FIELD OF THE INVENTION
The present invention relates to novel oxazole derivatives of tetracyclines
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. This invention also relates to novel tetracycline intermediates useful
for making the novel compounds and novel methods for producing the novel
compounds and the intermediate compounds.
BACKGROUND OF THE INVENTION
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 303 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 0, 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-(dimethy!amino)- 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. PaL 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. This invention describes the
synthesis of novel tetracycline compounds which demonstrate significant in vitro and
in vivo activity vs. tetracycline and minocycline susceptible strains and some
tetracycline and minocycline resistant strains, that is, those harboring the tetM
(ribosomal protection) resistance determinants.
Duggar, U.S. Pat. No. 2,482,055, discloses the preparation of Aureomycin.RTM. 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. PaL No.
3,148,212, reissued as U.S. Pat. No. RE 26,253, and Petisi et al., U.S. PaL 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 a!., 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. Marteil 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-

substitutedamino-6-demethyl-6-deoxytetracyclines which have broad spectrum
antibacterial activity.
In summary, none of the above patents teach or suggest the novel compounds of this
application. In addition, none of the above patents teach or suggest novel tetracycline
compounds of the invention having activity against tetracycline and minocycline
resistant strains as well as strains which are normally susceptible to tetracyclines.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided compounds represented
by Formula (I);

wherein:
X is selected from hydrogen, amino, NR11R12, alkyl of 1 to 12 carbon atoms optionally
substituted , aryl of 6, 10 or 14 carbon atoms optionally substituted, vinyl optionally
substituted, alkynyl of 2 to 12 carbon atoms optionally substituted and halogen;
A" is a moiety selected from the group:

R11 and R12 are each independently H or alkyl of 1 to 12 carbon atoms or

R11 and R12 when optionally taken together with the nitrogen atom to which each is
attached form a 3 to 7 mernbered saturated hydrocarbon ring;
Y is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted, aryl
of 6, 10 or 14 carbon atoms optionally substituted, alkenyl of 2 to 12 carbon atoms
optionally substituted, vinyl, alkynyl of 2 to 12 carbon atoms optionally substituted
and halogen;
R is selected from alkyl of 1 to 12 carbon atoms optionally substituted, alkenyl of 2 to
12 carbon atoms optionally substituted, alkynyl of 2 to 12 carbon atoms optionally
substituted, -CH2NR1R2, aryl of 6,10 or 14 carbon atoms optionally substituted,
aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl of 7 to 13 carbon atoms
optionally substituted, SR3, heteroaryl of 5 or 6 ring atoms optionally substituted,
containing 1 to 4 heteroatorns which may be the same or different, independently
selected from nitrogen, oxygen and sulfur, and heteroarylcarbonyl of 5 or 6 ring
atoms optionally substituted containing 1 to 4 heteroatorns which may be the same or
different, independently selected from nitrogen, oxygen and sulfur,
R1 and R2 are each independently H or alkyl of 1 to 12 carbon atoms or
R1 and R2 when optionally taken together with the nitrogen atom to which each is
attached form a 3 to 7 mernbered saturated hydrocarbon ring;
R3 is alkyl of 1 to 12 carbon atoms optionally substituted, -CHraryl optionally
substituted, aralkyl of 7 to 16 carbon atoms optionally substituted, aroyl,
-CH2(CO)OCH2aryI optionally substituted, -CH2-alkenyl of 2 to 12 carbon atoms
optionally substituted, and -CH2-alkyny! of 2 to 12 carbon atoms optionally
substituted;
with the provisos that when X is NR1R2 and R1 is hydrogen, then R2 is methyl, ethyl,
n-propyl, n-butyl, 1-methylethyl, 1 -methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;
and that when R1 is methyl or ethyl then R2 is methyl, ethyl, n-propyl, 1-methylethyl,
n-propyl, 1-methylpropyl, or 2-methyipropyl;
or a tautomer or pharmaceutically acceptable salts thereof.

Definitions
The term alkyl as a group or part of a group means a straight or branched alkyl
moiety of 1 to 12 carbon atoms which can be optionally independently substituted
with 1 to 3 substituents selected from the group halogen, amino, cyano, cycloaikyl of
3 to 6 carbon atoms, alkyl of 1 to 12 carbon atoms, aryl optionally substituted, phenyl,
hydroxyl, alkoxy of 1 to 12 carbon atoms, NH-alkyl of 1 to 12 carbon atoms, N-
cycloalkyl of 3 to 6 carbon atoms, NH-(alkyl of 1 to 12 carbon atoms)-aryi optionally
substituted and heterocyclyl of 3 to 8 membered ring. 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 alkyl is
substituted by heterocyclyl of 4 to 7 ring members (e.g. pyrroiidinyl)
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 substituted aryl, phenyl, heteroaryl,
halogen, amino, cyano, alkyl of 1 to 12 carbon atoms, hydroxyl, and alkoxy of 1 to 12
carbon atoms.
The term vinyl means a moiety CH2=CH-.
As used herein the term alkoxy as a group or part of a group refers to alkyl-O-
wherein alkyl is hereinbefore defined.
As used herein the term aryl as a group or part of a group, e.g., aralkyl, aroyl, means
an aromatic moiety having 6,10 or 14 carbon atoms preferably 6 to 10 carbon atoms,
which can be optionally substituted with 1 to 3 substituents independently selected
from halogen, nitro, cyano, alkenyl, hydroxyl, alkyl, haloalkyl, alkoxy, benzyloxy,
amino, alkylamino, dialkylamino, carboxyf, alkoxycarbonyl, methylenedioxy and

phenyl. In particular, aryl is phenyl or naphthyl optionally substituted with 1 to 3
substituents. Substituted phenyl may optionally be the moiety

The term aralkyl as used herein of 7 to 15 carbon atoms means an alkyl substituted
with an aryl group in which the aryl and alkyl group are previously defined. Non-
limiting exemplary aralkyl groups include benzyl and phenethyl and the like.
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, CI, 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.
As used herein, R1 and Ft2 and R11 and R12 when optionally taken together with the
nitrogen atom to which each is attached form a 3 to 7 membered saturated
hydrocarbon ring, where a non-limiting example is pyrrolidinyl,


The term aroyl means an aryl-C(O)- group in which the aryi 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.
Heteroaryl rings may optionally be substituted with 1 to 3 substitutents selected from
the group halogen, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino, alkoxy,
aryloxy, -CH2OCOCH3 and carboxy. Non-limiting heteroaryl moieties optionally
substituted include: furanyl, thienyl, pyridyl, tetrazolyl, imidazo, thiazolyl and the like.
Further included are benzofuranyl, benzothienyl and quinoiinyl.
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 3 to 8 membered ring
containing one to three heteroatoms selected from nitrogen, oxygen and sulfur.
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 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:

One embodiment of this invention is where R of Formula (I) is selected from the
group alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkyl-
(heterocyclyl) selected from moieties of the group

Another embodiment of the invention is where Ft of Formula (I) is phenyl optionally
substituted with 1 to 3 substituents. In a preferred embodiment R is selected from
moieties of the group

A further preferred embodiment of the invention is where R is heteroaryl. In a
preferred embodiment R is selected from moieties of the group

An additional embodiment of the invention is where R is alkyl of 1 to 6 carbon atoms
optionally substituted, alkenyl of 2 to 6 carbon atoms optionally substituted,

optionally substituted. In a preferred embodiment R is selected from moieties of the
group

Preferred compounds of the invention include those selected from the group:
(6aR,7aS,8S,11aS)-5,8-bis(dimethylamino)-2-(2,2-diphenylvinyl)-9,11a,12-trihydroxy-
11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -d][1,3]oxazole-10-
carboxamide,
(7aS,8S,11aS)-8-{dimethylamino)-9,11a,13-trihydroxy-2-(2-methyl-1-propenyl)-
11,12-dioxo-7,7a,8,11,11 a, 12-hexahydronaphthaceno[2,1 -d][1,3]oxa20le-10-
carboxamide,
(5aR,7aS,8S,11aS)-2-fert--butyl-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-11,13-
dioxo-6,6a,7,7a,8,11,11 a,13-odahydrotetraceno[2,1 -d][1,3]oxazole-10-carboxamide,
(6aR, 7aS,8S,11aS)-5,8-bis(dimethylamino)-2-[(E)-2-(2-furyl)ethenyl]-9,11a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno[2,1 -d][1,3]oxazole-
10-carboxamide,
(6aR,7aS,8S,11aS)-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-11,13-dioxo-2-[(£)-2-
phenylethenyl]-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -d][1,3]oxazole-10-
carboxamide,

(6aR,7aS,8S,11aS)-5,8-bis(dinnethylamino)-9,11a,12-trihydroxy-2-[(E)-2-(4-
methoxyphenyl)ethenyl]-11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -
d][1,3]oxazole-10-carboxamide,
(6aR,7aS,8S, 11 aS)-5,8-bis(dimethylamino)-9,11a, 12-trihydroxy-2-[(E)-2-(3-
methoxyphenyl)ethenyi]-11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -
d][1,3]oxazole-10-carboxamide,
(6aR,7aS,8S, 11 aS)-5,8-bis(dimethylamino)-9,11 a,12-trihydroxy-2-[(E)-2-(2-
methoxyphenyl)ethenyr|-11,13-dioxo-6,6a,7,7a,8,11,11a,13-ociahydrotetraceno[2,1-
d][1,3]oxazole-10-carboxamide,
(6aR,7aS,8S,11aS)-5,8-bis(dimetriylamino)-2-[(E)-2-(4-flurophenyl)ethenyl]-
9,11 a, 12-trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno[2,1 -
d][1,3]oxazole-10-carboxamide,
(6aR,7aS,85,11aS)-5,8-bis(dimethylamino)-2-[(E)-2-(2-fluorophenyl)ethenyi]-
9,11 a, 12-trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno[2,1 -
d][1,3]oxazole-10-carboxamide,
(6aR,7aS,8S,11aS)-2-(criloromethyl)-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-
11,13-dioxo-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno[2,1 -d][1,3]oxazole-10-
carboxamide,
(6aR,7aS,8S,11aS)-5,8-bis(dimethylamino)-2-[(dimethylarnino)methyi]-9,11a,12-
trihydroxy-11,13-dloxo-6,6a,7,7a,8,11,11a,13-octahydrotetraceno[2,1-d][1,3]oxazole-
10-carboxamide,
(6aR,7aS,8S,11 aS)-5,8-bis(dimethylamino)-9,11 a,12-trihydroxy-11,13-dioxo-2-
(pyrrolidin-1 -ylmethyl)-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -d][1,3]oxazoIe-
10-carboxamide,

(6aR,7aS,8S,11aS)-5,8-bis(dimethylarnino)-9,11a,12-trihydroxy-11,13-dioxo-2-
[(propylamino)methyl]-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1-d][1,3]oxazole-
10-carboxamide,
(6aR,7aS,8S,11aS)-2-[(butylamino)methyl]-5,8-bis(dimethylamino)-9,11 a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno[2,1 -d][1,3]oxazole-
10-carboxamide,
(6aR,7aS,8S,11aS)-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-11,13-dioxo-2-
[(propylamino)methyi]-6,6a,7,7a,8,11,11 a,13-octarrydrotetraceno[2,1-d][1,3]oxazole-
10-carboxamide and
(6aR,7aS,8S,11aS)-2-[(fert-butylarnino)methyl]-5,8-bis(dimethylamino)-9,11a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno[2,1 -d][1,3]oxazole-
10-carboxamide.
Preferred compounds of the invention include those selected from the group:
(7aS,8S, 11 aS)-8-(dimethylamino)-2-[4-(dimethylamino)phenyl]-9,11 a,13-trihydroxy-
11,12-dioxo-7,7a,8,11,11 a, 12-hexahydronaphthaceno[2,1 -d][1,3]oxazole-10-
carboxamide,
(6aR,7aS,8S,11aS)-2-fert-butyl-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-11,13-
dioxo-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno[2,1 -d][1,3]oxazole-10-carboxamide,
(6aR,7aS,8S, 11 aS)-5,8-bis(dimethylamino)-9,11 a,12-trihydroxy-2-(4-methylpheny!)-
11,13-dioxo-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno[2,1 -d][1,3Joxazole-10-
carboxamide,
(7aS,8S, 11 aS)-5,8-bis(dimethylamino)-2-{3-fluorophenyl)-9,11a,13-trihydroxy-11,12-
dioxo-7,7a,8,11,11 a, 12-hexahydrotetraceno[2,1 -d][1,3]oxazoie-10-carboxamide,

