COMPOSES AROMATIQUES SUBSTITUES POUR LE TRAITEMENT D'INFECTIONS RESISTANT AUX ANTIBIOTIQUES

SUBSTITUTED AROMATIC COMPOUNDS FOR TREATMENT OF ANTIBIOTIC RESISTANT INFECTIONS

Abrégé français

L'invention concerne des composés de formule générale (Y) dans laquelle A représente un hydrocarbure aromatique cyclique et R¿1? représente un carbone directement lié à un oxygène, et également lié à un azote par l'intermédiaire d'un carbone saturé, l'un au moins parmi R¿2?, R¿3? et R¿4? représentant un substituant riche en électrons. Ces agents actifs sont utiles pour traiter des patients souffrant d'infections à organismes gram-positifs, tels que le streptocoque, le staphylocoque, l'anthracis, des bactéries gram-négatives comme celle de l'espèce Neisseria, des levures et des mycobactéries. Ces agents sont efficaces contre les souches dont on connaît la résistance à d'autres agents antimicrobiens.

Abrégé anglais

This invention relates to compounds of general formula (Y) wherein A is an
aromatic hydrocarbon ring system and R1 is a carbon bound directly to an
oxygen and is also bound to a nitrogen through a saturated carbon and wherein
at least one of R2, R3 and R4 is an electron-rich substituent. The active
agents are useful for treating patients suffering from infections including
gram positive organisms, such as streptococcus, staphylococcus, anthracis,
gram negative bacteria such as neisseria species, yeasts and mycobacterium.
They are effective against strains which have shown resistance to other
antimicrobial agents.

Revendications

24
What we claim is:
1. A method of treating or preventing infection caused by
bacteria, mycobacterium or fungi by administration of a
composition containing as an active agent a bacteria,
mycobacterium or yeast growth-inhibiting effective
amount of a compound of the formula:
<IMG>
wherein A is a hydrocarbon aromatic ring system, R1 is
bound directly to an oxygen and is also bound to a
nitrogen through a saturated carbon or carbon chain,
with R1 being of the structure CHOZX wherein Z may be
hydrogen, a second bond to the oxygen, or may be
carboxyl, ether or ester moiety wherein the ether or ester
moiety may be alkyl of 1-8 carbons, phenyl, phenylalkyl,
wherein the alkyl moiety consists of 1-4 carbons
and wherein any said alkyl or phenyl group may,
additionally, be substituted with hydroxy, alkyl of 1-2
carbons, alkenyl of 2-3 carbons, halo, amino, or alkyl
amino group and X is (CH2)~ N((CH2)n(CH3))m wherein ~ is 1
to 3, n is ~6, m is 1 or 2 with the proviso that when
m is 2, at least one of n is < 3, or X may be (CH2)o J
wherein o is 0-4 and J is a saturated nitrogen-containing
ring system with up to 10 carbon atoms in the ring
system and may have up to 4 bridge carbons, and
wherein any saturated ring system may be substituted with
alkyl, alkenyl, halo, alkoxy or haloalkyl moieties of
1-5 carbons or with phenyl, phenoxy, phenylalkyl,
phenylalkoxy, carboxy or carbonyl groups, wherein the
carboxy or carbonyl groups, including keto or ester

25
moieties, with alkyl groups having 1-4 carbons, alkenyl
groups of 2-5 carbons or phenylalkyl wherein the alkyl
is of 1-3 carbons or phenylalkoxy wherein the alkyl is
of 1-3 carbons and, further, wherein X and Z may be
linked to form a heterocyclic ring system and (a) is
0-4 with the proviso that at least one of (a) is not 1,
R2, R3 and R4 may be alkyl (including cycloalkyl), a
saturated, nitrogen-containing ring of 4-10 atoms,
alkoxy, aryl, aryloxy, aryloxyalkyl, amino, amino-alkyl,
alkyl-aminoalkyl, arylamino, alkenyl, arylalkenyl,
arylalkylaminoalkyl, carboxyalkyl, hydroxy, halo,
alkenyl, or alkenyloxy, halo-substituted alkyl, wherein
any alkyl has 1-8 carbons, alkenyl has 2-8 carbons,
wherein halo is chloro, fluoro or bromo and aryl is a
ring system of 1-3 rings and wherein any alkyl or aryl
at R2, R3 and R4 may be further substituted with halo
(including multiple halo subtitutions), aryl of 1-2
rings, alkyl, haloalkyl or alkoxy, with the proviso
that at least one of R2, R3 and R4 is an electron-rich
substituent.
2. A method of claim 1 of treating or preventing infection
caused by bacteria, mycobacterium or fungi by administration
of a composition containing as an active agent
a bacteria, mycobacterium or yeast growth-inhibiting
effective amount of a compound of the formula:
<IMG>
wherein any of R2, R3, R4, R5, R6, R7 and R8 may be H,
alkyl (including cycloalkyl), a saturated,
nitrogen-containing ring of 4-10 atoms, alkoxy, aryl, aryloxy,
aryloxyalkyl, amino, amino-alkyl, alkyl-aminoalkyl,
arylamino, alkenyl, arylalkenyl, arylalkylaminoalkyl,

