U.S. patent application number 13/574900 was filed with the patent office on 2012-11-22 for spiroindoline compounds for use as anthelminthics.
Invention is credited to Christophe Pierre Alain Chassaing, Anja Regina Heckeroth, Sandra Koch, Jurgen Lutz, Ulrich Sonderin, Manfred Uphoff, Britta von Oepen.
Application Number | 20120295931 13/574900 |
Document ID | / |
Family ID | 42062539 |
Filed Date | 2012-11-22 |
United States Patent
Application |
20120295931 |
Kind Code |
A1 |
Lutz; Jurgen ; et
al. |
November 22, 2012 |
SPIROINDOLINE COMPOUNDS FOR USE AS ANTHELMINTHICS
Abstract
This invention relates to spiroindoline compounds for the
treatment of helminth infections and the treatment of parasitosis,
such as caused by helminth infections. This invention also relates
to uses of the compounds to make medicaments and treatments
comprising the administration of the compounds to animals in need
of the treatments. Moreover this invention relates to
pharmaceutical compositions and kits comprising the compounds.
Inventors: |
Lutz; Jurgen; (Schwabenheim,
DE) ; Koch; Sandra; (Schwabenhein, DE) ;
Uphoff; Manfred; (Schwanbenhein, DE) ; Heckeroth;
Anja Regina; (Schwabenhein, DE) ; von Oepen;
Britta; (Schwabenhein, DE) ; Sonderin; Ulrich;
(Schwabenhein, DE) ; Chassaing; Christophe Pierre
Alain; (Schwabenhein, DE) |
Family ID: |
42062539 |
Appl. No.: |
13/574900 |
Filed: |
February 4, 2011 |
PCT Filed: |
February 4, 2011 |
PCT NO: |
PCT/EP2011/051639 |
371 Date: |
July 24, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61302312 |
Feb 8, 2010 |
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Current U.S.
Class: |
514/278 ;
546/17 |
Current CPC
Class: |
C07D 471/10 20130101;
A61K 45/06 20130101; A61K 31/444 20130101; A61K 31/438 20130101;
A61P 33/00 20180101; Y02A 50/423 20180101; Y02A 50/30 20180101;
A61P 33/10 20180101 |
Class at
Publication: |
514/278 ;
546/17 |
International
Class: |
A61K 31/438 20060101
A61K031/438; A61P 33/00 20060101 A61P033/00; C07D 471/10 20060101
C07D471/10 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 5, 2010 |
EP |
10152817.2 |
Claims
1. A pharmaceutical composition comprising a) one or more compounds
of the formula (I) and pharmaceutically acceptable solvates,
N-oxides and salts thereof, ##STR00011## wherein Y=O, S;
Q=--CH.sub.2--CH(CH.sub.3)--, --CH.sub.2--CH.sub.2--O,
--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.dbd.CH--, --CH.sub.2--CH.sub.2--CH.sub.2--;
R.sup.1=H, F, Cl, CH.sub.3, OCH.sub.3, CF.sub.3; R.sup.2=H, F, Cl,
CH.sub.3, OCH.sub.3, CF.sub.3; A.sup.1=H, halogen,
C.sub.1-C.sub.4-alkyl; A.sup.2=H, halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylthio, wherein
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy and
C.sub.1-C.sub.4-alkylthio are optionally perfluorinated; A.sup.3=H,
halogen, C.sub.1-C.sub.4-alkyl; A.sup.4=H, halogen,
C.sub.1-C.sub.4-alkyl; B.sup.1=H, F, Cl, CH.sub.3, CF.sub.3;
B.sup.2=H, F, Cl, CH.sub.3, CF.sub.3, NO.sub.2; B.sup.3=H, F, Cl,
CH.sub.3, CF.sub.3, CN, OCH.sub.3, OCF.sub.3; B.sup.4=H, F, Cl,
CH.sub.3, CF.sub.3; B.sup.5=H, F, Cl, CH.sub.3, CF.sub.3.sup.-; and
b) one or more pharmaceutically acceptable excipients, and/or one
or more pharmaceutically acceptable active ingredients which differ
in structure from component a).
2. The pharmaceutical composition according to claim 1, wherein in
formula (I) Y=O, S; Q=--CH.sub.2--CH(CH.sub.3)--,
--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.dbd.CH--, --CH.sub.2--CH.sub.2--CH.sub.2--;
preferably --CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.dbd.CH--; R.sup.1=H, F, Cl, CH.sub.3, OCH.sub.3,
CF.sub.3; R.sup.2=H, F, Cl, CH.sub.3, OCH.sub.3, CF.sub.3;
A.sup.1=H, halogen, C.sub.1-C.sub.4-alkyl; A.sup.2=H, halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio, wherein C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-alkylthio are optionally
perfluorinated; A.sup.3=H, halogen, C.sub.1-C.sub.4-alkyl;
A.sup.4=H, halogen, C.sub.1-C.sub.4-alkyl; B.sup.1=H, F, Cl,
CH.sub.3, CF.sub.3; B.sup.2=H, F, Cl, CH.sub.3, CF.sub.3, NO.sub.2;
B.sup.3=H, F, Cl, CH.sub.3, CF.sub.3, CN, OCH.sub.3, OCF.sub.3;
B.sup.4=H, F, Cl, CH.sub.3, CF.sub.3; B.sup.5=H, F, Cl, CH.sub.3,
CF.sub.3.
3. The pharmaceutical composition according to claim 1, wherein in
formula (I), Y=O, S, preferably O; Q=--CH.sub.2--CH.dbd.CH--;
R.sup.1=H, F, Cl, CH.sub.3, OCH.sub.3, CF.sub.3; R.sup.2=H, F, Cl,
CH.sub.3, OCH.sub.3, CF.sub.3; A.sup.1=H, Cl; A.sup.2=H, F, Cl, Br,
CH.sub.3, OCH.sub.3, OCF.sub.3, CF.sub.3, SCF.sub.3; A.sup.3=H, Cl;
A.sup.4=H, Cl; B.sup.1=H, F, Cl, CH.sub.3, CF.sub.3; B.sup.2=H, F,
Cl, CH.sub.3, CF.sub.3; B.sup.3=H, F, Cl, CH.sub.3, CF.sub.3, CN,
OCH.sub.3, OCF.sub.3; B.sup.4=H, F, Cl, CH.sub.3, CF.sub.3;
B.sup.5=H, F, Cl, CH.sub.3, CF.sub.3.
4. The pharmaceutical composition according to claim 1 wherein in
formula (I) a) at least one of the radicals R.sup.1, R.sup.2,
A.sup.1, A.sup.2, A.sup.3, A.sup.4, B.sup.1, B.sup.2, B.sup.3,
B.sup.4, B.sup.5 is different from hydrogen, or b) at least one of
the radicals R.sup.1, R.sup.2, A.sup.1, A.sup.2, A.sup.3, A.sup.4
is different from hydrogen, or c) at least one of the radicals
R.sup.1, R.sup.2, B.sup.1, B.sup.2, B.sup.3, B.sup.4, B.sup.5 is
different from hydrogen, or d) at least one of the radicals
A.sup.1, A.sup.2, A.sup.3, A.sup.4, B.sup.1, B.sup.2, B.sup.3,
B.sup.4, B.sup.5 is different from hydrogen, or e) at least one of
the radicals R.sup.1, R.sup.2 is different from hydrogen, or f) at
least one of the radicals A.sup.1, A.sup.2, A.sup.3, A.sup.4 is
different from hydrogen, or g) at least one of the radicals
B.sup.1, B.sup.2, B.sup.3, B.sup.4, B.sup.5 is different from
hydrogen, or h) at least two of the radicals R.sup.1, R.sup.2,
A.sup.1, A.sup.2, A.sup.3, A.sup.4, B.sup.1, B.sup.2, B.sup.3,
B.sup.4, B.sup.5 are different from hydrogen, or i) at least one of
the radicals R.sup.1, R.sup.2, A.sup.1, A.sup.2, A.sup.3, A.sup.4,
B.sup.1, B.sup.2, B.sup.3, B.sup.4, B.sup.5 is F or Cl.
5. A method of treating a parasitic infection in an animal
comprising administering to the animal the pharmaceutical
composition of claim 1.
6. The method according to claim 5, wherein the parasitic infection
is a helminth infection.
7. The method according to claim 5, wherein the pharmaceutical
composition is administered orally.
8. The method according to claim 5, wherein the pharmaceutical
composition is administered parenterally.
9. A compound selected from the group consisting of ##STR00012##
##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017##
##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022##
##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027##
##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032##
##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037##
##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042##
##STR00043## ##STR00044## and pharmaceutically acceptable solvates,
N-oxides and salts thereof.
10. A pharmaceutical composition, wherein the composition
comprises: a) one or more compounds as defined in claim 9, and b)
one or more pharmaceutically acceptable excipients, and/or one or
more pharmaceutically acceptable active ingredients which differ in
structure from component a).
11. A method of treating a parasite infection in an animal,
comprising administering to the animal a pharmaceutical composition
as defined in claim 10.
12. The method of claim 11, wherein the parasite infection is a
helminth infection.
13. The method of claim 12, wherein the helminth infection is a
nematode infection.
14. A kit, wherein the kit comprises: a) one or more compounds as
defined in claim 1, and b) one or more other components selected
from the group consisting of an excipient, an active ingredient, an
apparatus for combining the compound of component a) with an
excipient and/or active ingredient, an apparatus for administering
the compound of component a) to an animal, and a diagnostic
tool.
15-16. (canceled)
17. The method as claimed in claim 11, wherein one or more of the
parasites are resistant to one or more antiparasitic compounds.
18. The method of claim 11, wherein the animal is a non-human
mammal.
19. The method of claim 5, wherein the animal is a non-human
mammal.
20. The method of claim 5, wherein one or more of the parasites are
resistant to one or more antiparasitic compounds.
21. The method of claim 6, wherein the helminth infection is a
nematode infection.
22. The method of claim 11, wherein the pharmaceutical composition
is administered orally.
23. The method of claim 11, wherein the pharmaceutical composition
is administered parenterally.
Description
FIELD OF THE INVENTION
[0001] This invention relates to certain spiroindoline compounds
that are useful as medicaments, more specifically as medicaments
for non-human animals. The medicament can preferably be used for
the treatment of parasitic infections such as helminth infections
and especially for the treatment of parasitoses, such as caused by
helminth infections. This invention also relates to uses of the
compounds to make medicaments and treatments comprising the
administration of the compounds to animals in need of the
treatments. This invention also relates to novel spiroindoline
compounds and the preparation of said compounds. Moreover this
invention relates to pharmaceutical compositions and kits
comprising the compounds.
BACKGROUND OF THE INVENTION
[0002] Parasitic diseases in animals cause substantial suffering
and economic losses throughout the world. Thus, treatment of
parasitic infections remains an important global endeavor. The
causative organisms include helminths, such as nematodes, cestodes,
and trematodes. These organisms can infect, for example, the
stomach, intestinal tract, lymphatic system, muscle tissues,
kidney, liver, lungs, heart, and brain of animals.
[0003] There are many known drugs (or"anthelmintic agents")
available to treat various helminith parasite infections, see,
e.g., McKellar, Q. A., et al., "Veterinary anthelmintics: old and
new," Review: Trends in Parasitology, 20(10), 456-61 (October
2004). These anthelmintic agents treat specifically either nematode
or trematode infections or have a broader anthelmintic spectrum. An
example of an anthelmintic agent with sole effect on cestodes
(tapeworms) is praziquantel. Some primary nematicidal compounds
like fenbendazole, mebendazole, oxfendazole, albendazole have a
broader spectrum than nematodes and treat cestode infections as
well. Closantel, rafoxanide and triclabendazole are examples of
specific compounds for the treatment of trematode infections
(flukes).
[0004] While many parasitic infections can be treated with known
drugs, evolutionary development of resistance by the parasites can
render such drugs obsolete over time, see, e.g., Jabbar, A., et
al., "Anthelmintic resistance: the state of play revisited," Life
Sciences, 79, 2413-31 (2006). In addition, known drugs may have
other deficiencies, such as limited spectrum of activity and the
need for repeated treatments.
[0005] In WO 94/29309 and WO 98/28297 spiro-substituted azacyclic
compounds are disclosed which are useful as neurokinin antagonists.
In WO 98/25605 and WO 99/64002 spiro-substituted azacyclic
compounds are disclosed which are useful as modulators of
chemokinine receptor activity and melanocortin receptor agonists
respectively. In WO 03/106457 A1 spiroindoline derivatives with
insecticidal properties are disclosed.
[0006] There still exists a need for new medicaments, such as
antiparasitic agents to ensure safe, effective, and convenient
treatment of a wide range of parasitic helminth infections over a
long period of time.
SUMMARY OF THE INVENTION
[0007] Surprisingly it has been found that certain spiroindoline
compounds can be used as medicaments, especially as antiparasitic
agents such as anthelmintic agents.
[0008] Briefly, this invention relates to compounds that can
generally be used as a medicament for animals. The compounds
correspond in structure to formula (I)
##STR00001##
[0009] , wherein [0010] Y=O, S; [0011]
Q=--CH.sub.2--CH(CH.sub.3)--, --CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.dbd.CH--, --CH.sub.2--CH.sub.2--CH.sub.2--; [0012]
R.sup.1=H, F, Cl, CH.sub.3, OCH.sub.3, OF.sub.3; [0013] R.sup.2=H,
F, Cl, CH.sub.3, OCH.sub.3, OF.sub.3; [0014] A.sup.1=H, halogen,
C.sub.1-C.sub.4-alkyl; [0015] A.sup.2=H, halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio, wherein C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-alkylthio are optionally
perfluorinated such as CF.sub.3, OCF.sub.3, SCF.sub.3; [0016]
A.sup.3=H, halogen, C.sub.1-C.sub.4-alkyl; [0017] A.sup.4=H,
halogen, C.sub.1-C.sub.4-alkyl; [0018] B.sup.1=H, F, Cl, CH.sub.3,
CF.sub.3; [0019] B.sup.2=H, F, Cl, CH.sub.3, CF.sub.3, NO.sub.2;
[0020] B.sup.3=H, F, Cl, CH.sub.3, CF.sub.3, CN, OCH.sub.3,
OCF.sub.3; [0021] B.sup.4=H, F, Cl, CH.sub.3, CF.sub.3; [0022]
B.sup.5=H, F, Cl, CH.sub.3, CF.sub.3.
[0023] The compounds of the formula (I) and pharmaceutically
acceptable solvates, N-oxides and salts thereof are hereinafter
together referred to as "compound(s) according to this
invention".
[0024] This invention is directed, in part, to a compound of the
formula (I) and pharmaceutically acceptable solvates, N-oxides and
salts thereof, for use as a medicament, preferably a medicament for
animals, e.g. for treating parasitic infections such as helminth
infections in animals. This invention also is directed, in part, to
using at least one compound of the formula (I) and pharmaceutically
acceptable solvates, N-oxides and salts thereof to prepare a
medicament for treating an infection including diseases caused by
such infections (e.g., parasitoses caused by a helminth infection)
in animals.
[0025] This invention also is directed, in part, to novel
spiroindoline compounds, methods for making the compounds, and
intermediates thereof. The preferred embodiments specified in this
description for the compounds represent likewise preferred
embodiments for the intermediates.
[0026] This invention also is directed, in part, to pharmaceutical
compositions. The pharmaceutical compositions comprise a) at least
one spiroindoline compound according to this invention, preferably
a novel spiroindoline compound, and b) at least one excipient,
and/or at least one active compound (preferably anthelmintic
compound) which differs in structure from the component a).
[0027] This invention also is directed, in part, to methods for
treating a parasitic infection in animals, particularly a treatment
of parasitoses caused by a helminth infection. The methods comprise
administering at least one compound according to this invention to
the animal.
