Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-10
2003-03-04
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S326000, C514S327000, C514S352000, C514S354000, C546S194000, C546S208000, C546S210000, C546S223000
Reexamination Certificate
active
06528531
ABSTRACT:
BACKGROUND OF THE INVENTION
Parasitic protozoa are responsible for a wide variety of infections in man and animals. Many of the diseases are life threatening to the host and cause considerable economic loss in animal husbandry. For example, malaria remains a significant health threat to humans despite massive international attempts to eradicate the disease; trypanosomiasis such as Chagas disease caused by
Trypanosoma cruzi
and African sleeping sickness caused by
T. brucei
are not uncommon in Africa and South America; and opportunistic infections in immunocompromised hosts caused by
Pneumocystis carinii, Toxoplasma gondii
, Cryptosporidium sp. are becoming increasingly significant in the developed countries.
A protozoal infection of great economic importance is coccidiosis, a widespread disease of domesticated animals produced by infections by protozoa of the genus Eimeria. Some of the most significant of Eimeria species are those in poultry namely
E. tenella, E. acervulina, E. necatrix, E. brunetti
and
E. maxima
. The disease is responsible for high levels of morbidity and mortality in poultry and can result in extreme economic losses.
In some protozoal diseases, such as Chagas disease, there is no satisfactory treatment; in others, drug-resistant strains of the protozoa may develop. Accordingly, there exists a continued need to identify new and effective anti-protozoal drugs.
U.S. Pat. No. 5,792,778 discloses compounds of the formula:
in which HAr may be 4-pyridyl, Ar may be 4-fluorophenyl, R
2
may be substituted 4-piperidyl and R
3
may be hydrogen.
SUMMARY OF THE INVENTION
The instant invention is concerned with diarylpyrrole derivatives which are useful as antiprotozoal agents. Thus, it is an object of this invention to describe such compounds. It is a further object to describe processes for the preparation of such compounds. Another object is to describe methods and compositions which use the compounds as the active ingredient thereof. Further objects will become apparent from reading the following description.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of formula I:
or a physiologically acceptable salt thereof,
wherein
n is 0 or 1;
m is 0, 1 or 2;
p is 1, 2 or 3;
X is
(1) a bond,
(2) (CR
a
R
a
)
p
,
(3) C
3-7
cycloalkylene, or
(4) C
3-7
cycloalkylidene;
R is halogen;
R
1
is
(1) hydrogen or
(2) C
1-6
alkyl;
R
2
and R
3
are independently selected from
(1) hydrogen,
(2) C
1-6
alkyl optionally substituted with OR
b
,
(3) C
2-6
alkenyl,
(4) C
2-6
alkynyl,
(4) phenyl optionally substitued with OR
b
,
(5) benzyl optionally substitued with OR
b
,
(6) CO
2
R
b
; or
R
2
+R
3
represent ═O; or
when X is a bond or (CR
a
R
a
)
p
, R
2
and R
4
together complete a 4- to 7-membered non-aromatic ring containing 1 or 2 heteroatoms independently selected from O and S(O)
m
, and said ring being optionally substituted with 1 to 5 groups independently selected from oxo, OR
b
, CH
2
OR
b
, CH
2
OC(O)R
b
and C
1-6
alkyl; or
when X is a bond or (CR
a
R
a
)
p
, R
2
and R
5
together complete a 4- to 7-membered non-aromatic ring containing 0 to 2 heteroatoms independently selected from O and S(O)
m
, said ring being optionally substituted with 1 to 5 groups independently selected from oxo, OR
b
, CH
2
OR
b
, CH
2
OC(O)R
b
and C
1-6
alkyl;
R
4
is
(1) OR
b
,
(2) OC(O)R
b
,
(3) OC(O)OR
b
,
(4) OC(O)(CH
2
)
m
NR
b
R
b
,
(5) OSO
2
R
b
,
(6) S(O)
m
R
b
(7) OP(O)(OR
b
)
2
, or
(8) CO
2
R
b
; or
R
4
+R
6
represent ═O; or
R
4
, R
5
and the carbon atoms to which they are attached form a 3- to 7-membered non-aromatic ring containing 1 or 2 heteroatoms independently selected from O or S(O)
m
, said ring being optionally substituted with 1 to 5 groups independently selected from oxo, OR
b
, CH
2
OR
b
, CH
2
OC(O)R
b
and C
1-6
alkyl; or
R
5
and R
6
are independently selected from
(1) hydrogen,
(2) C
1-12
alkyl,
(3) C
2-12
alkenyl,
(4) C
2-12
alkynyl,
(5) C
3-7
cycloalkyl-(C
1-6
alkyl)
n
,
(6) mono-, bi- or tricyclic heterocyclyl-(C
1-6