26
carboxyalkyl, hydroxy, halo, alkenyl, or alkenyloxy,
halo-substituted alkyl, wherein any alkyl has 1-8
carbons, alkenyl has 2-8 carbons, wherein halo is chloro,
fluoro or bromo and aryl is a ring system of 1-3 rings
and wherein any alkyl or aryl may be further substituted
with halo (including multiple halo subtitutions),
aryl of 1-2 rings, alkyl, haloalkyl or alkoxy, with the
proviso that at least one of R2, R3, R4, R5, R6, R7 and R8
is an electron-rich substituent and one of R1, R9 or R10
is bound directly to an oxygen and is also bound to a
nitrogen through a saturated carbon or carbon chain,
being of the structure CHOZX wherein Z may be hydrogen,
a second bond to the oxygen, or may be carboxyl, ether
or ester moiety wherein the ether or ester moiety may
be alkyl of 1-8 carbons, phenyl, phenylalkyl, wherein
the alkyl moiety consists of 1-4 carbons and wherein
any said alkyl or phenyl group may, additionally, be
substituted with hydroxy, alkyl of 1-2 carbons, alkenyl
of 2-3 carbons, halo, amino, or alkyl amino group and X
is (CH2)~ N((CH2)n(CH3))m wherein ~ is 1-3, n is ~6, m is
1 or 2 with the proviso that when m is 2, at least one
n is < 3, or X may be (CH2)o J wherein o is 0-4 and J is a
saturated nitrogen-containing ring system with up to 10
carbon atoms in the ring system and may have up to 4
bridge carbons, and wherein any saturated ring system
may be substituted with alkyl, alkenyl, halo, alkoxy or
haloalkyl moieties of 1-5 carbons or with phenyl,
phenoxy, phenylalkyl, phenylalkoxy, carboxy or carbonyl
groups, wherein the carboxy or carbonyl groups, including
keto or ester moieties, with alkyl groups having 1-4
carbons, alkenyl groups of 2-5 carbons or phenylalkyl
wherein the alkyl is of 1-3 carbons or phenylalkoxy
wherein the alkyl is of 1-3 carbons and, furthermore, X
and Z may be linked to form a heterocyclic ring system.
3. A method of claim 2 wherein at least two of R2, R3, R4,

27
R5, R6, R7 and R8 are Cl or F3C.
4. A method of claim 2 wherein Z=H, X=CH2-(2-piperidine)
R2 and R4 are Cl.
5. A method of claim 2 wherein R9 is CHOZX and Z=H,
X=CH2-N(C4H9)(C3H7) and R5 and R6 are Cl.
6. A method of claim 2 wherein R1 is CHOZX and Z=H,
X=(CH2)2NH(C3H7) and R3 is Cl.
7. A method of claim 2 wherein R1 is CHOZX and Z=H,
X=(CH2)2NH(C3H7), R3 is Cl and R5 is CF3.
8. A method of of claim 1 of treating or preventing
infection caused by bacteria, mycobacterium or fungi by
administration of a composition containing as an active
agent a bacteria, mycobacterium or yeast growth-inhibiting
effective amount of a compound of the formula:
<IMG>
wherein any of R2, R3, R4, R5, R6, R7 and R8 may be H,
alkyl (including cycloalkyl), a saturated,
nitrogen-containing ring of 4-10 atoms, alkoxy, aryl, aryloxy,
aryloxyalkyl, amino, amino-alkyl, alkyl-aminoalkyl,
arylamino, alkenyl, arylalkenyl, arylalkylaminoalkyl,
carboxyalkyl, hydroxy, halo, alkenyl, or alkenyloxy,
halo-substituted alkyl, wherein any alkyl has 1-8
carbons, alkenyl has 2-8 carbons, wherein halo is chloro,
fluoro or bromo and aryl is a ring system of 1-3 rings
and wherein any alkyl or aryl may be further

28
substituted with halo (including multiple halo subtitutions),
aryl of 1-2 rings, alkyl, haloalkyl or alkoxy, with the
proviso that at least one of R2, R3, R4, R5, R6, R7 and R8
is an electron-rich substituent and one of R1, is bound
directly to an oxygen and is also bound to a nitrogen
through a saturated carbon or carbon chain, being of
the structure CHOZX wherein Z may be hydrogen, a second
bond to the oxygen, or may be carboxyl, ether or ester
moiety wherein the ether or ester moiety may be alkyl
of 1-8 carbons, phenyl, phenylalkyl, wherein the alkyl
moiety consists of 1-4 carbons and wherein any said
alkyl or phenyl group may, additionally, be substituted
with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3
carbons, halo, amino, or alkyl amino group and X is
(CH2)~ N((CH2)n(CH3))m wherein ~ is 1-3, n is ~ 6, m is 1
or 2 with the proviso that when m is 2, at least one n
is < 3, or X may be (CH2)o J wherein o is 0-4 and J is a
saturated nitrogen-containing ring system with up to 10
carbon atoms in the ring system and may have up to 4
bridge carbons, and wherein any saturated ring system
may be substituted with alkyl, alkenyl, halo, alkoxy or
haloalkyl moieties of 1-5 carbons or with phenyl,
phenoxy, phenylalkyl, phenylalkoxy, carboxy or carbonyl
groups, wherein the carboxy or carbonyl groups, including
keto or ester moieties, with alkyl groups having 1-4
carbons, alkenyl groups of 2-5 carbons or phenylalkyl
wherein the alkyl is of 1-3 carbons or phenylalkoxy
wherein the alkyl is of 1-3 carbons and, furthermore, X
and Z may be linked to form a heterocyclic ring system.
9. A method of claim 8 wherein Z=H, X=CH2-(2-piperidine)
R6 = Cl, R7 = OCH3, R3 = 4-Cl-phenyl.
10. A method of claim 8 wherein Z=H, X=CH2-(2-piperidine)
R6 = Cl, R7 = OCH3, R3 = 3,4 dichloro-phenyl.
11. A method of claim 8 wherein Z=H, X=CH2-(2-piperidine)

29
R6 Cl, R7=CF3, R3=4-Cl-phenyl .
12. A method of claim 8 wherein Z=H, X=CH2-(2-piperidine)
R6 CF3, R7=OCH3, R3=3, 4-diclhoro-phenyl.
13. A method of claim 1 of treating or preventing infection
caused by bacteria, mycobacterium or fungi by administration
of a composition containing as an active agent
a bacteria, mycobacterium or yeast growth-inhibiting
effective amount of a compound of the formula:
<IMG>
wherein any of R2, R3, R4, R5, and R6, may be H, alkyl
(including cycloalkyl), a saturated, nitrogen-containing
ring of 4-10 atoms, alkoxy, aryl, aryloxy,
aryloxyalkyl, amino, amino-alkyl, alkyl-aminoalkyl,
arylamino, alkenyl, arylalkenyl, arylalkylaminoalkyl,
carboxyalkyl, hydroxy, halo, alkenyl, or alkenyloxy,
halo-substituted alkyl, wherein any alkyl has 1-8
carbons, alkenyl has 2-8 carbons, wherein halo is chloro,
fluoro or bromo and aryl is a ring system of 1-3 rings
and wherein any alkyl or aryl may be further substituted
with halo (including multiple halo subtitutions),
aryl of 1-2 rings, alkyl, haloalkyl or alkoxy, with the
proviso that at least one of R2, R3, R4, R5, R6, R7 and R8
is an electron-rich substituent and one of R1, is bound
directly to an oxygen and is also bound to a nitrogen
through a saturated carbon or carbon chain, being of
the structure CHOZX wherein Z may be hydrogen, a second
bond to the oxygen, or may be carboxyl, ether or ester
moiety wherein the ether or ester moiety may be alkyl
of 1-8 carbons, phenyl, phenylalkyl, wherein the alkyl
moiety consists of 1-4 carbons and wherein any said
alkyl or phenyl group may, additionally, be substituted

