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US Patent Application 20100068272 - HYDROXYAMIDINE AND HYDROXYGUANIDINE COMPOUNDS AS UROKINASE INHIBITORS

Application 20100068272 Filed on September 14, 2009. Published on March 18, 2010

Inventors

Assignee

US Classes

424/474, Coated pills or tablets514/255.01, Nitrogen or -C(=X)-, wherein X is chalcogen, bonded directly to the piperazine ring544/387, Plural -C(=X)- groups bonded directly to the piperazine ring514/604, Q is monocyclic564/92Benzene ring in a substituent E

Attorney, Agent or Firm

Foreign Documents

  • 103 23 898.0 DE 05/26/2003

International Classes

A61K 9/28
A61K 31/495
C07D 241/04
A61K 31/18
C07C 311/00
A61P 35/00


Claims


1. A pharmaceutical composition, which comprises, as an active compound, at least one compound of the formula ##STR00005## wherein E is ##STR00006## B is --SO2-- or --CO--;X is --NR1 or --CHR1;Z is --R4, --OR4 or --NH--R4;Y is --OR2 or --NHR2;R1 is in each case independently --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, unsubstituted or substituted;R2 is --H, --OR1, --COR1, --CON(R1)2 or --COOR1;R3 is --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, unsubstituted or substituted, or --COR6 or --COOR6 or an oligo- or polyalkyleneoxy radical;R4 is --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, unsubstituted or substituted, or a cyclic radical;R6 is --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, or a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of --C1-C.sub.3-alkyl, --C1-C.sub.3-alkoxy, halogen, --OR6, =O, --NO2, --CN, --COOR6, --N(R6)2, --NR6COR.sup.6, --NR6CON(R6)2 and --OCOR6;said alkyl, alkenyl and alkynyl moieties being straight-chained or branched and being unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, --OR6, --OCOR6, --N(R6)2, --NR6COR.sup.6, --NR6CON(R6)2, COOR6, and a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of --C1-C.sub.3-alkyl, --C1-C.sub.3-alkoxy, halogen, --OR6, =O, --NO2, --CN, --COOR6, --N(R6)2, --NR6COR.sup.6, --NR6CON(R6)2 and --OCOR6, or a salt of said compound;and a pharmaceutically customary carrier, diluent or/and adjuvant.

2. The pharmaceutical composition of claim 1, wherein said composition further comprises a compound of the formula ##STR00007## wherein R1, R3, R4, and R6 are as defined in claim 1; or a salt of said compound.

3. The pharmaceutical composition of claim 1, wherein R4 is ##STR00008##

4. The pharmaceutical composition of claim 1, wherein R4 is a substituted or unsubstituted C1-C.sub.3-alkyl-aryl radical, wherein said substituted C1-C.sub.3-alkyl-aryl radical is substituted in at least on of the meta- and para-positions with a substituent selected from the group consisting of halogen and αα-NO2.

5. The pharmaceutical composition of claim 1, wherein said active compound is selected from the group consisting ofbenzylsulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide;4-chlorobenz- ylsulfonyl-(D)-Ser-N-Me-Ala-(4-hydroxyguanidinobenzyl)amide;4-chlorobenzyl- sulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide;benzylsulfonyl-(D)-Se- r-N-Me-Gly-(4-hydroxyguanidinobenzyl)amide; and4-chlorobenzylsulfonyl-(D)-Ser-Ala-(4-hydroxyguanidinobenzyl)amide;or a physiologically compatible salt thereof.

6. The pharmaceutical composition of claim 5, in which the compound is benzylsulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide hydrogen sulfate or benzylsulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide sulfate.

7. The pharmaceutical composition of claim 1, wherein said composition is in an orally administrable form.

8. The pharmaceutical composition of claim 1, wherein said compound is present as a sulfate or hydrogen sulfate salt.

9. A method for treating a tumor susceptible to urokinase inhibition associated with pathological overexpression of urokinase and/or urokinase receptor comprising administering to a subject in need of such treatment a pharmaceutically effective amount of at least one compound of the formula ##STR00009## wherein E is ##STR00010## B is --SO2-- or --CO--;X is --NR1 or --CHR1;Z is --R4, --OR4 or --NH--R4;Y is --OR2 or --NHR2;R1 is in each case independently --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, unsubstituted or substituted;R2 is --H, --OR1, --COR1, --CON(R1)2 or --COOR1;R3 is --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, unsubstituted or substituted, or --COR6 or --COOR6 or an oligo- or polyalkyleneoxy radical;R4 is --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, unsubstituted or substituted, or a cyclic radical;R6 is --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, or a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of --C1-C.sub.3-alkyl, --C1-C.sub.3-alkoxy, halogen, --OR6, =O, --NO2, --CN, --COOR6, --N(R6)2, --NR6COR.sup.6, --NR6CON(R6)2 and --OCOR6;said alkyl, alkenyl and alkynyl moieties being straight-chained or branched and being unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, --OR6, --OCOR6, --N(R6)2, --NR6COR.sup.6, --NR6CON(R6)2, COOR6 , and a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of --C1-C.sub.3-alkyl, --C1-C.sub.3-alkoxy, halogen, --OR6, =O, --NO2, --CN, --COOR6, --N(R6)2, --NR6COR.sup.6, --NR6CON(R6)2 and --OCOR6, or a salt of said compound.

