 mg (5 mmol) of p-nitrophenol and 1.03 g (5 mmol) Njli-Pentamethyleneamidinoacetic acid hydrochloride in 20 ml DI.IP given. The reaction mixture was left with stirring Stand for 2 hours at Rt under a nitrogen atmosphere. Thereafter

409809/1181

2338383

became DL-α-aminobenzylpenicillin TÄA salt (2.25 g, 5 mmol) added and stirring continued for 24 hours. The mixture was then filtered and the piltrate was in 300 ml Ä ° poured. The precipitate formed was filtered off and purified by suspending in 300 ml MC, which with 1.5 ml TÄA had been added. The purified product was filtered and vacuum dried.

Example 11

Using the corresponding ct-aminoarylmethylpenicillins and acids or acid chlorides, the following derivatives could be synthesized:

Ch

Ar * A. ^R l H-
H- R ₂ E ₃ Labor
white
example C ⁶ H ⁵ " D.
DL CH ₃ CH- H- \ ^ " 0% J *% ~ a
Z C ₆ H ₅ - D. -CH ₂ - H- tf * W \ 1 C ₆ H ₅ - D. -CH ₂ - CH ₃ - 1 C ₆ H ₅ - D. -CH ₂ - HC ₃ H ₇ - - (CH ₂ J ₂ - 1 ^C 6 ^H 5 ~ L. -CH (CH ₃ ) CH ₂ - H- - (CH ₂ ) ₃ - 2 C ₅ H ₅ - DL CH ₃ CH ₂ fcH- H- Z C ₆ H ₅ - D. 1,4-C ₆ H ₄ - C ₂ H ₅ - - (CH J- Z ^C 6 ^H 5 " DL
DL - (CH ₂ ) "-" CH- / pit \ * C ₆ H ₅ - L. (CH ₃ ) ₂ fc- H- Z 4-HOC, H _c - D. -CH ₂ - - (CH ² / - 1 4-HOC-H--
D J D. -CH ₂ - - (CH ₂ J ₂ - 1

409809/1181

- 29 - R ₁ Ro Rt Working D. July ^ 3 way Ar D. A. H- - ^(CH 2> 5- example L. C ₂ H ₅ - - (CH ₂ ) 3- Z 4-H0C, H _c -
O 3 L. - (Ci ₂ V HC ₃ H ₇ - - (CH ₂ ) ₃ - Z 4-H0C, H _c -
O J L. - ^(c v ₂ - H- - (CH ₂ ) ₂ - 1 4-HOCJU-
O J D. -CH (CH ₃ ) CH ₂ - H- - (CH ₂ ), - 1 4-HOC ₆ H ₅ - DL - (CH ₂ V H- - (CH ₂ ) ₂ - 2 4-HOC ₆ H ₅ - DL CH ₃ CH ₂ CH- C ₂ II ₅ - - (CH ₂ ) 3- Z 4-H0CJU-
D J D.
L. H- Z 4-H0C, H_-
D J D. MC ₆ H ₄ - H-
H- - (CH ₂ ) ₂ -
- (CH ₂ ) ₂ - Z 4-HOCII- D. H- - (CH ₂ ) ₂ - λ
1 4-HOC ₅ H-
4-HOC ₆ H ₅ - D. CH ₃ CH-
CH ₃ CH- H- -CCH ₂ ) ₃ - 1 2-C ₄ H ₃ S- L. -CH ₂ - CH ₃ - - (CH ₂ ) ₂ - 1 2-C ₄ II ₃ S- D. -CH ₂ - C ₂ H ₅ - - (CH ₂ ) 3- 1 2-C ₄ II ₃ S- DL -CH ₂ - H- "(CH ₂ ) ₂ - Z 2-C ₄ H ₃ S- D. - (CH ₂ ) ₂ - H- - (CH ₂ ) ₄ - Z 2-C ₄ H ₃ S- D. 1,4-C ₆ H ₄ - H- - (CH ₂ ) ₂ - Z 2-C ₄ H ₃ S- D. CH ₃ - - ^(αΐ 2> 2- 1 3-C ₄ H ₃ S- DL
DL -CH ₂ - H- - (CH ₂ V 1 3-C ₄ H ₃ S- L. -CH ₂ - H-
CH ₃ - - (CH ₂ ) ₂ -
- (CH ₂ ) ₂ - a 3-C ₄ H ₃ S- DL - (CH ₂ ) ₂ - UC ₃ H ₇ - - (CH ₂ ) 3- ζ
ζ 3-C ₄ H ₃ S-
3-C ₄ H ₃ S- D. CH ₃ CH- H- - ^(CH 2> ₅ - ζ 3-C ₄ H ₃ S- DL -CH (CH ₃ ) CH ₂ - H- - (CH ₂ ) ₂ - ζ 3-C ₄ H ₃ S- L. -CH ₂ - C ₂ H ₅ - - (CH ₂ ) 3- ζ 3-C ₄ H ₃ S- H- - (CH ₂ ) ₄ - 2. 3-C ₄ H ₃ S- 1,4-C ₆ H ₄ - Z 3-C ₄ H ₃ S-

409809/1181

Example 12

6- [D-2-Plieny "l-2- (acei; imidoylaininoacetamido) acetamido jpenicillanic acid

(II: Ar = GgH ₅ ; A = -CH ₂ -; R ₁ and R ₂ = H; R ₄ = CH ₅ )

A suspension of 1.58 g (3.5 mmol) of da-aminobenzylpenicillin TÄA salt in 35 ml of dry DMf was treated with 0.5 ml (3.5 mmol) of TÄA ", the mixture being reduced to O ^{0 in an ice bath} G was cooled and stirred vigorously. Acetimidoylaminoacetyl chloride hydrochloride (595 mg, 3.5 mmol) was added to the mixture, which was stirred in the cold for an additional 30 minutes. An additional 595 mg (3.5 mmol) of the acid chloride and 0.12. 5 ml (3.5 mmol) of Ii ¹ LA. Were added and the stirring was continued for 30 minutes at 0 G and 30 minutes at Rt. The mixture was then filtered and the clear filtrate was poured into 400 ml of Λ suspended in 5 ml MG after filtration, to which 1 ml TÄA had been added. After stirring for 5 hours at Rt, the product was filtered and vacuum-dried; 755 mg (48% yield),

IR peaks (microns; KBr): 3.0 (b), 3.3, 5.62, 6.0, 6.2, 6.5, 6.85, 7.2, 7.6, 8.1 and 8.85.

NMR peaks (PPM; DMSO-D ₆ ): 1.47 (d, 6H), 2.18 (3H), 4.0 (s, 1H), 4.15 (2H), 5.25-5, 84 (c, 3H), 7.38 (7H) and 9.2 (b, 2H)

Example 13

Using the procedure of Example 12, 1.35 g (3 mmoles) of da-aminobenzylpenicillin TÄA salt, 1.1 g (7 mmoles) of formimidoyl aminoacetyl chloride hydrochloride and 0.98 ml (7 mmoles) of TIA in 15 ml dry DMi ¹ reacted and gave 913 mg (72 # yield) 6- [D-2-phenyl-2- (formimidoylaminoaoetamido) -acetamidojpenicillanic acid (II: Ar = ^G 6 ^H 5 '^ ⁼

R ₄ = Eh

409809/1181

Example 14

6- [D-2-phenyl-2- (propionimidoylaminoacetamido) acetamido] penicillanic acid (II: Ar = GgH ₅ ; A = -CH ₂ -5 R ₁ and R ₃ = H; R ₄ = C

A mixture of 4.5 g (10 mmol) of Da-aminobenzylpenicillin TÄA-fialz and 1 g (10 mmol) of TÄA in 80 ml of DMF was after cooling to -30 C with 1.0 g (5.2 mmol) of propionimidoylaminoacetyl chloride -Hydrochloride treated ,, whereby the mixture ^{was stirred at -20 ° to -30 0} C for 20 minutes. During this time a further 1 g amount of the acid chloride was added and stirring was continued for a further 20 minutes. Then a further 1 g of triethylamine and 1 g of the acid chloride were added, whereupon the process was repeated after another 20 minutes of cooling in the cold, so that a total of 4.0 g of acid chloride and 3 g of amine were added. Then allowed the reaction mixture to a temperature of 2O ⁰ C accept. After filtering, the yellow filtrate was added to one liter of chloroform. The crude product was washed with chloroform and vacuum dried and then dissolved in 20 ml DMF, to which 1 ml TÄA had been added. The insoluble matter was filtered off, and the filtrate was added to 200 ml of chloroform. The product formed was filtered off and the cleaning process was repeated again, so that finally 1.6 g of the desired material were present. Traces of the solvent were removed by triturating the product with and then vacuum drying; 1.5 g (33% yield).