[0028] This invention also is directed, in part, to a kit. The kit
comprises at least one spiroindoline compound according to this
invention, preferably a novel spiroindoline compound. In addition,
the kit comprises at least one other component, such as another
ingredient (e.g., an excipient or active ingredient), and/or an
apparatus for combining the compound with another ingredient,
and/or an apparatus for administering the compound, and/or a
diagnostic tool.
[0029] Further benefits of Applicants' invention will be apparent
to one skilled in the art from reading this specification.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0030] Compounds According to this Invention
[0031] The invention relates to compounds of formula (I) and
pharmaceutically acceptable solvates, N-oxides and salts thereof
for use as a medicament. The compounds generally correspond in
structure to formula (I)
##STR00002##
[0032] , wherein [0033] Y=O, S; [0034]
Q=--CH.sub.2--CH(CH.sub.3)--, --CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.dbd.CH--, --CH.sub.2--CH.sub.2--CH.sub.2--; [0035]
R.sup.1=H, F, Cl, CH.sub.3, OCH.sub.3, CF.sub.3; [0036] R.sup.2=H,
F, Cl, CH.sub.3, OCH.sub.3, CF.sub.3; [0037] A.sup.1=H, halogen,
C.sub.1-C.sub.4-alkyl; [0038] A.sup.2=H, halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio, wherein C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-alkylthio are optionally
perfluorinated such as CF.sub.3, OCF.sub.3, SCF.sub.3; [0039]
A.sup.3=H, halogen, C.sub.1-C.sub.4-alkyl; [0040] A.sup.4=H,
halogen, C.sub.1-C.sub.4-alkyl; [0041] B.sup.1=H, F, Cl, CH.sub.3,
CF.sub.3; [0042] B.sup.2=H, F, Cl, CH.sub.3, CF.sub.3, NO.sub.2;
[0043] B.sup.3=H, F, Cl, CH.sub.3, CF.sub.3, CN, OCH.sub.3,
OCF.sub.3; [0044] B.sup.4=H, F, Cl, CH.sub.3, CF.sub.3; [0045]
B.sup.5=H, F, Cl, CH.sub.3, CF.sub.3.
[0046] In a preferred compound of formula (I) [0047] Y=O, S,
preferably O; [0048] Q=--CH.sub.2--CH(CH.sub.3)--,
--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.dbd.CH--, --CH.sub.2--CH.sub.2--CH.sub.2--,
preferably --CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.dbd.CH--, more preferably --CH.sub.2--CH.dbd.CH--;
[0049] R.sup.1=H, F, Cl, CH.sub.3, OCH.sub.3, CF.sub.3; [0050]
R.sup.2=H, F, Cl, CH.sub.3, OCH.sub.3, CF.sub.3; [0051] A.sup.1=H,
halogen, C.sub.1-C.sub.4-alkyl; [0052] A.sup.2=H, halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-alkylthio, wherein C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-alkylthio are optionally
perfluorinated such as CF.sub.3, OCF.sub.3, SCF.sub.3; [0053]
A.sup.3=H, halogen, C.sub.1-C.sub.4-alkyl; [0054] A.sup.4=H,
halogen, C.sub.1-C.sub.4-alkyl; [0055] B.sup.1=H, F, Cl, CH.sub.3,
CF.sub.3; [0056] B.sup.2=H, F, Cl, CH.sub.3, CF.sub.3, NO.sub.2;
[0057] B.sup.3=H, F, Cl, CH.sub.3, CF.sub.3, CN, OCH.sub.3,
OCF.sub.3; [0058] B.sup.4=H, F, Cl, CH.sub.3, CF.sub.3; [0059]
B.sup.5=H, F, Cl, CH.sub.3, CF.sub.3.
[0060] In a more preferred compound of formula (I), [0061] Y=O, S,
preferably O; [0062] Q=--CH.sub.2--CH.dbd.CH--; [0063] R.sup.1=H,
F, Cl, CH.sub.3, OCH.sub.3, CF.sub.3; [0064] R.sup.2=H, F, Cl,
CH.sub.3, OCH.sub.3, CF.sub.3; [0065] A.sup.1=H, Cl; [0066]
A.sup.2=H, F, Cl, Br, CH.sub.3, OCH.sub.3, OCF.sub.3, CF.sub.3,
SCF.sub.3; [0067] A.sup.3=H, Cl; [0068] A.sup.4=H, Cl; [0069]
B.sup.1=H, F, Cl, CH.sub.3, CF.sub.3; [0070] B.sup.2=H, F, Cl,
CH.sub.3, CF.sub.3; [0071] B.sup.3=H, F, Cl, CH.sub.3, CF.sub.3,
CN, OCH.sub.3, OCF.sub.3; [0072] B.sup.4=H, F, Cl, CH.sub.3,
CF.sub.3; [0073] B.sup.5=H, F, Cl, CH.sub.3, CF.sub.3.
[0074] In another preferred compound of formula (I), [0075] Y=O, S;
[0076] Q=--CH.sub.2--CH(CH.sub.3)--, --CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.dbd.CH--, --CH.sub.2--CH.sub.2--CH.sub.2--; [0077]
R.sup.1=H, F, Cl, CH.sub.3, OCH.sub.3, CF.sub.3; [0078] R.sup.2=H,
F, Cl, CH.sub.3, OCH.sub.3, CF.sub.3; [0079] A.sup.1=H, halogen,
C.sub.1-C.sub.4-alkyl; [0080] A.sup.2=H, halogen,
C.sub.1-C.sub.4-alkyl, OCF.sub.3, SCF.sub.3, CF.sub.3; [0081]
A.sup.3=H, halogen, C.sub.1-C.sub.4-alkyl; [0082] A.sup.4=H,
halogen, C.sub.1-C.sub.4-alkyl; [0083] B.sup.1=H, F, Cl, CH.sub.3,
CF.sub.3; [0084] B.sup.2=H, F, Cl, CH.sub.3, CF.sub.3; [0085]
B.sup.3=H, F, Cl, CH.sub.3, CF.sub.3, CN; [0086] B.sup.4=H, F, Cl,
CH.sub.3, CF.sub.3; [0087] B.sup.5=H, F, Cl, CH.sub.3,
CF.sub.3.
[0088] In another preferred compound of formula (I) [0089] Y=O, S,
preferably O; [0090] Q=--CH.sub.2--CH(CH.sub.3)--,
--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--,
CH.sub.2--CH.dbd.CH--, --CH.sub.2--CH.sub.2--CH.sub.2--, preferably
--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.dbd.CH--, more preferably --CH.sub.2--CH.dbd.CH--;
[0091] R.sup.1=H, F, Cl, CH.sub.3, OCH.sub.3, CF.sub.3; [0092]
R.sup.2=H, F, Cl, CH.sub.3, OCH.sub.3, CF.sub.3; [0093] A.sup.1=H,
halogen, C.sub.1-C.sub.4-alkyl; [0094] A.sup.2=H, halogen,
C.sub.1-C.sub.4-alkyl, OCF.sub.3, SCF.sub.3, CF.sub.3; [0095]
A.sup.3=H, halogen, C.sub.1-C.sub.4-alkyl; [0096] A.sup.4=H,
halogen, C.sub.1-C.sub.4-alkyl; [0097] B.sup.1=H, F, Cl, CH.sub.3,
CF.sub.3; [0098] B.sup.2=H, F, Cl, CH.sub.3, CF.sub.3; [0099]
B.sup.3=H, F, Cl, CH.sub.3, CF.sub.3, CN; [0100] B.sup.4=H, F, Cl,
CH.sub.3, CF.sub.3; [0101] B.sup.5=H, F, Cl, CH.sub.3,
CF.sub.3.
[0102] In still another preferred compound of formula (I), [0103]
Y=O, S, preferably O; [0104] Q=--CH.sub.2--CH.dbd.CH--; [0105]
R.sup.1=H, F, Cl, CH.sub.3, OCH.sub.3, CF.sub.3; [0106] R.sup.2=H,
F, Cl, CH.sub.3, OCH.sub.3, CF.sub.3; [0107] A.sup.1=H, Cl; [0108]
A.sup.2=H, F, Cl, Br, OCF.sub.3, CF.sub.3; [0109] A.sup.3=H, Cl;
[0110] A.sup.4=H, Cl; [0111] B.sup.1=H, F, Cl, CH.sub.3, CF.sub.3;
[0112] B.sup.2=H, F, Cl, CH.sub.3, CF.sub.3; [0113] B.sup.3=H, F,
Cl, CH.sub.3, CF.sub.3, CN; [0114] B.sup.4=H, F, Cl, CH.sub.3,
CF.sub.3; [0115] B.sup.5=H, F, Cl, CH.sub.3, CF.sub.3.
[0116] In some preferred compounds of formula (I) at least one of
the radicals R.sup.1, R.sup.2, A.sup.1, A.sup.2, A.sup.3, A.sup.4,
B.sup.1, B.sup.2, B.sup.3, B.sup.4, B.sup.5 is different from
hydrogen.
[0117] In other preferred compounds of formula (I) at least one of
the radicals R.sup.1, R.sup.2, A.sup.1, A.sup.2, A.sup.3, A.sup.4
is different from hydrogen.
[0118] In other preferred compounds of formula (I) at least one of
the radicals R.sup.1, R.sup.2, B.sup.1, B.sup.2, B.sup.3, B.sup.4,
B.sup.5 is different from hydrogen.
[0119] In other preferred compounds of formula (I) at least one of
the radicals A.sup.1, A.sup.2, A.sup.3, A.sup.4, B.sup.1, B.sup.2,
B.sup.3, B.sup.4, B.sup.5 is different from hydrogen.
[0120] In other preferred compounds of formula (I) at least one of
the radicals R.sup.1, R.sup.2 is different from hydrogen.
[0121] In other preferred compounds of formula (I) at least one of
the radicals A.sup.1, A.sup.2, A.sup.3, A.sup.4 is different from
hydrogen.
[0122] In other preferred compounds of formula (I) at least one of
the radicals B.sup.1, B.sup.2, B.sup.3, B.sup.4, B.sup.5 is
different from hydrogen.
[0123] In other preferred compounds of formula (I) at least two of
the radicals R.sup.1, R.sup.2, A.sup.1, A.sup.2, A.sup.3, A.sup.4,
B.sup.1, B.sup.2, B.sup.3, B.sup.4, B.sup.5 are different from
hydrogen.
[0124] In other preferred compounds of formula (I) at least one of
the radicals R.sup.1, R.sup.2, A.sup.1, A.sup.2, A.sup.3, A.sup.4,
B.sup.1, B.sup.2, B.sup.3, B.sup.4, B.sup.5 is F or Cl.
[0125] In some preferred compounds of formula (I) at least one of
the radicals R.sup.1, R.sup.2, A.sup.1, A.sup.2, A.sup.3, A.sup.4,
B.sup.1, B.sup.2, B.sup.3, B.sup.4, B.sup.5 is different from
hydrogen and Q is --CH.sub.2--CH.dbd.CH--.
[0126] In other preferred compounds of formula (I) at least one of
the radicals R.sup.1, R.sup.2, A.sup.1, A.sup.2, A.sup.3, A.sup.4
is different from hydrogen and Q is --CH.sub.2--CH.dbd.CH--.
[0127] In other preferred compounds of formula (I) at least one of
the radicals R.sup.1, R.sup.2, B.sup.1, B.sup.2, B.sup.3, B.sup.4,
B.sup.5 is different from hydrogen and Q is
--CH.sub.2--CH.dbd.CH--.
[0128] In other preferred compounds of formula (I) at least one of
the radicals A.sup.1, A.sup.2, A.sup.3, A.sup.4, B.sup.1, B.sup.2,
B.sup.3, B.sup.4, B.sup.5 is different from hydrogen and Q is
--CH.sub.2--CH.dbd.CH--.
[0129] In other preferred compounds of formula (I) at least one of
the radicals R.sup.1, R.sup.2 is different from hydrogen and Q is
--CH.sub.2--CH.dbd.CH--.
[0130] In other preferred compounds of formula (I) at least one of
the radicals A.sup.1, A.sup.2, A.sup.3, A.sup.4 is different from
hydrogen and Q is --CH.sub.2--CH.dbd.CH--.
[0131] In other preferred compounds of formula (I) at least one of
the radicals B.sup.1, B.sup.2, B.sup.3, B.sup.4, B.sup.5 is
different from hydrogen and Q is --CH.sub.2--CH.dbd.CH--.
[0132] In other preferred compounds of formula (I) at least two of
the radicals R.sup.1, R.sup.2, A.sup.1, A.sup.2, A.sup.3, A.sup.4,
B.sup.1, B.sup.2, B.sup.3, B.sup.4, B.sup.5 are different from
hydrogen and Q is --CH.sub.2--CH.dbd.CH--.
[0133] In other preferred compounds of formula (I) at least one of
the radicals R.sup.1, R.sup.2, A.sup.1, A.sup.2, A.sup.3, A.sup.4,
B.sup.1, B.sup.2, B.sup.3, B.sup.4, B.sup.5 is F or Cland Q is
--CH.sub.2--CH.dbd.CH--.
[0134] a) Salts, Solvates and N-Oxides
[0135] A salt of the compounds of the formula (I) may be
advantageous due to one or more of the salt's physical properties,
such as pharmaceutical stability in differing temperatures and
humidities; crystalline properties; and/or a desirable solubility
in water, oil, or other solvent. In some instances, a salt may be
used as an aid in the isolation, purification, and/or resolution of
the compound. Acid and base salts can typically be formed by, for
example, mixing the compound with an acid or base, respectively,
using various known methods in the art. To the extent a salt of the
compound is intended to be administered in vivo (i.e. to an animal)
for a therapeutic benefit, the salt is pharmaceutically
acceptable.
[0136] Salts may also be of advantage in the synthesis of the
compounds according to this invention. For instance intermediates
of the formula 7, may advantageously be used in form of their salts
in the preparation process of the compounds according to this
invention.
[0137] In general, an acid addition salt can be prepared by
reacting a free base compound with an approximately stoichiometric
amount of an inorganic or organic acid. Examples of often suitable
inorganic acids for making (pharmaceutically acceptable) salts
include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic,
sulfuric, and phosphoric acid. Examples of often suitable organic
acids for making (pharmaceutically acceptable) salts generally
include, for example, aliphatic, cycloaliphatic, aromatic,
araliphatic, heterocyclic, carboxylic, and sulfonic classes of
organic acids. Specific examples of often suitable organic acids
include cholic, sorbic, lauric, acetic, trifluoroacetic, formic,
propionic, succinic, glycolic, gluconic, digluconic, lactic, malic,
tartaric acid, citric, ascorbic, glucuronic, maleic, fumaric,
pyruvic, aspartic, glutamic, aryl carboxylic acid (e.g., benzoic),
anthranilic acid, mesylic, stearic, salicylic, p-hydroxybenzoic,
phenylacetic, mandelic, embonic (pamoic), alkylsulfonic (e.g.,
ethanesulfonic), arylsulfonic (e.g., benzenesulfonic), pantothenic,
2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic,
.beta.-hydroxybutyric, galactaric, galacturonic, adipic, alginic,
butyric, camphoric, camphorsulfonic, cyclopentanepropionic,
dodecylsulfic, glycoheptanoic, glycerophosphic, heptanoic,
hexanoic, nicotinic, 2-naphthalesulfonic, oxalic, palmoic,
pectinic, 3-phenylpropionic, picric, pivalic, thiocyanic, tosylic,
and undecanoic acid. In some such embodiments, for example, the
salt comprises a trifluoroacetate, mesylate, or tosylate salt. In
other embodiments, the salt comprises a hydrochloric acid salt.
