US2002169153A1PendingUtilityA1
Substituted aromatic compounds for treatment of antibiotic resistant infections
Priority: Mar 26, 1998Filed: Jun 11, 2001Published: Nov 14, 2002
Est. expiryMar 26, 2018(expired)· nominal 20-yr term from priority
Inventors:William Y. Ellis
C07C 215/30C07D 211/22A61K 31/4458C07C 2603/24C07C 215/28A61K 31/137C07C 2603/26
38
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
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. They are effective against strains which have shown resistance to other antimicrobial agents.
Claims
exact text as granted — not AI-modifiedWhat 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:
wherein A is a hydrocarbon aromatic ring system, R 1 is bound directly to an oxygen and is also bound to a nitrogen through a saturated carbon or carbon chain, with R 1 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 (CH 2 ) 1 N((CH2) n (CH 3 )) m wherein l ‘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 (CH 2 ) 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, 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, 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, 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 R 2 , R 3 and R 4 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 R 2 , R 3 and R 4 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:
wherein any of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 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 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is an electron-rich substituent and one of R 1 , R 9 or R 10 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 (CH 2 ) l 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 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 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are Cl or F 3 C.
4 . A method of claim 2 wherein Z═H, X═CH 2 -(2-piperidine) R 2 and R 4 are Cl.
5 . A method of claim 2 wherein R 9 is CHOZX and Z═H, X═CH 2 -N(C 4 H 9 ) (C 3 H 7 ) and R 5 and R 6 are Cl.
6 . A method of claim 2 wherein R 1 is CHOZX and Z═H, X═(CH 2 ) 2 NH(C 3 H 7 ) and R 3 is Cl.
7 . A nethod of claim 2 wherein R 1 is CHOZX and Z═H, X═(CH 2 ) 2 NH(C 3 H 7 ), R 3 is Cl and R 5 is CF 3 .
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:
wherein any of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 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 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is an electron-rich substituent and one of R 1 , 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 (CH 2 ) l 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 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═CH 2 -(2-piperidine) R 6 ═Cl, R 7 ═OCH 3 , R 3 ═4-Cl-phenyl.
10 . A method of claim 8 wherein Z═H, X═CH 2 -(2-piperidine) R 6 ═Cl, R 7 ═OCH 3 , R 3 ═3,4 dichloro-phenyl.
11 . A method of claim 8 wherein Z═H, X═CH 2 -(2-piperidine) R 6 ═Cl, R 7 ═CF 3 , R 3 ═4-Cl-phenyl.
12 . A method of claim 8 wherein Z═H, X═CH 2 -(2-piperidine) R 6 ═CF 3 , R 7 ═OCH 3 , R 3 ═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:
wherein any of R 2 , R 3 , R 4 , R 5 , and R 6 , 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 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is an electron-rich substituent and one of R 1 , 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 (CH 2 ) l 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 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═CH 2 -(2-piperidine) R 3 and R 5 are 4-Cl-phenyl.
15 . A method of claim 13 wherein Z═H, X═CH 2 -(2-piperidine) R 3 ═Cl, R 5 ═4—OCH 3 -phenyl.
16 . A method of claim 13 wherein Z═H, X═CH 2 CH 2 (2-piperidine) R 3 ═Cl, R 5 ═4—OCH 3 -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:
wherein any (a) is 1-3 and R 2 , and R 3 , 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 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is an electron-rich substituent and one of R 1 , 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 (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 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.
18 . A method of claim 17 wherein the active agent is desbutylhalofantrine.
19 . A method of claim 17 wherein the active agent is chosen from among compounds wherein
Z
X
R 2 ,
n
R 3
n
H
piperidinyl
(#1)
CF 3
1
CF 3
1
H
piperidinyl
(#2)
Cl
1
CF 3
1
H
piperidinyl
(#3)
Cl
2
CF 3
1
H
piperidinyl
(#4)
Br
1
Br
1
H
piperidinyl
(#5)
Cl
1
Cl
1
H
CH 2 -piperidinyl
(#6)
Cl
1
Cl
1
H
piperidinyl
(#7)
CF 3
2
Cl
2
H
piperidinyl
(#8)
CF 3
1
CF 3
1
H
CH 2 -piperidinyl
(#9)
Cl
2
CF 3
1
ZX =
(#10)
CF 3
1
CF 3
1
H
CH 2 NHCH(CH 2 CH 3 ) 2
(#11)
CF 3
1
CF 3
1
H
(CH 2 )NH(CH 2 ) 3 CH 3
(#12)
CF 3
1
Cl
2
20 . A compound of the formula:
wherein A is a hydrocarbon aromatic ring system, R 1 is bound directly to an oxygen and is also bound to a nitrogen through a saturated carbon or carbon chain, with R 1 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 (CH 2 ) o J 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, 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, 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 R 2 , R 3 and R 4 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 R 2 , R 3 and R 4 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.Join the waitlist — get patent alerts
Track US2002169153A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.