NMR peaks (PPM: D ₃ O): 1.3 (t, 3H), 1.4 (d, 6H), 2.65 (q., 2H), 4.2 (s, 1H), 4, 25 (s, 2H), 5.45 (s, 2H), 5.58 (s, 1H) and 7.5 (s, 5H).

Example 15

Using the procedure of Example 14, the following homologs can be obtained using the appropriate starting materials can be synthesized:

£ 09809/1181

From booty X

36.5

38.0

6 5

NMR peaks - PPM-J2O

0.9 (t, 3H), 1.A (s, 6H), 1.2-2.0 (q, 2H), 2.2-2.6 (t, 2H), 3.8 (s, lH), - 4.2 (d, 2H), 5.3 (s, 2H), 5.4 (s, lH) and 7.3 (s, 5H).

1.0-1.6 (2xd, 1211), 2.4-3.0 (2H), 3.8 (s, lH), A.2 (d, 2H), 5.3'5 (8.2H) ₁ 5.5 (S ₁ IH) and 7.3 ( s, 5H).

Example 16

When applying the .Working method v> n Example 14 and using the The following penicillins could be found in the corresponding output compounds produced v / earth:

-CH ₂ "A. - ^R l ^R 2 H- ^R A H- * -CH ₂ A. - CH ₃ - CH ₃ - CH ₃ - D. -CH ₂ - H- CH ₃ - CH ₃ - D. - (CH 2 ^ 2 " C ₂ H ₅ - HC ₃ H ₇ - HC ₃ H ₇ - DL - (CH 2 2 ~ H- H- H- DL - (CH 2> 3- 1-C ₃ H ₇ - H- H- D. H- D.

409809/1181

Ar

SV

SV

^C 6 ^H 5-

4-HOC.H.-6 4

4-K0C, H. -6 4

4-H0C, H. -6 4

4-HQC, H.-6 4

4-HOC ₆ H ₄ -4-KOC ₆ H ₄ -

4-HOC.H.-o 4

4-H0C, H, -6 4

4-H0C, H.-6 4

4-H0C, H.-6 4

4-HOC.IL-6 4

2-C ₄ H ₃ S-2-C ₄ H ₃ SZC ₄ H ₃ S-

DL

DL

DL

DL

CH ₃ CH-

CH ₃ CH ₇ CH-

-CH (CH ₃ ) CEi ₂ -

-CH ₂ - -CH ₂ - -CH ₂ -

-CH ₂ CH (CH ₃ ) -1,4-C ₆ H ₄ -

-CH ₂ - -CH ₂ -

H-H- H-H- H-

^CH 3-H-

H-

H-

H-

H-

H-

HC ₃ H ₇ -

H-

H-

CH ₃ -

C ₂ H ₅ -

H- H-

H— H-H- H-

C ₂ H ₅ -H-

C ₂ H ₅ -

H-

H-

CH ₃ -

H-

H-

^C 2 ^H 5 ~ H-

2-C.H-S-4 3

2-C ₄ H ₃ S-

2-C.H-S-4 3

2-C ₄ H ₃ S-2-C ₄ H ₃ S-3-C ₄ H ₃ S-3-C ₄ H ₃ S-3-C ₄ H ₃ S-3-C ₄ H ₃ S-

3-C.H-S-4 3

3-C ₄ H ₃ S-3-C ₄ H ₃ S-3-C ₄ H ₃ S-

DL

DL

-CH ₂ -

- (CH ₂ ) 3-CH3CH-

-CH ₂ -

CH ₃ CH ₂ CH- -CH (CH ₃ ) CH ₂ - -CH ₂ CH (CH ₃ ) -1,4-C ₆ H ₄ -

H-

H-

H-

H-

H-

1-C

H-

n-e

H— H— H-H- H-

CH ₃ - HC ₃ H ₇ -H-

^C 2 ^H 5 "H-

CH ₃ -H-

HH- H- HH- CH ₃ -

CH

n-C 3 ^H 7 H- C ₂ H 5 " H- CH ₃ - H- CII ₃ - 1-C 3 ^H 7 CH ₃ H- H- H- CH ₃ .

409809/1 181

Example 17

6- [D-2-phenyl-2- (p ~ phenyl acetimidoylaminoaetamido) acetamido] penioillanic acid

(II: Ar = OgH ₅ ; A = -CH ₂ -; R ₁ and R ₂ = H; R

To 13.5 g (0.03 mol) of da-aminobenzylpenicillin TÄA salt and 3 g (0.03 mol) of TÄA in 240 ml of dry DMl? was added after cooling to -30 ⁰ C 4.2 g (0.015 mole) of p-Chlorphenylacetiniidoyl-aminoacetylchlorid hydrochloride. After stirring in the cold for 45 minutes, 4.2 g (0.015 mol) of further salt chloride were added, whereupon 3 g (0.03 mol) of TlA were added after a further 45 minutes. Additional additions were made every 45 minutes until a total of 16.8 grams (0.06 moles) of acid chloride and 9.09 grams (0.09 moles) of TAA had been added to the penicillin salt. After the reaction mixture became Rt, it was filtered. The filtrate was poured into 2.5 liters of chloroform. The precipitate formed was filtered off, washed successively with chloroform and Ä and vacuum-dried; 5.6 g. The crude product was in 50 ml DM]? dissolved, which contained 4 g TÄA. A small amount of the insoluble material was filtered off. The filtrate was added to 700 ml of chloroform and the precipitate formed was filtered off with suction. The product was further purified by triturating it twice with 80 ml MG which contained 2 g Q3ÄA. Then it was rubbed again with MC alone. After vacuum drying, the pure product was in an amount of 4.8 g (28 consecutive yield) _o

MR peaks (PPM; DMSO-D ₆ ): 1.4 (d, 6H), 3.4-4.3 (s, 6H), 5.3 (s, 2H), 5.8 (s, 1H ), 7-7.7 (s, 11H) and 9.0 (s, 2H).

Example 18

Using the procedure of Example 17, one can proceed starting of the D-α-aminobenzylpeiiicil 1 ~ n-TAA salt and the corresponding Acid chloride, produce the following derivatives:

409809/1181

C _C H.CHCONH 6 5,

Yield ^ NMR Peaks - PPM; DMSO-D ^

CH ₅ - 4.7 1.5 (d, 6H), 4.0-5.2 (n, 911), 5.3 (s, 2H), 5.8 (s, 1H),

7-8.0 (n, 12H).

P-CH ₀ OCJI.- 9.8 * 1.4 (d, 6H), 3.8 (s, 3H), 3.95 (s, 1H), 4.3 (s, 3H), 6 4

5.3 (s, 2H), 5.8 (s, 1H), 6.3-8.0 (n, 10H).

P-Cr ₃ C ₆ H ₄ - 6.8 * 1.4 (d, 6H), 4.0 (S ₁ IH), 4.2 (s, 2H), 5.25 (s, 2JI),

5. 7 (see IH), 6, 8-8 (ia, 14H).

^ -ClC ₆ H ₄ - 12.0 1.3 (d, 6H), 3.8 (s, 1H), 4.1 (s, 2H), 5.2 (s, 2H),

5.62 (s, lH), 5.8-7.0 (s, 3H), 7.0-7.8 (m, 9H), 8.35 (s, 2H).

2-C ₄ H ₃ S- 17.0 1.4 (d, 6H), 4.0 (s, 3H), 5.2-5.5 (s, 2H), 5 * .7 (d, 1H),

7-7.6 (s, 6H), 7.6-7.9 (5H), 8.6-9.3 (t, 2H).

P-FC ₅ H ₄ -. 16.0 1.4 (d, 6H), 4 (s, 1H), 4.3 (s, 2H), 4-5.3 (s, 6H),

5.3 (s, 2H), 5.8 (s, 1H), 7-7.6 (s, 7H>, 7.6-8 (m, 2H).

8.5 1.45 (d, 6H)., 3.9 (s, 1H), 4.2 (s, 2H), 5.25 (s, 2H), 4.4-5.8 (s, 7H), 5.8 (s, 1H), 7-8 (2xs, 12H), 9.0 (s, 2H).

2-CH ₃ C ₆ H ₄ - 5.1 1.4 (d, 6H), 2.4 (s, 3H), 4.0 (s, 1H), 4.3 (s

5.25 (s, 2H), 5.3-6.2 (m, 8H), 7-8 (m, 10H).

^ -ClC ₆ H ₄ - 8.7 1.4 (d, 6H), 3.9 (s, lH), 4.2 (s, 2H), 5-6.6 (m, aH),

7-8 (m, IIH), 9.05 (t, 2H).