30
with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3
carbons, halo, amino, or alkyl amino group and X is
(CH2)~ N((CH2)n(CH3))m wherein ~ is 1-3, n is ~6, m is 1
or 2 with the proviso that when m is 2, at least one n
is < 3, or X may be (CH2)o J wherein o is 0-4 and J is a
saturated nitrogen-containing ring system with up to 10
carbon atoms in the ring system and may have up to 4
bridge carbons, and wherein any saturated ring system
may be substituted with alkyl, alkenyl, halo, alkoxy or
haloalkyl moieties of 1-5 carbons or with phenyl,
phenoxy, phenylalkyl, phenylalkoxy, carboxy or carbonyl
groups, wherein the carboxy or carbonyl groups,
including keto or ester moieties, with alkyl groups having
1-4 carbons, alkenyl groups of 2-5 carbons or phenylalkyl
wherein the alkyl is of 1-3 carbons or phenylalkoxy
wherein the alkyl is of 1-3 carbons, and, furthermore,
X and Z may be linked to form a heterocyclic ring
system.
14. A method of claim 13 wherein Z=H, X=CH2-(2-piperidine)
R3 and R5 are 4-Cl-phenyl.
15. A method of claim 13 wherein Z=H, X=CH2-(2-piperidine)
R3=Cl, R5=4-OCH3-phenyl.
16. A method of claim 13 wherein Z=H, X=CH2CH2(2-piperidine)
R3=Cl, R5=4-OCH3-phenyl
17. A method of of claim 1 of treating or preventing
infection caused by bacteria, mycobacterium or fungi by
administration of a composition containing as an active
agent a bacteria, mycobacterium or yeast growth-inhibiting
effective amount of a compound of the formula:

31
<IMG>
wherein any (a) is 1-3 and R2, and R3, may be H, alkyl
(including cycloalkyl), a saturated, nitrogen-containing
ring of 4-10 atoms, alkoxy, aryl, aryloxy, aryloxyalkyl,
amino, amino-alkyl, alkyl-aminoalkyl, arylamino,
alkenyl, arylalkenyl, arylalkylaminoalkyl, carboxyalkyl,
hydroxy, halo, alkenyl, or alkenyloxy, halo-substituted
alkyl, wherein any alkyl has 1-8 carbons,
alkenyl has 2-8 carbons, wherein halo is chloro, fluoro
or bromo and aryl is a ring system of 1-3 rings and
wherein any alkyl or aryl may be further substituted
with halo (including multiple halo subtitutions), aryl
of 1-2 rings, alkyl, haloalkyl or alkoxy, with the
proviso that at least one of R2, R3, R4, R5, R6, R7 and R8
is an electron-rich substituent and one of R1, is bound
directly to an oxygen and is also bound to a nitrogen
through a saturated carbon or carbon chain, being of
the structure CHOZX wherein Z may be hydrogen, a second
bond to the oxygen, or may be carboxyl, ether or ester
moiety wherein the ether or ester moiety may be alkyl
of 1-8 carbons, phenyl, phenylalkyl, wherein the alkyl
moiety consists of 1-4 carbons and wherein any said
alkyl or phenyl group may, additionally, be substituted
with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3
carbons, halo, amino, or alkyl amino group and X is
(CH2)~ N((CH2)n(CH3))m wherein ~ is 1-3, n is ~6, m is 1
or 2 with the proviso that when m is 2, at least one n
is < 3, or X may be (CH2)o J wherein o is 0-4 and J is a
saturated nitrogen-containing ring system with up to 10

32
carbon atoms in the ring system and may have up to 4
bridge carbons, and wherein any saturated ring system
may be substituted with alkyl, alkenyl, halo, alkoxy or
haloalkyl moieties of 1-5 carbons or with phenyl,
phenoxy, phenylalkyl, phenylalkoxy, carboxy or carbonyl
groups, wherein the carboxy or carbonyl groups, including
keto or ester moieties, with alkyl groups having 1-4
carbons, alkenyl groups of 2-5 carbons or phenylalkyl
wherein the alkyl is of 1-3 carbons or phenylalkoxy
wherein the alkyl is of 1-3 carbons, and, furthermore,
X and z may be linked to form a heterocyclic ring
system.
18. A method of claim 17 wherein the active agent is
desbutyl-halofantrine.
19. A method of claim 17 wherein the active agent is chosen
from among compounds wherein
Z X R2, n R3 n