(6aR,7aS,85,11aS)-2-(4-cyanophenyl)-5,8-bis(dimeihylamino)-9,11 a,12-trihydroxy-
11,13-dioxo-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno[2,1 -d][1,3]oxazole-10-
carboxamide,
(6aR,7aS,8S,11aS)-5,8-bis(dimethy!amino)-2-[4-(dimethylamino)phenyl]-9,11a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -d][1,3]oxazole-
10-carboxamide,
(6aR,7aS,8S,11aS}-2-(5-tert-fautyl-2-hydroxyphenyi)-5,8-bis(dimethylamino)-
9,11 a,12-trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -
d][1,3]oxazole-10-carboxamide,
(6aR,7aS,8S,11 aS)-2-[4-(benzyloxy)phenyI]-5,8-bis(cfimethyIamino)-9,11 a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a, 13-octariydrotetraceno[2,1 -d][1,3]oxazole-
10-carboxamide,
(6aR,7aS,8S,11 aS)-2-(2,4-dihydroxyphenyl)-5,8-bis(dimethylamino)-9,11 a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1-d][1,3]oxazole-
10-carboxamide,
(6aR,7aS,85,11aS)-5,8-bis(dimethylamino)-2-(3-fIuoro-4-methoxyphenyl)-9,11a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1-d][1,3]oxazole-
10-carboxamide,
(6aR,7aS,8S,11aS)-2-(1,3-benzodioxol-5-y])-5,8-bis(dimethylamino)-9I11a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -d][1,3]oxazole-
10-carboxamide,
(6aR>7aS,8Sl11aS)-5,8-bis(dimethy!amino)-9,11a,12-trihydroxy-11,13-dioxo-2-
(2,4,6-trimethoxyphenyl)-6l6a,7,7a,8,11,11a,13-ociahydrotetraceno[2,1-
d][1,3]oxazole-10-carboxamide,

(6aR,7aS,8S, 11 aS)-5,8-bis(dimethylamino)-9,11 a,12-trihydroxy-11,13-dioxo-2-
(2,4,5-triethoxyphenyl)-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno[2,1 -d][1,3]oxazole-
10-carboxamide,
(6aR,7aS,8S,11 aS)-5,8-bis(dimethylamino)-9,11 a,12-trihydroxy-2-(1 -methyl-1H-
indol-2-yl)-11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1-d][1,3]oxazole-
10-carboxamide,
(6aR,7aS,8S,11 aS^^^terf-butylprienyO-S.S-bisCdimetliylaminoJ-g.l 1 a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -d][1 ^joxazole-
10-carboxamide and
(6aR,7aS,8S,11aS)-5,8-bis(dimethylamino)-2-[4-(hexyloxy)phenyl]-9,11a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno(2,1 -d][1,3]oxazote-
10-carboxamide.
Preferred compounds include those selected from the group:
(BaR, 7aS, 8S, 11 aS)-5,8-bis(dimethylamino)-9,11 a, 12-trihydroxy-11,13-dioxo-2-thien-
3-yl-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno[2,1 -d][1,3]oxazole-10-carboxamide,
(6aR,7aS,85,11 aS)-2-(1 -benzofuran-2-yl)-5,8-bis(dimethyiamino)-9,11 a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno[2,1 -d][1,3]oxazole-
10-carboxamide,
(6aR,7aS,8S,11aS)-5,8-bis(dimethylamino)-2-(2-furyl)-9,11 a,12-trihydroxy-11,13-
dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -d][1,3]oxazole-10-carboxamide,
{5-[(6aR,7aS,8S, 11 aS)-10-(aminocarbonyl)-5,8-bis(dimethylamino}-9,11 a, 12-
trihydroxy-11,13-dioxo-6,6a,7,7a, 8,11,11 a, 13-ocfahydrotetraceno[2,1 -d][1,3]oxazol-2-
yf]-2-furyl}methyl acetate,
(5aR,7aS,8S,11 aS)-2-(1 -benzothien-3-yl)-5,8-bis(dimethylamino)-9,11 a,12-

trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1-d][1,3]oxazole-
10-carboxamide,
(6aR,7aS,8S,11aS)-5,8-bis(dimethy!amino)-9,11a,12-(rihydroxy-11,13-dioxo-2-(1,3-
thiazol-2-yl)-6,6a,7,7a,8,11,11a,13<;ctahydrotetraceno[2,1-d][1,3]oxazole-10-
carboxamide,
(6aR, 7aS,8S, 11 aS)-5,8-bis(dimethylamino)-9,11 a, 12-trihydroxy-11,13-dioxo-2-
pyridin-4-yl-6,6a,7,7a,8,11,11a,13-octahydrotetraceno[2,1-d][1,3]oxazole-10-
carboxamide and
(6aR,7aS,8S,11 aS}-5,8-bis(dfmethylamino)-9,11 a, 12-trihydroxy-11,13-dioxo-2-
pyridin-3-yi-6,6a,7,7a,8, 11,11 a, 13-octahydrotetraceno[2,1 -d][1,3]oxazote-10-
carboxamide.
An additional embodiment of the invention is a process for the preparation of
a compound of the formula

X is selected from hydrogen, amino, NR1R2, alkyl of 1 to 12 carbon atoms optionally
substituted., aryl of 6,10 or 14 carbon atoms optionally substituted, vinyl optionally
substituted, alkynyl of 2 to 12 carbon atoms optionally substituted and halogen;
R1 and R2 are each independently H or alkyl of 1 to 12 carbon atoms or

R1 and R2 when optionally taken together with the nitrogen atom to which each is
attached form a 3 to 7 membered saturated hydrocarbon ring;
Y is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted, aryl
of 6,10 or 14 carbon atoms optionally substituted, alkenyl of 2 to 12 carbon atoms
optionally substituted, vinyl, alkynyi of 2 to 12 carbon atoms optionally substituted
and halogen;
comprising the steps:
a. reacting 7-(substtuted)-8-(substituted)-9-amino-6-dernethyf-6-
deoxytetracyciine of the formula

or a pharmaceutically acceptable salt thereof
with 2-chlorotrimethoxyethane in an aprotic solvent to afford a chloro compound of
the formula

b. reacting the chloro compound with an amine R1R2NH to form a substituted
amine of the formula


c. hydrolyzing the substituted amine with acid to give a compound of the formula

d. isolating the compound or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the process X is N(CH3)2 and the amine R1R2NH is t-
butyl amine.
In a preferred embodiment of the process the compound [4S-(4α,4aα,5aα,12aα)]-
4,7-Bis(dimethylamino)-9-[2-(1,1 -dimethylethylamino)acetylamino]-
1,4.4a,5,5a,6,11.12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-
naphthacenecarboxamide or a pharmaceutically acceptable salt thereof is prepared.
A further embodiment of the invention is a process for the preparation of a
compound of the formula


