U.S. patent application number 13/474399 was filed with the patent office on 2014-03-06 for oximes for treatment of peripheral and central nervous system exposure to acetyl cholinesterase inhibitors.
This patent application is currently assigned to SOUTHWEST RESEARCH INSTITUTE. The applicant listed for this patent is Christopher J. Bemben, Bismarck Campos, Richard M. Corbett, Donald M. Maxwell, Stanton F. McHardy, Michael W. Tidwell. Invention is credited to Christopher J. Bemben, Bismarck Campos, Richard M. Corbett, Donald M. Maxwell, Stanton F. McHardy, Michael W. Tidwell.
Application Number | 20140066421 13/474399 |
Document ID | / |
Family ID | 50072118 |
Filed Date | 2014-03-06 |
United States Patent
Application |
20140066421 |
Kind Code |
A1 |
McHardy; Stanton F. ; et
al. |
March 6, 2014 |
OXIMES FOR TREATMENT OF PERIPHERAL AND CENTRAL NERVOUS SYSTEM
EXPOSURE TO ACETYL CHOLINESTERASE INHIBITORS
Abstract
The present invention relates to non-charged oxime compounds
which are acetyl cholinesterase (AChE) reactivators of inhibited
AChE and which protect against organophosphate poisoning both
peripherally and in the central nervous system. Also disclosed are
pharmaceutical compositions and methods for preparing the
reactivator compounds and associated intermediates.
Inventors: |
McHardy; Stanton F.; (San
Antonio, TX) ; Corbett; Richard M.; (San Antonio,
TX) ; Maxwell; Donald M.; (Baltimore, MD) ;
Tidwell; Michael W.; (Lakehills, TX) ; Campos;
Bismarck; (San Antonio, TX) ; Bemben; Christopher
J.; (San Antonio, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
McHardy; Stanton F.
Corbett; Richard M.
Maxwell; Donald M.
Tidwell; Michael W.
Campos; Bismarck
Bemben; Christopher J. |
San Antonio
San Antonio
Baltimore
Lakehills
San Antonio
San Antonio |
TX
TX
MD
TX
TX
TX |
US
US
US
US
US
US |
|
|
Assignee: |
SOUTHWEST RESEARCH
INSTITUTE
San Antonio
TX
|
Family ID: |
50072118 |
Appl. No.: |
13/474399 |
Filed: |
May 17, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13197550 |
Aug 3, 2011 |
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13474399 |
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Current U.S.
Class: |
514/210.2 ;
514/274; 514/297; 514/307; 514/318; 514/329; 514/331; 514/339;
514/343; 514/350; 544/316; 546/106; 546/144; 546/194; 546/224;
546/233; 546/268.1; 546/276.4; 546/276.7; 546/298 |
Current CPC
Class: |
C07D 401/12 20130101;
C07C 251/38 20130101; A61K 31/445 20130101; C07D 219/12 20130101;
A61K 31/4468 20130101; C07D 217/16 20130101; A61K 31/44 20130101;
A61K 31/4439 20130101; A61K 31/472 20130101; C07D 211/34 20130101;
A61K 31/4545 20130101; A61K 31/506 20130101; A61K 31/4453 20130101;
C07D 211/26 20130101; C07D 211/58 20130101; A61K 31/4427 20130101;
A61K 31/473 20130101; C07D 213/64 20130101; A61K 45/06
20130101 |
Class at
Publication: |
514/210.2 ;
514/274; 514/297; 514/307; 514/318; 514/329; 514/331; 514/339;
514/343; 514/350; 544/316; 546/106; 546/144; 546/194; 546/224;
546/233; 546/268.1; 546/276.4; 546/276.7; 546/298 |
International
Class: |
C07D 213/64 20060101
C07D213/64; A61K 31/506 20060101 A61K031/506; A61K 31/473 20060101
A61K031/473; A61K 31/472 20060101 A61K031/472; A61K 31/4545
20060101 A61K031/4545; A61K 31/4468 20060101 A61K031/4468; A61K
31/445 20060101 A61K031/445; A61K 31/4439 20060101 A61K031/4439;
A61K 31/44 20060101 A61K031/44; C07D 219/12 20060101 C07D219/12;
C07D 217/16 20060101 C07D217/16; C07D 401/12 20060101 C07D401/12;
C07D 211/34 20060101 C07D211/34; A61K 45/06 20060101 A61K045/06;
A61K 31/4427 20060101 A61K031/4427 |
Goverment Interests
GOVERNMENT RIGHTS CLAUSE
[0002] This invention was made with United States Government
support under Contract No. HDTRA1-10-C-0041 awarded by the Defense
Threat Reduction Agency. The Government has certain rights in this
invention.
Claims
1. An acetyl cholinesterase reactivator compound of the formula:
##STR00043## wherein: M is independently an optionally substituted
hetero-bicyclic amine, heterocyclic amine or heteroaryl amine
group, where Z is connected to M via the nitrogen; V is
independently a hydrogen, alkyl (C1 to C5) groups, benzyl or
substituted benzyl groups; Z is independently an optionally
substituted methylene or methine group from 1 to 8 carbon atoms in
length and wherein in the case of optionally substituted methylene
or methine, Z can also be connected to R.sub.1 to form a
heterocyclic or bicyclic heteratom ring from 3 to 10 atoms; and X
is independently H, cyano (CN) or COR, wherein said R group is
alkyl (C1 to C3).
2. The acetyl cholinesterase reactivator compound of claim 1
wherein the reactivator is present as the E or Z isomer with
respect to the oxime moiety.
3. The acetyl cholinesterase reactivator compound of claim 1
wherein said compound comprises a pharmaceutically acceptable salt
comprising an acid addition salt or base addition salt.
4. The acetyl cholinesterase reactivator compound of claim 3
wherein said pharmaceutically acceptable salt comprises one or more
of the following salts: acetate, adipate, aspartate, benzoate,
besylate, bicarbonate/carbonate, bisulphate/sulphate, borate,
citrate, formate, fumarate, gluconate, glucuronate,
hexafluorophosphate, hydrochloride/chloride, hydrobromide/bromide,
hydroiodide/iodide, lactate, malate, maleate, malonate, mandelates,
mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate,
nitrate, oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, pyroglutamate, salicylate,
saccharate, stearate, succinate, sulfonate, stannate, tartrate,
tosylate, and trifluoroacetate salts.
