IP Library › Granted Patent US 8,076,285

Granted Patent B2

US 8,076,285 · App. 12/249,888 · Granted Dec 13, 2011

Lysobactin amides

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,076,285
App. No.: 12/249,888
Granted: Dec 13, 2011
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention relates to lysobactin amides and methods for their preparation, as well as their use for manufacturing medicaments for the treatment and/or prophylaxis of diseases, in particular bacterial infectious diseases.

Claims (194)

1. A compound of formula

in which

R 1 represents 2-methylprop-1-yl, 2,2-dimethylprop-1-yl, 2,2-dimethylbut-1-yl, trimethylsilylmethyl, benzyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl or 1,3-thiazol-4-ylmethyl,

whereby benzyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl and 1,3-thiazol-4-ylmethyl may be substituted with 1 or 2 substituents selected independently of one another from the group consisting of halogen, trifluoromethyl, methyl and methoxy,

R 2 represents 2-methylprop-1-yl, 2,2-dimethylprop-1-yl, 2,2-dimethylbut-1-yl, trimethylsilylmethyl, benzyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl or 1,3-thiazol-4-ylmethyl,

R 3 represents hydrogen, C 1 -C 4 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkylmethyl, phenyl, benzyl, 5- or 6-membered heteroaryl or 5- or 6-membered heteroarylmethyl,

whereby cycloalkyl, cycloalkylmethyl, phenyl, benzyl, heteroaryl and heteroarylmethyl may be substituted with 1 to 4 substituents selected independently of one another from the group consisting of halogen, cyano, hydroxy, amino, trifluoromethyl, trifluoromethoxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, hydroxycarbonyl, C 1 -C 4 -alkoxycarbonyl, aminocarbonyl, C 1 -C 4 -alkylaminocarbonyl and 5- or 6-membered heterocyclyl which is bonded via nitrogen,

R 4 represents C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkylmethyl, phenyl, benzyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylmethyl, trimethylsilylmethyl or 2-amino-2-oxoethyl,

whereby alkyl may be substituted with 1 to 3 substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, mercapto, 1,4,5,6-tetrahydropyrimidin-2-ylamino and [amino(imino)methyl]amino,

and

R 5 represents C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkylmethyl, phenyl, benzyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylmethyl, trimethylsilylmethyl or 2-amino-2-oxoethyl,

and

R 6 represents C 1 -C 6 -alkyl,

whereby alkyl is substituted with a substituent selected from the group consisting of amino, 1,4,5,6-tetrahydropyrimidin-2-ylamino, [amino-(imino)methyl]amino, 2-pyridyl, 3-pyridyl and 4-pyridyl,

R 7 represents C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkylmethyl, phenyl, benzyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylmethyl or trimethylsilylmethyl,

and

R 8 represents C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkylmethyl, phenyl, benzyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylmethyl, trimethylsilylmethyl or 2-amino-2-oxoethyl,

whereby alkyl may be substituted with 1 to 3 substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, mercapto, 1,4,5,6 -tetrahydropyrimidin-2-ylamino and [amino(imino)methyl]amino,

and

R 9 represents hydrogen, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkylmethyl, phenyl, benzyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylmethyl, trimethylsilylmethyl or 2-amino-2-oxoethyl,

and

R 10 represents hydrogen, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkylmethyl, phenyl, benzyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylmethyl, trimethylsilylmethyl, 2-amino-2-oxoethyl, 2-amino-1-hydroxy-2-oxoethyl, (aminosulfonyl)(hydroxy)methyl, 2-(C 1 -C 4 -alkylamino)-2-oxoethyl or 2-(C 1 -C 4 -alkylamino)-1-hydroxy-2-oxoethyl,

whereby alkyl may be substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, mercapto, 1,4,5,6-tetrahydropyrimidin-2-ylamino and [amino(imino)methyl]amino,

and

R 11 represents C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkylmethyl, phenyl, benzyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylmethyl, trimethylsilylmethyl, 2-amino-2-oxoethyl, 2-amino-1-hydroxy-2-oxoethyl, (aminosulfonyl)(hydroxy)methyl, 2-(C 1 -C 4 -alkylamino)-2-oxoethyl or 2-(C 1 -C 4 -alkylamino)-1-hydroxy-2-oxoethyl,

whereby alkyl may be substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, mercapto, 1,4,5,6-tetrahydropyrimidin-2-ylamino and [amino(imino)methyl]amino,

and

or one of the salts thereof,

except a compound of formula

in which

and

R 12 represents hydrogen or methyl,

or one of the salts thereof.