wherein:
X is selected from hydrogen, amino, NR1R2, alkyl of 1 to 12 carbon atoms optionally
substituted , aryl of 6,10 or 14 carbon atoms optionally substituted, vinyl, optionally
substituted, alkynyl of 2 to 12 carbon atoms optionally substituted and halogen;
R1 and R2 are each independently H or alkyl of 1 to 12 carbon atoms or
R1 and R2 when optionally taken together with the nitrogen atom to which each is
attached form a 3 to 7 membered saturated hydrocarbon ring;
Y is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted, aryl
of 6,10 or 14 carbon atoms optionally substituted, alkenyl of 2 to 12 carbon atoms
optionally substituted, vinyl, alkynyl of 2 to 12 carbon atoms optionally substituted
and halogen;
or a pharmaceutically acceptable salt thereof
comprising the steps:
a. reacting 7-(substituted)-8-(substftuted)-9-amino-6-demethyl-6-
deoxytetracycline of the formula

or a pharmaceutically acceptable salt thereof
with 2-chlorotrimethoxyethane in an aprotic solvent to afford a chloro compound of
the formula


b. reacting the chloro compound with acid to give 9-(2-
chIoromethylcarbonylamino)substituted-6-demethyl-6-deoxytetracycline of the
formula

c. reacting the 9-(2-chloromethylcarbonylamino)substrtuted-6-demethyl-6-
deoxytetracycline with amine R1 R2NH to give a compound of the formula

d. isolating the compound or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the process X is N(CH3)2 and the amine R1R2NH is t-
butyl amine.
In a preferred embodiment of the process the compound [4S-(4α,4aα,5aα,12aα)]-
4,7-Bis(dimethylamino)-9-[2-(1,1-dimethylethylamino)acetyiamino]-

1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-
naphthacenecarboxamide or a pharmaceutically acceptable salt thereof is prepared.
An additional embodiment of the invention is a compound of the formula

X is selected from hydrogen, amino, NR1R2, alkyl of 1 to 12 carbon atoms optionally
substituted , aryl of 6,10 or 14 carbon atoms optionally substituted, vinyl optionally
substituted, alkynyl of 2 to 12 carbon atoms optionally substituted and halogen;
R1 and R2 are each independently H or alkyl of 1 to 12 carbon atoms or
R1 and R2 when optionally taken together with the nitrogen atom to which each is
attached form a 3 to 7 membered saturated hydrocarbon ring;
Y is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted, aryl
of 6, 10 or 14 carbon atoms optionally substituted, alkenyl of 2 to 12 carbon atoms
optionally substituted, vinyl, alkynyl of 2 to 12 carbon atoms optionally substituted
and halogen;
produced by the process comprising the steps:
a. reacting 7-(substituted)-8-(substituted)-9-amino-6-demethyl-6-
deoxytetracycline of the formula


or a pharmaceutically acceptable salt thereof
with 2-chlorotrimethoxyethane in an aprotic solvent to afford a chloro compound of
the formula

b. reacting the chloro compound with an amine R1R2NH to form a substituted
amine of the formula

c. hydrolyzing the substituted amine with acid to give a compound of the formula


d. isolating the compound or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the process X is N(CH3)2and the amine R1R2NH is t-
butyl amine.
In a preferred embodiment of the process the compound [4S-(4a,4aa,5aa,12acc)]-
4,7-Bis{dimethy1amino)-9-[2-(1,1 -dimethy!ethylarnino)acetylamino]-
1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-
naphthacenecarboxamide or a pharmaceuticaily acceptable salt thereof is prepared.
In an additional embodiment of the invention a compound of the formula

wherein:
X is selected from hydrogen, amino, NR1R2, alkyl of 1 to 12 carbon atoms optionally
substituted , aryl of 6,10 or 14 carbon atoms optionally substituted, vinyl optionally
substituted, alkynyl of 2 to 12 carbon atoms optionally substituted and halogen;
R1 and R2 are each independently H or alkyl of 1 to 12 carbon atoms or
when optionally taken together with the nitrogen atom to which each is attached form
a 3 to 7 membered saturated hydrocarbon ring;
Y is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted, aryl
of 6, 10 or 14 carbon atoms optionally substituted, alkenyl of 2 to 12 carbon atoms

optionally substituted, vinyl, alkynyl of 2 to 12 carbon atoms optionally substituted
and halogen;
or a pharmaceutically acceptable salt thereof
produced by the process comprising the steps:
a. reacting 7-(substituted)-8-(substituted)-9-amino-6-demethyl-6-
deoxytetracycline of the formula

or a pharmaceutically acceptable salt thereof
with 2-chlorotrimethoxyethane in an aprotic solvent to afford a chloro compound of
the formula
b. reacting the chloro compound with acid to give 9-(2-
chlorome1hylcarbonyIamino)substituted-6-demethyl-6-deoxytetracycline of the
formula
c. reacting the 9-(2-chIoromethylcarbonylamino)substituted-6-demethyl-6-
deoxytetracycline with amine R1R2NH to give a compound of the formula


d. isolating the compound or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the process X is N(CH3)2and the amine R1R2NH is t-
butyl amine.
In a preferred embodiment the compound [4S-(4α,4aα,5aα,12aα)]-4,7-
Bis(dimethylamino)-9-[2-(1,1-dimethylethylamino)acetylamino]-1,4,4a,5,5a,6,11,12a-
octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideora
pharmaceutically acceptable salt thereof is prepared by the process.

DESCRIPTION OF THE PREFERRED EMBODIMENTS
The novel compounds of the present invention may be readily prepared in
accordance with the following Scheme I.
The starting 7-{substituted)-8-(substituted)-9-amino-6-demethyl-6-deoxytetracyclines
1 or pharmaceutically acceptable salts thereof where X and Y are hereinbefore
defined are reacted with aldehyde RCHO in the presence of 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) to afford benzoxazole 2 and 3 (Procedure A). As
further described, reaction of 7-(substituted)-8-(substituted)-9-amino-6-demethyl-6-
deoxytetracyclines 1 or pharmaceutically acceptable salts thereof where X and Y are
hereinbefore defined are reacted with 2-chlorc-1,1,1-trimethoxy-ethane in an aprotic
solvent such as N,N-dimethylformamide (DMF) to give chloromethyl-benzoxazole 4,
optionally isolated, then converted to substituted amine 5 by further reaction with an
amine 9 (Procedure B). Hydrolysis of amine 5 affords 9-(2-substituted aminomethyl
carbonylamino)substituted-6-dimethyl-6-deoxytetracycline 6 (Procedure D).
Hydrolysis of chloromethylbenzoxazole 4 gives 9-(2-chloromethylcarbonyl-
amino)siibstituted-6-demethyl-6-deoxytetracycline 7 which may be further reacted
with amine 9 to give 9-(2-substituted aminomethyl carbonylamino)substituted-6-
dimethyl-6-deoxytetracycline 6.
Additionally, reaction of 7-(substituted)-8-(substituted)-9-amino-6-demethyl-6-
deoxytetracyclines 1 or pharmaceutically acceptable salts thereof with
thiocarbonyldiimidazole provides thio 8 followed by alkylation with RCH2Br in the
presence of an amine which includes N,N-diisopropy!ethy!amine affords oxazole 10
(Procedure C).
Preferably, amine 9 in the preparation of 9-(2-substituted aminomethyl
carbonylamino)substituted-6-dimethyI-6-deoxytetracycline 6, in Scheme I is t-
butylamine.

