U.S. patent application number 14/711203 was filed with the patent office on 2015-09-03 for positive allosteric modulators and uses thereof.
The applicant listed for this patent is Bionomics Limited. Invention is credited to Audrey Fluck, Bruno Giethlen, Andrew Harvey, Dharam Paul, Laurent Schaeffer.
Application Number | 20150246029 14/711203 |
Document ID | / |
Family ID | 46602008 |
Filed Date | 2015-09-03 |
United States Patent
Application |
20150246029 |
Kind Code |
A1 |
Harvey; Andrew ; et
al. |
September 3, 2015 |
Positive Allosteric Modulators and Uses Thereof
Abstract
The present invention relates to compounds useful in the
positive modulation of the alpha 7 nicotinic acetylcholine receptor
(.alpha.7nAChR). The invention also relates to the use of these
compounds in the treatment or prevention of a broad range of
diseases in which the positive modulation of .alpha.7nAChR is
advantageous, including neurodegenerative and neuropsychiatric
diseases and also inflammatory diseases.
Inventors: |
Harvey; Andrew; (Goodwood,
AU) ; Fluck; Audrey; (Dangolsheim, FR) ;
Giethlen; Bruno; (Altorf, FR) ; Paul; Dharam;
(Flinders Park, AU) ; Schaeffer; Laurent;
(Durrenentzen, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bionomics Limited |
Thebarton |
|
AU |
|
|
Family ID: |
46602008 |
Appl. No.: |
14/711203 |
Filed: |
May 13, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13983476 |
Oct 14, 2013 |
9062013 |
|
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PCT/AU2012/000084 |
Feb 2, 2012 |
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14711203 |
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Current U.S.
Class: |
514/348 ;
435/375; 514/349; 514/352; 514/371; 514/407; 514/465; 514/617 |
Current CPC
Class: |
A61K 31/426 20130101;
A61P 25/18 20180101; C07D 277/46 20130101; A61P 25/22 20180101;
C07D 231/40 20130101; C07D 317/46 20130101; A61P 25/24 20180101;
C07C 233/59 20130101; A61K 31/415 20130101; A61P 29/00 20180101;
A61K 31/357 20130101; C07C 233/60 20130101; A61P 25/14 20180101;
A61K 31/4409 20130101; C07C 311/46 20130101; C07C 2602/50 20170501;
C07C 2601/02 20170501; C07D 209/46 20130101; A61P 25/28 20180101;
A61P 25/00 20180101; A61K 31/4412 20130101; C07D 213/75 20130101;
C07D 275/06 20130101; A61P 25/16 20180101; A61K 31/167 20130101;
C07C 311/16 20130101 |
International
Class: |
A61K 31/4412 20060101
A61K031/4412; A61K 31/357 20060101 A61K031/357; A61K 31/167
20060101 A61K031/167; A61K 31/4409 20060101 A61K031/4409; A61K
31/426 20060101 A61K031/426; A61K 31/415 20060101 A61K031/415 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 2, 2011 |
AU |
2011900319 |
Claims
1.-21. (canceled)
22. A method for the treatment of cognitive deficits associated
with neurodegeneration or neuropsychiatric diseases, said method
including the step of administering a compound of formula (I) or a
salt thereof: ##STR00124## wherein R.sub.1 is selected from
optionally substituted aryl, optionally substituted heteroaryl
(excluding optionally substituted porphyrins), or optionally
substituted heterocyclyl; R.sub.2 is selected from C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 alkenyl, F, Br, Cl, CN, or C.sub.1-C.sub.4
haloalkyl; R.sub.3 is selected from hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 alkenyl, F, Br, Cl, CN, or C.sub.1-C.sub.4
haloalkyl; or R.sub.2 and R.sub.3 together form C.sub.4-9
cycloalkyl or C.sub.4-9 cycloalkenyl; R.sub.4 is selected from
optionally substituted heteroaryl, optionally substituted
heterocyclyl, or optionally substituted aryl; R.sub.5 is selected
from hydrogen or optionally substituted alkyl; wherein when both
R.sub.2 and R.sub.3 are Cl, R.sub.4 is an optionally substituted
heteroaryl or optionally substituted heterocyclyl, and provided
that the following compounds are excluded: ##STR00125##
##STR00126## or a pharmaceutically acceptable salt thereof, or a
composition comprising a compound as defined above, or a
pharmaceutically acceptable salt thereof.
23. A method for the treatment of inflammatory diseases, said
method including the step of administering a compound of formula
(I) or a salt thereof: ##STR00127## wherein R.sub.1 is selected
from optionally substituted aryl, optionally substituted heteroaryl
(excluding optionally substituted porphyrins), or optionally
substituted heterocyclyl; R.sub.2 is selected from C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 alkenyl, F, Br, Cl, CN, or C.sub.1-C.sub.4
haloalkyl; R.sub.3 is selected from hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 alkenyl, F, Br, Cl, CN, or C.sub.1-C.sub.4
haloalkyl; or R.sub.2 and R.sub.3 together form C.sub.4-9
cycloalkyl or C.sub.4-9 cycloalkenyl; R.sub.4 is selected from
optionally substituted heteroaryl, optionally substituted
heterocyclyl, or optionally substituted aryl; R.sub.5 is selected
from hydrogen or optionally substituted alkyl; wherein when both
R.sub.2 and R.sub.3 are Cl, R.sub.4 is an optionally substituted
heteroaryl or optionally substituted heterocyclyl, and provided
that the following compounds are excluded: ##STR00128##
##STR00129## or a pharmaceutically acceptable salt thereof, or a
composition comprising a compound as defined above, or a
pharmaceutically acceptable salt thereof.
24. A method of positively modulating .alpha.7nAChRs in a cell by
contacting the cell with a compound of formula (I) or a salt
thereof: ##STR00130## wherein R.sub.1 is selected from optionally
substituted aryl, optionally substituted heteroaryl (excluding
optionally substituted porphyrins), or optionally substituted
heterocyclyl; R.sub.2 is selected from C.sub.1-C.sub.4 alkyl,
C.sub.3-C.sub.5 alkenyl, F, Br, Cl, CN, or C.sub.1-C.sub.4
haloalkyl; R.sub.3 is selected from hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 alkenyl, F, Br, Cl, CN, or C.sub.1-C.sub.4
haloalkyl; or R.sub.2 and R.sub.3 together form C.sub.4-9
cycloalkyl or C.sub.4-9 cycloalkenyl; R.sub.4 is selected from
optionally substituted heteroaryl, optionally substituted
heterocyclyl, or optionally substituted aryl; R.sub.5 is selected
from hydrogen or optionally substituted alkyl; wherein when both
R.sub.2 and R.sub.3 are Cl, R.sub.4 is an optionally substituted
heteroaryl or optionally substituted heterocyclyl, and provided
that the following compounds are excluded: ##STR00131##
##STR00132## or a salt thereof, to said cell.
25. A method for the treatment of cognitive deficits associated
with neurodegeneration or neuropsychiatric diseases, said method
including the step of administering a compound of formula (II) or a
salt thereof: ##STR00133## wherein R.sub.1 is selected from
optionally substituted aryl, optionally substituted heteroaryl or
optionally substituted heterocyclyl; R.sub.2 and R.sub.3 together
form C.sub.4-9 cycloalkyl; R.sub.4 is selected from optionally
substituted heteroaryl, optionally substituted heterocyclyl, or
optionally substituted aryl; and R.sub.5 is selected from hydrogen
or optionally substituted alkyl, or a pharmaceutically acceptable
salt thereof, or a composition comprising a compound as defined
above, or a pharmaceutically acceptable salt thereof.
26. A method for the treatment of inflammatory diseases, said
method including the step of administering a compound of formula
(II) or a salt thereof: ##STR00134## wherein R.sub.1 is selected
from optionally substituted aryl, optionally substituted heteroaryl
or optionally substituted heterocyclyl; R.sub.2 and R.sub.3
together form C.sub.4-9 cycloalkyl; R.sub.4 is selected from
optionally substituted heteroaryl, optionally substituted
heterocyclyl, or optionally substituted aryl; and R.sub.5 is
selected from hydrogen or optionally substituted alkyl, or a
pharmaceutically acceptable salt thereof, or a composition
comprising a compound as defined above, or a pharmaceutically
acceptable salt thereof.
27. A method of positively modulating .alpha.7nAChRs in a cell by
contacting the cell with a compound of formula (II) or a salt
thereof: ##STR00135## wherein R.sub.1 is selected from optionally
substituted aryl, optionally substituted heteroaryl or optionally
substituted heterocyclyl; R.sub.2 and R.sub.3 together form
C.sub.4-9 cycloalkyl; R.sub.4 is selected from optionally
substituted heteroaryl, optionally substituted heterocyclyl, or
optionally substituted aryl; and R.sub.5 is selected from hydrogen
or optionally substituted alkyl, or a salt thereof, to said
cell.
28. A method for the treatment of cognitive deficits associated
with neurodegeneration or neuropsychiatric diseases, said method
including the step of administering a compound represented by
formula (Ia), or a salt thereof: ##STR00136## wherein each R.sub.1'
is independently selected from the group consisting of cyano, halo,
nitro, optionally substituted lower alkyl, optionally substituted
aryl, optionally substituted aryloxy, optionally substituted
arylalkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, optionally substituted C.sub.3-7
cycloalkyl, --OR, --C(O)R, --C(O)OR, --OC(O)R (where R is selected
from hydrogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
C.sub.3-7 cycloalkyl, optionally substituted heterocyclyl,
optionally substituted heteroaryl, and optionally substituted
aryl), --C(O)NR'R'', --NR'C(O)R'', --S(O).sub.2--NR'R'' and
--NR'R'' (where R' and R'' are independently selected from hydrogen
or lower alkyl), --S(O)R''' (where R''' is lower alkyl, or
cycloalkyl), --S(O).sub.2R''' (where R''' is lower alkyl,
cycloalkyl or OH), or any two adjacent R.sub.1' together form
heterocyclyl or heteroaryl; n is 0 or an integer from 1 to 5;
R.sub.2 is selected from C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5
alkenyl, F, Br, Cl, CN, or C.sub.1-C.sub.4 haloalkyl; R.sub.3 is
selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5
alkenyl, F, Br, Cl, CN, or C.sub.1-C.sub.4 haloalkyl; or R.sub.2
and R.sub.3 together form C.sub.4-9 cycloalkyl or C.sub.4-9
cycloalkenyl; R.sub.4 is selected from optionally substituted
heteroaryl, optionally substituted heterocyclyl, or optionally
substituted aryl; R.sub.5 is selected from hydrogen or optionally
substituted alkyl; wherein when both R.sub.2 and R.sub.3 are Cl,
R.sub.4 is an optionally substituted heteroaryl or optionally
substituted heterocyclyl, and provided that the following compounds
are excluded: ##STR00137## or a pharmaceutically acceptable salt
thereof, or a composition comprising a compound as defined above,
or a pharmaceutically acceptable salt thereof.
29. A method for the treatment of inflammatory diseases, said
method including the step of administering a compound represented
by formula (Ia), or a salt thereof: ##STR00138## wherein each
R.sub.1' is independently selected from the group consisting of
cyano, halo, nitro, optionally substituted lower alkyl, optionally
substituted aryl, optionally substituted aryloxy, optionally
substituted arylalkyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl, optionally substituted
C.sub.3-7 cycloalkyl, --OR, --C(O)R, --C(O)OR, --OC(O)R (where R is
selected from hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted C.sub.3-7 cycloalkyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, and optionally
substituted aryl), --C(O)NR'R'', --NR'C(O)R'', --S(O).sub.2--NR'R''
and --NR'R'' (where R' and R'' are independently selected from
hydrogen or lower alkyl), --S(O)R''' (where R''' is lower alkyl, or
cycloalkyl), --S(O).sub.2R''' (where R''' is lower alkyl,
cycloalkyl or OH), or any two adjacent R.sub.1' together form
heterocyclyl or heteroaryl; n is 0 or an integer from 1 to 5;
R.sub.2 is selected from C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5
alkenyl, F, Br, Cl, CN, or C.sub.1-C.sub.4 haloalkyl; R.sub.3 is
selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5
alkenyl, F, Br, Cl, CN, or C.sub.1-C.sub.4 haloalkyl; or R.sub.2
and R.sub.3 together form C.sub.4-9 cycloalkyl or C.sub.4-9
cycloalkenyl; R.sub.4 is selected from optionally substituted
heteroaryl, optionally substituted heterocyclyl, or optionally
substituted aryl; R.sub.5 is selected from hydrogen or optionally
substituted alkyl; wherein when both R.sub.2 and R.sub.3 are Cl,
R.sub.4 is an optionally substituted heteroaryl or optionally
substituted heterocyclyl, and provided that the following compounds
are excluded: ##STR00139## or a pharmaceutically acceptable salt
thereof, or a composition comprising a compound as defined above,
or a pharmaceutically acceptable salt thereof.
30. A method for the treatment of cognitive deficits associated
with neurodegeneration or neuropsychiatric diseases, said method
including the step of administering a compound represented by
formula (Ib), or a salt thereof: ##STR00140## wherein each R.sub.1'
is independently selected from the group consisting of cyano, halo,
nitro, optionally substituted lower alkyl, optionally substituted
aryl, optionally substituted aryloxy, optionally substituted
arylalkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, optionally substituted C.sub.3-7
cycloalkyl, --OR, --C(O)R, --C(O)OR, --OC(O)R (where R is selected
from hydrogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
C.sub.3-7 cycloalkyl, optionally substituted heterocyclyl,
optionally substituted heteroaryl, and optionally substituted
aryl), --C(O)NR'R'', --NR'C(O)R'', --S(O).sub.2--NR'R'' and
--NR'R'' (where R' and R'' are independently selected from hydrogen
or lower alkyl), --S(O)R''' (where R''' is lower alkyl, or
cycloalkyl), --S(O).sub.2R''' (where R''' is lower alkyl,
cycloalkyl or OH), or any two adjacent R.sub.1' together form
heterocyclyl or heteroaryl; n is 0 or an integer from 1 to 5;
R.sub.2 is selected from C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5
alkenyl, C.sub.1-C.sub.4 haloalkyl, F, Cl or Br; R.sub.3 is
selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5
alkenyl, C.sub.1-C.sub.4 haloalkyl, or Br; or R.sub.2 and R.sub.3
together form C.sub.4-9 cycloalkyl or C.sub.4-9 cycloalkenyl;
R.sub.4 is selected from optionally substituted heteroaryl,
optionally substituted heterocyclyl, or optionally substituted
aryl; R.sub.5 is independently selected from hydrogen, or
optionally substituted alkyl; provided that the following compound
is excluded: ##STR00141## or a pharmaceutically acceptable salt
thereof, or a composition comprising a compound as defined above,
or a pharmaceutically acceptable salt thereof.
31. A method for the treatment of inflammatory diseases, said
method including the step of administering a compound represented
by formula (Ib), or a salt thereof: ##STR00142## wherein each
R.sub.1' is independently selected from the group consisting of
cyano, halo, nitro, optionally substituted lower alkyl, optionally
substituted aryl, optionally substituted aryloxy, optionally
substituted arylalkyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl, optionally substituted
C.sub.3-7 cycloalkyl, --OR, --C(O)R, --C(O)OR, --OC(O)R (where R is
selected from hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted C.sub.3-7 cycloalkyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, and optionally
substituted aryl), --C(O)NR'R'', --NR'C(O)R'', --S(O).sub.2--NR'R''
and --NR'R'' (where R' and R'' are independently selected from
hydrogen or lower alkyl), --S(O)R'' (where R''' is lower alkyl, or
cycloalkyl), --S(O).sub.2R''' (where R''' is lower alkyl,
cycloalkyl or OH), or any two adjacent R.sub.1' together form
heterocyclyl or heteroaryl; n is 0 or an integer from 1 to 5;
R.sub.2 is selected from C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5
alkenyl, C.sub.1-C.sub.4 haloalkyl, F, Cl or Br; R.sub.3 is
selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5
alkenyl, C.sub.1-C.sub.4 haloalkyl, or Br; or R.sub.2 and R.sub.3
together form C.sub.4-9 cycloalkyl or C.sub.4-9 cycloalkenyl;
R.sub.4 is selected from optionally substituted heteroaryl,
optionally substituted heterocyclyl, or optionally substituted
aryl; R.sub.5 is independently selected from hydrogen, or
optionally substituted alkyl; provided that the following compound
is excluded: ##STR00143## or a pharmaceutically acceptable salt
thereof, or a composition comprising a compound as defined above,
or a pharmaceutically acceptable salt thereof.
32. A method for the treatment of cognitive deficits associated
with neurodegeneration or neuropsychiatric diseases, said method
including the step of administering a compound represented by
formula (Ic), or a salt thereof: ##STR00144## wherein each R.sub.1'
is independently selected from the group consisting of cyano, halo,
nitro, optionally substituted lower alkyl, optionally substituted
aryl, optionally substituted aryloxy, optionally substituted
arylalkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, optionally substituted C.sub.3-7
cycloalkyl, --OR, --C(O)R, --C(O)OR, --OC(O)R (where R is selected
from hydrogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
C.sub.3-7 cycloalkyl, optionally substituted heterocyclyl,
optionally substituted heteroaryl, and optionally substituted
aryl), --C(O)NR'R'', --NR'C(O)R'', --S(O).sub.2--NR'R'' and
--NR'R'' (where R' and R'' are independently selected from hydrogen
or lower alkyl), --S(O)R''' (where R''' is lower alkyl, or
cycloalkyl), --S(O).sub.2R''' (where R''' is lower alkyl,
cycloalkyl or OH), or any two adjacent R.sub.1' together form
heterocyclyl or heteroaryl; n is 0 or an integer from 1 to 5;
R.sub.2 is selected from C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5
alkenyl, C.sub.1-C.sub.4 haloalkyl, F, Cl or Br; R.sub.3 is
selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5
alkenyl, C.sub.1-C.sub.4 haloalkyl, or Br; or R.sub.2 and R.sub.3
together form C.sub.4-9 cycloalkyl or C.sub.4-9 cycloalkenyl;
R.sub.4 is selected from heteroaryl which may be independently
substituted by one to three substituents selected from halogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, --OH, phenyl,
benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2, --NHC.sub.1-4
alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2, mercapto,
--S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is
lower alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is
lower alkyl, cycloalkyl or OH); or aryl which may be independently
substituted by one to three substituents selected from halogen,
C.sub.2-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, --OH, phenyl,
benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2, --NHC.sub.1-4
alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2, mercapto,
--S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is
lower alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is
lower alkyl, cycloalkyl or OH); and R.sub.5 is independently
selected from hydrogen, or lower alkyl, or a pharmaceutically
acceptable salt thereof, or a composition comprising a compound as
defined above, or a pharmaceutically acceptable salt thereof.