2-C ₄ H ₃ O-. 8.4 * 1.5 (d, 6H), 4.0 (s, 1H), 4.2 (s, 2H), 5.4 (s, 2H),

5.9 (s, lH), 4.7-6.2 (s, 6H), 6.9 (s, lH), 7.2-7.7 (s, 5H), 7.8 (s, lH), 8.15 (s, lH).

409809/1181

R yield, % NMR-Peeks - PPM; DMSO-Γ> _ή 4 ο

5V5 '* IT4 (d; 6H), 3.9 (s, lH), 4.1 (s, 2H), ..478-6 (m, llH), 7.2 (e, 7H), 7.7 (s, 2H), 8.0 (s, 1H).

7.4 * 1.4 (d, 6H), 4.0 (overlap «L) s, 3H), 5.0-7.0 (ia, 9H), 7.4 (s, 5H), 7.8 (s, 3H), 9.0 (t, 2H).

♦ Not sampled over 500 Hz

Example 19

Using the procedure of Example 17, pus also following the corresponding starting materials « Perieil 1 ir.-analogue «manufacture:

6- [D-2-i ^> henyl-2- (N- {o-chlorobenziicidoyl} N-ynethylaminoacet <'iraido) aert -.- imldojpcnicillan-6- [DL-2-1 * heiyl-2- (N- iN ^l -ethyl-mi luorobenz inidoyl JHiino

acetaraidojpt'nicillan- 6- [I) -2-'Phenyl-2- (K- {in-methoxyphenylacctiiaidoyl} -

/ uninoacctar _; n do) acetamidojpenicil.lan- 6- [DL-2-phenyl-2- (2-N- {o-tri £ luoro-

mGthylbenzimi.doyl} aminopropiona ^ iido) acetamidoJpenicillan- 6- [DL-2-

^/ Phcnyl-2- (4 - N- {N ^l -n-propyl-m-bromophenylacet inidoyl Jaminobutyramido) acetamido] penicillaii-6- [D ^ -p-hydroxyphenyl - ^ - (N- (N ¹ -methyl- ^ trifluorophenyl

acetimidoyl} cminoacetanido) acetaniido] penlcillan- 6 ~ lD-2-p-hydroxypheny] -

2- (N- {m-methoxybenzinidoyl} aminoacetainido) acetainidö3penicIllan- 6- [L- 2-

p-Mydroxypheny1-2- (3-N- {o-chlorobenzimidoyllarainobutyranido) acetamido] penicillan— 6- [D-2-a-thienyl-2- (N- {o-chlorobenzimidoyl} N-ynethylaminoacetaraido) -

acetamidojpenicilian- 6- [DL-2-a-thienyl-2- (N- (N'-ethyl-m-fluorobenzini-

doyl} aminoacetamido) acetamido] penicillan- 6- [L-2-a-thienyl-2 - (N- {nnr.ethc :: y

phenylacetitnidoyl} aciinoacetaniido) acetaido3penicillan— 6- {DL-2-a-thicnyl ·

2- (2-N- (o-trifluoronethylbenziraidoyl} aininopropionaQido) acetamidoJpenicillan-

409809/1181

6_ [D-2-3-Thieny 1-2- (AN- (N'-n-propyl-m-bromophenylacetimidoylaniinobutyra «ido) acetamldo] penicillan-6- [D-2-3-thienyl-2- (3- li- {o-chloro-

benzioidoyl} aminobutyramido) acetamido] penicillan-6- [DL-2-g-thienyl-

2- (N- (N'-ethyl-mf luorobenzlmidoyDaaiinoacetanido) acetamido] penicillan-6- [D-2-i ⁾ henyl-2- (N- (N ^l -methyl-3,5-dichloroben2inidoyl} aminoacetamido) acetamido] -penicillan- 6- [D-2-p-hydroxyphenyl-2- (N- {3,5-dichlorobenzinidoyl} -

ominoacetaoiido) acetamido Jpenicillan S.

Example 20

6- [l) -2-Phenyl-2- (2-pyrrolinylaminoaoetamido) acetainido] penicillanic acid

(II: Ar = CgHc; A = -CHp-; R ₁ = H; Rp and R- together

A suspension of 4.5 g (0.01 mol) Da-aminobenzylpenicillin-ECO salt in 85 ml of dry DMF was cooled in a salt-ice bath to -10 ⁰ C and then treated with 985 mg (0.01 mol) 2-pyrrolinylaminoacetyl chloride hydrochloride and 1.01 g (0.01 mol) of TÄA. Stirring was continued for 30 minutes, after which - always with cooling - a further 985 mg (0.01 mol) of acid chloride and 1.01 g (0.01 mol) of TÄA were added. The mixture was stirred for an additional hour. The ice bath was then removed and the mixture was allowed to assume Rt; the mixture was stirred for a further 45 minutes. The solid substance was then filtered off, and the clear filtrate was added dropwise to one liter of Ä with vigorous stirring. The crude product was filtered off and suspended in 20 ml MC, which contained 3 ml TÄA. After stirring for an additional 5 hours at, the purified product was filtered off, washed with A and vacuum dried.

4098 0 9/1181

Example 21

Using the procedure described in Example 20 were able to use the appropriate. Acid chloride and a-Aminoarylmethylpenioilline the following derivatives are produced:

Ar # Ä -CK ₂ - H - (CH ₂ V ^R 2 \ Vs " S. -CH, - CIi ₃ - (CHj) ₃ - Vs " D. ~ ^ic v ₂ - ■■ KC ₃ H ₇ - - (CH ₂ ), - - (CHj) ₃ - Vs " BL 2 3 H- - (CHj) ₃ - - (CH ₂ ) 3- Vs- DL - (CHj) ₃ - H- - (CHj) ₃ - - (CH ₂ ) ₃ - V5- L. CH ₃ CH- C ₂ H ₅ - - (CHj) ₂ - - (CHj) ₄ - Vs- L. (CH ₃ ^ H- - (CHj) ₂ - "• ^(CH 2 ^} 3- Vs- DL -CH (CH ₃ ) CK ₂ - CH ₃ - - (CHj) ₆ - - (CH ₂ ) 3- Vs- DL ¹ » ⁴ ~ V4" H- - (CHj) ₃ - - (CHj) ₃ - Vs- E. 1,4-C ₆ K ₄ - H- - (CH ₂ ) ₃ ~ - (CH ₂ ) 3- Vs " B. -CMf- CH ₃ - - (CHj) ₄ - Vs " D. -Si ₂ - H- Vs- IS Ma ₂ - CH ₃ - Vs- 3> L -CCH ₂ ) ₂ » ^C 6 ^H 5 ~ Vs- L. "^ 2 ^ 2" P-ClC ₆ H ₄ - Vs- L. CH3CH- P-CF ₃ C ₆ H ₄ - Vs " DL CH ^ CH ₂ CH- 0 4 2 C ₆ H ₅ - L. -CH ₂ CH (CH ₃ ) - .-BrC ₆ H ₄ - Vs- 1- . -CK ₂ - C ₆ H ₅ - Vs- P. -CM ₂ - 0-C ₄ H ₃ S- Vs- ΰ 3-C ₅ H ₄ N-

