Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-14
2001-08-14
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06274598
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the treatment of antibiotic-resistant infections, including particularly infections caused by bacteria, Mycobacteria and fungi. A preferred group of compositions of the invention contain as active agents compounds containing pyridyl, quinolyl or benzoquinolyl ring systems substituted on the nitrogen-containing ring at the carbon oposite the nitrogen by a carbon bound to an oxygen which is also bound to a nitrogen through a saturated carbon or carbon chain, or, in the case of the pyridyl ring system, the substituent at the 4 position of the pyridyl ring may be an alkyl which may be substituted with halo, hydroxy, alkoxy, amino or alkylamino.
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.
Mefloquine is quinolyl compound having two trifluoromethyl groups attached to the quinolyl ring. This compound has been used to treat malaria. It has also been found to have some activity against bacterial pathogens in vitro.
SUMMARY OF THE INVENTION
This invention comprises compositions containing as active agents compounds which have pyridyl or quinolyl ring systems (including benzoquinolyl ring systems) substituted at the carbon opposite the nitrogen by a carbon bound directly to an oxygen and to a nitrogen through a saturated carbon or carbon chain or, in the case of pyridyl, an alkyl, alkenyl, alkyloxy, alkenyloxy, amino or alkylamino group wherein alkyl has 1-6 carbons, alkenyl has 2-6 carbons, wherein said alkyl or alkenyl groups may, optionally, have amino, hydroxy or halo substituents. Preferred compounds of the invention are those wherein the quinolyl ring system has at least one electron-rich substituent on the quinolyl ring system, including, for example, halo, phenyl, hydroxy, alkoxy or trihalomethyl substituents and the substituent at the carbon directly opposite the nitrogen atom is of the structure —CHOYX wherein Y may be 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 n is ≦5, m is 1 or 2 with the proviso that when m is 2, n is ≦3, or X may be CH
2
N(CH
2
)
q
wherein q may be up to 10, which is cyclized and may have up to 4 bridge carbons or X is a saturated six-member nitrogen containing ring which may be substituted, wherein the piperidinyl moiety is bound through the carbon at the 2 position of the ring to the CHOY through a carbon atom. The six member ring may have 1-4 bridge carbons to produce complex ring systems such as quinuclidinyl ring systems.
The active agents are useful for treating patients suffering from infections including gram positive bacteria, gram negative bacteria, fungi and mycobacteria. They are effective against strains which have shown resistance to other antimicrobial agents.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that compositions of the following formula:
A—B—N—Z(n)
wherein N is a quinolyl, pyridyl or benzoquinolyl ring substituted at the carbon opposite the nitrogen on the nitrogen-containing ring by B—A wherein B is a carbon (C′) bound to an oxygen, (═O, OH, Oalk, OCOalk, OCOaryl, OCOphenyl alkyl, or an oxygen in a cyclic moiety wherein aryl is phenyl or naphthyl and alkyl has 1-4 carbons and may be substituted hydroxy, or with 1-2 halo atoms) and wherein said carbon C′ is also bound A, which is a saturated carbon which is bond directly to a nitrogen-containing saturated chain or nitrogen-containing saturated ring system (for example, piperidinyl or quinuclidinyl ring systems), 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. Z is R
1(m)
and/or R
2(n)
wherein at least one of R
1
and R
2
is an electron-rich substituent and m and n may be 1-4 and wherein R
1
and/or R
2
may be alkyl, alkoxy, aryl, aryloxy, aryloxyalkyl, amino, aminoalkyl, alkylaminoalkyl, arylamino, alkenyl, arylalkenyl, arylalkylaminoalkyl, carboxyalkyl, hydroxy, halo, alkenyl, alkenyloxy, herein any alkyl has 1-8 carbons, alkenyl has 2-8 carbons, halo is chloro, fluoro or bromo and aryl is a ring system of 1-3 rings. Preferred electron-rich substituents are chosen from moieties containing unsaturated ring systems (such as phenyl, phenoxy and naphthyl), halo (preferably chloro, fluoro) trihalomethyl, alkoxy, alkenyloxy, alkylamino and aminoalkylamino groups wherein any alkyl has 1-8 carbons. However, when N is quinolyl, if the 2 position on the quinolyl ring is substituted with trihalomethyl and the 8 position is substituted with trihalomethyl or phenyl, the 6 or 7 position on the ring system must be further substituted with an electron-rich substituent such as halo or alkoxy. The preferred compounds of the invention require specifically a large substituent such as phenyl, phenoxy, naphthyl, trihalomethyl (particularly trifluoromethyl) or quinuclidinyl groups at the 2 position on the ring system. Any alkyl or aryl moiety may further be substituted with halo, hydroxy, amino, alkylamino, alkylamino groups having 1-4 carbons or alkenyl, alkenylamino of 2-4 carbons.
When N is a pyridyl ring, the 2 and 6 positions of the pyridyl ring must be substituted with aryl groups wherein aryl is phenyl or naphthyl. Compounds may be made by usual means. The following schemes are appropriate:
Particularly preferred compounds are of the formula:
wherein P is phenyl or napthyl, q is 1-3, and, in N(alkyl)
(1 or 2)
, alkyl is of 1-8 carbons which may be substituted with halo or alkoxy and R
5
is H or alkyl of 1-4 carbons and, in formula II, wherein at least 1 of R
1
or R
2
is halo, haloalkyl, dihaloaklyl, trihaloalkyl or alkoxy, or compounds of the formula:
wherein P is phenyl or napthyl, R
5
is H or alkoxy, J is a saturated nitrogen containing ring attached at the 2 position of ring J which may be substituted with halo or alkoxy and, in Formula IV, at least 1 of R
1
is halo, haloalkyl, dihaloaklyl, trihaloalkyl or alkoxy.
In compounds of formula I and II, the N-dialkyl compounds are active against mycobacteria, but not against gram negative organisms or bacteria. Hence, for broad spectrum activity, compounds of wherein, for N(alkyl) (
1
or
2
) mono subsitution (
(1)
) are preferred.
Materials and Methods
Active agents of the invention were tested for activity against several infectious organisms. Testing for inhibitory effect against antibiotic-resistant organisms was accomplished in the following manner:
Media
The strains were streaked on blood agar plates (trypticase 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 Laboratory Standards for rapidly growing bacteria. Candida species and related fungi 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 standa
Ellis William Y.
Kunin Calvin M.
Arwine Elizabeth
Harris Charles H.
The United States of America as represented by the Secretary of
Weddington Kevin E.
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