33. A method for the treatment of inflammatory diseases, said
method including the step of administering a compound represented
by formula (Ic), or a salt thereof: ##STR00145## wherein each
R.sub.1' is independently selected from the group consisting of
cyano, halo, nitro, optionally substituted lower alkyl, optionally
substituted aryl, optionally substituted aryloxy, optionally
substituted arylalkyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl, optionally substituted
C.sub.3-7 cycloalkyl, --OR, --C(O)R, --C(O)OR, --OC(O)R (where R is
selected from hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted C.sub.3-7 cycloalkyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, and optionally
substituted aryl), --C(O)NR'R'', --NR'C(O)R'', --S(O).sub.2--NR'R''
and --NR'R'' (where R' and R'' are independently selected from
hydrogen or lower alkyl), --S(O)R''' (where R''' is lower alkyl, or
cycloalkyl), --S(O).sub.2R''' (where R''' is lower alkyl,
cycloalkyl or OH), or any two adjacent R.sub.1' together form
heterocyclyl or heteroaryl; n is 0 or an integer from 1 to 5;
R.sub.2 is selected from C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5
alkenyl, C.sub.1-C.sub.4 haloalkyl, F, Cl or Br; R.sub.3 is
selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5
alkenyl, C.sub.1-C.sub.4 haloalkyl, or Br; or R.sub.2 and R.sub.3
together form C.sub.4-9 cycloalkyl or C.sub.4-9 cycloalkenyl;
R.sub.4 is selected from heteroaryl which may be independently
substituted by one to three substituents selected from halogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, --OH, phenyl,
benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2, --NHC.sub.1-4
alkyl, --N(C.sub.1-4alkyl).sub.2, --CN, --NO.sub.2, mercapto,
--S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is
lower alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is
lower alkyl, cycloalkyl or OH); or aryl which may be independently
substituted by one to three substituents selected from halogen,
C.sub.2-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, haloalkyl, C.sub.1-6 haloalkoxy, --OH, phenyl, benzyl,
phenoxy, benzyloxy, benzoyl, --NH.sub.2, --NHC.sub.1-4 alkyl,
--N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2, mercapto,
--S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is
lower alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is
lower alkyl, cycloalkyl or OH); and R.sub.5 is independently
selected from hydrogen, or lower alkyl, or a pharmaceutically
acceptable salt thereof, or a composition comprising a compound as
defined above, or a pharmaceutically acceptable salt thereof.
34. A method for the treatment of cognitive deficits associated
with neurodegeneration or neuropsychiatric diseases, said method
including the step of administering a compound represented by
formula (IIa), or a salt thereof: ##STR00146## wherein each
R.sub.1' is independently selected from the group consisting of
cyano, halo, nitro, optionally substituted lower alkyl, optionally
substituted aryl, optionally substituted aryloxy, optionally
substituted arylalkyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl, optionally substituted
C.sub.3-7 cycloalkyl, --OR, --C(O)R, --C(O)OR, --OC(O)R (where R is
selected from hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted C.sub.3-7 cycloalkyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, and optionally
substituted aryl), --C(O)NR'R'', --NR'C(O)R'', --S(O).sub.2--NR'R''
and --NR'R'' (where R' and R'' are independently selected from
hydrogen or lower alkyl), --S(O)R''' (where R''' is lower alkyl, or
cycloalkyl), --S(O).sub.2R''' (where R''' is lower alkyl,
cycloalkyl or OH), or any two adjacent R.sub.1' together form
heterocyclyl or heteroaryl; n is 0 an integer from 1 to 5; R.sub.2
and R.sub.3 together form C.sub.4-9 cycloalkyl; R.sub.4 is selected
from optionally substituted heteroaryl, optionally substituted
heterocyclyl, or optionally substituted aryl; and R.sub.5 is
independently selected from hydrogen or optionally substituted
alkyl, or a pharmaceutically acceptable salt thereof, or a
composition comprising a compound as defined above, or a
pharmaceutically acceptable salt thereof.
35. A method for the treatment of inflammatory diseases, said
method including the step of administering a compound represented
by formula (IIa), or a salt thereof: ##STR00147## wherein each
R.sub.1' is independently selected from the group consisting of
cyano, halo, nitro, optionally substituted lower alkyl, optionally
substituted aryl, optionally substituted aryloxy, optionally
substituted arylalkyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl, optionally substituted
C.sub.3-7 cycloalkyl, --OR, --C(O)R, --C(O)OR, --OC(O)R (where R is
selected from hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted C.sub.3-7 cycloalkyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, and optionally
substituted aryl), --C(O)NR'R'', --NR'C(O)R'', --S(O).sub.2--NR'R''
and --NR'R'' (where R' and R'' are independently selected from
hydrogen or lower alkyl), --S(O)R''' (where R''' is lower alkyl, or
cycloalkyl), --S(O).sub.2R''' (where R''' is lower alkyl,
cycloalkyl or OH), or any two adjacent R.sub.1' together form
heterocyclyl or heteroaryl; n is 0 an integer from 1 to 5; R.sub.2
and R.sub.3 together form C.sub.4-9 cycloalkyl; R.sub.4 is selected
from optionally substituted heteroaryl, optionally substituted
heterocyclyl, or optionally substituted aryl; and R.sub.5 is
independently selected from hydrogen or optionally substituted
alkyl, or a pharmaceutically acceptable salt thereof, or a
composition comprising a compound as defined above, or a
pharmaceutically acceptable salt thereof.
36. A method according to claim 22, wherein R.sub.1 is an
optionally substituted aryl or optionally substituted heteroaryl
group.
37. A method according to claim 23, wherein R.sub.1 is an
optionally substituted aryl or optionally substituted heteroaryl
group.
38. A method according to claim 22, wherein R.sub.4 is selected
from heteroaryl or aryl each of which may be independently
substituted by one to three substituents selected from halogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, --OH, phenyl,
benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2, --NHC.sub.1-4
alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2, mercapto,
--S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is lower
alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is lower
alkyl, cycloalkyl or OH).
39. A method according to claim 23, wherein R.sub.4 is selected
from heteroaryl or aryl each of which may be independently
substituted by one to three substituents selected from halogen,
C.sub.1-6alkyl, C.sub.1-6 alkoxy, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, --OH,
phenyl, benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2,
--NHC.sub.1-4alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2,
mercapto, --S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is lower
alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is lower
alkyl, cycloalkyl or OH).
40. A method according to claim 22, where R.sub.4 is selected from:
(a) ##STR00148## wherein Hal is a halogen; m is 0, 1 or 2; and each
R.sub.6 is independently selected from halogen, hydroxy, CN,
NO.sub.2, haloalkyl, aryl, heteroaryl, C.sub.1-3 alkoxy, C.sub.1-3
alkyl, or CO.sub.2R' (where R' is a lower alkyl or H); or (b) a
heteroaryl substituted from 1 to 3 times from a group selected from
C.sub.1-C.sub.3 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl,
C.sub.2-6 alkenyl, C.sub.1-6 haloalkoxy, --OH, phenyl, benzyl,
phenoxy, benzyloxy, benzoyl, --NH.sub.2, --NHC.sub.1-4alkyl,
--N(C.sub.1-4alkyl).sub.2, --CN, --NO.sub.2, mercapto, C.sub.1-6
alkylcarbonyl, C.sub.1-6alkoxycarbonyl, CO.sub.2H, --S(O)R'''
(where R''' is lower alkyl or cycloalkyl) and --S(O).sub.2R'''
(where R''' is lower alkyl, cycloalkyl or OH).
41. A method according to claim 23, where R.sub.4 is selected from:
(a) ##STR00149## wherein Hal is a halogen; m is 0, 1 or 2; and each
R.sub.6 is independently selected from halogen, hydroxy, CN,
NO.sub.2, haloalkyl, aryl, heteroaryl, C.sub.1-3 alkoxy, C.sub.1-3
alkyl, or CO.sub.2R' (where R' is a lower alkyl or H); or (b) a
heteroaryl substituted from 1 to 3 times from a group selected from
C.sub.1-C.sub.3 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, --OH,
phenyl, benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2,
--NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2, --CN, --NO.sub.2,
mercapto, C.sub.1-6 alkylcarbonyl, C.sub.1-6alkoxycarbonyl,
CO.sub.2H, --S(O)R''' (where R''' is lower alkyl or cycloalkyl) and
--S(O).sub.2R''' (where R''' is lower alkyl, cycloalkyl or OH).
42. A method according to claim 40, wherein the heteroaryl is
pyridinyl, pyrazolyl or thiazolyl.
43. A method according to claim 41, wherein the heteroaryl is
pyridinyl, pyrazolyl or thiazolyl.
44. A method according to claim 22, wherein R.sub.2 and R.sub.3 are
C.sub.1-C.sub.4 alkyl, or a pharmaceutically acceptable salt
thereof.
45. A method according to claim 23, wherein R.sub.2 and R.sub.3 are
C.sub.1-C.sub.4 alkyl, or a pharmaceutically acceptable salt
thereof.
46. A method according to claim 22, wherein R.sub.2 and R.sub.3 are
methyl or ethyl.
47. A method according to claim 23, wherein R.sub.2 and R.sub.3 are
methyl or ethyl.
48. A method according to claim 22, wherein R.sub.5 is hydrogen or
C.sub.1-3 alkyl.
49. A method according to claim 23, wherein R.sub.5 is hydrogen or
C.sub.1-3 alkyl.
50. A method according to claim 22, wherein n is 0, 1, 2, or 3, and
R.sub.1', when present, is halogen, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.1-6 haloalkoxy, --OH, phenyl, benzyl, phenoxy, benzyloxy,
benzoyl, --NH.sub.2, --NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2,
--CN, --NO.sub.2, mercapto, --S(O).sub.2NH.sub.2,
--S(O).sub.2NHC.sub.1-4 alkyl, --S(O).sub.2N(C.sub.1-4
alkyl).sub.2, C.sub.1-6 alkylcarbonyl, C.sub.1-5 alkoxycarbonyl,
CO.sub.2H, --S(O)R''' (where R''' is lower alkyl or cycloalkyl) and
--S(O).sub.2R''' (where R''' is lower alkyl, cycloalkyl or OH).
51. A method according to claim 23, wherein n is 0, 1, 2, or 3, and
R.sub.1', when present, is halogen, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.1-6 habalkoxy, --OH, phenyl, benzyl, phenoxy, benzyloxy,
benzoyl, --NH.sub.2, --NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2,
--CN, --NO.sub.2, mercapto, --S(O).sub.2NH.sub.2,
--S(O).sub.2NHC.sub.1-4 alkyl, --S(O).sub.2N(C.sub.1-4
alkyl).sub.2, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkoxycarbonyl,
CO.sub.2H, --S(O)R''' (where R''' is lower alkyl or cycloalkyl) and
--S(O).sub.2R''' (where R''' is lower alkyl, cycloalkyl or OH).
Description
FIELD OF THE INVENTION
[0001] The present invention relates to chemical compounds useful
in the positive modulation of the alpha 7 nicotinic acetylcholine
receptor (.alpha.7nAChR). The invention also relates to the use of
these compounds in the treatment or prevention of a broad range of
diseases in which the positive modulation of .alpha.7nAChR is
advantageous, including neurodegenerative and neuropsychiatric
diseases and also inflammatory diseases.
BACKGROUND
[0002] The alpha 7 nicotinic acetylcholine receptors
(.alpha.7nAChRs) are rapidly desensitizing ligand-gated ion
channels that are abundantly expressed in the cerebral cortex and
the hippocampus, a limbic structure intimately linked to attention
processing and memory formation. .alpha.7nAChRs modulate
neurotransmitter release and are responsible for direct fast
excitatory neurotransmission. At the cellular level, activation of
.alpha.7nAChRs can regulate interneuron excitability, modulate the
release of excitatory and inhibitory neurotransmitters, and
contribute to neuroprotective effects.
[0003] Several lines of evidence indicate that attention and
cognitive impairment, which are characteristic of neurological and
psychiatric disorders such as Alzheimer's disease (AD),
schizophrenia, Parkinson's Disease (PD), multiple sclerosis,
attention deficit hyperactivity disorder (ADHD), mild cognitive
impairment (MCI), age associated memory impairment (AAMI), may
involve degeneration or hypo-function of cholinergic input.
Moreover, genetic linkage has identified .alpha.7AChRs as a
predisposing factor related to sensory gating deficits. Thus,
targeting the .alpha.7nAChRs represents a therapeutic strategy for
ameliorating cognitive deficits associated with neurodegenerative
and neuropsychiatric diseases.
[0004] A number of reports also suggest that .alpha.7nAChRs mediate
protection against neurotoxicity induced by amyloid beta and
excitotoxic insults. Peripherally, .alpha.7-nAChRs are expressed in
macrophages and their stimulation is essential for inhibiting the
release of proinflammatory cytokines (e.g. TNF-a, IL-1) via the
cholinergic anti-inflammatory pathway which is triggered in
response to signals from the vagus nerve. Thus, the clinical use of
agonists of the .alpha.7nAChRs could also represent a strategy
against inflammatory diseases.
[0005] Selective positive allosteric modulation (PAM) of the
.alpha.7nAChR is a recent therapeutic approach for treating these
disease states. A key advantage of this approach is that modulation
only occurs in the presence of endogenous agonist thereby
preserving the temporal and spatial integrity of neurotransmission.
At least two different profiles of PAMs have been described thus
far for .alpha.7nAChRs: Type I modulators that predominately affect
the apparent peak current and agonist sensitivity, and Type II
modulators that also cause a modification of the desensitization
profile of agonist response. Several potent PAMs have been
described (for example, 5-hydroxyindole, NS-1738) that increase
acetylcholine sensitivity with only marginal effects on the
desensitization kinetics of the .alpha.7nAChR channel. Others such
as PNU-120596, show profound effects on receptor desensitization in
addition to enhanced sensitivity to acetylcholine and increased
current amplitude.
##STR00001##
[0006] The present invention seeks to address some of the
shortcomings of the prior art therapeutics and is directed to a new
class of compounds which are thought to exhibit positive modulation
of .alpha.7nAChR.
SUMMARY OF THE INVENTION
[0007] In one aspect the invention provides compounds of formula
(I) or salts thereof:
##STR00002##
[0008] wherein [0009] R.sub.1 is selected from optionally
substituted aryl, optionally substituted heteroaryl (excluding
optionally substituted porphyrins), or optionally substituted
heterocyclyl; [0010] R.sub.2 is selected from C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 alkenyl, F, Br, Cl, CN, or C.sub.1-C.sub.4
haloalkyl; [0011] R.sub.3 is selected from hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 alkenyl, F, Br, Cl, CN, or
C.sub.1-C.sub.4 haloalkyl; or [0012] R.sub.2 and R.sub.3 together
form C.sub.4-9 cycloalkyl or C.sub.4-9 cycloalkenyl; [0013] R.sub.4
is selected from optionally substituted heteroaryl, optionally
substituted heterocyclyl, or optionally substituted aryl; [0014]
R.sub.5 is selected from hydrogen or optionally substituted alkyl;
[0015] wherein when both R.sub.2 and R.sub.3 are Cl, R.sub.4 is an
optionally substituted heteroaryl or optionally substituted
heterocyclyl, [0016] provided that the following compounds are
excluded:
##STR00003## ##STR00004##
[0017] In an embodiment R.sub.1 is an optionally substituted aryl
group and more preferably an optionally substituted phenyl
group.
[0018] Accordingly, in a further aspect the invention provides
compounds of formula (Ia) or salts thereof:
##STR00005##
[0019] wherein [0020] each R.sub.1' is independently selected from
the group consisting of cyano, halo, nitro, optionally substituted
lower alkyl, optionally substituted aryl, optionally substituted
aryloxy, optionally substituted arylalkyl, optionally substituted
heteroaryl, optionally substituted heterocyclyl, optionally
substituted C.sub.3-7 cycloalkyl, --OR, --C(O)R, --C(O)OR, --OC(O)R
(where R is selected from hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted C.sub.3-7 cycloalkyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, and optionally
substituted aryl), --C(O)NR'R'', --NR'C(O)R'', --S(O).sub.2--NR'R''
and --NR'R'' (where R' and R'' are independently selected from
hydrogen or lower alkyl), --S(O)R''' (where R''' is lower alkyl, or
cycloalkyl), --S(O).sub.2R''' (where R''' is lower alkyl,
cycloalkyl or OH), or any two adjacent R.sub.1' together form
heterocyclyl or heteroaryl; [0021] n is 0 or an integer from 1 to
5; [0022] R.sub.2 is selected from C.sub.1-C.sub.4 alkyl,
C.sub.3-C.sub.5 alkenyl, F, Br, Cl, CN, or C.sub.1-C.sub.4
haloalkyl; [0023] R.sub.3 is selected from hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 alkenyl, F, Br, Cl, CN, or
C.sub.1-C.sub.4 haloalkyl; or [0024] R.sub.2 and R.sub.3 together
form C.sub.4-9 cycloalkyl or C.sub.4-9 cycloalkenyl; [0025] R.sub.4
is selected from optionally substituted heteroaryl, optionally
substituted heterocyclyl, or optionally substituted aryl; [0026]
R.sub.5 is selected from hydrogen or optionally substituted alkyl;
[0027] wherein when both R.sub.2 and R.sub.3 are Cl, R.sub.4 is an
optionally substituted heteroaryl or optionally substituted
heterocyclyl, [0028] provided that the following compounds are
excluded:
##STR00006##
[0029] In another embodiment R.sub.3 and R.sub.2 together form a
C.sub.4-C.sub.9 cycloalkyl.
[0030] Accordingly, in a further aspect the invention provides
compounds of formula (II) or salts thereof:
##STR00007##
[0031] wherein [0032] R.sub.1 is selected from optionally
substituted aryl, optionally substituted heteroaryl or optionally
substituted heterocyclyl; [0033] R.sub.2 and R.sub.3 together form
C.sub.4-9 cycloalkyl; [0034] R.sub.4 is selected from optionally
substituted heteroaryl, optionally substituted heterocyclyl, or
optionally substituted aryl; and [0035] R.sub.5 is selected from
hydrogen or optionally substituted alkyl.
[0036] In a further aspect the invention provides a method for the
treatment or prevention of cognitive deficits associated with
neurodegeneration or neuropsychiatric diseases, said method
including the step of administering a compound of formula (I), (Ia)
or (II), or a pharmaceutically acceptable salt thereof, or a
composition comprising a compound of formula (I), (Ia) or (II), or
a pharmaceutically acceptable salt thereof.
[0037] In still a further aspect the invention provides a method
for the treatment or prevention of inflammatory diseases, said
method including the step of administering a compound of formula
(I), (Ia) or (II), or a pharmaceutically acceptable salt thereof,
or a composition comprising a compound of formula (I), (Ia) or
(II), or a pharmaceutically acceptable salt thereof.
[0038] In another aspect the invention provides the use of a
compound of formula (I), (Ia) or (II), or a salt thereof in the
manufacture of a medicament for the treatment or prevention of
cognitive deficits associated with neurodegeneration or
neuropsychiatric diseases.
[0039] In another aspect the invention provides the use of a
compound of formula (I), (Ia) or (II), or a salt thereof in the
manufacture of a medicament for the treatment or prevention of
inflammatory diseases.
[0040] In another aspect of the invention there is provided a
method of positively modulating .alpha.7nAChRs in a cell by
contacting the cell with a compound of formula (I), (Ia) or (II),
or a pharmaceutically acceptable salt thereof, to said cell.
