Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-09
2003-07-01
Berch, Mark (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S092000, C544S096000, C544S142000, C544S281000, C544S350000, C546S084000, C546S121000, C546S174000, C546S198000, C546S276700, C548S154000, C548S181000, C548S216000, C548S218000, C548S221000, C548S231000, C548S236000, C548S238000, C548S247000, C548S324100, C514S374000, C514S375000, C514S376000, C514S365000, C514S368000, C514S378000, C514S392000, C514S410000
Reexamination Certificate
active
06586452
ABSTRACT:
BACKGROUND OF THE INVENTION
Nodulosporic acid and related component nodulisporic acid A1 are antiparasitic agents and ectoparasiticidal agents isolated from the fermentation culture of Nodulisporiuim sp. MF-5954 (ATCC 74245). These three compounds have the following structures as disclosed in U.S. Pat. No. 5,399,582 and J. G. Ondeyka et al.
J. Am. Chem. Soc
. 1997, 119(38), 8809-8816.
Derivatives of nodulisporic acid are disclosed in U.S. Pat. No. 5,962,499.
SUMMARY OF THE INVENTION
This invention relates to new acaricidal, antiparasitic, insecticidal and anthelmintic agents related to the nodulisporic acids, to processes for their preparation, compositions thereof, their use in the treatment of parasitic infections, including helminthiasis, in human and animals, and their use in the treatment of parasitic infections in plants or plant products.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds having the formula I:
wherein
represents a single or a double bond;
X is (1) a bond, or
(2) C(R
x
)(R
y
);
Y is (1) a bond, or
(2) C(R
x
)(R
y
);
Z is (1) H,
(2) C(R
x
)(R
y
)(R
z
),
(3) a group selected from R
z
; or
X—Y is (1) C(R
x
)═C(R
x
) or
(2) C≡C, or
Y—Z is (1) C(R
x
)═C(R
x
)(R
z
) or
(2) C≡C(R
z
);
R
1
is (1) hydrogen,
(2) optionally substituted C
1
-C
10
alkyl,
(3) optionally substituted C
2
-C
10
alkenyl,
(4) optionally substituted C
2
-C
10
alkynyl,
(5) optionally substituted C
3
-C
8
cycloalkyl,
(6) optionally substituted C
5
-C
8
cycloalkenyl,
(7) optionally substituted aryl,
(8) optionally substituted 5- or 6-membered heterocycle containing from 1 to 4 heteroatoms independently selected from O, S and NR
c
,
where the substitutents on the alkyl, alkenyl, alkynyl are 1 to 3 groups selected from R′, the substituents on aryl is 1 to 3 groups selected from R″, and the substituents on cycloalkyl and cycloalkenyl are 1 to 3 groups independently selected from R″, oxo and thiono;
R
2
, R
3
, and R
4
are independently OR
a
, OCO
2
R
b
, OC(O)NR
c
R
d
; or
R
1
+R
2
represent ═O, ═NOR
a
, ═N—NR
c
R
d
, ═CR
a
CO
2
R
a
, ═CR
a
C(O)NR
c
R
d
, ═CR
a
CN, ═CR
a
C(O)R
a
, or ═CR
a
R
a
;
R
5
is (1) hydrogen,
(2) OR
a
or
R
4
+R
5
represent ═O, ═NOR
a
, ═N—NR
c
R
d
or ═CR
a
R
a
;
R
a
is (1) H,
(2) optionally substituted C
1
-C
10
alkyl,
(3) optionally substituted C
3
-C
10
alkenyl,
(4) optionally substituted C
3
-C
10
alkynyl,
(5) optionally substituted C
3
-C
15
cycloalkyl,
(6) optionally substituted C
5
-C
10
cycloalkenyl,
(7) optionally substituted aryl,
(8) optionally substituted heteroaryl,
(9) optionally substituted 3- to 10-membered heterocycle containing 1 to 4 heteroatoms selected from O, S and NR
g
,
(10) a benzene ring fused to a 4- to 8-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and NR
g
,
(11) a 4- or 8-membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and NR
g
fused to a 4- or 8-membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and NR
g
, and
where the substituents on the aryl, alkyl, alkenyl, alkynyl groups are 1 to 10 groups selected from R′; the substituents on aryl, heteroaryl and benzene are 1 to 5 groups selected from R″; and the substituents on cycloalkyl, cycloalkenyl and heterocycle are 1 to 10 groups selected from R″, oxo and thiono;
R
b
is (1) a group selected from R
a
,
(2) optionally substituted C
2
-C
6
alkanoyl,
R
c
and R
d
are independently selected from R
b
, hydroxy, C
1
-C
5
alkoxy, C
1
-C
5
alkoxycarbonyl, aminocarbonyl, C
1
-C
5
alkylaminocarbonyl and C
1
-C
5
dialkylaminocarbonyl; or
R
c
and R
d
together with the N to which they are attached form a 3- to 10-membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)
m
, and NR
g