H piperidinyl (#1) CF3 1 CF3 1

H piperidinyl (#2) Cl 1 CF3 1

H piperidinyl (#3) Cl 2 CF3 1

H piperidinyl (#4) Br 1 Br 1

H piperidinyl (#5) Cl 1 Cl 1

H CH2-piperidinyl (#6) Cl 1 Cl 1

H piperidinyl (#7) CF3 2 Cl 2

H piperidinyl (#8) CF3 1 CF3 1

H CH2-piperidinyl (#9) Cl 2 CF3 1

ZX= <IMG> CF3 1 CF3 1
H CH2NHCH(CH2CH3)2 (#11) CF3 1 CF3 1
H (CH2)NH(CH2)3CH3 (#12) CF3 1 Cl 2

33
20. A compound of the formula:
<IMG>
wherein A is a hydrocarbon aromatic ring system, R1 is
bound directly to an oxygen and is also bound to a nitrogen
through a saturated carbon or carbon chain, with R1
being of the structure CHOZX wherein Z may be hydrogen, a
second bond to the oxygen, or may be carboxyl, ether or
ester moiety.wherein the ether or ester moiety may be
alkyl of 1-8 carbons, phenyl, phenylalkyl, wherein the
alkyl moiety consists of 1-4 carbons and wherein any said
alkyl or phenyl group may, additionally, be substituted
with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3 carbons,
halo, amino, or alkyl amino group and X (CH2)oJ
wherein o is 2-4 and J is a saturated nitrogen-containing
ring system with up to 10 carbon atoms in the ring system
and may have up to 4 bridge carbons, and wherein any
saturated ring system may be substituted with alkyl,
alkenyl, halo, alkoxy or haloalkyl moieties of 1-5 carbons
or with phenyl, phenoxy, phenylalkyl, phenylalkoxy, carboxy
or carbonyl groups, wherein the carboxy or carbonyl
groups, including keto or ester moieties, with alkyl
groups having 1-4 carbons, alkenyl groups of 2-5 carbons
or phenylalkyl wherein the alkyl is of 1-3 carbons or
phenylalkoxy wherein the alkyl is of 1-3 carbons, and (a)
is 0-4 with the proviso that at least one of (a) is not 1,
R2, R3 and R4 may be alkyl (including cycloalkyl), a
saturated, nitrogen-containing ring of 4-10 atoms, alkoxy,

34
aryl, aryloxy, aryloxyalkyl, amino, amino-alkyl,
alkyl-aminoalkyl, arylamino, alkenyl, arylalkenyl, arylalkyl-
aminoalkyl, carboxyalkyl, hydroxy, halo, alkenyl, or
alkenyloxy, halo-substituted alkyl, wherein any alkyl has
1-8 carbons, alkenyl has 2-8 carbons, wherein halo is
chloro, fluoro or bromo and aryl is a ring system of 1-3
rings and wherein any alkyl or aryl at R2, R3 and R4 may be
further substituted with halo (including multiple halo
subtitutions), aryl of 1-2 rings, alkyl, haloalkyl or
alkoxy, with the proviso that at least one of R2, R3 and R4
is an electron-rich substituent.
21. A compound of claim 20 wherein A is a benzene ring.
22. A compound of claim 20 wherein A is a phenanthrene ring.
23. A compound of claim 20 wherein A is naphthalene ring.
24. A compound of claim 20 wherein A is anthracene ring.

Description

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1
Title: Substituted Aromatic Compounds for Treatment of
Antibiotic Resistant Infections
Field of the Invention:
This invention relates to the treatment of antibiotic-
resistant infections, including particularly infections
caused by bacteria, mycobacteria, fungi and yeasts. A
preferred group of compositions of the invention contain as
l0 active agents compounds containing aryl ring systems, in-
cluding phenyl, naphthyl and anthracene ring systems, sub-
stituted by a carbon bound to an oxygen which is also bound
to a nitrogen through a saturated carbon or carbon chain
which may be substituted with halo, hydroxy, alkoxy, amino
or alkylamino are disclosed, In preferred embodiments, the
aryl ring system is further substituted by at least two halo
substituents or halo-substituted substituents.
Background of the Invention:
The benefit from use of antibiotics as a means of
treating infections has been increasingly compromised by the
development of resistant strains of microorganisms. Most of
the new drugs are derivatives of older compounds. It is
necessary to develop new agents that will respond to the
current needs for medicinals that will effectively control
pathogenic microbial populations that are resistant to
antibiotics.
Halofantrine is a known antimalarial having a phenan-
threne ring system substituted by a carbon bound to an
oxygen which is also bound to a nitrogen through a saturated
CHZ-CH2 chain to tertiary nitrogen having two butyl sub-
stituents. The phenanthrene ring system is further substi-
tuted with 2 chlorines and one trifluoromethyl.
Summary of the Invention:
This invention relates to compounds of the general
~ formula:

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2
A
R3(a) (a)
.2(a)
R~
wherein A is a aromatic hydrocarbon ring system and R~ is a
carbon bound directly to an oxygen and is also bound to a
nitrogen through a saturated carbon and wherein at least one
of RZ, R3 and R4 is an electron-rich substituent.
The active agents are useful for treating patients
suffering from infections including gram positive organisms,
such as streptococcus, staphylococcus, anthracis, gram
negative bacteria such as neisseria species, yeasts and
mycobacterium. These compounds are effective against
strains which have shown resistance to other antimicrobial
agents.
Detailed Description of the invention:
This invention relates to compounds that have use in
treating several infectious diseases which are now resistant
to treatment to conventionally used antibiotics. Some of
the compounds described herein have had previously been
suggested for use in treating malaria. Some of the com-
pounds are newly discovered. Most of the compounds are
lipophilic. The lipid solubility of these compounds should
permit the drugs to enter into cells, including cells of the
central nervous system. Many of the compounds could be also
be absorbed from the intestinal tract when given orally.
They may be administered as cyclodextrin inclusion complexes
to increase bioavailability. They may also be administered
transdermally. Using patches for transdermal administration
makes it possible to more easily control dosage.
The active agents for use in accord with the teachings
of this disclosure are of the general formula:

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3
A
Rs(a)
a)
wherein A is an aromatic ring system and R~ is bound directly
to an oxygen and is also bound to a nitrogen through a
saturated carbon. R~ is of the structure CHOZX wherein Z may
be hydrogen, a second bond to the oxygen, or may be carbox-
yl, ether or ester moiety wherein the ether or ester moiety
may be alkyl of 1-8 carbons, phenyl, phenylalkyl, wherein
the alkyl moiety consists of 1-4 carbons and wherein any
said alkyl or phenyl group may, additionally, be substituted
with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3 carbons,
halo, amino, or alkyl amino group, X is (CH2)~N((CH2)~(CH3))m
wherein ~ is 1-3, n is <6, m is 1 ,or 2 with the proviso that
when m is 2, at least one n is <3, or X may be (CH2)o where-
in 0 is 0-4 and J is a saturated nitrogen-containing ring
system with up to 10 carbon atoms in the ring system and
may have up to 4 bridge carbons, wherein any saturated ring
system may be substituted with alkyl, alkenyl, halo, alkoxy
or haloalkyl moieties of 1-5 carbons or with phenyl, phe-
noxy, phenylalkyl, phenylalkoxy, carboxy or carbonyl groups,
wherein the carboxy or carbonyl groups, including keto or
ester moieties with alkyl groups of 1-4 carbons, alkenyl
groups of 2-5 carbons or phenylalkyl wherein the alkyl is of
1-3 carbons or phenylalkoxy wherein the alkyl is of 1-3
carbons. Regarding substituents of Rz(a), R3(a) and R4(a), a
may be 0-4 with the proviso that at least one a is not 0.
R2, R3 and R4 may be alkyl (including cycloalkyl), a satu-
rated, nitrogen-containing ring of 4-10 atoms, alkoxy, aryl,
aryloxy, aryloxyalkyl, amino, amino-alkyl, alkyl-aminoalkyl,

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arylamino, alkenyl, arylalkenyl, arylalkylaminoalkyl,
carboxyalkyl, hydroxy, halo, alkenyl, alkenyloxy, haloalkyl
(including perhaloalkyl), wherein any alkyl has 1-8 carbons,
alkenyl has 2-8 carbons, wherein halo is chloro, fluoro or
bromo and aryl is a ring system of 1-3 rings with the provi-
sion that at least one of R2, R3 and R4 is an electron-rich
substituent. Z and X may be linked to form a heterocylic
ring system. Furthermore, any alkyl or aryl at R2, R3 and R4
may be further substituted with aryl of 1-2 rings, halo,
(including multiple halo substitutions) alkyl, haloalkyl or
alkoxy. Preferred halo substituents are chloro or bromo and
a preferred haloalkyl is trifluoromethyl.
Compounds wherein X is (CHZ)o and o is 2-4 are novel.
Particularly useful compounds are those of Formulas I,
II, III and IV.
R2 R3 R4
R~ Rs
Formula I
R8
Rg R~ R~ o
In compounds of Formula I, any of RZ_8 may be substituents
designated under R2, R3 and R4 in the general formula above,
with the proviso that at least one of RZ_8 is an electron-
rich substituent and any one of R~, R9 or Rio is a substituent
as defined as R~ in the general formula. Preferred compounds
are those having at least two halos groups on the compound,
with chloro or trifluoromethyl being particularly preferred
groups.
R4 Rs
Rg R6 Formula II
00
R2 ~R~
Ry Rg

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In compounds of Formula II, any of R2_8 may be substituents
identified as R2, R3 or R4 in the general formula with the
proviso that at least one substituents is an electron-rich
moiety and R~ is as designated for R~ (CHOZX) for the general
5 formula above. Many of the preferred compounds have at
least two halo or halo-substituted substituents.
Ra
R3 R5
R2 ~ Formula III
R~
wherein R~ is defined as in the general formula and RZ_6 is
defined in the same manner as RZ, R3 and R4 in the general
formula. May of the preferred compounds have least two halo
or halo-substituted substituents.
A particularly valuable compound of Formula II is of
the formula:
CI
CI
0 0 oCH
\ 3
2 5 pH-C H
Compounds of Formulas I, II and III can be made using
the following methods:

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3.5 -BislArvl)phenvltoluene
O CH3
I I 1.) AclO / HZSO~ ~ Q
Ar-C-CH3 ~ ~C104
2.) HCLO~ Ar O Ar
0
CH3N021
KOt-~u
CH3
CH3
I ~ Sn / HCI
Ar ~ Ar I ~ ~~iCl ; j ;CHI
NH2 Ar~Ar d i
N OZ
NaNOz I
HBi=~ /
cH, ,
CH3 _
NaBH~ \,
I
Ar I ~ Ar - Ar t ~'~Ar
Nz
~A~~
Ar = ~ ~ ~ X Where X is mono- or di- halo, alkoxy, or halogen subst;tuted
alkyl. Otherwise X ishydrogen.

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Preparing starting materials:
O _
--OH "-- II
X CHO ~- CH3C ~ ~ Y X ~ ~ _ CH=CHC ~ ~ Y
CH3Mgl
CHOCH3 CH3 O
Ph3P=CHOCH3 '- I
X CH-CHCI ~ ~ Y X ~ ~ CH-C'-IC ~ ~ Y
PPA
-H20
CH3
\ \
X
Y
/_
A general method for production:
p 0 ~'
1 I
CH;C-NHR + CH~CHzCH~CHZLi CH3C-NR + n8u
N8SICCI, (Phl3P O~ O 1.)KOtBu
ArCH, ArCH2Br ArCHZP(Ph)3 Br 2.)HCHO ~ p'~H=CH2
- o~J
m-CI-Ph-OOH
in CHC13
O
ArCHOHCHZNRz RZNH ArCH/ \CH2

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WO 99/48461 PCT/US99/06494
8
- Side Chain Introductions
NBSICCIa AgNO~
AI'CH3 --~. ArCH2Br ArCHO
_........__._......_...._......_.._._.__........_....__._._._.._........_~.i~..
__....
Cr03 BH3 PbjOAcy~
ArCH3 --~~- ArCOOH --.~ ArCHzOH ---r- ArCHO
(2) IPyrINz (1 )
BHs
(1) -f- Li(CHz)"CN ---~- ArCHOH(CHZ);,CN ---~- ArCHOH(CHZ)"CH~NH2
n=1,2
O Li 0 _ _____________________________._.
(1) -f.- LiCH~C-~NR --~.~- ArCHOHCHZCNHR BHP ArCHOHCH~CH2NHR
O O aH,
-f- BrZnCH2CNRz ---"- ArCHOHCH2CNHR2 '-j"' ArCHOHCH2CH2NHR2
(2) -~ 2-Br-PyridineIBuLi ~ A~ \ I Hz / ~'c OH
MeOHJHC! AfC-'
N N
................................_._.._._._._...._.._.___.......__.________._._.
_..__...__...... H__._.
0
EtOHIH~ ~ ~ Claisen 0
ArC-OEt ~ ArC'CHZCOZEt
0
(2) SO~Ch ( ~ GHzN2
ArC--CI -"~ ArC-CHpNy ---r~ ArC-CHZBr
BHP ~ ~2~'~
ArCHOHCHpNR2 '~'-' ArC-CHZNRZ ,t,,~
0
ArCHOHCHpNR2 ~zNH
ArC~~CH2

