Patent Grant
8101590
The present invention relates to 9-aminocarbonylsubstituted derivatives of glycylcyclines which are useful as antibiotic agents and exhibit antibacterial activity against a wide spectrum of organisms including organisms which are resistant to tetracyclines and other antibiotics.
Since 1947 a variety of tetracycline antibiotics have been synthesized and described for the treatment of infectious diseases in man and animals. Tetracyclines inhibit protein synthesis by binding to the 30S subunit of the bacterial ribosome preventing binding of aminoacyl RNA (Chopra, Handbook of Experimental Pharmacology, Vol. 78, 317-392, Springer-Verlag, 1985). Resistance to tetracyclines has emerged among many clinically important microorganisms which limit the utility of these antibiotics. There are two major mechanisms of bacterial resistance to tetracyclines: a) energy-dependent efflux of the antibiotic mediated by proteins located in the cytoplasmic membrane which prevents intracellular accumulation of tetracycline (S. B. Levy, et al., Antimicrob. Agents Chemotherapy 33, 1373-1374 (1989); and b) ribosomal protection mediated by a cytoplasmic protein which interacts with the ribosome such that tetracycline no longer binds or inhibits protein synthesis (A. A. Salyers, B. S. Speers and N. B. Shoemaker, Mol. Microbiol, 4:151-156, 1990). The efflux mechanism of resistance is encoded by resistance determinants designated tetA-tetL. They are common in many Gram-negative bacteria (resistance genes Class A-E), such as Enterobacteriaceae, Pseudomonas, Haemophilus and Aeromonas, and in Gram-positive bacteria (resistance genes Class K and L), such as Staphylococcus, Bacillus and Streptococcus. The ribosomal protection mechanism of resistance is encoded by resistance determinants designated TetM, N and O, and is common in Staphylococcus, Streptococcus, Campylobacter, Gardnerella, Haemophilus and Mycoplasma (A. A. Salyers, B. S. Speers and N. B. Shoemaker, Mol. Microbiol, 4:151-156 1990).
A particularly useful tetracycline compound is 7-(dimethylamino)-6-demethyl-6-deoxytetracycline, known as minocycline (see U.S. Pat. No. 3,148,212, U.S. Pat. No. RE 26,253 and U.S. Pat. No. 3,226,436 discussed below). However, strains harboring the tetB (efflux in gram-negative bacteria) mechanism, but not tetK (efflux in Staphylococcus) are resistant to minocycline. Also, strains carrying tetM (ribosomal protection) are resistant to minocycline.
Duggar, U.S. Pat. No. 2,482,055, discloses the preparation of Aureomycin® by fermentation which have antibacterial activity. Growich et al., U.S. Pat. No. 3,007,965, disclose improvements to the fermentation preparation. Beereboom et al., U.S. Pat. No. 3,043,875 discloses tetracycline derivatives Boothe et al., U.S. Pat. No. 3,148,212, reissued as U.S. Pat. No. RE 26,253, and Petisi et al., U.S. Pat. No. 3,226,436, discloses tetracycline derivatives which are useful for treating bacterial infections. Blackwood et al., U.S. Pat. No. 3,200,149 discloses tetracycline derivatives which possess microbiological activity. Petisi et al., U.S. Pat. No. 3,338,963 discloses tetracycline compounds which have broad-spectrum antibacterial activity. Bitha et al., U.S. Pat. No. 3,341,585 discloses tetracycline compounds which have broad-spectrum antibacterial activity. Shu, U.S. Pat. No. 3,360,557 discloses 9-hydroxytetracyclines which have been found to possess antibacterial activity. Zambrano, U.S. Pat. No. 3,360,561 discloses a process for preparing 9-nitrotetracyclines. Martell et al., U.S. Pat. No. 3,518,306 discloses tetracyclines which possess in vivo antibacterial activity.
In U.S. Pat. No. 5,021,407 a method of overcoming the resistance of tetracycline resistant bacteria is disclosed. The method involves utilizing a blocking agent compound in conjunction with a tetracycline type antibiotic. This patent does not disclose novel tetracycline compounds which themselves have activity against resistant organisms. Described in U.S. Pat. No. 5,494,903 are 7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines which have broad spectrum antibacterial activity.
Despite the advances being made to overcome the resistance of tetracycline resistant bacteria, there remains a need for newer and better antibiotics to overcome the increasing incidence of resistance. The present invention provides such antibiotics.
In summary, none of the above patents teach or suggest the novel derivatives of glycylcyclines of this application.
This invention is concerned with 9-aminocarbonylsubstituted derivatives of glycylcyclines represented by Formula I which have antibacterial activity; with methods of treating infectious diseases in humans and other animals when administering these new compounds; with pharmaceutical preparations containing these compounds; and with novel processes for the production of compounds of Formula I.
In accordance with the present invention, there is provided compounds represented by Formula (I);
wherein:
A is a moiety
or is absent;
R1 is selected from hydrogen, —OH, amino, —NR7R8, halogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group phenyl, heteroaryl, halogen, amino, cyano, alkyl, hydroxyl, alkoxy, aryl, alkynyl and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, and alkynyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, alkyl, hydroxyl, and alkoxy;
R2 is selected from hydrogen, halogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group phenyl, heteroaryl, halogen, amino, cyano, alkyl, hydroxyl, alkoxy, aryl, alkynyl and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, and alkynyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, alkyl, hydroxyl, and alkoxy;
R3 is the moiety R9,
R4 is selected from hydrogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group phenyl, heteroaryl, halogen, amino, cyano, alkyl, hydroxyl, alkoxy, aryl, alkynyl and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, alkynyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, alkyl, hydroxyl, and alkoxy, aryl of 6, 10 or 14 carbon atoms said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, N-(alkyl of 1 to 12 carbon atoms)-aryl, said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl of 7 to 13 carbon atoms optionally substituted, SR3, heteroaryl optionally substituted and heteroarylcarbonyl optionally substituted;
R5 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl of 6, 10 or 14 carbon atoms, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl, may be optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl, —CH2(CO)OCH2aryl, said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryloxy and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted, heteroaryl optionally substituted, aryl of 6, 10 or 14 carbon atoms optionally substituted, alkynyl of 2 to 12 carbon atoms optionally substituted, cycloalkyl 3 to 6 ring atoms, aryl-CH═CH—, cycloalkyl-alkyl; and adamantyl;
R6 is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, and cycloalkyl of 3 to 6 carbon atoms;
R7 and R8 are each independently H or alkyl of 1 to 12 carbon atoms or R7 and R8 when optionally taken together with the nitrogen atom to which each is attached form a 3 to 8 membered heterocyclyl ring;
R9 is aralkyl of 7 to 16 carbon atoms optionally substituted or alkyl of 1 to 12 carbon atoms;
R10 is H or alkyl of 1 to 12 carbon atoms;
or a pharmaceutically acceptable salt thereof.
An embodiment of this invention provides compounds of Formula I wherein R1 is —NR7R8, R7 is hydrogen, R8 is methyl, ethyl, n-propyl, n-butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl or a pharmaceutically acceptable salt thereof.
Another embodiment of this invention provides compounds of Formula I wherein R1 is —NR7R8, R7 is methyl or ethyl, R8 is methyl, ethyl, n-propyl, 1-methylethyl, n-propyl, 1-methylpropyl, or 2-methylpropyl or a pharmaceutically acceptable salt thereof.
A further embodiment of this invention provides compounds of Formula I wherein R1 is —NR7R8, R7 and R8 are taken together with the nitrogen atom to which each is attached form a 3 to 8 membered heterocyclyl ring or a pharmaceutically acceptable salt thereof.
Another embodiment of this invention provides compounds of Formula I wherein R2 is H or a pharmaceutically acceptable salt thereof.
Another embodiment of this invention provides compounds of Formula I wherein A is a moiety
or a pharmaceutically acceptable salt thereof.
A further embodiment of this invention provides compounds of Formula I wherein A is absent or a pharmaceutically acceptable salt thereof.
A further embodiment of this invention provides compounds of Formula I wherein R3 is a moiety
or a pharmaceutically acceptable salt thereof.
A further additional embodiment of this invention provides compounds of Formula I wherein R3 is a moiety
or a pharmaceutically acceptable salt thereof.
An embodiment of this invention provides compounds of Formula I wherein R3 is a moiety
and R6 and R10 are H or a pharmaceutically acceptable salt thereof.
An additional embodiment of this invention provides compounds of Formula I wherein R3 is a moiety
and R6 and R10 are H or a pharmaceutically acceptable salt thereof.
A further embodiment of this invention provides compounds of Formula I wherein R3 is R9 or a pharmaceutically acceptable salt thereof.
An additional embodiment of this invention provides compounds of Formula I wherein A is the moiety,
R3 is the moiety
R5 is aryl of 6 carbon atoms or a pharmaceutically acceptable salt thereof.
A further embodiment of this invention provides compounds of Formula I wherein A is the moiety
R3 is the moiety,
R4 is 1,1-dimethylethyl and
R5 is aryl of 6 carbon atoms or a pharmaceutically acceptable salt thereof.