5. The acetyl cholinesterase reactivator compound of claim 3
wherein said pharmaceutically acceptable salt comprises a base salt
comprising one or more of the following: aluminium, calcium,
choline, diethylamine, diolamine, glycine, lysine, magnesium,
meglumine, olamine, potassium, sodium, and zinc.
6. The acetyl cholinesterase reactivator compound of claim 1
wherein said compound is isotopically labeled.
7. The acetyl cholinesterase reactivator compound of claim 6
wherein said isotropic labeling comprises labeling with one or more
of the following: 2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C,
.sup.36Cl, .sup.18F, .sup.123I, .sup.125I, .sup.13N, .sup.15N,
.sup.15O, .sup.17O, .sup.18O, .sup.32P, and .sup.35S.
8. A method comprising attenuating the effects on a mammal caused
by the inhibition of AChE by administering to said mammal an
effective amount of a compound, or a pharmaceutically acceptable
salt thereof, having the following structure: ##STR00044## wherein:
M is independently an optionally substituted hetero-bicyclic amine,
heterocyclic amine or heteroaryl amine group, where Z is connected
to M via the nitrogen; V is independently a hydrogen, alkyl (C1 to
C5) groups, benzyl or substituted benzyl groups; Z is independently
an optionally substituted methylene or methine group from 1 to 8
carbon atoms in length and wherein in the case of optionally
substituted methylene or methine, Z can also be connected to
R.sub.1 to form a heterocyclic or bicyclic heteratom ring from 3 to
10 atoms; and X is independently H, cyano (CN) or COR, wherein said
R group is alkyl (C1 to C3).
9. The method of claim 8 wherein said compound is administered at a
dosage of 1.0 mg to 2000 mg per day.
10. The method of claim 8 wherein said compound is administered
prior to exposure to a chemical agent wherein said agent inhibits
AChE.
11. The method of claim 8 wherein said compound is administered
after exposure to a chemical agent wherein said agent inhibits
AChE.
12. The method of claim 8 further comprising administering an AChE
inhibitor.
13. An acetyl cholinesterase reactivator compound of the formula:
##STR00045## wherein: L is independently an optionally substituted
3-azabicyclo[3.1.0]hexane group; Y is independently an optionally
substituted 5- or 6-membered heterocycle or heteroaryl group; Z is
independently an oxygen, optionally substituted nitrogen or
optionally substituted methylene or methine group from 1 to 8
carbon atoms in length and wherein in the case of optionally
nitrogen or optionally substituted methylene or methine; R.sub.1 is
independently H or optionally substituted alkyl (C1 to C7), benzyl
or optionally substituted benzyl, phenyl, optionally substituted
phenyl, heterocyclic, heteroaryl and optionally substituted
heterocyclic or optionally substituted heteroaryl; and X is
independently H, cyano (CN) or COR, wherein said R group is alkyl
(C1 to C3).
14. The acetyl cholinesterase reactivator compound of claim 13
wherein the reactivator is present as the E or Z isomer with
respect to the oxime moiety.
15. The acetyl cholinesterase reactivator compound of claim 13
wherein said compound comprises a pharmaceutically acceptable salt
comprising an acid addition salt or base addition salt.
16. The acetyl cholinesterase reactivator compound of claim 15
wherein said pharmaceutically acceptable salt comprises one or more
of the following salts: acetate, adipate, aspartate, benzoate,
besylate, bicarbonate/carbonate, bisulphate/sulphate, borate,
citrate, formate, fumarate, gluconate, glucuronate,
hexafluorophosphate, hydrochloride/chloride, hydrobromide/bromide,
hydroiodide/iodide, lactate, malate, maleate, malonate, mandelates,
mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate,
nitrate, oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, pyroglutamate, salicylate,
saccharate, stearate, succinate, sulfonate, stannate, tartrate,
tosylate, and trifluoroacetate salts.
17. The acetyl cholinesterase reactivator compound of claim 15
wherein said pharmaceutically acceptable salt comprises a base salt
comprising one or more of the following: aluminium, calcium,
choline, diethylamine, diolamine, glycine, lysine, magnesium,
meglumine, olamine, potassium, sodium, and zinc.
18. The acetyl cholinesterase reactivator compound of claim 13
wherein said compound is isotopically labeled.
19. The acetyl cholinesterase reactivator compound of claim 18
wherein said isotropic labeling comprises labeling with one or more
of the following: 2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C,
.sup.36Cl, .sup.18F, .sup.123I, .sup.125I, .sup.13N, .sup.15N,
.sup.15O, .sup.17O, .sup.18O, .sup.32P, and .sup.35S.
20. A method comprising attenuating the effects on a mammal caused
by the inhibition of AChE by administering to said mammal an
effective amount of a compound, or a pharmaceutically acceptable
salt thereof, having the following structure: ##STR00046## wherein:
L is independently an optionally substituted
3-azabicyclo[3.1.0]hexane group; Y is independently an optionally
substituted 5- or 6-membered heterocycle or heteroaryl group; Z is
independently an oxygen, optionally substituted nitrogen or
optionally substituted methylene or methine group from 1 to 8
carbon atoms in length and wherein in the case of optionally
nitrogen or optionally substituted methylene or methine; R.sub.1 is
independently H or optionally substituted alkyl (C1 to C7), benzyl
or optionally substituted benzyl, phenyl, optionally substituted
phenyl, heterocyclic, heteroaryl and optionally substituted
heterocyclic or optionally substituted heteroaryl; and X is
independently H, cyano (CN) or COR, wherein said R group is alkyl
(C1 to C3).
21. The method of claim 20 wherein said compound is administered at
a dosage of 1.0 mg to 2000 mg per day.
22. The method of claim 20 wherein said compound is administered
prior to exposure to a chemical agent wherein said agent inhibits
AChE.
23. The method of claim 20 wherein said compound is administered
after exposure to a chemical agent wherein said agent inhibits
AChE.
24. The method of claim 20 further comprising administering an AChE
inhibitor.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation-in-part of
co-pending U.S. patent application Ser. No. 13/197,550, filed on
Aug. 3, 2011, the entire disclosure of which is incorporated herein
by reference.
FIELD OF THE INVENTION
[0003] The present invention relates to non-charged oxime compounds
which are acetyl cholinesterase (AChE) reactivators of nerve-agent
inhibited AChE and which protect against organophosphate poisoning
both peripherally and in the central nervous systems (CNS).