10. The method of claim 9, wherein the tumor is a primary tumor susceptible to urokinase inhibition.

11. The method of claim 9, wherein the compound is in a composition which is in a form suitable for oral administration.

12. The method of claim 9, wherein the compound is in a composition which is in the form of tablets, coated tablets, capsules, pellets, a solution, an emulsion or/and suspension.

13. The method of claim 9, wherein the living organism is a human.

14. The method of claim 9, wherein said disease is lung cancer, breast cancer, colon carcinoma, pancreatic carcinoma, or metastases thereof.

15. A method for treating diseases characterized by the formation of metastases associated with pathological overexpression of urokinase and/or urokinase receptor comprising administering to a subject in need of such treatment a pharmaceutically effective amount of at least one compound of the formula ##STR00011## wherein E is ##STR00012## B is --SO2-- or --CO--;X is --NR1 or --CHR1;Z is --R4, --OR4 or --NH--R4;Y is --OR2 or --NHR2;R1 is in each case independently --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, unsubstituted or substituted;R2 is --H, --OR1, --COR1, --CON(R1)2 or --COOR1;R3 is --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, unsubstituted or substituted, or --COR6 or --COOR6 or an oligo- or polyalkyleneoxy radical;R4 is --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, unsubstituted or substituted, or a cyclic radical;R6 is --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, or a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of --C1-C.sub.3-alkyl, --C1-C.sub.3-alkoxy, halogen, --OR6, =O, --NO2, --CN, --COOR6, --N(R6)2, --NR6COR.sup.6, --NR6CON(R6)2 and --OCOR6,said alkyl, alkenyl and alkynyl moieties being straight-chained or branched and being unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, --OR6, --OCOR6, --N(R6)2, --NR6COR.sup.6, --NR6CON(R6)2, COOR6 , and a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of --C1-C.sub.3-alkyl, --C1-C.sub.3-alkoxy, halogen, --OR6, =O, --NO2, --CN, --COOR6, --N(R6)2, --NR6COR.sup.6, --NR6CON(R6)2 and --OCOR6, or a salt of said compound.

16. A compound of the formula ##STR00013## wherein E is ##STR00014## B is --SO2-- or --CO--;X is --NR1 or --CHR1,Z is --R4, --OR4 or --NH--R4;Y is --OR2 or --NHR2;R1 is in each case independently --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, unsubstituted or substituted;R2 is --H, --OR1, --COR1, --CON(R1)2 or --COOR1;R3 is --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, unsubstituted or substituted, or --COR6 or --COOR6 or an oligo- or polyalkyleneoxy radical;R4 is --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, unsubstituted or substituted, or a cyclic radical;R6 is --H, --C1-C.sub.6-alkyl, --C2-C.sub.6-alkenyl or --C2-C.sub.6-alkynyl, or a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of --C1-C.sub.3-alkyl, --C1-C.sub.3-alkoxy, halogen, --OR6, =O, --NO2, --CN, --COOR6, --N(R6)2, --NR6COR.sup.6, --NR6CON(R6)2 and --OCOR6;said alkyl, alkenyl and alkynyl moieties being straight-chained or branched and being unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, --OR6, --OCOR6, --N(R6)2, --NR6COR.sup.6, --NR6CON(R6)2, COOR6, and a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of --C1-C.sub.3-alkyl, --C1-C.sub.3-alkoxy, halogen, --OR6, =O, --NO2, --CN, --COOR6, --N(R6)2, --NR6COR.sup.6, --NR6CON(R6)2 and --OCOR6, or a salt of said compound.

17. The compound of claim 16, wherein R4 is ##STR00015##

18. The compound of claim 16, wherein R4 is a substituted or unsubstituted C1-C.sub.3-alkyl-aryl radical, wherein said substituted C1-C.sub.3-alkyl-aryl radical is substituted at least on one of the meta- and para-positions with a substituent selected from the group consisting of halogen and αα-NO2.

19. A compound selected from the group consisting ofbenzylsulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide;4-chlorobenz- ylsulfonyl-(D)-Ser-N-Me-Ala-(4-hydroxyguanidinobenzyl)amide;4-chlorobenzyl- sulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide,benzylsulfonyl-(D)-Se- r-N-Me-Gly-(4-hydroxyguanidinobenzyl)amide; and4-chlorobenzylsulfonyl-(D)-Ser-Ala-(4-hydroxyguanidinobenzyl)amide;or a physiologically compatible salt thereof.

20. The compound of claim 19, wherein said compound is benzylsulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide hydrogen sulfate or benzylsulfonyl-(D)-Ser-Gly-(4-hydroxyguanidinobenzyl)amide sulfate.

21. The compound of claim 16, wherein said compound is present as a sulfate or hydrogen sulfate salt.

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