An additional embodiment of this invention provides compounds of Formula I
wherein:
A is a moiety
R1 is —NR7R8;
R2 is hydrogen;
R3 is the moiety
R4 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, and aryloxy wherein said aryl and aryloxy is optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryloxy and phenyl;
R5 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl of 6, 10 or 14 carbon atoms, and aryloxy wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl, may be optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl, —CH2(CO)OCH2aryl, said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryloxy and phenyl, heteroaryl optionally substituted, aryl of 6, 10 or 14 carbon atoms optionally substituted, cycloalkyl 3 to 6 ring atoms, aryl-CH═CH—, cycloalkyl-alkyl; and adamantyl;
R6 is hydrogen;
R7 and R8 are each independently H or alkyl of 1 to 12 carbon atoms;
R9 is aralkyl of 7 to 16 carbon atoms optionally substituted or alkyl of 1 to 12 carbon atoms;
R10 is H;
or a pharmaceutically acceptable salt thereof.
Further embodiments of the invention are the following specifically preferred compounds of Formula I or pharmaceutically acceptable salts thereof:
Further embodiments of the invention are the following specifically preferred compounds of Formula I or pharmaceutically acceptable salts thereof:
Additional further embodiments of the invention are the following specifically preferred compounds of Formula I or pharmaceutically acceptable salts thereof:
Further embodiments of the invention are the following specifically preferred compounds of Formula I or pharmaceutically acceptable salts thereof:
Additional further embodiments of the invention are the following specifically preferred compounds of Formula I or pharmaceutically acceptable salts thereof:
Further embodiments of the invention are the following specifically preferred compounds of Formula I or pharmaceutically acceptable salts thereof:
Further embodiments of the invention are the following specifically preferred compounds of Formula I or pharmaceutically acceptable salts thereof:
An additional embodiment of this invention are compounds represented by Formula (II):
wherein:
R4 is selected from hydrogen, alkyl of 1 to 12 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group phenyl, heteroaryl, halogen, amino, cyano, alkyl, hydroxyl, alkoxy, aryl, alkynyl and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, alkynyl of 2 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, alkyl, hydroxyl, and alkoxy, aryl of 6, 10 or 14 carbon atoms said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, N-(alkyl of 1 to 12 carbon atoms)-aryl, said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl of 7 to 13 carbon atoms optionally substituted, SR3, heteroaryl optionally substituted and heteroarylcarbonyl optionally substituted;
R5 is selected from alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl of 6, 10 or 14 carbon atoms, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl, may be optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl, —CH2(CO)OCH2aryl, said aryl optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryloxy and phenyl, alkenyl of 2 to 12 carbon atoms optionally substituted, heteroaryl optionally substituted, aryl of 6, 10 or 14 carbon atoms optionally substituted, alkynyl of 2 to 12 carbon atoms optionally substituted, cycloalkyl 3 to 6 ring atoms, aryl-CH═CH—, cycloalkyl-alkyl; and adamantyl;
R6 is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl, and cycloalkyl of 3 to 6 carbon atoms;
R10 is H or alkyl of 1 to 12 carbon atoms;
Q is —OR11, Cl, Br or I;
R11 is H, benzyl optionally substituted with nitro or a moiety of the formula
R12 is alkyl of 1 to 6 carbon atoms.
The compounds having Formula II are useful as chemical intermediates for making the compounds having formula I and the pharmaceutically acceptable salt thereof wherein: A is a moiety
and R3 is the moiety
where R4 and R5 are as defined above.
An embodiment of the invention provides compounds of Formula II wherein R4 is t-butyl, R5 is alkyl of 1 to 6 carbon atoms, and R11 is benzyl optionally substituted with nitro.
Another embodiment of the invention provides compounds of Formula II wherein R4 is alkyl of 1 to 6 carbon atoms, R5 is phenyl optionally substituted and R11 is benzyl optionally substituted with nitro.
An embodiment of the invention provides compounds of Formula II wherein R5 is alkyl of 1 to 6 carbon atoms, R4 is t-butyl and R11 is H.
A further embodiment of the invention provides compounds of Formula II wherein R5 is alkyl of 1 to 6 carbon atoms, R4 is t-butyl, Q is —OR11, R11 is
and R12 is alkyl of 1 to 6 carbon atoms.
Another embodiment of the invention provides compounds of Formula II wherein R6 and R10 are H.
Further embodiments of the invention provides the following specifically preferred compounds of Formula II or pharmaceutically acceptable salts thereof.
Additional embodiments of the invention are the following specifically preferred compounds of Formula II or pharmaceutically acceptable salts thereof.
A further embodiment of the invention is the following specifically preferred compound of Formula II or pharmaceutically acceptable salts thereof.
For the compounds of the invention defined above and referred to herein, unless otherwise noted, the following terms are defined:
The term alkyl means a straight or branched alkyl moiety of 1 to 12 carbon atoms optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, phenyl, hydroxyl, alkoxy of 1 to 12 carbon atoms, N-alkyl of 1 to 12 carbon atoms, N-cycloalkyl of 3 to 6 carbon atoms, heterocyclyl of 3 to 8 ring atoms, aryl, aryloxy and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl, aryloxy and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl. In some embodiments of the invention alkyl is a moiety of 1 to 6 carbon atoms. In other embodiments of the invention alkyl is a moiety of 1 to 3 carbon atoms. In other embodiments of the invention alkyl is 1,1-dimethylethyl also termed t-butyl. In some embodiments of the invention when alkyl is a methyl group wherein optional substitution is two independent phenyl rings. Non-limiting examples of alkyl are methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl.
The term alkenyl means a straight or branched carbon chain of 2 to 12 carbon atoms having at least one site of unsaturation optionally independently substituted with 1 to 3 substituents selected from the group optionally independently substituted with 1 to 3 substituents selected from the group phenyl, heteroaryl, halogen, amino, cyano, alkyl, hydroxyl, alkoxy, aryl, alkynyl and N-(alkyl of 1 to 12 carbon atoms)-aryl, wherein said aryl and aryl of N-(alkyl of 1 to 12 carbon atoms)-aryl may optionally be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl. In some embodiments of the invention alkenyl is a vinyl moiety CH2═CH—.
As used herein the term alkoxy refers to alkyl-O— wherein alkyl is hereinbefore defined. Non limiting examples include: methoxy and ethoxy.
As used herein the term aryl means an aromatic moiety having 6, 10 or 14 carbon atoms preferably 6 to 10 carbon atoms, optionally substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, aryl-C(O)—, CH3—C(O)—NH—, aralkyl, aryloxy, heterocyclyl and phenyl. In particular, aryl is phenyl or naphthyl optionally substituted with 1 to 3 substituents.
The term aralkyl as used herein of 7 to 16 carbon atoms means an alkyl substituted with an aryl group in which the aryl and alkyl group are as defined herein. Non-limiting exemplary aralkyl groups include benzyl and phenethyl and the like.
Perhaloalkyl as used herein means an alkyl moiety of 1 to 6 carbon atoms in which each hydrogen atom is substituted with a halogen atom, an exemplary example is trifluoromethyl.
Phenyl as used herein refers to a 6-membered carbon aromatic ring.
As used herein the term alkynyl includes both straight chain and branched moieties containing 2 to 12 carbon atoms having at least one carbon to carbon triple bond optionally substituted with 1 to 3 substituents independently selected from the group halogen, amino, cyano, alkyl of 1 to 12 carbon atoms, hydroxyl, and alkoxy of 1 to 12 carbon atoms.
As used herein the term halogen or halo means F, Cl, Br or I.
As used herein the term cycloalkyl means a saturated monocyclic ring having from 3 to 6 carbon atoms. Exemplary cycloalkyl rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In an embodiment of the invention cycloalkyl is a moiety of 5 or 6 carbon atoms.
The term aroyl means an aryl-C(O)— group in which the aryl group is as previously defined. Non-limiting examples include benzoyl and naphthoyl.
The term heteroaryl means an aromatic heterocyclic, monocyclic ring of 5 or 6 ring atoms containing 1 to 4 heteroatoms independently selected from O, N and S or bicyclic aromatic rings of 8 to 20 ring atoms containing 1 to 4 heteroatoms independently selected from O, N and S. Heteroaryl rings may optionally be substituted with 1 to 3 substitutents independently selected from the group alkyl, halogen, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino, alkoxy, aryloxy, —CH2OCOCH3 and carboxy. Non-limiting heteroaryl moieties optionally substituted include: furanyl, benzofuranyl, benzothienyl, thienyl, pyridinyl, quinolinyl, tetrazolyl, imidazo, thiazolyl and the like.
Where terms are used in combination, the definition for each individual part of the combination applies unless defined otherwise. For instance, aralkyl refers to an aryl group, and alkyl refers to the alkyl group as defined above. Also, aryloxy refers to a arylO— group.
The term heteroarylcarbonyl means a heteroaryl-C(O)— group in which the heteroaryl group is as previously defined.
The term heterocyclyl as used herein represents a saturated ring of 3 to 8 ring atoms containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments of the invention a saturated ring of 5 or 6 ring atoms is preferred. Representative examples are pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.
