U.S. patent application number 12/542399 was filed with the patent office on 2010-03-11 for substituted aniline derivatives.
This patent application is currently assigned to H. Lundbeck A/S. Invention is credited to Nikolay Khanzhin, Andreas Ritzen, Daniel Rodriguez Greve, Mario Rottlander, Christian Wenzel Tornoe, William Patrick Watson.
Application Number | 20100063044 12/542399 |
Document ID | / |
Family ID | 36654136 |
Filed Date | 2010-03-11 |
United States Patent
Application |
20100063044 |
Kind Code |
A1 |
Tornoe; Christian Wenzel ;
et al. |
March 11, 2010 |
SUBSTITUTED ANILINE DERIVATIVES
Abstract
The present invention relates to aniline derivatives of formula
I: ##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, Z and q
are as defined herein; or salts thereof and their use.
Inventors: |
Tornoe; Christian Wenzel;
(Kgs. Lyngby, DK) ; Rottlander; Mario; (Greve,
DK) ; Rodriguez Greve; Daniel; (Stenlose, DK)
; Khanzhin; Nikolay; (Humlebaek, DK) ; Ritzen;
Andreas; (Vanlose, DK) ; Watson; William Patrick;
(Vanlose, DK) |
Correspondence
Address: |
LUNDBECK RESEARCH USA, INC.;ATTENTION: STEPHEN G. KALINCHAK, LEGAL
215 COLLEGE ROAD
PARAMUS
NJ
07652
US
|
Assignee: |
H. Lundbeck A/S
Valby-Copenhagen
DK
|
Family ID: |
36654136 |
Appl. No.: |
12/542399 |
Filed: |
August 17, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11312664 |
Dec 20, 2005 |
7601870 |
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12542399 |
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PCT/DK05/00560 |
Sep 2, 2005 |
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11312664 |
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60609856 |
Sep 13, 2004 |
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Current U.S.
Class: |
514/231.2 ;
514/277; 514/438; 514/625; 544/106; 544/335; 546/290; 549/29;
549/72; 558/241; 560/24; 564/218 |
Current CPC
Class: |
C07D 215/12 20130101;
C07C 255/60 20130101; A61P 25/22 20180101; A61P 31/18 20180101;
A61P 31/22 20180101; A61P 25/08 20180101; A61P 25/16 20180101; A61P
25/36 20180101; A61P 25/28 20180101; C07D 333/24 20130101; A61P
21/04 20180101; A61P 25/32 20180101; C07C 237/04 20130101; C07C
233/29 20130101; A61P 43/00 20180101; A61P 25/06 20180101; C07D
521/00 20130101; C07D 207/32 20130101; A61P 25/30 20180101; A61P
29/00 20180101; C07C 233/43 20130101; A61P 31/12 20180101; C07C
233/15 20130101; C07C 311/08 20130101; C07C 271/28 20130101; A61P
25/34 20180101; A61P 31/04 20180101; C07D 265/30 20130101; A61P
25/02 20180101; C07D 207/09 20130101; A61P 25/00 20180101; A61P
27/16 20180101; A61P 25/14 20180101 |
Class at
Publication: |
514/231.2 ;
564/218; 560/24; 558/241; 544/335; 546/290; 549/29; 549/72;
544/106; 514/625; 514/277; 514/438 |
International
Class: |
A61K 31/167 20060101
A61K031/167; C07C 233/01 20060101 C07C233/01; C07C 271/28 20060101
C07C271/28; C07C 333/08 20060101 C07C333/08; C07D 239/02 20060101
C07D239/02; C07D 213/63 20060101 C07D213/63; C07D 333/02 20060101
C07D333/02; C07D 333/22 20060101 C07D333/22; C07D 265/30 20060101
C07D265/30; A61P 25/00 20060101 A61P025/00; A61P 25/22 20060101
A61P025/22; A61P 25/06 20060101 A61P025/06; A61P 25/30 20060101
A61P025/30; A61K 31/5375 20060101 A61K031/5375; A61K 31/44 20060101
A61K031/44; A61K 31/381 20060101 A61K031/381 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 13, 2004 |
DK |
PA200401394 |
Claims
1. A compound having the general formula I: ##STR00019## wherein: Z
is O or S; q is 1; R.sup.1 and R.sup.2 are each independently
selected from the group consisting of halogen, cyano, amino,
C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl,
halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yloxy, C.sub.3-8-cycloalk(en)yloxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy, and
C.sub.3-8-heterocycloalk(en)yloxy; R.sup.3 is selected from the
group consisting of C.sub.1-8-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
Aryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(en/yn-
)yl, Heteroaryl-C.sub.1-6-alk(en/yn)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
amino-C.sub.1-6-alk(en/yn)yl, amino-C.sub.3-8-cycloalk(en)yl,
amino-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yloxy-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yloxy-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy-C.sub.1-6-alk(en/yn)yl-
, halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl and
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl; and R.sup.4
is selected from the group consisting of halogen, cyano,
C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
Aryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.3-8-heterocycloalk(en)yl, halo-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(-
en/yn)yl, NR.sup.5R.sup.6 and R.sup.7NH--C.sub.1-6-alk(en/yn)yl;
wherein; R.sup.5 and R.sup.6 are each independently selected from
the group consisting of hydrogen, Aryl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.3-8-cycloalk(en)yl,
Aryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Heteroaryl-C.sub.1-6-alk(en/yn)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl and
Heteroaryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl, with
the proviso that R.sup.5 and R.sup.6 can not both be hydrogen; and
R.sup.7 is selected from the group consisting of
C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl, Aryl,
halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl and
Heteroaryl; or Z is O or S; q is 0; R.sup.1 and R.sup.2 are each
independently selected from the group consisting of
C.sub.3-8-heterocycloalk(en)yl, Heteroaryl, and
C.sub.3-8-heterocycloalk(en)yloxy; R.sup.3 is selected from the
group consisting of
C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(en/yn-
)yl, Heteroaryl-C.sub.1-6-alk(en/yn)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl, and
Heteroaryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-16-alk(en/yn)yl; and
R.sup.4 is selected from the group consisting of
C.sub.3-8-heterocycloalk(en)yl, Heteroaryl,
Aryl-C.sub.3-8-heterocycloalk(en)yl,
halo-C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(-
en/yn)yl, NR.sup.5R.sup.6 and R.sup.7NH--C.sub.1-6-alk(en/yn)yl;
wherein: R.sup.5 and R.sup.6 are each independently selected from
the group consisting of Heteroaryl-C.sub.1-6-alk(en/yn)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl and
Heteroaryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl and
R.sup.7 is Heteroaryl; or a pharmaceutically acceptable salt
thereof.