[0138] In general, a base addition salt can be prepared by reacting
a free acid compound with an approximately stoichiometric amount of
an inorganic or organic base. Examples of base addition salts may
include, for example, metallic salts and organic salts. Metallic
salts, for example, include alkali metal (group Ia) salts, alkaline
earth metal (group IIa) salts, and other physiologically acceptable
metal salts. Such salts may be made from aluminum, calcium,
lithium, magnesium, potassium, sodium, and zinc. For example, a
free acid compound may be mixed with sodium hydroxide to form such
a base addition salt. Organic salts may be made from amines, such
as trimethylamine, diethylamine, N,N'-dibenzylethylenediamine,
chloroprocaine, ethanolamine, diethanolamine, ethylenediamine,
meglumine (N-methylglucamine), and procaine. Basic
nitrogen-containing groups may be quaternized with agents such as
C.sub.1-C.sub.6-alkyl halides (e.g., methyl, ethyl, propyl, and
butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g.,
dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain
halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides,
bromides, and iodides), arylalkyl halides (e.g., benzyl and
phenethyl bromides), and others.
[0139] A solvate of a compound of the formula (I) may be formed by
aggregation of said compound of the formula (I) with solvent
molecules such as water, alcohols, for example ethanol, aromatic
solvents such as toluene, ethers, halogenated organic solvents such
as dichloromethane, preferably in a definite proportion by
weight.
[0140] An N-oxide of a compound of the formula (I) may be formed by
oxidation of an N-atom in an amine or N-heterocycle such as
pyridine by oxidation agents such as hydrogen peroxide, peracids or
inorganic oxidation agents such as potassium peroxymonosulfate
(oxone).
[0141] b) Isomers
[0142] The compounds according to this invention and their
intermediates may exist in various isomeric forms. A reference to a
compound according to this invention or an intermediate thereof
always includes all possible isomeric forms of such compound.
[0143] In some embodiments, a compound according to this invention
may have two or more isomers, such as optical isomers or
conformational isomers. For example, compounds with
Q=--CH.sub.2--CH.dbd.CH-- can have a cis or trans configuration. In
some preferred embodiments, such compound has the trans
configuration, in other embodiments, the compound has the cis
configuration. In a preferred embodiment this compound has trans
configuration. For instance the compounds 1 to 6 and 10 to 99 of
Table I below can have cis (Z) or trans (E) configuration,
preferred is their trans (E) configuration.
[0144] Unless otherwise stated, a compound structure that does not
indicate a particular conformation is intended to encompass
compositions of all the possible conformational isomers of the
compound, as well as compositions comprising fewer than all the
possible conformational isomers. In some embodiments, the compound
is a chiral compound (Q=--CH.sub.2--CH(CH.sub.3)--). In some
embodiments, the compound is a non-chiral compound.
Treatment Methods Using Compounds According to this Invention
[0145] The compounds of the formula (I) and pharmaceutically
acceptable solvates, N-oxides and salts thereof may generally be
used as a medicament for animals. In some embodiments of this
invention, one or more, preferably one compound according to this
invention is administered to treat infections such as parasitic
infections (e.g. helminth infections) of an animal (or make a
medicament to treat infections such as parasitic infections of an
animal). In one embodiment one or more, preferably one compound
according to this invention is administered to treat parasitoses of
an animal (or make a medicament to treat parasitoses of an
animal).
[0146] The term "(parasitic) infection" includes conditions
associated with or caused by one or more (parasitic) pathogens;
said conditions include clinical conditions (parasitoses) and
sub-clinical conditions. The term "treatment of parasitic
infection" thus includes both the treatment of parasitoses and the
treatment of sub-clinical conditions. The treatment of a parasite
infection generally implies the suppression of parasite (e.g.
helminth) burdens in the animal below that level at which economic
loss occurs.
[0147] Sub-clinical conditions are typically conditions not
directly leading to clinical symptoms in the parasite infected
animal but leading to economic losses. Such economic losses can be
e.g. by depression of growth in young animals, lower feed
efficiency, lower weight gain in meat producing animals, lower milk
production in ruminants, lower egg production in laying hens, or
lower wool-production in sheep.
[0148] The term "parasitoses" relates to clinically manifest
pathologic conditions and diseases associated with or caused by an
infection by one or more parasites, such as, for example parasitic
gastroenteritis or anemia in ruminants e.g. sheep and goats or
colic in horses.
[0149] In general, the prevention or treatment of parasitic
infection including parasitoses is achieved by administering one or
more, preferably one compound according to this invention to treat
a parasitic infection such as a helminth infection.
[0150] Thus the invention provides a method of treating a
(parasitic) infection such as a helminth infection, including
parasitoses, which comprises administering to the animal an
antiparasitically, preferably an anthelmintically, effective amount
of one or more compounds according to this invention. Preferably
nematode, cestode or trematode infections are treated, more
preferably nematode infections.
[0151] "Treating (parasitic) infections" includes treating
parasitoses and means to partially or completely inhibit the
development of (parasitic) infections of an animal susceptible to
(parasitic) infection, reduce or completely eliminate the symptoms
of infections of an animal having infections, and/or partially or
completely cure infections of an animal having infections. This can
be achieved by alleviating or reducing pathogen numbers such as
parasite numbers in an animal.
[0152] Preferably "treating (parasitic) infections" means that the
parasite count is reduced, after a first administration, by an
amount ranging from 5% to about 100%. The effect of the compounds
according to this invention can be e.g. ovicidal, larvicidal,
and/or adulticidal or a combination thereof. The effect can
manifest itself directly, i.e. killing the parasites either
immediately or after some time has elapsed, for example when
molting occurs, or by destroying their eggs, or indirectly, e.g.
reducing the number of eggs laid and/or the hatching rate.
Alternatively the parasite is not killed but paralyzed and is then
dislodged and excreted by the host animal.
[0153] The compounds according to this invention may affect the
movement, growth and viability of parasitic helminths, especially
nematodes and may cause hypercontraction of the body wall muscles
leading to paralysis or spasmodic contractions of body parts.
[0154] In a preferred embodiment the compounds according to this
invention are used to treat a helminth infection, such as an
infection caused by one or more helminths selected from the group
consisting of a) cestodes: e.g. Anaplocephala spp.; Dipylidium
spp.; Diphyllobothrium spp.; Echinococcus spp.; Moniezia spp.;
Taenia spp.; b) trematodes e.g. Dicrocoelium spp.; Fasciola spp.;
Paramphistomum spp.; Schistosoma spp.; or c) nematodes, e.g.;
Ancylostoma spp.; Anecator spp.; Ascaridia spp.; Ascaris spp.;
Brugia spp.; Bunostomum spp.; Capillaria spp.; Chabertia spp.;
Cooperia spp.; Cyathostomum spp.; Cylicocyclus spp.;
Cylicodontophorus spp.; Cylicostephanus spp.; Craterostomum spp.;
Dictyocaulus spp.; Dipetalonema spp; Dirofilaria spp.; Dracunculus
spp.; Enterobius spp.; Filaroides spp.; Habronema spp.; Haemonchus
spp.; Heterakis spp.; Hyostrongylus spp.; Metastrongylus spp.;
Meullerius spp. Necator spp.; Nematodirus spp.; Nippostrongylus
spp.; Oesophagostomum spp.; Onchocerca spp.; Ostertagia spp.;
Oxyuris spp.; Parascaris spp.; Stephanurus spp.; Strongylus spp.;
Syngamus spp.; Toxocara spp.; Strongyloides spp.; Teladorsagia
spp.; Toxascaris spp.; Trichinella spp.; Trichuris spp.;
Trichostrongylus spp.; Triodontophorous spp.; Uncinaria spp.,
and/or Wuchereria spp.; preferably nematode infections are treated,
such as infections by Trichostrongylus axei, Trichostrongylus
colubriformis, Haemonchus contortus, Ascaridia galli, and/or
Oesophagostomum dentatum.
[0155] It is contemplated that the compounds according to this
invention may be used to treat animals, including humans and
non-human animals, especially non-human mammals. Such non-human
mammals include, for example, livestock mammals (e.g., swine,
livestock ruminats like bovines, sheep, goats, etc.), laboratory
mammals (e.g., mice, rats, jirds, etc.), companion mammals (e.g.,
dogs, cats, equines, etc.), and wild and zoo mammals (e.g.,
buffalo, deer, etc.). It is contemplated that the compounds
according to this invention also are suitable to treat non-mammals,
such as poultry (e.g., turkeys, chickens, ducks, etc.) and fish
(e.g., salmon, trout, koi, etc.).
[0156] In some embodiments, one or more, preferably one compound
according to this invention is used to treat an infection by a
helminth, such as a nematode, cestode or trematode, preferably a
nematode (such as Haemonchus contortus), that is resistant to one
or more other anthelmintic agents. In some embodiments, the
compound according to this invention is active against a helminth,
such as a nematode, cestode or trematode, preferably a nematode
such as Haemonchus contortus, that is resistant to one or more of
the following anthelmintics: an avermectin (e.g., ivermectin,
selamectin, doramectin, abamectin, and eprinomectin); a milbemycin
(moxidectin and milbemycin oxime); a pro-benzimidazole (e.g.,
febantel, netobimin, and thiophanate); a benzimidazole derivative,
such as a thiazole benzimidazole derivative (e.g., thiabendazole
and cambendazole) or a carbamate benzimidazole derivative (e.g.,
fenbendazole, albendazole (oxide), mebendazole, oxfendazole,
parbendazole, oxibendazole, flubendazole, and triclabendazole); an
imidazothiazole (e.g., levamisole and tetramisole); a
tetrahydropyrimidine (morantel and pyrantel), an organophosphate
(e.g., trichlorphon, haloxon, dichlorvos, and naphthalophos); a
salicylanilide (e.g., closantel, oxyclozanide, rafoxanide, and
niclosamide); a nitrophenolic compound (e.g., nitroxynil and
nitroscanate); benzenedisulfonamide (e.g., clorsulon); a
pyrazinoisoquinoline (e.g., praziquantel and epsiprantel); a
heterocyclic compound (e.g., piperazine, diethylcarbamazine, and
phenothiazine); dichlorophen, an arsenical (e.g., thiacetarsamide,
melorsamine, and arsenamide); cyclooctadepsipeptide (e.g.,
emodepside); and a paraherquamide.
[0157] In some such embodiments, for example, the compound
according to this invention is active against a helminth (for
example, Haemonchus contortus) resistant to an avermectin, such as
ivermectin. In other embodiments, the compound according to this
invention is alternatively or additionally active against a
helminth (for example, Haemonchus contortus) resistant to a
benzimidazole derivative, such as fenbendazole. In other
embodiments, the compound according to this invention is
alternatively or additionally active against a helminth (for
example, Haemonchus contortus) resistant to levamisole. And, in
other embodiments, the compound according to this invention is
alternatively or additionally active against a helminth (for
example, Haemonchus contortus) resistant to pyrantel.
[0158] The compounds according to this invention may be
administered in various dosage forms. The term "dosage form" means
that the compounds according to this invention are formulated into
a product suitable for administering to the animal via the
envisaged dosage route. Such dosage forms are sometimes referred to
herein as formulations or pharmaceutical composition.
[0159] Dosage forms useful in the current invention can be liquid,
semi-solid or solid dosage forms.
[0160] Liquid dosage forms of the compounds are generally
solutions, suspensions or emulsions. A solution is a mixture of two
or more components that form a single phase that is homogeneous
down to the molecular level. A suspension consists of insoluble
solid particles dispersed in a liquid medium, with the solid
particles accounting for about 0.5% to about 30% of the suspension.
The liquid may be aqueous, oily, or both. An emulsion is a
heterogeneous dispersion of one immiscible liquid in another; it
relies on an emulsifying agent for stability. A dry powder (or
granule) for reconstitution is reconstituted as a solution or as a
suspension immediately prior to injection. The principal advantage
of this dosage form is that it overcomes the problem of instability
in solution or suspension.
[0161] One possible dosage route is the oral dosage route, wherein
the compound according to this invention is administered via the
mouth. Oral dosage forms suitable for oral administration comprise
liquids (e.g. drench or drinking water formulations), semi-solids
(e.g. pastes, gels), and solids (e.g. tablets, capsules, powders,
granules, chewable treats, premixes and medicated blocks).
[0162] A drench is a liquid oral formulation that is administered
directly into the mouth/throat of an animal, especially a livestock
animal, by means of a "drench gun" or syringe or another suitable
device. When the composition is administered in the animal
recipient's drinking water or as a drench, it may be convenient to
use a solution or suspension formulation. This formulation can be,
for example, a concentrated suspension that is mixed with water or
a dry preparation that is mixed and suspended in the water.
[0163] Semi-solid oral formulations (pastes or gels) are generally
administered via an applicator directly into the mouth of an animal
or mixed with the feed.
[0164] Solid oral formulations are either administered directly to
an animal (tablet, capsule) or mixed with the feed or via medicated
feed blocks.
[0165] When the oral formulation is administered via a non-human
animal's feed, it may, for example, be fed as a discrete feed or as
a chewable treat. Alternatively (or additionally), it may, for
example, be intimately dispersed in the animal recipient's regular
feed, used as a top dressing, or in the form of solid pellets,
paste or liquid that is added to the finished feed. When the oral
formulation is administered as a feed additive, it may be
convenient to prepare a "premix" in which the oral formulation is
dispersed in a liquid or solid carrier. This "premix" is, in turn,
dispersed in the animal's feed using, for example, a conventional
mixer.
[0166] Several modified-release delivery systems have been
developed, that take advantage of the unique anatomy of the
ruminant forestomach, i.e. for intra-ruminal administration. An
intraruminal bolus is a specific formulation for ruminants (cattle,
sheep, goats, buffalos, camelids, deer etc). It is a veterinary
delayed release delivery system which remains in the
rumeno-reticular sac of a ruminant animal over an extended period
of time and in which the therapeutically active substance has a
predictable and delayed release pattern. Such intraruminal boluses
are usually administered using a balling gun or another suitable
device.
[0167] It is contemplated that the compounds according to this
invention may alternatively be administered via non-oral dosage
routes, such as topically (e.g., via a spot-on, pour-on or
transdermal patch), or parenterally (e.g., subcutaneous injection,
intravenous injection, intramuscular injection, etc.).
[0168] For instance the compounds according to this invention may
be administered topically using a transdermal formulation (i.e. a
formulation that passes through the skin). Alternatively the
compounds according to this invention may be administered topically
via the mucosa.
[0169] Topical dosage forms suitable for topical administration
comprise liquids (e.g. bath, spray, spot-on), semi-solids (e.g.
creams, gels), and solids (e.g. patches, powders, collars). Typical
topical formulations for animals are liquid or semi-liquid dosage
forms. Typical formulations for transdermal and mucosal
administration include, for example, pour-ons, spot-ons, dips,
sprays, mousses, shampoos, powders, gels, hydrogels, lotions,
solutions, creams, ointments, dusting powders, dressings, foams,
films, skin patches, limb bands, collars, ear tags, wafers,
sponges, fibers, bandages, and microemulsions. When a liquid
formulation is used topically on skin, it can be administered by,
for example, pouring on (pour-on or spot-on), spreading, rubbing,
atomizing, spraying, dipping, bathing, or washing.
[0170] The pour-on or spot-on methods, for example, comprise
applying the formulation to a specific location of the skin or
coat, such as on the neck or backbone of the animal. This may be
achieved by, for example, applying a swab or drop of the pour-on or
spot-on formulation to a relatively small area of the recipient
animal's skin or coat (i.e., generally no greater than about 10% of
the animal recipient's skin or coat). In some embodiments, the
compound according to this invention is dispersed from the
application site to wide areas of the fur due to the spreading
nature of the components in the formulation and the animal's
movements while, in parallel, being absorbed through the skin and
distributed via the animal recipient's fluids and/or tissues.
