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:
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 car- boxyl , 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, addi- tionally, be substituted with hydroxy, alkyl of 1-2 carbons, alkenyl of 2-3 carbons, halo, amino, or alkyl amino group and X is (CH2) t 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)oJ 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, 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.
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:
Formula I
wherein any of R2, R3, R4, B^ , 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 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, R, R5, R6, R7 and R8 is an electron-rich substituent and one of R1 , Rg 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 carboxy1 , 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) tN( (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)oJ 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, phe- noxy, phenylalkyl, phenylalkoxy, carboxy or carbonyl groups, wherein the carboxy or carbonyl groups, includ- ing 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,
Rc5 ' , R ^6, ' , R-, and R„ 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 Rg is CHOZX and Z=H, X=CH2- N(C4H9) (C3H7) and R5 and R6 are Cl .
A method of claim 2 wherein R1 is CHOZX and Z=H, X=(CH2)2NH(C3H7) and R3 is Cl .
A nethod of claim 2 wherein R1 is CHOZX and Z=H, X=(CH2)2NH(C3H7) , R3 is Cl and R5 is CF3.
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:
Formula II
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 substi-
tuted 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 L 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)oJ 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, phe- noxy, phenylalkyl, phenylalkoxy, carboxy or carbonyl groups, wherein the carboxy or carbonyl groups, includ- ing 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 = 0CH3, R3 = 3,4 dichloro-phenyl .
11. A method of claim 8 wherein Z=H, X=CH,- (2-piperidine)
R6=C1 , R7=CF3 , R3=4 -C1 -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:
Formula III
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, Rg, 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) tN( (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)oJ 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, phe- noxy, 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=C1, R5=4-OCH3-phenyl.
16. A method of claim 13 wherein Z=H, X=CH2CH2 (2-piperidine) R3=C1, R5=4-OCH3-phenyl
17. A method of of claim 1 of treating or preventing infec- tion 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:
Formula IV
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, carboxy- alkyl, 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 carboxy1 , 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)tN( (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)0J 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, phe- noxy, 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
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
H CH2NHCH(CH2CH3)2 (#11) CF3 1 CF3 1
H (CH2)NH(CH2)3CH3 (#12) CF3 1 Cl 2
0. A compound of the formula:
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 carboxy1, 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,
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 R 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.