[0041] In a further aspect of the invention there is provided a
pharmaceutical composition for use as a neuroprotective agent, the
composition comprising an effective amount of a compound of formula
(I), (Ia) or (II), or a pharmaceutically acceptable salt thereof
and optionally a carrier or diluent.
[0042] In still a further aspect of the invention there is provided
a pharmaceutical composition for use as an anti-inflammatory agent,
the composition comprising an effective amount of a compound of
formula (I), (Ia) or (II), or a pharmaceutically acceptable salt
thereof and optionally a carrier or diluent.
[0043] In another aspect of the invention there is provided a
process for the preparation of compounds of formula (I), (Ia) or
(II), or salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0044] The term "alkyl" as used alone or in combination herein
refers to a straight or branched chain saturated hydrocarbon group.
The term "C.sub.1-12 alkyl" refers to such a group containing from
one to twelve carbon atoms and "lower alkyl" refers to C.sub.1-6
alkyl groups containing from one to six carbon atoms, such as
methyl ("Me"), ethyl ("Et"), n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl and the like.
[0045] The term "cycloalkyl" refers to non-aromatic, saturated
non-aromatic carbocycles. The term "C.sub.4-9 cycloalkyl", for
instance, refers to such a group having from 4 to 9 carbon atoms.
Examples include cyclobutyl, cyclopentyl and cyclohexyl.
[0046] The term "alkenyl" refers to a straight or branched
hydrocarbon containing one or more double bonds, preferably one or
two double bonds. The term "C.sub.2-12 alkenyl", for instance,
refers to such a group containing from two to twelve carbon atoms.
Examples of alkenyl include allyl, 1-methylvinyl, butenyl,
iso-butenyl, 1, 3-butadienyl, 3-methyl-2-butenyl, 1,3-butadienyl,
1,4-pentadienyl, 1-pentenyl, 1-hexenyl, 3-hexenyl, 1,3-hexadienyl,
1,4-hexadienyl and 1,3,5-hexatrienyl.
[0047] The term "cycloalkenyl" refers to cyclic alkenyl groups
having a single cyclic ring or multiple condensed rings, and at
least one point of internal unsaturation, preferably incorporating
4 to 11 carbon atoms. Examples of suitable cycloalkenyl groups
include, for instance, cyclobut-2-enyl, cyclopent-3-enyl,
cyclohex-4-enyl, cyclooct-3-enyl, indenyl and the like.
[0048] The term "alkynyl" refers to a straight or branched
hydrocarbon containing one or more triple bonds, preferably one or
two triple bonds. The term "C.sub.2-12 alkynyl", for instance,
refers to such a group containing from two to twelve carbon atoms.
Examples include 2-propynyl and 2- or 3-butynyl.
[0049] The term "alkoxy" as used alone or in combination refers to
a straight or branched chain alkyl group covalently bound via an
oxygen linkage (--O--) and the terms "C.sub.1-6 alkoxy" and "lower
alkoxy" refer to such groups containing from one to six carbon
atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,
t-butoxy and the like.
[0050] The term "aryl" refers to carbocyclic (non-heterocyclic)
aromatic rings or ring systems. The aromatic rings may be mono- or
bi-cyclic ring systems. The aromatic rings or ring systems are
generally composed of 5 to 10 carbon atoms. Examples of suitable
aryl groups include but are not limited to phenyl, biphenyl,
naphthyl, tetrahydronaphthyl, and the like.
[0051] Preferred aryl groups include phenyl, naphthyl, indenyl,
azulenyl, fluorenyl or anthracenyl.
[0052] The term "heteroaryl" refers to a monovalent aromatic
carbocyclic group, preferably of from 2 to 10 carbon atoms and 1 to
4 heteroatoms selected from oxygen, nitrogen and sulfur within the
ring. Preferably the heteroatom is nitrogen. Such heteroaryl groups
can have a single ring (e.g., pyridyl, pyrrolyl or furyl) or
multiple condensed rings (e.g., indolizinyl or benzothienyl).
[0053] The term "heterocyclyl" refers to a monovalent saturated or
unsaturated group having a single ring or multiple condensed rings,
preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms
selected from nitrogen, sulfur, oxygen, selenium or phosphorous
within the ring.
[0054] Examples of 5-membered monocyclic heterocyclyl and
heteroaryl groups include furyl, thienyl, pyrrolyl, H-pyrrolyl,
pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3
and 1,2,4 oxadiazolyls) thiazolyl, isoxazolyl, furazanyl,
isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl,
imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls),
tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4
thiadiazolyls).
[0055] Examples of 6-membered monocyclic heterocyclyl and
heteroaryl groups include pyridyl, pyrimidinyl, pyridazinyl,
pyranyl, pyrazinyl, piperidinyl, 1,4-dioxanyl, morpholinyl,
1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl and
triazinyl.
[0056] Examples of 8, 9 and 10-membered bicyclic heterocyclyl and
heteroaryl groups include 1H thieno[2,3-c]pyrazolyl,
thieno[2,3-b]furyl, indolyl, isoindolyl, benzofuranyl,
benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl,
quinolinyl, quinoxalinyl, uridinyl, purinyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl,
naphthyridinyl, pteridinyl and the like.
[0057] The term "arylalkyl" refers to carbocyclic aromatic rings or
ring systems as previously described and substituted by an alkyl
group, also as previously described. Unless otherwise indicated the
aryl substituent is attached by the alkyl part of the substituent.
Likewise the terms "aryl C.sub.1-12 alkyl", "aryl C.sub.2-12
alkenyl" and "aryl C.sub.2-12 alkynyl" refer to carbocyclic
aromatic rings or ring systems as previously described and
substituted by a C.sub.1-12 alkyl, C.sub.2-12 alkenyl or C.sub.2-12
alkynyl group, as previously described.
[0058] The terms "halo" and "halogen" refers to fluoro, chloro,
bromo and iodo groups.
[0059] The term "halo alkyl" group has one or more of the hydrogen
atoms on an alkyl group replaced with halogens. A notable example
is --CF.sub.3.
[0060] The term "aryloxy" refers to an aryl group as earlier
described linked to the parent structure via an oxygen linkage
(--O--). A notable example is phenoxy. Similarly the term
"heteroaryloxy" refers to a heteroaryl group as earlier described
linked to the parent structure via an oxygen group. A notable
example is a 4, 6 or 7-benzo[b]furanyloxy group.
[0061] The term "optionally substituted" means that a group may
include one or more substituents. One or more hydrogen atoms on the
group may be replaced by substituent groups independently selected
from halogens (for example halo alkyl such as --CF.sub.3),
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.pC.sub.3-7 cycloalkyl, --(CH.sub.2).sub.pC.sub.4-7
cycloalkenyl, --(CH.sub.2).sub.p aryl, --(CH.sub.2).sub.p
heterocyclyl, --(CH.sub.2).sub.p heteroaryl,
--C.sub.6H.sub.4S(O).sub.qC.sub.1-6 alkyl, --C(Ph).sub.3, --CN,
--OR, --O--(CH.sub.2).sub.1-6--R, --O--(CH.sub.2).sub.1-6--OR,
--OC(O)R, --C(O)R, --C(O)OR, --OC(O)NR'R'', --NR'R'', --NRC(O)R',
--NRC(O)NR'R'', --NRC(S)NR'R'', --NRS(O).sub.2R', --NRC(O)OR',
--C(NR)NR'R'', --C(.dbd.NOR')R, --C(.dbd.NOH)NR'R'', --C(O)NR'R'',
--C(.dbd.NCN)--NR'R'', --C(.dbd.NR)NR'R'', --C(.dbd.NR')SR'',
--NR'C(.dbd.NCN)SR'', --CONRSO.sub.2R', --C(S)NR'R'',
--S(O).sub.qR, --SO.sub.2NR'R'', --SO.sub.2NRC(O)R',
--OS(O).sub.2R, --PO(OR).sub.2 and --NO.sub.2;
[0062] where p is 0-6, q is 0-2 and each R, R' and R'' is
independently selected from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.4-7 cycloalkenyl,
aryl, heterocyclyl, heteroaryl, C.sub.1-6 alkylaryl, C.sub.1-6
alkylheteroaryl, and C.sub.1-6 alkylheterocyclyl, wherein the
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,
heterocyclyl, heteroaryl, C.sub.1-6 alkylaryl, C.sub.1-6
alkylheteroaryl, or C.sub.1-6 alkylheterocyclyl, may be optionally
substituted with one to six of same or different groups selected
from halogen, hydroxy, lower alkyl, lower alkoxy, --CO.sub.2H,
CF.sub.3, CN, phenyl, NH.sub.2 and --NO.sub.2; or when R' and R''
are attached to the same nitrogen atom, they may, together with the
atom to which they are attached, form a 5 to 7 membered nitrogen
containing heterocyclic ring.
[0063] A list of preferred optional substituents includes: halogen
(in particular, Cl, Br or F), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl (in
particular --CF.sub.3), C.sub.1-6 haloalkoxy (such as --OCF.sub.3),
--OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2,
mercapto, --S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is
lower alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is
lower alkyl, cycloalkyl or OH).
[0064] Unless otherwise defined and only in respect of the ring
atoms of non-aromatic carbocyclic or heterocyclic compounds, the
ring atoms of such compounds may also be optionally substituted
with one or two .dbd.O groups, instead of or in addition to the
above described optional substituents.
[0065] When the optional substituent is or contains an alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl
group, the group may itself be optionally substituted with one to
six of the same or different substituents selected from halogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl (in particular --CF.sub.3), C.sub.1-6
haloalkoxy (such as --OCF.sub.3), --OH, phenyl, benzyl, phenoxy,
benzyloxy, benzoyl, --NH.sub.2, --NHC.sub.1-4 alkyl, --N(C.sub.1-4
alkyl).sub.2, --CN, --NO.sub.2, mercapto, --S(O).sub.2NH.sub.2,
--S(O).sub.2NHC.sub.1-4 alkyl, --S(O).sub.2N(C.sub.1-4
alkyl).sub.2, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkoxycarbonyl,
CO.sub.2H, --S(O)R''' (where R''' is lower alkyl or cycloalkyl) and
--S(O).sub.2R''' (where R''' is lower alkyl, cycloalkyl or OH).
[0066] In an embodiment R.sub.2 is selected from C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 alkenyl, C.sub.1-C.sub.4 haloalkyl, F, Cl or
Br, and R.sub.3 is selected from hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.3-C.sub.5 alkenyl, C.sub.1-C.sub.4 haloalkyl, or Br.
[0067] Accordingly, in another aspect the invention provides
compounds of formula (Ib), or salts thereof:
##STR00008##
[0068] wherein [0069] each R.sub.1' is independently selected from
the group consisting of cyano, halo, nitro, optionally substituted
lower alkyl, optionally substituted aryl, optionally substituted
aryloxy, optionally substituted arylalkyl, optionally substituted
heteroaryl, optionally substituted heterocyclyl, optionally
substituted C.sub.3-7 cycloalkyl, --OR, --C(O)R, --C(O)OR, --OC(O)R
(where R is selected from hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted C.sub.3-7 cycloalkyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, and optionally
substituted aryl), --C(O)NR'R'', --NR'C(O)R'', --S(O).sub.2--NR'R''
and --NR'R'' (where R' and R'' are independently selected from
hydrogen or lower alkyl), --S(O)R''' (where R''' is lower alkyl, or
cycloalkyl), --S(O).sub.2R''' (where R''' is lower alkyl,
cycloalkyl or OH), or any two adjacent R.sub.1' together form
heterocyclyl or heteroaryl; [0070] n is 0 or an integer from 1 to
5; [0071] R.sub.2 is selected from C.sub.1-C.sub.4 alkyl,
C.sub.3-C.sub.5 alkenyl, C.sub.1-C.sub.4 haloalkyl, F, Cl or Br;
[0072] R.sub.3 is selected from hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.3-C.sub.5 alkenyl, C.sub.1-C.sub.4 haloalkyl, or Br; or
[0073] R.sub.2 and R.sub.3 together form C.sub.4-9 cycloalkyl or
C.sub.4-9 cycloalkenyl; [0074] R.sub.4 is selected from optionally
substituted heteroaryl, optionally substituted heterocyclyl, or
optionally substituted aryl; [0075] R.sub.5 is independently
selected from hydrogen, or optionally substituted alkyl; provided
that the following compound is excluded:
##STR00009##
[0076] In relation to compounds of formula (I), (Ia), or (Ib) the
following definitions may also apply: [0077] a) R.sub.2 and R.sub.3
are both C.sub.3-C.sub.5 alkenyl, C.sub.1-C.sub.3 alkyl (preferably
methyl), or Br, or R.sub.2 and R.sub.3 together form a
C.sub.4-C.sub.9 cycloalkyl ring. [0078] b) R.sub.2 and R.sub.3 are
both CH.sub.3. [0079] c) R.sub.2 and R.sub.3 are both
C.sub.3-C.sub.5 alkenyl. [0080] d) R.sub.2 and R.sub.3 together
form a C.sub.4-C.sub.9 cycloalkyl ring, preferably cyclopentyl or
cyclohexyl ring.
[0081] In relation to compounds of formula (I), (Ia) or (II) the
following additional definitions may also apply: [0082] e) R.sub.2
and R.sub.3 are both C.sub.3-C.sub.5 alkenyl, C.sub.1-C.sub.3 alkyl
(preferably methyl), or Br, or R.sub.2 and R.sub.3 together form a
C.sub.4-C.sub.9 cycloalkyl ring, and R.sub.4 is selected from
heteroaryl or aryl each of which may be independently substituted
by one to three substituents selected from halogen (in particular,
Cl, Br or F), C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl (in particular --CF.sub.3),
C.sub.1-6 haloalkoxy (such as --OCF.sub.3), --OH, phenyl, benzyl,
phenoxy, benzyloxy, benzoyl, --NH.sub.2, --NHC.sub.1-4 alkyl,
--N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2, mercapto,
--S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is
lower alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is
lower alkyl, cycloalkyl or OH). [0083] f) R.sub.2 and R.sub.3 are
both CH.sub.3, and R.sub.4 is selected from heteroaryl or aryl each
of which may be independently substituted by one to three
substituents selected from halogen (in particular, Cl, Br or F),
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl (in particular --CF.sub.3), C.sub.1-6
haloalkoxy (such as --OCF.sub.3), --OH, phenyl, benzyl, phenoxy,
benzyloxy, benzoyl, --NH.sub.2, --NHC.sub.1-4 alkyl, --N(C.sub.1-4
alkyl).sub.2, --CN, --NO.sub.2, mercapto, --S(O).sub.2NH.sub.2,
--S(O).sub.2NHC.sub.1-4 alkyl, --S(O).sub.2N(C.sub.1-4
alkyl).sub.2, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkoxycarbonyl,
CO.sub.2H, --S(O)R''' (where R''' is lower alkyl or cycloalkyl) and
--S(O).sub.2R''' (where R''' is lower alkyl, cycloalkyl or OH).
[0084] g) R.sub.2 and R.sub.3 are both C.sub.3-C.sub.5 alkenyl, and
R.sub.4 is selected from heteroaryl or aryl each of which may be
independently substituted by one to three substituents selected
from halogen (in particular, Cl, Br or F), C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl (in particular --CF.sub.3), C.sub.1-6 haloalkoxy (such as
--OCF.sub.3), --OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl,
--NH.sub.2, --NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN,
--NO.sub.2, mercapto, --S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4
alkyl, --S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6
alkylcarbonyl, C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R'''
(where R''' is lower alkyl or cycloalkyl) and --S(O).sub.2R'''
(where R''' is lower alkyl, cycloalkyl or OH). [0085] h) R.sub.2
and R.sub.3 together form a C.sub.4-C.sub.9 cycloalkyl ring,
preferably cyclopentyl or cyclohexyl ring, and R.sub.4 is selected
from heteroaryl or aryl each of which may be independently
substituted by one to three substituents selected from halogen (in
particular, Cl, Br or F), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl (in
particular --CF.sub.3), C.sub.1-6 haloalkoxy (such as --OCF.sub.3),
--OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2,
mercapto, --S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is
lower alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is
lower alkyl, cycloalkyl or OH).
[0086] In relation to compounds of formula (Ia) or (Ib) the
following additional definitions may also apply: [0087] i) R.sub.2
and R.sub.3 are both C.sub.3-C.sub.5 alkenyl, C.sub.1-C.sub.3 alkyl
(preferably methyl), or Br, or R.sub.2 and R.sub.3 together form a
C.sub.4-C.sub.9 cycloalkyl ring, and R.sub.4 is selected from
heteroaryl or aryl each of which may be independently substituted
by one to three substituents selected from halogen (in particular,
Cl, Br or F), C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl (in particular --CF.sub.3),
C.sub.1-6 haloalkoxy (such as --OCF.sub.3), --OH, phenyl, benzyl,
phenoxy, benzyloxy, benzoyl, --NH.sub.2, --NHC.sub.1-4 alkyl,
--N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2, mercapto,
--S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is
lower alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is
lower alkyl, cycloalkyl or OH), and n is 0, 1 or 2, and when
present, each R.sub.1' is independently selected from halogen (in
particular, Cl, Br or F), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl (in
particular --CF.sub.3), C.sub.1-6 haloalkoxy (such as --OCF.sub.3),
--OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2,
mercapto, --S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is
lower alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is
lower alkyl, cycloalkyl or OH). [0088] j) R.sub.2 and R.sub.3 are
both CH.sub.3, and R.sub.4 is selected from heteroaryl or aryl each
of which may be independently substituted by one to three
substituents selected from halogen (in particular, Cl, Br or F),
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl (in particular --CF.sub.3), C.sub.1-6
haloalkoxy (such as --OCF.sub.3), --OH, phenyl, benzyl, phenoxy,
benzyloxy, benzoyl, --NH.sub.2, --NHC.sub.1-4 alkyl, --N(C.sub.1-4
alkyl).sub.2, --CN, --NO.sub.2, mercapto, --S(O).sub.2NH.sub.2,
--S(O).sub.2NHC.sub.1-4 alkyl, --S(O).sub.2N(C.sub.1-4
alkyl).sub.2, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkoxycarbonyl,
CO.sub.2H, --S(O)R''' (where R''' is lower alkyl or cycloalkyl) and
--S(O).sub.2R''' (where R''' is lower alkyl, cycloalkyl or OH), and
n is 0, 1 or 2, and when present, each R.sub.1' is independently
selected from halogen (in particular, Cl, Br or F), C.sub.1-6
alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 haloalkyl (in particular --CF.sub.3), C.sub.1-6
haloalkoxy (such as --OCF.sub.3), --OH, phenyl, benzyl, phenoxy,
benzyloxy, benzoyl, --NH.sub.2, --NHC.sub.1-4 alkyl, --N(C.sub.1-4
alkyl).sub.2, --CN, --NO.sub.2, mercapto, --S(O).sub.2NH.sub.2,
--S(O).sub.2NHC.sub.1-4 alkyl, --S(O).sub.2N(C.sub.1-4
alkyl).sub.2, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkoxycarbonyl,
CO.sub.2H, --S(O)R''' (where R''' is lower alkyl or cycloalkyl) and
--S(O).sub.2R''' (where R''' is lower alkyl, cycloalkyl or OH).