[0171] Parenteral formulations and delivery systems for non-oral
routes comprise liquids (e.g. solutions, suspensions, emulsions,
and dry powders for reconstitution), semi-solids and solids (e.g.
implants). The majority of implants that are used in veterinary
medicine are compressed tablets or dispersed matrix systems in
which the drug is uniformly dispersed within a nondegradable
polymer or alternatively extrusion products.
Pharmaceutical Compositions
[0172] This invention also is directed to pharmaceutical
compositions (or medicaments) comprising one or more, preferably
one compound according to this invention. The compositions also may
(and preferably will) comprise one or more pharmaceutically
acceptable excipients.
[0173] Pharmaceutical compositions of the present invention may be
manufactured by, for example, processes known in the art. These
processes include, for example, a variety of known mixing,
dissolving, granulating, emulsifying, encapsulating, entrapping,
and lyophilizing processes. Optimal formulation depends on, for
example, the dosage route (e.g. oral, injection, topical).
[0174] Solid dosage forms, for example, may be prepared by, for
example, intimately and uniformly mixing the compounds with
fillers, binders, lubricants, glidants, disintegrants, flavoring
agents (e.g., sweeteners), buffers, preservatives,
pharmaceutical-grade dyes or pigments, and controlled release
agents.
[0175] Oral dosage forms other than solids may be prepared by
mixing the compounds with, for example, one or more solvents,
viscosity-enhancing agents, surfactants, preservatives,
stabilizers, resins, fillers, binders, lubricants, glidants,
disintegrants, co-solvents, sweeteners, flavorings, perfuming
agents, buffers, suspending agents, and pharmaceutical-grade dyes
or pigments.
[0176] Contemplated binders include, for example, gelatin, acacia,
and carboxymethyl cellulose.
[0177] Contemplated lubricants include, for example, magnesium
stearate, stearic acid, and talc.
[0178] Contemplated disintegrants include, for example, corn
starch, alginic acid, sodium carboxymethylcellulose, and sodium
croscarmellose.
[0179] Contemplated buffers include, for example, sodium citrate,
and magnesium and calcium carbonate and bicarbonate.
[0180] Contemplated solvents include, for example, water,
petroleum, animal oils, vegetable oils, mineral oil, and synthetic
oil. Physiological saline solution or glycols (e.g., ethylene
glycol, propylene glycol, or polyethylene glycol) also may be
included. The solvent preferably has sufficient chemical properties
and quantity to keep the compounds solubilized at temperatures in
which the composition is stored and used.
[0181] Contemplated viscosity-enhancing agents include, for
example, polyethylene, methylcellulose, sodium
carboxymethylcellulose, hydroxypropyl-methylcellulose,
hydroxypropylcellulose, sodium alginate, carbomer, povidone,
acacia, guar gum, xanthan gum, tragacanth, methylcellulose,
carbomer, xanthan gum, guar gum, povidone, sodium
carboxymethylcellulose, magnesium aluminum silicate, carboxyvinyl
polymers, carrageenan, hydroxyethyl cellulose, laponite,
water-soluble salts of cellulose ethers, natural gums, colloidal
magnesium aluminum silicateor finely divided silica, homopolymers
of acrylic acid crosslinked with an alkyl ether of pentaerythritol
or an alkyl ether of sucrose, and carbomers.
[0182] Contemplated surfactants include, for example,
polyoxyethylene sorbitan fatty acid esters; polyoxyethylene
monoalkyl ethers; sucrose monoesters; lanolin esters and ethers;
alkyl sulfate salts; and sodium, potassium, and ammonium salts of
fatty acids.
[0183] Contemplated preservatives include, for example, phenol,
alkyl esters of parahydroxybenzoic acid (e.g., methyl
p-hydroxybenzoate (or "methylparaben") and propyl p-hydroxybenzoate
(or "propylparaben")), sorbic acid, o-phenylphenol benzoic acid and
the salts thereof, chlorobutanol, benzyl alcohol, thimerosal,
phenylmercuric acetate and nitrate, nitromersol, benzalkonium
chloride, and cetylpyridinium chloride.
[0184] Contemplated stabilizers include, for example, chelating
agents and antioxidants.
[0185] Solid dosage forms also may comprise, for example, one or
more excipients to control the release of the compounds. For
example, it is contemplated that the compounds may be dispersed in,
for example, hydroxypropylmethyl cellulose. Some oral dosage forms
(e.g., tablets and pills) also may be prepared with enteric
coatings.
[0186] Topical dosage route uses, for example, a concentrated
liquid or semi-liquid solution, suspension (aqueous or
non-aqueous), emulsion (water-in-oil or oil-in-water), or
microemulsion comprising a compounds dissolved, suspended, or
emulgated in a pharmaceutically-acceptable liquid vehicle. In such
embodiments, a crystallization inhibitor optionally may generally
be present.
[0187] Such a pour-on or spot-on formulation can be prepared by
dissolving, suspending, or emulsifying the compounds in a suitable
skin-fitted solvent or solvent mixture. Other excipients may be
included as well, such as, for example, a surfactant, colorant,
antioxidant, stabilizer, adhesive, etc. Contemplated solvents
include, for example, water, alkanol, glycol, polyethylene glycol,
polypropylene glycol, glycerin, benzyl alcohol, phenylethanol,
phenoxyethanol, ethyl acetate, butyl acetate, benzyl benzoate,
dipropylene glycol monomethyl ether, diethylene glycol monobutyl
ether, acetone, methyl ethyl ketone, aromatic and/or aliphatic
hydrocarbons, vegetable or synthetic oil, DMF, liquid paraffin,
silicone, dimethylacetamide, N-methylpyrrolidone, or
2,2-dimethyl-4-oxy-methylene-1,3-dioxolane.
[0188] In some embodiments, a topical formulation (particularly a
pour-on or spot-on formulation) comprises a carrier that promotes
the absorption or penetration of the compounds through the skin
into the blood stream, other bodily fluids (lymph), and/or body
tissue (fat tissue). Contemplated examples of dermal penetration
enhancers include, for example, dimethylsulfoxide, isopropyl
myristate, dipropylene glycol pelargonate, silicone oil, aliphatic
esters, triglycerides, and fatty alcohols.
[0189] Topical formulations also (or alternatively) may comprise,
for example, one or more spreading agents. These substances act as
carriers that assist in distributing an active ingredient over the
animal recipient's coat or skin. They may include, for example,
isopropyl myristate, dipropylene glycol pelargonate, silicone oils,
fatty acid esters, triglycerides, and/or fatty alcohols. Various
spreading oil/solvent combinations also may be suitable, such as,
for example, oily solutions, alcoholic and isopropanolic solutions
(e.g., solutions of 2-octyl dodecanol or oleyl alcohol), solutions
of esters of monocarboxylic acids (e.g., isopropyl myristate,
isopropyl palmitate, lauric acid oxalic ester, oleic acid oleyl
ester, oleic acid decyl ester, hexyl laurate, oleyl oleate, decyl
oleate, and caproic acid esters of saturated fatty alcohols having
a carbon chain of 12 to 18 carbons), solutions of esters of
dicarboxylic acids (e.g., dibutyl phthalate, diisopropyl
isophthalate, adipic acid diisopropyl ester, and di-n-butyl
adipate), or solutions of esters of aliphatic acids (e.g.,
glycols). When the formulation comprises a spreading agent, it also
may be advantageous to include a dispersant, such as, for example,
pyrrolidin-2-one, N-alkylpyrrolidin-2-one, acetone, polyethylene
glycol or ether or ester thereof, propylene glycol, or synthetic
triglycerides.
[0190] When formulated in, for example, an ointment, it is
contemplated that the compounds may be mixed with, for example,
either a paraffinic or a water-miscible ointment base. When
formulated in a cream, it is contemplated that the compounds may be
formulated with, for example, an oil-in-water cream base. In some
instances, the aqueous phase of the cream base includes, for
example at least about 30% (w/w) of a polyhydric alcohol, such as
propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,
polyethylene glycol, or a mixture thereof.
[0191] Injectable formulations may be prepared according to, for
example, the known art using suitable solvents, solubilizing
agents, protecting agents, dispersing agents, wetting agents,
and/or suspending agents. Contemplated carrier materials include,
for example, water, ethanol, butanol, benzyl alcohol, glycerin,
1,3-butanediol, Ringer's solution, isotonic sodium chloride
solution, bland fixed oils (e.g., synthetic mono- or diglycerides),
vegetable oil (e.g., corn oil), dextrose, mannitol, fatty acids
(e.g., oleic acid), dimethyl acetamide, surfactants (e.g., ionic
and non-ionic detergents), N-methylpyrrolidone, propylene glycol,
and/or polyethylene glycols (e.g., PEG 400). Contemplated
solubilizing agents include, for example, polyvinyl pyrrolidone,
polyoxyethylated castor oil, polyoxyethylated sorbitan ester, and
the like. Contemplated protecting agents include, for example,
benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester,
n-butanol, and the like.
[0192] In some embodiments, a parenteral formulation is, for
example, prepared from sterile powders or granules having one or
more of the carriers materials discussed above for other
formulations. The compounds is, for example, dissolved or suspended
in a liquid comprising water, polyethylene glycol, propylene
glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,
benzyl alcohol, sodium chloride, and/or various buffers. The pH
generally may be adjusted, if necessary, with a suitable acid,
base, or buffer.
[0193] Other inert ingredients may generally be added to the
composition as desired. To illustrate, it is contemplated that
these may include, for example, lactose, mannitol, sorbitol,
calcium carbonate, sodium carbonate, tribasic calcium phosphate,
dibasic calcium phosphate, sodium phosphate, kaolin, compressible
sugar, starch, calcium sulfate, dextro or microcrystalline
cellulose, colloidal silicon dioxide, starch, sodium starch
glycolate, crospovidone, microcrystalline cellulose, tragacanth,
hydroxypropylcellulose, pregelatinized starch, povidone,
ethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, and methylcellulose.
[0194] Further aspects regarding formulation of drugs and various
excipients are found in, for example, Gennaro, A. R., et al., eds.,
Remington: The Science and Practice of Pharmacy (Lippincott
Williams & Wilkins, 20th Ed., 2000). Another source regarding
formulation of drugs and various excipients is found in, for
example, Liberman, H. A., et al., eds., Pharmaceutical Dosage Forms
(Marcel Decker, New York, N.Y., 1980).
[0195] The concentration of the compounds according to this
invention in the applied dosage form may vary widely depending on,
for example, the dosage route. In general, the concentration is
from about 1 to about 70% (by weight). In some such embodiments,
for example, the concentration is from about 1 to about 50% (by
weight), or from about 10 to about 50% (by weight). In other
embodiments, the concentration is from about 35 to about 65% (by
weight), from about 40 to about 60% (by weight), from about 45 to
about 55% (by weight), or about 50% (by weight).
[0196] In another aspect the present invention thus provides a
pharmaceutical composition comprising an anthelmintically effective
amount of one or more, preferably one compound according to this
invention and one or more pharmaceutically acceptable
excipients.
[0197] The formulation type chosen for a dosage form in any
instance will depend upon the particular purpose envisaged and the
physical, chemical and biological properties of the compound
according to this invention.
[0198] The compounds and pharmaceutical compositions according to
this invention are useful in treating parasitic infections such as
helminth infections of animals. An "effective amount," is the
amount or quantity of a compound that is required to alleviate or
reduce parasite numbers in an animal, and/or to inhibit the
development of parasite infections in an animal, in whole or in
part.
[0199] This amount is readily determined by observation or
detection of the pathogen numbers such as parasite numbers both
before and after contacting the sample of pathogens such as
parasites including their stages with the compound according to
this invention, directly and/or indirectly, e.g., by contacting
articles, surfaces, foliage, or animals with the compound.
[0200] This can be evaluated by counting parasites (especially
helminthes) directly after necroscopy of the host animal.
[0201] The reduction of parasite numbers, especially
gastrointestinal helminth parasites can be alternatively measured
in-directly by faecal egg or differential larval counts. In this
case the effective amount of the compound is determined by the
reduction of the number of excreted helminth eggs or larvae in the
faeces of the treated animal before and after treatment. For an in
vivo administration the compound according to this invention, is
preferably administered to an animal in an effective amount which
is synonymous with "pharmaceutically effective amount" or
"anthelmintically effective amount".
[0202] A single administration of a compound according to this
invention is typically sufficient to treat a parasitic infection
such as a helminth infection, preferably a nematode, cestode or
trematode infection, more preferably a nematode infection. Although
such a single dose is typically preferred, it is contemplated that
multiple doses can be used. When the compound according to this
invention is orally administered, the total dose to treat a disease
such as a helminth infection is generally greater than about 0.01
mg/kg (i.e., milligram of compound according to this invention per
kilogram body weight of the treated animal). In some such
embodiments, the total dose is from about 0.01 to about 100 mg/kg,
from about 0.01 to about 50 mg/kg, from about 0.1 to about 25
mg/kg, or from about 1 to about 20. For sheep, for example, the
dose is generally from about 0.5 to about 15 mg/kg, from about 1 to
about 10 mg/kg. The same dose range may be suitable for other
dosage routes. For example, in some embodiments, the same dose
range is used for subcutaneous administration. The desired dose,
however, may be less in some instances where the compound according
to this invention is administered intravenously.
[0203] If the compound according to this invention is administered
parenterally via an injection, the concentration of the compound
according to this invention in the dosage form preferably is
sufficient to provide the desired therapeutically effective amount
of the compound according to this invention in a volume that is
acceptable for parenteral administration.
[0204] Factors affecting the preferred dosage may include, for
example, the parasite species infection to be treated and the
development stages of the parasites, the type (e.g., species and
breed), age, size, sex, diet, activity, and condition of the of the
infected animal; the dosage route; pharmacological considerations,
such as the activity, efficacy, pharmacokinetic, and toxicology
profiles of the particular composition administered; and whether
the compound according to this invention being administered as part
of a combination of active ingredients. Thus, the preferred amount
of the compound according to this invention can vary, and,
therefore, can deviate from the typical dosages set forth above.
Determining such dosage adjustments is generally within the skill
of those in the art.
Examples of Contemplated Combination Therapies
[0205] The methods and pharmaceutical compositions of this
invention encompass methods wherein a compound according to this
invention is the sole active ingredient administered to the
recipient animal. It is contemplated, however, that the methods and
pharmaceutical compositions also encompass combination therapies
wherein a compound is administered in combination with one or more
other pharmaceutically acceptable active ingredients. The other
active ingredient(s) may be, for example, one or more other
compounds according to this invention. Alternatively (or
additionally), the other active ingredient(s) may be one or more
pharmaceutically acceptable compounds that are not compounds
according to this invention. The other active ingredient(s) may
target the same and/or different parasites and conditions.
[0206] Contemplated active ingredient(s) that may be administered
in combination with the compounds include, for example,
pharmaceutically acceptable anthelmintics, insecticides and
acaricides, insect growth regulators, anti-inflammatories,
anti-infectives, hormones, dermatological preparations (e.g.,
antiseptics and disinfectants), and immunobiologicals (e.g.,
vaccines and antisera) for disease prevention.