BACKGROUND
[0004] Acetyl cholinesterase (AChE) is an important and essential
enzyme in the body, which is responsible for the degradation or
hydrolysis of acetyl choline, the neurotransmitter molecule
responsible for synaptic transmission. Inhibition of AChE can cause
a sharp increase in acetyl choline levels, causing overstimulation
of the cholinergic system at both central and peripheral sites,
resulting in the visual toxic signs commonly referred to as
cholinergic crisis. Organophorus agents, such as pesticides
(paraoxon, methylparaoxon, etc.) and nerve agents (Sarin,
Cyclosarin, Soman, Tabun, VX, etc) represent the bulk of the major
AChE inhibitor threat agents. Historically, various compounds have
been proposed from the class of compounds that possess the N-alkyl
bis-quaternary pyridinium moiety as a charged species. As a charged
species, there may be diminished ability to penetrate the
blood-brain barrier and protect against organophosphate poisoning
in the brain and central nervous system (CNS).
[0005] Therefore, the invention disclosed herein has identified
certain non-charged oxime based AChE reactivators with improved
blood-brain barrier penetration that may be effective at
reactivation of nerve agent-inhibited AChE and protect against
organophosphate poisoning both peripherally and in the CNS.
SUMMARY
[0006] The present disclosure is directed at an acetyl
cholinesterase (AChE) reactivator compound of the formula:
##STR00001##
wherein [0007] V is independently a hydrogen, alkyl (C1 to C5)
groups, benzyl or substituted benzyl groups; [0008] Z is
independently an optionally substituted methylene or methine group
from 1 to 8 carbon atoms in length and wherein in the case of
optionally substituted methylene or methine, Z can also be
connected to R.sub.1 to form a heterocyclic or bicyclic heteratom
ring from 3 to 10 atoms; [0009] R.sub.1 can independently be H or
optionally substituted alkyl (C1 to C7), or can be connected to Z
to form a heterocyclic or bicyclic heteratom ring from 3 to 10
atoms; [0010] R.sub.2 is independently H or optionally substituted
alkyl (C1 to C7), benzyl or optionally substituted benzyl, phenyl,
optionally substituted phenyl, heterocyclic, heteroaryl and
optionally substituted heterocyclic or optionally substituted
heteroaryl; and [0011] X is independently H, cyano (CN) or COR,
wherein said R group is alkyl (C1 to C3).
[0012] The present disclosure also relates to an acetyl
cholinesterase reactivator compound of the formula:
##STR00002##
wherein: [0013] Q is independently a carbonyl (C.dbd.O) group or a
bond between Y and the oxime group; [0014] Y is independently an
optionally substituted 5- or 6-membered heterocycle or heteroaryl
group; [0015] Z is independently an oxygen, optionally substituted
nitrogen or optionally substituted methylene or methine group from
1 to 8 carbon atoms in length and wherein in the case of optionally
nitrogen or optionally substituted methylene or methine, Z can also
be connected to R.sub.1 to form a heterocyclic or bicyclic
heteratom ring from 3 to 10 atoms; [0016] R.sub.1 can independently
be H or optionally substituted alkyl (C1 to C7), or can be
connected to Z to form a heterocyclic or bicyclic heteratom ring
from 3 to 10 atoms; [0017] R.sub.2 is independently H or optionally
substituted alkyl (C1 to C7), benzyl or optionally substituted
benzyl, phenyl, optionally substituted phenyl, heterocyclic,
heteroaryl and optionally substituted heterocyclic or optionally
substituted heteroaryl; [0018] X is independently H, cyano (CN) or
COR, wherein said R group is alkyl (C1 to C3).
[0019] The present disclosure also relates to a method comprising
attenuating the effects on a mammal cause by the inhibition of AChE
by administering to said mammal an effective amount of a compound,
or a pharmaceutically acceptable salt thereof, having the structure
of Formula I and/or Formula II noted above.
[0020] The present disclosure also relates to an acetyl
cholinesterase reactivator compound of the formula:
##STR00003##
wherein: [0021] M is independently an optionally substituted
hetero-bicyclic amine, heterocyclic amine or heteroaryl amine
group, where Z is connected to M via the nitrogen; [0022] V is
independently a hydrogen, alkyl (C1 to C5) groups, benzyl or
substituted benzyl groups; [0023] Z is independently an optionally
substituted methylene or methine group from 1 to 8 carbon atoms in
length and wherein in the case of optionally substituted methylene
or methine, Z can also be connected to R.sub.1 to form a
heterocyclic or bicyclic heteratom ring from 3 to 10 atoms; [0024]
X is independently H, cyano (CN) or COR, wherein said R group is
alkyl (C1 to C3).
[0025] The present disclosure also relates to an acetyl
cholinesterase reactivator compound of the formula:
##STR00004##
wherein: [0026] L is independently an optionally substituted
3-azabicyclo[3.1.0]hexane group; [0027] Y is independently an
optionally substituted 5- or 6-membered heterocycle or heteroaryl
group; [0028] Z is independently an oxygen, optionally substituted
nitrogen or optionally substituted methylene or methine group from
1 to 8 carbon atoms in length and wherein in the case of optionally
nitrogen or optionally substituted methylene or methine; [0029]
R.sub.1 is independently H or optionally substituted alkyl (C1 to
C7), benzyl or optionally substituted benzyl, phenyl, optionally
substituted phenyl, heterocyclic, heteroaryl and optionally
substituted heterocyclic or optionally substituted heteroaryl;
[0030] X is independently H, cyano (CN) or COR, wherein said R
group is alkyl (C1 to C3).
[0031] The present disclosure also relates to a method comprising
attenuating the effects on a mammal cause by the inhibition of AChE
by administering to said mammal an effective amount of a compound,
or a pharmaceutically acceptable salt thereof, having the structure
of Formula I, Formula II, Formula III and/or Formula IV noted
above.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 illustrates two preferred methods for the preparation
of AChE reactivator compounds disclosed herein.
[0033] FIG. 2 illustrates two additional preferred methods for
preparation of the AChE reactivator compounds disclosed herein.
[0034] FIG. 3 illustrates a preferred method for the synthesis of
the intermediate 12 identified in FIG. 2.
[0035] FIG. 4 illustrates a preferred method for the synthesis of
compound 13 prepared in FIG. 2.
[0036] FIG. 5 illustrates a preferred method for the synthesis of
the compound of compound 4 in FIG. 1.