CA 02325689 2000-09-25
WO 99148461 PCT/US99/06494
9
2-FIPERIDYL)-4, 5-DICHLORO-9-ANTHRACENEMETHAIvOL (WR Z18394
O
ii
Ol 1. Zn, NH40H
2. HC1
I
C1 O C.l C1 C1
z (37°,10)
CHO
CH;OCHCIZ 2-PyridYllithium
A1C1~, CHZCIZ
1 C1
3 (92%)
1 HO
H C H~O~ \
CH
HZ, PtOz
a ~ EtOH
C1 C1
C1 C1
4 (39-54%a) ~ (10%)

CA 02325689 2000-09-25
WO 99/48461 PCT/US99/06494
Compounds of the general formula wherein A is a phenan-
threne ring are known. Compounds of the following formula:
5
a)
Formula IV
R3(a)
0
R~
wherein R~ is a carbon bound directly to an oxygen and is
also bound to a nitrogen through a saturated carbon and is
of the structure CHOZX wherein Z may be hydrogen, a second
bond to the oxygen, or may be carboxyl, ether or ester
moiety wherein the ether or ester moiety may be alkyl of 1-8
carbons, phenyl, phenylalkyl, wherein the alkyl moiety
consists of 1-4 carbons and wherein any said alkyl or phenyl
group may, additionally, be substituted with hydroxy, alkyl
of 1-2 carbons, alkenyl of 2-3 carbons, halo, amino, or
alkyl amino group, X is (CHZ) ~N ( (CH2 ) ~ (CH3) ) m wherein i is 1-3 ,
n is <6, m is 1 or 2 with the proviso that when m is 2, at
least one n is <3, or X may be (CHZ)o as defined in the
general formula, wherein RZ and R3 are as defined in the
general formula and a is 0 to 3, with the proviso that for
at least one of RZ or R3 a is 1 - 3. Preferred halo substit-
uents are chloro or bromo and preferred haloalkyl is tri-
fluoromethyl. A particularly useful member of this group of
compounds is desbutylhalofantrin, a compound of the formula:

CA 02325689 2000-09-25
WO 99/48461 PCTNS99/06494
11
which has now been found to be superior to halofantrine for
treatment of malaria. (See U.S. Patent 5,711,966, which is
incorporated herein by reference in its entirety.)
The phenanthrenes may be made by several methods, in-
s cluding the following scheme:
CHZC02H CHO _
/ N0~ / ACZO F3C i ~' CF3
\ ~ ~~ I K~C03 ~~ I C=C
il
1 0 CF3 CF3 H COZH 02
F3 / / F3 Raney Nickel F3 / / CF3
NzH4~H20
\ C°C ~~ / ~ C=C \
II
H CO.,H 02 H C02Ht~HZ
c
CO H
F3C / / CF3 a) CSH110H0/HCl / ~ \ 2
\ I C-C \ I ~) HaH2POZ/CuSO~
F3C /
f I
II COZH NH2 \
.... C F 3
/ I \ C02H Z_BUP, - / ~ \ ~ N
F3C \ / F3C \ / I
CF3 . CF3
/
o I
/ ~ G H HZ/Pt C1
I MeOH/HC1 F
F3 .w
I
3~ CF3 '

CA 02325689 2000-09-25
WO 99/48461 PCT/US99/06494
12
The phenanthrene compounds may also be prepared using
the phenanthroic acid chlorides.
Example 1:
To a solution of 2g of 10-(~-bromoacetyl)-2,7-
dichlorophenanthrene in 25 ml of THF is added 2.9 g. of di-
n-heptylamine in 5 ml of THF at ambient temperature. After
one hour, the THF is evaporated, the residue triturated with
pentane, and filtered. The pentane residue is dissolved in
EtOH/THF and reacted with 0.42 g of NaBH4 for 1.5 hours. The
resulting reaction mixture is concentrated, the diluted with
HzH, extracted with EtZO, and acidified with gaseous HC1 to
yield the dichlorophenanthraceneaminoalcohol HC1 salt.
Several active agents of the invention were tested for
activity against several infectious organisms. Some of the
methods used in testing are described below.
Media:
The strains were streaked on blood agar plates (trypti-
case soy broth containing 5% sheep cells). A single colony
was isolated and grown in Mueller-Hinton Broth (MHB) as
recommended by the national Committee for Clinical Laborato-
ry Standards for rapidly growing bacteria. Candida species
and related yeasts were isolated in a similar manner on
brain-heart infusion agar (BHI).
Susceptibility tests:
The antibiotic susceptibility profile of each strain
was determined using standard microtiter dilution plates
obtained from the Clinical Microbiology Laboratory at Ohio
State University Hospitals. The Inocula were prepared by
suspending a 4 hour log phase growth in MHB visually equal
in turbidity of an 0.5 McFarland standard. Inocula were
further diluted and~added to microdilution trays to achieve
a final density of approximately 1 x 105 CFU/ml. The trays
were incubated for 16 to 20 hours at 35°C. The highest
dilution at which wells remained clear was considered to be
the minimum inhibitory concentration (MIC).
The MIC and minimum bacterial concentration (MBC) of
the strains to the active agents were determined by two-fold