[0207] Therefore this invention is also directed to the use as a
medicament of combinations comprising a) one or more compounds
according to this invention with b) one or more pharmaceutically
acceptable active compounds which differ in structure from
component a). The active compounds b) are preferably anthelmintic
compounds, more preferably selected from the group consisting of
avermectins (e.g., ivermectin, selamectin, doramectin, abamectin,
and eprinomectin); milbemycins (moxidectin and milbemycin oxime);
pro-benzimidazoles (e.g., febantel, netobimin, and thiophanate);
benzimidazole derivatives, such as a thiazole benzimidazole
derivative (e.g., thiabendazole and cambendazole) or a carbamate
benzimidazole derivatives (e.g., fenbendazole, albendazole (oxide),
mebendazole, oxfendazole, parbendazole, oxibendazole, flubendazole,
and triclabendazole); an imidazothiazoles (e.g., levamisole and
tetramisole); a tetrahydropyrimidine (morantel and pyrantel),
organophosphates (e.g., trichlorphon, haloxon, dichlorvos, and
naphthalophos); salicylanilides (e.g., closantel, oxyclozanide,
rafoxanide, and niclosamide); nitrophenolic compounds (e.g.,
nitroxynil and nitroscanate); benzenedisulfonamides (e.g.,
clorsulon); pyrazinoisoquinolines (e.g., praziquantel and
epsiprantel); heterocyclic compounds (e.g., piperazine,
diethylcarbamazine, and phenothiazine); dichlorophen, arsenicals
(e.g., thiacetarsamide, melorsamine, and arsenamide);
cyclooctadepsipeptides (e.g., emodepside); paraherquamides (e.g.
derquantel); and amino-acetonitrile compounds (e.g. monepantel, AAD
1566); amidine compounds (e.g., amidantel and tribendimidin),
including all pharmaceutically acceptable forms, such as salts,
solvates or N-oxides.
[0208] Preferred combinations are comprising a) one compound
selected from the group compounds 1 to 99 of Table I below (or
salts, solvates or N-oxides. thereof) and b) one compound selected
from the group consisting of anthelmintic avermectins (e.g.,
ivermectin, selamectin, doramectin, abamectin, emamectin and
eprinomectin); milbemycins (moxidectin and milbemycin oxime);
pro-benzimidazoles (e.g., febantel, netobimin, and thiophanate);
benzimidazole derivatives, such as thiazole benzimidazole
derivatives (e.g., thiabendazole and cambendazole), carbamate
benzimidazole derivatives (e.g., fenbendazole, albendazole (oxide),
mebendazole, oxfendazole, parbendazole, oxibendazole, flubendazole,
and triclabendazole); imidazothiazoles (e.g., levamisole and
tetramisole); tetrahydropyrimidines (morantel and pyrantel),
organophosphates (e.g., trichlorphon, haloxon, dichlorvos, and
naphthalophos); salicylanilides (e.g., closantel, oxyclozanide,
rafoxanide, and niclosamide); nitrophenolic compounds (e.g.,
nitroxynil and nitroscanate); benzenedisulfonamides (e.g.,
clorsulon); pyrazinoisoquinolines (e.g., praziquantel and
epsiprantel); heterocyclic compounds (e.g., piperazine,
diethylcarbamazine, and phenothiazine); dichlorophen, arsenicals
(e.g., thiacetarsamide, melorsamine, and arsenamide);
cyclooctadepsipeptides (e.g., emodepside); paraherquamides (e.g.
derquantel); amino-acetonitrile compounds (e.g. monepantel, AAD
1566); tribendimidine (amidine compound); and amidantel (amidine
compound); including all pharmaceutically acceptable forms, such as
salts.
[0209] Preferred combinations comprise at least one compound
selected from the group compounds 1 to 99 of Table I below (or
salts, solvates or N-oxides. thereof) and
[0210] abamectin, ivermectin, emamectin, eprinomectin, doramectin,
moxidectin, milbemycin oxime; or.
[0211] closantel, oxyclozanide, rafoxanide, niclosamide; or
[0212] nitroxynil, nitroscanate, clorsulon; or
[0213] praziquantel and epsiprantel.
[0214] Examples of such combinations are combinations of one of the
compounds 1 to 99 of Table I below with abamectin.
[0215] Other examples are combinations of one of the compounds 1 to
99 of Table I below with ivermectin.
[0216] Other examples are combinations of one of the compounds 1 to
99 of Table I below with emamectin.
[0217] Other examples are combinations of one of the compounds 1 to
99 of Table I below with eprinomectin.
[0218] Other examples are combinations of one of the compounds 1 to
99 of Table I below with doramectin.
[0219] Other examples are combinations of one of the compounds 1 to
99 of Table I below with moxidectin.
[0220] Other examples are combinations of one of the compounds 1 to
99 of Table I below with milbemycin oxime.
[0221] Other examples are combinations of one of the compounds 1 to
99 of Table I below with closantel.
[0222] Other examples are combinations of one of the compounds 1 to
99 of Table I below with oxyclozanide.
[0223] Other examples are combinations of one of the compounds 1 to
99 of Table I below with rafoxanide.
[0224] Other examples are combinations of one of the compounds 1 to
99 of Table I below with niclosamide.
[0225] Other examples are combinations of one of the compounds 1 to
99 of Table I below with nitroxynil.
[0226] Other examples are combinations of one of the compounds 1 to
99 of Table I below with nitroscanate.
[0227] Other examples are combinations of one of the compounds 1 to
99 of Table I below with clorsulon.
[0228] Other examples are combinations of one of the compounds 1 to
99 of Table I below with praziquantel.
[0229] Other examples are combinations of one of the compounds 1 to
99 of Table I below with epsiprantel.
[0230] Other examples are combinations of one of the compounds 1 to
99 of Table I below with emodepside; or
[0231] Examples of such combinations are combinations of a salt of
one of the compounds 1 to 99 of Table I below with abamectin.
[0232] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with ivermectin.
[0233] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with emamectin.
[0234] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with eprinomectin.
[0235] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with doramectin.
[0236] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with moxidectin.
[0237] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with milbemycin oxime.
[0238] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with closantel.
[0239] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with oxyclozanide.
[0240] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with rafoxanide.
[0241] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with niclosamide.
[0242] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with nitroxynil.
[0243] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with nitroscanate.
[0244] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with clorsulon.
[0245] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with praziquantel.
[0246] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with epsiprantel.
[0247] Other examples are combinations of a salt of one of the
compounds 1 to 99 of Table I below with emodepside.
[0248] Examples of such combinations are combinations of a solvate
of one of the compounds 1 to 99 of Table I below with
abamectin.
[0249] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with ivermectin.
[0250] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with emamectin.
[0251] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with eprinomectin.
[0252] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with doramectin.
[0253] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with moxidectin.
[0254] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with milbemycin oxime.
[0255] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with closantel.
[0256] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with oxyclozanide.
[0257] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with rafoxanide.
[0258] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with niclosamide.
[0259] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with nitroxynil.
[0260] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with nitroscanate.
[0261] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with clorsulon.
[0262] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with praziquantel.
[0263] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with epsiprantel.
[0264] Other examples are combinations of a solvate of one of the
compounds 1 to 99 of Table I below with emodepside.
[0265] Examples of such combinations are combinations of an N-oxide
of one of the compounds 1 to 99 of Table I below with
abamectin.
[0266] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with ivermectin.
[0267] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with emamectin.
[0268] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with eprinomectin.
[0269] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with doramectin.
[0270] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with moxidectin.
[0271] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with milbemycin oxime.
[0272] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with closantel.
[0273] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with oxyclozanide.
[0274] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with rafoxanide.
[0275] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with niclosamide.
[0276] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with nitroxynil.
[0277] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with nitroscanate.
[0278] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with clorsulon.
[0279] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with praziquantel.
[0280] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with epsiprantel.
[0281] Other examples are combinations of an N-oxide of one of the
compounds 1 to 99 of Table I below with emodepside.
[0282] The compounds of the current invention can be combined with
pharmaceutically acceptable insecticides or acaricides. Such
pharmaceutically acceptable insecticides and acaricides include,
for example, acetamiprid, acetoprole, amitraz, amidoflumet,
avermectin, azadirachtin, bifenthrin, bifenazate, buprofezin,
bistrifluoron, chlorfenapyr, chlorfluazuron, chlorantraniliprole,
chlorpyrifos, chromafenozide, clothianidin, cyantraniliprole,
cyflumetofen, .beta.-cyfluthrin, cyhalothrin, .lamda.-cyhalothrin,
cymiazole cypermethrin, cyromazine, deltamethrin, demiditraz,
diafenthiuron, diazinon, diflubenzuron, dimefluthrin, dinotefuran,
emamectin, esfenvalerate, ethiprole, fenoxycarb, fenpropathrin,
fenvalerate, fipronil, flonicamid, flubendiamide, flucythrinate,
tau-fluvalinate, flufenoxuron, halofenozide, hexaflumuron,
imidacloprid, indoxacarb, lufenuron, metaflumizone, methoprene,
metofluthrin, methoxyfenozide, nitenpyram, novaluron, noviflumuron,
permethrin, phosmet, profluthrin, protrifenbute, pymetrozine,
pyrafluprole, pyrethrin, pyridalyl, pyrifluquinazon, pyriprole,
pyriproxyfen, rotenone, ryanodine, spinetoram, spinosad,
spirodiclofen, spiromesifen, spirotetramat, sulfoxaflor,
tebufenozide, tebufenpyrad, teflubenzuron, tefluthrin,
tetrachlorvinphos, tetramethylfluthrin, thiacloprid, thiamethoxam,
tolfenpyrad, tralomethrin, and triflumuron. General references
discussing antiparasitic agents, such as insecticides and
acaricides, include, for example, The Pesticide Manual, 13th
Edition, C. D. S. Tomlin, Ed., British Crop Protection Council,
Farnham, Surrey, U.K. (2003).
[0283] In some contemplated embodiments, the compounds are
administered with pyridylmethylamine derivatives, such as, for
example, pyridylmethylamine derivatives discussed in European
Patent Appl. EP0539588 or Intl Patent Appl. Publ.
WO2007/115643.
[0284] In some contemplated embodiments, the compounds is
administered with nodulisporic acids and derivatives thereof, such
as, for example, compounds discussed in U.S. Pat. No. 5,399,582;
5,945,317; 5,962,499; 5,834,260; 6,221,894; or 5,595,991; or Intl
Patent Appl. Publ. 1996/29073.
[0285] Pharmaceutically acceptable insect growth regulators
include, for example, methoprene, pyriproxyfen,
tetrahydroazadirachtin, chlorfluazuron, cyromazine, diflubenzuron,
fluazuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron,
ifenuron, tebufenozide, and triflumuron. These compounds tend to
provide both initial and sustained treatment of parasite infections
at all stages of insect development, including eggs, on the animal
subject, as well as within the environment of the animal
subject.
[0286] Other antiparasitic compounds contemplated to be useful in
combination therapies with the compounds include, for example,
imidazo[1,2-b]pyridazine compounds discussed in US Patent Appl.
Publ. No. 2005-0182059; 1-(4-Mono and
di-halomethylsulphonylphenyl)-2-acylamino-3-fluoropropanol
compounds discussed U.S. Pat. No. 7,361,689;
trifluoromethanesulfonanilide oxime ether compounds discussed in
U.S. Pat. No. 7,312,248;
n-[(phenyloxy)phenyl]-1,1,1-trifluoromethanesulfonamide and
n-[(phenylsulfanyl)phenyl]-1,1,1-trifluoromethanesulfonamide
compounds discussed in US Patent Appl. Publ. 2006-0281695; and
2-phenyl-3-(1H-pyrrol-2-yl)acrylonitrile compounds discussed in US
Appl. Publ. 2006/0128779; isoxazoline compounds discussed in WO
Patent Appl, Publ. 2005-085216, WO 2007-026965, WO 2007-070606, WO
2007-075459, WO 2007-079162, WO 2007-105814, WO 2007-125984, WO
2008-019760, WO 2008-122375, WO 2008-150393, WO 2009-002809, WO
2009-003075, WO 2009-022746, WO 2009-035004, WO 2009-045999, WO
2009-051956, WO 2009-035004.
[0287] In the contemplated combination therapies, the compounds
according to this invention may be administered before,
simultaneously, and/or after the other active ingredient(s). In
addition, the compounds according to this invention may be
administered in the same composition as the other active
ingredient(s) and/or in separate compositions from the other active
ingredient(s). Further, the compounds according to this invention
and other active ingredient(s) may be administered via the same
and/or different dosage route.
[0288] When the compounds according to this invention are
administered in a combination therapy, the weight ratio of the
active ingredients may vary widely. Factors influencing this ratio
include, for example, the particular compounds; the identity of the
other active ingredient(s) be administered in the combination
therapy; the dosage route of the compounds and other active
ingredient(s); the target condition and pathogen; the type (e.g.,
species and breed), age, size, sex, diet, activity, and condition
of the animal; and pharmacological considerations, such as the
activity, efficacy, pharmacokinetic, and toxicology profiles of the
compounds and other active ingredient(s). In some contemplated
embodiments, for example, the weight ratio of the compounds to the
other active ingredient(s) is, for example, is from about 1:3000 to
about 3000:1. In some such instances, the weight ratio is from
about 1:300 to about 300:1. In other such instances, the weight
ratio is from about 1:30 and about 30:1.
[0289] In addition to other active ingredients, it is contemplated
that the compounds may be administered with one or more other
compounds that beneficially affects (e.g. enhances or prolongs) the
activity (or other characteristic, such as safety) of the
compounds. For example, it is contemplated that the compounds may
be administered with one or more synergists, such as, for example,
piperonyl butoxide (PBO) and triphenyl phosphate (TPP). Other
synergists include, for example,
N-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboxamide (also
known as "ENT 8184" or "MGK 264") and Verbutin (also known as
"MB-599").
[0290] This invention also is directed to kits that are, for
example, suitable for use in performing the methods of treatment
described above. The kit comprises a therapeutically effective
amount of one or more spiroindoline compounds of this invention,
and an additional component. The additional component(s) may be,
for example, one or more of the following: another ingredient
(e.g., an excipient or active ingredient), an apparatus for
combining the compound of this invention with another ingredient
and/or for administering the compound of this invention, or a
diagnostic tool.
[0291] The compounds used according to this invention show an
excellent activity in treating parasite infections and in addition
are acceptable for the animals treated.
EXAMPLES
[0292] The following examples are merely illustrative, and not
limiting to the remainder of the disclosure in any way.
[0293] The methods described in the examples can be easily adapted
by a person skilled in the art to make other compounds according to
this invention, and intermediates thereof. For instance, a person
skilled in the art could replace in the examples the exemplified
starting compounds by other compounds of the formulae 3, 5, 8 or 9
(e.g. commercially available compounds), perform routine adaptions
of the reaction conditions, if any, and use them for the synthesis
of further compounds according to this invention.
A: Synthesis of Compounds According to this Invention
[0294] The preparation of spiroindoline-3,4'-piperidine building
blocks 4 is described in Scheme 1. A mixture of an appropriately
substituted phenyl hydrazine 3 or corresponding hydrochloride and
N-protected piperidine-4-carbaldehyde 1 or
4-(alkoxymethylene)piperidine 2 in the presence of an acid affords
the formation of the intermediate indole (not shown). Suitable
protecting groups (PG) for the nitrogen of 1 and 2 include, but are
not limited to, preferably tert-butyl carbamate (Boc), benzyl
carbamate (Cbz), allyl carbamate (Alloc), 9-fluorenylmethyl
carbamate (Fmoc), and the like. Suitable acids include, but are not
limited to, trifluoroacetic acid, p-toluenesulfonic acid and the
like. Reduction of the intermediate indole to the indoline can be
accomplished by a number of reducing agents. Suitable reducing
agents include, but are not limited to, alkali metal aluminum
hydrides such as lithium aluminium hydride, alkali metal
borohydrides such as sodium borohydride and the like. The solvents
include ethereal solvents such as tetrahydrofuran or dioxane,
aromatic solvents such as toluene, alcoholic solvents such as
ethanol, methanol, or isopropanol or mixtures thereof. The reaction
temperature ranges from about -78.degree. C. to 120.degree. C.,
preferably about -20.degree. C. to 80.degree. C. A general
procedure to 4 is described in Maligres, P. E; et al. Tetrahedron
1997, 53, 10983-10992. Other synthetic routes to
spiroindoline-3,4'-piperidines 4 beside the Fischer indole type
route, are disclosed in patent applications WO 2003-106457, WO
2006-090261, WO 2005-063745, WO 2008-157741.