ÄÜS803 / 1181

"1

..C ₄ M ₅ - D. -CCS ₂ I ₂ - H- a- -CCH H- L ₂ I ₃ - JHQ ₄ H ₃ O- 4-WC ₄ H ₄ - D. -CH ₂ - CH ₃ - CH ₅ - -CCH CH ₃ - -CCHj) ₃ - 4-WC ₄ I ₄ - B. -CH ₂ - HC ₃ H ₇ - ^ - C "» H—— -CCH H- -CCHj) ₃ - 4-MOC ₄ I ₄ - D. -CH ₂ - H- Si— -CCHj) ₅ - DL -CCHj) ₂ - SV
H- H- -CCH -CCHj) ₃ - 4-WC ₄ I ₄ - SL
L. -CCHj) ₃ -
CH ₃ CH- H- -CCH ² ) ⁴ ! 4-HOC ₆ H ₄ - L. -CH (CH ₃ ) CHj- ä- -CCHj) ₃ - 4-HOC ₆ H ₄ - D. 1.4-C ₆ H ₄ - CH ₃ - - (CHj) ₃ - 4-HOC ₆ H ₄ - D. 1,4-C ₆ H ₄ - -CCHj) ₄ - 4-HOC ₆ H ₄ - D. -CH ₂ - I ₂ ) j- H- 4-WC ₄ I ₄ -
4-WC ₄ I ₄ - D.
L. - (CH ₂ ) -
CH ₃ -CHjCH- Ij) ₃ - H-
U), - «-BrC-H, - SL -CH ₂ - ' -CCH 4-wcJh ₄ - D. -CIl ₂ - iS j) ₂ - ^B - ^c ioV 4-WC ₄ H ₄ - BL
B. 1.4-C ₆ H ₄ - -CCH ₂ ) ₂ - aC ₄ H ₃ O- 4-WC ₆ H ₄ - B. 1.4-C ₆ H ₄ - 2> ₂ -. J-CH ₃ OC ₆ H 2-C ₄ H ₃ S- B. -CH ₂ - -CCHj) ₃ - 2-C ₄ H ₃ S- B. -CH ₂ - -CCHj) ₃ - 2-C ₄ H ₃ S- SL -CH ₂ - 2-C ₄ H ₃ S- L. CHjCH- 2-C ₄ H ₃ S- L. 1,4-C ₄ M ₄ - 2-C ₄ H ₃ S- B. -CH ₂ - 2 ^} 2 " ^H ~ 2-C ₄ H ₃ S- B. -CH ₂ - ₂ ) ₂ - ^ "^ io ¹¹ ?" 2-C ₄ H ₃ S- L. -CH ₂ - 2 ^} 2 ~ ^C 6 ^H 5 " 2-C ₄ H ₃ S-
2-C ₄ H ₃ S- SL
L. CH ₃ CH ₂ CH- *) j- --ClC ₆ H ₄ - 2-C ₄ H ₃ S- B. -CH ₂ - 2 3 ^A 3 0 η 2-C ₄ H ₃ S-
3-C ₄ H ₃ S- L.
B. -CH ₂ -
-CH ₂ - ₂ ) ₂ - ^ -C ₅ H ₄ N- 3-C ₄ H ₃ S- B. -CH, -
i ~) - -CCHj) ₃ - 3-C ₄ H ₃ S-
3-C ₄ H ₃ S- BL
L.

A09809 / 1181

4 ^H 3 ^S ~ L. -CH (CH ₃ ) CH ₂ - H- - (CH ₂ ) j- 3-C ₄ H ₃ S- DL 1,4-C ₆ R ₄ - H- 3-C ₄ H ₃ S- D. 1.4-C ₆ H ₄ - CHj> - (CH ₂ ) ₄ - 3-C ₄ H ₃ S- D. -CH ₂ - aC ₄ H ₄ N- 3-C ₄ H ₃ S- D. -CH ₂ - 0-C ₄ H ₃ O- 3-C ₄ H ₃ S- DL 1,4-C ₆ H ₄ - 1-C ₃ H ₇ - 3-C ₄ H ₃ S-
3-C ₄ H ₃ S- L.
L. CH ₃ CH- CH ₃ -
P-FC ₆ H ₄ CH ₂ - 3-C ₄ H ₃ S- L. -CH ₂ CH (CH ₃ ) - ^C 6 ^H 5 ~ ^C 6 ^H 5 " D. - (CH ₂ ), - 3,4-Cl ₂ C ₆ H ₃ C ₆ H ₅ - DL -CH, - 3,5-Cl ₂ C ₆ H ₃ 4-HOC ₆ H ₄ - D. - ^(CH 2> 3- 3,5-Cl ₂ C ₆ H ₃ Example 22 PB - (CH ₂ ), - - (CH ₂ ), - - (CH ₂ ), - - (CH ₂ ) ₆ - - (CH ₂ ), - - (CH ₂ ) ₂ -

Using the procedure of Example 1, everyone could The following penicillins can be obtained from the appropriate starting materials:

Ar

D. -CH ₂ - - (CH ₂ ) J- ^C 6 ^H 57 D. -CH ₂ - - (CHj) ₅ - In-FC ₆ H ₄ CH ₂ - Μ - (CH ₂ ) J- - (CH ₂ ), - C ₆ H ₅ CH ₂ - Ι CH ₃ CH ₂ CH- - (CH ₂ ) ₄ - O-BrC, H, - I. CCHj) ₂ C- - (CH ₂ ), - 0-C ₄ H ₃ S- L. -CH ₂ CH (CHj) - - (CH ₂ ) J- PC ₄ H ₃ O-

409809/1181

Ar * 0 D. A. -COi ₂ ), - ^R 3 Vs- S. X 1.4-C ₆ H ₄ - - (CV ₃ - * - ^CH ₃ sv 4-1OC ₆ H ₄ - D. D. -CH ₂ - - ^<CH 2 ⁾ S- S ^H 5 " 4-HOC ₆ H ₄ - SL DL -CH ₂ - - (CH ₂ ), - ^ FC ₆ H ₄ CR ₂ - 4-HOC ₆ H ₄ - SL L. -CCB ₂ > 3- C ₆ H ₅ CH ₂ - 4-HOC-H, -
0 * SL D. -CCi ₂ ), - -CCBj) ₅ - a-C.K.N-
4 4 4-HOC ₆ H ₄ - S. D. CH ₃ CH ₂ CH- -CCH ₂ ) ₆ - Ia-CH ₃ OC ₆ H ₄ CH ₂ - 4-HOC ₆ H ₄ - L. DL -CH ₂ CH (CH ₃ ) - 3'-C-H, N-
5 4 4-HOC ₆ H ₄ - D. D. 1.4-C ₆ H ₄ - «CCE ₂ ) ₅ - 0-ClC ₆ H ₄ CH ₂ - 2-C ₄ H ₃ S- S. D. -CH ₂ - --CCV ₄ -. IS-FC ₆ H ₄ CH ₂ - 2-C ₄ H ₃ S- SL D. -CH ₂ - -CCH ₂ ) ₅ - SC ₁₀ H ₇ - 2-C ₄ H ₃ S- SL -CH ₂ - £ -BrC _g K ₄ - 2-C ₄ H ₃ S- S. - (CH ₂ ), - -CCBj) ₃ - S-CF ₃ C ₆ H ₄ - 2-C ₄ H ₃ S- BL -CH ₂ CH (CH ₃ ) - ■ - ^<C V.4 " • β- € ₄ Η ₃ 0- 2-C ₄ H ₃ Sl S. 1, * - C ₆ H ₄ - -ί «2> 5- B ₁ -ClC ₆ Il ₄ CH ₂ - 2-C ₄ H ₃ S- D. 1.4-C ₆ H ₄ - .-CBVs- .C ₆ H ₅ - SV S. -CK ₂ -. -CO! ₉ } ₄ - CH ₃ - Vs- DL - (CH ₂ ), - ■ -CCBj) ₅ - nC ₃ H _? - 4-KOC ₆ H ₄ - -CH ₂ - -Cai ₂ ) ₅ - M- 3-C ₄ H ₃ S- -CH ₂ - -CCH ₂ > ₅ - ^ FC ₆ M ₄ CH ₂ - 3-C ₄ H ₃ S- —CH, - -CCH ₂ ) ₃ - 0-BrC ₆ U ₄ - 3-C ₄ H ₃ S- -CH ₂ - -CCBj) ₄ - f * SJ - 3-C ₄ Il ₃ S- CH ₃ CH ₂ CH- - (CH ₂ ) 3- 0-BrC ₆ H ₄ - 3-C ₄ H ₃ S- CH ₃ CH ₂ CH- - (CH ₂ ) 3- as- € H., OC ₆ H ₄ CK ₂ - 3-C ₄ H ₃ S- -CH (CH ₃ ) CH ₂ - - (CH ₂ ) 3- 2-C ₅ H ₄ N- 3-C ₄ H ₃ S- 1,4-C ₆ H ₄ - - (CH ₂ V SV 3-C ₄ H ₃ S- - (CH ₂ ) ₂ - -CCHj) ₄ - ^a " ^S 10 ^K 7" 3-C ₄ H ₃ S- - (CH ₂ ) ₂ - - (CH ₂ ) ₅ - HC ₃ K ₇ - 3-C ₄ H ₃ S- -CH ₂ - - (CH ₂ ) ₅ - CH ₃ - 3-C ₄ H ₃ S- -CH ₂ -. H

409809/1181

Example 23

6- [S-2 ~ phenyl ~ 2- (2-thenoimidoylaminoacetainido) acetamide] penicillanic acid sodium sal ζ

To a solution of 1.0 g (19 mk-ol) 6- [D-2-pienyl-2- (2 ~ thenoimidoylaEinoacetamidoJaoetamidoIpenicillanäure in 7 ml dioxane and 4-C τϋ V / water, the sxl2 10 G from ge garbage 1; γ / orden v / ar, 160 mg (19 mmol)! Tatriurcicarfaor ^ -:., Dissolved in 10 ml V / water, were stirred. The solution was stirred for 10 minutes and then dialyzed for 30 minutes, before the filtrate of the freeze-drying

ice cream,
underfoot? / iirde | The solid matter contained therein is slurried in 4C ml of chloroform, filtered and vacuum-dried; 88'w isg,

In common ^T 73ias, 'bsi. Terv / encLung suitable bases as Aus ^ sr.ggrip.terir?.! ? -. ·:.: \ Λ dx ^ sirfrsprechenden Kalitui> y Oalciuri- "and I ^ agnes incisal ze βοτ / ίΐ further piiamaaeiitiscli air2ept? .B-1ε j'-letallsslss the 6- [l '~ 2-Plie- ivl-2-'2 ~ -; IieiLoiEiidoylaminoacetai; iidc) -acöt? - "iid0jpenieillan-3äure as well as the other deeply closed penicillins,

6- (D-2-Phenyl -2- · ^f '3-aiQidi'xiO "jroüionaBiido) - Example 24"".."