CA 02325689 2000-09-25
WO 99/48461 PCT/US99/06494
13
dilutions in Mueller-Hinton broth. Susceptibility tests for
ATCC-obtained microorganisms and clinical isolates of gram
positive bacteria including methicillin-susceptible and
resistant staphylococci, streptococci, pneumococci and gram
negative bacteria, including Enterobacteriaceae, Pseudomo-
nas, Hemophilus and Neisseria, were performed in microtiter
plates as described above.
Compounds of the invention were dissolved in 1 ml of
methanol and stored in aliquots at -70°C. They were diluted
in Mueller-Hinton broth for final screening. Compositions
were tested in 0.1 ml volumes by serial dilution in micro-
titer plates against Staphylococcus aureus methicillin-
sensitive ATCC 29213 and the methicillin-resistant wild type
T67738, as described above. The T67738 was resistant to
most antimicrobial drugs, including ciprofloxacin.
The most active compounds were studied further by time
and dose-related killing curve analysis using large inocula
( 1 X 10~ CFU/ml ) .
The dosage and method of administration will depend on
the location of the infection, the condition of the patient
and the availability of professional supervision. Methods
of administration include parenteral, oral, buccal, nasal or
endotracheal routes. The active agents may be administered
as sprays. For nasal administration, the active agent may
be delivered as a powder that is snorted. Inclusion com-
plexes such as cyclodextrin inclusion complexes would be
particularly useful for buccal administration of these
active agents.
The compounds of the invention may also be admin-
istered topically by any means, including by rectal route.
Suppositories, solutions fox use as retention enemas, and
creams or jellies are appropriate carriers for use in rectal
administration. The agents may be administered directly to
infected tissue. For example, in case of open wounds, the
active agents may be administered in the form of sprays or
ointments.
Compounds of the invention may be applied to the skin

CA 02325689 2000-09-25
WO 99/48461 PCT/US99/06494
14
or mucosa, including the vaginal mucosa, using creams,
jellies, suppositories, or solutions. The active agents of
the invention may be delivered directly to the epithelial
tissue topically. For example, during surgery compositions
containing the active agents of the invention to the applied
directly to target tissues and prosthetic devices. The
compositions could be given by aerosol into the trachea or
administered in mist along with other agents into the respi-
ratory tract.
l0 The compositions of the invention may also be used
prophylactically to protect from infection by pathogenic
organisms.
Dosage forms containing about 25 to 1000 mg for admin
istration by mouth are suggested for use in adults. Howev
er, because the condition and size of the patient and the
infectring organisms may differ greatly, eventual dosage
requirements must be adjusted by the physician. Hence,
dosage suggestions are provided to give general guidance to
those of skill in the art. In accord with the purposes of
providing such guidance, the following data is provided.
The information provided is useful
The concentration required to provide benefit was
studied in culture and provides guidance for effective
concentration in the blood of the infected animal. The
results of these studies may be seen in Tables I and II

CA 02325689 2000-09-25
WO 99/48461 PCT/US99/06494
N
-rl
N
!~
N
N
f1
~i
M f'1
r~
M ~'
x ~'
"' U
U U O
a v ,~ n ~
w s~ a ~, ,~
ctf o
tx
a U
~
.
Ub
~ r-1
V U II
d'
II d, ,o
,
fx II
II
.,..r
b
~1 ~ ~1
.~ .p.f .~
N '.. N '~ N '"'
v ~. v~
~ ~ ~
v
~
1 H 1 0
G 0 'N~
INM 'NM
~
H x ~o H x ~r x ~n
.~ +~
H N N ~ ~
~ ri ~C ri Rf f~f
O 1C .~C
~ ~
V ~ .v
v v
v o x o a x
~
H ~C R', Gy N G4 N v N
LC1 O 117 O In
e-1 r-i N N

CA 02325689 2000-09-25
WO 99148461 PCT/US99/06494
16
ro
ro d' CO M
r1 I~ t--1CO
t0 f-1~O
U ~ O
.4J O 01 O
U N ~ N
ro
3 3
0
v v v
w ~I
O
U ~ I
O 0
O tl~ f,
. ., ?
1
O w ~ . f~ p ~
G
U O
N LY ,~ ~ 7, ?~
O
>~+~ S - ~
.~
~ ~ .C
ro ,--a~
U U p , U ~
O O ~ d
'
~
,~ ''i''~ II U U
' ~ O O
ro cx cx w
w .i~ U ro d'
I I I
h M ~ h h
~ U
b
0
~ ,--I1 ~ .--i
1
l U U ~ ro U U
-a
O ~ ~
x ~ ' Lx ~
M
w
,O U U
..
,, ,~ II
rN-IaO '.L'PU U
~ U Z Z
O O N N
o z
ro
x x ?'
x U U ~ .-i ~ .-.~
N N
U >< ~ ~ ~ ~ b
~< - . . .
O
'~ '~ '~ b y,a
O N
x x ~ v ~ ~ a,
x _
O UJ
N N N Qr f.~ >y !fir
U 0 .r.l.r.l .,.i''~I
Qr
~ ro ~ N N N N
O U x
v v v 'r
x x x I I H I I U
ro~ H H x 5C H x x x
.-I O O O U U U U U
N d ~ U U p x x ~ x x x
~
~ ~ ~
'
d' ~ '''''~''''~ ~ x x ~I x x
x
0 ~ o o
w w ~ (Y.,Q; W N N W N N N
O Lf1 O
r! ri N

CA 02325689 2000-09-25
WO 99/48461 PCT/US99/06494
17
.~,
v
U
t0
O
U
to tW o
tn M O tI1 l~ In O N 00 N M In
(JJ r-I M M e-1 r1 M l0 O l0 M r-'1
Ul ~r-I
N
O
d
>H
N
. O
W --1~ '-ie-iri N ~ rl ri r-1 N
O
U :~
,. U M
r., G4 W G4 1-1r-1r-1 ri U G4 W W r-I
~ U U U
U f~;I U U U t U U V U
I
U
4-I ~ ~ rl N e-1e-i'-1 N e-IN e-I rl e--1
4-1
W
N L~ie-1rl ~-1rl rl Li1Gr-1.-i G=i W GL
y U U U an U U U U U U U U
10 rl N
v
n n n
rl N M d' l!1~ v v ~ '~ N M
x
v v v v v ~, ~, M
U
..-I .~ U
f-Irl rl r-~ri r~ r1 ri ~ N N
x x
U U
n, a, x x
~ ~s ~s ~s ~ ~i ''~ ~i ~s "~ ~ U z
D w a. x --
' I N
G~I~.1I~1 LL ~ N ~ QI N x
b U V U
.- N ?CI f~ i1~~?. tl~W U f~ f~
1 >
. II
w ~ N~ x x x x x x x x x N x x
~n o m o u~ o m
ml e-i N N M M