[0089] k) R.sub.2 and R.sub.3 are both C.sub.3-C.sub.5 alkenyl, and
R.sub.4 is selected from heteroaryl or aryl each of which may be
independently substituted by one to three substituents selected
from halogen (in particular, Cl, Br or F), C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl (in particular --CF.sub.3), C.sub.1-6 haloalkoxy (such as
--OCF.sub.3), --OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl,
--NH.sub.2, --NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN,
--NO.sub.2, mercapto, --S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4
alkyl, --S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6
alkylcarbonyl, C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R'''
(where R''' is lower alkyl or cycloalkyl) and --S(O).sub.2R'''
(where R''' is lower alkyl, cycloalkyl or OH), and n is 0, 1 or 2,
and when present, each R.sub.1' is independently selected from
halogen (in particular, Cl, Br or F), C.sub.1-6 alkyl, C.sub.1-6
alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl
(in particular --CF.sub.3), C.sub.1-6 haloalkoxy (such as
--OCF.sub.3), --OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl,
--NH.sub.2, --NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN,
--NO.sub.2, mercapto, --S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4
alkyl, --S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6
alkylcarbonyl, C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R'''
(where R''' is lower alkyl or cycloalkyl) and --S(O).sub.2R'''
(where R''' is lower alkyl, cycloalkyl or OH). [0090] l) R.sub.2
and R.sub.3 together form a C.sub.4-C.sub.9 cycloalkyl ring,
preferably cyclopentyl or cyclohexyl ring, and R.sub.4 is selected
from heteroaryl or aryl each of which may be independently
substituted by one to three substituents selected from halogen (in
particular, Cl, Br or F), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl (in
particular --CF.sub.3), C.sub.1-6 haloalkoxy (such as --OCF.sub.3),
--OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2,
mercapto, --S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H, S(O)R''' (where R''' is lower
alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is lower
alkyl, cycloalkyl or OH), and n is 0, 1 or 2, and when present,
each R.sub.1' is independently selected from halogen (in
particular, Cl, Br or F), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl (in
particular --CF.sub.3), C.sub.1-6 haloalkoxy (such as --OCF.sub.3),
--OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2,
mercapto, --S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is
lower alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is
lower alkyl, cycloalkyl or OH).
[0091] In another aspect the invention provides compounds of
formula (Ic), or salts thereof:
##STR00010##
[0092] wherein [0093] each R.sub.1' is independently selected from
the group consisting of cyano, halo, nitro, optionally substituted
lower alkyl, optionally substituted aryl, optionally substituted
aryloxy, optionally substituted arylalkyl, optionally substituted
heteroaryl, optionally substituted heterocyclyl, optionally
substituted C.sub.3-7 cycloalkyl, --OR, --C(O)R, --C(O)OR, --OC(O)R
(where R is selected from hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted C.sub.3-7 cycloalkyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, and optionally
substituted aryl), --C(O)NR'R'', --NR'C(O)R'', --S(O).sub.2--NR'R''
and --NR'R'' (where R' and R'' are independently selected from
hydrogen or lower alkyl), --S(O)R''' (where R''' is lower alkyl, or
cycloalkyl), --S(O).sub.2R''' (where R''' is lower alkyl,
cycloalkyl or OH), or any two adjacent R.sub.1' together form
heterocyclyl or heteroaryl; [0094] n is 0 or an integer from 1 to
5; [0095] R.sub.2 is selected from C.sub.1-C.sub.4 alkyl,
C.sub.3-C.sub.5 alkenyl, C.sub.1-C.sub.4 haloalkyl, F, Cl or Br;
[0096] R.sub.3 is selected from hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.3-C.sub.5 alkenyl, C.sub.1-C.sub.4 haloalkyl, or Br; or
[0097] R.sub.2 and R.sub.3 together form C.sub.4-9 cycloalkyl or
C.sub.4-9 cycloalkenyl; [0098] R.sub.4 is selected from heteroaryl
which is optionally independently substituted by one to three
substituents selected from halogen (in particular, Cl, Br or F),
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl (in particular --CF.sub.3), C.sub.1-6
haloalkoxy (such as --OCF.sub.3), --OH, phenyl, benzyl, phenoxy,
benzyloxy, benzoyl, --NH.sub.2, --NHC.sub.1-4 alkyl,
--N(C.sub.1-4alkyl).sub.2, --CN, --NO.sub.2, mercapto,
--S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is
lower alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is
lower alkyl, cycloalkyl or OH); or aryl which is optionally
independently substituted by one to three substituents selected
from halogen (in particular, Cl, Br or F), C.sub.2-6 alkyl,
C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl (in particular --CF.sub.3), C.sub.1-6 haloalkoxy (such as
--OCF.sub.3), --OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl,
--NH.sub.2, --NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN,
--NO.sub.2, mercapto, --S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4
alkyl, --S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6
alkylcarbonyl, C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R'''
(where R''' is lower alkyl or cycloalkyl) and --S(O).sub.2R'''
(where R''' is lower alkyl, cycloalkyl or OH); and [0099] R.sub.5
is independently selected from hydrogen, or lower alkyl.
[0100] In relation to compounds of formula (II) in an embodiment
R.sub.1 is an optionally substituted aryl group and more preferably
an optionally substituted phenyl group.
[0101] Accordingly in another aspect the invention provides
compounds of formula (IIa) or salts thereof:
##STR00011##
[0102] wherein [0103] each R.sub.1' is independently selected from
the group consisting of cyano, halo, nitro, optionally substituted
lower alkyl, optionally substituted aryl, optionally substituted
aryloxy, optionally substituted arylalkyl, optionally substituted
heteroaryl, optionally substituted heterocyclyl, optionally
substituted C.sub.3-7 cycloalkyl, --OR, --C(O)R, --C(O)OR, --OC(O)R
(where R is selected from hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted C.sub.3-7 cycloalkyl, optionally substituted
heterocyclyl, optionally substituted heteroaryl, and optionally
substituted aryl), --C(O)NR'R'', --NR'C(O)R'', --S(O).sub.2--NR'R''
and --NR'R'' (where R' and R'' are independently selected from
hydrogen or lower alkyl), --S(O)R''' (where R''' is lower alkyl, or
cycloalkyl), --S(O).sub.2R''' (where R''' is lower alkyl,
cycloalkyl or OH), or any two adjacent R.sub.1' together form
heterocyclyl or heteroaryl; [0104] n is 0 an integer from 1 to 5;
[0105] R.sub.2 and R.sub.3 together form C.sub.4-9 cycloalkyl;
[0106] R.sub.4 is selected from optionally substituted heteroaryl,
optionally substituted heterocyclyl, or optionally substituted
aryl; and [0107] R.sub.5 is independently selected from hydrogen or
optionally substituted alkyl.
[0108] Preferably, for compounds of formulae (II) and (IIa) the
cycloalkyl ring is C.sub.4-C.sub.7 or more preferably
C.sub.5-C.sub.7, such as cyclopentyl, cyclohexyl, and cycloheptyl.
More preferably the cycloalkyl ring is cyclohexyl or
cyclopentyl.
[0109] In relation to compounds of formula (IIa) the following
definitions may apply: [0110] m) R.sub.2 and R.sub.3 together form
a cyclohexyl or cyclopentyl ring. [0111] n) R.sub.2 and R.sub.3
together form a cyclohexyl or cyclopentyl ring, and R.sub.4 is
selected from heteroaryl or aryl each of which may be independently
substituted by one to three substituents selected from halogen (in
particular, Cl, Br or F), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl (in
particular --CF.sub.3), C.sub.1-6 haloalkoxy (such as --OCF.sub.3),
--OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2,
mercapto, --S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is
lower alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is
lower alkyl, cycloalkyl or OH). [0112] o) R.sub.2 and R.sub.3
together form a cyclohexyl or cyclopentyl ring, and R.sub.4 is
selected from heteroaryl or aryl each of which may be independently
substituted by one to three substituents selected from halogen (in
particular, Cl, Br or F), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl (in
particular --CF.sub.3), C.sub.1-6 haloalkoxy (such as --OCF.sub.3),
--OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2,
mercapto, --S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H and sulfone (in particular
--S(O).sub.2C.sub.1-4 alkyl), and n is 0, 1 or 2, and when present,
each R.sub.1' is independently selected from halogen (in
particular, Cl, Br or F), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl (in
particular --CF.sub.3), C.sub.1-6 haloalkoxy (such as --OCF.sub.3),
--OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2,
mercapto, --S(O).sub.2NH.sub.2, --S(O).sub.2NHC.sub.1-4 alkyl,
--S(O).sub.2N(C.sub.1-4 alkyl).sub.2, C.sub.1-6 alkylcarbonyl,
C.sub.1-6 alkoxycarbonyl, CO.sub.2H, --S(O)R''' (where R''' is
lower alkyl or cycloalkyl) and --S(O).sub.2R''' (where R''' is
lower alkyl, cycloalkyl or OH).
[0113] In relation to compounds of formula (Ia), (Ib), or (IIa) one
or more of the following preferred definitions (where appropriate)
may also apply: [0114] p) each R.sub.1' is independently selected
from C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkyl, halo
(preferably Cl, F, or Br), S(O).sub.2NR'R'' (where R' and R'' are
independently hydrogen or C.sub.1-C.sub.3 alkyl), optionally
substituted heteroaryl, CF.sub.3, boronic ester, or S(O).sub.2R'''
where R''' is lower alkyl; [0115] q) R.sub.5 is H.
[0116] In a further embodiment and reference to any one of formula
(I), (Ia), (Ib), (Ic), (II) or (IIa), the following additional
preferred definitions may also apply.
[0117] R.sub.4 is selected from: [0118] (a)
##STR00012##
[0119] wherein Hal is a halogen; [0120] m is 0, 1 or 2; and [0121]
each R.sub.6 is independently selected from halogen, hydroxy, CN,
NO.sub.2, haloalkyl, aryl, heteroaryl, C.sub.1-3 alkoxy, C.sub.1-3
alkyl, or CO.sub.2R' (where R' is a lower alkyl or H); [0122] or
[0123] (b) a heteroaryl substituted from 1 to 3 times from a group
selected from C.sub.1-C.sub.3 alkyl, C.sub.1-6 alkoxy, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl (in particular
--CF.sub.3), C.sub.1-6 haloalkoxy (such as --OCF.sub.3), --OH,
phenyl, benzyl, phenoxy, benzyloxy, benzoyl, --NH.sub.2,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, --CN, --NO.sub.2,
mercapto, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkoxycarbonyl,
CO.sub.2H, --S(O)R''' (where R''' is lower alkyl or cycloalkyl) and
--S(O).sub.2R''' (where R''' is lower alkyl, cycloalkyl or OH).
Preferred heteroaryl groups for R.sub.4 include pyridinyl,
pyrazolyl and thiazolyl.
[0124] In yet a further embodiment and with reference to formulae
(I) and (II): [0125] R.sub.1 is phenyl; phenyl independently
substituted by one or two substituents selected from halogen,
--SO.sub.2NR'R'' (where R' and R'' independently represent H or
lower alkyl), C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; heterocyclyl or
heteroaryl; [0126] R.sub.2 and R.sub.3 are the same and represent
C.sub.1-4 alkyl, (formula (I)) or together a C.sub.5-C.sub.6
cycloalkyl (formula (I) and formula (II)); [0127] R.sub.4 is
heteroaryl or heteroaryl independently substituted one or two times
by C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, halogen, or C.sub.1-4
alkoxy; or is phenyl or phenyl independently substituted one or two
times by C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, halogen, or
C.sub.1-4 alkoxy; and [0128] R.sub.5 is H or lower alkyl.
[0129] In the list below (which are representative examples of
compounds of the present invention) the structures contain one or
more stereogenic centers, the respective structures are depicted in
an arbitrary absolute configuration. These structures also include
the respective structure having the opposite stereochemistry and
the corresponding racemate:
##STR00013## ##STR00014## ##STR00015##
[0130] In certain embodiments, the compounds are selected from
those depicted below:
##STR00016##
TABLE-US-00001 R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 phenyl
CH.sub.3 CH.sub.3 ##STR00017## H ##STR00018## CH.sub.3 CH.sub.3
##STR00019## H phenyl CH.sub.3 CH.sub.3 ##STR00020## H ##STR00021##
CH.sub.3 CH.sub.3 ##STR00022## H phenyl CH.sub.3 CH.sub.3
##STR00023## H ##STR00024## CH.sub.3 CH.sub.3 ##STR00025## H phenyl
CH.sub.3 CH.sub.3 ##STR00026## H ##STR00027## CH.sub.3 CH.sub.3
##STR00028## H ##STR00029## CH.sub.3 CH.sub.3 ##STR00030## H phenyl
cyclopentyl ##STR00031## H ##STR00032## cyclopentyl ##STR00033## H
phenyl cyclohexyl ##STR00034## H ##STR00035## cyclohexyl
##STR00036## H phenyl cyclopentyl ##STR00037## H ##STR00038##
cyclopentyl ##STR00039## H phenyl cyclopentyl ##STR00040## H
##STR00041## cyclopentyl ##STR00042## H phenyl CH.sub.3 CH.sub.3
##STR00043## H ##STR00044## CH.sub.3 CH.sub.3 ##STR00045## H
##STR00046## CH.sub.3 CH.sub.3 ##STR00047## H ##STR00048## CH.sub.3
CH.sub.3 ##STR00049## H phenyl CH.sub.3 CH.sub.3 ##STR00050## H
##STR00051## CH.sub.3 CH.sub.3 ##STR00052## H phenyl
CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 ##STR00053## H ##STR00054##
CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 ##STR00055## H phenyl cyclopentyl
##STR00056## H ##STR00057## cyclopentyl ##STR00058## H ##STR00059##
CH.sub.3 CH.sub.3 ##STR00060## H ##STR00061## CH.sub.3 CH.sub.3
##STR00062## H ##STR00063## CH.sub.3 CH.sub.3 ##STR00064## H
##STR00065## CH.sub.3 CH.sub.3 ##STR00066## H ##STR00067## CH.sub.3
CH.sub.3 ##STR00068## H
[0131] The salts of the compounds of the invention are preferably
pharmaceutically acceptable, but it will be appreciated that
non-pharmaceutically acceptable salts also fall within the scope of
the present invention, since these are useful as intermediates in
the preparation of pharmaceutically acceptable salts.
[0132] It will be appreciated that the compounds of the invention,
and the salts thereof, can be presented in the form of
pharmaceutically acceptable derivatives. The term "pharmaceutically
acceptable derivative" includes pharmaceutically acceptable esters,
prodrugs, solvates and hydrates of the compounds of formulae (I),
(Ia), (Ib), (Ic), (II), or (IIa), or salts thereof.
Pharmaceutically acceptable derivatives may include any
pharmaceutically acceptable hydrate or any other compound or
prodrug which, upon administration to a subject, is capable of
providing (directly or indirectly) a compound of formula (I), (Ia),
(Ib), (Ic), (II), or (IIa), or an active metabolite or residue
thereof.
[0133] The pharmaceutically acceptable salts include acid addition
salts, base addition salts, and the salts of quaternary amines and
pyridiniums. The acid addition salts are formed from a compound of
the invention and a pharmaceutically acceptable inorganic or
organic acid including but not limited to hydrochloric,
hydrobromic, sulfuric, phosphoric, methanesulfonic,
toluenesulphonic, benzenesulphonic, acetic, propionic, ascorbic,
citric, malonic, fumaric, maleic, lactic, salicylic, sulfamic, or
tartaric acids. The counter ion of quaternary amines and
pyridiniums include chloride, bromide, iodide, sulfate, phosphate,
methansulfonate, citrate, acetate, malonate, fumarate, sulfamate,
and tartrate. The base addition salts include but are not limited
to salts such as sodium, potassium, calcium, lithium, magnesium,
ammonium and alkylammonium. Also, basic nitrogen-containing groups
may be quaternised with such agents as lower alkyl halides, such as
methyl, ethyl, propyl, and butyl chlorides, bromides and iodides;
dialkyl sulfates like dimethyl and diethyl sulfate; and others. The
salts may be made in a known manner, for example by treating the
compound with an appropriate acid or base in the presence of a
suitable solvent.
[0134] The compounds of the invention may be in crystalline form
and/or as solvates (e.g. hydrates) and it is intended that both
forms be within the scope of the present invention. The term
"solvate" is a complex of variable stoichiometry formed by a solute
(in this invention, a compound of the invention) and a solvent.
Such solvents should not interfere with the biological activity of
the solute. Solvents may be, by way of example, water, ethanol or
acetic acid. Methods of solvation are generally known within the
art.
[0135] The term "pro-drug" is used in its broadest sense and
encompasses those derivatives that are converted in vivo to the
compounds of the invention. Such derivatives would readily occur to
those skilled in the art, and include, for example, compounds where
a free hydroxy group is converted into an ester derivative or a
ring nitrogen atom is converted to an N-oxide. Examples of ester
derivatives include alkyl esters, phosphate esters and those formed
from amino acids, preferably valine. Any compound that is a prodrug
of a compound of the invention is within the scope and spirit of
the invention.
[0136] The term "pharmaceutically acceptable ester" includes
biologically acceptable esters of compound of the invention such as
sulphonic, phosphonic and carboxylic acid derivatives.
[0137] Thus, in another aspect of the invention, there is provided
a prodrug or pharmaceutically acceptable ester of a compound of the
invention or of salt thereof.
[0138] It will be appreciated that the compounds of the invention
have at least one asymmetric centre, and therefore are capable of
existing in more than one stereoisomeric form. The invention
extends to each of these forms individually and to mixtures
thereof, including racemates. The isomers may be separated
conventionally by chromatographic methods or using a resolving
agent. Alternatively the individual isomers may be prepared by
asymmetric synthesis using chiral intermediates. Where the compound
has at least one carbon-carbon double bond, it may occur in Z- and
E-forms with all isomeric forms of the compounds being included in
the present invention.
[0139] The invention also includes where possible a salt or
pharmaceutically acceptable derivative such as a pharmaceutically
acceptable ester, solvate and/or prodrug of the above mentioned
embodiments of the invention.
[0140] In another aspect of the invention, there is provided a
pharmaceutical composition that comprises a therapeutically
effective amount of one or more of the aforementioned compounds or
pharmaceutically acceptable salts thereof, including
pharmaceutically acceptable derivatives thereof, and optionally a
pharmaceutically acceptable carrier or diluent.
[0141] In another aspect, the present invention provides
pharmaceutical compositions for use as a positive allosteric
modulator of .alpha.7nAChRs, more particularly as an
anti-inflammatory or neuroprotective agent, the composition
comprising an effective amount of a compound of Formula (I), (Ia),
(Ib), (Ic), (II), or (IIa), or a pharmaceutically acceptable salt
thereof, including a pharmaceutically acceptable derivative
thereof, and optionally a pharmaceutically acceptable carrier or
diluent.
[0142] The term "composition" is intended to include the
formulation of an active ingredient with encapsulating material as
carrier, to give a capsule in which the active ingredient (with or
without other carrier) is surrounded by carriers.