2. The compound according to claim 1, wherein R.sup.1 and R.sup.2
are each independently selected from the group consisting of
halogen, amino, C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl and
halo-C.sub.1-6-alk(en/yn)yl.
3. The compound according to claim 1, wherein q is 0.
4. The compound according to claim 1, wherein q is 1.
5. The compound according to claim 4, wherein Z is an oxygen
atom.
6. The compound according to claim 1, wherein R.sup.3 is selected
from the group consisting of C.sub.1-8-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
Heteroaryl-C.sub.1-6-alk(en/yn)yl and
amino-C.sub.1-6-alk(en/yn)yl.
7. The compound according to claim 1, wherein R.sup.4 is selected
from the group consisting of halogen, C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Heteroaryl,
Aryl-C.sub.3-8-heterocycloalk(en)yl, NR.sup.5R.sup.6 and
R.sup.7NH--C.sub.1-6-alk(en/yn)yl, wherein R.sup.5, R.sup.6 and
R.sup.7 are as previously defined.
8. The compound according to claim 7, wherein R.sup.4 is
NR.sup.5R.sup.6 and R.sup.5 and R.sup.6 are each independently
selected from the group consisting of hydrogen,
Aryl-C.sub.1-6-alk(en/yn)yl, C.sub.1-6-alk(en/yn)yl and
Heteroaryl-C.sub.1-6-alk(en/yn)yl with the proviso that R.sup.5 and
R.sup.6 cannot both be hydrogen.
9. The compound according to claim 7, wherein R.sup.4 is
R.sup.7NH--C.sub.1-6-alk(en/yn)yl and R.sup.7 is Aryl.
10. The compound according to claim 1, wherein any Aryl is
optionally substituted with one or more substituents independently
selected from the group consisting of amino, halogen, cyano,
C.sub.1-6-alk(en/yn)yl, halo-C.sub.1-6-alk(en/yn)yl, hydroxy,
C.sub.1-6-alk(en/yn)yloxy, halo-C.sub.1-6-alk(en/yn)yloxy,
di-(C.sub.1-6-alk(en/yn)yl)amino, C.sub.1-6-alk(en/yn)yl-CO--NH--
and C.sub.1-6-alk(en/yn)yl-sulfonamide; or two adjacent
substituents may together with the Aryl group to which they are
attached form a 4-8 membered ring, which optionally contains one or
two heteroatoms and is optionally substituted with one or more
C.sub.1-6-alk(en/yn)yl groups.
11. The compound according to claim 1, wherein any Heteroaryl is
optionally substituted with one or more substituents independently
selected from the group consisting of halogen,
halo-C.sub.1-6-alk(en/yn)yl, C.sub.1-6-alk(en/yn)yl, Aryl,
C.sub.1-6-alk(en/yn)yloxy and C.sub.1-6-alk(en/yn)yl-phenoxy.
12. The compound according to claim 1, wherein the compound is
being selected from the group consisting of:
N-(4-Bromo-2,6-dimethyl-phenyl)-2-thiophen-2-yl-acetamide,
2-Bicyclo[2.2.1]hept-2-yl-N-(2,4-difluoro-6-morpholin-4-yl-phenyl)-acetam-
ide,
2-Cyclopentyl-N-{2,6-dimethyl-4-[2-(4-trifluoromethyl-phenyl)-pyrroli-
din-1-yl]-phenyl}-acetamide,
N-(4-Azepan-1-yl-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide,
2-Cyclopentyl-N-(2,6-dimethyl-4-pyrrol-1-yl-phenyl)-acetamide,
N-(2,4-Dimethyl-6-quinolin-3-yl-phenyl)-2-(4-fluoro-phenyl)-acetamide,
N-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-4,6-dimethyl-phenyl]-2-(4-fluoro-
-phenyl)-acetamide,
N-[2,4-Dimethyl-6-(2,2,5-trimethyl-2,3-dihydro-benzofuran-7-yl)-phenyl]-2-
-(4-fluoro-phenyl)-acetamide,
{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester,
[4-(4-Fluoro-benzylamino)-2,6-dimethyl-phenyl]-carbamic acid propyl
ester,
[2,6-Dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic
acid propyl ester,
[4-(3-Fluoro-4-trifluoromethyl-benzylamino)-2,6-dimethyl-phenyl]-carbamic
acid propyl ester,
{2,6-Dimethyl-4-[(4-methyl-2-phenyl-pyrimidin-5-ylmethyl)-amino]-phenyl}--
carbamic acid propyl ester,
{2,6-Dimethyl-4-[(6-p-tolyloxy-pyridin-3-ylmethyl)-amino]-phenyl}-carbami-
c acid propyl ester,
{4-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester,
{4-[(3-Fluoro-4-trifluoromethyl-benzyl)-methyl-amino]-2,6-dimethyl-phenyl-
}-carbamic acid propyl ester,
2-Cyclopentyl-N-{2,6-dimethyl-4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-a-
mino]-phenyl}-acetamide,
N-{2,6-Dimethyl-4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-phenyl}--
3,3-dimethyl-butyramide,
N-{2-Bromo-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-6-trifluoromethyl-phe-
nyl}-3-cyclohexyl-propionamide,
{4-[(3-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid ethyl ester,
{2,6-Dimethyl-4-[(4-trifluoromethyl-phenylamino)-methyl]-phenyl}-carbamic
acid ethyl ester,
{4-[(4-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester,
{4-[(4-Chloro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester,
{2,6-Dimethyl-4-[(4-trifluoromethyl-phenylamino)-methyl]-phenyl}-carbamic
acid propyl ester,
{4-[(3,5-Difluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester,
{4-[(3-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester,
N-(4-Bromo-2-methyl-6-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide,
{4-[(4-Methoxyphenylamino)-methyl]-2,6-dimethylphenyl}-carbamic
acid propyl ester,
{2,6-Dimethyl-4-[(4-trifluoromethylphenylamino)-methyl]-phenyl}-carbamic
acid 2-methoxyethyl ester,
N-{4-[(5-Chloro-pyridin-2-ylamino)-methyl]-2,6-dimethylphenyl}-2-cyclopen-
tylacetamide,
2-Cyclopentyl-N-{4-[(2,6-dichloro-pyridin-4-ylamino)-methyl]-2,6-dimethyl-
phenyl}-acetamide,
N-{2-Chloro-6-methyl-4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-phe-
nyl}-2-(3-fluoro-phenyl)-acetamide,
3,3-Dimethyl-N-[2-methyl-6-morpholin-4-yl-4-(4-trifluoromethylbenzylamino-
)-phenyl]-butyramide, and
2-Cyclopentyl-N-{2,6-dichloro-4-[(5-trifluoromethylpyridin-2-ylamino)-met-
hyl]-phenyl}-acetamide; or a pharmaceutically acceptable salt
thereof.
