DE1645998A1 - Substituted 6- (1-aminocycloalkylcarboxamido) penicillanic acids - Google Patents

Description

DR. EULE DR. BERG DIPL.-ING. STAPF

PATENT LAWYERS IC / KQQQ

8 MUNICH 2. HILBLESTRASSE 2O I O * t O i? O Q

• " Dr. Eule Dr. Berg Dipl.-Ing. Stopf, 8 MOndien 2, HilblestroSe 20

Be / Be

Attorney File 16 572

Your reference Our reference date 2.5 »S @ P 19fi7

American Home Products Corporation Few York / ö. S, A.

"Substituted 6- (i-AminocyöloalkylcarDoxamido) · peiiioilla acids ".

The invention "relates to new., Synthetic penicillins with strong effectiveness against gram-negative and gram-positive microorganisms, as well as entanglement in their production. "■

Oasis AHP-3992-f -2-

00S832 / 1845

(0611) * 5 U 20 81 Ttlogram ·! PATENTEULE MOnchsn Sank: Bayariidie Vtreinsfcank Munich 453100 Postscheck, Mönchin «3 43

The new penicillins of the present invention are compounds of the general J-formula (I):

GO - HH - CH CH C

C - U - CH - COOH

Il

and their salts, where in the '.Formula R, R, H ^ and R * hydrogen, lower-alkyl (for example methyl, ethyl, = n-propyl or butyl), halogen (for example chlorine or bromine) »nitro and / or SuIfο, where one or two of the radicals H, R, R and R * are always other than water

1 2 ■? material, and when any of R @ ste R, H, R ^ and R ^ is lower alkyl and the rest are hydrogen, lower alkyl of at least two carbon atoms contains the lower alkyl radical © contain 1 to 6, preferably 1 to 4 carbon atoms.

The new compounds of the general formula (I) are prepared by reacting a 4 * -substituted-2,5-oxazölidindione (also known as N-carboxy amino acid aahydiide or NCA) of formula (II)

R ² R ¹ .
100 G

_Y

- (\ KH CO

r3 R ⁴

009832 / 184S " ³ ~

(where "in the formula E, R, H ^ and E ^{mean the above K} meanings) mil; 6-Aminopeiiieiilinsatur (6-APA). Preferably a mixture of 6-APA, methylene chloride and triethylamine is prepared first and the selected Then add N-carboxy anhydride while stirring is continued * Alternatively, the carboxy anhydride can be dissolved separately in another mixture of methylene chloride and triethylamine before it is mixed with the first mixture of 6-APA, methylene chloride and triethylamine of the general formula (I), which are based on the reaction between 6-APA and the N-oxyamino acid anhydride, can then be obtained from organic solvents using conventional methods such as nitration, concentration, water extraction and precipitation from organic solvents, as indicated .

The K-Öarboxysäureanhydrides, which are used to manufacture the new Penicillic acid compounds of this invention are suitable, can according to known. Processes are produced, for example in. The German patent application Kr. A 42 42? are described. (British Patent Publication 977 609)

The new connections peeled off according to the present invention cover a wide area. antibacterial effectiveness and are used as therapeutic agents for poultry and mammals, as well as in ß'ensciien ₉ sur Beiianälun ^ by grain-susceptible and gram-negative bacteria.

OÖ9832 / 1t4S

1645398

mild infectious diseases, either parenteral or oral use. You can find it as a nutrient as well Determine supplements at Ti erfutt application.

It is clear to the person skilled in the art that the compounds according to the invention in their acid form or in the form of the therapeutic effective salts can be used, e.g. the sodium or potassium salts or acid addition salts such as hydrochloride sulphate or fumarate, or in the form of pharmaceutical acceptable salts produced by the reaction of penicillin compounds with an amine or diamine base, e.g. procaine or various N-N'-disubstituted alkylenediamines, such as N, N'-dibenzylethylenediamine, can be prepared.

It is also clear to those skilled in the art that the Compounds of the invention in suitable dosage forms including solutions, suspensions, tablets, capsules and using conventional solvents, Suspensions and excipients can be used. the The invention therefore also provides a pharmaceutical preparation which contains a compound of the general formula (I) and a pharmaceutically acceptable carrier.

The following examples explain the invention without limit the scope of the invention.