DETAILED DESCRIPTION
[0037] It is to be understood that the invention is not limited in
its application to the details of construction and the arrangement
of components set forth in the following description or illustrated
in the drawings. The invention is capable of other embodiments and
of being practiced or of being carried out in various ways. Also,
it is to be understood that the phraseology and terminology used
herein is for the purpose of description and should not be regarded
as limiting. The use of "including," "comprising," or "having" and
variations thereof herein is meant to encompass the items listed
thereafter and equivalents thereof as well as additional items.
[0038] The compounds of the present invention are directed to
pharmaceutical countermeasures or antidote compositions for
treating disorders or conditions associated with exposure to AChE
inhibitors such as organophosphate pesticides and nerve agents. The
compounds of the present invention may therefore serve as
reactivators of both native and/or organophosphate-inhibited acetyl
cholinesterase (AChE). Reference to a reactivator may be understood
as that situation where, e.g., enzyme dephosphorylation occurs to
generate the active enzyme (AChE) and is relatively faster than
oxime dephosphorylation, which generates the phosphorylated
enzyme.
[0039] Accordingly, the compounds of the present invention serve as
reactivators of nerve agent organophosphate-inhibited human and/or
mammalian acetyl cholinesterase (AChE), including AChE inhibited by
Sarin, Cyclosarin (GF), Tabun, Soman, VX and other structurally
related organophosphate nerve agents.
[0040] More particularly, the reactivator compounds of the present
invention include compounds of Formula I below:
##STR00005##
wherein: [0041] V is independently a hydrogen, alkyl (C1 to C5)
groups, benzyl or substituted benzyl groups; [0042] Z is
independently an optionally substituted methylene or methine group
from 1 to 8 carbon atoms in length. In the case of optionally
substituted methylene or methine, Z can also be connected to
R.sub.1 to form a heterocyclic or bicyclic heteratom ring from 3 to
10 atoms; [0043] R.sub.1 can independently be H or optionally
substituted alkyl (C1 to C7), or can be connected to Z to form a
heterocyclic or bicyclic heteratom ring from 3 to 10 atoms; [0044]
R.sub.2 is independently H or optionally substituted alkyl (C1 to
C7), benzyl or optionally substituted benzyl, phenyl, optionally
substituted phenyl, heterocyclic, heteroaryl and optionally
substituted heterocyclic or optionally substituted heteroaryl;
[0045] X is independently H, cyano (CN) or COR, wherein said R
group is alkyl (C1 to C3); and [0046] wherein the oxime moiety can
exist as either the E or Z isomer form. In addition, the above
Formula I may be present in the form of a pharmaceutically
acceptable salt.
[0047] The present invention is also directed at reactivators
having the structure of Formula II:
##STR00006##
wherein: [0048] Q is independently a carbonyl (C.dbd.O) group or a
bond between Y and the oxime group; [0049] Y is also independently
an optionally substituted 5- or 6-membered heterocycle or
heteroaryl group such as oxazole, triazole, imidazole, oxadiazole,
pyridine, pyrimidine or pyrazine; [0050] Z is independently an
oxygen, optionally substituted nitrogen or optionally substituted
methylene or methine group from 1 to 8 carbon atoms in length. In
the case of optionally nitrogen or optionally substituted methylene
or methine, Z can also be connected to R.sub.1 to form a
heterocyclic or bicyclic heteratom ring from 3 to 10 atoms; [0051]
R.sub.1 can independently be H or optionally substituted alkyl (C1
to C7), or can be connected to Z to form a heterocyclic or bicyclic
heteratom ring from 3 to 10 atoms; [0052] R.sub.2 is independently
H or optionally substituted alkyl (C1 to C7), benzyl or optionally
substituted benzyl, phenyl, optionally substituted phenyl,
heterocyclic, heteroaryl and optionally substituted heterocyclic or
optionally substituted heteroaryl; [0053] X is independently H,
cyano (CN) or COR, wherein said R group is alkyl (C1 to C3); and
[0054] wherein the oxime moiety can exist as either the E or Z
isomer form. In addition, the above Formula II may be present in
the form of a pharmaceutically acceptable salt.
[0055] The present invention is also directed at reactivators
having the structure of Formula III:
##STR00007##
wherein: [0056] M is independently an optionally substituted
hetero-bicyclic amine, heterocyclic amine or heteroaryl amine
group, where Z is connected to M via the nitrogen; [0057] V is
independently a hydrogen, alkyl (C1 to C5) groups, benzyl or
substituted benzyl groups; [0058] Z is independently an optionally
substituted methylene or methine group from 1 to 8 carbon atoms in
length and wherein in the case of optionally substituted methylene
or methine, Z can also be connected to R.sub.1 to form a
heterocyclic or bicyclic heteratom ring from 3 to 10 atoms; [0059]
X is independently H, cyano (CN) or COR, wherein said R group is
alkyl (C1 to C3); and wherein the oxime moiety can exist as either
the E or Z isomer form. In addition, the above Formula III may be
present in the form of a pharmaceutically acceptable salt.
[0060] The present disclosure also relates to an acetyl
cholinesterase reactivator compound of the formula:
##STR00008##
wherein: [0061] L is independently an optionally substituted
3-azabicyclo[3.1.0]hexane group; [0062] Y is independently an
optionally substituted 5- or 6-membered heterocycle or heteroaryl
group; [0063] Z is independently an oxygen, optionally substituted
nitrogen or optionally substituted methylene or methine group from
1 to 8 carbon atoms in length and wherein in the case of optionally
nitrogen or optionally substituted methylene or methine; [0064]
R.sub.1 is independently H or optionally substituted alkyl (C1 to
C7), benzyl or optionally substituted benzyl, phenyl, optionally
substituted phenyl, heterocyclic, heteroaryl and optionally
substituted heterocyclic or optionally substituted heteroaryl;
[0065] X is independently H, cyano (CN) or COR, wherein said R
group is alkyl (C1 to C3); and [0066] wherein the oxime moiety can
exist as either the E or Z isomer form. In addition, the above
Formula IV may be present in the form of a pharmaceutically
acceptable salt.
[0067] It may be understood that with respect to the oxime moiety,
the Z designation is that situation where the two groups of higher
priority (according to the Cahn-Ingold-Prelog priority rules) are
on the same side of the double bond. If the two groups of higher
priority are on opposite sides of the double bond, it is designated
as the E isomer. In related context, the compounds of Formula I,
II, III and IV may also have optical centers and therefore may
occur in different enantiomeric configurations. Accordingly, the
general formulas identified above should be understood to
preferably include all enantiomers, diastereomers and other
stereoisomers of the defined compounds as well as racemic and other
mixtures thereof.
