Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-09
2002-06-04
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S381000, C549S414000, C549S472000, C549S473000, C549S059000, C549S060000, C548S417000, C514S410000, C514S422000, C514S423000, C514S444000, C514S453000, C514S461000
Reexamination Certificate
active
06399786
ABSTRACT:
BACKGROUND OF THE INVENTION
Nodulisporic acid is an antiparasitic agent and ectoparasiticidal agent isolated from the fermentation culture of Nodulisporium sp. MF-5954 (ATCC 74245), and having the following structure:
Nodulisporic acid is disclosed as “Compound 1” in U.S. Pat. No. 5,399,582. Also disclosed therein are “Compound 2” and “Compound 3”:
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
R
1
is
(1) hydrogen,
(2) C(O)H,
(3) optionally substituted (C═O)
p
—R
x
, wherein the substituent is one to ten groups independently selected from R
z
, OR
a
, OC(O)R
b
, CO
2
R
b
, NR
c
COR
d
, CONR
c
R
d
, and NR
c
R
d
,
(4) C
1
-C
10
alkoxy,
(5) C
1
-C
10
alkylthio,
(6) CO
2
R
b
,
(7) CONR
c
R
d
,
(8) CONR
c
SO
2
R
d
,
(9) CN,
R
2
is
(1) hydrogen,
(2) OR
a
,
(3) SR
a
; or
R
1
+R
2
represent ═O; or
R
1
and R
2
together with the carbon atom to which they are attached form a 5- to 7-membered ring containing 0 to 2 heteroatoms selected from O, S(O)
m
and N, optionally substituted with 1 to 4 groups independently selected from R
a
;
R
3
is
(1) hydrogen,
(2) OR
a
,
(3) NR
c
R
d
,
(4) NR
c
OR
d
,
(5) NR
c
SO
2
R
d
,
(6) NR
e
CONR
c
R
d
,
(7) NR
c
CO
2
R
d
; or
R
2
+R
3
represent a bridging oxygen atom;
R
4
is hydrogen, or
R
2
and R
4
together represents a bond between the carbon atoms to which they are attached;
R
a
is
(1) H,
(2) optionally substituted R
y
,
(3) optionally substituted C(O)R
x
,
(4) PO(OR
b
)
2
,
(5) SO
2
R
b
,
(6) a natural or unnatural mono-, di- or tri-saccharide composed of any furanose or pyranose, or combination thereof; wherein said substituent for R
x
and R
y
are 1 to 10 groups independently selected from R
z
, hydroxy, C
1
-C
6
alkoxy, OC(O)R
b
, CO
2
R
b
, NR
c
COR
d
, CONR
c
R
d
, and NR
c
R
d
,
R
b
is
(1) hydrogen
(2) optionally substituted R
y
, wherein said substituents are 1 to 10 groups independently selected from R
z
, hydroxy, C
1
-C
6
alkoxy, OC(O)C
1
-C
6
alkyl, carboxy, CO
2
C
1
-C
6
alkyl, NR
c
COR
d
, CONR
c
R
d
, and NR
c
R
d
,
(3) a natural or unnatural mono-, di- or tri-saccharide composed of any furanose or pyranose, or combination thereof;
R
c
is
(1) hydrogen,
(2) optionally substituted R
y
, wherein said substituents are 1 to 10 groups independently selected from R
z
, hydroxy, C
1
-C
6
alkoxy, OC(O)C
1
-C
6
alkyl, carboxy, CO
2
C
1
-C
6
alkyl, NHCOC
1
-C
6
alkyl, CONH(C
1
-C
6
alkyl), NH
2
, NH(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)
2
,
R
d
is independently selected from R
c
; 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 N, optionally substituted with 1 to 4 groups independently selected from R
e
;
R
e
is halogen, cyano, oxo or optionally substituted R
x
wherein said substituents are 1 to 10 groups independently selected from R
z
, hydroxy, C
1
-C
6
alkoxy, OC(O)C
1
-C
6
alkyl, carboxy, CO
2
C
1
-C
6
alkyl, NHCOC
1
-C
6
alkyl, CONH(C
1
-C
6
alkyl), NH
2
, NH(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)
2
,
R
x
is
(1) C
1
-C
10
alkyl,
(2) C
2
-C
10
alkenyl,
(3) C
2
-C
10
alkynyl,
(4) C
3
-C
8
cycloalkyl,
(5) C
5
-C
8
cycloalkenyl,
(6) aryl,
(7) a 5- or 6-membered heterocycle containing from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;
R
y
is
(1) C
1
-C
10
alkyl,
(2) C
3
-C
10
alkenyl,
(3) C
3
-C
10
alkynyl,
(4) C
3
-C
8
cycloalkyl,
(5) C
5
-C
8
cycloalkenyl,
(6) aryl,
(7) a 5- or 6-membered heterocycle containing from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;
R
z
is
(1) C
1
-C
5
alkyl,
(2) C
2
-C
5
alkenyl,
(3) C
3
-C
8
cycloalkyl,