.... ". acetamido jpenic ^ lläAASl

A dilution of 1.7 g (3.8 mmol} 6- [D-2-I ^J henvl-2- (3-amidincpropionamido) acetanilide-penicillic acid in 2C ml "water was added with 0-5 tablespoons (3 * 3 millimoles) treated with it. 5 minutes in rubble, a small amount of Unlb-s3.iches could be filtered off; the filtrate was left to freeze troublesome with it.

In a corresponding v / eise komit-an das Ar_jicni ~ ju2sals as well as others pharmaceutically acceptable sal. ^ e, the ε-i "of organic amines derive from the .above mentioned penicillin as well as from the other penicillins described here "manufactured four,

4ÖÖ8ÜS / 11

Example 25

iline tablet matrix was prepared by doing the following Ingredients mixed in the given weight ratios:

Succrose, U.S.P. 80.0 Tapioca starch 12.5 Magnesium stearate 7.5

A sufficient amount of 6- [D-2-phenyl-2- (3-amidinopropionamido) -acetamido] penicillic acid was added to this basic substance so that tablets could be produced, each containing 25 » and 250 mg of active substance, respectively.

Example 26

A suspension of the sodium salt of 6-j.D-2-phenyl-2- (amidinoacetamido) acetamidojpenicillanic acid was obtained manufactured with the following composition:

Penicillin _{compound 31 S} 42 g * 70% aqueous sorbitol 714.29 g glycerine, USP 185.35 S Guinmiakasia (10 ^ ige

Solution) 100.00 ml

Polyvinylpyrrolidone G, 50 g propyl p-hydroxybenzoate C, Q72 g distilled water to make up to 1 liter 0.094 g

The suspension can contain various sweeteners and flavors as well as acceptable dyes can be added. 1 ml of the suspension contains approximately 25 mg of the penicillin compound.

Example 27

Capsules with 25, 100 and 250 mg of active substance were made prepared by adding a sufficient amount of 6— [Β — 2 — phenyl-

409809/1181

2- (p-chlorobenzinidoylaminoacetamido) acetamidojpenicillanic acid into the following mixture (proportions in parts by weight specified) incorporated:

calcium carbonate, TJ.S.P. 17.5

Di c alc iumpho sphat 18.9

Magnesium trisilicate 4.2

Lactose, U.S.P. . 6.2

Potato starch 5.2

Magnesium stearate 1.0

Example 28

A form of the suitable for parenteral administration Sodium salt of 6- [D-2-phenyl-2- (acetimidoylaminoaeetamido) -acetamidojpenicillanic acid was made by intimately mixing the penicillin compound with sodium citrate (4 wt .- $) dissolved in so much polyethylene glycol 200 that the final concentration of the penicillin compound 25 mg of active substance per ml. The solution obtained was sterilized by filtration and filled into ampoules in a sterile manner. In appropriate The other derivatives according to the invention could also be processed will.

Preparation A Amidinoalkanecarboxylic acids

1. 3-amidinopropionic acid hydrochloride

a. Methyl β-carbomethoxypropionimidate hydrochloride

Through a solution of 8.2 g (0.256 moles) of anhydrous Methanol and 29 g (0.256 moles) of commercially available methyl 3-cyanopropionate anhydrous hydrogen chloride gas was blown into 20 ml of A with cooling to 0 C. Once the theoretical amount of gas had been absorbed (approx. 9.4 g), the gas supply was interrupted and the sealed reaction mixture in a freezer

409809/1181

turned off overnight. The precipitate formed was filtered off, washed with A and dried in vacuo; 36.2 g (78 % yield); F. 80 - 82 ⁰ C.

b. ß-carbomethoxypropionamidine hydrochloride

Was added to a suspension of 16.5 g (G, 09 mol) of methyl ßcarbomethoxy-propionimidate hydrochloride in 20 ml of methanol were dissolved at ice bath temperatures 12 ml of the same solvent in which _s 1.7g ammonia gas rcaren given. The reaction mixture was left to stand for 2 hours at rt, with stirring, whereupon the insoluble material had to be filtered off and the pebble had to evaporate to almost dryness. The remaining solid white residue was treated with ethanol, filtered and dried; 7.8 g (51.5 follow yield); P. 132 - 134 ⁰ O,

c. 3-amidinopropionic acid hydrochloride

A solution of 7.8 g (0.047 mol) of β-carbomethoxypropionamidine hydrochloride in 217 ml of 12N ECl was heated on a steam bath for one hour. The solution was then cooled and evaporated to dryness in vacuo; the residue was triturated several times with ethylene dichloride and filtered; 7.1 g (99 '/ age yield); IO 138-140 ⁰ G. McElvain et al. Jo Am. Soc., _71_, 40 (1949) report that _s the melting point of crude product 131-137 ° is 0.

2. Starting from the corresponding nitrile and amine or When using the general procedure according to preparation A-1a-c, ammonia can be given the following amidinoalkanecarboxylic acid- Produce hydrochlorides, which serve as intermediates and lead to the products according to the invention.

409809/1181

- (CH ₂ ) H- ^R 2 H- 5 ~ H- S —N H- A. QI ₃ - H- H- * CA-CO-H-HCl
R ₃ rN ^ ² H- -CH ₂ - ^R i CH ₃ - HC ₃ H ₇ - CH ₃ - ^R 3 H- -CH ₂ - H- 1-C ₃ H ₇ - H- H- H- -CH ₂ - CH ₃ - H- H- - (CH ₂ ), - CH- H- H- - (CH ₂ ) ₂ - H- H- H- -CH ₂ - C ₂ H ₅ - H- H- CH ₃ CH- n-C H - H- H- (CH ₃ ) ₂ C- CH, - H- ¹ ^ ₃ "? - (CH ₃ ) ₂ C- 3
H- H- XCH ₃ ) ₂ b ~ CH, - CH ₃ - 2.-BrC ₆ H ₄ - "* ^ CH ₂ - 3
H- H- E-CK ₃ C ₆ H ₄ CH ₂ - -CCH ₂ J ₂ - Έ- H- 2-C ₄ H ₄ N- -CCH ₂ J ₂ - H- H- .-CH ₃ C ₆ H ₄ - -CCH ₂ J ₂ - H- H- PC ₄ H ₃ S- -CH ₂ - H- H- 4-C ₅ H ₄ N- -tCH ₂ ) ₃ - H- H- -CH ₂ - H- H- -CH ₂ - H- H- ^{1st 4} - ^C 6 ^H 4- H- 1,4-C ₆ H ₄ - H- 1,4-C ₆ H ₄ -

H- ⁿ - ^C ₃ ^H ₇ - ° - ^C1C 6 ^H 4 ^C V " ^C V

409809/1

233838S

"ι H- H- ^R 3 A. H- H- ^ ClC ₆ H ₄ CH ₂ - 1.4-CH ₄ - ^C 2 ^H 5 ~ Η— 0-C ₁₀ H ₇ - 1,4-C ₆ H ₄ - H- H- H- 1,4-C ₆ H ₄ - H- Η— C ₆ H- 1,4-CH- H- H- 0-CJC ₆ H ₄ - 1,4-CH ₄ - Η—
H* H-
H- 2-C.H.N-
4 4 1,4-C ₆ H ₄ - CH ₃ -. H-
H- C ₆ H ₅ CH ₂ -
2-C ₄ H ₃ O- 3,4-Cl ₂ C ₆ H ₃ -
3,5-Cl ₂ CH- 1,4-C ₆ H ₄ -

* In the synthesis of intermediates in which A is methylene or alkylidene with 2 to 3 carbon atoms and R, aryl or mean a heterocyclic radical, the t-butyl ester is used for the preferred route of synthesis, which is then removed in the final stage with the aid of dilute acid, e.g. trifluoroacetic acid, at room temperature.