##STR00003##
[0295] The spiroindoline-3,4'-piperidine isonicotinic acid amides 6
can be prepared by reacting spiroindole-3,4'-piperidines 4 with
isonicotinic acyl halides 5 such as acyl chloride, as shown in
Scheme 2. The acyl halides are readily formed using halogenation
agents such as thionyl chloride, oxalyl chloride, thionyl bromide,
cyanuric fluoride or N,N-diethylaminosulfur trifluoride.
Pyridine-4-carbonyl halides 5 are coupled with amines 4 in the
presence of a base in an inert solvent to afford the amides 6.
Inorganic bases such as alkali metal carbonates, alkali metal
hydrogencarbonates or alkali hydroxides can be used for the
coupling as well as organic bases such as preferably tertiary
amines such as trietylamine, diisopropylethylamine, etc., or
aromatic amines such as pyridine or imidazole, etc. Also polymer
bound bases such as polymer-supported
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine (BEMP) can be used for the amide coupling. Solvents utilized
include lower halocarbon solvents such as dichloromethane,
chloroform, etc., etheral solvents such as tetrahydrofuran,
dioxane, etc. or amide solvents such as dimethylformamide,
N-methylpyrrolidinone etc.
##STR00004##
[0296] Numerous alternative methods are known to generate amides
directly from carboxylic acids and amines utilizing coupling
reagents such as carbodiimides (e.g. dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride),
uronium/guanidinium salts such as
N-[(1H-benzotriazol-1-yl)dimethylamino)methylene]-N-methyl-methanaminium
hexafluorophosphate N-oxide (HBTU) or 1,1'-carbonyldiimidazole
beside others. Active esters or mixed anhydrides of isonicotinic
acids can also be used for the synthesis of amides 6. Other
suitable amide coupling procedures are disclosed in Goodman, M.;
Felix, A.; Moroder, L.; Toniolo, C. in volume E22a of Methods of
Organic Chemistry (Houben-Weyl), Synthesis of Peptides and
Peptidomimetics, 4th edition, Georg Thieme Verlag, Stuttgart--New
York, 2002.
[0297] Amides 6 can be readily converted into corresponding
thioamides utilizing Lawesson's Reagen or phoshorus pentasulfide in
inert solvents like ethereal solvents such as tetrahydrofuran or
dioxane or aromatic solvents such as toluene under reflux
conditiones. Thioamides can be further reacted in the same manner
as the amides to afford corresponding thioamide analogs of 10.
[0298] The protected nitrogen of amide 6 can be deprotected by
suitable deprotection procedures applicable for the particular
protecting group to yield the spirocyclic amine 7. Suitable methods
for deprotection are described by Greene and Wuts, in Protective
Groups in organic synthesis, 3rd edition, John Wiley & Sons,
Inc., New York, 1999. For example, if compound 6 is protected by
tert-butyl-carbamate (Boc) suitable deprotection methods are, but
are not limited to treatment with trifluoroacetic acid in
dichloromethane or hydrochloric acid in anhydrous dioxane as shown
in Scheme 3. The resulting piperidinium salts can be neutralized
with base to yield the corresponding piperidines 7. Suitable bases
include, but are not limited to alkali metal carbonates, alkali
metal hydrogencarbonates, alkali hydroxides as well as organic
bases such as tertiary amines etc.
##STR00005##
[0299] The spirocyclic amine 7 may be functionalized to a tertiary
amine 10 by alkylation with an alkylation agent 8 or by reductive
amination with suitable aldehydes 9 as shown in Scheme 4.
Alkylation agents may be electrophiles containing halides such as
iodo or preferably chloro and bromo and sulfonates such as
p-toluenesulfonates, trifluoromethanesulfonates etc., which may be
reacted in organic solvents such as dichloromethane, chloroform,
1,2-dichloroethane or preferably amide solvents such as
dimethylformamide and N-methylpyrrolidinone, in the presence of
suitable bases such as tertiary amines such as trietylamine,
diisopropylethylamine, etc., or inorganic bases such as alkali
metal carbonates, alkali metal hydrogencarbonates. Optionally, the
alkylation may be catalyzed by halide salts such as sodium iodide,
potassium iodide or tetrabutylammonium iodide. Alternatively, a
compound of formula 7 may be reacted with an aldehyde 9, wherein
T=--CH(CH.sub.3)--, --CH.sub.2--O--, --CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--O--, --CH.dbd.CH--,
--CH.sub.2--CH.sub.2--, at a temperature between ambient
temperature and 100.degree. C. in an organic solvent such as
tetrahydrofuran or ethanol or mixtures of solvents in the presence
of an reducing agent such as borane-pyridine complex, sodium
borohydride, sodium (triacetoxy)borohydride, sodium
cyanoborohydride or such like, to produce a compound of formula
10.
##STR00006##
[0300] Alkylation agents 8 are preferably used for the preparation
of 10. Suitable compounds are commercially available or can be
prepared from corresponding carboxylic acids 11 or carboxylic acid
esters 12 such as methyl ester or ethyl esters etc. (R.sup.3=methyl
or ethyl) as shown in Scheme 5. Compounds 12 are reduced to
alcohols then converted to halides preferably bromo and chloro,
wherein T=--CH(CH.sub.3)--, --CH.sub.2--O--,
--CH.sub.2--CH.sub.2--O--, --CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CH.dbd.CH--, --CH.sub.2--CH.sub.2--. Suitable reducing agents
include, but are not limited to, aluminum hydrides preferably
lithium aluminum hydride, diisobutylaluminum hydride, borohydrides
such as triethylborohydrides, borane dimethyl sulfide complex and
triethoxysilane. Alcohols 13 can be converted to halides with
various reagents; the most common are halogen acids and inorganic
acid halides such as thionyl chloride, phosphorus pentachloride,
phosphorus tribromide, phosphorus oxibromide. A favored
halogenation procedure is the use of triphenylphosphine in
combination with carbon tetrabromide or carbon tetrachloride in
inert solvents such as dichloromethane. Several methods are known
to a person skilled in the art to convert carboxylic acids to
corresponding alcohols. A convenient procedure is for example the
in situ transformation of 11 to the corresponding mixed anhydrides
by reagents such as isobutyl chloroformate which can then be
reduced to the corresponding alcohols 13 with several reducing
agents such as sodium borohydride.
##STR00007##
Synthesis Examples
[0301] The following examples are for illustrative purposes only
and are not intended to limit the scope of the invention. The
compounds were named using Symyx.RTM.draw version 3.1.Net software
(Symyx Technologies, Inc.)
Example 1
(2-chloro-4-pyridyl)-(5-chlorospiro[indoline-3,4'-piperidine]-1-yl)methano-
ne (Intermediate of formula 7)
##STR00008##
[0302] Step A:
Tert-butyl-4-(methoxymethylene)piperidine-1-carboxylate
[0303] Methoxymethyl(triphenyl)phosphonium chloride (342.0 g, 1
mol) was suspended in ether (1100 ml). Within 30 min a solution of
n-butyllithium in hexane (400 ml, 3.5 M, 1.4 mol) was added
dropwise at -10.degree. C. The resulting mixture was stirred for 1
h at 0-5.degree. C. and afterwards a solution of
tert-butyl-4-oxopiperidine-1-carboxylate (199.3 g, 1 mol) in ether
(1100 ml) was added slowly at -20.degree. C. The suspension was
allowed to warm up to room temperature and was stirred for
additional 2 h. The formed precipitate was filtered off, and washed
with ether (300 ml). The filtrate and the combined organic washes
were concentrated to give a yellow oil, which was then dissolved in
tert-butyl methyl ether (270 ml) and washed with water (150 ml).
The organic layer was separated and dried over magnesium sulfate.
After removal of the organic solvent the crude product was purified
by flash chromatography on a silica gel column (2.7 kg; 10 to 30%
tert-butyl methyl ether/petrolether). 140 g (617 mmol, 62%) of the
desired product as a light yellow oil were obtained. MS (ES)
m/z=172.1 [M-tert-butyl+H].sup.+.
Step B: Tert-butyl
5-chlorospiro[indoline-3,4'-piperidine]-1'-carboxylate
[0304] Tert-butyl 4-(methoxymethylene)piperidine-1-carboxylate (6.0
g, 26.4 mmol) and 4-chlorophenylhydrazine hydrochloride (4.73 g,
26.4 mmol) were suspended in chloroform (300 ml) under an argon
atmosphere. At 4.degree. C. ethanol (0.5 ml) and trifluoroacetic
acid (6.0 ml) were added sequentially to the stirred reaction
mixture, which was allowed to stir overnight at 50.degree. C. The
dark green suspension was cooled down to room temperature and was
poured into a mixture of ice water (250 ml) and concentrated
ammonium hydroxide solution (100 ml) and was stirred for 90 min.
The organic layer was separated and the aqueous phase was extracted
with dichloromethane (3.times.50 ml). The combined organic phases
were washed with brine, dried over anhydrous magnesium sulfate and
concentrated to yield a brown solid which was further dried under
vacuum. The crude tert-butyl
5-chlorospiro[indole-3,4'-piperidine]-1'-carboxylate was dissolved
in ethanol (100 ml) and a suspension of sodium borohydride (3.1 g,
81.8 mmol) in ethanol (100 ml) was added within 30 min at room
temperature while stirring. After 12 h the reaction mixture was
concentrated and re-dissolved in dichloromethane. The organic phase
was washed twice with water, afterwards with brine and dried over
anhydrous magnesium sulfate. The organic solvent was removed to
afford a brown solid (7.0 g, 21.7 mmol, 82%). The product was used
for the next step without further purification.
[0305] MS (ES) m/z=323.1 [M+H].sup.+
Step C: 2-Chloropyridine-4-carbonyl chloride
[0306] 2-Chloropyridine-4-carboxylic acid (20.0 g, 127 mmol) was
added slowly to thionyl chloride (120 ml) at room temperature.
After addition of dimethylformamide (0.05 ml) the reaction mixture
was heated under reflux for 2.5 h. The thionyl chloride was removed
in vacuo and the remaining liquid was diluted in toluene (100 ml).
The solution was concentrated to afford a yellow oil (20.2 g, 115
mmol, 91%) which was taken to the next step without further
purification.
Step D: Tert-butyl
5-chloro-1-(2-chloropyridine-4-carbonyl)spiro[indoline-3,4'-piperidine]-1-
'-carboxylate
[0307] Tert-butyl
5-chlorospiro[indoline-3,4'-piperidine]-1'-carboxylate (30.0 g,
92.9 mmol) was dissolved in dichloromethane (200 ml) and
triethylamine (11.3 g, 112 mmol) was added. A solution of
2-chloropyridine-4-carbonyl chloride (18.2 g, 103 mmol) in
dichloromethane (50 ml) was added within 15 min at 0.degree. C. The
brown reaction mixture was allowed to warm up to room temperature
and was stirred for 2 h. After addition of water (200 ml) the
organic phase was separated, dried over anhydrous magnesium
sulfate, followed by evaporation to afford a crude brown solid
(36.1 g). The crude product was suspended in methanol (220 ml) and
stirred at 0.degree. C. After 2 h the solid was filtered off,
washed with cold methanol and dried to yield a beige product (29.5
g, 63.8 mmol, 69%). The magnesium sulfate which was used to dry the
dichloromethane phase was extracted with dichloromethane. After
solvent evaporation another crop of a white crystalline product was
obtained (9.1 g, 19.7 mmol, 21%). MS (ES) m/z=406
[M-tert-butyl+H].sup.+.
Step E:
(2-chloro-4-pyridyl)-(5-chlorospiro[indoline-3,4'-piperidine]-1-yl-
)methanone
[0308] Tert-butyl
5-chloro-1-(2-chloropyridine-4-carbonyl)spiro[indoline-3,4'-piperidine]-1-
'-carboxylate (38.0 g, 82.2 mmol) was slowly added to a vigorously
stirred solution of HCl in dioxane (4 M, 500 ml) under nitrogen at
room temperature. The reaction mixture was stirred at room
temperature for 16 h. Then the suspension was poured on ice (750 g)
and neutralized with 2000 ml of a sodium bicarbonate solution (10%)
over a period of 2 h. The precipitate was filtered off and washed
with water (500 ml) and ethyl acetate (200 ml). The remaining solid
was dried at 50.degree. C. in vacuo to afford a beige material (27
g, 74.5 mmol, 91%). MS (ES) m/z=363.1 [M+H].sup.+.
Example 2
[5-chloro-1'-[(E)-3-(2,3-dichlorophenyl)allyl]spiro[indoline-3,4'-piperidi-
ne]-1-yl]-(2-chloro-4-pyridyl)methanone (Compound 25)
Step A: (E)-3-(2,3-dichlorophenyl)prop-2-en-1-ol
[0309] (E)-3-(2,3-dichlorophenyl)prop-2-enoic acid (1.09 g, 5.02
mmol) was dissolved in dry THF (25 ml). Triethylamine (607 mg, 6.0
mmol) was added and the solution was cooled to 0.degree. C. Then,
isobutyl chloroformate (785 mg, 5.75 mmol) was added and a white
precipitate was formed immediately. The suspension was stirred for
1 h at 0.degree. C. and the solids were filtered off. Water (1 ml)
was added to the filtrate followed by the addition of sodium
borohydride (378 mg, 10.0 mmol) in one portion. The solution was
stirred for 1 h at 0.degree. C. and then carefully quenched with 2N
HCl solution. The solution was extracted with ethyl acetate and the
organic layer was washed with saturated sodium chloride solution
and finally dried over sodium sulfate. After concentration of the
organic layer under reduced pressure, the crude product was
purified by flash chromatography over a pre-packed silica column
using a heptane/ethyl acetate gradient. After purification and
concentration of the product fractions a white solid was obtained
(998 mg, 4.91 mmol, 98% yield). MS (EI) m/z=204.1 M.
Step B: 1-[(E)-3-bromoprop-1-enyl]-2,3-dichloro-benzene
[0310] (E)-3-(2,3-dichlorophenyl)prop-2-en-1-ol (998 mg, 4.91 mmol)
was dissolved in dichloromethane (25 ml) and
triphenylphosphine-polymer bound (3.2 g, 4.86 mmol, 1.52 mmol/g)
was added. Tetrabromomethane (1.63 g, 4.91 mmol) was added and the
suspension was stirred at ambient temperature for 1 h. The
polymerbound triphenylphoshine was filtered off and the solvent was
evaporated in vacuo. The crude mixture was purified by flash
chromatography over a pre-packed silica column (100% heptane).
After purification a colorless solid (1.01 g, 3.80 mmol, 77%) was
obtained. MS (EI) m/z=266.0 M.
Step C: 2-Chloropyridine-4-carbonyl chloride
[0311] 2-Chloropyridine-4-carboxylic acid (366 mg, 2.32 mmol) was
suspended in dichloromethane (10 ml) and cooled to 0.degree. C.
Then, oxalyl chloride (1.47 g, 11.6 mmol) and a few drops of
dimethylformamide were added to the suspension. The mixture was
allowed to warm to ambient temperature and stirred for 1.5 h. The
solvent and the excess of oxalyl chloride were removed in vacuo and
co-evaporated with dry toluene (20 ml). The product was used
without further purification in the next reaction.
Step D: Tert-butyl
5-chloro-1-(2-chloropyridine-4-carbonyl)spiro[indoline-3,4'-piperidine]-1-
'-carboxylate
[0312] 2-Chloropyridine-4-carbonyl chloride (366 mg, 2.32 mmol) was
dissolved in dichloromethane (10 ml) and a mixture of tert-butyl
5-chlorospiro[indoline-3,4'-piperidine]-1'-carboxylate (750 mg,
2.32 mmol, Example 1, step B) and triethylamine (705 mg, 6.97 mmol)
in dichloromethane (5 ml) was added dropwise at 0.degree. C. The
ice water bath was removed and the mixture was stirred overnight at
room temperature. A saturated aqueous solution of sodium carbonate
was added and the organic layer was separated, dried over sodium
sulfate and concentrated under reduced pressure. The crude mixture
was purified by flash chromatography over a pre-packed silica
column using a heptane/ethyl acetate gradient. The collected
fractions gave an off-white solid (832 mg, 1.80 mmol, 78%) which is
used without analysis in the next reaction.