[0143] The pharmaceutical compositions or formulations include
those suitable for oral, rectal, nasal, topical (including buccal
and sub-lingual), vaginal or parenteral (including intramuscular,
sub-cutaneous and intravenous) administration or in a form suitable
for administration by inhalation or insufflation.
[0144] The compounds of the invention, together with a conventional
adjuvant, carrier, or diluent, may thus be placed into the form of
pharmaceutical compositions and unit dosages thereof, and in such
form may be employed as solids, such as tablets or filled capsules,
or liquids such as solutions, suspensions, emulsions, elixirs, or
capsules filled with the same, all for oral use, in the form of
suppositories for rectal administration; or in the form of sterile
injectable solutions for parenteral (including subcutaneous)
use.
[0145] Such pharmaceutical compositions and unit dosage forms
thereof may comprise conventional ingredients in conventional
proportions, with or without additional active compounds or
principles, and such unit dosage forms may contain any suitable
effective amount of the active ingredient commensurate with the
intended daily dosage range to be employed. Formulations containing
ten (10) milligrams of active ingredient or, more broadly, 0.1 to
one hundred (100) milligrams, per tablet, are accordingly suitable
representative unit dosage forms.
[0146] The compounds of the present invention can be administered
in a wide variety of oral and parenteral dosage forms. It will be
obvious to those skilled in the art that the following dosage forms
may comprise, as the active component, either a compound of the
invention or a pharmaceutically acceptable salt of a compound of
the invention.
[0147] For preparing pharmaceutical compositions from the compounds
of the present invention, pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories, and dispensable
granules. A solid carrier can be one or more substances which may
also act as diluents, flavouring agents, solubilisers, lubricants,
suspending agents, binders, preservatives, tablet disintegrating
agents, or an encapsulating material.
[0148] In powders, the carrier is a finely divided solid that is in
a mixture with the finely divided active component.
[0149] In tablets, the active component is mixed with the carrier
having the necessary binding capacity in suitable proportions and
compacted in the shape and size desired.
[0150] The powders and tablets preferably contain from five or ten
to about seventy percent of the active compound. Suitable carriers
are magnesium carbonate, magnesium stearate, talc, sugar, lactose,
pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,
sodium carboxymethylcellulose, a low melting wax, cocoa butter, and
the like. The term "preparation" is intended to include the
formulation of the active compound with encapsulating material as
carrier providing a capsule in which the active component, with or
without carriers, is surrounded by a carrier, which is thus in
association with it. Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets, and lozenges can be
used as solid forms suitable for oral administration.
[0151] For preparing suppositories, a low melting wax, such as an
admixture of fatty acid glycerides or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogenous mixture is then poured into
convenient sized moulds, allowed to cool, and thereby to
solidify.
[0152] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
sprays containing in addition to the active ingredient such
carriers as are known in the art to be appropriate.
[0153] Liquid form preparations include solutions, suspensions, and
emulsions, for example, water or water-propylene glycol solutions.
For example, parenteral injection liquid preparations can be
formulated as solutions in aqueous polyethylene glycol
solution.
[0154] Sterile liquid form compositions include sterile solutions,
suspensions, emulsions, syrups and elixirs. The active ingredient
can be dissolved or suspended in a pharmaceutically acceptable
carrier, such as sterile water, sterile organic solvent or a
mixture of both.
[0155] The compounds according to the present invention may thus be
formulated for parenteral administration (e.g. by injection, for
example bolus injection or continuous infusion) and may be
presented in unit dose form in ampoules, pre-filled syringes, small
volume infusion or in multi-dose containers with an added
preservative. The compositions may take such forms as suspensions,
solutions, or emulsions in oily or aqueous vehicles, and may
contain formulation agents such as suspending, stabilising and/or
dispersing agents. Alternatively, the active ingredient may be in
powder form, obtained by aseptic isolation of sterile solid or by
lyophilisation from solution, for constitution with a suitable
vehicle, eg. sterile, pyrogen-free water, before use.
[0156] Aqueous solutions suitable for oral use can be prepared by
dissolving the active component in water and adding suitable
colorants, flavours, stabilising and thickening agents, as
desired.
[0157] Aqueous suspensions suitable for oral use can be made by
dispersing the finely divided active component in water with
viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, or other well known
suspending agents.
[0158] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. These preparations may contain, in
addition to the active component, colorants, flavours, stabilisers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilising agents, and the like.
[0159] For topical administration to the epidermis the compounds
according to the invention may be formulated as ointments, creams
or lotions, or as a transdermal patch. Ointments and creams may,
for example, be formulated with an aqueous or oily base with the
addition of suitable thickening and/or gelling agents. Lotions may
be formulated with an aqueous or oily base and will in general also
contain one or more emulsifying agents, stabilising agents,
dispersing agents, suspending agents, thickening agents, or
colouring agents.
[0160] Formulations suitable for topical administration in the
mouth include lozenges comprising active agent in a flavoured base,
usually sucrose and acacia or tragacanth; pastilles comprising the
active ingredient in an inert base such as gelatin and glycerin or
sucrose and acacia; and mouthwashes comprising the active
ingredient in a suitable liquid carrier.
[0161] Solutions or suspensions are applied directly to the nasal
cavity by conventional means, for example with a dropper, pipette
or spray. The formulations may be provided in single or multidose
form. In the latter case of a dropper or pipette, this may be
achieved by the patient administering an appropriate, predetermined
volume of the solution or suspension. In the case of a spray, this
may be achieved for example by means of a metering atomising spray
pump. To improve nasal delivery and retention the compounds
according to the invention may be encapsulated with cyclodextrins,
or formulated with other agents expected to enhance delivery and
retention in the nasal mucosa.
[0162] Administration to the respiratory tract may also be achieved
by means of an aerosol formulation in which the active ingredient
is provided in a pressurised pack with a suitable propellant such
as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane,
trichlorofluoromethane, or dichlorotetrafluoroethane, carbon
dioxide, or other suitable gas. The aerosol may conveniently also
contain a surfactant such as lecithin. The dose of drug may be
controlled by provision of a metered valve.
[0163] Alternatively the active ingredients may be provided in the
form of a dry powder, for example a powder mix of the compound in a
suitable powder base such as lactose, starch, starch derivatives
such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone
(PVP). Conveniently the powder carrier will form a gel in the nasal
cavity. The powder composition may be presented in unit dose form
for example in capsules or cartridges of, e.g., gelatin, or blister
packs from which the powder may be administered by means of an
inhaler.
[0164] In formulations intended for administration to the
respiratory tract, including intranasal formulations, the compound
will generally have a small particle size for example of the order
of 5 to 10 microns or less. Such a particle size may be obtained by
means known in the art, for example by micronisation.
[0165] When desired, formulations adapted to give sustained release
of the active ingredient may be employed.
[0166] The pharmaceutical preparations are preferably in unit
dosage forms. In such form, the preparation is subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packeted
tablets, capsules, and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or
it can be the appropriate number of any of these in packaged
form.
[0167] The invention also includes the compounds in the absence of
carrier where the compounds are in unit dosage form.
[0168] The amount of the compound of the invention to be
administered may be in the range from about 10 mg to 2000 mg per
day, depending on the activity of the compound and the disease to
be treated.
[0169] Liquids or powders for intranasal administration, tablets or
capsules for oral administration and liquids for intravenous
administration are the preferred compositions.
[0170] The pharmaceutical preparations of the compounds according
to the present invention may be co-administered with one or more
other active agents in combination therapy. For example the
pharmaceutical preparation of the active compound may be
co-administered (for example, separately, concurrently or
sequentially), with one or more other agents used to treat
cognitive impairment or mood disorders such as acetylcholine
esterase inhibitors, antipsychotics, and antidepressants.
[0171] It is believed that the compounds of the invention may be
beneficial in treating patients with cognition impairment or aid in
increasing cognition. Without wanting to be bound by theory it is
believed that this effect may be brought about by positive
allosteric modulation of alpha 7 nicotinic acetylcholine receptors
(.alpha.7nAChRs).
[0172] It is envisaged that the compounds may additionally be
useful in the treatment of patients, including a mammal and
especially a human, suffering from neuropsychiatric diseases and
neurodegenerative diseases involving a dysfunction of the
cholinergic system, and further conditions of memory and/or
cognition impairment, including, for example, schizophrenia,
anxiety, mania, depression, manic depression (as examples of
neuropsychiatric disorders), Tourette's syndrome, Parkinson's
disease, Huntington's disease (as examples of neurodegenerative
diseases), and/or cognitive disorders (such as Alzheimer's disease,
Lewy Body Dementia, Amyotrophic Lateral Sclerosis, memory
impairment, memory loss, cognition deficit, attention deficit,
Attention Deficit Hyperactivity Disorder).
[0173] Neurodegenerative disorders include, but are not limited to,
treatment and/or prophylaxis of Alzheimer's diseases, Pick's
disease, diffuse Lewy Body disease, progressive supranuclear palsy
(or Steel-Richardson syndrome), multisystem degeneration (or
Shy-Drager syndrome), motor neuron diseases including amyotrophic
lateral sclerosis, degenerative ataxias, cortical basal
degeneration, ALS-Parkinson's-Dementia complex of Guam, subacute
sclerosing panencephalitis, Huntington's disease, Parkinson's
disease, synucleinopathies, primary progressive aphasia,
striatonigral degeneration, Machado-Joseph disease/spinocerebellar
ataxia type 3, olivopontocerebellar degenerations, Gilles De La
Tourette's disease, bulbar, pseudobulbar palsy, spinal muscular
atrophy, spinobulbar muscular atrophy (Kennedy's disease), primary
lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffmann
disease, Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff
disease, familial spastic disease, Wohlfart-Kugelberg-Welander
disease, spastic paraparesis, progressive multifocal
leukoencephalopathy, prion diseases (such as Creutzfeldt-Jakob,
Gerstmann-Straussler-Scheinker disease, Kuru and fatal familial
insomnia), and neurodegenerative disorders resulting from cerebral
ischemia or infarction including embolic occlusion and thrombotic
occlusion as well as intracranial hemorrhage of any type
(including, but not limited to, epidural, subdural, subarachnoid
and intracerebral), and intracranial and intravertebral lesions
(including, but not limited to, contusion, penetration, shear,
compression and laceration).
[0174] In addition, the compounds of the invention may be used to
treat age-related dementia and other dementias and conditions with
memory loss including age-related memory loss, senility, vascular
dementia, diffuse white matter disease (Binswanger's disease),
dementia of endocrine or metabolic origin, dementia of head trauma
and diffuse brain damage, dementia pugilistica and frontal lobe
dementia.
[0175] The invention provides methods of treating subjects
suffering from memory impairment due to, for example, Alzheimer's
disease, mild cognitive impairment due to aging, schizophrenia,
Parkinson's disease, multiple sclerosis, Huntington's disease,
Pick's disease, Creutzfeldt-Jakob disease, depression, aging, head
trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct
dementia and other neurological conditions, as well as HIV and
cardiovascular diseases.
[0176] For certain of the abovementioned conditions it is clear
that the compounds may be used prophylactically as well as for the
alleviation of symptoms.
[0177] References herein to "treatment" or the like are to be
understood to include such prophylactic treatment, as well as
therapeutic treatments.
[0178] The compounds of the present invention as agents which
modulate the .alpha.7 nAChR may be particularly useful in the
therapeutic or prophylactic treatment of diseases such as
schizophrenia, bi-polar disorder, anxiety, AD, ADHD, mild cognitive
impairment, Parkinson's Disease, Huntington's disease, Tourette's
syndrome, brain trauma, jetlag and nicotine addiction,
[0179] Accordingly in a further aspect of the invention, there is
provided a means for ameliorating the cognitive deficits associated
with neurodegenerative and neuropsychiatric diseases and also
inflammatory diseases by the application of a positive allosteric
modulators of .alpha.7nAChRs selected from a compound of Formula
(I), (Ia), (Ib), (Ic), (II), or (IIa), or salt thereof, including a
pharmaceutically acceptable derivative thereof, or a composition
comprising the compound of Formula (I), (Ia), (Ib), (Ic), (II), or
(IIa), or salt thereof, or a pharmaceutically acceptable derivative
thereof.
[0180] In another aspect of the invention a method is provided for
preventing or treating cognitive deficits involving dysfunction of
the cholinergic system including the step of administrating a
compound of Formula (I), (Ia), (Ib), (Ic), (II), or (IIa), or salt
thereof, or a composition comprising the compound or salt
thereof.
[0181] In another preferred form of the invention there is provided
a method for preventing or treating neurodegenerative or
neuropsychiatric disorders including the step of administrating a
compound of Formula (I), (Ia), (Ib), (Ic), (II), or (IIa), or a
pharmaceutically acceptable salt thereof, including a
pharmaceutically acceptable derivative thereof, or a composition
comprising the compound or pharmaceutically acceptable salt
thereof, or pharmaceutically acceptable derivative thereof.
[0182] In a further aspect of the present invention, there is
provided the use of a compound of Formula (I), (Ia), (Ib), (Ic),
(II), or (IIa), or salt thereof, in the preparation of a medicament
for the treatment (therapeutic or prophylactic) of disease states
in which modulation of .alpha.7nAChRs would be beneficial.
[0183] In a further aspect of the invention there is provided a
process for the production of the compounds of Formula (I), (Ia),
(Ib), (Ic), (II), or (IIa), or salts thereof, including
pharmaceutically acceptable derivatives thereof.
##STR00069##
[0184] Compounds of the formula I can be prepared by synthetic
procedures as depicted in Scheme A. Cinnamate esters 1 may be from
commercial sources or prepared by Doebner modification of
Knoevenagel condensation of an aryl/heteroaryl aldehyde. Typically,
an aryl/heteroaryl aldehyde 1 and ester of malonic acid 2 is heated
in pyridine/piperidine mixture. Numerous modification of this
procedure as well as other alternatives such as Aldol-type
condensation or Wittig reaction of aryl or heteroaryl carbonyl
compounds are possible and will be readily apparent to those
skilled in the art. Cyclopropanation of olefin was carried out by
reacting cinnamate ester 3 with phosphorus ylides as described in
J. Med. Chem. 2001, 44, 3302. The requisite ylides can be purchased
or prepared by known methods. Those skilled in the art will
understand that cyclopropanation of olefins could be achieved by
alternative methods, such as Simmons-Smith type reaction of
cinnamate ester with Furukawa reagents as described in Tetrahedron
1969, 25, 2647 or ring forming reaction of cinnamate ester with
sulphur ylides as described in Synthesis 2008, 20, 3279. Ester 4
where R.sub.2 and R.sub.3 are bromo or chloro can be prepared by
heating a mixture of cinnamate ester 3 and ethyl trihaloacetate as
depicted in Scheme B. Numerous modifications of this procedure such
as use of trihaloacetic acid in acetic anhydride as described in J.
Org. Chem. 1988, 53, 4945 are possible and will be readily apparent
to those skilled in the art. Similarly, ester 4 where R.sub.2 and
R.sub.3 are fluoro can be prepared by heating cinnamate 3 with a
difluoro carbine generated from suitable reagent such as
trimethylsilyl fluorosulfonyldifluoroacetate as described in J.
Fluorine Chem. 2004, 125, 459.
##STR00070##
[0185] Esters 4 where R.sub.2 and R.sub.3 together form a
cycloalkyl or cycloalkenyl group can be prepared by from
corresponding spiro group containing phosphorus ylides.
Alternatively, phosphorus ylides where R.sub.2 and R.sub.3 contains
terminal alkene group can be reacted with cinnamate esters,
followed by ring-closure metathesis as described in J. Chem. Res.
2006, 9, 591 to form ester 4 where R.sub.2 and R.sub.3 together
form cycloalkenyl group, which could be further reduced to form
corresponding cycloalkyl group containing ester 4. Ester 4 can be
hydrolysed to acid 5 by using known procedures and then reacted
with thionyl chloride to offer acid chloride 6 where X is Cl. The
acid chloride can be then reacted with amine to offer compounds of
formula I. Numerous alternative amide formation procedures could be
used such as direct coupling of acid with amine in presence of
dicyclohexyldiimide or other diimides, conversion of acid to
reactive anhydride and then coupling with amine. Compounds of
formula I where R.sub.1 is --SO.sub.2NH.sub.2 may be prepared by
Freidel-Crafts sulphonation of compound I where R.sub.1 is H with
ClSO.sub.2OH in DCM followed reaction with ammonia as described in
Synthetic Communications 1994, 24, 671. Those skilled in the art
will understand that various modifications of this procedure such
as replacement of ClSO.sub.2OH with thionyl chloride or
ClSO.sub.2-alkyl or ClSO.sub.2NH.sub.2 as described in Chemische
Berichte 1959, 92, 509 could be used to prepare corresponding
sulphonamide/sulphone derivatives. Also, compounds of formula I
where R.sub.1 is halogen can be prepared by using halogenated
starting material compound 3 where R.sub.1 is halogen or
halogenation of compound I where R.sub.1 is H as depicted in scheme
C. The halogenated material can further be functionalised using
known chemistry such as Suzuki coupling, Sonogashira coupling
etc.
##STR00071##
[0186] Another variation is to add, remove or modify the
substituents of the product to form new derivatives. This could be
achieved again by using standard techniques for functional group
inter-conversion, well known in the industry such as those
described in Comprehensive organic transformations: a guide to
functional group preparations by Larock R C, New York, VCH
Publishers, Inc. 1989.
[0187] Examples of possible functional group inter-conversions are:
--C(O)NRR' from --CO.sub.2CH.sub.3 by heating with or without
catalytic metal cyanide, e.g. NaCN, and HNRR' in CH.sub.3OH;
--OC(O)R from --OH with e.g., ClC(O)R' in pyridine;
--NR--C(S)NR'R'' from --NHR with an alkylisothiocyanate or
thiocyanic acid; --NRC(O)OR from --NHR with alkyl chloroformate;
--NRC(O)NR'R'' from --NHR by treatment with an isocyanate, e.g.
