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1. WO1987003878 - NOUVEAUX DERIVES 8-SUBSTITUES D'UN ACIDE ANHYDROOCTONIQUE, LEURS PROCEDES DE PREPARATION, PREPARATIONS PHARMACEUTIQUES LES CONTENANT ET INTERMEDIAIRES

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

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Claims

1 . A compound of the formula


wherein Y is hydrogen halogen such as fluoro or chloro, amino, acylamino, azido, mercapto, thiocarboxy, acyloxy,


wherein AA is an amino acid or a peptide sequence containing 2-4 amino acid residues and W is hydroxy, amino, benzyloxy or an amino acid or peptide sequence containing 2-4 amino acid residues; or a
physiologically acceptable salt thereof.

2. A compound according to claim 1, wherein Y is an acylamino group, where the acyl residue is an amino acid or peptide sequence, with 2 to 4 amino acid residues; or physiologically acceptable salts thereof.

3. A compound according to the claims 1 and 2 wherein Y is an acylamino group -NHCORa wherein RaCO- is an amino acid or an amino acid sequence containing 2-4 amino acid residues whereby the amino acid and the amino acid residue are independently selected from glycyl, histidyl, arginyl methionyl, alanyl, phenylalanyl, lysyl, ornithyl, norvalyl, valyl, norleucyl, isoleucyl, leucyl, prolyl or 2-aminopimelyl, either in the L- or in the D-configuration; or physiologically acceptable salts thereof.

4. A compound according to claim 1 wherein Y is



wherein AA is an amino acid or a peptide sequence containing 2-4 amino acid residues chosen from the group consisting of glycyl, norvalyl, alanyl, phenylalanyl, histidyl, lysyl, ornithyl, valyl, leucyl, arginyl, norleucyl, isoleucyl, methionyl, prolyl or 2-aminopimelyl, either in the L- or in the D-configuration and W is hydroxy, amino, benzyloxy or an amino acid or peptide sequence containing 2-4 amino acid residues chosen from the group above either in the L- or in the D-configuration; or a physiologically acceptable salt thereof.

5. A compound according to one of the claims 1-4 in form of a
physiologically acceptable salt.

6. A compound according to claim 5 in form of an ammonium salt.

7. A pharmaceutical preparation comprising as an active ingredient a compound according to any of claims 1-6 or a physiologically acceptable salt thereof.

8. A pharmaceutical preparation according to claim 7 comprising the active ingredient in association with a pharmaceutical carrier.

9. A pharmaceutical preparation according to claim 7 designed
for systemic administration.

10. A pharmaceutical preparation according to claim 7 in dosage unit form.

11. A compound according to any of claims 1-6 for use as a drug.

12. A compound according to any of claims 1-6 for use as a drug for treatment of infectious diseases.

13. The use of a compound according to any of the claims 1-4 or a physiologically acceptable salt thereof for preparation of a
pharmaceutical preparation comprising as an active ingredient an amount of said compound for the treatment of infectious diseases.

14. A method for the treatment of bacterial infections in an animal or human host in need of such treatment, comprising administering a therapeutically effective amount of a compound according to any of the claims 1-6.

15. A process for preparing a compound of the formula


wherein Y is hydrogen, halogen such as chloro or fluoro, amino, acylamino, azido, acyloxy, mercapto, thiocarboxy,



wherein AA is an amino acid or a peptide sequence containing 2-4 amino acid residues and W is hydroxy, amino, benzyloxy or an amino acid or peptide sequence containing 2-4 amino acid residues; or a
physiologically acceptable salt thereof characteri zed i n that

A. Reacting a compound of the formu la

with a nucleophilic reagent followed by removal of optional protecting groups in which formula X is a leaving group, R2-R4 are the same or different and selected from hydrogen or a protecting groups such as acyl, allyl, tetrahydropyranyl, silyl or cyclic acetal, R1 is hydrogen or a protecting group such as alkyl contaiaing 1-6 carbon atoms, benzyl or allyl, leading to information of a compound of formula I, wherein Y is halogen, amino, acyloxy, azido, mercapto or thiocarboxy;

B. Reacting a hydroxy-ester


in which formula R 1-R4 are as defined under A; with a phosphorus- or sulfur-based electrophilic reagent followed by removal of optional protecting groups, leading to formation of a compound of formula I wherein Y is fluoro, chloro, thiocarboxy or azido;

C. Reductive amination of an aldehyde of the formula


in which formula R1-R4 are protecting groups as defined under A with an amine H2N-R 9 wherein R9 is hydrogen, benzyl or allyl followed by removal of protecting groups to formation of a compound of formula I wherein Y is amino;

D. Reacting an amine of the formula


with an amino acid or amino acid sequence with the formula


to formation of a compound of the formula

followed by removal of protecting groups, in which formulas R1-R4 are as defined under A; R11 is lower alkyl, ω-amino lower alkyl, benzyl or 2-thioethyl; R10 is lower alkyl or R10 and R11 together form a cyclic derivative containing 2-5 carbon atoms;
A is hydroxy or a carboxyl-activating group;
Z is an amino-protecting group;
Q1 is a group containing from 0-3 units of an optionally protected amino acid residue such as glycyl, alanyl, phenylalanyl, lysyl, ornithyl, norvalyl, valyl, arginyl, norleucyl, isoleucyl, histidyl, leucyl, methionyl, prolyl or 2-aminopimelyl.

E. Reacting an azide of the formula


with an amino acid or amino acid sequence of the formula


to formation of a compound of the formula

followed by removal of protecting groups, in which formulas R 1-R4 are as defined under A; R10, R11, Z, Q1 are as defined under D;

F. Reacting a hydroxy ester or thiol of the formula



with a glycine derivative of the formula


to formation of a compound of the formula


followed by removal of protecting groups, in which formulas R1-R4 are as defined under A; Z is defined under D; Q is a group containing 1-4 units of an amino acid residue defined under D; W is amino, benzyloxy or a protected amino acid or peptide sequence containing 2-4 amino acid residues; whereupon a compound obtained is optionally converted into a physiologically acceptable salt.

16. A chemical intermediate of the formula


wherein R2-R4 are the same or different and selected from hydrogen or protecting groups such as tert. butyl dimethyl silyl, benzyl;
R1 is a protecting group such as benzyl or allyl.
Y1 is hydrogen, a halogen such as fluoro or chloro, amino, azido, mercapto, acylamino, thiocarboxy, acyloxy.

17. A chemical intermediate according to claim 16 wherein Y1 is azido.

18. A compound which after administration to a living organism is transformed into a compound


wherein Y is hydrogen, a halogen such as chloro or fluoro, amino, azido or mercapto

and exerting its effect in this structural form.

19. A compound according to claim 18 wherein Y is amino.

20. Compounds, processes, pharmaceutical preparations and methods of treatment as claimed in any of the claims 1-19 and substantially as described.