As shown in Scheme II, the starting 7-(substituted)-8-(substiiuted)-9-amino-6-
demethyl-6-deoxytetracyclines 1 or pharmaceutically acceptable salts thereof where
X and Y are hereinbefore defined are reacted with a methyl orthoester to afford
methyl benzoxazole derivative 11. Acid hydrolysis of methyl benzoxazole derivative
11 affords N-acetyl derivative 12.


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.
Pharmaceutically acceptable salts of 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. The salt
formation preferentially occurs with the C(4)-dimethylamino group when forming
inorganic salts. 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 il 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 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.
1. NCCLS. 2000. Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria That Grow Aerobically; Approved Standards: M7-A5, vol. 20.
National Cornrnitte for Clinical Laboratory Standards, Wayne, PA.

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 about 2.0 mg/kg of body weight to about
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, intrastemal 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 earners 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 of compounds of the invention 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 oiis. 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 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.
Example of Procedure A
EXAMPLE 1
(6aR,7aS,85,11aS)-5,8-bis(dimethylamino)-2-(2,2-diphenylvinyl)-9,11a,12-trihydroxy-
11,13-dioxo-6,6a,7,7a, 8,11,11 a, 13-octahydrotetraceno[2,1 -d][1,3]oxazole-10- .
carboxamide

9-aminominocycline sulfate salt (0.500g, 0.748 mmol) is dissolved in
anhydrous DMF and treated with p-phenylcinnamaldehyde (0.779g, 3.74 mmol, 5
equivalents) The solution is then treated with DDQ (0.085 g, 0.374 mmol, 0.5
equivalents) and stirred at room temperature for 5 min. ES+ mass spectrometry
showed a 1:1 ratio of product and starting material. A second portion of DDQ (0.068
g, 0.300 mmol, 0.4 equivalents) is added. After approximately 5 minutes, acetonitrile
(7.5 mL) is added, and the entire reaction mixture is poured slowly into ether (750
mL) The pink solid is removed by filtration and washed with fresh ether to yield
0.480g of the crude product. This material is dissolved in water (75 mL) to give a
solution at pH 2.2, which is extracted with dichloromethane (2 X 100 mL) The pH of
the aqueous layer is raised to 3.0 with aqueous ammonia, and the solution is again

extracted with dichloromethane (2 X 100 mL) The four organic extracts are dried
(Na2S04), filtered and concentrated to a volume of about 2 mL A small portion of
methanol (1 mL) is added, and the concentrated solution is treated dropwise with 1M
HCI in ether. The solid precipitate is filtered, washed with fresh ether and dried under
vacuum the product as its HCI salt.
Selected 1H NMR signals: 5 4.26 (s, 1H), 7.13 (s, 1H), 726-7.45 (m, 8H), 7.63 (s,
1H), 9.08(s, 1H),9.54(s,1H).
The compounds of this invention listed below in Examples 2 to 37 are prepared
substantially following the method described in detail hereinabove in Example 1
using procedure A.
EXAMPLE 2
(7aS,8S, 11 aS)-8-(dimethylamino)-9,11 a, 13-trihydroxy-2-(2-methyl-1 -propenyl)-
11,12-dioxo-7,7a,8,11,11 a,12-hexahydronaphthaceno[2,1 -d][1,3]oxazole-10-
carboxamide

MS m/z 492 (M+H)
HRMS: calcd for C26H26N307,491.16925; found (ESI+), 492.1765

EXAMPLE 3
(7aS, 8S, 11 aS)-8-{dimethyIamino)-2-[4-(dimethylamino)pheny!]-9,11 a, 13-trihydroxy-
11,12-dioxo-7,7a,8,11,11 a,12-hexahydronaphthaceno[2,1 -d][1,3]oxazole-10-
carboxamide

HRMS: calcd for C^NaO^ 566.1958; found (ESI+), 557.2030
EXAMPLE 4
(6aR,7aS,8S,11aS)-2-tert-butyl-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-11,13-
dioxo-6,6a,7,7a,8,11,11 a, 13-ocfahydrotetraceno[2,1 -d][1,3]oxazole-10-carboxamide

- MS (ESI) m/z539.3 (M+H);
MS (ESI) m/z 270 A (M+2H);
HRMS: calcd for C^H^O? • HCI, 574.2194; found (ESI-), 537.23462;

(6aR,7aS,8S,11aS)-5,8-bis(dimethylamino)-9,11al12-trihydroxy-2-(4-methylphenyl)-
11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -d][1,3]oxazole-10-
carboxamide

MS (ESI) m/z 573.3 (M+H);
MS (ESI) m/z287 (M+2H);
HRMS: calcd for QnHaMOy' HCI, 608.2038; found (ESI-), 571.21905;
EXAMPLE 6
(7aS,8S, 11 aS)-5,8-bis(dimethylamino)-2-(3-fluorophenyl)-9,11 a, 13-trihydroxy-11,12-
dioxo-7,7a,8,11,11 a,12-hexahydrotetraceno[2,1 -d][1,3]oxazole-10-carboxamide


(6aR,7aS,8S,11 aS)-2-(4-cyanophenyl)-5,8-bis(dirnethylamino)-9,11 a, 12-trihydroxy-
11,13-dioxo-6,6a,7,7a,8,11,1 la,13-octahydrotetraceno[2,1-d][1,3]oxazo)e-10-
carboxamide

MS (ESI) m/z 584.4 (M+H);
HRMS.-calcdforC^HjgNsCVHCI, 619.1834; found (ESI-), 582.19817;
EXAMPLE 8
(6aR,7aS,8S,11 aS)-5,8-bis(dimethy!amino)-2-[4-{dimetfiylamino)phenyO-9,11 a, 12-
trihydroxy-11,13-dioxo-6,5a,7,7a(8,11,11 a,13-octahydrotetraceno[2,1 -d][1,3]oxazole-