HN.dbd.C.dbd.O or RN.dbd.C.dbd.O; --NRC(O)R' from --NHR by
treatment with ClC(O)R' in pyridine; --C(.dbd.NR)NR'R'' from
--C(NR'R'')SR''' with H.sub.3NR.sup.+OAc.sup.- by heating in
alcohol; --C(NR'R'')SR from --C(S)NR'R'' with R-I in an inert
solvent, e.g. acetone; --C(S)NR'R'' (where R' or R'' is not
hydrogen) from --C(S)NH.sub.2 with HNR'R''; --C(.dbd.NCN)--NR'R''
from --C(.dbd.NR'R'')--SR with NH.sub.2CN by heating in anhydrous
alcohol, alternatively from --C(.dbd.NH)--NR'R'' by treatment with
BrCN and NaOEt in EtOH; --NR--C(.dbd.NCN)SR from --NHR' by
treatment with (RS).sub.2C.dbd.NCN; --NR''SO.sub.2R from --NHR' by
treatment with ClSO.sub.2R by heating in pyridine; --NR'C(S)R from
--NR'C(O)R by treatment with Lawesson's reagent
[2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide];
--NRSO.sub.2CF.sub.3 from --NHR with triflic anhydride and base,
--CH(NH.sub.2)CHO from --CH(NH.sub.2)C(O)OR' with Na(Hg) and
HCl/EtOH; --CH.sub.2C(O)OH from --C(O)OH by treatment with
SOCl.sub.2 then CH.sub.2N.sub.2 then H.sub.2O/Ag.sub.2O; --C(O)OH
from --CH.sub.2C(O)OCH.sub.3 by treatment with PhMgX/HX then acetic
anhydride then CrO.sub.3; R--OC(O)R' from RC(O)R' by R''CO.sub.3H;
--CCH.sub.2OH from --C(O)OR' with Na/R'OH; --CHCH.sub.2 from
--CH.sub.2CH.sub.2OH by the Chugaev reaction; --NH.sub.2 from
--C(O)OH by the Curtius reaction; --NH.sub.2 from --C(O)NHOH with
TsCl/base then H.sub.2O; --CHC(O)CHR from --CHCHOHCHR by using the
Dess-Martin Periodinane regent or
CrO.sub.3/aqH.sub.2SO.sub.4/acetone; --C.sub.6H.sub.5CHO from
--C.sub.6H.sub.5CH.sub.3 with CrO.sub.2Cl.sub.2; --CHO from --CN
with SnCl.sub.2/HCl; --CN from --C(O)NHR with PCl.sub.5;
--CH.sub.2R from --C(O)R with N.sub.2H.sub.4/KOH; --S(O).sub.2R
from --SR with mCPBA.
[0188] In order that the present invention may be more readily
understood, we provide the following non-limiting examples.
EXAMPLES--GENERAL PROCEDURE
[0189] All anhydrous solvents were commercially obtained and stored
in Sure-Seal bottles under nitrogen. All other reagents and
solvents were purchased as the highest grade available and used
without further purification. Thin-layer chromatography (TLC)
analysis of reaction mixtures was performed using Merck silica gel
60 F254 TLC plates and visualized using ultraviolet light. Silica
gel 60 (40-63 .mu.m, Merck) was used for flash chromatography.
Melting points were measured using an Electrothermal 1002 apparatus
and were uncorrected. .sup.1H NMR (300 MHz) and .sup.13C NMR (75
MHz) spectra were obtained on a Bruker Advance 300 NMR spectrometer
using residual signal of deuterated NMR solvent as internal
reference. Mass spectral data and purity of all compounds were
acquired on an Agilent LCMS-Ion Trap-1200 Series. Mass spectra were
obtained on an Agilent Ion Trap applying electrospray ionization
(ESI). Purity of all compounds was obtained using a Nucleodur 3
.mu.m 4.6.times.150 mm reverse-phase column.
[0190] The eluent was a linear gradient with a flow rate of 1.3
mL/min from 95% A and 5% B to 5% A and 95% B in 8.5 min (solvent A,
H.sub.2O with 0.1% HCO.sub.2H; solvent B, acetonitrile with 0.1%
HCO.sub.2H). The compounds were detected at their maximum of
absorbance.
[0191] In the examples below, in case the structures contain one or
more stereogenic centers, the respective structure is depicted in
an arbitrary absolute configuration. These structures also include
the respective structure having the opposite stereochemistry and
the corresponding racemate.
[0192] General Procedures
[0193] General Procedure A: Aldol Condensation to
.alpha.,.beta.-Unsaturated Esters
[0194] A solution of the aldehyde (1.0 equiv.) and monoethyl
malonate (1.3 equiv.) in anhydrous pyridine (5 equiv.) containing
piperidine (0.1 equiv.) was refluxed for 12 h under an argon
atmosphere. The reaction mixture was cooled to room temperature,
quenched with 2N HCl, and extracted with ether. The extracts were
washed with water, saturated NaHCO.sub.3, and brine. The organic
solution was dried over Na.sub.2SO.sub.4 and concentrated in vacuo.
The crude mixture was purified by FC (SiO.sub.2,
cyclohexane/CH.sub.2Cl.sub.2) to furnish the pure
.alpha.,.beta.-unsaturated ester.
[0195] General Procedure B: Cyclopropanation of
.alpha.,.beta.-Unsaturated Esters
[0196] To a suspension of the alkylphosphonium iodide (1.0 equiv.)
in anhydrous THF (0.3 M) at -78.degree. C. was added n-BuLi (2.0 M
in cyclohexane, 1.0 equiv.) under an argon atmosphere. The
resulting mixture was warmed to 0.degree. C. and stirred for 30
min. The reaction mixture was cooled to -78.degree. C. followed by
the addition of a solution of the .alpha.,.beta.-unsaturated ester
(1.0 equiv.) in anhydrous THF (0.5 M). The reaction mixture was
stirred for 2 h at 0.degree. C., then slowly warmed to 25.degree.
C., and stirred overnight. The solution was poured onto 1N HCl. The
aqueous layer was extracted with EtOAc. The combined organic layers
were sequentially washed with saturated NaHCO.sub.3, brine, dried
over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude
cyclopropane was purified by flash chromatography (SiO.sub.2,
cyclohexane/CH.sub.2Cl.sub.2) to furnish the pure cyclopropyl
ester.
[0197] General Procedure C: Saponification of Esters
[0198] To the ester (1.0 equiv.) in solution in THF:water (1:4)
(0.4 M), was added NaOH (1.1 equiv.). The mixture was stirred
overnight at 60.degree. C. and concentrated in vacuo. The aqueous
layer was first extracted with Et.sub.2O and poured onto 1N HCl and
then twice extracted with EtOAc. EtOAc extractions were combined
and washed with brine, dried over Na.sub.2SO.sub.4 and concentrated
in vacuo to furnish the pure carboxylic acid.
[0199] General Procedure D: Amide Bond Formation through Acid
Chloride Intermediates
[0200] To the carboxylic acid (1.0 equiv.) was added thionyl
chloride (10.0 equiv.) at 0.degree. C. and 2 drops of anhydrous DMF
under an argon atmosphere. The mixture was stirred for 2 h at room
temperature before the mixture was concentrated in vacuo.
Co-evaporation with toluene, in vacuo, was used to remove the
remaining thionyl chloride. The crude acid chloride was dissolved
in anhydrous DCM under an argon atmosphere, cooled to 0.degree. C.
and Et.sub.3N (5.0 equiv.) was added followed by the addition of
aniline/amine (1.0 equiv.). The mixture was stirred for 16 h at rt.
The reaction mixture was directly purified by flash chromatography
(SiO.sub.2, cyclohexane/EtOAc) to furnish the pure amide.
[0201] General Procedure E: Formation of Sulfonamides
[0202] Chlorosulfonic acid (12-16 equiv.) was added drop-wise at
0.degree. C. to a solution of the arene (1.0 equiv.) in chloroform
(0.5 M) under an argon atmosphere. The reaction mixture was stirred
at rt for 30 min, then poured into a water/ice/brine mixture. The
phases were separated and the aqueous layer extracted with
Et.sub.2O twice. The combined organic extracts were dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The crude sulfonyl
chloride was dissolved in a 0.5 M solution of ammonia in dioxane
(10.0 equiv.), stirred at rt for 45 min and evaporated to dryness
under vacuum overnight. The crude sulfonamide was taken up in 4N
HCl in dioxane and concentrated in vacuo. The crude sulfonamide was
purified by flash chromatography (SiO.sub.2, cyclohexane/EtOAc then
EtOAc/MeOH) or triturated with EtOAc/MeOH to give the pure
sulfonamide.
[0203] General Procedure F: Amide Bond Formation through
EDCl/HOBt
[0204] To a solution of the carboxylic acid (1.0 equiv.) in
anhydrous DCM (0.15-0.20 M) was added Et.sub.3N (1.3-2.0 equiv.),
the amine/aniline (1.0 equiv.), HOBt monohydrate (0.1 equiv.) at rt
and then EDCI (1.3 equiv.) was added at 0.degree. C. under an argon
atmosphere. The mixture was stirred for 12 h at it before being
concentrated in vacuo. The residue was dissolved in EtOAc and the
organics were washed with 1N HCl, saturated NaHCO.sub.3, brine,
dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude
mixture was purified by flash chromatography (SiO.sub.2,
cyclohexane/AcOEt) to furnish the pure amide.
Ethyl 2,2-dimethyl-trans-3-phenylcyclopropanecarboxylate
##STR00072##
[0206] Isopropyltriphenylphosphonium iodide (21.6 g, 50 mmol) and
ethyl cinnamate (8.81 g, 50 mmol) were reacted as described under
General Procedure B to furnish the title compound (6.58 g, 60%) as
a colorless oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.31-7.15 (m, 5H), 4.18 (q, J=7.3 Hz, 2H), 2.70 (d, J=5.6 Hz, 1H),
1.96 (d, J=5.6 Hz, 1H), 1.38 (s, 3H), 1.31 (t, J=7.3 Hz, 3H), 0.93
(s, 3H).
2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid
##STR00073##
[0208] Ethyl 2,2-dimethyl-trans-3-phenylcyclopropanecarboxylate
(6.58 g, 30.1 mmol) was reacted as described under General
Procedure C to furnish the title compound (5.15 g, 90%) as a white
solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.33-7.17 (m, 5H),
2.77 (d, J=5.9 Hz, 1H), 1.99 (d, J=5.9 Hz, 1H), 1.45 (s, 3H), 0.96
(s, 3H).
Ethyl 4-chloro-cinnamate
##STR00074##
[0210] 4-Chlorobenzaldehyde (4.20 g, 30 mmol) and mono-ethyl
malonate (4.60 ml, 39 mmol) were reacted as described under General
Procedure A to furnish the title compound (5.68 g, 89%) as a
colorless oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.63 (d,
J=16.0 Hz, 1H), 7.46-7.42 (m, 2H), 7.38-7.32 (m, 2H), 6.41 (d,
J=16.0 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H).
Ethyl
trans-3-(4-chlorophenol)-2,2-dimethylcyclopropanecarboxylate
##STR00075##
[0212] Isopropyltriphenylphosphonium iodide (8.65 g, 20 mmol) and
ethyl 4-chloro-cinnamate (4.21 g, 20 mmol) were reacted as
described under General Procedure B to furnish the title compound
(2.42 g, 48%) as a colorless oil. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.26-7.24 (m, 2H), 7.11-7.08 (m, 2H), 4.18 (q, J=7.2 Hz,
2H), 2.63 (d, J=5.8 Hz, 1H), 1.91 (d, J=5.8 Hz, 1H), 1.42 (s, 3H),
1.30 (t, J=7.2 Hz, 3H), 0.91 (s, 3H). ESIMS m/z [M+H].sup.+
253.1.
trans-(4-Chlorophenol)-2,2-dimethylcyclopropanecarboxylic acid
##STR00076##
[0214] Ethyl
trans-3-(4-chlorophenyl)-2,2-dimethylcyclopropanecarboxylate (2.42
g, 9.6 mmol) was reacted as described under General Procedure C to
furnish the title compound (1.98 g, 92%) as a white solid. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.28-7.25 (m, 2H), 7.12-7.09 (m,
2H), 2.70 (d, J=5.8 Hz, 1H), 1.93 (d, J=5.8 Hz, 1H), 1.42 (s, 3H),
0.94 (s, 3H).
Ethyl trans-2-phenylspiro[2.4]heptane-1-carboxylate
##STR00077##
[0216] Cyclopentyltriphenylphosphonium bromide (10.3 g, 25 mmol)
and ethyl cinnamate (4.40 g, 25 mmol) were reacted as described
under General Procedure B to furnish the title compound (3.72 g,
61%) as a colorless oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.32-7.11 (m, 5H), 4.22-4.13 (m, 2H), 2.77 (d, J=5.7 Hz, 1H), 2.15
(d, J=5.7 Hz, 1H), 1.91-1.85 (m, 2H), 1.72-1.27 (m, 9H).
trans 2-Phenylspiro[2.4]heptane-1-carboxylic acid
##STR00078##
[0218] Ethyl trans-2-phenylspiro[2.4]heptane-1-carboxylate (3.72 g,
15.2 mmol) was reacted as described under General Procedure C to
furnish the title compound (3.19 g, 96%) as a white solid. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.33-7.11 (m, 5H), 2.83 (d, J=5.6
Hz, 1H), 2.17 (d, J=5.6 Hz, 1H), 1.97-1.32 (m, 8H).
Ethyl trans-2-phenylspiro[2.5]octane-1-carboxylate
##STR00079##
[0220] Cyclohexyltriphenylphosphonium bromide (12.8 g, 30 mmol) and
ethyl cinnamate (5.29 g, 30 mmol) were reacted as described under
General Procedure B to furnish the title compound (0.30 g, 4%) as a
colorless oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.31-7.17
(m, 5H), 4.18 (q, J=7.0 Hz, 2H), 2.72 (d, J=5.9 Hz, 1H), 1.98 (d,
J=5.9 Hz, 1H), 1.80-1.75 (m, 2H), 1.65-1.06 (m, 11H).
trans-2-Phenylspiro[1.5]octane-1-carboxylic acid
##STR00080##
[0222] Ethyl trans-2-phenylspiro[2.5]octane-1-carboxylate (300 mg,
1.16 mmol) was reacted as described under General Procedure C to
furnish the title compound (224 mg, 83%) as a white solid. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.32-7.19 (m, 5H), 2.78 (d, J=5.7
Hz, 1H), 2.00 (d, J=5.7 Hz, 1H), 1.82-1.07 (m, 10H).
Example 1a
2,2-Dimethyl-trans-N-(5-methylthiazol-2-yl)-3-phenylcyclopropanecarboxamid-
e
##STR00081##
[0224] 2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (250
mg, 1.32 mmol) and 2-amino-5-methylthiazole (150 mg, 1.31 mmol)
were reacted as described under General Procedure D to furnish the
title compound (232 mg, 61%) as a yellow foam. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.33-7.17 (m, 6H), 7.02 (s, 1H), 2.95 (d,
J=5.6 Hz, 1H), 2.37 (s, 3H), 2.08 (d, J=5.6 Hz, 1H), 1.44 (s, 3H),
1.03 (s, 3H). mp 132-135.degree. C. ESIMS m/z [M+H].sup.+
287.1.
Example 1b
(1R,3R)-2,2-dimethyl-N-(5-methylthiazol-2-yl)-3-(4-sulfamoylphenyl)cyclopr-
opane carboxamide
##STR00082##
[0226] Example 1a (138 mg, 0.48 mmol) was reacted as described
under General Procedure E to give the title compound (147 mg, 84%)
as a white foam. .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta. 12.15
(br s, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 7.32
(br s, 2H), 7.13 (s, 1H), 2.71 (d, J=5.9 Hz, 1H), 2.43 (d, J=5.9
Hz, 1H), 2.33 (s, 3H), 1.32 (s, 3H), 0.88 (s, 3H). ESIMS m/z
[M+H].sup.+ 366.1.
Example 2a
2,2-Dimethyl-trans-3-phenyl-N-(3-(trifluoromethyl)-1H-pyrazol-5-yl)cyclopr-
opanecarboxamide
##STR00083##
[0228] 2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (250
mg, 1.32 mmol) and 3-trifluoromethyl-1H-pyrazole-5-ylamine (198 mg,
1.31 mmol) were reacted as described under General Procedure D to
furnish the title compound (392 mg, 93%) as a white solid. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.32-7.22 (m, 6H), 5.72-5.64 (m,
2H), 3.43 (d, J=6.1 Hz, 1H), 2.98 (d, J=6.1 Hz, 1H), 1.42 (s, 3H),
1.07 (s, 3H). mp 68-71.degree. C. ESIMS m/z [M+H].sup.+ 324.1.
Example 2b
2,2-Dimethyl-trans-3-(4-sulfamoylphenyl)-N-(3-(trifluoromethyl)-1H-pyrazol-
-5-yl)cyclopropanecarboxamide
##STR00084##
[0230] Example 2a (260 mg, 0.80 mmol) was reacted as described
under General Procedure E to give the title compound (103 mg, 32%)
as a white foam. .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta. 13.48
(br s, 1H), 11.16 (bs, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3
Hz, 2H), 7.34 (br s, 2H), 6.39 (br s, 1H), 2.69 (d, J=5.8 Hz, 1H),
2.31 (d, J=5.8 Hz, 1H), 1.33 (s, 3H), 0.89 (s, 3H). mp
210-213.degree. C. ESIMS m/z [M+H].sup.+ 403.1.
Example 3a
trans-N-(5-Chloro-2,4-dimethoxyphenyl)-2,2-dimethyl-3-phenylcyclopropaneca-
rboxamide
##STR00085##
[0232] 2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (500
mg, 2.63 mmol) and 5-chloro-2,4-dimethoxyaniline (493 mg, 2.63
mmol) were reacted as described under General Procedure D to
furnish the title compound (620 mg, 66%) as a beige solid. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.49 (s, 1H), 7.78 (s, 1H),
7.30-7.19 (m, 5H), 6.53 (s, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 2.83
(d, J=5.7 Hz, 1H), 1.86 (d, J=5.7 Hz, 1H), 1.42 (s, 3H), 0.97 (s,
3H). mp 160-162.degree. C. ESIMS m/z [M+H].sup.+ 360.2.
Example 3b
trans-N-(5-Chloro-2,4-dimethoxyphenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)c-
yclopropanecarboxamide
##STR00086##
[0234] Example 3a (175 mg, 0.49 mmol) was reacted as described
under General Procedure E to give the title compound (112 mg, 53%)
as a white solid. .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta., 9.44
(s, 1H), 8.09 (s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.2 Hz,
2H), 7.33 (s, 2H), 6.86 (s, 1H), 3.94 (s, 3H), 3.87 (s, 3H),
2.66-2.62 (m, 2H), 1.33 (s, 3H), 0.87 (s, 3H). mp 248-251.degree.
C. ESIMS m/z [M+H].sup.+ 439.2.
Example 4a
trans-N-(5-Chloro-2-methoxyphenyl)-2,2-dimethyl-3-phenylcyclopropanecarbox-
amide
##STR00087##
[0236] 2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (1.90
mg, 10 mmol) and 4-chloro-2-methoxyaniline (1.58 mg, 10 mmol) were
reacted as described under General Procedure F to furnish the title
compound (490 mg, 15%) as a white solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.52 (s, 1H), 7.98 (s, 1H), 7.32-7.19 (m, 5H),
6.98 (dd, J=8.7, 2.5 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 3.92 (s, 3H),
2.85 (d, J=5.7 Hz, 1H), 1.88 (d, J=5.7 Hz, 1H), 1.42 (s, 3H), 0.99
(s, 3H). mp 155-157.degree. C. ESIMS m/z [M+H].sup.+ 330.1.
Example 4b
trans-N-(5-Chloro-2-methoxyphenyl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclo-
propanecarboxamide
##STR00088##
[0238] Example 4a (430 mg, 1.30 mmol) was reacted as described
under General Procedure E to give the title compound (357 mg, 67%)
as a white solid. .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta. 9.58
(s, 1H), 8.24 (s, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz,
2H), 7.33 (s, 2H), 7.12-7.05 (m, 2H), 3.89 (s, 3H), 2.78 (d, J=5.9
Hz, 1H), 2.64 (d, J=5.9 Hz, 1H), 1.33 (s, 3H), 0.88 (s, 3H). mp
129-133.degree. C. ESIMS m/z [M+H].sup.+ 409.1.