2. The compound of claim 1 , whereby

R 10 represents C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkylmethyl, phenyl, benzyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylmethyl, trimethylsilylmethyl, 2-amino-2-oxoethyl, 2-amino-1-hydroxy-2-oxoethyl, (aminosulfonyl)(hydroxy)methyl, 2-(C 1 -C 4 -alkylamino)-2-oxoethyl or 2-(C 1 -C 4 -alkylamino)-1-hydroxy-2-oxoethyl,

whereby alkyl may be substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, mercapto, 1,4,5,6-tetrahydropyrimidin-2-ylamino and [amino(imino)methyl]amino,

and

or one of the salts thereof.

3. The compound of claim 1 , whereby

R 1 represents 2-methylprop-1-yl, 2,2-dimethylprop-1-yl, 2,2-dimethylbut-1-yl, trimethylsilylmethyl, benzyl, 2-pyridylmethyl or 3-pyridylmethyl,

whereby benzyl, 2-pyridylmethyl and 3-pyridylmethyl may be substituted with 1 or 2 substituents selected independently of one another from the group consisting of halogen, trifluoromethyl and methyl,

R 2 represents 2-methylprop-1-yl, 2,2-dimethylprop-1-yl, 2,2-dimethylbut-1-yl, trimethylsilylmethyl, benzyl, 2-pyridylmethyl or 3-pyridylmethyl,

whereby benzyl, 2-pyridylmethyl and 3-pyridylmethyl may be substituted with 1 or 2 substituents selected independently of one another from the group consisting of halogen, trifluoromethyl and methyl,

R 3 represents C 1 -C 4 -alkyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl or 4-pyridyl,

whereby phenyl, benzyl, 2-pyridyl, 3-pyridyl and 4-pyridyl may be substituted with 1 to 4 substituents selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylamino,

R 4 represents C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkylmethyl, benzyl, 5- or 6-membered heteroarylmethyl or trimethylsilylmethyl,

whereby alkyl may be substituted with a hydroxy substituent,

and

whereby cycloalkylmethyl, benzyl and heteroarylmethyl may be substituted with 1 to 4 substituents selected independently of one another from the group consisting of halogen, cyano, hydroxy, amino, trifluoromethyl, trifluoromethoxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, hydroxycarbonyl, C 1 -C 4 -alkoxycarbonyl, aminocarbonyl and C 1 -C 4 -alkylaminocarbonyl,

R 5 represents C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkylmethyl, phenyl, benzyl, 5- or 6-membered heteroarylmethyl or trimethylsilylmethyl,

whereby alkyl may be substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, mercapto, 1,4,5,6-tetrahydropyrimidin-2-ylamino and [amino(imino)methyl]amino,

and

whereby cycloalkylmethyl, phenyl, benzyl and heteroarylmethyl may be substituted with 1 to 4 substituents selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylamino,

R 6 represents C 1 -C 6 -alkyl,

whereby alkyl is substituted with a substituent selected from the group consisting of amino, 1,4,5,6-tetrahydropyrimidin-2-ylamino, [amino-(imino)methyl]amino, 2-pyridyl, 3-pyridyl and 4-pyridyl,

R 7 represents C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkylmethyl, phenyl, benzyl, 5- or 6-membered heteroarylmethyl or trimethylsilylmethyl,

whereby alkyl may be substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, mercapto, 1,4,5,6-tetrahydropyrimidin-2-ylamino and [amino(imino)methyl]amino,

and

R 8 represents C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkylmethyl, benzyl, 5- or 6-membered heteroarylmethyl or trimethylsilylmethyl,

whereby alkyl may be substituted with a hydroxy substituent,

and

R 9 represents hydrogen, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, phenyl, trimethylsilylmethyl or 2-amino-2-oxoethyl,

whereby methyl may be substituted with a substituent selected from the group consisting of hydroxy, amino and mercapto,

and

whereby cycloalkyl and phenyl may be substituted with 1 to 4 substituents selected independently of one another from the group consisting of halogen, cyano, hydroxy, amino, trifluoromethyl, trifluoromethoxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylamino,