13. A pharmaceutical composition comprising one or more
pharmaceutically acceptable carriers or diluents; and a compound of
claim 1 or a pharmaceutically acceptable salt thereof.
14. A method of increasing ion flow in a potassium channel of a
mammal, the method comprising administering the composition of
claim 13 to the mammal.
15. The method according to claim 14, wherein the method is for the
treatment of a disorder or disease being responsive to an increased
ion flow in a potassium channel, and a therapeutically effective
amount of the composition is administered.
16. The method according to claim 15, wherein the disorder or
disease to be treated is selected from the group consisting of a
seizure disorder, an anxiety disorder, a neuropathic pain disorder,
a migraine pain disorder, a neurodegenerative disorder, stroke,
cocaine abuse, nicotine withdrawal, ethanol withdrawal and
tinnitus.
17. The method according to claim 16, wherein the seizure disorder
is selected from the group consisting of acute seizure, convulsion,
status epilepticus, epilepsy, an epileptic syndrome and an
epileptic seizure.
18. The method according to claim 16, wherein the anxiety disorder
is selected from the group consisting of anxiety, a disease or
disorder related to panic attack, agoraphobia, panic disorder with
agoraphobia, panic disorder without agoraphobia, agoraphobia
without a history of panic disorder, specific phobia, social
phobia, a phobia, obsessive-compulsive disorder, post-traumatic
stress disorder, an acute stress disorder, generalized anxiety
disorder, anxiety disorder due to general medical condition,
substance-induced anxiety disorder, separation anxiety disorder, an
adjustment disorder, performance anxiety, a hypochondriacal
disorder disorders, an anxiety disorder due to a general medical
condition, substance-induced anxiety disorder and anxiety disorder
not otherwise specified.
19. The method according to claim 16, wherein the neuropathic pain
disorder and migraine pain disorder is selected from the group
consisting of allodynia, hyperalgesic pain, phantom pain,
neuropathic pain related to diabetic neuropathy, neuropathic pain
related to trigeminal neuralgia and neupathic pain related to
migraine.
20. The method according to claim 16, wherein the neurodegenerative
disorder is e selected from the group consisting of Alzheimer's
disease, Huntington's chorea, multiple sclerosis, amyotrophic
lateral sclerosis, Creutzfeld-Jakob's disease, Parkinson's disease,
an encephalopathy induced by AIDS, an encephalopathy induced by
rubella viruses, a herpes virus, borrelia, a trauma-induced
neurodegeneration, a neuronal hyperexcitation state and a
neurodegenerative disease of the peripheral nervous system.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compounds, which are
openers of the KCNQ family potassium ion channels. The compounds
are useful in the treatment of disorders and diseases being
responsive to opening of the KCNQ family potassium ion channels,
one such disease is epilepsy.
BACKGROUND OF THE INVENTION
[0002] Ion channels are cellular proteins that regulate the flow of
ions, including potassium, calcium, chloride and sodium into and
out of cells. Such channels are present in all animal and human
cells and affect a variety of processes including neuronal
transmission, muscle contraction, and cellular secretion.
[0003] Humans have over 70 genes encoding potassium channel
subtypes (Jentsch Nature Reviews Neuroscience 2000, 1, 21-30) with
a great diversity with regard to both structure and function.
Neuronal potassium channels, which are found in the brain, are
primarily responsible for maintaining a negative resting membrane
potential, as well as controlling membrane repolarisation following
an action potential.
[0004] One subset of potassium channel genes is the KCNQ family.
Mutations in four out of five KCNQ genes have been shown to
underlie diseases including cardiac arrhythmias, deafness and
epilepsy (Jentsch Nature Reviews Neuroscience 2000, 1, 21-30).
[0005] The KCNQ4 gene is thought to encode the molecular correlate
of a potassium channel found in outer hair cells of the cochlea and
in Type 1 hair cells of the vestibular apparatus, in which,
mutations can lead to a form of inherited deafness.
[0006] KCNQ1 (KvLQT1) is co-assembled with the product of the KCNE1
(minimal K(+)-channel protein) gene in the heart to form a
cardiac-delayed rectifier-like K(+) current. Mutations in this
channel can cause one form of inherited long QT syndrome type 1
(LQT1), as well as being associated with a form of deafness
(Robbins Pharmacol Ther 2001, 90, 1-19).
[0007] The genes KCNQ2 and KCNQ3 were discovered in 1988 and appear
to be mutated in an inherited form of epilepsy known as benign
familial neonatal convulsions (Rogawski Trends in Neurosciences
2000, 23, 393-398). The proteins encoded by the KCNQ2 and KCNQ3
genes are localised in the pyramidal neurons of the human cortex
and hippocampus, regions of the brain associated with seizure
generation and propagation (Cooper et al. Proceedings National
Academy of Science USA 2000, 97, 4914-4919).
[0008] KCNQ2 and KCNQ3 are two potassium channel subunits that form
"M-currents" when expressed in vitro. The M-current is a
non-inactivating potassium current found in many neuronal cell
types. In each cell type, it is dominant in controlling membrane
excitability by being the only sustained current in the range of
action potential initiation (Marrion Annual Review Physiology 1997,
59, 483-504). Modulation of the M-current has dramatic effects on
neuronal excitability, for example activation of the current will
reduce neuronal excitability. Openers of these KCNQ channels, or
activators of the M-current, will reduce excessive neuronal
activity and may thus be of use in the treatment of seizures and
other diseases and disorders characterised by excessive neuronal
activity, such as neuronal hyperexcitability including convulsive
disorders, epilepsy and neuropathic pain.