Example 5a
trans-N-(5-Chloro-2-methoxyphenyl)-3-(4-chlorophenyl)-2,2-dimethylcyclopro-
panecarboxamide
##STR00089##
[0240] trans-3-(4-Chlorophenyl)-2,2-dimethylcyclopropanecarboxylic
acid (200 mg, 0.89 mmol) and 4-chloro-2-methoxyaniline (140 mg,
0.89 mmol) were reacted as described under General Procedure D to
furnish the title compound (120 mg, 37%) as a white solid. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.50 (d, J=2.5 Hz, 1H), 7.99 (br
s, 1H), 7.27-7.24 (m, 2H), 7.13 (d, J=8.3 Hz, 2H), 6.99 (dd, J=8.7,
2.5 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 3.92 (s, 3H), 2.80 (d, J=5.6
Hz, 1H), 1.84 (d, J=5.6 Hz, 1H), 1.40 (s, 3H), 0.97 (s, 3H). mp
162-164.degree.. ESIMS m/z [M+H].sup.+ 364.1.
Example 6a
trans-N-(5-Chloro-2-methoxyphenyl)-2-phenylspiro[2,4]heptane-1-carboxamide
##STR00090##
[0242] trans-2-Phenylspiro[2.4]heptane-1-carboxylic acid (400 mg,
1.85 mmol) and 4-chloro-2-methoxyaniline (291 mg, 1.85 mmol) were
reacted as described under General Procedure D to furnish the title
compound (560 mg, 85%) as a beige solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.52 (d, J=2.5 Hz, 1H), 7.97 (br s, 1H),
7.33-7.14 (m, 5H), 6.99 (dd, J=8.7, 2.5 Hz, 1H), 6.79 (d, J=8.7 Hz,
1H), 3.91 (s, 3H), 2.90 (d, J=5.5 Hz, 1H), 2.05 (d, J=5.5 Hz, 1H),
1.96-1.91 (m, 2H), 1.71-1.42 (m, 6H). mp 133-135.degree. C. ESIMS
m/z [M+H].sup.+ 356.2.
Example 6b
trans-N-(5-Chloro-2-methoxyphenyl)-2-(4-sulfamoylphenyl)spiro[2.4]heptane--
1-carboxamide
##STR00091##
[0244] Example 6a (200 mg, 0.56 mmol) was reacted as described
under General Procedure E to give the title compound (140 mg, 58%)
as a white solid. .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta. 9.53
(s, 1H), 8.22 (br s, 1H), 7.75 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.3
Hz, 2H), 7.27 (s, 2H), 7.09-06 (m, 2H), 3.86 (s, 3H), 2.93 (d,
J=5.5 Hz, 1H), 2.72 (d, J=5.5 Hz, 1H), 1.85-1.74 (m, 2H), 1.62-1.45
(m, 6H). mp 210-212.degree. C. ESIMS m/z [M+H].sup.+ 435.2.
Example 7a
trans-N-(5-Chloro-2-methoxyphenyl)-2-phenylspiro[2.5]octane-1-carboxamide
##STR00092##
[0246] trans-2-Phenylspiro[2.5]octane-1-carboxylic acid (220 mg,
0.95 mmol) and 4-chloro-2-methoxyaniline (150 mg, 0.95 mmol) were
reacted as described under General Procedure D to furnish the title
compound (270 mg, 77%) as a white foam. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.49 (d, J=3.0 Hz, 1H), 8.00 (s, 1H), 7.32-7.20
(m, 5H), 6.99 (dd, J=8.4, 3.0 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 3.92
(s, 3H), 2.87 (d, J=5.8 Hz, 1H), 1.91 (d, J=5.8 Hz, 1H), 1.85-1.81
(m, 2H), 1.66-1.16 (m, 8H). ESIMS m/z [M+H].sup.+ 370.2.
Example 7b
trans-N-(5-Chloro-2-methoxyphenyl)-2-(4-sulfamoylphenyl)spiro[2.5]octane-1-
-carboxamide
##STR00093##
[0248] Example 7a (150 mg, 0.40 mmol) was reacted as described
under General Procedure E to give the title compound (125 mg, 70%)
as a white solid. .sup.1H NMR (300 MHz, d.sub.3-MeOD) .delta. 8.11
(d, J=2.4 Hz, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H),
7.09-6.98 (m, 2H), 3.93 (s, 3H), 2.81 (d, J=5.6 Hz, 1H), 2.56 (d,
J=5.6 Hz, 1H), 1.84-1.80 (m, 2H), 1.67-1.21 (m, 8H). mp
118-121.degree. C. ESIMS m/z [M+H].sup.+ 449.2.
Example 8a
trans-N-(2,6-dimethoxypyridin-3-yl)-2-phenylspiro[2.4]heptane-1-carboxamid-
e
##STR00094##
[0250] trans-2-Phenylspiro[2.4]heptane-1-carboxylic acid (300 mg,
1.39 mmol) and 2,6-dimethoxy-pyridin-3-ylamine (214 mg, 1.39 mmol)
were reacted as described under General Procedure D to furnish the
title compound (260 mg, 52%) as a purple solid. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.54 (d, J=8.2 Hz, 1H), 7.61 (br s, 1H),
7.32-7.14 (m, 5H), 6.30 (d, J=8.2 Hz, 1H), 4.02 (s, 3H), 3.89 (s,
3H), 2.87 (d, J=5.7 Hz, 1H), 2.05 (d, J=5.7 Hz, 1H), 1.93-1.90 (m,
2H), 1.67-1.42 (m, 6H). mp 131-133.degree. C. ESIMS m/z [M+H].sup.+
353.2.
Example 8b
trans-N-(2,6-Dimethoxypyridin-3-yl)-2-(4-sulfamoylphenyl)spiro[2.4]heptane-
-1-carboxamide
##STR00095##
[0252] Example 8a (170 mg, 0.47 mmol) was reacted as described
under General Procedure E to give the title compound (105 mg, 63%)
as a white solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.49
(d, J=8.5 Hz, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.67 (br s, 1H), 7.27
(d, J=8.4 Hz, 2H), 6.30 (d, J=8.5 Hz, 1H), 4.91 (s, 2H), 4.02 (s,
3H), 3.89 (s, 3H), 2.93 (d, J=5.5 Hz, 1H), 2.14 (d, J=5.5 Hz, 1H),
1.94-1.90 (m, 2H), 1.75-1.31 (m, 6H). mp 112-115.degree. C. ESIMS
m/z [M+H].sup.+ 432.3.
Example 9a
trans-2-phenyl-N-(4-(trifluoromethylphenyl)spiro[2.4]heptane-1-carboxamide
##STR00096##
[0254] trans-2-Phenylspiro[2.4]heptane-1-carboxylic acid (300 mg,
1.39 mmol) and 4-trifluoromethyl-phenylamine (224 mg, 1.39 mmol)
were reacted as described under General Procedure D to furnish the
title compound (300 mg, 60%) as a white solid. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.69 (d, J=8.8 Hz, 2H), 7.58-7.52 (m, 3H),
7.33-7.20 (m, 3H), 7.15-7.12 (m, 2H), 2.92 (d, J=5.5 Hz, 1H), 2.06
(d, J=5.5 Hz, 1H), 1.93-1.91 (m, 2H), 1.73-1.60 (m, 4H), 1.52-1.40
(m, 2H). mp 171-173.degree. C. ESIMS m/z [M+H].sup.+ 360.2.
Example 9b
trans-2-(4-sulfamoylphenyl)-N-(4-(trifluoromethyl)phenyl)spiro[2.4]heptane-
-1-carboxamide
##STR00097##
[0256] Example 9a (190 mg, 0.47 mmol) was reacted as described
under General Procedure E to give the title compound (145 mg, 63%)
as a white solid. .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta. 10.57
(s, 1H), 7.83-7.75 (m, 4H), 7.65 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.3
Hz, 2H), 7.29 (br s, 1H), 4.00 (s, 1H), 2.78 (d, J=5.7 Hz, 1H),
2.48 (d, J=5.7 Hz, 1H), 1.90-1.72 (m, 2H), 1.68-1.41 (m, 5H),
1.26-1.15 (m, 1H). mp 234-236.degree. C. ESIMS m/z [M+H].sup.+
439.2.
Example 10a
2,2-Dimethyl-trans
-3-phenyl-N-(pyridin-4-yl)cyclopropanecarboxamide
##STR00098##
[0258] 2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (250
mg, 1.31 mmol) and 4-aminopyridine (123 mg, 1.31 mmol) were reacted
as described under General Procedure D to furnish the title
compound (326 mg, 93%) as a white foam. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.48-8.45 (m, 2H), 8.35 (br s, 1H), 7.63-7.60
(m, 2H), 7.31-7.16 (m, 5H), 2.87 (d, J=5.7 Hz, 1H), 1.96 (d, J=5.7
Hz, 1H), 1.40 (s, 3H), 0.97 (s, 3H). ESIMS m/z [M+H].sup.+
267.1.
Example 10b
2,2-Dimethyl-trans-N-(pyridin-4-yl)-3-(4-sulfamoylphenyl)cyclopropanecarbo-
xamide
##STR00099##
[0260] Example 10a (230 mg, 0.86 mmol) was reacted as described
under General Procedure E to give the title compound (80 mg, 27%)
as a white solid. .sup.1H NMR (300 MHz, d.sub.6-DMSO) .delta. 10.64
(br s, 1H), 8.43-8.41 (m, 2H), 7.77 (d, J=8.3 Hz, 2H), 7.60-7.57
(m, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.34 (br s, 2H), 2.69 (d, J=5.9
Hz, 1H), 2.31 (d, J=5.9 Hz, 1H), 1.33 (s, 3H), 0.90 (s, 3H). mp
270-274.degree. C. ESIMS m/z [M+H].sup.+ 346.2.
Example 11a
trans-3-[4-(dimethylsulfamoyl)phenyl]-2,2-dimethylcyclopropanecarboxylic
acid
##STR00100##
[0262] 2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (4.0
g, 21.0 mmol) was reacted as described under General Procedure E
using dimethylamine in THF (instead of ammonia in dioxane) to
furnish the title compound (1.4 g, 95%) as a white solid. .sup.1H
NMR (300 MHz, d.sub.4-methanol) .delta. 7.72 (d, J=8.1 Hz, 2H),
7.45 (d, J=8.1 Hz, 2H), 2.69-2.66 (m, 7H), 2.12 (d, J=6.0 Hz, 1H),
1.40 (s, 3H), 0.94 (s, 3H).
Example 11b
trans-N-(5-Chloro-2-methoxyphenyl)-3-[4-(dimethylsulfamoyl)phenyl]-2,2-dim-
ethylcyclopropanecarboxamide
##STR00101##
[0264] Example 11a (300 mg, 1.0 mmol) and 4-chloro-2-methoxyaniline
(159 mg, 1.0 mmol) were reacted as described under General
Procedure F to furnish the title compound (342 mg, 79%) as a white
solid. .sup.1H NMR (300 MHz, CDCl3) .delta. 8.49 (brs, 1H), 8.03
(brs, 1H), 7.69 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.3 Hz, 2H),
7.02-6.98 (m, 1H), 6.80 (d, J=8.7 Hz, 1H), 3.92 (s, 3H), 2.88 (d,
J=5.5 Hz, 1H), 2.70 (s, 6H), 1.98 (d, J=5.5 Hz, 1H), 1.42 (s, 3H),
0.97 (s, 3H). ESIMS m/z [M+H].sup.+ 437.1.
Example 12a
Ethyl
trans-3-(4-bromophenyl)-2,2-dimethylcyclopropanecarboxylate
##STR00102##
[0266] Isopropyltriphenylphosphonium iodide (8.65 g, 20.0 mmol) and
ethyl 4-bromo-cinnamate (5.10 g, 20.0 mmol) were reacted as
described under General Procedure B to furnish the title compound
(3.21 g, 54%) as a colourless oil. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.40 (d, J=8.3 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H),
4.18 (q, J=7.1 Hz, 2H), 2.62 (d, J=5.5 Hz, 1H), 1.91 (d, J=5.5 Hz,
1H), 1.36 (s, 3H), 1.30 (t, J=7.1 Hz, 3H), 0.91 (s, 3H).
Example 12b
trans-3-(4-bromophenyl)-2,2-dimethylcyclopropanecarboxylic acid
##STR00103##
[0268] Ethyl
trans-3-(4-bromophenyl)-2,2-dimethylcyclopropanecarboxylate (3.21
g, 10.8 mmol) was reacted as described under General Procedure C to
furnish the title compound (2.57 g, 88%) as a white solid. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.40 (d, J=7.9 Hz, 2H), 7.05 (d,
J=7.9 Hz, 2H), 2.68 (d, J=5.8 Hz, 1H), 1.93 (d, J=5.8 Hz, 1H), 1.42
(s, 3H), 0.94 (s, 3H).
Example 12c
trans-N-(5-Chloro-2-methoxyphenyl)-3-(4-bromophenyl)-2,2-dimethylcycloprop-
anecarboxamide
##STR00104##
[0270] trans-3-(4-Bromophenyl)-2,2-dimethylcyclopropanecarboxylic
acid (200 mg, 0.74 mmol) and 4-chloro-2-methoxyaniline (120 mg,
0.74 mmol) were reacted as described under General Procedure D to
furnish the title compound (270 mg, 89%) as a white solid. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.50 (brs, 1H), 7.98 (brs, 1H),
7.41 (d, J=8.1 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 6.99 (dd, J=8.7,
2.5 Hz, 1H), 6.80 (d, J=8.7 Hz, 1H), 3.91 (s, 3H), 2.78 (d, J=5.6
Hz, 1H), 1.83 (d, J=5.6 Hz, 1H), 1.39 (s, 3H), 0.97 (s, 3H). mp
170-172.degree.. ESIMS m/z [M+H].sup.+ 410.1.
Example 13a
trans-N-(2-methoxypyridin-3-yl)-2,2-dimethyl-3-phenylcyclopropanecarboxami-
de
##STR00105##
[0272] 2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (400
mg, 2.1 mmol) and 2-methoxy-3-pyridinamine (261 mg, 2.1 mmol) were
reacted as described under General Procedure D to furnish the title
compound (550 mg, 88%) as a white solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.69-8.64 (m, 1H), 7.90 (s, 1H), 7.85-7.83 (m,
1H), 7.32-7.19 (m, 5H), 6.92-6.88 (m, 1H), 4.06 (s, 3H), 2.84 (d,
J=5.7 Hz, 1H), 1.90 (d, J=5.7 Hz, 1H), 1.41 (s, 3H), 0.98 (s, 3H).
mp 152-154.degree. C. ESIMS m/z [M+H].sup.+ 297.2.
Example 13b
trans-N-(2-methoxypyridin-3-yl)-2,2-dimethyl-3-(4-sulfamoylphenyl)cyclopro-
panecarboxamide
##STR00106##
[0274] Example 13a (200 mg, 0.67 mmol) was reacted as described
under General Procedure E to give the title compound (95 mg, 38%)
as a white solid. .sup.1H NMR (300 MHz,
CDCl.sub.3/d.sub.4-methanol) .delta. 8.40 (d, J=7.8 Hz, 1H),
7.71-7.68 (m, 3H), 7.21 (d, J=8.3 Hz, 2H), 6.78 (dd, J=7.8, 5.1 Hz,
1H), 3.91 (s, 3H), 2.69 (d, J=5.8 Hz, 1H), 2.02 (d, J=5.8 Hz, 1H),
1.27 (s, 3H), 0.83 (s, 3H). mp 216-218.degree. C. ESIMS m/z
[M+H].sup.+ 376.2.
Example 14a
Ethyl 2,2-diethyl-trans-3-phenylcyclopropanecarboxylate
##STR00107##
[0276] 3-Pentyltriphenylphosphonium bromide (8.27 g, 20 mmol) and
ethyl cinnamate (3.52 g, 20.0 mmol) were reacted as described under
General Procedure B to furnish the title compound (460 mg, 9%) as a
colorless oil containing 14% of an isomeric impurity. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.33-7.12 (m, 5H), 4.16 (q, J=7.1 Hz,
2H), 2.70 (d, J=5.8 Hz, 1H), 1.94 (d, J=5.8 Hz, 1H), 1.77-1.22 (m,
7H), 0.98-0.80 (m, 6H).
Example 14b
2,2-Diethyl-trans-3-phenylcyclopropanecarboxylic acid
##STR00108##
[0278] Ethyl 2,2-diethyl-trans-3-phenylcyclopropanecarboxylate (460
g, 1.9 mmol) was reacted as described under General Procedure C to
furnish the title compound (353 mg, 86%) as a white solid
containing 25% of an isomeric impurity. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.35-7.11 (m, 5H), 2.75 (d, J=5.8 Hz, 1H), 1.97
(d, J=5.8 Hz, 1H), 1.81-1.19 (m, 4H), 1.02-0.81 (m, 6H).
Example 14c
trans-N-(5-Chloro-2-methoxyphenyl)-2,2-diethyl-3-phenylcyclopropanecarboxa-
mide
##STR00109##
[0280] 2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (350
mg, 1.6 mmol) and 4-chloro-2-methoxyaniline (253 mg, 1.6 mmol) were
reacted as described under General Procedure F to furnish the title
compound (430 mg, 75%) as a yellow oil containing 30% of an
isomeric impurity. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.50
(brs, 1H), 8.01 (brs, 1H), 7.32-7.19 (m, 5H), 7.00-6.96 (m, 1H),
6.79 (d, J=8.7 Hz, 1H), 3.90 (s, 3H), 2.85 (d, J=5.8 Hz, 1H), 1.87
(d, J=5.8 Hz, 1H), 1.80-1.21 (m, 4H), 1.00-0.82 (m, 6H). ESIMS m/z
[M+H].sup.+ 358.2.
Example 14d
trans-N-(5-Chloro-2-methoxyphenyl)-2,2-diethyl-3-(4-sulfamoylphenyl)cyclop-
ropanecarboxamide
##STR00110##
[0282] Example 14c (250 mg, 0.70 mmol) was reacted as described
under General Procedure E to give the title compound (150 mg, 49%)
as a white solid containing 28% of an isomeric impurity. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.47 (brs, 1H), 8.00 (brs, 1H),
7.84 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 7.02-6.98 (m, 1H),
6.81 (d, J=8.7 Hz, 1H), 4.79 (s, 2H), 3.92 (s, 3H), 2.89 (d, J=5.8
Hz, 1H), 1.94 (d, J=5.8 Hz, 1H), 1.76-1.20 (m, 4H), 1.00-0.86 (m,
6H). ESIMS m/z [M+H].sup.+ 437.2.