R 10 represents hydrogen, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, phenyl, trimethylsilylmethyl, 2-amino-2-oxoethyl, 2-amino-1-hydroxy-2-oxoethyl, (aminosulfonyl)(hydroxy)methyl, 2-(C 1 -C 4 -alkylamino)-2-oxoethyl or 2-(C 1 -C 4 -alkylamino)-1-hydroxy-2-oxoethyl,

whereby alkyl may be substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, mercapto, 1,4,5,6-tetrahydropyrimidin-2-ylamino and [amino(imino)methyl]amino,

and

R 11 represents methyl or ethyl,

whereby methyl and ethyl may be substituted with a substituent selected from the group consisting of hydroxy, amino, mercapto, 1,4,5,6-tetrahydropyrimidin-2-ylamino and [amino(imino)methyl]amino,

or one of the salts thereof,

except the compounds of formula (Ia), in which

R 1 represents 2-methylprop-1-yl, 2,2-dimethylprop-1-yl, 2,2-dimethylbut-1-yl, trimethylsilylmethyl, benzyl, 2-pyridylmethyl or 3-pyridylmethyl,

whereby benzyl, 2-pyridylmethyl and 3-pyridylmethyl may be substituted with 1 or 2 substituents selected independently of one another from the group consisting of halogen, trifluoromethyl and methyl,

R 2 represents 2-methylprop-1-yl, 2,2-dimethylprop-1-yl, 2,2-dimethylbut-1-yl, trimethylsilylmethyl, benzyl, 2-pyridylmethyl or 3-pyridylmethyl,

whereby benzyl, 2-pyridylmethyl and 3-pyridylmethyl may be substituted with 1 or 2 substituents selected independently of one another from the group consisting of halogen, trifluoromethyl and methyl,

and

R 12 represents hydrogen or methyl,

or one of the salts thereof.

4. The compound of claim 3 , whereby

R 1 represents 2-methylprop-1-yl, 2,2-dimethylprop-1-yl, 2,2-dimethylbut-1-yl, trimethylsilylmethyl or benzyl,

whereby benzyl may be substituted with 1 or 2 substituents selected independently of one another from the group consisting of halogen, trifluoromethyl and methyl,

or one of the salts thereof.

5. The compound of claim 3 , whereby

R 3 represents phenyl, benzyl, 2-pyridyl, 3-pyridyl or 4-pyridyl,

or one of the salts thereof.

6. The compound of claim 3 , whereby

R 10 represents C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, phenyl, trimethylsilylmethyl, 2-amino-2-oxoethyl, 2-amino-1-hydroxy-2-oxoethyl, (aminosulfonyl)-(hydroxy)methyl, 2-(C 1 -C 4 -alkylamino)-2-oxoethyl or 2-(C 1 -C 4 -alkylamino)-1-hydroxy-2-oxoethyl,

whereby alkyl may be substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, mercapto, 1,4,5,6-tetrahydropyrimidin-2-ylamino and [amino(imino)methyl]amino,

and

or one of the salts thereof.

7. The compound of claim 1 , whereby

R 1 represents 2,2-dimethylprop-1-yl, 2,2-dimethylbut-1-yl, trimethylsilylmethyl or 3-pyridylmethyl,

R 2 represents 2,2-dimethylprop-1-yl, 2,2-dimethylbut-1-yl, trimethylsilylmethyl or 3-pyridylmethyl,

R 3 represents C 1 -C 4 -alkyl, 3-pyridyl or phenyl,

whereby 3-pyridyl or phenyl may be substituted with a substituent selected from the group consisting of halogen, cyano, methyl, methoxy, dimethylamino and diethylamino,

R 4 represents —CH(OH)—C 1 -C 5 -alkyl or —CH(OH)phenyl,

whereby —CH(OH)phenyl may be substituted with 1 to 3 substituents selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -dialkylamino,

R 5 represents C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkylmethyl, benzyl or trimethylsilylmethyl,

R 6 represents linear C 2 -C 4 -alkyl,

whereby alkyl is substituted with a substituent selected from the group consisting of amino, 1,4,5,6-tetrahydropyrimidin-2-ylamino and [amino(imino)methyl]amino,

R 7 represents C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkylmethyl, benzyl or trimethylsilylmethyl,

R 8 represents C 1 -C 4 -alkyl, —CH 2 —OH, —CH(OH)—C 1 -C 5 -alkyl or —CH(OH)-phenyl,

R 9 represents hydrogen, C 1 -C 6 -alkyl, hydroxymethyl or 2-amino-2-oxoethyl,

R 10 represents hydrogen, C 1 -C 4 -alkyl, 2-amino-2-oxoethyl or 2-amino-1-hydroxy-2-oxoethyl,

whereby C 1 -C 4 -alkyl may be substituted with a substituent selected from the group consisting of amino and hydroxy, with the exception that R 10 is not 4-aminobut-1-yl,

R 11 represents methyl,

whereby methyl is substituted with a substituent selected from the group consisting of hydroxy and amino,

or one of the salts thereof,

except the compounds of formula (Ia), in which

R 1 represents 2,2-dimethylprop-1-yl, 2,2-dimethylbut-1-yl, trimethylsilylmethyl or 3-pyridylmethyl,

R 2 represents 2,2-dimethylprop-1-yl, 2,2-dimethylbut-1-yl, trimethylsilylmethyl or 3-pyridylmethyl,

and

R 12 represents hydrogen or methyl,

or one of the salts thereof.