3. N.N'-diethylamldinoeacetic acid hydrochloride

a. N-ethyl-carboethoxyacetamide

To 15.0 g (0.1 mol) of carboethoxyacetyl chloride in 150 ml Benzene was added 9.9 g (0.22 mol) of ethylamine in 50 ml of the same solvent with cooling. The reaction mixture was under Stirring turned off at Rt overnight and then filtered. That Piltrate was washed with water, dried over sodium sulfate and concentrated to dryness. The residue was used several times Washed isopropyl ether and vacuum dried. The raw product was used for the next reaction stage without further purification.

b. Methyl N-ethyl-oarboethoxyacetimidate

A solution of 9.54 g (0.06 mol) of N-ethylcarboethoxyacetamide in 20 ml of benzene was heated to reflux and, with stirring, with 5.69 ml (0.06 mol) of dimethyl sulfate in the course of 2.5 hours offset; the resulting mixture was for a further 16 hours Heated to reflux. The cooled mixture was carefully mixed with

409809/1 181

6n sodium hydroxide solution neutralized, whereupon the organic Phase was separated off and dried over sodium sulfate. To Removal of the solvent under reduced pressure was the crude product, which without further purification for the next Heaktionsstufe was used.

c. NjN'-diethylcarboethoxyacetamidine hydrochloride

To a solution of 3.46 g (0.02 mol) of methyl N-ethyl-carbethoxy-acetimidate 900 mg (0.02 mol) of ethylamine were added to 30 ml of X. The reaction mixture was several hours stirred at Ht. Anhydrous HCl-Gae was slowly added to the The reaction mixture was initiated until the formation of the amidine hydrochloride ceased. The product was filtered and vacuum dried.

d. N, N · diethylamidinoeacetic acid hydrochloride

A solution of 2.2 g (0.01 mol) of N, N'-diethylcarboethoxyacetamidine hydrochloride in 60 ml of 12N HCl was converted into the free acid in the same way as in Preparation A-1-c is described.

4. Using the procedure of Preparation A-2a-d using the appropriate starting materials, the following could be made Intermediate products are obtained which are required for the synthesis of the compounds according to the invention.

^R l CH ₃
i-C R ₂ -N \
C-A-CO-H- HCl A. CH ₃
CH ₃ R ₃ -N -CCH ₂ V ^R 2 ^R 3 - (CH ₂ ) ₃ -
CH Ch- H- 3 ^H 7- CH ₃ -
1-C ₃ H - H- CH ₃ -
CH ₃ -

409809/1181

-H

^H ~ ^C 2 ^H 5 " ^C 2 ^H ₅ - CH CH ₉ CH-

H-

^(αΐ 2> 3- (CH ₂ ) ₅ - ^(CH 2 ⁾ 2-

(CH ₂ ) 3-

- (CH ₂ ) 3-

(CHp ₆ -

(CHp ₆ - ^(CH 2> 5-

(CH ₂ ) ₅ -

^H ~ ⁿ " ^C 3 ^H 7- ⁿ - ^C 3» 7- - (CHp ₃ -

CH ₃ - CH ₃ - CH ₃ - -CH ₂ -

CH ₃ - ¹ H- 2-ClC ₆ H ₄ - - (CIIp ₃ - C_H, - H- IB-CF-C ₄ -H.- CH-CH-C ¹ H-

2 5 3 ο <»^ i

CH ₃ - CH ₃ - £ -FC ₆ H ₄ - CH ₃ CH- CH ₃ - CH ₃ - ^ -CH ₃ OC ₆ H ₄ - -CH ₂ -

H- C ₂ H ₅ - C ₂ H ₅ - MC ₆ H ₄ -

CH3- H- 2-C ₅ H ₄ N- 1,4-C ₆ H ₄ -

CH ₃ - H- 2TClC ₆ H ₄ - 1.4-C ₆ H ₄ -

CH, - CH_- CH, - 1,4-C, H.-

YY J D H

^C 6 ^H 5- -CH ₂ - -T-FC ₆ H ₄ CH ₂ - -CH ₂ - C ₆ H ₅ CH ₂ - - (CHp ₃ - 0-BrC ₆ H ₄ - CH ₃ CH ₂ OI- 0-C ₄ H ₃ S- (CHp ₂ C- 3-C ₄ H ₃ O-
η-ΓΗ Γ Η - -CH ₂ CIl (QI ₃ )
1 Δ-Γ H - ■ Ε- ^ω 364
UC ₄ H ₄ M- I ₁ * 1. ₆ Η ₄
- (CH ₂ ) ₃ - B-CH ₃ OC ₆ H ₄ - CH ₃ CH ₂ CH- 3-C ₅ H ₄ N-
η — Π Γ VI ΓΗ - -CH ₂ CH (CH ₃ )
1 LC H - • Ε- 6 4 2
^P - ^C 1O ^H 7- -CH ₂ - J ₁ -BrC ₆ H ₄ -
_ ftrf Λ · U -CH ₂ -
fm \ J ^ -CF ₃ C ₆ H ₄ -
^C 6 ^H 5- - (CH ₂ ) ₂ -
¹ ^ -C ₆ V 2-C ₅ H ₄ N- -CH (CH ₃ ) CH ₂ ^ ^C 10 ^H 7- - (CH ₂ ) ₂ - HC ₃ H ₇ - - (CHp ₂ - CH ₃ - -CH ₂ -

A09809 / 1181

5. 3- (2-Imidazolinyl) propionic acid hydrochloride "38389

To a solution of 7.65 ml (0.1 H mol) of ethylenediamine in 120 ml 21.8 g (0.12 Mo]) of methyl β-carbomethoxy propionimidate hydrochloride were added to anhydrous ethanol. The resulting The mixture was refluxed overnight. Thereafter, the mixture was cooled and filtered, and the filtrate became to concentrated in an oil. The oil became more concentrated with 600 ml HCl was added and the solution was heated on a steam bath for 1.5 hours. Then the solution was under reduced pressure again concentrated to an oil, which after trituration first with ethylenediochloride and then with acetone the desired Product in the form of a solid white substance in the amount of 15.0 g.

6. Starting from the required iminoester, which is described in here described manner has been produced, and the corresponding diamines were able to use the general working conditions according to preparation A-5 the following intermediate products are obtained, which lead to the products according to the invention: r

CA-CO ₂ H-HCl R ₃ -N

H- - (CH ₂ V -CH ₂ - H- H- - (Qi ₂ V CH ₃ CH- H- - (Cu ₂ ) ₃ - -CH ₂ - H- . - ^(c v ₅ - -CH ₂ - CH ₃ - -CH ₂ - Ti-C ₃ H ₇ - - (CH ₂ V -CH (CH ₃ ) CII ₂ - H- - (CH ₂ V CH ₃ CH ₂ OH- C ₂ H ₅ - - (CH ₂ ) 3- C ₂ H ₅ - - (CH ₂ ) 3- - (CH ₂ ) ₂ - CH ₃ - - (CH ₂ V (CHj) ₂ C- H- - (CH ₂ -V - (CH ₂ ) ₂ - H- - (CH ₂ V 1,4-C ₆ K ₄ -

409809/1181

2338383

Preparation B

Amidinoalkanecarboxylic acid chloride

1x 3-amidinopropionyl chloride hydrochloride

A solution τοη 1.52 g (0.1 mol) amidinopropionic acid hydrochloride in 18 ml of thionyl chloride was stirred "at Rt over Compartment parked. The excess solvent-reactant was then removed under reduced pressure, whereupon the product could be isolated as a yellow gum which crystallized on standing; 1.5 g. '

2. In the manner described above, from the corresponding acid hydrochlorides and thionyl chloride too the other acid chlorides, which are necessary for the acylation of the α-Aminoarylmethylpenicillins are required.

Preparation G

Imidoylaminoalkanecarboxylic acids . *

1. Isobutyrimidoylaminoacetic acid hydrochloride

a. Ethyl isobutyrimidate hydrochloride

Hydrogen chloride gas was slowly blown into a solution of 34.5 g (0.5 mol) of isobutyronitrile in 25.3 g of absolute alcohol (ethanol), which was kept at ^{0 0} O in an ice-water bath. After 1.5 hours the feed pipe was removed; .the mixture remained at Rt for several days. The solvent was then removed under reduced pressure and the clear oil which remained as a residue was treated with 400 ml of A *. The precipitate formed was filtered off after stirring overnight and washed with 1 and vacuum dried; 51.8 g (68 foige yield); F. 100 to 101.5 ⁰ C

b. Isobutyrimidoylaminoacetic acid hydrochloride

250 ml of a 33 $ solution of potassium carbonate in water were mixed with

409809/1181

vers ow 51.0 g (0.55 mol) Ä ^ hylisobutyrimidat hydrochloride /, was extracted after which the free base with 500 ml. 1 The! Extract was dried over sodium sulfate and calibrated to an oil; the remaining base, 27.7 g, was combined with 9.0 g of glycine and 24 ml of amyl alcohol. After refluxing for two hours, the mixture was cooled and the precipitated product was filtered off, washed with X and dried; 16.4 g; P. 208 - 210 ⁰ C (with decomposition).