[0068] As may be appreciated, the compounds herein are preferably
non-charged, which may be understood as the feature where the
compound itself as identified in the general formula above does not
include a charged atom or functional group. As noted, this may then
facilitate blood-brain barrier penetration. However, as noted,
pharmaceutically acceptable salts of the compounds of Formula I,
II, III and IV may also be employed and include the acid addition
and base salts thereof. The phrase "pharmaceutically acceptable",
as used in connection with compositions of the invention, refers to
molecular entities and other ingredients of such compositions that
are physiologically tolerable and do not typically produce untoward
reactions when administered to a mammal (e.g., human). Preferably,
as used herein, the term "pharmaceutically acceptable" means
approved by a regulatory agency of the Federal or a state
government or listed in the U.S. Pharmacopeia or other generally
recognized pharmacopeia for use in mammals, and more particularly
in humans.
[0069] Some examples of pharmaceutically acceptable salt forms
include, but are not limited to: acetate, adipate, aspartate,
benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate,
borate, citrate, formate, fumarate, gluconate, glucuronate,
hexafluorophosphate, hydrochloride/chloride, hydrobromide/bromide,
hydroiodide/iodide, lactate, malate, maleate, malonate, mandelates,
mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate,
nitrate, oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, pyroglutamate, salicylate,
saccharate, stearate, succinate, sulfonate, stannate, tartrate,
tosylate, and trifluoroacetate salts.
[0070] Suitable base salts are preferably formed from bases which
form non-toxic salts. Some examples include, but are not limited
to, the aluminium, calcium, choline, diethylamine, diolamine,
glycine, lysine, magnesium, meglumine, olamine, potassium, sodium,
and zinc salts.
[0071] The compounds of the present invention may be used as part
of a combination therapy, including their administration as
separate entities or combined in a single delivery system. The
combination therapies may include, but are not limited to
combination with an AChE inhibitor such as atropine and/or an
anticonvulsant such as diazepam or midazolam.
[0072] The compounds of this invention may be preferably
administered via either the oral, parenteral (such as subcutaneous,
intraveneous, intramuscular, intrasternal and infusion techniques),
intranasal or topical routes to mammals. In general, these
compounds are most desirably administered to humans in doses
ranging from about 1.0 mg to about 2000 mg per day, although
variations will necessarily occur depending upon the weight and
condition of the subject being treated and the particular route of
administration chosen.
[0073] The compounds of the present invention may be administered
alone or in combination with pharmaceutically acceptable carriers
or diluents by either of the above routes previously indicated, and
such administration may be carried out in single or multiple doses.
More particularly, the reactivator compounds of the invention may
be administered in a wide variety of different dosage forms, i.e.,
they may be combined with various pharmaceutically acceptable inert
carriers in the form of tablets, capsules, lozenges, troches, hard
candies, powders, sprays, creams, salves, suppositories, jellies,
gels, pastes, lotions, ointments, aqueous suspensions, organic
suspensions, injectable solutions, injectable suspensions, elixirs,
syrups, and the like. Such carriers may include solid diluents or
fillers, sterile aqueous media and various non-toxic organic
solvents, etc. Moreover, oral pharmaceutical compositions can be
suitably sweetened and/or flavored. In general, the therapeutically
effective compounds of this invention are present in such dosage
forms at concentration levels ranging about 5.0% to about 70% by
weight.
[0074] For oral administration, tablets containing various
excipients such as microcrystalline cellulose, sodium citrate,
calcium carbonate, dicalcium phosphate and glycine may be employed
along with various disintegrants such as starch, together with
granulation binders like polyvinylpyrrolidone, sucrose, gelatin and
acacia. Additionally, lubricating agents such as magnesium
stearate, sodium lauryl sulfate and talc are preferred for
tabletting purposes. Solid compositions of a similar type may also
be employed as fillers in gelatine capsules; preferred materials in
this connection also include lactose or milk sugar as well as high
molecular weight polyethylene glycols. When aqueous suspensions
and/or elixirs are desired for oral administration, the active
ingredient may be combined with various sweetening or flavoring
agents, coloring matter or dyes, and, if so desired, emulsifying
and/or suspending agents as well, together with such diluents as
water, ethanol, propylene glycol, glycerin and various like
combinations thereof.
[0075] For parenteral administration, solutions or suspensions of a
compound of the present invention in either sesame or peanut oil,
cotton seed oil or in aqueous propylene glycol may be employed. The
aqueous solutions should be suitably buffered (preferably pH>8)
if necessary and the liquid diluents first rendered isotonic. These
aqueous solutions are preferred for intravenous injection purposes.
The oily solutions are preferred for intra-articular, intramuscular
and subcutaneous injection purposes. The preparation of all these
solutions under sterile conditions is readily accomplished by
standard pharmaceutical techniques well-known to those skilled in
the art. Additionally, it is also possible to administer the
compounds of the present invention topically when treating
inflammatory conditions of the skin and this may preferably be done
by way of creams, jellies, gels, pastes, ointments and the like, in
accordance with standard pharmaceutical practice.
[0076] The reactivator compounds of the present invention may exist
in both unsolvated and solvated forms. The term `solvate` is used
herein to describe a molecular complex comprising the compound of
the invention and an amount of one or more pharmaceutically
acceptable solvent molecules, such as water.
[0077] The reactivator compounds of the present invention may also
include isotopically labeled compounds, which are identical to
those recited in the above referenced formula, but for the fact
that one or more atoms are replaced by an atom having an atomic
mass or mass number different from the atomic mass or mass number
usually found in nature thereby allowing for improved detection
and/or tracking of the compound. Examples of isotopes suitable for
inclusion in the compounds of the invention include, but are not
limited to, isotopes of hydrogen, such as .sup.2H and .sup.3H,
carbon, such as .sup.11C, .sup.13C and .sup.14C, chlorine, such as
.sup.36Cl, fluorine, such as .sup.18F, iodine, such as .sup.123I
and .sup.125I, nitrogen, such as .sup.13N and .sup.15N, oxygen,
such as .sup.15O, .sup.17O and .sup.18O, phosphorus, such as
.sup.32P, and sulphur, such as .sup.35S.
[0078] Certain isotopically-labeled reactivator compounds herein,
for example, those incorporating a radioactive isotope, may be
preferred in drug and/or substrate tissue distribution studies. The
radioactive isotopes tritium, i.e. .sup.3H, and carbon-14, i.e.