Example 15a
trans-2-phenyl-N-[2-chloro-4-(trifluoromethyl)phenyl]spiro[2.4]heptane-1-c-
arboxamide
##STR00111##
[0284] trans-2-Phenylspiro[2.4]heptane-1-carboxylic acid (300 mg,
1.39 mmol) and 2-chloro-4-trifluoromethyl-phenylamine (272 mg, 1.39
mmol) were reacted as described under General Procedure D to
furnish the title compound (312 mg, 57%) as a white solid. .sup.1H
NMR (300 MHz, d.sub.6-DMSO) .delta. 9.91 (s, 1H), 8.20 (d, J=8.5
Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.67 (d, J=8.5, 1.6 Hz, 1H), 7.31
(t, J=7.3 Hz, 2H), 7.22-7.16 (m, 3H), 2.80 (d, J=5.7 Hz, 1H), 2.70
(d, J=5.7 Hz, 1H), 1.82-1.73 (m, 2H), 1.66-1.42 (m, 5H), 1.29-1.10
(m, 1H). mp 131-133.degree. C. ESIMS m/z [M+H].sup.+ 394.3.
Example 15b
trans-2-(4-sulfamoylphenyl)-N-[2-chloro-4-(trifluoromethyl)phenyl]spiro[2.-
4]heptane-1-carboxamide
##STR00112##
[0286] Example 15a (200 mg, 0.5 mmol) was reacted as described
under General Procedure E to give the title compound (144 mg, 61%)
as a white solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.62
(d, J=8.5 Hz, 1H), 7.99 (s, 1H), 7.88 (d, J=8.5 Hz, 2H), 7.67 (s,
1H), 7.54 (d, J=8.5 Hz, 1H), 7.31 (d, J=8.5 Hz, 2H), 4.75 (s, 2H),
3.00 (d, J=5.4 Hz, 1H), 2.18 (d, J=5.4 Hz, 1H), 1.98-1.80 (m, 2H),
1.77-1.59 (m, 5H), 1.44-1.31 (m, 1H). mp 111-113.degree. C. ESIMS
m/z [M+H].sup.+ 473.3.
Example 16a
Ethyl 3-methyl-cinnamate
##STR00113##
[0288] 3-Methylbenzaldehyde (12.0 g, 100 mmol) and mono-ethyl
malonate (15.5 ml, 130 mmol) were reacted as described under
General Procedure A to furnish the title compound (16.7 g, 88%) as
a yellow oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.66 (d,
J=16.0 Hz, 1H), 7.34-7.18 (m, 4H), 6.42 (d, J=16.0 Hz, 1H), 4.26
(q, J=7.2 Hz, 2H), 2.37 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).
Example 16b
Ethyl trans-2,2-dimethyl-3-m-tolyl-cyclopropanecarboxylate
##STR00114##
[0290] Isopropyltriphenylphosphonium iodide (17.3 g, 40 mmol) and
ethyl 3-methylcinnamate (7.6 g, 40 mmol) were reacted as described
under General Procedure B to furnish the title compound (7.0 g,
75%) as a colorless oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.17 (t, J=7.4 Hz, 1H), 7.03-6.95 (m, 3H), 4.18 (q, J=7.2 Hz, 2H),
2.66 (d, J=5.8 Hz, 1H), 2.33 (s, 3H), 1.93 (d, J=5.8 Hz, 1H), 1.38
(s, 3H), 1.30 (t, J=7.2 Hz, 3H), 0.93 (s, 3H).
Example 16c
trans-2,2-Dimethyl-3-m-tolyl-cyclopropanecarboxylic acid
##STR00115##
[0292] Ethyl trans-2,2-dimethyl-3-m-tolyl-cyclopropanecarboxylate
(7.0 g, 30 mmol) was reacted as described under General Procedure C
to furnish the title compound (5.4 g, 89%) as a yellow oil. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.18 (t, J=7.4 Hz, 1H), 7.05-6.95
(m, 3H), 2.72 (d, J=5.8 Hz, 1H), 2.33 (s, 3H), 1.96 (d, J=5.8 Hz,
1H), 1.43 (s, 3H), 0.96 (s, 3H).
Example 16d
trans-N-(3,4-Difluoro-phenyl)-2,2-dimethyl-3-m-tolyl-cyclopropanecarboxami-
de
##STR00116##
[0294] trans-2,2-Dimethyl-3-m-tolyl-cyclopropanecarboxylic acid
(2.04 g, 10 mmol) and 3,4-difluoroaniline (1.29 g, 10 mmol) were
reacted as described under General Procedure D to furnish the title
compound (2.9 g, 92%) as a brown solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.70-7.64 (m, 1H), 7.47 (s, 1H), 7.20-6.96 (m,
6H), 2.79 (d, J=5.6 Hz, 1H), 2.33 (s, 3H), 1.80 (d, J=5.6 Hz, 1H),
1.40 (s, 3H), 0.97 (s, 3H). mp 110-113.degree. C. ESIMS m/z
[M+H].sup.+ 316.2.
Example 16e
trans-N-(3,4-Difluoro-phenyl)-2,2-dimethyl-3-(3-methyl-4-sulfamoyl-phenyl)-
-cyclopropane carboxamide
##STR00117##
[0296] Example 16d (93 mg, 0.30 mmol) was reacted as described
under General Procedure E to give the title compound (5.1 mg, 11%)
as a white solid. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.89
(d, J=8.1 Hz, 1H), 7.76-7.69 (m, 1H), 7.28-7.16 (m, 4H), 2.73 (d,
J=6.0 Hz, 1H), 2.65 (s, 3H), 2.19 (d, J=6.0 Hz, 1H), 1.38 (s, 3H),
0.96 (s, 3H). mp 195-198.degree. C. ESIMS m/z [M+H].sup.+
395.3.
Example 17a
trans-N-(5-Chloro-2-methoxyphenyl)-2,2-dimethyl-3-m-tolyl-cyclopropanecarb-
oxamide
##STR00118##
[0298] trans-2,2-Dimethyl-3-m-tolyl-cyclopropanecarboxylic acid
(2.04 g, 10 mmol) and 4-chloro-2-methoxyaniline (2.73 g, 13.4 mmol)
were reacted as described under General Procedure D to furnish the
title compound (3.9 g, 85%) as a white solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.52 (s, 1H), 7.99 (s, 1H), 7.18 (t, J=7.7 Hz,
1H), 7.04-6.96 (m, 4H), 6.86-6.69 (m, 1H), 3.92 (s, 3H), 2.80 (d,
J=5.5 Hz, 1H), 2.34 (s, 3H), 1.86 (d, J=5.5 Hz, 1H), 1.40 (s, 3H),
0.98 (s, 3H). mp 148-150.degree. C. ESIMS m/z [M+H].sup.+
344.3.
Example 17b
trans-N-(5-Chloro-2-methoxyphenyl)-2,2-dimethyl-3-(3-methyl-4-sulfamoyl-ph-
enyl)-cyclopropane carboxamide
##STR00119##
[0300] Example 17a (131 mg, 0.38 mmol) was reacted as described
under General Procedure E to give the title compound (4.1 mg, 3%)
as a beige solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.49
(s, 1H), 8.00 (s, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.17-7.12 (m, 2H),
7.00 (d, J=8.6 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 4.74 (s, 2H), 3.92
(s, 3H), 2.84 (d, J=5.8 Hz, 1H), 2.67 (s, 3H), 1.93 (d, J=5.8 Hz,
1H), 1.42 (s, 3H), 0.98 (s, 3H). mp 118-121.degree. C. ESIMS m/z
[M+H].sup.+ 423.4.
Example 18a
Ethyl 3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-acrylate
##STR00120##
[0302] 2,2-difluoro-1,3-benzodioxole-5-carboxaldehyde (5.0 g, 26.9
mmol) and mono-ethyl malonate (4.1 ml, 34.9 mmol) were reacted as
described under General Procedure A to furnish the title compound
(5.6 g, 82%) as a white solid. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.61 (d, J=16.0 Hz, 1H), 7.26-7.22 (m, 2H), 7.06 (d, J=7.9
Hz, 1H), 6.33 (d, J=16.0 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 1.33 (t,
J=7.1 Hz, 3H).
Example 18b
Ethyl
trans-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-2,2-dimethyl-cyclopropa-
necarboxylate
##STR00121##
[0304] Isopropyltriphenylphosphonium iodide (4.32 g, 10 mmol) and
ethyl 3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-acrylate (2.56 g, 10
mmol) were reacted as described under General Procedure B to
furnish the title compound (1.62 g, 54%) as a colorless oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.96 (d, J=7.1 Hz, 1H),
6.89 (s, 1H), 6.87 (d, J=7.1 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 2.66
(d, J=5.8 Hz, 1H), 1.88 (d, J=5.8 Hz, 1H), 1.36 (s, 3H), 1.30 (t,
J=7.2 Hz, 3H), 0.92 (s, 3H).
Example 18c
trans-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-2,2-dimethyl-cyclopropanecarb-
oxylic acid
##STR00122##
[0306] Ethyl
trans-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-2,2-dimethyl-cyclopropanecar-
boxylate (1.62 g, 5.4 mmol) was reacted as described under General
Procedure C to furnish the title compound (1.37 g, 93%) as a white
solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.97 (d, J=7.5 Hz,
1H), 6.89 (s, 1H), 6.87 (d, J=7.5 Hz, 1H), 2.72 (d, J=5.8 Hz, 1H),
1.90 (d, J=5.8 Hz, 1H), 1.42 (s, 3H), 0.96 (s, 3H).
Example 18d
trans-N-(5-Chloro-2-methoxyphenyl)-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)--
2,2-dimethyl-cyclopropane carboxamide
##STR00123##
[0308]
trans-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-2,2-dimethyl-cycloprop-
anecarboxylic acid (450 mg, 1.7 mmol) and 4-chloro-2-methoxyaniline
(318 mg, 2.0 mmol) were reacted as described under General
Procedure D to furnish the title compound (80 mg, 12%) as a white
solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.49 (s, 1H), 7.98
(s, 1H), 7.02-6.90 (m, 4H), 6.80 (d, J=8.7 Hz, 1H), 3.92 (s, 3H),
2.82 (d, J=5.5 Hz, 1H), 1.81 (d, J=5.5 Hz, 1H), 1.39 (s, 3H), 0.98
(s, 3H). mp 120-122.degree. C. ESIMS m/z [M+H].sup.+ 410.3.
[0309] Pharmacology
Example 1
CellLux Fluorescence Assay to Detect Agonists and Positive
Allosteric Modulators of .alpha.7 nAChR
[0310] Compounds were screened for positive allosteric modulation
(PAM) of .alpha.7nACh receptors on the CellLux (Perkin Elmer) with
a fluorescence-based calcium assay. Activation of the .alpha.7nAChR
by endogenous ligands, results in a calcium flux which can be
measured using ion specific fluorescent dyes. The fluorescence
assay was run in a high throughput format on the CellLux, an
automated fluorescent plate reader with liquid handling
capabilities. The assay measured intracellular calcium changes in a
GH4C1 cell line stably expressing .alpha.7nACh receptors, when
treated with compounds that positively modulated an ACh-induced
response. Compound was added first to identify any agonist activity
followed by ACh addition (EC20 concentration) to measure PAM
activity.
[0311] Prior to assay, .alpha.7/GH4C1 cells were seeded in 96-well
plates (PDL-coated) and incubated for 48 hours at 33.degree. C. in
5% CO.sub.2. The cells were grown in F10Ham media plus 15% horse
serum, 2.5% FCS, 2 mM penicillin, 2 mM streptomycin, 2 mM glutamine
and 10 mM Hepes (Invitrogen). 0.5 mM sodium butyrate, a growth
arrestor, was added to the cells during the incubation period to
increase expression of a nAChR. On the day of assessment, the media
was removed and the cells were washed with HBSS buffer (1 mM
CaCl.sub.2, 0.5 mM MgCl.sub.2, 0.4 mM MgSO.sub.4, 5 mM KCL, 0.4 mM
KHPO.sub.4, 4 mM NaHCO.sub.3, 137 mM NaCl, 0.3 mM
Na.sub.2HPO.sub.4, 5.5 mM glucose and 1M Hepes, pH7.4) and then
Fluo-4 Direct Calcium dye (Molecular Probes) was added. The cells
were incubated with dye for 30 minutes at 33.degree. C. Compound
addition, ACh addition and fluorescence measurement was performed
on the CellLux, a high throughput imaging system. Fluorescent
excitation is at 495 nm and emission at 516 nm.
[0312] The CellLux recorded fluorescent responses at 5 second
intervals starting with a 10 second baseline reading, the compound
was then added and the response was read for 1 minute. ACh was then
added and the response read for a further 2 minutes, a total of 4
minutes. This protocol detects agonist and PAM activity of
compounds at the .alpha.7nAChR.
[0313] Compounds were tested at 6 doses, in triplicate, 0.03, 0.1,
0.3, 1, 3 and 10 uM. Working stocks were prepared in DMSO from 10
mM DMSO stocks and then 10.times. starting stocks were prepared by
diluting 1:100 in HBSS buffer (0.1% DMSO final). A 10.times.
starting dilution of an EC20 concentration of ACh was prepared in
HBSS buffer (0.1% DMSO final). Negative control was HBSS buffer
(0.1% DMSO final).
[0314] Data was analysed by calculating % potentiation of compound
compared to the ACh control response, where ACh potentiation was
set at 0%. Peak/base values were calculated for each compound
concentration (n=3) using AssayPro program (CellLux) and these
values were used to determine % potentiation based on the ACh
control peak/base value. Compounds were identified as active if
they showed potentiation over the control ACh response. For active
compounds % potentiation values were analysed to determine compound
EC50 values using GraphPad Prism 4.
Example 2
Electrophysiology for a7 nAChR Positive Allosteric Modulator
Activity
[0315] Compounds were screened for positive allosteric modulation
(PAM) of a7 nACh receptors using the whole-cell patch clamp
technique. The .alpha.7nAChR activates and desensitizes very
rapidly. Rapid ligand application and response recording is
crucial. The current was measured in a GH4C1 cell line stably
expressing .alpha.7nAChR, when treated with compounds that
positively modulated an ACh-induced response. Compound was added
first to identify any agonist activity followed by Ach addition
(EC20 concentration) to measure PAM activity.
[0316] .alpha.7/GH4C1 cells were seeded in T75 flasks and incubated
for 48 hours at 33.degree. C. in 5% CO.sub.2, prior to patch-clamp
recording. The cells were grown in F10Ham media plus 15% horse
serum, 2.5% FCS, 2 mM penicillin, 2 mM streptomycin, 2 mM glutamine
and 10 mM Hepes (Invitrogen). 0.5 mM sodium butyrate, a growth
arrestor, was also added to the cells during the incubation period
to increase .alpha.7 nAChR expression. On the day of assay the
media was removed, the cells were centrifuged and re-suspended in
bath solution (160 mM NaCl, 4.5 mM KCl, 2 mM CaCl.sub.2, 1 mM
MgCl.sub.2, 5 mM glucose and 10 mM Hepes, pH7.4).
[0317] Whole-cell nAChR currents were recorded in .alpha.7/GH4C1
cells clamped at -60 mV using a planar electrode patch clamp system
(Port-A-Patch, Nanion) interfaced to an EPC10 patch clamp amplifier
(Heka electronic) Cells were continuosly bathed in a solution
containing (mM): 160 NaCl, 4.5 KCl, 7.66 CaCl.sub.2, 1 MgCl.sub.2,
5 glucose and 10 Hepes, pH7.4, NaOH, 310-320 mOsmol.Kg.sup.-1). ACh
was rapidly applied for 1 sec using a gravity feed perfusion system
(Nanion Technologies) under direct digital control of the EPC 10
amplifier. Other drugs were perfused directly into the bath. Cells
were washed for 2-3 minutes in between ACh applications to allow
adequate recovery from desensitization. PAM activity was measured
by applying compound with and without ACh (EC20 concentration).
[0318] Compounds were tested at 6 doses, 0.03, 0.1, 0.3, 1, 3 and
10 uM on 2-3 cells. Working stocks were prepared in DMSO from 10 mM
DMSO stocks and then final stocks were prepared by diluting 1:200
in external bath solution (0.5% DMSO final). An EC20 concentration
of ACh was prepared in external bath solution.
[0319] Peak current and area under the curve were measured using
Fitmaster (HEKA) software. PAM activity was measured by %
potentiation which was calculated from peak current or area under
the curve values based on the ACh control response.
Concentration-response curves and EC.sub.50 values were analysed
using GraphPad Prism 4.
Example 3
Animal Model of Cognitive Enhancement--T-Maze Continuous
Alternation Task (T-CAT)
[0320] The cognition enhancing properties of the compounds in the
invention were evaluated in an animal model where cognitive
impairment is pharmacologically induced. Scopolamine is a
muscarinic receptor antagonist which is used as a
standard/reference drug for inducing cognitive deficits in healthy
humans and animals.
[0321] The T-maze Continuous Alternation Task (T-CAT) measures
spontaneous alternation, which is the innate tendency of mice to
alternate free choices in a T-maze over a series of successive
runs. This sequential procedure relies on working memory and is
sensitive to various pharmacological manipulations affecting memory
processes.
[0322] The T-maze apparatus is made of gray Plexiglas with a main
stem (55 cm long.times.10 cm wide.times.25 cm high) and two arms
(30 cm long.times.10 cm wide.times.25 cm high) positioned at 90
degree angle relative to the main stem. A start box (15 cm
long.times.10 cm wide) is separated from the main stem by a sliding
door. Sliding doors are also provided to close specific arms during
the forced-choice alternation task.
[0323] The experimental protocol consists of one single session,
which starts with 1 "forced-choice" trial, followed by 14
"free-choice" trials. In the first "forced-choice" trial, the
animal is confined for 5 s in the start arm and then it is released
while either the left or right goal arm is blocked by a sliding
door. The animal will negotiate the maze, eventually enter the open
goal arm, and return to the start position. Immediately after the
return to the start position, the left or right goal door is opened
and the animal is allowed to choose freely between the left and
right goal arm ("free choice" trials). The animal is considered to
have entered an arm when it places its four paws in the arm. A
session is terminated and the animal is removed from the maze as
soon as 14 free-choice trials have been performed or 10 min have
elapsed, whichever event occurs first. The percentage of
alternation over the 14 free-choice trials is determined for each
mouse and is used as an index of working memory performance. This
percentage is defined as entry in a different arm of the T-maze
over successive visits (i.e., left-right-left-right, etc).
[0324] Scopolamine administered 20 min prior the initiation of the
T-maze session is used to induce disruption in the spontaneous
alternation of mice. Test compounds are administered 60 min prior
the start of the T-maze session in order to evaluate their ability
to reverse the scopolamine effect.
[0325] The apparatus is cleaned between each animal using alcohol
(70.degree.). Urine and feces are removed from the maze. During the
trials, animal handling and the visibility of the operator are
minimized as much as possible.
[0326] The supporting compounds listed below were screened in the
fluorescence-based calcium assay and gave significant potentiation
of ACh at compound concentrations <10 uM: 1b, 2b, 3b, 4b, 6b,
7b, 8b, 11b, 12c, 13b, 14c, 15b, 16e, 17b, 18d.
[0327] The supporting compounds listed below were screened in the
T-CAT model and showed significant improvement relative to the
scopolamine treated mice: 2b, 4b, 5a, 6b, 9b, 10b.
* * * * *