[0009] Retigabine (D-23129;
N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl
ester) and analogues thereof are disclosed in EP554543. Retigabine
is an anti-convulsive compound with a broad spectrum and potent
anticonvulsant properties, both in vitro and in vivo. It is active
after oral and intraperitoneal administration in rats and mice in a
range of anticonvulsant tests including: electrically induced
seizures, seizures induced chemically by pentylenetetrazole,
picrotoxin and N-methyl-D-aspartate (NMDA) and in a genetic animal
model, the DBA/2 mouse (Rostock et al. Epilepsy Research 1996, 23,
211-223). In addition, retigabine is active in the amygdala
kindling model of complex partial seizures, further indicating that
this compound has potential for anti-convulsive therapy. In
clinical trials, retigabine has recently shown effectiveness in
reducing the incidence of seizures in epileptic patients (Bialer et
al. Epilepsy Research 2002, 51, 31-71).
[0010] Retigabine has been shown to activate a K(+) current in
neuronal cells and the pharmacology of this induced current
displays concordance with the published pharmacology of the
M-channel, which recently was correlated to the KCNQ2/3 K(+)
channel heteromultimer. This suggests that activation of KCNQ2/3
channels may be responsible for some of the anticonvulsant activity
of this agent (Wickenden et al. Molecular Pharmacology 2000, 58,
591-600) and that other agents working by the same mechanism may
have similar uses.
[0011] KCNQ 2 and 3 channels have also been reported to be
upregulated in models of neuropathic pain (Wickenden et al. Society
for Neuroscience Abstracts 2002, 454.7), and potassium channel
modulators have been hypothesized to be active in both neuropathic
pain and epilepsy (Schroder et al. Neuropharmacology 2001, 40,
888-898).
[0012] Retigabine has also been shown to be beneficial in animal
models of neuropathic pain (Black burn-Munro and Jensen European
Journal of Pharmacology 2003, 460, 109-116), and it is thus
suggested that openers of KCNQ channels will be of use in treating
pain disorders including neuropathic pain.
[0013] The localisation of KCNQ channel mRNA is reported in brain
and other central nervous system areas associated with pain
(Goldstein et al. Society for Neuroscience Abstracts 2003,
53.8).
[0014] In addition to a role in neuropathic pain, the expression of
mRNA for KCNQ 2-5 in the trigeminal and dorsal root ganglia and in
the trigeminal nucleus caudalis implies that openers of these
channels may also affect the sensory processing of migraine pain
(Goldstein et al. Society for Neuroscience Abstracts 2003,
53.8).
[0015] Recent reports demonstrate that mRNA for KCNQ 3 and 5, in
addition to that for KCNQ2, are expressed in astrocytes and glial
cells. Thus KCNQ 2, 3 and 5 channels may help modulate synaptic
activity in the CNS and contribute to the neuroprotective effects
of KCNQ channel openers (Noda et al., Society, for Neuroscience
Abstracts 2003, 53.9).
[0016] Retigabine and other KCNQ modulators may thus exhibit
protection against the neurodegenerative aspects of epilepsy, as
retigabine has been shown to prevent limbic neurodegeneration and
the expression of markers of apoptosis following kainic
acid-induced status epilepticus in the rat (Ebert et al. Epilepsia
2002, 43 Suppl 5, 86-95). This may have relevance for preventing
the progression of epilepsy in patients, i.e. be
anti-epileptogenic. Retigabine has also been shown to delay the
progression of hippocampal kindling in the rat, a further model of
epilepsy development (Tober et al. European Journal Of Pharmacology
1996, 303, 163-169).
[0017] It is thus suggested that these properties of retigabine and
other KCNQ modulators may prevent neuronal damage induced by
excessive neuronal activation, and such compounds may be of use in
the treatment of neurodegenerative diseases, and be disease
modifying (or antiepileptogenic) in patients with epilepsy.
[0018] Given that anticonvulsant compounds such as benzodiazepines
and chlormethiazole are used clinically in the treatment of the
ethanol withdrawal syndrome and that other anticonvulsant compounds
e.g. gabapentin, are very effective in animal models of this
syndrome (Watson et al. Neuropharmacology 1997, 36, 1369-1375),
other anticonvulsant compounds such as KCNQ openers are thus
expected to be effective in this condition.
[0019] mRNA for KCNQ 2 and 3 subunits are found in brain regions
associated with anxiety and emotional behaviors such as bipolar
disorder e.g. hippocampus and amygdala (Saganich et al. Journal of
Neuroscience 2001, 21, 4609-4624), and retigabine is reportedly
active in some animal models of anxiety-like behavior (Hartz et al.
Journal of Psychopharmacology 2003, 17 suppl 3, A28,B16), and other
clinically used anticonvulsant compounds are used in the treatment
of bipolar disorder. Thus, KCNQ openers may be useful for the
treatment of anxiety disorders and bipolar disorder.
[0020] WO 200196540 discloses the use of modulators of the
M-current formed by expression of KCNQ2 and KCNQ3 genes for
insomnia, while WO 2001092526 discloses that modulators of KCNQ5
can be utilized for the treatment of sleep disorders.
[0021] WO01/022953 describes the use of retigabine for prophylaxis
and treatment of neuropathic pain such as allodynia, hyperalgesic
pain, phantom pain, neuropathic pain related to diabetic neuropathy
and neuropathic pain related to migraine.
[0022] WO02/049628 describes the use of retigabine for the
treatment of anxiety disorders such as anxiety, generalized anxiety
disorder, panic anxiety, obsessive compulsive disorder, social
phobia, performance anxiety, post-traumatic stress disorder, acute
stress reaction, adjustment disorders, hypochondriacal disorders,
separation anxiety disorder, agoraphobia and specific phobias.
[0023] WO97/15300 describes the use of retigabine for the treatment
of neurodegenerative disorders such as Alzheimer's disease;
Huntington's chorea; sclerosis such as multiple sclerosis and
amyotrophic lateral sclerosis; Creutzfeld-Jakob disease;
Parkinson's disease; encephalopathies induced by AIDS or infection
by rubella viruses, herpes viruses, borrelia and unknown pathogens;
trauma-induced neurodegenerations; neuronal hyperexcitation states
such as in medicament withdrawal or intoxication; and
neurodegenerative diseases of the peripheral nervous system such as
polyneuropathies and polyneuritides.