.sup.14C, are particularly preferred for this purpose in view of
their relative ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e. .sup.2H,
may afford certain therapeutic advantages resulting from greater
metabolic stability, for example, increased in vivo half-life or
reduced dosage requirements, and hence may be preferred in some
circumstances. Substitution with positron emitting isotopes, such
as .sup.11C, .sup.18F, .sup.15O and .sup.13N, may be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy. Isotopically-labeled reactivator compounds
herein may generally be prepared by conventional techniques known
to those skilled in the art or by processes analogous to those
described in the accompanying examples and preparations using an
appropriate isotopically-labeled reagent in place of the
non-labeled reagent previously employed.
[0079] Reactivator compounds of Formula I herein were assessed for
affinity and reactivation of nerve agent-inhibited recombinant
human AChE. Reactivation studies were conducted with commercially
obtained recombinant human AChE and assayed by a robotic
spectrophotometric assay using acetylthiocholine as substrate at pH
7.4 and 25.degree. C. via the procedure established by Ellman
(Biochem Pharmacol 1961, 7, 88-95). The time-course of reactivation
of nerve agent-inhibited AChE was determined by adding various
concentrations of reactivator compounds of the above-referenced
formula to agent-inhibited AChE. Samples of the compound/inhibited
AChE mixture were removed at sequential times to measure the
compound-induced recovery of AChE activity. The time-course of AChE
reactivation at each compound concentration [OX] was analyzed
kinetically as a pseudo first-order reaction. The observed
first-order reaction constant (k.sub.obs) was fitted to the
Michaelis-Menten function:
k.sub.obs=kr[OX]/(KD+[OX])
where kr is the maximal first-order reactivation rate constant for
the reactivator compound considered and 1/KD is its affinity for
AChE. In vitro reactivation studies were conducted against AChE
that has been inhibited with the nerve agent GF (cyclosarin).
Reactivator compounds of the herein referenced general formula
within this invention showed 10-80% reactivation of GF-inhibited
human AChE at concentrations from 500 nM to 1 mM and time points
from 8 to 240 minutes.
[0080] The reactivator compounds of Formula I may preferably be
prepared by the methods described below, together with synthetic
methods known in the art of organic chemistry, or modifications and
derivatisations that are familiar to those of ordinary skill in the
art. During any of the following synthetic sequences it may be
preferred and/or desirable to protect sensitive or reactive groups
on any of the molecules concerned. This can be achieved by means of
conventional protecting groups, such as those described in T. W.
Greene, Protective Groups in Organic Chemistry, John Wiley &
Sons, 1981; and T. W. Greene and P. G. M. Wuts, Protective Groups
in Organic Chemistry, John Wiley & Sons, 1991, which are hereby
incorporated by reference.
[0081] Reactivator compounds of Formula I and/or their
pharmaceutically acceptable salts may preferably be prepared
according to the following reaction Schemes I and II as discussed
herein and respectively illustrated in FIGS. 1 and 2. Isolation and
purification of the products may be accomplished by standard
procedures, which are known to a chemist of ordinary skill. The
following schemes and discussion are exemplary of the processes for
making compounds of general formula I. It is to be understood,
however, that the synthetic scheme, as fully described herein, is
not intended to be limited by the details of the following
examples.
[0082] FIG. 1 illustrates two preferred methods for the preparation
of reactivator compounds having the basic structure of the above
referenced general formula, where Z, R.sub.1 and R.sub.2 are
defined as above. Referring to FIG. 1, compounds of formula I can
be purchased or prepared using synthetic methods known in the art
of organic chemistry, or modifications and derivatisations that are
familiar to those of ordinary skill in the art. Referring to FIG.
1, an amine of formula I can be treated with a tartrate ester such
as compound 2 in an alcoholic solvent such as ethanol or methanol,
at temperatures ranging from room temperature to 75.degree. C.,
preferably at or around 45.degree. C., to provide the dimeric amide
of general formula 3. Compounds of formula 3 can then be treated
under acidic sodium periodate conditions in solvents such as
alcohol or water, preferably ethanol and water, to provide the
intermediate amide-aldehyde (not depicted), which can then be
immediately reacted with hydroxylamine hydrochloride, alone or in
the presence of a tertiary amine base, such as triethylamine, to
produce the desired compounds of formula 4. An alternative method
for the preparation of compounds of formula 4 is also described in
FIG. 1. Compounds of formula I can be treated with the gloxylate
oximes, such as ethyl 2-(hydroxyimino)acetate 5 in a suitable
solvent such as ethanol, DMF or acetonitrile, or reacted neat with
the compound of formula I, at temperatures ranging from room
temperature to 150.degree. C., preferably at about 80.degree. C.,
to produce the desired amide-oxime compounds of formula 4.
[0083] FIG. 2 illustrates another preferred method for the
preparation of reactivator compounds having the general formula
above, where Y, Z, R.sub.1 and R.sub.2 are defined as above, Y is
an oxygen or nitrogen atom of appropriate substitution, W is
independently CH (methine) or N (nitrogen) and `Hal` represents
halogen groups, such as fluoride, chloride, bromide or iodide.
Referring to FIG. 2, an alcohol or amine of formula 6 can be
reacted with a di-halogenated heterocyclic compound of formula 7 to
form the desired heteroaryl ether or heteroaryl amine of formula 8.
Conditions for this reaction include the use of a suitable base
such as sodium hydride (NaH) or potassium tert-butoxide (KOtBu) in
solvents such as tetrahydrofuran (THF) or diethyl ether, at
temperatures ranging from room temperature to 100.degree. C.,
preferably around 60.degree. C., to provide the desired compounds
of formula 8. Treatment of compounds of formula 8 with a suitable
Grignard reagent or organolithium reagent, such as Isopropyl
magnesium chloride (iPrMgCl) or n-butyl lithium (n-BuLi) and
dimethylformamide, in solvents such as toluene, THF or ether, at
temperatures ranging from -100.degree. C. to room temperature,
provides the corresponding aldehyde (not depicted), which can then
be immediately reacted with hydroxylamine hydrochloride, in a
solvent such as ethanol or dichloromethane, alone or in the
presence of a tertiary amine base, such as triethylamine, to
produce the desired oxime compounds of formula 9.
[0084] As also illustrated in FIG. 2, ketone compounds of formula
12 can also be prepared from the compounds of formula 8 via two
methods. Treatment of compounds of formula 8 with a suitable
Grignard reagent or organolithium reagent, such as Isopropyl
magnesium chloride (iPrMgCl) or n-butyl lithium (n-BuLi) and the
Weinreb amide 10, in solvents such as toluene, THF or ether, at
temperatures ranging from -100.degree. C. to room temperature,
provides the corresponding ketone compounds of formula 12.
