Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-22
2003-02-25
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S255000
Reexamination Certificate
active
06525079
ABSTRACT:
This invention relates to nitrogen-containing heterocyclic substances having parasiticidal properties, in particular to N-aryl/heteroaryl-substituted heterocycles.
International Patent Application publication number WO98/24767 and European Patent Application publication number EP 0 846 686 A1 disclose certain 1-N-arylpyrazole substances with a 4-cyclopropyl moiety and a 4-heterocyclyl moiety respectively, as having antiparasitic properties.
According to the present invention, there is provided a compound of formula (I),
wherein A is N or CR
5
,
B is Nor CR
6
,
wherein R
5
and R
6
are each independently selected from H, C
1-4
alkyl optionally substituted by one or more halo, CN and halo,
or when A and B are CR
5
and CR
6
, respectively, they can be taken together to form a fused benzo- or pyridino-ring,
which fused ring is optionally substituted by one or two halo substituents and, when the pyridino-fused ring is present, optionally bears an oxide substituent on the nitrogen of said pyridino-ring,
R
1
is a 5-membered heteroaryl group selected from furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl and isoxazol-5-yl, each of which is optionally substituted by one or two substituents independently selected from halo, C
1-4
alkyl optionally substituted by one or more halo, and (C
1-4
alkyl optionally substituted by one or more halo)S(O)
n
, or R
1
is a group of formula (II)
wherein R
7
is H, C
1-4
alkyl optionally substituted by one or more halo, or C
1-4
alkoxy optionally substituted by one or more halo,
R
8
and R
9
are either each independently selected from H, chloro, fluoro, bromo and C
1-4
alkyl optionally substituted by one or more halo, or, when taken together with the carbon atom to which they are attached, form a C
3-6
cycloalkyl group,
R
10
and R
11
are either each independently selected from H, chloro, fluoro, bromo and C
1-4
alkyl optionally substituted by one or more halo, or, when R
8
and R
9
taken together do not form part of a cycloalkyl group, R
10
and R
11
together with the carbon atom to which they are attached, form a C
5-7
cycloalkyl group,
E is N or CR
2
, wherein
R
2
is H, NH
2
, halo, NHCH
2
(phenyl optionally substituted by C
1-4
alkoxy), CO
2
(C
1-4
alkyl optionally substituted by one or more halo) or S(O)
n
(C
1-4
alkyl optionally substituted by one or more halo),
X is N or CR
12
, wherein
R
12
is halo.
R
3
is halo,
R
4
is C
1-4
alkyl optionally substituted by one or more halo, C
1-4
alkoxy optionally substituted by one or more halo, S(O)
n
(C
1-4
alkyl optionally substituted by one or more halo), halo or SF
5
, and
n is 0, 1 or 2,
with the provisos that (i) when B is N, then A and/or E is also N, and (ii) when E is N then A and/or B is also N,
or a pharmaceutically-, agriculturally- or veterinarily-acceptable salt thereof, or solvate of any such compound or salt (hereinafter referred to as “the substances of the invention”).
Alkyl groups may be straight or branched where the number of carbon atoms allows. S(O)
n
alkyl and alkoxy groups incorporate such alkyl moieties. Halo means fluoro, chloro, bromo or iodo.
Pharmaceutically-, agriculturally or veterinarily-acceptable salts are well-known in the art and include, for example those mentioned by Berge et al in
J.Pharm.Sci
., 66, 1-19 (1977). Suitable acid addition salts are formed from acids which form non-toxic salts and include the hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate, bisulphate, phosphate, hydrogenphosphate, acetate, gluconate, lactate, salicylate, citrate, tartrate, ascorbate, succinate, maleate, fumarate, formate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate and p-toluenesulphonate salts.
Solvates (e.g. hydrates) are generally well-known in the art and can be prepared by standard methods.
Preferably the “ABNEC” ring moiety in the compound of formula (I) above is a pyrrol-1-yl, 1,2,3-triazol- 1 -yl, 1,2,4-triazol-1-yl, imidazol-1-yl or indol-1-yl moiety.