8 g (0.055 mol) of the free base in 200 ml of A * were treated with HCl gas. After stirring for 50 minutes, the product was filtered off and dried; 9.9 g »F. 155-170 ⁰ O (with decomposition).

2. The following acid hydrochlorides were used as intermediates synthesized which lead to the products according to the invention. For this purpose, the procedure according to preparation B-1a-b applied and the required raw materials used in each case.

) -A-OO ₂ H.HGl

409809/1181

^R 2 H- H- 2338389 -CH ₂ - H- ^CH 3 " A. -CH ₂ - *H- H- C ₂ K ₅ - -CH ₂ - H- H- -CH ₂ - H- H- H- -CH ₂ - H- H- H- - (CH ₂ ), - * CH ₃ - H- H- fr * \ t \ * 1-C ₃ H ₇ - H- 1-C ₃ H ₇ - CH ₃ CH ₂ Hh- *H- H- CH ₃ - -CH (CH ₃ ) CH ₂ - HC ₃ H ₇ - H- H- H- H- C ₂ H ₅ - *H- H- H- -CH ₂ CH (CH ₃ ) - CH ₃ - H- H- '6 4 *H- H- H- —CH, - * 11-C ₃ H ₇ - H- ^ -ClC ₆ H ₄ CH ₂ - -CH, - MC ₃ H ₇ - H- ^C 6 ^H 5 ~ -CH ₂ - H- H- Ji-CH ₃ OC ₆ H ₄ - -CH ₂ - H- H- £ -CF C ₆ H ₄ - -CH ₂ - H- H- Jt-ClC ₆ H ₄ - -CH ₂ - H- H- 2-C ₄ H S- -CH ₂ - H- H- -CH ₂ - H- H- -CH ₂ - H- H- P-CH ₃ C ₆ H ₄ - -CH ₂ - H-
ft H- H-ClC ₆ H ₄ - -CH ₂ - H- H- 2-C ₄ H ₃ O- -CH ₂ - H- H- -CH ₂ - H- H- o-ClC-H, -
6 4 -CH ₂ - H- H- Bi-CH ₃ OC ₆ H ₄ CH ₂ - -CH ₂ - CH ₃ - H- 0-CF ₃ C ₆ H ₄ - CH ₃ CH- H- H- Bi-CH ₃ OC ₆ H ₄ - -CH - H- H ~ * o-ClC-H, - CH ₃ CH ₂ CH- H- H-

409809/1181

In the table above, the intermediates are marked with an *, "in which Rp ^{urid r} a both denote hydrogen. For the preparation of these intermediates, a condensation of lormamidine with the required amino acid was preferably used, according to the instructions of Uyeda et al., J Biol. Chem. 240, 1701 (1965).

3. N-CN'-methylacetimidoylminoacetic acid hydrochloride a. Ethyl g-methylacetimidate

! Driethyloxoniuinfluoroborat, prepared from 91 g (0.64 mol) of boron trifluorine etherate and 44.4 g (0.48 mol) of epiohlorohydrin in 300 ml Ä, according to the method of Meerwein et al., J. Prakt., 154 , 83 (1940), which was dissolved in 75 ml of MO, were added dropwise with 23.6 g (0.04 MOL) of N-methyl acetamide, which was dissolved in 200 ml of the same solvent, while cooling to 10-15 °. The resulting solution was stirred Rt and then turned off overnight. 76 g of a 50% strength potassium carbonate solution were then slowly added to the solution with stirring. The mixture was filtered and the filtrate was dried over sodium sulfate and concentrated in vacuo to leave an oil. This residue was used for the next reaction step without further purification.

b. M "- (] Jf ^l -Methylacetimidoyl) aminoacetic acid hydrochloride

A solution of 10.1 (0.12 mol) ethyl N-methylacetimidate and 4.5 g (0.06 mol) glycine in 36 ml amyl alcohol was refluxed for 1.5 hours. The deposited precipitate, which had formed on cooling the reaction mixture, was filtered and washed several times with A * and then vacuum-dried. The product obtained in this way was suspended in 250 ml of oil and then treated with gaseous HOl until it had been converted into the hydrochloric, which was filtered off and dried.

409809/1181

4 · Exodus from the appropriately substituted mines and amino acids were able to produce the following intermediates, which are suitable for the production of the end products according to the invention were required, can be obtained.

C ₂ H ₅ -
H-
H- E.-M
* Il Rj) -A-CO ₂ H-HCl - A. ¹ I. H-
H- Ε, H -CH ₂ -
- (CH ₂ ), - H- HC ₃ H ₇ - HC ₃ H ₇ - CH ₃ CH-
1,4-C ₆ H ₄ - H-
H- C ₂ H ^_5-7 C ₂ V
»3- " ^(CH 2 ⁾ 2 ~ H- 1-C ₃ H ₇ - CH ₃ - -CH ₂ - H-
H-
H- C ₂ H ₅ -
HC ₃ H ₇ - -CH ₂ - H- CH ₃ - 2-CF ₃ C ₅ H ₄ - -CH ₂ -
-c « ₂ -
-CH ₂ - C ₂ H ₅ -
H- .-FC ₆ H ₄ -
3,5-Cl ₂ C ₆ Il ₃ - -CH ₂ - H- 3,4-Cl ₂ C ₆ H ₃ -

409809/1181

5. 2- (Nn-Propyl-N-oarboacymethyl) amino-1-aza-cyclohept-2-ene »HGl

A solution of 14.1 g (0.1 mol) of O-ethylcaprolactim, Benson et al., J. Am. Chem. Soc, 70, 2115 (1948), and 5.85 g (0.05 mol) N-n-Propylglycine, Greco et al., J. Med. Chem., £, 861 (1962), in 40 ml of amyl alcohol was heated to reflux for 2 hours. The reaction mixture was then cooled and the precipitate was filtered off, washed several times old Ä ° and dried. A suspension of this product in 175 ml was 1.5 hours treated with gaseous HCl. After stirring for three hours at rt the solid substance was filtered off and vacuum dried. The product was used for the further reactions without further purification.

6. Using the procedure described above, preparation 0-5, the following intermediate products could be produced from the required Laotlmen and amino acids:

1-A-CO ₂ H-HCl

H- - «3
H- H-- H- CH ₃
H- H- CH ₃
H- 5 " C ₂ H

-CH ₂ -

- (CH ₂ ) ₃ - -CH ₂ -

- (CHj) ₂

- (CH ₂ ) ₃ - CH ₃ CH-

- (CHj) ₃ - (CH ₃ ) ₂ C-

- (CHj) ₃ - -CH (CH ₃ ) CH ₂ -

- (CHj) ₃ - 1.AC ₆ H ₄ -

- (CHj) ₄ - HC ₆ H ₄ -

⁾ 3 "" ^CH 2 "

A09809 / 1181

7. F-carboxymethylimidazoline II hydrochloride

a. OT-carbobenzyloxymethylimidazoline

To a solution of 14.0 g (0.2 mol) of imidaz & in 150 ml of dry DMF, 22.9 g (0.1 mol) of benzyl bromo acetate were added dropwise with cooling. Once the addition was completed, the reaction mixture was several hours at 50 - 60 ⁰ C is heated, then cooled and diluted with 250 ml of water «The product was extracted with Ä and the extracts were combined and washed several times with saturated brine!. The λ phase was dried over sodium sulfate and concentrated to an oil which was used for the further reaction without further purification.

b. OT-Oarboxymethylimidazoline Hydrochloride

A suspension of 10.9 g (0.05 mol) IT-carbobenzyloxymethylimidazoline and 50 mg of 5% palladium-on-carbon in 100 ml of ethanol was shaken in a hydrogen atmosphere at atmospheric pressure. As soon as the theoretical amount of hydrogen has been absorbed the spent catalyst was filtered off and the filtrate was treated with one equivalent of hydrogen chloride, which was dissolved in ethyl acetate treated. The solution then present was concentrated to dryness in vacuo; the residue was triturated with Ä and filtered.