(4) aryl, optionally substituted by 1 to 4 groups selected from C
1
-C
5
alkyl, C
2
-C
5
alkenyl, C
1
-C
5
alkoxy, hydroxy, amino, cyano, halogen, OC(O)C
1
-C
6
alkyl, carboxy, Co
2
C
1
-C
6
alkyl, NHCOC
1
-C
6
alkyl, CONH(C
1
-C
6
alkyl), NH(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)
2
,
(5) halogen,
(6) cyano,
(7) oxo,
(8) a 5- or 6-membered heterocycle containing from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen optionally substituted by 1 to 4 groups selected from C
1
-C
5
alkyl, C
2
-C
5
alkienyl, C
1
-C
5
alkoxy, hydroxy, oxo, amino, cyano, halogen, OC(O)C
1
-C
6
alkyl, carboxy, CO
2
C
1
-C
6
alkyl, NHCOC
1
-C
6
alkyl, CONH(C
1
-C
6
alkyl), NH(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)
2
,
m is 0to 2;
n is 0 or 1;
p is 0 or 1; or
a pharmaceutically acceptable salt thereof.
The present invention provides in another aspect pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. Such compositions may further comprise one or more other active ingredients such as anthelmintic agents, insect regulators, ecdosyne agonists and fipronil.
The present invention provides in another aspect a method for treating parasitic diseases in a mammal which comprises administering an antiparasitic amount of a compound of Formula I. The treatment may further comprise co-administering one or more other active ingredients such as anthelmintic agents, insect regulators, ecdosyne agonists and fipronil.
In one subset of compounds of formula I, n is 0.
In another subset of compounds of formula I, n is 1.
In another subset of compounds of formula I, R
1
is H, and R
2
is H, OR
a
or SR
a
. Preferably, R
2
is OR
a
or SR
a
wherein R
a
is H, optionally substituted C
1
-C
6
alkyl, optionally substituted C
3
-C
6
alkenyl, or optionally substituted aryl, wherein the substituent is 1 to 4 groups independently selected from R
z
, hydroxy, C
1
-C
6
alkoxy, OC(O)R
b
, CO
2
R
b
, NR
c
COR
d
, CONR
c
R
d
, and NR
c
R
d
. Examples of R
2
include, but are not limited to, hydrogen, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, allyloxy, 6-methoxycarbonyl-n-hexyloxy, benzyloxy, 2-oxo-5-pyrrolidinylmethoxy, 2-acetamidoethoxy, 2-methyl-2-acetylethoxy, 2-(2-oxo-1-pyrrolidinyl)ethoxy, 2-(2,5-dioxo-1-pyrrolidinyl)ethoxy, 2-cyanoethoxy, 3-furanyl-methoxy, 4-imidazolylmethoxy, 2-(4-methyl-5-thiazolyl)ethoxy, methylthio, ethylthio, phenylthio, 2-methoxyphenylthio.
In another subset of compounds of formula I, R
2
is H, and R
1
is R
x
, optionally substituted with one to ten groups independently selected from R
z
, OR
a
, OC(O)R
b
, CO
2
R
b
, NR
c
COR
d
, CONR
c
R
d
, and NR
c
R
d
. In one embodiment R
1
is selected from C
1-6
alkyl, C
3-6
alkenyl and aryl. Examples of R
1
include, but are not limited to, methyl, allyl, 2-thienyl, 2-furanyl.
In another subset of compounds of formula I, R
1
and R
2
together is an oxo group.
In another subset of compounds of formula I, R
2
and R
4
together form a bond across the carbon atoms to which they are attached.
In a preferred embodiment, compounds of formula I have the stereoconfiguratioin is shown:
“Alkyl” as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. “Alkenyl”, “alkynyl” and other like terms include carbon chains containing at least one unsaturated C—C bond. Examples of alkenyl groups include allyl, homoallyl and the like. Examples of alkynyl groups include propargyl, homopropargyl and the like.
Alkanoyl means alkylcarbonyl in which alkyl is as defined above.
Alkenoyl means alkenylcarbonyl in which alkenyl is as defined above.
The term “cycloalkyl” means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well a
Colletti Steven L.
Fisher Michael H.
Meinke Peter T.
Wyvratt Matthew J.
Higel Floyd D.
Merck & Co. , Inc.
Rose David L.
Shameem Golam M. M.
Yang Mollie M.
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