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
2001-09-18
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S194000
Reexamination Certificate
active
06291480
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,
n is
0 or 1;
m is
0, 1 or 2;
p is
1 or 2 or 3;
R is
halogen;
R
1
is
(1) hydrogen or
(2) C
1-6
alkyl;
R
2
is
(1) C
3-12
alkyl optionally substituted with 1 to 5 groups selected
from R
a
,
(2) C
1-2
alkyl substituted with 1 to 3 groups selected from R
a
,
(3) C
2-12
alkenyl optionally substituted with 1 to 5 groups selected
from R
a
,
(4) C
2-12
alkynyl optionally substituted with 1 to 5 groups selected
from R
a
,
(5) C
3-7
cycloalkyl-(C
1-6
alkyl)
n
, optionally substituted with 1 to 5
groups selected from R
a
and C
1-6
alkyl,
(6) aryl-(C
1-6
alkyl)
n
wherein aryl is optionally substituted with 1
to 5 groups selected from Rb,
(7) heteroaryl-(C
1-6
alkyl)
n
wherein heteroaryl is optionally
substituted with 1 to 5 groups selected from R
b
,
R
3
is
(1) O or
(2) CH
3
;
R
a
is
(1) halogen,
(2) N
3
,
(3) CN,
(4) NO
2
, or
(5) P(O)(OR
C
)
2
;
R
b
is
(1) a group selected from R
a
,
(2) C
1-6
alkyl optionally substituted with 1 to 6 groups selected
from R
a
, OR
c
, OCOR
c
, NR
c
R
c
, NHCOR
c
, NHSO
2
R
c
,
(3) aryl optionally substituted with 1 to 3 groups selected from R
a
,
OR
c
, OCOR
c
; NR
c
R
c
, NHCOR
c
, NHSO
2
R
c
,
(4) heteroaryl optionally substituted with 1 to 3 groups selected
from R
a
, OR
c
, OCOR
c
, NR
c
R
c
, NHCOR
c
, NHSO
2
R
c
,
(5) C(O)OR
c
,
(6) C(O)R
c
,
(7) S(O)
m
R
c
,
(8) OR
c
,
(9) OC(O)NR
c
R
c
,
(10) OC(O)OR
c
,
(11) OC(O)R
c
,
(12) OSO
2
R
c
(13) NR
c
R
c
,
(14) NR
d
SO
2
R
c
,
(15) NR
d
C(O)OR
c
,
(16) NR
d
C(O)R
c
,
(17) NR
d
C(O)NR
c
R
c
;
R
c
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
c
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-R
d
;
R
d
is
(1) hydrogen or
(2) C
1-6
alkyl.
with the proviso that the following compounds are excluded: 2-(4-fluorophenyl)-5-(1-benzyl-4-piperidinyl)-3-(4-pyridinyl)pyrrole and 2-(4-fluorophenyl)-5-(1-phenyl-4-piperidinyl)-3-(4-pyridinyl)pyrrole.
In one subset of formula I R
2
is C
3-12
alkyl. Preferably R
2
is C
2-6
alkyl, and more preferably ethyl.
In another subset of formula I R
2
is C
3-6
cycloalkyl or C
3-6
cycloalkyl-C
1-3
alkyl wherein said cycloalkyl is optionally substituted with 1 or 2 groups selected from R
a
and C
1-3
alkyl.
In another subset of formula I, R
2
is aryl-C
1-3
alkyl wherein said aryl is substituted with 1 to 3 groups selected from R
b
.
In another subset of formula I, R
2
is heteroaryl-C
1-3
alkyl wherein said heteroaryl is optionally substituted with 1 to 3 groups selected from R
b
.
Compounds of formula Ia represent one embodiment of formula I:
wherein R
2
is C
3-12
alkyl, C
3-6
cycloalkyl or C
3-6
cycloalkyl-C
1-3
alkyl wherein said cycloalkyl is optionally substituted with 1 or 2 groups selected from R
a
and C
1-3
alkyl, aryl-C
1-3
alkyl wherein said aryl is substituted with 1 to 3 groups selected from R
b
, heteroaryl-C
1-3
alkyl wherein said heteroaryl is optionally substituted with 1 to 3 groups selected from R
b
.
In one subset of formula Ia, R
2
is C
3-6
alkyl. Examples of C
3-6
alkyl include n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 2-pentyl, 3,3-dimethylbutyl, 2-hexyl, 4-methyl-2-pentyl, 2-ethylbutyl, 2-methylbutyl, and 2-methylpentyl.
In another subset of formula Ia, R
2
is C
3-6
cycloalkyl or C
3-6
cycloalkyl-C
1-3
alkyl wherein said cycloalkyl is optionally substituted with 1 or 2 groups selected from C
1-3
alkyl; examples include cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, 2-methylcyclopentyl and cyclohexyl.
In another subset of formula Ia, R
2
is substituted benzyl in which the substituents are one or two groups selected from halogen, OR
c
, OC(O)R
c
, OC(O)NR
c
R
c
, OC(O)OR
c
, C
1-3
alkyl optionally substituted with OR
c
, NR
c
R
c
, and cyano. Examples of substituted benzyl include 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 2-chloro-4-hydroxybenzyl, 2,4-dihydroxybenzyl, 4-(N-phenylcarbamoyloxy)benzyl, 4-hydroxy-2-methoxybenzyl, 4-acetoxybenzyl, 4-(propanoyloxy)benzyl, 4-(2-hydroxyethyl)benzyl, 4-(3-(N,N-dimethylamino)propyl)-benzyl, 3-ethoxy-4-methoxybenzyl, 3-ethoxy-4-hydroxybenzyl, 2-methylbenzyl, 2-cyanobenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-trifluoromethoxy-benzyl, 2-difluoromethoxybenzyl, 3-bromo-4-fluorobenzyl, 4-methylbenzyl, 4-nitro-benzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl and 3,4-difluoro-benzyl.
In another subset of formula Ia, R
2
is heteroaryl-methyl wherein said heteroaryl is optionally substituted with 1 or 2 groups selected from S(O)
m
R
c
, C
1-6
alkyl optionally substituted with hydroxy, and halogen. Examples of heteroaryl portion of the heteroaryl include 5-(methylthio)-2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-quinolinyl, 2-quinolinyl, 6-methyl-2-pyridyl, 2-methyl-4-thiazolyl, 5-t-butyl-1,2,4-oxadiazol-3-yl, 2-pyrimidinyl, 2-thiazolyl, 5-methyl-2-thienyl, 2-imidazolyl, 1-methyl-2-pyrrolyl, 2-furyl, 4-methyl-5-imidazolyl, 3-thienyl, 5-methyl-2-furyl, 5-(hydroxymethyl)-2-furyl, 3-methyl-2-thienyl, 3-methyl-2-pyrrolyl, 2-thiazolyl, 5-ethyl-2-thiazolyl, 2-methyl-3-pyridyl and 4-imidazolyl.
As used herein, unless otherwise defined or limited, the following definitions apply:
“Alkyl” includes straight or branched carbon chains of the designated length. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
“Alkenyl” includes straight and branched carbon chains of the designated length having at least one carbon-
Biftu Tesfaye
Feng Danqing Dennis
Fisher Michael H.
Liang Gui-Bai
Ponpipom Mitree M.
Davis Zinna Northington
Merck & Co. , Inc.
Rose David L.
Yang Mollie M.
LandOfFree
Diaryl piperidyl pyrrole derivatives as antiprotozoal agents does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Diaryl piperidyl pyrrole derivatives as antiprotozoal agents, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Diaryl piperidyl pyrrole derivatives as antiprotozoal agents will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2518413