MS (ESI) m/z602.2 (M+H);
MS (ESI) m/z301.8 (M+2H);
HRMS: calcd for C^NsOr' HCI, 637.2303; found (ESI-), 600.24521;

EXAMPLE 9
(6aR,7aS,8S,11 aS)-5,8-bis(dimethylamino)-2-(2,2-diphenylvinyl)-9,11 a,12-trihydroxy-
11,13Hdioxo-6,6a,7,7a,8,11,11a,13-octahydrotetraceno[2,1-d][1,3]oxazole-10-
carboxamide

MS (ES!) m/z 661.3 (M+H);
MS (ESI) m/z331.3 (M+2H);
HRMS: calcd for CaH36N407 • HCI, 696.2351; found (ESI-), 659.24957;
EXAMPLE 10
(6aR,7aS,8S, 11 aS)-2-(5-fe^birtyl-2-hydroxyphenyl)-5,8-bis(dimethylamino)-
9,11a,12-trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11a,13-octahydrotetraceno[2,1-
d][1,3]oxazole-10-carboxamide

MS (ESI) m/z 631.4 (M+H);
HRMS: calcd for C34H3aN4OB • HCI, 666.2456; found (ESI+), 631.27753;

EXAMPLE 11
(6aR,7aS,85,11aS)-2-[4-(ben2yloxy)phenyl]-5,8-bi£(dimethylamino)-9r11a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno[2,1 -d][1,3]oxazoIe-
10-carboxamide

HRMS: calcd for C^HSMOB • HCI, 700.2300; found (ESI+), 665.26096;
EXAMPLE 12
(6aR,7aS, 85,11 aS)-2-(2,4-dihydroxyphenyl)-5,8-bis(dimethyiamino)-9,11 a, 12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -d][1,3]oxa2ole-
10-carboxamide

MS (ESI) m/z 591.2 (M+H);
HRMS: calcd for C30H30N4Q9' HCI, 626.1780; found (ESI-), 589.1927;

EXAMPLE 13
(6aR,7aS,8S,11 aS)-5,8-bis(dimethylamino)-2-(3-fluoro-4-methoxyphenyl)-9,11 a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -d][1,3]oxazole-
10-carboxamide

MS (ESI) m/z 607.3 (M+H);
MS (ESI) m/z 304 (M+2H);
HRMS: calcd for C3iH31FN40a' HCI, 642.1893; found (ESI-), 605.20519;
EXAMPLE 14
(6aR,7aS,8SJ1aS)-2-(1,3-benzodioxol-5-yl)-5,8-bis(dimethylamino)-9,11a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -d][1,3]oxazole-
10-carboxamide

MS (ESI) m/z 603.3 (M+H);
MS (ESI) m/z 302.1 (M+2H);
HRMS: calcd for C31H30N4O9 " HCI, 638.1780; found (ESI+), 603.20953;

EXAMPLE 15
(6aR,7aS,8S,11aS)-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-11,13-dioxo-2-(2,4,6-
trimethoxyphenyl)-6,6a,7,7a,8,11,11a,13-octahydrotetraceno[2,1-d][1,3]oxazole-10-
carboxamide

MS (ESI) m/z 649.2 (M+H);
HRMS: calcd for C33H36N4O10 • HCI, 684.2198; found (ESI-), 647.23441;
EXAMPLE 16
(6aR,7aS,85,11aS)-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-11,13-dioxo-2-(2,4,5-
triethoxyphenyl)-6,6a,7,7a,8,11,11a,13-octahydrotetraceno[2,1-d][1,3]oxazole-10-
carboxamide

MS (ESI) m/z 691.3 (M+H);
HRMS: calcd for C^H^Ou, ■ HCI, 726.2668; found (ESI+), 691.29817;

EXAMPLE 17
(6aR,7aS,8S,11aS)-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-11,13-dioxo-2-thien-
3-yl-6,6a,7,7a,8,11,11 a, 13-octahydrotetraceno[2,1 -d][1,3]oxazole-10-carboxamide

MS (ESI) m/z 565.2 (M+H);
MS (ESI) m/z 283.4 (M+2H);
HRMS: calcd for QaHzg^OyS ■ HCI, 600.1445; found (ESI-), 563.15992;
EXAMPLE 18
(6aR,7aS,8S,11aS)-2-(1-benzofuran-2-yt)-5,8-bis(dimethylamino)-9,11a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a, 13-ociahydrotetraceno[2,1 -d][1,3]oxazole-
10-carboxamide

MS (ESI) m/z599.3 (M+H);
HRMS: calcd for C^o^Oa ■ HCI, 634.1830; found (ESI-), 597.19811;

EXAMPLE 19
(6aR,7aS,8S,11aS)-5,a-bis(dimethylamfno)-9,11a,12-trihydroxy-2-(1-methyf-1 H-
indol-2-yl)-11,13-di'oxo-6,6a,7,7a,8)11,11aT13-octahydrQtetraceno[2,1-11aS)-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-11,13-dioxo-2-
[(propylamino)methyl]-6,6a,7,7a,8,11,11a,13-octahydrotetraceno[2,1 -d][1,3]oxazole-
10-carboxamide

9-aminominocycline sulfate salt (1.0 g, 1.50 mmol) is dissolved in DMF (50 mL) and
treated with a solution of 2-chloro-1,1,1-trimethoxyethane (0.463 g, 3.00 mmol, 2
equivalents). The reaction is stirred at room temperature until mass spectrometry
shows conversion to the chloromethylbenzoxazole derivative. The solution is then
treated with n-propylamine (10 mL, excess) and stirred until mass spectrometry
shows conversion to the /r-propylaminornethy! benzoxazole. The mixture is
concentrated under reduced pressure to remove excess n-propyfamine, and then
poured slowly into ether (1 L) and HCI/ether is added to precipate the salt. The solid
is rinsed with fresh ether and dried under vacuum. The crude solid is dissolved in
water (100 mL) giving a solution at pH 2. The pH is raised successively by 0.5 units
with aqueous ammonia, and extracted with dichloromethane. The fractions extracted
at pH 4-4.5 are combined, dried (Na2S04), filtered and concentrated nearly to
dryness. A small volume of methanol is added and the solution is treated with 1M
-)CI in ether. The precipitated solid is collected by filtration, washed with fresh ether
md dried under vacuum to yield 0.067 g of the product as fts HCI salt.
Selected 1H NMR signals: 5 0.94 (t, 3H), 1.73 (m, 2H), 4.31 (s, 1H), 4.65 (s, 2H),
-78 (s, 1H), 9.15 (s, 1H), 9.67 (s, 1H).