Alternatively, compounds of formula 8 can be coupled with the vinyl
stannane reagent 11, utilizing a suitable catalyst such as
tetrakistriphenylphosphine palladium (0), to produce the
corresponding vinyl ether (not depicted), which can be hydrolyzed
with HCl to produce the ketone compounds of formula 12. Ketone
compounds of formula 12 can be reacted under a variety of
conditions to produce the desired keto-oxime compounds of formula
13. Suitable conditions for this transformation include
trimethylsilyl chloride and nitrosyl chloride, potassium
tert-butoxide and tert-butyl nitrite (tBuNO.sub.2) or isoamyl
nitrite.
[0085] As illustrated in FIG. 3, a method is identified for the
synthesis of the intermediate 12 prepared above in FIG. 2.
Referring to FIG. 3, an alcohol or amine of general formula 6 can
be reacted with a halogenated-methyl ketone heterocyclic compound
of general formula 14 to form the desired heteroaryl ether or
heteroaryl amine of general formula 12. Conditions for this
reaction include the use of a suitable base such as sodium hydride
(NaH) or potassium tert-butoxide (KOtBu) in solvents such as
tetrahydrofuran (THF) or diethyl ether, at temperatures ranging
from room temperature to 100.degree. C., preferably around
60.degree. C., to provide the desired compounds of general formula
12. Other conditions for this transformation involve the use of a
suitable palladium catalyst, such as Pd(OAc).sub.2 and a ligand, in
solvent such as DMF or THF. Intermediate 12 can be taken on to the
desired compounds of Formula II as described above in FIG. 2.
[0086] FIG. 4 identifies another method for the synthesis of the
compound of general formula 13, prepared above in FIG. 2. Referring
to FIG. 4, a halogenated heteroaryl ketone of general formula 14
can be reacted under a variety of conditions to produce the desired
keto-oxime intermediate of general formula 15. Suitable conditions
for this transformation include trimethylsilyl chloride and
nitrosyl chloride, potassium tert-butoxide and tert-butyl nitrite
(tBuNO.sub.2) or isoamyl nitrite. Compound 15 can then be reacted
with the alcohol or amine of general formula 6, under similar
conditions to those described above for compound 12 above (Scheme
III) to provide the desired compounds of general formula 13.
[0087] FIG. 5 identifies yet another method for the synthesis of
the compound of general formula 4, prepared above in FIG. 1.
Referring to FIG. 5, an amine of general formula I can be treated
with methyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate, 16 neat at
temperatures ranging from room temperature to 130.degree. C.,
preferably at or around 120.degree. C., to provide the amide of
general formula 17. Compounds of formula 17 can then be treated
under HCl/THF or other suitable acidic conditions to deprotect the
acetonide moiety and provide the desired diol (not depicted).
Treatment of the diol with acidic sodium periodate conditions in
solvents such as alcohol or water, preferably ethanol and water, to
provide the intermediate amide-aldehyde (not depicted), which can
then be immediately reacted with hydroxylamine hydrochloride, alone
or in the presence of a tertiary amine base, such as triethylamine,
to produce the desired compounds of general formula 4.
[0088] Finally, compounds of Formula I and II prepared in FIGS.
1-5, as well as Formulas III and IV, may have a pharmaceutically
acceptable salt form prepared under standard conditions by one
skilled in the art. As a representative example, amide-oxime and
keto-oxime compounds of formulas 4, 9 or 13 (FIGS. 1 and 2) can be
dissolved in a suitable solvent such as methanol, ethanol,
dichloromethane, ethyl acetate or isopropyl acetate and treated
with a suitable acid, such as an anhydrous solution of HCl in
ether, to produce the corresponding hydrochloric acid salt
form.
[0089] The following examples were prepared according to the
schemes identified in FIGS. 1-5 and the description provided
herein.
TABLE-US-00001 Example Structure IUPAC Name Example 1 ##STR00009##
N-(2-(diethylamino)ethyl)-2- (hydroxyimino)acetamide hydrochloride
Example 2 ##STR00010## N-((1-benzylpiperidin-4-yl)methyl)-2-
(hydroxyimino)acetamide hydrochloride Example 3 ##STR00011##
N-(1-benzylpiperidin-4-yl)-2- (hydroxyimino)acetamide hydrochloride
Example 4 ##STR00012## 6-((1-benzylpiperidin-4-
yl)methoxy)nicotinaldehyde oxime hydrochloride Example 5
##STR00013## 2-(hydroxyimino)-N-(3-(1,2,3,4- tetrahydroacridin-9-
ylamino)propyl)acetamide hydrochloride Example 6 ##STR00014##
2-(hydroxyimino)-N-(4-(1,2,3,4- tetrahydroacridin-9-
ylamino)butyl)acetamide hydrochloride Example 7 ##STR00015##
2-(hydroxyimino)-N-(6-(1,2,3,4- tetrahydroacridin-9-
ylamino)hexyl)acetamide hydrochloride Example 8 ##STR00016##
2-(hydroxyimino)-N-(7-(1,2,3,4- tetrahydroacridin-9-
ylamino)heptyl)acetamide hydrochloride Example 9 ##STR00017##
2-(hydroxyimino)-N-(5-(1,2,3,4- tetrahydroacridin-9-
ylamino)pentyl)acetamide hydrochloride Example 10 ##STR00018##