alkyl)
n
, wherein said heterocyclyl contains 3 to 12 ring atoms 1 to 4 of which are independently selected from O and S(O)
m
,
(7) aryl-(C
1-6
alkyl)
n
,
(8) heteroaryl-(C
1-6
alkyl)
n
,
(9) CO
2
R
b
, or
(10) OR
b
,
wherein alkyl, alkenyl and alkynyl are optionally substituted with 1 to 5 groups independently selected from R
c
, cycloalkyl and heterocyclyl are optionally substituted with 1 to 5 groups independently selected from R
c
, alkyl, and spirofused C
3-6
cycloalkylidene, and aryl and heteroaryl are optionally substituted with 1 to 3 groups independently selected from R
d
, or
R
5
, R
6
and the carbon atoms to which they are attached form a 3- to 7-membered non-aromatic ring containing 0 to 2 heteroatoms independently selected from O and S(O)
m
, optionally substituted with 1 to 5 groups independently selected from oxo, OR
b
, CH
2
OR
b
, CH
2
OC(O)R
b
and C
1-6
alkyl; or
when X is (CR
a
R
a
)
p
, R
5
and any one of the R
a
may together complete a 3- to 7-membered non-aromatic carbocyclic ring;
R
7
is
(1) O or
(2) methyl;
R
a
is
(1) hydrogen, or
(2) C
1-6
alkyl, or
R
b
is
(1) hydrogen,
(2) C
1-12
alkyl
(3) C
2-12
alkenyl,
(4) C
2-12
alkynyl,
(5) C
3-7
cycloalkyl-(C
1-6
alkyl)
n
,
(6) heterocyclyl-(C
1-6
alkyl)
n
,
(7) aryl-(C
1-6
alkyl)
n
, or
(8) heteroaryl-(C
1-6
alkyl)
n
,
wherein alkyl, cycloalkyl, heterocyclyl, alkenyl and alkynyl are optionally substituted with up to 5 groups independently selected from R
c
, and aryl and heteroaryl are optionally substituted with up to 3 groups independently selected from R
d
, or two R
b
groups attached to the same nitrogen atom together complete a 4- to 7-membered ring optionally containing an additional heteroatom selected from O, S and N—Rf;
R
c
is
(1) halogen,
(2) S(O)
m
R
e
,
(3) OR
e
,
(4) OC(O)NR
e
R
e
,
(5) OC(O)OR
e
,
(6) OC(O)R
e
,
(7) OSO
2
R
e
(8) OCF
3
,
(9) CF
3
,
(10) C(O)OR
e
(11) C(O)R
e
(12) oxo,
(13) N
3
,
(14) CN,
(15) NO
2
, or
(16) P(O)(OR
e
)
2
;
R
d
is
(1) a group selected from R
c
,
(2) C
1-6
alkyl optionally substituted with 1 to 6 groups selected from R
c
,
(3) aryl optionally substituted with 1 to 3 groups selected from R
c
,
(4) heteroaryl optionally substituted with 1 to 3 groups selected from R
c
,
(5) NR
e
R
e
,
(6) NR
f
SO
2
R
e
,
(7) NR
f
C(O)OR
e
,
(8) NR
f
C(O)R
e
,
(9) NR
f
C(O)NR
e
R
e
;
R
e
is
(1) hydrogen,
(2) C
1-2
alkyl optionally substituted with 1 to 5 groups selected from halogen, CN, OH and C
1-10
alkoxy optionally substituted with oxiranyl, hydroxy or C
1-6
alkyl,
(3) C
2-12
alkenyl,
(4) C
2-12
alkynyl,
(5) C
3-7
cycloalkyl-(C
1-6
alkyl)
n
,
(6) aryl(C
1-6
alkyl)
n
optionally substituted with NO
2
, C
1-6
alkyl, C
1-6
alkoxy, or halogen,
(7) heteroaryl(C
1-6
alkyl)
n
, or
two R
e
groups together with the nitrogen atom to which they are attached form a 3- to 7-membered ring optionally containing an additional heteroatom selected from O, S and N—Rf;
R
f
is
(1) hydrogen or
(2) C
1-6
alkyl.
In one subset of compouds of formula I R is 4-fluoro.
In another subset of compounds of formula I R
1
is hydrogen.
In another subset of compounds of formula I n of (R
7
)
n
is 0.
In another subset of compouds of formula I R
3
is hydrogen, and R
2
is hydrogen, methyl, hydroxy methyl, C
1-3
alkoxy methyl, phenyl, or C
1-3
alkoxyphenyl; or when X is a bond or (CR
a
R
a
)
p
, R
2
and R
4
together complete a 4- to 7-membered non-aromatic ring containing 1 or 2 heteroatoms independently selected from O and S(O)
m
, and said ring being optionally substituted with 1 to 5 groups independently selected from oxo, OR
b
, CH
2
OR
b
, and C
1-6
alkyl; or when X is a bond or (CR
a
R
a
)
p
, R
2
and R
5
together complete a 4- to 7-membered non-aromatic ring containing 0 to 2 heteroatoms independently selected from O and S(O)
m
, said ring being optionally substituted with 1 to 5 groups independently selected from oxo, OR
b
, CH
2
OR
b
, and C
1-6
alkyl.
In another subset of compounds of formula I X is a bond, (CR
a
R
a
)
p
wherein p is 1 or 2, or C
3-6
cycloalkylene. Examples of X being (CR
a
R
a
)
p
incl
Bitfu Tesfaye
Bugianesi Robert L.
Feng Danqing D.
Fisher Michael H.
Liang Gui-Bai
Covington Raymond
Merck & Co. , Inc.
Rose David L.
Rotman Alan L.
Yang Mollie M.
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