8. The compound of claim 7 , whereby

R 1 represents 2,2-dimethylprop-1-yl, 2,2-dimethylbut-1-yl or trimethylsilylmethyl,

or one of the salts thereof.

9. The compound of claim 7 , whereby

R 2 represents 2,2-dimethylprop-1-yl or 3-pyridylmethyl,

or one of the salts thereof.

10. The compound of claim 7 , whereby

R 3 represents phenyl,

whereby phenyl may be substituted with a substituent selected from the group consisting of halogen, cyano, methyl, methoxy, dimethylamino and diethylamino,

or one of the salts thereof.

11. The compound of claim 7 , whereby

R 8 represents —CH(OH)—C 1 -C 5 -alkyl or —CH(OH)phenyl,

or one of the salts thereof.

12. The compound of claim 7 , whereby

R 10 represents methyl, ethyl, 2-amino-2-oxoethyl or 2-amino-1-hydroxy-2-oxoethyl,

whereby methyl and ethyl may be substituted with a hydroxy substituent,

or one of the salts thereof.

13. A method for preparing a compound of formula (I) of claim 1 , whereby

[A] a compound of formula

in which

R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 have the meaning indicated in claim 1 ,

is first reacted with a compound of formula

in which

R 1 and R 2 have the meaning indicated in claim 1 ,

Y 1 represents tert-butoxycarbonyl or benzyloxycarbonyl, and

X 1 represents halogen or hydroxy,

and subsequently with an acid, by hydrogenolysis or with an acid and by hydrogenolysis

[B] a compound of formula

in which

R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 have the meaning indicated in claim 1 ,

is first reacted with a compound of formula

in which

R 1 , R 2 and R 3 have the meaning indicated in claim 1 , and

Y 1 represents tert-butoxycarbonyl or benzyloxycarbonyl,

and subsequently in a 4-stage synthesis

a) with a fluoride reagent such as tetrabutylammonium fluoride,

b) with an acid,

c) with a dehydrating reagent, where appropriate in the presence of a base,

and

d) by hydrogenolysis.

14. The method of claim 13 , whereby the compound of formula (II) is prepared by reacting a compound of formula

first with a compound of formula

in which

R 13 represents cyanomethyl, p-nitrophenyl, o-nitrophenyl, 2,4-dinitrophenyl, 2,4,5-trichlorophenyl, pentachlorophenyl, pentafluorophenyl (Pfp), N-hydroxyphthalimidyl, N-hydroxysuccinimidyl (O-Su), 1-hydroxypiperidinyl or 5-chloro-8-hydroxyquinolinyl,

and subsequently in a 3-stage synthesis

a) with an acid,

b) with a dehydrating reagent, where appropriate in the presence of a base,

and

c) by hydrogenolysis.

15. A medicament which comprises a compound of claim 1 and at least one additional compound having antibacterial activity.

16. A medicament comprising a compound of claim 1 in combination with an inert, nontoxic, pharmaceutically acceptable excipient.

17. The medicament of claim 16 which is formulated for intravenous administration.

18. A method for controlling bacterial infections in humans or animals, which comprises administering an antibacterially effective amount of at least one compound of claim 1 or a medicament of claim 15 to the human or animal subject in need thereof.

19. The method of claim 18 , wherein the compound or the medicament is administered orally or parenterally.

20. The method of claim 13 , wherein X 1 represents bromine, chlorine, fluorine, or hydroxy.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 4, 2009

From: VON NUSSBAUM, FRANZ; BECK, HARTMUT; BRUNNER, NINA; ENDERMANN, RAINER; KOEBBERLING, JOHANNES; RAGOT, JACQUES; TELSER, JOACHIM; SCHUHMACHER, JOACHIM; ANLAUF, SONJA; CANCHO-GRANDE, YOLANDA; GRESCHAT, SUSANNE; MILITZER, HANS-CHRISTIAN; SCHIFFER, GUIDO

To: BAYER HEALTHCARE AG

Reel/Frame 022784/0390 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 4, 2009

From: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT

To: AICURIS GMBH & CO. KG

Reel/Frame 022784/0616 →

MERGER Recorded Jun 4, 2009

From: BAYER HEALTHCARE AG

To: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT

Reel/Frame 022802/0371 →