2-(2-((1-benzylpiperidin-4- yl)methoxy)pyrimidin-5-yl)-2-
oxoacetaldehyde oxime hydrochloride Example 11 ##STR00019##
2-(6-((1-benzylpiperidin-4- yl)methoxy)pyridin-3-yl)-2-
oxoacetaldehyde oxime hydrochloride Example 12 ##STR00020##
2-((1-benzylpiperidin-4- yl)methoxy)pyrimidine-5-carbaldehyde oxime
hydrochloride Example 13 ##STR00021## 2-(6-(3-
(diethylamino)propoxy)pyridin-3-yl)-2- oxoacetaldehyde oxime
hydrochloride Example 14 ##STR00022## 6-(3-
(diethylamino)propoxy)nicotinaldehyde oxime hydrochloride Example
15 ##STR00023## N-(1-benzylpiperidin-4-yl)-2-
(hydroxyimino)-3-oxobutanamide hydrochloride Example 16
##STR00024## 2-(1-benzylpiperidin-4-ylamino)-N-
hydroxy-2-oxoacetimidoyl cyanide hydrochloride Example 17
##STR00025## N-((1-benzylpiperidin-4-yl)methyl)-2-
(hydroxyimino)-3-oxobutanamide hydrochloride Example 18
##STR00026## 2-((1-benzylpiperidin-4- yl)methylamino)-N-hydroxy-2-
oxoacetimidoyl cyanide hydrochloride Example 19 ##STR00027##
2-(6-(((1R,5S,6r)-3-benzyl-3- azabicyclo[3.1.0]hexan-6-
yl)methoxy)pyridin-3-yl)-2- oxoacetaldehyde oxime hydrochloride
Example 20 ##STR00028## 2-(6-((1-(3,4- dimethoxybenzyl)piperidin-4-
yl)methoxy)pyridin-3-yl)-2- oxoacetaldehyde oxime hydrochloride
Example 21 ##STR00029## 2-(6-((1-benzylpiperidin-4-
yl)methoxy)pyridin-2-yl)-2- oxoacetaldehyde oxime hydrochloride
Example 22 ##STR00030## N-hydroxy-2-oxo-2-(3-(1,2,3,4-
tetrahydroacridin-9- ylamino)propylamino)acetimidoyl cyanide
hydrochloride Example 23 ##STR00031##
N-(3-(6,7-dimethoxy-1-phenyl-3,4-
dihydroisoquinolin-2(1H)-yl)propyl)-2- (hydroxyimino)acetamide
hydrochloride Example 24 ##STR00032## 2-(6-((1-benzylazetidin-3-
yl)methoxy)pyridin-3-yl)-2- oxoacetaldehyde oxime hydrochloride
Example 25 ##STR00033## N-(3-(6,7-dimethoxy-1-phenyl-3,4-
dihydroisoquinolin-2(1H)-yl)propyl)-2-
(hydroxyimino)-3-oxobutanamide hydrochloride Example 26
##STR00034## N-(3-(6,7-dimethoxy-3,4-
dihydroisoquinolin-2(1H)-yl)propyl)-2-
(hydroxyimino)-3-oxobutanamide hydrochloride Example 27
##STR00035## 2-(6-((1-(3,4- dimethoxybenzyl)pyrrolidin-3-
yl)methoxy)pyridin-3-yl)-2- oxoacetaldehyde oxime hydrochloride
Example 28 ##STR00036## 2-(2-((1-benzylpiperidin-4-
yl)methoxy)pyridin-4-yl)-2- oxoacetaldehyde oxime hydrochloride
Example 29 ##STR00037## 2-(6-((1-benzylpyrrolidin-3-
yl)methoxy)pyridin-3-yl)-2- oxoacetaldehyde oxime hydrochloride
Example 30 ##STR00038## 2-(6-((1-(3,4- dimethoxybenzyl)piperidin-2-
yl)methoxy)pyridin-3-yl)-2- oxoacetaldehyde oxime hydrochloride
Example 31 ##STR00039## 2-(6-((1-(3,4- dimethoxybenzyl)piperidin-3-
yl)methoxy)pyridin-3-yl)-2- oxoacetaldehyde oxime hydrochloride
Example 32 ##STR00040## 2-(6-((1-benzylpiperidin-4-
yl)methylamino)pyridin-3-yl)-2- oxoacetaldehyde oxime hydrochloride
Example 33 ##STR00041## N-((1-(3,4-dimethoxybenzyl)piperidin-
4-yl)methyl)-2-(hydroxyimino)-3- oxobutanamide hydrochloride
Example 34 ##STR00042## 2-(2-((1-benzylpiperidin-4-
yl)methoxy)pyridin-3-yl)-2- oxoacetaldehyde oxime hydrochloride
MDR/MDCK Assay Description and Data
[0090] Compounds within this invention were screened in the
MDR/MDCK assay, which has been found to be a reasonable in vitro
predictor for efflux activity associated with the blood-brain
barrier. See, Wang, Q. et al, Evaluation of the MDR-MDCK Cell Line
As a Permeability Screen For The Blood Brain Barrier, Int. J.
Pharm. 2005, 288(2) 349-359. The assay is a bidirectional assay in
a transwell format system, assessing the permeability of compounds
across a Madin Darby canine kidney cell line transfected with human
MDR-1 gene. Efflux is assessed based on ratios from the basolateral
and apical sides of the chamber.
[0091] The MDR/MDCK data for select compounds is highlighted in
Table I below. As can be seen, the compounds herein demonstrate a
range of brain penetration classifications.
TABLE-US-00002 TABLE I Papp Brain (.times.10.sup.-6 cm/s)
Penetration Compound A-B B-A Efflux Classification
N-((1-benzylpiperidin-4-yl)methyl)-2- 3.19 19.8 6.2 Moderate
(hydroxyimino)acetamide hydrochloride N-(2-(diethylamino)ethyl)-2-
<0.51 <0.67 ND Low (hydroxyimino)acetamide hydrochloride
2-(hydroxyimino)-N-(3-(1,2,3,4-tetrahydroacridin-9- 0.21 4.37 21
Low ylamino)propyl)acetamide hydrochloride
2-(hydroxyimino)-N-(5-(1,2,3,4-tetrahydroacridin-9- 0.3 7.92 26 Low
ylamino)pentyl)acetamide hydrochloride
2-(2-((1-benzylpiperidin-4-yl)methoxy)pyrimidin-5- 9.2 12.3 1.3
High yl)-2-oxoacetaldehyde oxime hydrochloride
2-(6-((1-benzylpiperidin-4-yl)methoxy)pyridin-3-yl)- 13.5 9.54 0.7
High 2-oxoacetaldehyde oxime hydrochloride
2-((1-benzylpiperidin-4-yl)methylamino)-N-hydroxy- 0.07 0.44 5.9
Low 2-oxoacetimidoyl cyanide hydrochloride
N-((1-benzylpiperidin-4-yl)methyl)-2-(hydroxyimino)- 17.4 21.3 1.2
High 3-oxobutanamide hydrochloride
2-(6-(3-(diethylamino)propoxy)pyridin-3-yl)-2- 6.46 18.6 2.9 High
oxoacetaldehyde oxime hydrochloride 1,1'-methylenebis(4- <0.57
<0.57 ND Low (hydroxyimino)methyl)pyridinium)methanesulfonate
(MMB4 DMS-Control bis-pyridinium)
* * * * *