The term alkylheterocyclyl means an alkyl-heterocyclyl group in which the alkyl and heterocyclyl group are independently previously defined. Non-limiting exemplary alkylheterocyclyl groups include moieties of the formulae:
Some of the compounds of Formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For instance, compounds of Formula (I) which exist as tautomers are depicted below:
The present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
Proton sponge is [1,8-bis(dimethylamino)naphthalene, N,N,N′,N′-tetramethyl-1,8-naphthalenediamine].
Alkali metal carbonate includes lithium, potassium and sodium carbonate.
DMPU is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
N-butyl-glycylcycline (N-bu-glycyl) is
N-propyl-glycylcycline (N-prop-glycyl) is
The compounds of this invention may be prepared according to the following schemes: (1) from commercially available starting materials or: (2) from known starting materials which can be prepared as described in literature procedures or: (3) from new intermediates described in the schemes and experimental procedures.
The synthesis of acyloxy intermediate 8 is shown in Scheme 1. Reaction of amine R4NH2, preferably t-butylamine, with ester 1 provides the substituted amino ester 2. Preparation of the intermediate 4 is accomplished by using Proton Sponge as base to effect the acylation of substituted amino ester 2 with chloromethyl chloroformate 3. Treatment of intermediate 4 with the tetrabutylammonium salt 5 of carboxylic acids gives the benzyl protected acyloxy intermediate 6. The benzyl protecting group is removed by catalytic reduction to give carboxylic acid 7 which is activated to a mixed anhydride with chloroformate ClCO2R12 where R12 is alkyl of 1 to 6 carbon atoms, for example iso-butyl chloroformate to give acyloxycarbamate intermediate 8. In an alternate route, silyl esters may optionally be used in place of the benzyl ester of intermediate 4, treating with the appropriate carboxylic acid followed by deblocking the silyl ester with tetrabutylammonium fluoride or magnesium bromide to afford carboxylic acid 7. Optionally, carboxylic acid 7 may be activated through the use of coupling agents not limited to di-t-butyl dicarbonate (Boc2O); e.g., benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (also known asBop); benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (also known as PyBop); O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU); Bromotris-pyrollidino-phosphonium hexafluorophosphate; 2-Chloro-N-methylpyridinium iodide (CMPI); dicyclohexylcarbodiimide (DCC); 1,3-diisopropylcarbodiimide (DIC); 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC); or Carbonyl diimidazole.
As shown in Scheme 2, reaction of activated acyloxycarbamate intermediate 8 with 7,8-disubstituted-9-aminotetracycline 9 in the presence of triethylamine and DMPU gives acyloxycarbamate 10.
Additional acyloxy carbamate compounds may be synthesized via routes as shown in Schemes 3 and 4. Treatment of chloromethyl chloroformate 3 with ethanethiol in the presence of triethylamine (TEA) gives carbonothioate 11. Compound 12 is prepared by reacting carbonothioate 11 with carboxylic acid tetrabutylammonium salt 5 in tetrahydrofuran. Chlorination of compound 12 with sulfuryl chloride in the presence of catalytic amount of boron trifluoroetherate affords chloro intermediate 13 (using the methods described in M. Folkmann and F. J. Lund, Synthesis, December 1990, 1159-1166).
As further seen in Scheme 4 acyloxycarbamates 16 and 17 where R4 is preferably n-butyl or n-propyl are synthesized by treatment of either 14 or 15 where R4 is preferably n-butyl or n-propyl with the chloro intermediate 13 to give acyloxycarbamates 16 and 17 respectively.
As shown in Scheme 5, carbamates of glycylcycline where R4 is preferably propyl 18 may also be prepared by reaction with chloro intermediate 19 in the presence of an alkali metal carbonate preferably sodium carbonate, and DMPU in acetonitrile to afford preferred compounds (21 and 22).
As shown in Scheme 6, reaction of chloro intermediate 13 with 7,8-disubstituted-9-aminotetracycline 9 in the presence of triethylamine and DMPU gives carbamate 23.
As further shown in Scheme 7, compounds of Formula I may generally be prepared by removal of the benzyl protecting group from benzyl protected acyloxy intermediate 24 to give carboxylic acid 25 which is activated to a mixed anhydride with a chloroformate ClCO2R12 where R12 is alkyl of 1 to 6 carbon atoms, for example iso-butyl chloroformate to give acyloxycarbamate intermediate 26. Further reaction of 7,8-disubstituted-9-aminotetracycline 9 with acyloxycarbamate mixed anhydride intermediate 26 in the presence of triethylamine and DMPU affords compounds of Formula (I).
Reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the various functionalities present on the molecule must be consistent with the chemical transformations proposed. This may necessitate judgement as to the order of synthetic steps, protecting groups, if required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions. Such restrictions to the substituents which are compatible with the reaction conditions will be apparent to one skilled in the art.
Some of the compounds of the hereinbefore described schemes have center of asymmetry. The compounds may, therefore, exist in at least two and often more stereoisomeric forms. The present invention encompasses all stereoisomers of the compounds whether free from other stereoisomers or admixed with other stereoisomers in any proportion and thus includes, for instance, racemic mixture of enantiomers as well as the diastereomeric mixture of isomers. The absolute configuration of any compound may be determined by conventional X-ray crystallography.
The compounds of the invention may be obtained as metal complexes such as aluminum, calcium, iron, magnesium, manganese and complex salts; inorganic and organic salts and corresponding Mannich base adducts using methods known to those skilled in the art (Richard C. Larock, Comprehensive Organic Transformations, VCH Publishers, 411-415, 1989). Preferably, the compounds of the invention are obtained as inorganic salts such as hydrochloric, hydrobromic, hydroiodic, phosphoric, nitric or sulfate; or organic salts such as acetate, benzoate, citrate, cysteine or other amino acids, fumarate, glycolate, maleate, succinate, tartrate alkylsulfonate or arylsulfonate. In all cases, the salt formation occurs with the C(4)-dimethylamino group. The salts are preferred for oral and parenteral administration.
Standard Pharmacological Test Procedures
Methods for In Vitro Antibacterial Evaluation
The Minimum Inhibitory Concentration (MIC)
Antimicrobial susceptibility testing. The in vitro activities of the antibiotics are determined by the broth microdilution method as recommended by the National Committee for Clinical Laboratory Standards (NCCLS) (1). Mueller-Hinton II broth (MHBII)(BBL Cockeysville, Md.) is the medium employed in the testing procedures. Microtiter plates containing serial dilutions of each antimicrobial agent are inoculated with each organism to yield the appropriate density (105 CFU/ml) in a 100 μl final volume. The plates are incubated for 18-22 hours at 35° C. in ambient air. The minimal inhibitory concentration for all isolates is defined as the lowest concentration of antimicrobial agent that completely inhibits the growth of the organism as detected by the unaided eye.
Presented in Tables I-XIII are representative compounds of Formula I which were evaluated against a panel of 40 selected gram-positive and gram-negative bacteria strains by pre-incubation in water, mouse serum or human serum. Representative compounds were first incubated in mouse serum for an hour prior to the in vitro testing against a panel of selected gram-positive and gram-negative bacteria strains. All compounds were also pre-incubated in water for an hour prior to testing as control. Representative compounds of Formula I were incubated in human serum prior to MIC determination. Representative compounds of Formula I which demonstrated in vivo activity were further subjected to various stability tests. A summary of the in vitro testing data of representative examples of Formula I are shown in Table 1. Expanded in vitro data of selected examples (87 and 27) are shown in Table 2 and 5 respectively. MICs of representative examples of Formula I are further shown in Tables 3 and 4. Table 6 presents in vitro and in vivo activity of representative examples of compounds of Formula I against Staph. aureus Smith in mice. Table 7 presents in vivo (oral, iv) and in vitro (MIC) activity of representative examples of compounds of Formula I against E. coli in mice. Table 8 presents in vivo (oral, iv) and in vitro (MIC) activity of representative examples of compounds of Formula I, against Staph aureus Smith in mice. Table 9 presents in vitro (MIC) activity of representative examples of compounds of Formula I against E. Coli in human serum and water and also against Staph in human serum and water. Table 10 presents in vivo single oral dose (SOD) and single intravenous dose (SIV) ED50 data for representative examples of compounds of Formula I against Staph. Smith and E. Coli #311 in mammals.
E. coli GC 2236
E. coli GC 2231
E. coli GC 2235
E. coli GC 2232
E. coli GC 2233
E. coli GC 2234
E. coli GC 2270
E. coli GC 2271
E. coli GC 2272
E. coli GC 4559
E. coli GC 4560
E. coli GC 6465
E. coli GC 3226
E. coli GC 2203
E. coli GC 1073
Salmonella spp.