Step E:
(2-Chloro-4-pyridyl)-(5-chlorospiro[indoline-3,4'-piperidine]-1-yl-
)methanone
[0313] Tert-butyl
5-chloro-1-(2-chloropyridine-4-carbonyl)spiro[indoline-3,4'-piperidine]-1-
'-carboxylate was stirred in a 1:1 mixture of
dichloromethane/trifluoroacetic acid (20 ml) at room temperature
for 1 h. Then the reaction mixture was quenched with a saturated
aqueous solution of sodium bicarbonate. The layers were separated
and the organic layer was dried over sodium sulfate. After
evaporation in vacuo an off-white solid (650 mg, 1.79 mmol, 99%)
was obtained. The product was used without further purification in
the next reaction. MS (ES) m/z=362.0 [M+H].sup.+.
Step F:
[5-Chloro-1'-[(E)-3-(2,3-dichlorophenyl)allyl]spiro[indoline-3,4'--
piperidine]-1-yl]-(2-chloro-4-pyridyl)methanone
[0314]
(2-Chloro-4-pyridyl)-(5-chlorospiro[indoline-3,4'-piperidine]-1-yl)-
methanone (144 mg, 0.398 mmol) was dissolved in dry
dimethylformamide (2 ml) and polymer-supported
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine (BEMP) (399 mg, 0.878 mmol, 2.2 mmol/g) was added. The mixture
was stirred at 60.degree. C. for 30 min.
1-[(E)-3-bromoprop-1-enyl]-2,3-dichloro-benzene (158 mg, 0.594
mmol) and catalytic amounts of potassium iodide were added and the
reaction mixture was stirred at 100.degree. C. overnight. After
cooling down to ambient temperature, the resin was filtered off and
rinsed several times with dichloromethane. The filtrate was
evaporated in vacuo. The crude mixture was purified by flash
chromatography over a pre-packed silica column using a 99% heptane
1% triethylamine/ethyl acetate gradient. The remaining product was
purified for a second time by flash chromatography over a
pre-packed silica column using a gradient of 0.1 M ammonium
hydroxide in dichloromethane and methanol. After the second
purification step a white solid (118 mg, 0.216 mmol, 54% yield) was
obtained. MS (ES) m/z=548.0 [M+H].sup.+
Example 3
[0315] Compounds 8, 14, 15, 26, 27, 30, 31, 33, 34, 35, 36, 49 and
50 were synthesized according to Example 2, using the appropriate
starting compounds.
Example 4
(2-Chloro-4-pyridyl)-[11'-[(E)-3-(3,4-difluorophenyl)allyl]-5-fluoro-spiro-
[indoline-3,4'-piperidine]-1-yl]methanone (Compound 55)
Step A:
Tert-butyl-5-fluorospiro[indole-3,4'-piperidine]-1'-carboxylate
[0316] Tert-butyl-4-(methoxymethylene)piperidine-1-carboxylate (7.0
g, 30.8 mmol) was suspended in tert-butyl methyl ether (50 ml) and
acetonitrile (25 ml) and (4-fluorophenyl)hydrazine hydrochloride
(5.0 g, 30.8 mmol) and ethanol (0.5 ml) were added. Within 10 min
trifluoroacetic acid (9.1 g, 79.8 mmol) was added dropwise to the
grey suspension at 20.degree. C. The reaction mixture was stirred
for 6 h at 50.degree. C. and cooled down to room temperature. 25 ml
of an ammonium hydroxide solution (25%) were added while stirring.
The resulting red colored organic layer was washed with 15 ml brine
and dried over sodium sulfate. After removal of organic solvents in
vacuo a red oil (9.8 g) was obtained. The crude product was taken
directly to the next step without further purification.
Step B:
Tert-butyl-5-fluorospiro[indoline-3,4'-piperidine]-1'-carboxylate
[0317]
Tert-butyl-5-fluorospiro[indole-3,4'-piperidine]-1'-carboxylate
(9.8 g) was dissolved in 75 ml ethanol and cooled down to
10.degree. C. Sodium borohydride (2.3 g, 62 mmol) was added slowly
in four portions while keeping the temperature constant. The yellow
reaction mixture was allowed to reach room temperature and was
stirred for 20 h. The formed solid was filtered off and was washed
with cold ethanol (20 ml). Then it was suspended in water (50 ml)
and stirred for 30 min. The remaining solid material was filtered
off, washed with water (25 ml) and dried in vacuo at 50.degree. C.
to afford a beige colored solid (3.6 g, 11.7 mmol, 38% over two
steps) MS (ES) m/z=306.8 [M+H].sup.+.
Step C: Tert-butyl
1-(2-chloro-pyridine-4-carbonyl)-5-fluoro-spiro[indoline-3,4'-piperidine]-
-1'-carboxylate
[0318] 2-Chloropyridine-4-carbonyl chloride (1.38 g, 7.84 mmol) was
dissolved in dichloromethane (50 ml) under argon atmosphere and
triethylamine (1.85 ml, 13.3 mmol) was added. A solution of
tert-butyl-5-fluorospiro[indoline-3,4'-piperidine]-1'-carboxylate
(1.50 g, 4.9 mmol) in 20 ml dichloromethane was added dropwise to
the reaction mixture and stirred overnight at room temperature. The
organic phase was washed 4 times with saturated sodium bicarbonate
buffer, once with brine and was concentrated. The crude product was
purified by flash chromatography over a silica gel column using an
eluent consisting of dichloromethane and methanol 19:1. After
concentration of the collected fractions the product was obtained
as a red solid (1.6 g, 3.6 mmol, 73%). MS (ES) m/z=390.1
[M-tert-butyl+H].sup.+.
Step D:
(2-Chloro-4-pyridyl)-(5-fluorospiro[indoline-3,4'-piperidin-1-ium]-
-1-yl)methanone chloride
[0319] Tert-butyl
1-(2-chloropyridine-4-carbonyl)-5-fluoro-spiro[indoline-3,4'-piperidine]--
1'-carboxylate (5.46 g, 12.2 mmol) was slowly added to a vigorously
stirred solution of HCl in dioxane (4 M, 35 ml) under nitrogen at
room temperature. After 2 h the precipitate was filtered off,
washed with dioxane and diethyl ether and dried in vacuo. The crude
product (5 g) was used without further purification. MS (ES)
m/z=345.9 [M+H].sup.+.
Step E:
(2-Chloro-4-pyridyl)-[1'-[(E)-3-(3,4-difluorophenyl)allyl]-5-fluor-
o-spiro[indoline-3,4'-piperidine]-1-yl]methanone
[0320]
(2-Chloro-4-pyridyl)-(5-fluorospiro[indoline-3,4'-piperidin-1-ium]--
1-yl)methanone chloride (191 mg, 0.50 mmol) was dissolved in dry
dimethylformamide and N,N-diisopropylethylamine (0.174 ml, 1 mmol)
was added. A solution of
4-[(E)-3-bromoprop-1-enyl]-1,2-difluoro-benzene (117 mg, 0.50 mmol)
in 0.5 ml dimethylformamide was added dropwise and stirred for 40
min at room temperature. The reaction mixture was quenched with
water (5 ml) and dissolved with 20 ml dichloromethane. The organic
phase was washed three times with water (20 ml), once with brine
and dried over magnesium sulfate. The organic phase was
concentrated and dried in vacuo. The remaining residue was
dissolved in 3 ml acetonitrile and 0.1 ml dimethyl sulfoxide and
purified by reversed phase chromatography using a Sunfire.TM.
column (5 .mu.m, 19.times.100 mm, Waters Corp.) and acetonitrile
and aqueous 0.2% trifluoroacetic acid buffer as gradient. The
combined product fractions were treated with saturated aqueous
sodium bicarbonate buffer to obtain basic pH and the acetonitrile
was evaporated. The remaining aqueous solution was extracted three
times with dichloromethane. The combined organic phases were washed
with brine and dried over magnesium sulfate. After removal of the
solvent the beige product (56.7 mg, 0.114 mmol, 23%) was obtained.
MS (ES) m/z=497.9 [M+H].sup.+.
B: Analytics
[0321] a) HPLC Methods
Method 1
HPLC-MS System:
[0322] Agilent HPLC/MSD 1100 series composed of: Binary pump G
1312A included degasser G1379A, well plate sampler G1367A, column
oven G1316A, diode array detector G1315B, mass detector G1946D SL
with ESI-source and evaporating light detector Sedex 75.
Chromatographic System:
[0323] Column: Atlantis dC18 from Waters, 4.6*50 mm, 3.mu. Oven:
30.degree. C. ambient
Injection: 2.0 .mu.l
Eluents:
[0324] Solvent A: water/formic acid: 99.9/0.1 vol./vol. Solvent B:
acetonitrile/formic acid: 99.9/0.1 vol./vol. Flow: 1.0 ml/min
Gradient:
TABLE-US-00001 [0325] Time Solvent A Solvent B [min] [%] [%] 0.0 95
5 1.0 95 5 5.0 2 98 7.0 2 98
Run time: 10 min (equilibration included)
Detection Methods:
[0326] UV at 210 nm and 254 nm
[0327] ESI/MS (100-1000 m/z), positive ions
[0328] ELSD (Sedex 75)
Comment: Samples diluted in a 1 to 1 mixture of solvents A and B
prior to analysis
Method 2
HPLC-MS System:
[0329] Agilent HPLC/MSD 1100 series composed of: Binary pump G
1312A included degasser G1379A, well plate sampler G1367A, column
oven G1316A, diode array detector G1315B, mass detector G1946D SL
with ESI-source and evaporating light detector Sedex 75.
Chromatographic System:
Column: Chromolith Fast Gradient, RP-18e, 50*2 mm
[0330] Oven: 35.degree. C. ambient
Injection: 1.0 .mu.l
Eluents:
[0331] Solvent A: water/formic acid=99.9/0.1 vol./vol. Solvent B:
acetonitrile/formic acid=99.9/0.1 vol./vol. Flow: 1.2 ml/min
Gradient:
TABLE-US-00002 [0332] Time Solvent A Solvent B [min] [%] [%] 0.0 90
10 2.0 0 100 2.7 0 100 3.0 90 10
Run time: 3.5 min (equilibration included)
Detection Methods:
UV at 254 nm, 210 nm
[0333] ESI/MS (100-1000 m/z), positive ions
ELSD (Sedex 75)
[0334] Comment: dilute samples in a mixture of solvent A and B 1:1
prior to analysis
Method 3
HPLC-MS System:
[0335] Agilent LC/MSD Trap 1100 series composed of: Binary pump G
1312A included degasser G1379A, well plate sampler G1367A, column
oven G1316A, diode array detector G1315B, and mass detector G2445D
with APCI-source.
Chromatographic System:
Column: XBridge C18 von Waters, 4.6*50 mm., 2.5.mu.
[0336] Oven: 40.degree. C. ambient
Injection: 2.0 .mu.l
Eluents:
[0337] Solvent A: water/ammonia: 99.9/0.1 vol./vol. Solvent B:
acetonitrile 100% Flow: 1.0 ml/min
Gradient:
TABLE-US-00003 [0338] Time Solvent A Solvent B [min] [%] [%] 0.0 90
10 4.0 0 100 5.0 0 100 5.5 90 10
Run time: 8 min (equilibration included)
Detection Methods:
UV at 254 nm, 210 nm
[0339] APCI/MS (100-1500 m/z), positive ions Comment: Samples
diluted in a 1 to 1 mixture of solvents A and B prior to
analysis
Method 4
HPLC-MS System:
[0340] Agilent LC/MSD 1100 SL series composed of: Diode array
detector G1316A, mass detector Agilent LC/MSD-SL, evaporating light
detector and Alltech ELSD2000,
Chromatographic System:
Column: Phenomenex Gemini.RTM. C18, 150.times.4.6 mm, 5.0.mu.
Oven: 35.degree. C.
Injection: 1.0 .mu.l
Eluents:
[0341] Solvent A: 10 mM formic acid in acetonitrile Solvent B: 10
mM formic acid in water Flow: 1 ml/min
Gradient:
TABLE-US-00004 [0342] Time Solvent A Solvent B [min] [%] [%] 0.0 2
98 10.5 98 2 18 98 2
Detection Methods:
UV at 320-220 nm
[0343] ESI/MS (100-800 m/z), positive and negative ions
ELSD (Alltech ELSD2000)
[0344] Comment: dilute samples in a mixture of solvent A and B1:1
prior to analysis.
Method 5
HPLC-MS System:
[0345] Agilent LC/MSD 1200 SL series composed of: Diode array
detector Agilent G1315D and mass detector Agilent LC/MSD-SL.
Chromatographic System:
[0346] Column: Phenomenex Gemini.RTM. C18, 50.times.2.0 mm,
3.mu.
Oven: 30.degree. C.
Injection: 1 .mu.l
Eluents:
[0347] Solvent A: water/formic acid: 99.9/0.1 vol./vol. Solvent B:
acetonitrile/formic acid: 99.9/0.1 vol./vol. Flow: 0.8 ml/min
Gradient:
TABLE-US-00005 [0348] Time Solvent A Solvent B [min] [%] [%] 0.0 98
2 3.5 2 98 6 2 98
Run time: Detection: UV 220 nm-320 nm; 270 nm ESI/MS (85-1000 m/z),
positive ions Comment: Samples diluted in a 1 to 1 mixture of
solvents A and B prior to analysis
[0349] b) Analytical Data
[0350] Table I below provides for each of 99 synthesized compounds
of the formula (I) the structure, the calculated molecular weight
(MW) (gram/mol), the observed MS signal (m/z), the HPLC retention
time (RT) in minutes (min), and the HPLC-method used for
analysis.