009832/1845

"■■ '—5—

example 1

eillanic acid

ELn mixture of 10.8 g of 6-APA, 68 ml of methylene chloride and 8.7 ml of triethylamine has been stirred for 45 minutes at room temperature and quenched dam to -11 ⁰ C. 7 »5 · β N-Garboxy-2-chloro-5-methyl-1-aminö-eyclopentan-carbonön r. Acid anhydride was added and stirring was continued at -11 ⁰ G for 5 hours. The suspension was filtered and the filtrate was poured into 200 ml of ethyl ether. The solution was then concentrated to about 75 ml and 4 ml of acetic acid in 25 ml of ethyl acetate were added. The mixture was allowed to stand at -18 ° C for 18 hours and the products separated. This product was effective against Staphylocoecus aureus and Eascherichi coli. V

Example 2 . :

6-Ci-Mino-2-ethylcyclopentanecarboxaiQidQ) penicillanic acid. _;

A mixture of 10.8 g of 6-APA, 60 ml of methylene chloride and 8 ml of Iriäthylamin was two hours at room temperature stirred and filtered. The filtrate was diluted to 100 ml and there was a solution «the 8 g of N-Garboxy-1-amino-2-ethylcyclopentanecarboxylic anhydride, 4.5 © 1 Triethylamift and containing 50 ml of methylene chloride, added Bach 46 Hours of standing at room temperature, the device was

009832/1845

mixed filtered and the piltrate evaporated to an oil. This was dissolved in 1GG ml of methylene chloride and the solution with 500 ml of ethyl ether stirred. The ether treatment was repeated. The resulting combined pesticides weighed 11.2 g. This product was effective against Streptococcus pyrogenes and Staphylococcus aureus.

Example 3 '

If the procedure of Example 1 is followed, the after- ■ - ■ the following N-carboxyamino acid anhydrides with 6-IPA implemented in order to obtain the corresponding compounds according to the invention, which are indicated in the table below.

Tabel

N-carboxyamino acid anhydride Formed penicillanic acid pro ^ . ' dukt

2, J-Dimethyl-i-amino-cyclo- 6- (1-imino-2,3-dimethyl-cyclo- *

pentanecarboxylic acid pentancarboxamido) peni cillansäu

314-diethyl ^ i-aminocyclo- o-d

pentanoic acid tan-carboxamiäo) penicillanic acid

2-Bromo-3-methyl-1- amino- 6- (1-imino-2-bromo-3-methyl-cyclc

cyclopentanecarboxylic acid pentanecarboxamido) penicIHansäu-

■ ■ ". ^■: ■■ '■■ ...' [y '""■■ - ■': ■ ■ ■ ■" ^"re ι.

2-nitro-3-propyl-1-amino-6- (t-ifliino-2-nitro-3-propyl-cyc " cyclopentanecarboxylic acid lopentanecarboiamidojpenicillan-

acid

009932/1845

-7-

N-CarlaoxyamiiiosäurealhydTid Formed penicillanic acid pro- ^ - duct

^^ fö4methyli 6- (1-Amitio-2-sulfo-4-methiiyl-

cyclc ^ eatancartonsaure _? cyclopentancarl) oxainido) penicil-

% '" acid

lanic acid

Jyy
cyclopene-fcancarbonsättre cyclopentancarboxyamido) peni-

. cillansäuxe

Ü09832 / 1845

Claims (2)

Patent to ρ r ü c h e: 1. Process for the preparation of new compounds of the general formula L-Λ CO-NH-CH - CH ' .NH ₀ CN ^ CH ₃
CH - COOH R ⁵ R ⁴ and salts thereof (wherein in the formula the best of R, R, R ^ and R ⁴ is hydrogen, lower Allqrl, halogen, nitro and / or SuIfο, Torausgesetzt that one or two of R, R, R ^ and R ^{4 is} always a radical other than hydrogen and that if one of the radicals R, R, R ^ and R ^ are lower alkyl and the rest are hydrogen, the lower alkyl radical contains at least two carbon atoms), characterized in that an N-carboxy anhydride is the general formula. . CO NH CO (where R, R, R ^ and R ^ have the meanings given above, have reacted with 6-aminopenicillanic acid and, if desired, the compound formed is converted to a salt is delt. 00983 2/18 45 -9- 2. Connection of the lOrmel: R ² R ¹ CO - HH - CH CH HH Il CH COOH and salts thereof (where in the formula the radicals R, R, R ^ and R ^ are hydrogen, lower alkyl, halogen, nitro and / or sulfo aind, provided that one or two of the radicals R, R, B? and R always a radical other than hydrogen and that when one of the radicals R, R, R ⁷ and R ^ "is lower alkyl and the remainder are hydrogen, the lower alkyl radical contains at least two carbon atoms). 184 p