Salmonella spp. GC 566
S. cholerasius GC 1355
S. typhimurium GC 2172
P. aeruginosa GC 2214
S. aureus GC 1131
S. aureus GC 6466
S. aureus GC 6467
S. aureus GC 1079
S. aureus GC 4536
S. aureus GC 2216
S. aureus GC 6335
S. aureus GC 6469
S. epidermidis GC 4935
E. faecalis GC 4555
E. faecalis GC 2265
E. faecalis GC 2267
E. faecalis GC 2242
E. faecium GC 4556
E. faecium GC 2243
S. pneumoniae* GC
S. pneumoniae+ GC
S. pyogenes GC 4563
S. agalactiae GC 4564
c. albicans GC 3066
E. coli GC 2236
E. coli GC 2231
E. coli GC 2235
E. coli GC 2232
E. coli GC 2233
E. coli GC 2234
E. coli GC 2270
E. coli GC 2271
E. coli GC 2272
E. coli GC 4559
E. coli GC 4560
E. coli GC 6465
E. coli GC 3226
E. coli GC 2203
E. coli GC 1073
Salmonella spp. GC
Salmonella spp. GC
S. cholerasius GC
S. typhimurium GC
P. aeruginosa GC
S. aureus GC 1131
S. aureus GC 6466
S. aureus GC 6467
S. aureus GC 1079
S. aureus GC 4536
S. aureus GC 2216
S. aureus GC 6335
S. aureus GC 6469
S. epidermidis GC
E. faecalis GC 4555
E. faecalis GC 2265
E. faecalis GC 2267
E. faecalis GC 2242
E. faecium GC 4556
E. faecium GC 2243
S. pneumoniae* GC
S. pneumoniae+ GC
S. pyogenes GC
S. agalactiae GC
c. albicans GC 3066
E. coli GC 2236
E. coli GC 2231
E. coli GC 2235
E. coli GC 2232
E. coli GC 2233
E. coli GC 2234
E. coli GC 2270
E. coli GC 2271
E. coli GC 2272
E. coli GC 4559
E. coli GC 4560
E. coli GC 6465
E. coli GC 3226
E. coli GC 2203
E. coli GC 1073
Salmonella spp. GC 235
Salmonella spp. GC 566
S. cholerasius GC 1355
S. typhimurium GC 2172
P. aeruginosa GC 2214
S. aureus GC 1131
S. aureus GC 6466
S. aureus GC 6467
S. aureus GC 1079
S. aureus GC 4536
S. aureus GC 2216
S. aureus GC 6335
S. aureus GC 6469
S. epidermidis GC 4935
E. faecalis GC 4555
E. faecalis GC
E. faecalis GC
E. faecalis GC
E. faecium GC
E. faecium GC
S. pneumoniae*
S. pneumoniae+
S. pyogenes GC
S. agalactiae GC
c. albicans GC
E. coli GC 2236
E. coli GC 2231
E. coli GC 2235
E. coli GC 2232
E. coli GC 2233
E. coli GC 2234
E. coli GC 2270
E. coli GC 2271
E. coli GC 2272
E. coli GC 4559
E. coli GC 4560
E. coli GC 6465
E. coli GC 3226
E. coli GC 2203
E. coli GC 1073
Salmonella spp. GC 235
Salmonella spp.
S. cholerasius
S. typhimurium GC
P. aeruginosa GC
S. aureus GC 1131
S. aureus GC 6466
S. aureus GC 6467
S. aureus GC 1079
S. aureus GC 4536
S. aureus GC 2216
S. aureus GC 6335
S. aureus GC 6469
S. epidermidis GC
E. faecalis GC 4555
E. faecalis GC 2265
E. faecalis GC 2267
E. faecalis GC 2242
E. faecium GC 4556
E. faecium GC 2243
S. pneumoniae* GC
S. pneumoniae+ GC
S. pyogenes GC
S. agalactiae GC
c. albicans GC 3066
E. coli GC 2236
E. coli GC 2231
E. coli GC 2235
E. coli GC 2232
E. coli GC 2233
E. coli GC 2234
E. coli GC 2270
E. coli GC 2271
E. coli GC 2272
E. coli GC 4559
E. coli GC 4560
E. coli GC 6465
E. coli GC 3226
E. coli GC 2203
E. coli GC 1073
Salmonella spp. GC 235
Salmonella spp. GC 566
S. cholerasius GC 1355
S. typhimurium GC 2172
P. aeruginosa GC 2214
S. aureus GC 1131
S. aureus GC 6466
S. aureus GC 6467
S. aureus GC 1079
S. aureus GC 4536
S. aureus GC 2216
S. aureus GC 6335
S. aureus GC 6469
S. epidermidis GC 4935
E. faecalis GC 4555
E. faecalis GC 2265
E. faecalis GC 2267
E. faecalis GC 2242
E. faecium GC 4556
E. faecium GC 2243
S. pneumoniae* GC 4465
S. pneumoniae+
S. pyogenes GC
S. agalactiae GC
c. albicans GC
E. coli GC 2236
E. coli GC 2231
E. coli GC 2235
E. coli GC 2232
E. coli GC 2233
E. coli GC 2234
E. coli GC 2270
E. coli GC 2271
E. coli GC 2272
E. coli GC 4559
E. coli GC 4560
E. coli GC 6465
E. coli GC 3226
E. coli GC 2203
E. coli GC 1073
Salmonella spp. GC 235
Salmonella spp. GC 566
S. cholerasius GC 1355
S. typhimurium GC 2172
P. aeruginosa GC 2214
S. aureus GC 1131
S. aureus GC 6466
S. aureus GC 6467
S. aureus GC 1079
S. aureus GC 4536
S. aureus GC 2216
S. aureus GC 6335
S. aureus GC 6469
S. epidermidis GC 4935
E. faecalis GC 4555
E. faecalis GC 2265
E. faecalis GC 2267
E. faecalis GC 2242
E. faecium GC 4556
E. faecium GC 2243
S. pneumoniae* GC 4465
S. pneumoniae+
S. pyogenes GC
S. agalactiae GC
c. albicans GC
E. coli GC 2236
E. coli GC 2231
E. coli GC 2235
E. coli GC 2232
E. coli GC 2233
E. coli GC 2234
E. coli GC 2270
E. coli GC 2271
E. coli GC 2272
E. coli GC 4559
E. coli GC 4560
E. coli GC 6465
E. coli GC 3226
E. coli GC 2203
E. coli GC 1073
Salmonella spp. GC 235
Salmonella spp. GC 566
S. cholerasius GC 1355
S. typhimurium GC
P. aeruginosa GC 2214
S. aureus GC 1131
S. aureus GC 6466
S. aureus GC 6467
S. aureus GC 1079
S. aureus GC 4536
S. aureus GC 2216
S. aureus GC 6335
S. aureus GC 6469
S. epidermidis GC 4935
E. faecalis GC 4555
E. faecalis GC 2265
E. faecalis GC 2267
E. faecalis GC 2242
E. faecium GC 4556
E. faecium GC 2243
S. pneumoniae* GC
S. pneumoniae+ GC
S. pyogenes GC 4563
S. agalactiae GC 4564
c. albicans GC 3066
E. coli GC 2236
E. coli GC 2231
E. coli GC 2235
E. coli GC 2232
E. coli GC 2233
E. coli GC 2234
E. coli GC 2270
E. coli GC 2271
E. coli GC 2272
E. coli GC 4559
E. coli GC 4560
E. coli GC 6465
E. coli GC 3226
E. coli GC 2203
E. coli GC 1073
Salmonella spp. GC 235
Salmonella spp. GC 566
S. cholerasius GC 1355
S. typhimurium GC 2172
P. aeruginosa GC 2214
S. aureus GC 1131
S. aureus GC 6466
S. aureus GC 6467
S. aureus GC 1079
S. aureus GC 4536
S. aureus GC 2216
S. aureus GC 6335
S. aureus GC 6469
S. epidermidis GC 4935
E. faecalis GC 4555
E. faecalis GC 2265
E. faecalis GC 2267
E. faecalis GC 2242
E. faecium GC 4556
E. faecium GC 2243
S. pneumoniae* GC
S. pneumoniae+ GC
S. pyogenes GC 4563
S. agalactiae GC 4564
c. albicans GC 3066
E. coli GC 2236
E. coli GC 2231
E. coli GC 2235
E. coli GC 2232
E. coli GC 2233
E. coli GC 2234
E. coli GC 2270
E. coli GC 2271
E. coli GC 2272
E. coli GC 4559
E. coli GC 4560
E. coli GC 6465
E. coli GC 3226
E. coli GC 2203
E. coli GC 1073
Salmonella spp. GC 235
Salmonella spp. GC 566
S. cholerasius GC 1355
S. typhimurium GC 2172
P. aeruginosa GC 2214
S. aureus GC 1131
S. aureus GC 6466
S. aureus GC 6467
S. aureus GC 1079
S. aureus GC 4536
S. aureus GC 2216
S. aureus GC 6335
S. aureus GC 6469
S. epidermidis GC 4935
E. faecalis GC 4555
E. faecalis GC 2265
E. faecalis GC 2267
E. faecalis GC 2242
E. faecium GC 4556
E. faecium GC 2243
S. pneumoniae* GC
S. pneumoniae+ GC
S. pyogenes GC 4563
S. agalactiae GC 4564
c. albicans GC 3066
E. coli GC 2236
E. coli GC 2231
E. coli GC 2235
E. coli GC 2232
E. coli GC 2233
E. coli GC 2234
E. coli GC 2270
E. coli GC 2271
E. coli GC 2272
E. coli GC 4559
E. coli GC 4560
E. coli GC 6465
E. coli GC 3226
E. coli GC 2203
E. coli GC 1073
Salmonella spp. GC 235
Salmonella spp. GC 566
S. cholerasius GC 1355
S. typhimurium GC 2172
P. aeruginosa GC
S. aureus GC 1131
S. aureus GC 6466
S. aureus GC 6467
S. aureus GC 1079
S. aureus GC 4536
S. aureus GC 2216
S. aureus GC 6335
S. aureus GC 6469
S. epidermidis GC
E. faecalis GC 4555
E. faecalis GC 2265
E. faecalis GC 2267
E. faecalis GC
E. faecium GC
E. faecium GC
S. pneumoniae*
S. pneumoniae+
S. pyogenes
S. agalactiae
c. albicans GC
E. coli GC 2236
E. coli GC 2231
E. coli GC 2235
E. coli GC 2232
E. coli GC 2233
E. coli GC 2234
E. coli GC 2270
E. coli GC 2271
E. coli GC 2272
E. coli GC 4559
E. coli GC 4560
E. coli GC 6465
E. coli GC 3226
E. coli GC 2203
E. coli GC 1073