The compounds of this invention listed below in Examples 39 to 41 are prepared
substantially following the method described in detail hereinabove in Example 38
using procedure B.
(prepared from Procedure B)
EXAMPLE 39
(6aR,7aS,8S, 11 aS)-2-[(butylamino)methyl]-5,8-bis(dimethylamino)-9,11 a, 12-
trihydroxy-H.IS-dioxo-e.ea.y.Ta.B.n.lla.lS-octahydrotetracenop.l-cfltl.SJoxazole-
10-carboxamide

MS (ESI) m/z568.3 (M+H);
MS (ESI) m/z 284.8 (M+2H);
MS (ESI) m/z 305.2 (M+ACN+2H);
HRMS: calcd for CaH^NsOy • HCl, 603.2460; found (ESI+), 568.27616;

(6aR,7aS,8S,11aS)-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-11,13-dioxo-2-
[(propylamino)methyri-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1-d][1,3]oxazole-
10-carboxamide

MS (ESI) m/z554.3 (M+H);
MS (ESI) m/z277.7 (M+2H);
HRMS: calcdfor C^NsOr ■ HCI, 589.2303; found (ESI+), 554.2604;
(Procedure B)
EXAMPLE 41
(6aR,7aS,8S,11aS)-2-[(fe/f-butylamino)methyl]-5,8-bis(dimethylamino)-9,11a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a, 13-octahydrof etraceno[2,1 -d][1,3]oxazole-
10-carboxamide


9-aminominocycline sulfate salt (1.0 g, 1.50 mmol) is dissolved DMF (20 mL) and
treated with a solution of 2-chlorotrimethoxyethane (0.35 g, 2.2 mmol, 1.46
equivalents). The reaction is stirred at room temperature until mass spectrometry
showed conversion to the chloromethylbenzoxazoie derivative. The solution is then
treated with f-butylamine (7.3 mL, excess) and stirred until mass spectrometry
showed conversion to the f-butylaminomethyl benzoxazole. The mixture is
concentrated under reduced pressure to remove excess f-butylamine, and then
poured slowly into ether (1 L) and HCI/ether is added to precipate the salt. The solid
is rinsed with fresh ether and dried under vacuum. The crude solid is dissolved in
water (100 mL) giving a solution at pH 2. The pH is raised successively by 0.5 units
with aqueous ammonia, and extracted with dichloromethane. The fractions extracted
at pH 4-4.5 are combined, dried (Na^O^), filtered and concentrated nearly to
dryness. A small volume of methanol is added and the solution is treated with 1M
HCI in ether. The precipitated solid is collected by filtration, washed with fresh ether
and dried under vacuum to give the product as its HCI salt.
MS (ESI+) m/z 568.4 ((M+H)+);
MS (ESI+) m/z 284.9 ((M+2H)2+);
MS (ESI+) m/z 146.3 ((M'+H)-n);
HRMS: calcd for O^H^NgC^ • HCI, 603.2460; found (ESI-), 566.26087;
Example of Procedure C
EXAMPLE 42
(6aR,7aS,8S,11aS)-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-11,13-dioxo-2-
thioxo-2,3,6,6a,7,7a,8,11,11 a, 13-decahydrotetracen o[2,1 -d][1,3]oxazole-10-
carboxamide


To a solution of 9-amino-rnino disulfate (0.668 g, 1 mmol) in DMSO (30 rnL) is added
2 equivalents of 1,1-thiocarbonyldiimidazole. The reaction is then stirred at room
temperature for 2 to 12 hr (followed by MS(ES)). The mixture then triturated with
diethyl ether and the solid collected. Material is used in the next step without further
purification.
MS(ESI)/TI/Z515.2(M+H);
HRMS: caicd for C24H26N407S • H2S04, 612.1196; found (ESI+), 515.15934;
The compounds of this invention listed below in Examples 43 to 44 are prepared
substantially following the method described in detail hereinabove in Example 42
using procedure C.
Example of procedure C
(Procedure C)
EXAMPLE 43
benzyl ([(6aR,7aS,8S,11 aS)-10-(aminocarbonyl)-5,8-bis(dimethylamino)-9,11 a,12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11a,13-octahydrotetraceno[2,1-d][1l3]oxa20l-2-
yl]thio}acetate


To a solution of (6aR,7aS,8S,11aS)-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-
11,13-dioxo-2-thioxo-2,3,6,6a,7,7a,8,11,11 a,13-decahydrotetraceno[2,1 -
d][1,3]oxazole-10-carboxamide (Example 42) in N,N-dimethylformamide (DMF) is
added 2 equivalents of diisopropylethylamine, after stirring for 5 min. 1.2 equivalent
of benzyl-2-bromoacetate is added. The reaction mixture is stirred for 1 hr and
mixture triturated with diethyl ether and solid is collected. It is purified by extraction.
MS (ESI) m/z663.2 (M+H);
MS (ESI) m/z332.1 (M+2H);
HRMS: calcd for C33H34N4O9S • HCI, 698.1813; found (ESI+), 663.2115;
EXAMPLE 44
(6aR,7aS,8S, 11 aS)-5,8-bis(dimethylamino)-2-[(4-f iuorobenzyl)thio]-9,11 a, 12-
trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11 a,13-octahydrotetraceno[2,1 -d] [1,3]oxazole-
10-carboxamide

The compound of the example is prepared using procedure D in Example 43 using 4-
fluorobenzylbromide.
MS (ESI) m/z 622.9 (M+H);
HRMS: calcd for C31H3iFN407S • HCI, 658.1664; found (ESI+), 623.19689;

Example of Procedure D (Compound 1 to 4 to 6)
Example 45
[4S-<4a,4acc, 5acc, 12aa)]-4,7-Bis(dimethylamino)-9-[2-( 1,1-
dimethylethylamino)acetylamino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-
tetrahydroxy-1,11 -dioxo-2-naphthacenecarboxamide.
(mono HCI); (free base)

9-aminominocycline sulfate salt (1.0 g, 1.50 mmol) is dissolved DMF (20 mL) and
treated with a solution of 2-chlorotrimethoxyethane (0.35 g, 2.2 mmol, 1.47
equivalents). The reaction is stirred at room temperature until mass spectrometry
showed conversion to the chloromethylbenzoxazole derivative. The solution is then
treated with f-butylamine (7.3 mL, excess) and stirred until mass spectrometry
showed conversion to the f-butyiaminornethyl benzoxazole. The mixture is
concentrated under reduced pressure to remove excess f-butylamine, and then
poured slowly into ether (1 L) and HCI/ether is added to precipate the salt. The solid
is rinsed with fresh ether and dried under vacuum. The crude solid is dissolved in
water (100 mL) giving a solution at pH 2. The pH is raised successively by 0.5 units
with aqueous ammonia, and extracted with dichloromethane. The fractions extracted
at pH 4-4.5 are combined, dried (NaaSO*), filtered and concentrated nearly to
dryness. A small volume of methanol is added and the solution is treated with 1M
HCI in ether. The precipitated solid is collected by filtration, washed with fresh ether
and dried under vacuum to give the product as its HCI salt.