8. With the aid of the alkylation and hydrogenation described for preparation C-7a-b, when using the corresponding starting materials produce the following intermediate products which lead to the products according to the invention:

409809/1181

- (CHj) ₃ - - (CHj) ₃ - - (CHj) ₃ - - (CHj) ₂ -

- (CKj) ₆ -

- (CHj) ₃ - -CCHj) ₃ -

-CCHj) ₂ -

-CCH ₂ ) ₃ -

"CCH ₂ ) ₂ - -CCHj) ₂ - -CCHj) ₂ - -CCH ₂ ) J-

- 58 -

) -A-COJl-HCl

^R l * 2 h

-CCHj) ₂ - -CCHj) ₅ - -CCHj) ₂ -

I- 3,5-Cl ₂ C ₆ H ₃ -

CH ₃ - -CH ₂ - ^C 6 ^H 5- -CH ₂ - 2-ClC ₆ H ₄ - - (CHj) ₂ - 2-CF ₃ C ₆ H ₄ - - (CHj) ₂ -
nt hu 2-FC ₆ H ₄ -
■ -BrC, H.- AT ₃ (^ f-
CH ₃ CH ₂ CH- 3.4-Cl ₂ C ₆ H ₃ - - (CHj) ₂ - ^C 6 ^H 5 ~ -CHjCH (CH ₃ ) - 0-C ₄ H ₃ S- -CH ₂ - 3-C ₅ H ₄ N-
AJ " ¹ ti O— -CH ₂ -
- (CH) - PC ₄ H ₃ O-
H- ^v 2 2
-CCH ₂ ) ₃ - 0-C ₄ H ₄ N- -CH ₂ - ° - ^C 10 ^H 7- -CH ₂ - 0-C ₄ H ₃ O- -CHj- AC ₃ H ₇ - i. * - c ₆ V 2-CH ₃ OC ₆ H ₄ - ¹ ^ -C ₆ H ₄ " ⁰ " ^C 1O ^H 7" -CHj- ^C 6 ^H 5 " -CHj- C ₆ H ₅ CH ₂ -
1-C1CH - -CH ₂ -
CH ₃ CHjCH- OH
2-CH ₃ C ₆ H ₄ CH ₂ - -CHj- 4-C ₅ H ₄ N- -CHj- CH ₃ - 1.4-C ₆ H ₄ - 3,5-Cl, C _A H, - -CHj-

409809/1181

Preparation D

Imidoylaminoalkanecarboxylic acid chlorides

1. Foraimidoylaminoacetyl chloride hydrochloride

A suspension of 1.05 g (7.6 mmol) of pormimidoylaminoacetic acid hydrochloride in 30 ml of dry MO was treated with 1.57 g (7.6 mol) of phosphorus pentachloride; the mixture was shut down with stirring at Rt overnight. The product was suctioned off and vacuum dried; 1.09 g (91% yield).

2. Benzimidoylaminoacetyl chloride hydrochloride

To benzimidoylaminoacetic acid hydrochloride (2.2 g, 10 mmol) in 40 ml of dry IiG there was 2.5 g (12 mmol) of phosphorus pentachloride given; the mixture was laughed at and turned off with stirring. The product was filtered off, washed several times with MO (50 ml), chloroform (2 × 75 ml) and hexane (50 ml) and T vacuum dried, 2.5 g (99% yield).

3. In the above way, using the appropriate Acid hydrochloride the imidoylaminoalkanecarboxylic acid chloride hydrochloride win that the acylation of a-aminoarylmethylpenicillins are needed.

Preparations

1,3-diazacycloalk-2-enes

The 1,3-diazacycloalk-2-enes used as starting materials for Preparation C-8 required v / ground, are made according to known methods; Reference is made in particular to: laust et al, J. Am. Chem. Soc, 8J_, 2214 (1959), Baganz et al, Ber.,

409809/1181

95., 1S40 (1962) mid Oxley et ε · 1, J. Chciri. ooc, 497 (1947) and 859 (1950).

Preparation P

/ τι in. ο acids

1. The amino acids used as intermediates for the present Invention needed are either commercially available lieagentien or can be synthesized in the known "./eise, for example, according to the method of G-reenstein, et p, 1, "Chemistry of the Amino Acids," John, iley ά Sons, Inc., New York, Ii.Y., 1961, Vols. 1, 2 and 2

G-

Halogen ester

1 . Me required as intermediates II ;; logenesters are either commercial chemicals or can be easily produced in a known ', / eiseii, e.g. according to the ran'.ode by V /' agner et al, "Synthetic Organic Chemistry," John ..iley <x bong, Inc.,! Few York, II.Y., 1953, chapter

409809/1181

Claims (23)

Claims including the pharmaceutically acceptable basic salts thereof, wherein in the formulas Ar phenyl, 4-hydroxyphenyl, 2-thienyl or 3-thienyl, A 1,4-phenylene, alkylene having 1 to 3 carbon atoms or alkylidene with 2 to 3 carbon atoms, R ₁ and R ₂ each individually hydrogen or alkyl having 1 to 3 carbon atoms, R ₅ and R. each individually alkyl with 1 to 3 carbon atoms, naphthyl, thienyl, pyrryl, furyl, pyridyl, phenyl, benzyl, substituted phenyl or benzyl - where the substituent is chlorine, bromine, fluorine, methyl, 409809/1 181 Methoxy, irifluoromethyl, 3,4-di. chi or 3,5-dichloro can be - or hydrogen, R ₁ and Rp together are alkylene with 2 Ms 6 carbon atoms, R ₂ and R ₅ together are alkylene with 2 "to 4 carbon atoms, and Rp and R / together are alkylene with 3 "to 5 carbon atoms
"can mean. 2. Compounds according to claim 1, which have the D-configuration. 3. "Compounds according to claim 2, formula I, characterized in that Ar phenyl, R. ¥ hydrogen, R ₂ and R _y - if considered alone - hydrogen and Rp and R- if considered together" - alkylene with 2 to Mean 4 carbon atoms. 4. A compound according to claim 3 _} characterized in that A -CH ₂ - and R ₂ and R ^ are both hydrogen. 5. A compound according to claim 3, characterized in that A - (CIL ·, ^ - and R ₂ and R ₅ both mean "hydrogen. 6. A compound according to claim 3, characterized in that A -GH ₂ - and R ₂ and R ₅ together - (GH ₂ ) ₂ - mean. 7. Connection to. Claim 3, characterized in that A - (CH ₂ ) ₂ - and R ₂ and R ₇ together - (GIL,), -, - mean- 8. Compounds according to claim 2, formula II, characterized in that Ar phenyl, A -GH ₂ -, R ₂ and R ₅ both ¥ aster substance and R ^ hydrogen or alkyl having 1 to 3 carbon atoms "mean. 409809/1181 9. A compound according to claim 8, characterized in that Ii. Hydrogen "means. 10. A compound according to claim 8, characterized in that R is methyl ". 11. A compound according to claim 3, characterized in that R. means ethyl ". 12. A compound according to claim 8, characterized in that R. is n-propyl. 13. A compound according to claim 8, characterized in that R, i-propyl means. 14. Compounds according to claim 2, formula II, characterized in that Ar is phenyl, A is alkylene having 1 to 3 carbon atoms and R «. and R _{2 are} both hydrogen. 15. A compound according to claim 14, characterized in that A is -CHp- and R- is phenyl. 16. A compound according to claim 14, characterized in that A is -CH ₂ - and R. is p-chlorophenyl. 17. A compound according to claim 14, characterized in that A is -CHp- and R, p-iTuorophenyl. 18. A compound according to claim 14, characterized in that A is -CH ₂ - and 11, p-bromophenyl. 19. A compound according to claim 14 »characterized in that A is -CH ₂ - and R, 2-iDhienyl. 20. A compound according to claim 14, characterized in that A is -CH ₂ - and R. 2-puryl. 409809/1181 21. A compound according to claim 14, characterized in that A is -GH ₂ - and R. is 3,4-Dichlo.rphenyl. 22. A compound according to claim 14, characterized in that A is -OHp- and R, 3,5-dichlorophenyl. 23. Process for the preparation of compounds of the formulas I. or II according to claim 1, characterized in that a compound of the formula Ar-CH-CO-NH t NH ₂ ^ COOH or a salt thereof with a compound of the formula 0 R - A - 8 - X in which R r ι ¹ Λ «· - If or ^z « —C-N- represents - where R ₁ , R «, R ^, Rj and A have the meaning given in claim 1 and X is -OH or Cl - is reacted in the presence of an agent which splits off water or HCl, whereupon the compound obtained is optionally converted into a pharmaceutical transferred to acceptable basic salt. Pur Pfizer Inc., New YoTk _1n Ή.Υ. , V.St.A. Attorney 409809/1181