, said ring is optionally substituted with 1 to 5 groups independently selected from R″, thiono and oxo; said ring is further optionally fused to a benzene ring optionally substituted with 1 to 3 groups selected from R
e
; said ring is further optionally spirofused to a C
3
-C
7
cycloalkyl ring:
R
e
is (1) halogen,
(2) C
1
-C
7
alkyl,
(3) C
1
-C
3
perfluoroalkyl,
(4) S(O)
m
R
i
,
(5) cyano,
(6) nitro,
(7) R
i
O(CH
2
)
v
—,
(8) R
i
CO
2
(CH
2
)
v
—,
(9) R
i
OCO(CH
2
)
v
,
(10) optionally substituted aryl where the substituents are from 1 to 3 of halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, or hydroxy,
(11) SO
2
NR
i
R
i
, or
(12) amino;
R
f
is (1) H,
(2) C
1
-C
5
alkyl optionally substituted with 1 to 5 groups selected from halogen, cyano, hydroxy, C
1
-C
3
alkoxy, NR
g
R
h
, CO
2
R
i
and CONR
g
R
h
,
(3) C
2-6
alkenyl,
(4) C
2-6
alkynyl,
(5) C
3
-C
6
cycloalkyl,
(6) aryl optionally substituted with 1 to 4 groups independently selected from R
e
, or 2 adjacent substituents together form methylenedioxy, or
(7) aryl-C
1
-C
3
alkyl optionally substituted with 1 to 4 groups independently selected from R
e
, or 2 adjacent substituents together form methylenedioxy, or
two Rf groups together with the nitrogen atom to which they are attached form a a 3-to 10-membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)
m
, and NR
g
, said ring is optionally substituted with 1 to 5 groups independently selected from R″, thiono and oxo; said ring is further optionally fused to a benzene ring optionally substituted with 1 to 3 groups selected from R
e
; said ring is further optionally spirofused to a C
3
-C
7
cycloalkyl ring;
R
g
and R
h
are independently
(1) hydrogen,
(2) C
1
-C
10
alkyl optionally substituted with 1 to 10 groups selected from hydroxy, amino, C(O)R
i
, and CO
2
R
i
,
(3) aryl optionally substituted with 1 to 5 groups selected from halogen, amino, 1,2-methylenedioxy, C
1
-C
7
alkoxy, C
1
-C
7
alkyl and C
1
-C
3
perfluoroalkyl,
(4) aryl C
1
-C
6
alkyl, wherein the aryl is optionally substituted with 1 to 5 groups selected from halogen, amino, 1,2-methylenedioxy, C
1
-C
7
alkoxy, C
1
-C
7
alkyl and C
1
-C
3
perfluoroalkyl,
(5) C
3
-C
7
cycloalkyl optionally substituted with phenyl,
(6) C
1
-C
5
alkanoyl,
(7) C
1
-C
5
alkoxycarbonyl,
(8) aryl C
1
-C
5
alkoxycarbonyl,
(9) aminocarbonyl,
(10) C
1
-C
5
monoalkylaminocarbonyl
(11) C
1
-C
5
dialkylaminocarbonyl; or
R
g
and R
h
together with the N to which they are attached form a 3- to 7-membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)
m
, and NR
i
, optionally substituted with 1 to 3 groups independently selected from R
e
and oxo;
R
i
is (1) hydrogen,
(2) C
1
-C
3
perfluoroalkyl,
(3) C
1
-C
6
alkyl,
(4) optionally substituted aryl C
0
-C
6
alkyl, where the aryl substituents are from 1 to 3 groups independently selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, and hydroxy;
R
x
and R
y
are independently selected from the group consisting of
(1) hydrogen
(2) optionally substituted C
1
-C
10
alkyl,
(3) optionally substituted C
2
-C
10
alkenyl,
(4) optionally substituted C
2
-C
10
alkynyl, wherein the substituents on alkyl, alkenyl and alkynyl are 1 to 5 groups independently selected from R′,
(5) a group selected from R
z
, or
R
x
+R
y
is (1) ═NOR
a
,
(2) ═NNR
c
R
d
,
(3) ═NNR
c
SO
2
R
a
,
(4) ═CR
a
CO
2
R
a
, or
(5) ═O,
R
z
is (1) optionally substituted aryl,
(2) optionally substituted heterocyclyl,
(3) optionally substituted C
3
-C
8
cycloalkyl,
(4) optionally substituted C
5
-C
8
cycloalkenyl,
(5) (CHR
a
)
n
OR
a
,
(6) (CHR
a
)
n
OC(O)R
a
,
(7) (CHR
a
)
n
OC(O)OR
b
,
(8) (CHR
a
)
n
OC(O)NR
c
R
d
,
(9) (CHR
a
)
n
OSO2R
a
,
(10) (CHR
a
)
n
S(O)mR
a
,
(11) (CHR
a
)
n
SC(O)R
a
,
(12) (CHR
a
)
n
NR
c
R
d
,
(13) (CHR
a
)
n
NR
c
C(O)R
a
,
(14) (CHR
a
)
n
NR
c
C(O)OR
a
,
(15) (CHR
a
)
n
NR
c
C(O)C(O)OR
a
,
(16) (CHR
a
)
n
NR
c
C(O)NR
c
R
d
,
(17) (CHR
a
)
n
NR
c
SO2R
a
,
(18) (CHR
a
)
n
NR
c
C(O)P(O)R
a
,
(19) (CHR
a
)
n
NR
c
C(O)SR
a
,
(20) C(O)R
a
,
(21) C(O)OR
b
,
(22) C(O)NR
c
R
d
,
(23) C(O)N(OR
a
)R
c
,
(24) C(O)NR
c
NR
c
R
d
,
(25) C(O)NR
c
SO2R
a
,
(26) halogen,
(2
Berger Richard
Chakravarty Prasun K.
Colletti Steven L.
Fisher Michael H.
Kuo Howard C. H.
Berch Mark
Merck & Co. , Inc.
Rose David L.
Yang Mollie M.
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