[0024] KCNQ channel openers have also been found to be effective in
the treatment of stroke, therefore it can be expected that
selective KCNQ openers are effective in the treatment of stroke
(Schroder et al., Pflugers Arch., 2003; 446(5):607-16; Cooper and
Jan, Arch Neurol., 2003, 60(4):496-500; Jensen, CNS Drug Rev. 2002,
8(4):353-60).
[0025] KCNQ channels have been shown to be expressed in
dopaminergic and cholinergic circuits in the brain that are
associated with the brain's reward system, particularly the ventral
tegmental area (Cooper et al., J Neurosci, 2001, 21, 9529-9540).
Therefore, KCNQ channel openers are expected to be effective in
hyperexcitability disorders that involve the brain's reward system
such as cocaine abuse, nicotine withdrawal and ethanol
withdrawal.
[0026] Potassium channels comprised of the KCNQ4 subunits are
expressed in the inner ear (Kubisch et al. Cell., 1999 Feb. 5;
96(3):437-46) and opening of these channels is therefore expected
to treat tinnitus.
[0027] Hence, there is a great desire for novel compounds which are
potent openers of the KCNQ family of potassium channels.
[0028] Also desired are novel compounds with improved properties
relative to known compounds, which are openers of the KCNQ family
potassium channels, such as retigabine.
[0029] Improvement of one or more of the following parameters is
desired:
half-life, clearance, selectivity, interactions with other
medications, bioavailability, potency, formulability, chemical
stability, metabolic stability, membrane permeability, solubility
and therapeutic index. The improvement of such parameters may lead
to improvements such as: [0030] an improved dosing regime by
reducing the number of required doses a day, [0031] ease of
administration to patients on multiple medications, [0032] reduced
side effects, [0033] enlarged therapeutic index, [0034] improved
tolerability or [0035] improved compliance.
SUMMARY OF THE INVENTION
[0036] One object of the invention is the provision of compounds,
which are potent openers of the KCNQ family potassium channels.
[0037] The compounds of the invention are substituted aniline
derivatives of the below formula I or salts thereof
##STR00002##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, Z and q are as defined
below.
[0038] The invention provides a compound of formula I for use as a
medicament.
[0039] The invention provides a pharmaceutical composition
comprising a compound of formula I and a pharmaceutically
acceptable carrier or diluent.
[0040] The invention provides the use of a compound of formula I
for the preparation of a medicament for the treatment of seizure
disorders, anxiety disorders, neuropathic pain and migraine pain
disorders, neurodegenerative disorders, stroke, cocaine abuse,
nicotine withdrawal, ethanol withdrawal or tinnitus.
[0041] The invention furthermore concerns the use of a compound of
formula I in a method of treatment of seizure disorders, anxiety
disorders, neuropathic pain and migraine pain disorders,
neurodegenerative disorders, stroke, cocaine abuse, nicotine
withdrawal, ethanol withdrawal or tinnitus.
DEFINITION OF SUBSTITUENTS
[0042] The term heteroatom refers to a nitrogen, oxygen or sulphur
atom.
[0043] Halogen means fluoro, chloro, bromo or iodo.
[0044] Amino means NH.sub.2.
[0045] The expression "C.sub.1-6-alk(en/yn)yl" means
C.sub.1-6-alkyl, C.sub.2-6-alkenyl or C.sub.2-6-alkynyl. The term
"C.sub.1-6-alkyl" refers to a branched or unbranched alkyl group
having from one to six carbon atoms inclusive, including but not
limited to methyl, ethyl, prop-1-yl, prop-2-yl, 2-methyl-prop-1-yl,
2-methyl-prop-2-yl, 2,2-dimethyl-prop-1-yl, but-1-yl, but-2-yl,
3-methyl-but-1-yl, 3-methyl-but-2-yl, pent-1-yl, pent-2-yl,
pent-3-yl, hex-1-yl, hex-2-yl and hex-3-yl. The term
"C.sub.2-6-alkenyl" designates such groups having from two to six
carbon atoms and one double bond, including but not limited to
ethenyl, propenyl, and butenyl. The term "C.sub.2-6-alkynyl"
designates such groups having from two to six carbon atoms and one
triple bond, including but not limited to ethynyl, propynyl and
butynyl.
[0046] The expression "C.sub.1-8-alk(en/yn)yl" means
C.sub.1-8-alkyl, C.sub.2-8-alkenyl or C.sub.2-8-alkynyl. The term
"C.sub.1-8-alkyl" refers to a branched or unbranched alkyl group
having from one to eight carbon atoms inclusive, including but not
limited to methyl, ethyl, prop-1-yl, prop-2-yl, 2-methyl-prop-1-yl,
2-methyl-prop-2-yl, 2,2-dimethyl-prop-1-yl, but-1-yl, but-2-yl,
3-methyl-but-1-yl, 3-methyl-but-2-yl, pent-1-yl, pent-2-yl,
pent-3-yl, hex-1-yl, hex-2-yl and hex-3-yl, 1-heptyl, 2-heptyl,
3-heptyl and 4-heptyl. The term "C.sub.2-8-alkenyl" designates such
groups having from two to eight carbon atoms and one double bond,
including but not limited to ethenyl, propenyl, and butenyl. The
term "C.sub.2-8-alkynyl" designates such groups having from two to
eight carbon atoms and one triple bond, including but not limited
to ethynyl, propynyl and butynyl.
[0047] The expression "C.sub.3-8-cycloalk(en)yl" means
C.sub.3-8-cycloalkyl or C.sub.3-8-cycloalkenyl. The term
"C.sub.3-8-cycloalkyl" designates a monocyclic or bicyclic
carbocycle having three to eight C-atoms, including but not limited
to cyclopropyl, cyclopentyl, cyclohexyl, bicycloheptyl such as
2-bicyclo[2.2.1]heptyl. The term "C.sub.3-8-cycloalkenyl"
designates a monocyclic or bicyclic carbocycle having three to
eight C-atoms and one double bond, including but not limited to
cyclopropenyl, cyclopentenyl and cyclohexenyl.
[0048] The term "C.sub.3-8-heterocycloalk(en)yl" means
C.sub.3-8-heterocycloalkyl or C.sub.3-8-heterocycloalkenyl. The
term "C.sub.3-8-heterocycloalkyl" designates a monocyclic or
bicyclic ring system wherein the ring is formed by 3 to 8 atoms
selected from 2-7 carbon atoms and 1 or 2 heteroatoms independently
selected from N, S, or O. Examples of C.sub.3-8-heterocycloalkyles
are pyrrolidine, azepan, morpholine and piperidine. The term
"C.sub.3-8-heterocycloalkenyl" designates a monocyclic or bicyclic
ring system with one double bond, wherein the ring is formed by 3
to 8 atoms selected from 2-7 carbon atoms and 1 or 2 heteroatoms
independently selected from N, S, or O.