Preferably R
5
is H, C
1-4
alkyl optionally substituted by one or more halo, CN, or when B is CR
6
, together with the carbon atom to which it is attached and CR
6
, is a benzo- or pyridino-ring, which benzo- or pyridino-ring is optionally substituted by one or two halo groups, and, when the pyridino-ring is present, oxide on the nitrogen of said pyridino-ring. More preferably R
5
is H, CN, CH
3
or CF
3
, or when B is CR
6
, together with the carbon atom to which it is attached and CR
6
, is a benzo- or pyridino-ring, which benzo- or pyridino-ring is optionally substituted by one or two fluoro groups, and, when the pyridino-ring is present, oxide on the nitrogen of said pyridino-ring. Most preferably R
5
is H, CH
3
or CN.
Preferably R
6
is H, halo, C
1-4
alkyl optionally substituted by one or more halo, or when A is CR
5
, together with the carbon atom to which it is attached and CR
5
, is a benzo- or pyridino-ring, which benzo- or pyridino-ring is optionally substituted by one or two halo groups, and, when the pyridino-ring is present, oxide on the nitrogen of said pyridino-ring. More preferably R
6
is H, halo, CH
3
or CF
3
, or when A is CR
5
, together with the carbon atom to which it is attached and CR
5
, is a benzo- or pyridino-ring, which benzo- or pyridino-ring is optionally substituted by one or two fluoro groups, and, when the pyridino-ring is present, oxide on the nitrogen of said pyridino-ring. Most preferably, R
6
is H, Cl, Br or CH
3
.
Preferably R
1
is a furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl or isoxazol-5-yl group, each optionally substituted by one or two substituents independently selected from halo, C
1-4
alkyl optionally substituted by one or more halo, and (C
1-4
alkyl optionally substituted by one or more halo)S(O)
n
, or R
1
is a group of formula (II)
wherein R
7
is H or C
1-4
alkyl optionally substituted by one or more halo, R
8
and R
9
are each independently selected from H, chloro, fluoro or bromo, and R
10
and R
11
are both H. More preferably R
1
is furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl or isoxazol-5-yl group, each optionally substituted by one or two substituents independently selected from fluoro, chloro, bromo, CF
3
and CH
3
. or R
1
is a group of formula (II)
wherein R
7
is H, CH
3
or CF
3
, R
8
and R
9
are each independently selected from H, chloro, fluoro or bromo, and R
10
and R
11
are both H. Most preferably, R
1
is 3-bromisoxazol-5-yl, 2,2-dibromocyclopropyl, 2,2-dichlorocyclopropyl or 1-trifluoromethylcyclopropyl.
Preferably R
2
is H, NH
2
, halo or NHCH
2
(phenyl optionally substituted by C
1-4
alkoxy). More preferably R
2
is H, NH
2
, F, Cl or Br. Most preferably R
2
is H or NH
2
.
Preferably X is C-F, C-Cl or C-Br. More preferably X is C-Cl.
Preferably R
3
is chloro.
Preferably R
4
is methyl optionally substituted by one or more halo, methoxy optionally substituted by one or more halo, S(O)
n
(methyl optionally substituted by one or more halo), halo or SF
5
. More preferably R
4
is CF
3
, OCF
3
, SCF
3
or SF
5
.
The most preferred substances are those of the Examples below, and the salts and solvates thereof.
The compounds of the formula (I) may possess one or more asymmetric centres and so exist in two or more stereolsomeric forms. The present invention includes all the individual stereolsomers of the compounds of formula (I), salts, solvates and mixtures thereof.
Separation of diastereomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography such as H.P.L.C. of a stereoisomeric mixture of a compound of formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereomeric salts formed by reaction of the corresponding racemate with a suitably optically active acid or base.
The substances provided by the invention can be prepared by adaptation of methods disclosed in the art, spec
Banks Bernard Joseph
Chubb Nathan Anthony Logan
Benson Gregg C.
Munchhof Martha G.
Pfizer Inc.
Richardson Peter C.
Stockton Laura L.
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