Salmonella spp. GC 235
Salmonella spp. GC 566
S. cholerasius GC 1355
S. typhimurium GC 2172
P. aeruginosa GC 2214
S. aureus GC 1131
S. aureus GC 6466
S. aureus GC 6467
S. aureus GC 1079
S. aureus GC 4536
S. aureus GC 2216
S. aureus GC 6335
S. aureus GC 6469
S. epidermidis GC 4935
E. faecalis GC 4555
E. faecalis GC 2265
E. faecalis GC 2267
E. faecalis GC 2242
E. faecium GC 4556
E. faecium GC 2243
S. pneumoniae* GC 4465
S. pneumoniae+ GC 4465
S. pyogenes GC 4563
S. agalactiae GC 4564
c. albicans GC 3066
E. coli GC 2236
E. coli GC 2231
E. coli GC 2235
E. coli GC 2232
E. coli GC 2233
E. coli GC 2234
E. coli GC 2270
E. coli GC 2271
E. coli GC 2272
E. coli GC 4559
E. coli GC 4560
E. coli GC 6465
E. coli GC 3226
E. coli GC 2203
E. coli GC 1073
Salmonella spp. GC
Salmonella spp. GC
S. cholerasius GC 1355
S. typhimurium GC
P. aeruginosa GC
S. aureus GC 1131
S. aureus GC 6466
S. aureus GC 6467
S. aureus GC 1079
S. aureus GC 4536
S. aureus GC 2216
S. aureus GC 6335
S. aureus GC 6469
S. epidermidis GC
E. faecalis GC 4555
E. faecalis GC 2265
E. faecalis GC 2267
E. faecalis GC 2242
E. faecium GC
E. faecium GC
S. pneumoniae*
S. pneumoniae+
S. pyogenes GC
S. agalactiae GC
c. albicans GC
E. coli GC 2236
E. coli GC 2231
E. coli GC 2235
E. coli GC 2232
E. coli GC 2233
E. coli GC 2234
E. coli GC 2270
E. coli GC 2271
E. coli GC 2272
E. coli GC 4559
E. coli GC 4560
E. coli GC 6465
E. coli GC 3226
E. coli GC 2203
E. coli GC 1073
Salmonella spp. GC
Salmonella spp. GC
S. cholerasius
S. typhimurium GC
P. aeruginosa GC
S. aureus GC 1131
S. aureus GC 6466
S. aureus GC 6467
S. aureus GC 1079
S. aureus GC 4536
S. aureus GC 2216
S. aureus GC 6335
S. aureus GC 6469
S. epidermidis GC
E. faecalis GC
E. faecalis GC
E. faecalis GC
E. faecalis GC
E. faecium GC
E. faecium GC
S. pneumoniae*
S. pneumoniae+
S. pyogenes
S. agalactiae
c. albicans GC
E. coli
E. coli
Staph
Staph
aRange of MIC (minimum inhibitory concentration) for E. coli and Staph., including MRSA which are selected from those E. coli and Staph., presented in Tables I-XIII.
E. coli, tet(A-D), efflux
E. coli, tet (M,S,O) Tet (M)
E. coli (susceptible)
E. coli (IMP)
S. aureus, tet (M)
S. aureus, tet (K), efflux
S. aureus (susceptible)a
Enterococcus spp.
Streptococcus spp.
C. albicans
aStrain used for the in vivo testing
Representative examples of compounds of Formula I were further evaluated for oral efficacy, stability in physiological pH in mouse serum and human plasma.
E. coli
Staph.
E. coli
Staph. (water)
aRange of MIC (minimum inhibitory concentration) for E. coli and Staph., including MRSA which are selected from those E. coli and Staph., presented in Tables I-XIII.
E. coli
Staph.
E. coli
Staph. (water)
aRange of MIC (minimum inhibitory concentration) for E. coli and Staph. including MRSA which are selected from those E. coli and Staph., presented in Tables I-XIII.
E. coli, tet(A-D), efflux
E. coli, tet(M,S,O) Tet (M)
E. coli (susceptible)
E. coli (IMP)
S. aureus, tet (M)
S. aureus, tet (K), efflux
S. aureus (susceptible)a
Enterococcus spp.
Streptococcus spp.
C. albicans
aStrain used for in vivo testing
Representative examples of compounds of Formula I were tested for the oral efficacy using S. aureus Smith in mice. The summary of in vivo and in vitro activities of selected compounds are listed in Table 6.
aMIC (minimum inhibitory concentration)
bSOD (Single oral dose)
cSIV (Single intravenous dose)
Representative examples of compounds of Formula I were tested in vivo against gram-negative bacteria (E. coli) in mice. Results of the tests (MIC, oral and IV) are list in Table 7.
aMIC (minimum inhibitory concentration)
bSOD (Single oral dose)
cSIV (Single intravenous dose)
Test results of in vivo activity are shown in Table 8 for representative examples of compounds of Formula I.
aMIC (minimum inhibitory concentration)
bSOD (Single oral dose)
cSIV (Single intravenous dose)
E. coli
E. coli
Staph
Staph
E. coli #311
When the compounds of the invention are employed as antibacterials, they can be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
An effective amount of compound from 2.0 mg/kg of body weight to 100.0 mg/kg of body weight may be administered one to five times per day via any typical route of administration including but not limited to oral, parenteral (including subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques), topical or rectal, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA. The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred. These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.
The present invention further provides a method of treating bacterial infections in warm-blooded animals including man, which comprises providing to the afflicted warm-blooded animals an antibacterially effective amount of a compound or a pharmaceutical composition of a compound of the invention.
The invention will be more fully described in conjunction with the following specific examples which are not to be construed as limiting the scope of the invention.
To a solution of tert-butylamino-acetic acid benzyl ester in dichloromethane is added two equivalents of [1,8-bis(dimethylamino)naphthalene, N,N, N′,N′-tetramethyl-1,8-naphthalenediamine]. The reaction mixture is than cooled in an ice bath and one equivalent of chloromethyl chloroformate is added. The reaction is then warm to room temperature and continue to stir for 24 hr. It is then washed with water and then brine.
Tert-butylacetic acid and 1.0 M tetrabutylammonium hydroxide in methanol is stirred for an hour, methanol is removed and THF is added. To this solution is then added benzyl N-(tert-butyl)-N-[(chloromethoxy)carbonyl]glycinate and stirred at room temperature for 24 hr. Solvent is removed and residue is diluted with ether, then washed with water, then brine. It is dried over magnesium sulfate, filtered and solvent removed.
MS (ESI) m/z 394.25
Substantially following the method described in detail hereinabove in Reference Compound 2 using (tert-butyl-chloromethoxycarbonyl-amino)-acidic acid benzyl ester from Reference Compound 1 and the appropriate carboxylic acid, the reference compounds 3-55 of this invention listed below in Table A are prepared.
The product from Reference Compound 2, 10% palladium on carbon in ethyl acetate is hydrogenated in a Parr shaker at ca. 40 psi for about an hour. The catalyst is filtered and solvent removed to give the corresponding carboxylic acid product of the example MS(ESI) m/z 394.25.
Substantially following the method described in detail hereinabove in Reference Compound 56 the reference compounds 57-108 of this invention listed below in Table B are prepared using the appropriate benzyl esters of Reference Compounds 3-55.
To a solution of Reference Compound 56 in dichloromethane at room temperature is added 1.2 equivalent of [1,8-bis(dimethylamino)naphthalene, N,N,N′,N′-tetramethyl-1,8-naphthalenediamine] and 0.95 equivalent of iso-butylchloroformate. The reaction is stirred for 24 hour, diluted with dichloromethane, washed with dilute HCl, brine, then water. It is dried with sodium sulfate. Solvent removed and the product is used in the next step without further purification.