[0049] The term Aryl refers to monocyclic or bicyclic aromatic
systems of 5-10 carbon atoms, including but not limited to phenyl
and naphthyl. Any Aryl which is mentioned either alone or as a part
of a larger substituent is optionally substituted and may thus be
substituted with one or more substituents such as with 0, 1, 2, 3
or 4 substituents. Any Aryl which is mentioned either alone or as a
part of a larger substituent may thus be substituted with one or
more substituents independently selected from the group consisting
of amino, halogen, cyano, C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl,
C.sub.1-6-alkyl-C.sub.3-8-heterocycloalk(en)yl, hydroxy,
C.sub.1-6-alk(en/yn)yloxy, C.sub.3-8-cycloalk(en)yloxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy,
halo-C.sub.1-6-alk(en/yn)yloxy, halo-C.sub.3-8-cycloalk(en)yloxy,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy,
C.sub.1-6-alk(en/yn)ylamino, di-(C.sub.1-6-alk(en/yn)yl)amino,
C.sub.1-6-alk(en/yn)yl--CO--NH-- and
C.sub.1-6-alk(en/yn)yl-sulfonamide; or two adjacent substituents
may together with the Aryl group to which they are attached form a
4-8 membered ring, which optionally contains one or two heteroatoms
and which is optionally substituted with one or more
C.sub.1-6-alk(en/yn)yl groups. When two adjacent substituents
together with the Aryl group to which they are attached form a 4-8
membered ring, which optionally contains one or two heteroatoms,
then a ring system is formed by 4-8 atoms selected from 3-8 carbon
atoms and 0-2 heteroatoms independently selected from N, S, or O,
Such two adjacent substituents may together form:
--(CH.sub.2).sub.n--O--, --O--(CH.sub.2).sub.m--O--,
--CH.sub.2--O--(CH.sub.2).sub.p--O--,
--CH.sub.2--O--CH.sub.2--O--CH.sub.2--,
--O--C(CH.sub.3).sub.2--(CH.sub.2).sub.m--,
--(CH.sub.2).sub.n--S--, --S--(CH.sub.2).sub.m--S--,
--CH.sub.2--S--(CH.sub.2).sub.p--S-- or
--CH.sub.2--S--CH.sub.2--S--CH.sub.2--,
--S--C(CH.sub.3).sub.2--(CH.sub.2).sub.m--; wherein m is 1, 2 or 3,
n is 2, 3 or 4 and p is 1 or 2.
[0050] The term "Heteroaryl" refers to monocyclic or bicyclic
heteroaromatic systems of 5-10 atoms selected from 1, 2, 3, 4, 5,
6, 7, 8 or 9 carbon atoms and 1, 2, 3 or 4 heteroatoms
independently selected from N, S, or O, including but not limited
to pyridine, pyrrole, pyrimidine, quinoline, indole, thiophene,
furan, imidazoles such as 3H-imidazol and 1H-imidazol, triazoles
such as [1,2,3]triazole and [1,2,4]triazole, tetrazoles such as
2H-tetrazole and oxazole. Any Heteroaryl which is mentioned either
alone or as a part of a larger substituent is optionally
substituted and may thus be substituted with one or more
substituents such as with 0, 1, 2, 3 or 4 substituents. Any
Heteroaryl which is mentioned either alone or as a part of a larger
substituent may thus be substituted with one or more substituents
independently selected from the group consisting of halogen, cyano,
amino, halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl, Aryl,
Aryl-C.sub.1-6-alk(en/yn)yl, C.sub.1-6-alk(en/yn)yloxy,
C.sub.3-8-cycloalk(en)yloxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy,
C.sub.1-6-alk(en/yn)yl-phenoxy, C.sub.3-8-cycloalk(en)yl-phenoxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl-phenoxy,
amino-phenoxy, halo-phenoxy, cyano-phenoxy,
halo-C.sub.1-6-alk(en/yn)yl-phenoxy,
halo-C.sub.3-8-cycloalk(en)yl-phenoxy,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl-phenoxy,
C.sub.3-8-heterocycloalk(en)yl-phenoxy,
C.sub.1-6-alkyl-C.sub.3-8-heterocycloalk(en)yl-phenoxy,
hydroxy-phenoxy, C.sub.1-6-alk(en/yn)yloxy-phenoxy,
C.sub.1-6-cycloalk(en)yloxy-phenoxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy-phenoxy,
halo-C.sub.1-6-alk(en/yn)yloxy-phenoxy,
halo-C.sub.3-8-cycloalk(en)yloxy-phenoxy,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy-phenoxy,
C.sub.1-6-alk(en/yn)ylamino-phenoxy,
di-(C.sub.1-6-alk(en/yn)yl)amino-phenoxy,
C.sub.1-6-alk(en/yn)yl-CO--NH-phenoxy and
C.sub.1-6-alk(en/yn)yl-sulfonamide-phenoxy.
[0051] The term "halo-C.sub.1-6-alk(en/yn)yl" designates
C.sub.1-6-alk(en/yn)yl being substituted with one or more halogen
atoms, including but not limited to trifluoromethyl and
3,3,3-trifluoro-1-propyl. Similarly, halo-C.sub.3-8-cycloalk(en)yl
designates C.sub.3-8-cycloalk(en)yl being substituted with one or
more halogen atoms and "halo-phenoxy" designates phenoxy being
substituted with one or more halogen atoms.
[0052] The term "amino-C.sub.1-6-alk(en/yn)yl" designates
C.sub.1-6-alk(en/yn)yl being substituted with one amino group,
including but not limited to 1-amino-2-methyl-prop-1-yl and
1-amino-3-methyl-but-1-yl. Similarly,
amino-C.sub.3-8-cycloalk(en)yl designates C.sub.3-8-cycloalk(en)yl
being substituted with one amino group and
amino-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl designates
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl being wherein
C.sub.3-8-cycloalk(en)yl is substituted with one amino group.