CA 02325689 2000-09-25
WO 99/48461 PCT/US99/06494
18
Example 2:
Capsules of a formulation of active agent designated
#184366 for oral administration are prepared by containing
250 mg. of the active agent, 100 mg. starch, and 5 mg.
magnesium stearate. The capsules are administered daily or
twice a day to achieve a daily dosage of 500 mg. per day.
Example 3:
A preparation for application to the skin or mucosa may
be prepared in the following manner:
Ingredient ow/w
Compound #185308 15.0%
glyceryl monostearate 3.0%
Petrolatum 83.5%
Exaunple 4:
A formulation for administration as a retention enema
may be formulated in the following manner:
Ingredient w/w
Compound #218394 15%
Propylene glycol 850
When the active agent is administered to the mucosa of
the oral cavity, it may be administered as a buccal tablet
or spray for use in the oral-pharyngeal cavity and the nasal
cavities.
Example 5:
To 15 ml of phosphate buffered saline is added 3 mg of
compound #185308. The composition is placea in a nozzle
having a stopper with a smooth glass rod extending into the
solution. The composition is applied to boils using the
smooth glass rod as an applicator. The composition may also

CA 02325689 2000-09-25
WO 99/48461 PCT/US99/06494
19
be administered as a spray from a bottle with an atomizer.
Example 6:
To a 4 X 4 inch bandage having a smooth surface on one
side there is applied to the smooth surface .02 ml of the
solution prepared as a 2 ~M solution of active agent desig-
nated # 183308 in PBS. The prepared bandage is then en-
closed in a foil covering which is made air-tight. For
application, the bandage is unwrapped and is applied smooth
side down on the wound.
Example 7:
A composition is prepared for use on the skin or mucosa
in the following manner:
Ingredient %w/w
Agent designated #201683 0.5%
I5 propylene glycol 13.0%
Phosphate buffered saline 86.5%
When the active agent is administered to the mucosa of
the oral cavity, it may be administered as a buccal tablet
or spray for use in the oral-pharyngeal cavity and the nasal
cavities.

CA 02325689 2000-09-25
WO 99/48461 PCTNS99/06494
Example 8:
A composition prepared as a gel for application to the
skin:
Ingredient %w/w
5 active agent #1843660 0.5%
propylene glycol 10.0%
Polyethylene glycol 89.5%
Example 9:
A composition prepared for administration as a supposi-
10 tory:
Ingredient (%w/w)
Active agent #185308 0.5 mg
glyceryl monosterate 1.0 Gm
hydrogenated coconut oil 1.0 Gm
15 glyceryl monopalmitate 1.0 Gm
Example lo:
A composition for intravenous administration is pre-
pared comprising:
184366 300 mg.
20 10% glucose in 1/2 normal saline to 300 ml.
Regarding the compounds of Formula IV (Phenanthrenes),
the following examples are provided:
Example 11:
Capsules of a formulation of active agent designated
#1 for oral administration are prepared by containing 250
mg. of the active agent, 100 mg. starch, and 5 mg. magnesium
stearate. The capsules are administered daily or twice a

CA 02325689 2000-09-25
WO 99/48461 PCT/US99/06494
21
day to achieve a daily dosage of 500 mg. per day.
Example 12:
A preparation for application to the skin or mucosa may
be prepared in the following manner:
Ingredient %w/w
Compound #3 15.0%
glyceryl monostearate 3.0%
Petrolatum 83.5%
Example 13:
to A formulation for administration as a retention enema
may be formulated in the following manner:
Ingredient w/w
Compound #10 15%
Propylene glycol 85%
When the active agent is administered to the mucosa of
the oral cavity, it may be administered as a buccal tablet
or spray for use in the oral-pharyngeal cavity and the nasal
cavities.
Example 14:
To 15 ml of phosphate buffered saline is added 3 mg of
compound #11. The composition is placed in a bottle having
a stopper with a smooth glass rod extending into the solu-
tion. The composition is applied to boils using the smooth
glass rod as an applicator. The composition may also be
administered as a spray from a bottle with an atomizer.
Euample 15:
To a 4 X 4 inch bandage having a smooth surface on one

CA 02325689 2000-09-25
WO 99/48461 PCT/US99/06494
22
side there is applied to the smooth surface .02 ml of the
solution prepared as a 2 ~,M solution of active agent desig-
nated # 4 in PBS. The prepared bandage is then enclosed in
a foil covering which is made air-tight. For application,
the bandage is unwrapped and is applied smooth side down on
the wound.
Example 16:
A composition is prepared for use on the skin or mucosa
in the following manner:
Ingredient %w~w
Agent designated #9 0.5%
propylene glycol 13.0%
Phosphate buffered saline 86.5%
When the active agent is administered to the mucosa of
the oral cavity, it may be administered as a buccal tablet
or spray for use in the oral-pharyngeal cavity and the nasal
cavities.

CA 02325689 2000-09-25
WO 99/48461 PCTNS99/06494
23
Example 17:
A composition prepared as a gel for application to the
skin:
Ingredient %w/w
active agent designated #3 0.5%
propylene glycol 10.0%
Polyethylene glycol 89.5%
Example 18:
A composition prepared for administration as a supposi-
tory:
Ingredient (%w/w)
Active agent #8 0.5 mg
glyceryl monosterate 1.0 Gm
hydrogenated coconut oil 1.0 Gm
glyceryl monopalmitate 1.0 Gm
Example 19:
A composition for intravenous administration is pre-
pared comprising:
Desbutylhalofantrine: 300 mg.
10% glucose in 1/2 normal saline to 300 ml.
The compositions for intravenous administration are
particularly valuable for administration intravenously
during heart surgery and to patients suffering from endocar-
ditis.

Dessin représentatif