To a solution of t-butylacetic acid (0.025 mol, 3 g) in methanol is added tetrabutylammonium hydroxide (1M/methanol, 25 ml). The mixture is stirred for 1 h and the solvent removed to a residue. The residue is dissolved in 150 ml of methylene chloride and 150 ml of water and a solution of O-chloromethyl S-ethyl carbonothioate (0.025 mol, 3.85 f) in 50 ml of methylene chloride added. The mixture is stirred at room temperature for 24 h. The methylene chloride layer is separated, washed with water, brine and dried over sodium sulfate. The solvent is removed under vacuo and the residue stirred in 300 ml of ether for 24 h. The resulting white solid is filtered, the solid discarded and the solvent removed from the filtrate to give 6 g of a crude oil.
To a stirred solution of 3,3-dimethylbutyric acid ethylsulfanylcarbonyloxymethyl ester (Reference Compound 110) (0.025 ml, 6 g) in methylene chloride at −20° C. (dry ice/carbon tetrachloride) is added sulfuryl chloride 0.025 mol, 3.5 g). After 10 min, 0.1 ml of boron trifluoride etherate is added. The mixture is stirred at 0° C. for 1 h, at room temperature for 30 min. The volatiles are removed by distillation to yield 4.9 g of the desired acid chloride.
Following the procedure of Reference Compound 111 the corresponding acid chloride used in Examples 112 to 120 was prepared.
The product of the Reference Example was prepared using the conditions described by R. Sakamoto et al, Chem. Pharm. Bull. 32(6), 2241-2248 (1984).
The product of the Reference Example was prepared using the conditions described by R. Sakamoto et al, Chem. Pharm. Bull. 32(6), 2241-2248 (1984).
The product of the Reference Example was prepared using the conditions described by R. Sakamoto et al, Chem. Pharm. Bull. 32(6), 2241-2248 (1984).
Trans-cinnamic acid (23.1 mmol) and 1.0 M tetrabutylammonium hydroxide (22.2 mmol) in methanol are stirred for one hour, and the methanol is removed. THF is added. To this solution is added 2-(trimethylsilyl)ethyl 2-(tert-butyl((chloromethoxy)carbonyl)amino)-acetate (18.5 mmol) and the mixture is stirred at room temperature for 24 hr. The solvent is removed and the residue is diluted with ether. The resulting solution is washed with water and brine. The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 5.01 g (61%) MS (ESI) m/z 436.3.
Using substantially the same procedure as described above for Reference Compound 124 the following reference compounds were prepared from the appropriate carboxylic acids:
MS (ESI) m/z 510.3
MS (ESI) m/z 536.2
To a solution of n-Butylglycylcycline in acetonitrile/DMPA (1:5), sodium carbonate is added. The reaction mixture is stirred for 5 min and propanoic acid, 2-methyl-[(chlorocarbonyl)oxy]methyl ester prepared according to the methods described in M. Folkmann and F. J. Lund, Synthesis, December 1990, 1159-1166, is added. Stirring is continued for about 30 to 45 minute (or monitored by MS (ES)). Upon completion of the reaction, 0.5 mL of methanol is added and the mixture poured slowly into a mixture of isopropanol and ether. 1.0M HCl in ether is added and the solid is filtered. The solid is dissolved in water and is extracted with methylene chloride to give the product of the Example.
MS (ESI) m/z 730.28 (M+H);
Following the procedure of Example 1, and the corresponding acid chloride prepared by methods described in M. Folkmann and F. J. Lund, Synthesis, December 1990, 1159-1166 and N-butylglycylcycline or N-propylglycylcycline the following Examples 2-41 are prepared.
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl 4-methoxybenzoate and N-butylglycylcycline to give the product of the Example.
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl 4-methylbenzoate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 778.3 ((M+H)+);
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl 4-fluorobenzoate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 782.3 ((M+H)+);
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl 4-methylbenzoate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 764.3 ((M+H)+);
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl 4-methoxybenzoate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 780.3 ((M+H)+);
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl cyclobutanecarboxylate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 728.3 ((M+H)+);
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl 4-fluorobenzoate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 768.3 ((M+H)+);
The title compound is prepared by the procedure of Example 1, using Propanoic acid, 2,2-dimethyl-, [(chlorocarbonyl)oxy]methyl ester and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 730.3 ((M+H)+);
The title compound is prepared by the procedure of Example 1, using propanoic acid, 2-methyl-, [(chlorocarbonyl)oxy]methyl ester and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 716.3 ((M+H)+);
The title compound is prepared by the procedure of Example 1, using benzeneacetic acid, [(chlorocarbonyl)oxy]methyl ester and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 764.3 ((M+H)+;
The title compound is prepared by the procedure of Example 1, using benzeneacetic acid, [(chlorocarbonyl)oxy]methyl ester and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 778.3 ((M+H)+);
The title compound is prepared by the procedure of Example 1, using propanoic acid, 2,2-dimethyl-, [(chlorocarbonyl)oxy]methyl ester and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 744.3 ((M+H)+);
The title compound is prepared by the procedure of Example 1, using benzyl chloroformate and N-propylglycylcycline in the presence of sodium carbonate and DMPU in acetonitrile to give the product of the Example.
MS (ESI) m/z 706.3 ((M+H)+);
HRMS: calcd for C36H43N5O10.HCl, 741.2777. found (ESI), 706.31133;
The title compound is prepared by the procedure of Example 1, using ethyl chloroformate and N-propylglycylcycline in the presence of sodium carbonate and DMPU in acetonitrile to give the product of the Example.
MS (ESI) m/z 644.3 ((M+H)+);
HRMS: calcd for C31H41N5O10.HCl, 679.2620. found (ESI+), 644.29398;
The title compound is prepared by the procedure of Example 1, using isobutyl chloroformate and N-propylglycylcycline in the presence of sodium carbonate and DMPU in acetonitrile to give the product of the Example.
MS (ESI) m/z 672.3 ((M+H)+);
MS (ESI) m/z 336.9 ((M+2H)2+);
HRMS: calcd for C33H45N5O10.HCl, 707.2933. found (ESI+), 672.32618;
The title compound is prepared by the procedure of Example 1, using heptanoic acid, [(chlorocarbonyl)oxy]methyl ester and N-butylglycylcycline to give the product of the Example.
MS (ESI+) m/z 772.2 (M+H);
HRMS: calcd for C38H53N5O12.2.00HCl, 843.3224. found (ESI+), 772.37696;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl cyclobutanecarboxylate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 742.3 ((M+H)+);
HRMS: calcd for C36H47N5O12.2.00HCl, 813.2755. found (ESI+), 742.32898;
The title compound is prepared by the procedure of Example 1, using Heptanoic acid, [(chlorocarbonyl)oxy]methyl ester and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 758.4 ((M+H)+);
HRMS: calcd for C37H51N5O12.HCl, 793.3301. found (ESI+), 758.36175;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl 4-tert-butylbenzoate and N-butylglycylcycline to give the product of the Example.
MS (ESI+) m/z 820.2 (M+H);
HRMS: calcd for C42H53N5O12.HCl, 855.3458. found (ESI+), 820.37684;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl biphenyl-4-carboxylate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 840.3 ((M+H)+);
HRMS: calcd for C44H49N5O12.HCl, 875.3145. found (ESI+), 840.34337;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl 3,5-dimethylbenzoate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 792.3 ((M+H)+);
HRMS: calcd for C40H49N5O12.2.00HCl, 863.2911. found (ESI+), 792.34378;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl thiophene-2-carboxylate and N-butylglycylcycl me to give the product of the Example.
MS (ESI) m/Z 770.1 ((M+H)+);
HRMS: calcd for C36H43N5O12S.HCl, 805.2396. found (ESI+), 770.27084;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl biphenyl-4-carboxylate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 826.4 ((M+H)+);
MS (ESI) m/z 414 ((M+2H)2+);
HRMS: calcd for C43H47N5O12.HCl, 861.2988. found (ESI+), 826.32782;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl thiophene-2-carboxylate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 756.3 ((M+H)+);
MS (ESI) m/z 378.9 ((M+2H)2+);
HRMS: calcd for C35H41N5O12S.HCl, 791.2239. found (ESI+), 756.2532;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl 3,5-dimethylbenzoate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 778.3 ((M+H)+);
HRMS: calcd for C39H47N5O12.HCl, 813.2988. found (ESI+), 778.32984;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl thiophene-3-carboxylate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 756.3 ((M+H)+);
HRMS: calcd for C35H41N5O12S.HCl, 791.2239. found (ESI+), 756.2547;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl 4-tert-butylbenzoate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 806.4 ((M+H)+);
MS (ESI) m/z 403.9 ((M+2H)2+);
HRMS: calcd for C41H51N5O12.HCl, 841.3301. found (ESI+), 806.36024;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl thiophene-3-carboxylate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 770.3 ((M+H)+);
HRMS: calcd for C36H43N5O12S.HCl, 805.2396. found (ESI+), 770.27028;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl 2-furoate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 752.2 ((M−H)−);
HRMS: calcd for C36H43N5O13.HCl, 789.2624. found (ESI+), 754.29242;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl 2-furoate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 740.19 (M+H);
The title compound is prepared by the procedure of Example 1, using 1-[(chlorocarbonyl)oxy]ethyl acetate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 716.14 (M+H);
HRMS: calcd for C34H45N5O12, 715.3065. found (ESI+), 716.31469;
The title compound is prepared by the procedure of Example 1, using cyclohexanecarboxylic acid, [(chlorocarbonyl)oxy]methyl ester d N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 756.08 (M+H);
HRMS: calcd for C37H49N5O12, 755.3378. found (ESI+), 756.34507;
The title compound is prepared by the procedure of Example 1, using cyclohexanecarboxylic acid, [(chlorocarbonyl)oxy]methyl ester and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 70.64 (M+H);
HRMS: calcd for C38H51N5O12.HCl, 805.3301. found (ESI+), 770.36093;
The title compound is prepared by the procedure of Example 1, using butanoic acid, 3,3-dimethyl-, [(chlorocarbonyl)oxy]methyl ester and N-propylglycylcycline to give the product of the Example.