[0053] In the expressions
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(en/yn-
)yl, Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
Aryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.3-8-heterocycloalk(en)yl,
Heteroaryl-C.sub.1-6-alk(en/yn)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(-
en/yn)yl, C.sub.1-6-alk(en/yn)yloxy, C.sub.3-8-cycloalk(en)yloxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy,
C.sub.3-8-heterocycloalk(en)yloxy,
C.sub.1-6-alk(en/yn)yloxy-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yloxy-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy-C.sub.1-6-alk(en/yn)yl-
, halo-C.sub.1-6-alk(en/yn)yloxy, halo-C.sub.3-8-cycloalk(en)yloxy,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy,
amino-C.sub.1-6-alk(en/yn)yl, amino-C.sub.3-8-cycloalk(en)yl,
amino-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
R.sup.7NH--C.sub.1-6-alk(en/yn)yl, C.sub.1-6-alk(en/yn)ylamino,
di-(C.sub.1-6-alk(en/yn)yl)amino, C.sub.1-6-alk(en/yn)yl-CO--NH--,
C.sub.1-6-alk(en/yn)yl-sulfonamide C.sub.1-6-alk(en/yn)yl-phenoxy,
C.sub.3-8-cycloalk(en)yl-phenoxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl-phenoxy,
halo-phenoxy, halo-C.sub.1-6-alk(en/yn)yl-phenoxy,
halo-C.sub.3-8-cycloalk(en)yl-phenoxy,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl-phenoxy,
C.sub.3-8-heterocycloalk(en)yl-phenoxy,
C.sub.1-6-alkyl-C.sub.3-8-heterocycloalk(en)yl-phenoxy,
C.sub.1-6-alk(en/yn)yloxy-phenoxy,
C.sub.3-8-cycloalk(en)yloxy-phenoxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy-phenoxy,
halo-C.sub.1-6-alk(en/yn)yloxy-phenoxy,
halo-C.sub.3-8-cycloalk(en)yloxy-phenoxy,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy-phenoxy,
C.sub.1-6-alk(en/yn)ylamino-phenoxy,
di-(C.sub.1-6-alk(en/yn)yl)amino-phenoxy,
C.sub.1-6-alk(en/yn)yl-CO--NH-phenoxy and
C.sub.1-6-alk(en/yn)yl-sulfonamide-phenoxy the terms
"C.sub.1-6-alk(en/yn)yl", "C.sub.3-8-cycloalk(en)yl",
"C.sub.3-8-heterocycloalk(en)yl", "Aryl", "Heteroaryl",
"halo-C.sub.1-6-alk(en/yn)yl", "halo-C.sub.3-8-cycloalk(en)yl",
"halo-phenoxy", "amino-C.sub.1-6-alk(en/yn)yl",
"amino-C.sub.3-8-cycloalk(en)yl" and
"amino-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl" are as
defined above.
[0054] Any C.sub.1-6-alk(en/yn)yl which is mentioned either alone
or as a part of a larger substituent independently contains 1, 2,
3, 4, 5 or 6 carbon atoms.
[0055] Any C.sub.1-8-alk(en/yn)yl which is mentioned either alone
or as a part of a larger substituent independently contains 1, 2,
3, 4, 5, 6, 7 or 8 carbon atoms.
[0056] Any C.sub.3-8-cycloalk(en)yl which is mentioned either alone
or as a part of a larger substituent independently contains 3, 4,
5, 6, 7 or 8 carbon atoms.
[0057] Any C.sub.3-8-heterocycloalk(en)yl which is mentioned either
alone or as a part of a larger substituent independently contains
2, 3, 4, 5, 6 or 7 carbon atoms and 1 or 2 heteroatoms. Any Aryl
which is mentioned either alone or as a part of a larger
substituent independently contains 5, 6, 7, 8, 9 or 10 carbon
atoms.
[0058] Any Heteroaryl which is mentioned either alone or as a part
of a larger substituent independently contains 5, 6, 7, 8, 9 or 10
atoms selected from 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and 1,
2, 3 or 4 heteroatoms.
DESCRIPTION OF THE INVENTION
[0059] The present invention relates to substituted aniline
derivatives which are potent openers of KCNQ potassium
channels.
[0060] The present invention relates to a compound represented by
the general formula I or salts thereof:
##STR00003##
wherein
Z is O or S;
[0061] q is 0 or 1: each of R.sup.1 and R.sup.2 is independently
selected from the group consisting of halogen, cyano, amino,
C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl,
halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yloxy, C.sub.3-8-cycloalk(en)yloxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy,
C.sub.3-8-heterocycloalk(en)yloxy;
[0062] R.sup.3 is selected from the group consisting of
C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
Aryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(en/yn-
)yl, Heteroaryl-C.sub.1-6-alk(en/yn)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
amino-C.sub.1-6-alk(en/yn)yl, amino-C.sub.3-8-cycloalk(en)yl,
amino-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yloxy-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yloxy-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy-C.sub.1-6-alk(en/yn)yl-
, halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl and
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl; R.sup.4 is
selected from the group consisting of halogen, cyano,
C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
Aryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.3-8-heterocycloalk(en)yl, halo-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(-
en/yn)yl, NR.sup.5R.sup.6 and R.sup.7NH--C.sub.1-6-alk(en/yn)yl;
wherein R.sup.5 and R.sup.6 are independently selected from the
group consisting of hydrogen, Aryl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.3-8-cycloalk(en)yl,
Aryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Heteroaryl-C.sub.1-6-alk(en/yn)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl and
Heteroaryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yl with the
proviso that R.sup.5 and R.sup.6 are not hydrogen at the same time;
and R.sup.7 is selected from the group consisting of
C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl, Aryl,
halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl and
Heteroaryl.
[0063] In one embodiment of the compound of formula I R.sup.1 is
selected from the group consisting of C.sub.1-6-alk(en/yn)yloxy,
C.sub.3-8cycloalk(en)yloxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy,
C.sub.3-8-heterocycloalk(en)yloxy;
in a further embodiment of the compound of formula I R.sup.1 is
selected from the group consisting of halogen, cyan, amino,
C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl,
halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl and
C.sub.1-6-alk(en/yn)yloxy; in a further embodiment of the compound
of formula I, R.sup.1 is selected from the group consisting of
halogen, amino, C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl,
halo-C.sub.1-6-alk(en/yn)yl and C.sub.1-6-alk(en/yn)yloxy.
[0064] Typically R.sup.1 is selected from the group consisting of
halogen, amino, C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl and
halo-C.sub.1-6-alk(en/yn)yl.