Product from example 41 is treated with aqueous acid for one hour to 24 hour to give
mono HCL salt of example 45
MS (ESI+) m/2 586.4 ((M+H)+;
The following examples are prepared using similar method described in procedure D.
Example 46
[4S-{4a,4aa,5aa,12aa)]-4,7-Bis(dimethylamino)-9-[(dimethyamino)acetylamino]-
1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11 -dioxo-2-
naphthacenecarboxamide.

MS (FAB) m/z 558 ((M+HJ+;
Example 47
[4S-(4a,4aa,5aa,12aa)]-4,7-Bis(dimethylamino)-9-[I(n-butylamino)acetyl]amino]-
1,4,4a,5,5ap6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11 -dioxo-2-
naphthacenecarboxarnide.

MS (FAB) m/z586 ((M+H)+;

[4S-(4α,4aα,5aα,12aα)]-4,7-Bis(dimethylamino)-9-[[(propylamino)acetyl]amino]-
1,4,4a, 5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11 -dioxo-2-
naphthacenecarboxamide

Example 49
[4S-(4α,4aα.5aα,12aα)]-4,7-Bis(dimethylamino)-9-[(chloroacetyl)amino]-
1,4,4a,5,5a,6,11,12a-octafiydro-3,10,12,12a-tetrahydroxy-1,11 -dioxo-2-
naphthacenecarboxamide

AS (FAB) m/z549 ((M+H)+;

WE CLAIM:
1. A process for the preparation of a compound of the formufa

or a pharmaceutically acceptable salt thereof
wherein:
X is selected from hydrogen, amino, NR11R12, alkyi of 1 to 12 carbon atoms optionally
substituted , aryl of 6, 10 or 14 carbon atoms optionally substituted, vinyl, optionally
substituted, aikynyl of 2 to 12 carbon atoms optionally substituted and halogen;
R1 and R2 are each independently H or alkyl of 1 to 12 carbon atoms or
R1 and R2 when optionally taken together with the nitrogen atom to which each is
attached form a 3 to 7 membered saturated hydrocarbon ring;
R11 and R12 are each independently H or alkyl of 1 to 12 carbon atoms or
R11 and R12 when optionally taken together with the nitrogen atom to which each is
attached form a 3 to 7 membered saturated hydrocarbon ring;

Y is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted, aryl
of 6,10 or 14 carbon atoms optionally substituted, alkenyf of 2 to 12 carbon atoms
optionally substituted, vinyl, alkynyl of 2 to 12 carbon atoms optionally substituted
and halogen;
comprising the steps:
a. reacting 7-(substituted)-8-(substituted)-9-amino-6-demethyl-6-
deoxytetracydine of the formula

or a pharmaceutically acceptable salt thereof
with 2-chlorotrimethoxyethane in-an-aprotic solvent to afford a chloro compound of
the formula

b. reacting the chloro compound with an amine R1R2NH to form a substituted
amine of the formula


c. hydrolyzing the substituted amine with acid to give a compound of the formula

d. isolating the compound or a pharmaceuticaliy acceptable salt thereof.
2. The process as claimed in claim 1 wherein X is N(CH3)2.
3. The process as claimed in claim 1 or claim 2 wherein the amine R1R2NH is
t-butyl amine.
4. The process as claimed in any one of claims 1 to 3 wherein the aprotic
solvent is N,N-dimethylforrnamide.
5. The process as claimed in any one of claims 1 to 4 wherein [4S-
(4α,4aα,5aα,12aα)]-4,7-Bis(dimethylamino)-9-[2-(1,1 -
dimethy!ethyl amino)acetyiamino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-
tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide or a pharmaceuticaliy
acceptable salt thereof is prepared.
6. A process for the preparation of a compound of the formula


X is selected from hydrogen, amino, NF11R12, alkyl of 1 to 12 carbon atoms optionally
substituted , aryi of 6,10 or 14 carbon atoms optionally substituted, vinyl, optionally
substituted, alkynyi of 2 to 12 carbon atoms optionally substituted and halogen;
R1 and R2 are each independently H or alkyl of 1 to 12 carbon atoms or
R1 and R2 when optionally taken together with the nitrogen atom to which each is
attached form a 3 to 7 membered saturated hydrocarbon ring;
R11 and R12 are each independently H or alkyl of 1 to 12 carbon atoms or
R11 and R12 when optionally taken together with the nitrogen atom to which each is
attached form a 3 to 7 membered saturated hydrocarbon ring;
Y is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted, aryl
of 6, 10 or 14 carbon atoms optionally substituted, vinyl, alkenyl of 2 to 12 carbon
atoms optionally substituted, alkynyl of 2 to 12 carbon atoms optionally substituted
and halogen;
or a pharmaceutically acceptable salt thereof
comprising the steps:
a. reacting 7-(substituted)-8-(substituted)-9-amino-6-demethyi-6-
deoxytetracycline of the formula

or a pharmaceutically acceptable salt thereof
with 2-chlorotrimethoxyethane in an aprotic solvent to afford a chloro compound of
the formula


b. reacting the chloro compound with acid to give 9-(2-
chloromethylcartonylamino)substituted-6-demethyl-6-deoxytetracycline of the
formula
c. reacting the 9-(2chloromethy(carbonylamino)substituted-6-dernethyl-6-
deoxytetracycline with amine R1R2NH to give a compound of the formula

e. isolating the compound or a pharmaceutically acceptable salt thereof.
7 The process as claimed in claim 6 wherein X is N(CH3)2.
8. The process as claimed in claim 6 or claim 7 wherein the amine R1R2NH is
t-butyl amine.

9. The process as claimed in any one of claims 6 to 8 wherein the aprotic
solvent is N.N-dirnethylformarnide.
10. The process as claimed in any one of claims 6 to 9 wherein [4S-
(4α,45α,5aα, 12aα)]-4,7-Bis(dimethylamino)-9-[2-(1,1-
dimethylethytemino)acetylamino]-l ,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-
tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide or a pharmaceutically
acceptable salt thereof is prepared.

This invention provides compounds of the formula wherein
A", X and Y are defined in the specification. These compounds are useful as
antibacterial agents.