Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-25
2001-07-31
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S203000, C548S528000, C514S428000, C514S653000
Reexamination Certificate
active
06268383
ABSTRACT:
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 active agents compounds containing aryl ring systems, including phenyl, naphthyl and anthracene ring systems, substituted 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 phenanthrene ring system substituted by a carbon bound to an oxygen which is also bound to a nitrogen through a saturated CH
2
—CH
2
chain to tertiary nitrogen having two butyl substituents. The phenanthrene ring system is further substituted with 2 chlorines and one trifluoromethyl.
SUMMARY OF THE INVENTION
This invention relates to compounds of the general formula:
wherein A is a aromatic hydrocarbon ring system and R
1
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 R
2
, R
3
and R
4
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 compounds 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:
wherein A is an aromatic ring system and R
1
is bound directly to an oxygen and is also bound to a nitrogen through a saturated carbon. R
1
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 (CH
2
) N((CH2)
n
(CH
3
))
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 (CH
2
)
o
J wherein 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, phenoxy, 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 R
2
(a), R
3
(a) and R
4
(a), a may be 0-4 with the proviso that at least one a is not 0. R
2
, R
3
and R
4
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, 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 provision that at least one of R
2
, R
3
and R
4
is an electron-rich substituent. Z and X may be linked to form a heterocylic ring system. Furthermore, any alkyl or aryl at R
2
, R
3
and R
4
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 (CH
2
)
o
J and o is 2-4 are novel.
Particularly useful compounds are those of Formulas I, II, III and IV.
In compounds of Formula I, any of R
2-8
may be substituents designated under R
2
, R
3
and R
4
in the general formula above, with the proviso that at least one of R
2-8
is an electron-rich substituent and any one of R
1
, R
9
or R
10
is a substituent as defined as R
1
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.
In compounds of Formula II, any of R
2-6
may be substituents identified as R
2
, R
3
or R
4
in the general formula with the proviso that at least one substituents is an electron-rich moiety and R
1
is as designated for R
1
(CHOZX) for the general formula above. Many of the preferred compounds have at least two halo or halo-substituted substituents.
wherein R
1
is defined as in the general formula and R
2-6
is defined in the same manner as R
2
, R
3
and R
4
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:
Compounds of Formulas I, II and III can be made using the following methods:
Preparing starting materials:
A general method for production:
Compounds of the general formula wherein A is a phenanthrene ring are known. Compounds are of the following formula:
wherein R
1
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 (CH
2
)N((CH2)
n
(CH
3
))
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 (CH
2
)
o
J as defined in the general formula, wherein R
2
and R
3
are as defined in the general formula and a is 0 to 3, with the proviso that for at least one of R
2
or R
3
a is 1-3. Preferred halo substituents are chloro or bromo and preferred haloalkyl is trifluoromethyl. A particularly useful member of this group of compounds is desbutylhalofantrine. which has now been found to be superior to halofantrine for treatment of malaria. (See U.S. Pat. No. 5,711,966, which is incorporated herein by reference in its entirety.)
Th
Arwine Elizabeth
Dentz Bernard
Harris Charles H.
The United States of America as represented by the Secretary of
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