MS m/z 00-304761LMS;
HRMS: calcd for C36H49N5O12.HCl, 779.3145. found (ESI+), 744.34539;
The title compound is prepared by the procedure of Example 1, using Butanoic acid, 3,3-dimethyl-, [(chlorocarbonyl)oxy]methyl ester and N-butylglycylcycline to give the product of the Example.
MS m/z 00-304762LMS;
HRMS: calcd for C37H51N5O12.HCl, 793.3301. found (ESI+), 758.36071;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl 2,2-dimethylbutanoate and N-propylglycylcycline to give the product of the Example.
MS m/z 00-304763LMS;
HRMS: calcd for C36H49N5O12.HCl, 779.3145. found (ESI+), 744.3452;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl cyclopentylacetate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 770.7 (M+H);
HRMS: calcd for C38H51N5O12.HCl, 805.3301. found (ESI+), 770.36062;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl adamantane-1-carboxylate and N-butylglycylcycline to give the product of the Example.
MS (ESI) m/z 822.9 (M+H);
HRMS: calcd for C42H55N5O12.HCl, 857.3614. found (ESI+), 822.39184;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl cyclopentylacetate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 754.2 ((M−H)−);
HRMS: calcd for C37H49N5O12.HCl, 791.3145. found (ESI+), 756.34433;
The title compound is prepared by the procedure of Example 1, using [(chlorocarbonyl)oxy]methyl adamantane-1-carboxylate and N-propylglycylcycline to give the product of the Example.
MS (ESI) m/z 808.8 (M+H);
HRMS: calcd for C41H53N5O12.HCl, 843.3458. found (ESI+), 808.37604;
To a solution of 9-amino-minocycline monosulfate (0.0055 mol, 3.135 g, 1 equivalent) in a mixture of 12 ml of acetonitrile and 50 ml of DMPU is added 1.66 g (3 equivalents) of triethylamine and Reference Compound 109 (0.012 mole, 4.88 g), 3,3-Dimethyl-butyric acid [tert-butyl-(2-isobutoxycarbonyloxy-2-oxo-ethyl)-carbamoyloxy)-methyl ester. The reaction is stirred at room temperature for 2 hour, 1 mL methanol is added, stirred for 5 min. and the mixture is poured onto a mixture of 500 ml of ether and 100 ml of isopropanol. Solid is collected and purified by extraction to give 1.5 g of the product of the Example.
MS (ESI) m/z 758.55 (M+H);
HRMS: calcd for C37H51N5O12.HCl, 793.3301. found (ESI+), 758.36201;
Reference Compound 57 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 820.37 (M+H);
HRMS: calcd for C42H53N5O12.HCl, 855.3458. found (ESI+), 820.37574;
The title compound is prepared by reacting the product of the reaction of N-(tert-butyl)-N-({[(2,2-dimethylbutanoyl)oxy]methoxy}carbonyl)glycine using the conditions of Reference Compound 109 with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 758.63 (M+H);
HRMS: calcd for C37H51N5O12.HCl, 793.3301. found (ESI+), 758.36119;
Reference Compound 58 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 730.38 (M+H);
HRMS: calcd for C35H47N5O12.HCl, 765.2988. found (ESI+), 730.33002;
Reference Compound 59 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 754.09 ((M−H)−);
HRMS: calcd for C37H49N5O12.HCl, 791.3145. found (ESI+), 378.67644;
Reference Compound 60 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 778.34 (M+H);
HRMS: calcd for C39H47N5O12, 777.3221. found (ESI+), 778.33065;
Reference Compound 61 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 772.45 (M+H);
HRMS: calcd for C38H53N5O12.HCl, 807.3458. found (ESI+), 772.37695;
Reference Compound 62 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 716.3 (M+H);
HRMS: calcd for C34H45N5O12.HCl, 751.2832. found (ESI+), 716.31461;
Reference Compound 63 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 770.36 (M+H);
HRMS: calcd for C38H51N5O12.HCl, 805.3301. found (ESI−), 768.34546;
Reference Compound 64 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 792.32 (M+H);
HRMS: calcd for C40H49N5O12.HCl, 827.3145. found (ESI+), 792.34613;
Reference Compound 65 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 782.3 (M+H);
HRMS: calcd for C38H44FN5O12.HCl, 817.2737. found (ESI+), 782.30406;
Reference Compound 66 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 744.37 (M+H);
HRMS: calcd for C36H49N5O12.HCl, 779.3145. found (ESI+), 744.34481;
Reference Compound 67 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 770.4 (M+H);
HRMS: calcd for C38H51N5O12.HCl, 805.3301. found (ESI+), 770.35888;
Reference Compound 68 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 832.2 (M+H);
MS (ESI) m/z 416.6 (M+2H);
HRMS: calcd for C39H44F3N5O12.HCl, 867.2705. found (ESI+), 832.30055;
Reference Compound 69 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 728.34 (M+H);
HRMS: calcd for C35H45N5O12.HCl, 763.2832. found (ESI+), 728.31289;
Reference Compound 70 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 822.5 (M+H);
HRMS: calcd for C42H55N5O12.HCl, 857.3614. found (ESI+), 822.39237;
The title compound is prepared by the procedure of Example 42, using 1 equivalent of 9-amino-minocycline and 2 equivalents of isobutoxycarbonyl N-(butoxycarbonyl)-N-(tert-butyl)glycinate Reference Example 118 to give the product of the example.
MS (ESI) m/z 686.4 (M+H);
HRMS: calcd for C34H47N5O10.HCl, 721.3090. found (ESI+), 686.34079;
The title compound is prepared by the procedure of Example 42, using 1 equivalent of 9-amino-minocycline and 2 equivalents of isobutoxycarbonyl N-(tert-butyl)-N-(isobutoxycarbonyl)glycinate, Reference Example 119 to give the product of the example.
MS (ESI) m/z 686.3 (M+H);
MS (ESI) m/z 1371.7 (2M+H);
HRMS: calcd for C34H47N5O10.HCl, 721.3090. found (ESI−), 684.32433;
The title compound is prepared by the procedure of Example 42, using 1 equivalent of 9-amino-minocycline and 2 equivalents of isobutoxycarbonyl N-(tert-butyl)-N-(methoxycarbonyl)glycinate Reference Example 120 to give the product of the example.