[0351] Compounds of Formula (I)
##STR00009##
TABLE-US-00006 TABLE I No. A.sup.1 A.sup.2 A.sup.3 A.sup.4 B.sup.1
B.sup.2 B.sup.3 B.sup.4 B.sup.5 R.sup.1 R.sup.2 Y Q 1 H Cl H H H H
F H H H Cl O (--CH.sub.2--CH.dbd.CH--) (E) 2 H Cl H H H H CF.sub.3
H H H Cl O (--CH.sub.2--CH.dbd.CH--) (E,Z) 3 H Cl H H H H CH.sub.3
H H H Cl O (--CH.sub.2--CH.dbd.CH--) (E) 4 H Cl H H H H Cl H H H Cl
O (--CH.sub.2--CH.dbd.CH--) (E,Z) 5 H Cl H H H H F H F H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 6 H Cl H H H H H H H CH.sub.3 Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 7 H Cl H H H H CH.sub.3 H H H Cl O
(--CH.sub.2--CH.sub.2--O--) 8 H Cl H H H H F H H H Cl O
(--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--) 9 H Cl H H H H F H
H H Cl O (--CH.sub.2--CH.sub.2--CH.sub.2--O--) 10 H Cl H H H H H H
H Cl Cl O (--CH.sub.2--CH.dbd.CH--) (E) 11 H Br H H F H F H H H Cl
O (--CH.sub.2--CH.dbd.CH--) (E) 12 H CF.sub.3 H H F H F H H H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 13 H Cl H H H H F H F H H O
(--CH.sub.2--CH.dbd.CH--) (E) 14 H Cl H H F H H H H H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 15 H Cl H H H H F H F Cl Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 16 H CF.sub.3 H H F H F H H Cl Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 17 Cl H H H H H F H F H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 18 H H H Cl H H F H F H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 19 Cl H Cl H H H F H F H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 20 Cl Cl H H H H F H F H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 21 H Cl Cl H H H F H F H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 22 H Cl H Cl H H F H F H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 23 H OCF.sub.3 H H H H F H F H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 24 H Cl H H H H H H Cl H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 25 H Cl H H H H H Cl Cl H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 26 H Cl H H H H Cl H Cl H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 27 H Cl H H H H Cl Cl H H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 28 H F H H H H F H F Cl Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 29 H Cl H H H H H H Cl Cl Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 30 H Cl H H H H Cl H Cl Cl Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 31 H Cl H H H H H H F Cl Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 32 H Cl H H F H H H F Cl Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 33 H Cl H H H H F H F H CH.sub.3 O
(--CH.sub.2--CH.dbd.CH--) (E) 34 H Cl H H H H F H F H F O
(--CH.sub.2--CH.dbd.CH--) (E) 35 H Cl H H H H H H Cl CH.sub.3 Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 36 H Cl H H H H Cl H Cl CH.sub.3 Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 37 H Cl H H H H H H F CH.sub.3 Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 38 H Cl H H F H H H F CH.sub.3 Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 39 H Cl H H H H F H F H CF.sub.3 O
(--CH.sub.2--CH.dbd.CH--) (E) 40 H Cl H H F F F F F Cl Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 41 H Cl H H H H F F H H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 42 H CF.sub.3 H H H H Cl H H H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 43 H F H H H H F H F H CF.sub.3 O
(--CH.sub.2--CH.dbd.CH--) (E) 44 H OCF.sub.3 H H H H F H H H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 45 H OCF.sub.3 H H H H F F H H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 46 H Cl H H H H F H H CH.sub.3
CH.sub.3 O (--CH.sub.2--CH.dbd.CH--) (E) 47 H Cl H H H H CH.sub.3 H
H CH.sub.3 CH.sub.3 O (--CH.sub.2--CH.dbd.CH--) (E) 48 H Cl H H H H
F H F CH.sub.3 CH.sub.3 O (--CH.sub.2--CH.dbd.CH--) (E) 49 H
CF.sub.3 H H H H F H H H Cl O (--CH.sub.2--CH.dbd.CH--) (E) 50 H
CF.sub.3 H H H H CF.sub.3 H H H Cl O (--CH.sub.2--CH.dbd.CH--) (E)
51 H Cl H H H H Cl H F H Cl O (--CH.sub.2--CH.dbd.CH--) (E) 52 H Cl
H H F H H H Cl H Cl O (--CH.sub.2--CH.dbd.CH--) (E) 53 H Cl H H F H
H F Cl Cl Cl O (--CH.sub.2--CH.dbd.CH--) (E) 54 H Cl H H H H Cl Cl
H H F O (--CH.sub.2--CH.dbd.CH--) (E) 55 H F H H H H F F H H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 56 H Cl H H H H Cl H Cl H CH.sub.3 O
(--CH.sub.2--CH.dbd.CH--) (E) 57 H Cl H H H Cl H H H H Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 58 H Cl H H Cl H H H F Cl Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 59 H Cl H H H F Cl H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 60 H Cl H H H Cl H F H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 61 H F H H H H CH.sub.3 H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 62 H Cl H H H H Cl H H F H O
(--CH.sub.2--CH.dbd.CH--) (E) 63 H Cl H H H H CH.sub.3 H H CH.sub.3
H O (--CH.sub.2--CH.dbd.CH--) (E) 64 H Cl H H F F F F F CH.sub.3 Cl
O (--CH.sub.2--CH.dbd.CH--) (E) 65 H OCF.sub.3 H H H H CH.sub.3 H H
Cl H O (--CH.sub.2--CH.dbd.CH--) (E) 66 H F H H H H CN H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 67 H F H H Cl H Cl H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 68 H CF.sub.3 H H Cl H Cl H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 69 H F H H F H F H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 70 H F H H F H H H H Cl Cl O
(--CH.sub.2--CH.dbd.CH--) (E) 71 H CH.sub.3 H H H Cl Cl H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 72 H Cl H H H F CF.sub.3 H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 73 H Cl H H CF.sub.3 H F H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 74 H Cl H H F H CF.sub.3 H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 75 H Cl H H H NO.sub.2 H H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 76 H Cl H H H H Cl H H Cl H S
(--CH.sub.2--CH.dbd.CH--) (E) 77 H SCF.sub.3 H H H Cl Cl H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 78 H CH.sub.3 H H F H F H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 79 H CH.sub.3 H H Cl H Cl H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 80 H CH.sub.3 H H H Cl Cl H H F H O
(--CH.sub.2--CH.dbd.CH--) (E) 81 H F H H H F H H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 82 H CF.sub.3 H H H F H F H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 83 H F H H H F H F H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 84 H F H H F H H H F Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 85 H CH.sub.3 H H H H Cl H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 86 H CH.sub.3 H H H H F H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 87 H CH.sub.3 H H F H Cl H H Cl H O
(--CH.sub.2--CH.dbd.CH--) (E) 88 H CH.sub.3 H H H H OCF.sub.3 H H
Cl H O (--CH.sub.2--CH.dbd.CH--) (E) 89 H OCH.sub.3 H H H Cl Cl H H
Cl H O (--CH.sub.2--CH.dbd.CH--) (E) 90 H OCH.sub.3 H H H H
CF.sub.3 H H Cl H O (--CH.sub.2--CH.dbd.CH--) (E) 91 H OCH.sub.3 H
H H H Cl H H Cl H O (--CH.sub.2--CH.dbd.CH--) (E) 92 H OCH.sub.3 H
H H H F H H Cl H O (--CH.sub.2--CH.dbd.CH--) (E) 93 H OCH.sub.3 H H
F H F H H Cl H O (--CH.sub.2--CH.dbd.CH--) (E) 94 H OCH.sub.3 H H F
H Cl H H Cl H O (--CH.sub.2--CH.dbd.CH--) (E) 95 H CH.sub.3 H H H H
CH.sub.3 H H Cl H O (--CH.sub.2--CH.dbd.CH--) (E) 96 H CH.sub.3 H H
H H OCH.sub.3 H H Cl H O (--CH.sub.2--CH.dbd.CH--) (E) 97 H
CH.sub.3 H H H H CF.sub.3 H H Cl H O (--CH.sub.2--CH.dbd.CH--) (E)
98 H CH.sub.3 H H F H H H H Cl H O (--CH.sub.2--CH.dbd.CH--) (E) 99
H OCH.sub.3 H H H H CH.sub.3 H H Cl H O (--CH.sub.2--CH.dbd.CH--)
(E) No. MW calculated (g/mol) m/z RT (min) HPLC Method 1 496.41 496
1.465 METHOD 2 2 546.42 546 4.787, 4.834 (E,Z) METHOD 1 3 492.45
492 1.513 METHOD 2 4 512.87 512 4.742, 4.785 (E,Z) METHOD 1 5
514.40 514 4.649 METHOD 1 6 492.45 492 1.543 METHOD 2 7 496.44 496
4.685 METHOD 1 8 528.45 528 2.789 METHOD 5 9 514.43 514 4.509
METHOD 1 10 512.87 512 4.887 METHOD 1 11 558.85 560 4.481 METHOD 1
12 547.95 548 4.513 METHOD 1 13 479.96 480 4.430 METHOD 1 14 496.41
496 2.740 METHOD 5 15 548.85 548 2.966 METHOD 5 16 582.40 582 1.624
METHOD 2 17 514.40 514 1.557 METHOD 2 18 514.40 514 1.486 METHOD 2
19 548.85 548 1.616 METHOD 2 20 548.85 548 1.654 METHOD 2 21 548.85
550 1.634 METHOD 2 22 548.85 548 1.506 METHOD 2 23 563.95 564 1.645
METHOD 2 24 512.87 514 1.535 METHOD 2 25 547.31 548 3.006 METHOD 5
26 547.31 548 2.993 METHOD 5 27 547.31 548 3.216 METHOD 4 28 532.39
532 1.651 METHOD 2 29 547.31 548 1.645 METHOD 2 30 581.76 582 3.021
METHOD 5 31 530.86 530 2.905 METHOD 5 32 548.85 548 1.619 METHOD 2
33 493.98 494 2.636 METHOD 5 34 497.95 498 2.836 METHOD 5 35 526.89
528 2.943 METHOD 5 36 561.34 562 3.082 METHOD 5 37 510.44 510 1.524
METHOD 2 38 528.43 528 1.538 METHOD 2 39 547.95 548 1.656 METHOD 2
40 602.82 604 1.743 METHOD 2 41 514.40 514 1.664 METHOD 2 42 546.42
546 1.605 METHOD 2 43 531.50 532 1.603 METHOD 2 44 545.96 546 1.580
METHOD 2 45 563.95 564 1.599 METHOD 2 46 490.02 490 4.567 METHOD 3
47 486.06 486 4.772 METHOD 3 48 508.01 508 4.656 METHOD 3 49 529.96
530 3.599 METHOD 5 50 579.97 580 2.980 METHOD 5 51 530.86 530 1.620
METHOD 2 52 530.86 532 1.550 METHOD 2 53 583.29 584 1.652 METHOD 2
54 530.86 530 1.639 METHOD 2 55 497.95 498 1.625 METHOD 2 56 526.89
528 1.447 METHOD 2 57 512.87 512 2.811 METHOD 5 58 565.30 566 2.983
METHOD 5 59 530.86 530 2.882 METHOD 5 60 530.86 530 2.891 METHOD 5
61 475.99 476 3.497 METHOD 5 62 496.41 496 1.544 METHOD 2 63 472.03
472 3.436 METHOD 5 64 582.40 582 1.576 METHOD 2 65 542.00 542 1.584
METHOD 2 66 486.98 487 1.382 METHOD 2 67 530.86 532 1.605 METHOD 2
68 580.86 580 1.669 METHOD 2 69 497.95 498 1.526 METHOD 2 70 514.40
514 1.641 METHOD 2 71 526.89 526 1.626 METHOD 2 72 564.41 564 2.992
METHOD 5 73 564.41 564 2.957 METHOD 5 74 564.41 564 2.983 METHOD 5
75 523.42 523 2.859 METHOD 5 76 528.93 528 2.952 METHOD 5 77 612.93
612 1.708 METHOD 2 78 493.98 494 1.485 METHOD 2 79 526.89 528 1.632
METHOD 2 80 510.44 510 1.610 METHOD 2 81 479.96 480 1.491 METHOD 2
82 547.95 548 1.621 METHOD 2 83 497.95 498 1.513 METHOD 2 84 497.95
498 1.474 METHOD 2 85 492.45 492 1.514 METHOD 2 86 475.99 476 2.678
METHOD 5 87 510.44 510 2.769 METHOD 5 88 542.00 542 2.841 METHOD 5
89 542.89 544 1.547 METHOD 2 90 542.00 542 2.929 METHOD 5 91 508.45
508 1.476 METHOD 2 92 491.99 492 2.787 METHOD 5 93 509.98 510 2.816
METHOD 5 94 526.44 526 2.891 METHOD 5 95 472.03 472 1.598 METHOD 2
96 488.03 488 1.550 METHOD 2 97 526.00 526 1.567 METHOD 2 98 475.99
476 1.434 METHOD 2 99 488.03 488 1.460 METHOD 2
C: Biological Examples
[0352] Efficacy Against Haemonchus contortus in Jirds.
[0353] Compounds according to this invention (numbers refer to the
compound number in Table 1) were tested in vivo using Haemonchus
contortus in jirds (Meriones unguiculatus). The jirds were orally
infected with approximately 750-3.000 third-stage larvae of
Haemonchus contortus. Ten days after infection, the jirds in the
treatment groups were treated once either orally or subcutaneously
with compounds at a dose of 10 mg or 50 mg per kg bodyweight. Three
days after treatment, the jirds were necropsied, and the larvae
burden in the stomach was determined. During the study no
side-effects in jirds were observed. The efficacy was defined as
the reduction of the mean larvae count in the infected jirds of the
treatment group in comparison to the infected jirds in an untreated
control group (negative control).
[0354] a) The compounds with Nos 1, 2, 3, 4, 5, 12, 13, 17, 19, 22,
23, 26, 31, 32, 33, 36, 37 and 40 reduced the Haemonchus contortus
count by at least 50% when administered orally at 50 mg/kg bw.
[0355] b) The compounds with Nos 10, 11, 14, 57, 15, 16, 18, 20,
21, 24, 25, 27, 28, 29, 30, 34 and 35 reduced the Haemonchus
contortus count by at least 50% when administered subcutaneously at
50 mg/kg bw.
[0356] c) The compounds with Nos 43, 46, 49, 42, 50, 53, 58, 64,
65, 66, 68, 72, 73, 74, 76, 77, 81, 82, 85, 87, 90, 92, 93, 95, 98
and 99 reduced the Haemonchus contortus count by at least 50% when
administered orally at 10 mg/kg.
[0357] d) The compounds with Nos 41, 44, 45, 48, 51, 54, 59, 62,
63, 67, 69, 70, 71, 75, 78, 79, 80, 83, 84, 86, 88, 89, 91, 94, 96
and 97 reduced the Haemonchus contortus count by at least 50% when
administered subcutaneously at 10 mg/kg.
DEFINITIONS
[0358] The term "alkyl" (alone or in combination with another
term(s)) means a straight- or branched-chain saturated hydrocarbyl
substituent (i.e., a substituent containing only carbon and
hydrogen) typically containing from 1 to about 20 carbon atoms,
more typically from 1 to about 8 carbon atoms, and even more
typically from 1 to about 4 carbon atoms. Examples of such
substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl,
iso-butyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, and
octyl. The term "C.sub.1-C.sub.4-alkyl" includes methyl, ethyl,
n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl,
typically preferred are methyl and ethyl, even more preferred is
typically methyl.
[0359] The term "halogen" (alone or in combination with another
term(s)) means a fluorine radical ("fluoro", which may be depicted
as F), chlorine radical ("chloro", which may be depicted as Cl),
bromine radical ("bromo", which may be depicted as Br), or iodine
radical ("iodo", which may be depicted as I). Typically, fluoro or
chloro is preferred.
[0360] When a chemical formula is used to describe a mono-valent
substituent, the dash on the left side of the formula indicates the
portion of the substituent that has the free valence. To
illustrate, benzene substituted with --C(O)--OH has the following
structure:
##STR00010##
[0361] When a chemical formula is used to describe a di-valent (or
"linking") component between two other components of a depicted
chemical structure (the right and left components), the leftmost
dash of the linking component indicates the portion of the linking
component that is bound to the left component in the depicted
structure. The rightmost dash, on the other hand, indicates the
portion of the linking component that is bound to the right
component in the depicted structure. In Formula (I) and compounds 8
and 10 the leftmost dash indicates the portion of Q which is bound
to the nitrogen atom in the piperidine ring (Formula (I), 10) or
halogen atom (8), and the rightmost dash indicates the portion of Q
which is bound to the phenyl ring. Likewise in compounds 9, 11, 12
and 13 the leftmost dash indicates the portion of T which is bound
to the CO-group (9, 11, 12) or CH.sub.2OH-group (13), and the
rightmost dash indicates the portion of T which is bound to the
phenyl ring.
[0362] The term "pharmaceutically acceptable" is used adjectivally
to mean that the modified noun is appropriate for use in a
pharmaceutical product. When it is used, for example, to describe a
salt, solvate, N-oxide, active compound or excipient, it
characterizes the salt, solvate, N-oxide, active compound or
excipient as being compatible with the other ingredients of the
composition, and not deleterious to the intended recipient animal,
e.g. to the extent that the benefit(s) outweigh(s) the deleterious
effect(s).
[0363] The above detailed description of preferred embodiments is
intended only to acquaint others skilled in the art with the
invention, its principles, and its practical application so that
others skilled in the art may adapt and apply the invention in its
numerous forms, as they may be best suited to the requirements of a
particular use. This invention, therefore, is not limited to the
above embodiments, and may be variously modified.
* * * * *