MS (ESI) m/z 644.3 (M+H);
MS (ESI) m/z 322.6 (M+2H);
HRMS: calcd for C31H41N5O10.HCl, 679.2620. found (ESI−), 642.27736;
Reference Compound 71 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 742 (M−H);
HRMS: calcd for C36H49N5O12.HCl, 779.3145. found (ESI+), 744.34613;
Reference Compound 72 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 742.4 (M+H);
Reference Compound 73 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 796.4 (M−H);
Reference Compound 74 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 812.4 (M+H);
MS (ESI) m/z 406.7 (M+2H);
HRMS: calcd for C39H46FN5O13.HCl, 847.2843. found (ESI+), 812.31518;
Reference Compound 75 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 782.2 (M−H);
HRMS: calcd for C39H53N5O12.HCl, 819.3458. found (ESI+), 784.37621;
Reference Compound 76 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 790.4 (M−H);
HRMS: calcd for C40H49N5O12.HCl, 827.3145. found (ESI+), 792.34423;
Reference Compound 77 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 778.3 (M+H);
HRMS: calcd for C39H47N5O12.HCl, 813.2988. found (ESI+), 778.3299;
Reference Compound 78 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 744.5 (M+H);
HRMS: calcd for C36H49N5O12.HCl, 779.3145. found (ESI+), 744.34434;
Reference Compound 79 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 804.4 (M+H);
MS (ESI) m/z 402.7 (M+2H);
HRMS: calcd for C40H45N5O13.HCl, 839.2781. found (ESI+), 804.30779;
Reference Compound 80 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 767.4 (M+H);
HRMS: calcd for C37H46N6O12, 766.3174. found (ESI+), 767.32406;
Reference Compound 81 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 838.2 (M−H);
MS (ESI) f/z 113 (TFA-H);
HRMS: calcd for C44H49N5O12.HCl, 875.3145. found (ESI+), 840.34496;
Reference Compound 82 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 792.3 (M−H);
HRMS: calcd for C39H47N5O13.HCl, 829.2937. found (ESI+), 794.32511;
Reference Compound 83 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) f/z 803.4 (M+H);
HRMS: calcd for C40H46N6O12.HCl, 838.2941. found (ESI+), 803.32375;
Reference Compound 84 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 852.4 (M−H);
HRMS: calcd for C45H51N5O12.HCl, 889.3301. found (ESI−), 852.3463;
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl thiophene-2-carboxylate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 655.2 (M−H);
HRMS: calcd for C30H32N4O11S.HCl, 692.1555. found (ESI+), 657.18613;
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl 4-fluorobenzoate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 667.2 (M−H);
HRMS: calcd for C32H33FN4O11.HCl, 704.1897. found (ESI+), 669.22024;
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl 3,5-dimethylbenzoate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 679.2 (M+H);
HRMS: calcd for C34H38N4O11.HCl, 714.2304. found (ESI+), 679.26076;
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl pivalate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 631.2 (M+H);
HRMS: calcd for C30H38N4O11.HCl, 666.2304. found (ESI+), 631.26094;
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl 3,3-dimethylbutanoate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 643.3 (M−H);
HRMS: calcd for C31H40N4O11.HCl, 680.2460. found (ESI+), 645.27632;
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl 2,2-dimethylbutanoate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 645.2 (M+H);
HRMS: calcd for C31H40N4O11.HCl, 680.2460. found (ESI+), 645.27637;
Reference Compound 85 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 812.5 (M−H);
HRMS: calcd for C42H47N5O12.HCl, 849.2988. found (ESI+), 814.33029;
Reference Compound 86 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 812.5 (M−H);
HRMS: calcd for C42H47N5O12.HCl, 849.2988. found (ESI+), 814.33004;
Reference Compound 87 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 815.5 (M−H);
HRMS: calcd for C41H48N6O12.HCl, 852.3097. found (ESI−), 815.32484;
Reference Compound 88 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 813.5 (M−H);
HRMS: calcd for C41H46N6O12.HCl, 850.2941. found (ESI+), 815.32509;
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl 2-ethylbutanoate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 643.4 (M−H);
MS (ESI) m/z 1287.7 (2M−H);
HRMS: calcd for C31H40N4O11.HCl, 680.2460. found (ESI+), 645.27618;
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl cyclopentylacetate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 655.3 (M−H);
MS (ESI) m/z 1311.7 (2M−H);
HRMS: calcd for C32H40N4O11.HCl, 692.2460. found (ESI+), 657.27572;
The title compound is prepared by the procedure of Example 42, using [(chlorocarbonyl)oxy]methyl 4-tert-butylbenzoate in place of the Reference Compound 109 to give the product of the example.
MS (ESI) m/z 705.1 (M−H);
MS (ESI) m/z 1410.9 (2M−H);
HRMS: calcd for C36H42N4O11.HCl, 742.2617. found (ESI+), 707.29336;
Reference Compound 89 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 763.5 (M−H);
HRMS: calcd for C37H44N6O12.HCl, 800.2784. found (ESI+), 765.30896;
Reference Compound 90 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
HRMS: calcd for C37H44N6O12.HCl, 800.2784. found (ESI+), 765.3117;
Reference Compound 91 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 798.2 (M−H);
HRMS: calcd for C38H43F2N5O12.HCl, 835.2643. found (ESI+), 800.29464;
Reference Compound 92 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 780 (M−H);
HRMS: calcd for C38H44FN5O12.HCl, 817.2737. found (ESI+), 782.30558;
Reference Compound 93 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
HRMS: calcd for C39H44F3N5O12.HCl, 867.2705. found (ESI+), 832.30026;
Reference Compound 94 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 833.4 (M+H);
HRMS: calcd for C42H52N6O12.HCl, 868.3410. found (ESI−), 831.3565;
Reference Compound 95 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 838.4 (M−H);
HRMS: calcd for C44H49N5O12.HCl, 875.3145. found (ESI+), 840.34553;
Reference Compound 96 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 804.5 (M−H);
HRMS: calcd for C41H51N5O12.HCl, 841.3301. found (ESI+), 806.36101;
Reference Compound 97 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 820.2 (M−H);
HRMS: calcd for C41H51N5O13.HCl, 857.3250. found (ESI−), 820.34117;
Reference Compound 98 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 852.2 (M−H);
HRMS: calcd for C41H51N5O15.HCl, 889.3148. found (ESI+), 854.34728;
Reference Compound 99 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 822.1 (M−H);
HRMS: calcd for C40H49N5O14, 824.3349. found (ESI+), 824.3351;
Reference Compound 100 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 788.3 (M−H);
HRMS: calcd for C40H47N5O12.HCl, 825.2988. found (ESI+), 790.33068;
Reference Compound 101 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 816.5 (M−H);
HRMS: calcd for C41H47N5O13.HCl, 853.2937. found (ESI+), 818.3234;
Reference Compound 102 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 912 (M−H);
HRMS: calcd for C41H45F6N5O12.HCl, 949.2736. found (ESI+), 914.30367;
Reference Compound 103 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 876.1 (M−H);
HRMS: calcd for C45H59N5O13.HCl, 913.3876. found (ESI+), 878.41791;
Reference Compound 104 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 866.5 (M−H);
HRMS: calcd for C46H53N5O12.HCl, 903.3458. found (ESI), 868.37357;
Reference Compound 105 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 946.7 (M−H);
HRMS: calcd for C50H69N5O13.HCl, 983.4659. found (ESI−), 946.48106;
Reference Compound 106 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 819.1 (M−H);
HRMS: calcd for C40H48N6O13.HCl, 856.3046. found (ESI−), 819.32051;
Reference Compound 107 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 864.3 (M+H);
HRMS: calcd for C46H49N5O12.HCl, 899.3145. found (ESI−), 862.32855;
Reference Compound 108 is reacted under the conditions of Reference Compound 109 and the product of said reaction is further contacted with 9-aminominocycline using the conditions of Example 42 to give the product of the Example.
MS (ESI) m/z 866.3 (M−H);
HRMS: calcd for C45H49N5O13.HCl, 903.3094. found (ESI−), 866.32405;
To a solution of 107 mg (0.166 mmol) of N-propyl-glycylcycline (N-prop-glycyl) in DMPU (2 ml) is added 5 equivalents of sodium carbonate (95 mg, 0.9 mmol) followed by 2 equivalents of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-nitrophenyl carbonate (95 mg, 0.33 mmol) Reference Compound 121 and stirring for 2 hr at room temperature. The reaction mixture is filtered through diatomaceous earth and the filtrate added to a mixture of (1:4)(20 ml) ether:isopropyl alcohol and HCl (1M in ether) is added and the formed solid filtered, redissolved in water, the pH adjusted to about 2 and extracted with methylene chloride to give 15 mg of the product of the Example.
MS (ESI) m/z 728.5 (M+H);
MS (ESI) m/z 364.8 (M+2H);
HRMS: calcd for C34H41N5O13, 727.2701. found (ESI+), 728.27606;
The title compound is prepared by the procedure of Example 108, using N-butyl-glycylcycline (N-bu-glycyl) and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-nitrophenyl carbonate Reference Compound 121 to give the product of the Example.
MS (ESI) m/z 742.3 ((M+H)+);
The title compound is prepared by the procedure of Example 108, using N-propyl-glycylcycline (N-prop-glycyl) and 4-nitrophenyl (2-oxo-5-phenyl-1,3-dioxol-4-yl)methyl carbonate Reference Compound 122 to give the product of the Example.
MS (ESI) m/z 790.3 ((M+H)+);
HRMS: calcd for C39H43N5O13, 789.2857. found (ESI+), 790.29243;
The title compound is prepared by the procedure of Example 108, using N-propyl-glycylcycline (N-prop-glycyl) and [5-(4-methoxyphenyl)-2-oxo-1,3-dioxol-4-yl]methyl 4-nitrophenyl carbonate Reference Compound 123 to give the product of the Example.
MS (ESI) m/z 820.3 ((M+H)+);
The title compound is prepared by the procedure of Example 108, using N-butyl-glycylcycline (N-bu-glycyl) and 4-nitrophenyl (2-oxo-5-phenyl-1,3-dioxol-4-yl)methyl carbonate Reference Compound 122 to give the product of the Example.
MS (ESI) m/z 804.12 (M+H);
MS (ESI) m/z 402.58 (M+2H);
HRMS: calcd for C40H45N5O13, 803.3014. found (ESI+), 804.30946;
The title compound is prepared by the procedure of Example 108, using N-butyl-glycylcycline (N-bu-glycyl) and [5-(4-methoxyphenyl)-2-oxo-1,3-dioxol-4-yl]methyl 4-nitrophenyl carbonate Reference Compound 123 to give the product of the Example.
This application claims priority from provisional Application Ser. No. 60/713,112, filed on Aug. 31, 2005, the entire disclosure of which is hereby incorporated by reference.
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| Number | Date | Country |
|---|---|---|
| WO 0174761 | Oct 2001 | WO |
| WO 02072031 | Sep 2002 | WO |
| WO 2004064728 | Aug 2004 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20070049564 A1 | Mar 2007 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60713112 | Aug 2005 | US |