[0065] In one embodiment of the compound of formula I R.sup.2 is
selected from the group consisting of C.sub.1-6-alk(en/yn)yloxy,
C.sub.3-8-cycloalk(en)yloxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy,
C.sub.3-8-heterocycloalk(en)yloxy;
in a further embodiment of the compound of formula I R.sup.2 is
selected from the group consisting of halogen, cyano, amino,
C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl,
halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl and
C.sub.1-6-alk(en/yn)yloxy; in a further embodiment of the compound
of formula I, R.sup.2 is selected from the group consisting of
halogen, amino, C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl,
halo-C.sub.1-6-alk(en/yn)yl and C.sub.1-6-alk(en/yn)yloxy.
[0066] Typically R.sup.2 is selected from the group consisting of
halogen, amino, C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl and
halo-C.sub.1-6-alk(en/yn)yl.
[0067] To further illustrate without limiting the invention, an
embodiment concerns such compounds wherein R.sup.1 or R.sup.2 is
halogen such as chloro, bromo or fluoro; in a further embodiment
R.sup.1 and R.sup.2 are independently selected halogen atoms such
as chloro or bromo;
in a further embodiment R.sup.1 or R.sup.2 is amino; in a further
embodiment R.sup.1 or R.sup.2 is C.sub.1-6-alk(en/yn)yl such as
methyl; in a further embodiment R.sup.1 and R.sup.2 are
C.sub.1-6-alk(en/yn)yl such as methyl; in a further embodiment
R.sup.1 or R.sup.2 is C.sub.1-6-alk(en/yn)yl such as methyl and the
remainder of R.sup.1 and R.sup.2 is halogen such as chloro, or
bromo; in a further embodiment R.sup.1 or R.sup.2 is
C.sub.3-8-heterocycloalk(en)yl such as morpholinyl; in a further
embodiment R.sup.1 or R.sup.2 is optionally substituted Aryl such
as optionally substituted phenyl; in a further embodiment R.sup.1
or R.sup.2 is C.sub.1-6-alk(en/yn)yl such as methyl and the
remainder of R.sup.1 and R.sup.2 is optionally substituted Aryl
such as optionally substituted phenyl; in a further embodiment
R.sup.1 or R.sup.2 is optionally substituted Heteroaryl such as
optionally substituted quinolinyl; in a further embodiment R.sup.1
or R.sup.2 is halo-C.sub.1-6-alk(en/yn)yl such as
trifluoromethyl.
[0068] In one embodiment of the compound of formula I q is 0; in a
further embodiment q is 1.
[0069] In one embodiment of the compound of formula I q is I and Z
is an oxygen atom; in a further embodiment q is 1 and Z is a
sulphur atom.
[0070] In one embodiment of the compound of formula I R.sup.3 is
selected from the group consisting of
C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(en/yl-
, C.sub.1-6-alk(en/yn)yloxy-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yloxy-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy-C.sub.1-6-alk(en/yn)yl-
, halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl and
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl. In a further
embodiment of the compound of formula I R.sup.3 is selected from
the group consisting of C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
Aryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(en/yn-
)yl, Heteroaryl-C.sub.1-6-alk(en/yn)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
amino-C.sub.1-6-alk(en/yn)yl, amino-C.sub.3-8-cycloalk(en)yl,
amino-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl and
C.sub.1-6-alk(en/yn)yloxy-C.sub.1-6-alk(en/yn)yl. In a further
embodiment of the compound of formula I R.sup.3 is selected from
the group consisting of C.sub.1-8-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl--C.sub.1-6-alk(en/y-
n)yl, Heteroaryl-C.sub.1-6-alk(en/yn)yl,
amino-C.sub.1-6-alk(en/yn)yl and
C.sub.1-6-alk(en/yn)yloxy-C.sub.1-6-alk(en/yn)yl. Typically,
R.sup.3 is selected from the group consisting of
C.sub.1-8-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
Heteroaryl-C.sub.1-6-alk(en/yn)yl and
amino-C.sub.1-6-alk(en/yn)yl.
[0071] To further illustrate without limiting the invention, an
embodiment concerns such compounds wherein R.sup.3 is
C.sub.1-8-alk(en/yn)yl comprising 2, 3, 4, 5, 6, 7 or 8 carbon
atoms;
in a further embodiment R.sup.3 is C.sub.3-8-cycloalk(en)yl such as
cyclohexyl; in a further embodiment R.sup.3 is
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl such as
cyclopentyl-methyl, cyclohexyl-ethyl or bicycloheptyl-methyl; in a
further embodiment R.sup.3 is Aryl-C.sub.1-6-alk(en/yn)yl wherein
Aryl is optionally substituted, such as phenyl-methyl wherein
phenyl is optionally substituted; in a further embodiment R.sup.3
is Aryl-C.sub.3-8-cycloalk(en)yl wherein Aryl is optionally
substituted, such as phenyl-cyclopropyl wherein phenyl is
optionally substituted; in a further embodiment R.sup.3 is
Heteroaryl-C.sub.1-6-alk(en/yn)yl wherein Heteroaryl is optionally
substituted, such as thiophenyl-methyl wherein thiophenyl is
optionally substituted; in a further embodiment R.sup.3 is
amino-C.sub.1-6-alk(en/yn)yl such as 1-amino-2-methyl-prop-1-yl or
1-amino-3-methyl-but-1-yl.
[0072] To further illustrate without limiting the invention an
embodiment concerns such compounds of formula I wherein R.sup.3 is
not C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(en/yn)yl such as
C.sub.3-8-heterocycloalk(en)yl-methyl;
in a further embodiment R.sup.3 is not halo-methyl wherein halo
refers to e.g. chloro or bromo; in a further embodiment R.sup.3 is
not methyl; in a further embodiment q is I, Z is O and R.sup.3 is
different from 2-methyl-prop-2-yl.
[0073] In a further embodiment of the compound of formula I R.sup.4
is selected from the group consisting of
halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl and
halo-C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(-
en/yn)yl;
in a further embodiment R.sup.4 is selected from the group
consisting of halogen, cyano. C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
Aryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.3-8-heterocycloalk(en)yl,
halo-C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(-
en/yn)yl, NR.sup.5R.sup.6 and R.sup.7NH--C.sub.1-6-alk(en/yn)yl; in
a further embodiment R.sup.4 is selected from the group consisting
of halogen, C.sub.1-6-alk(en/yn)yl, C.sub.3-8-heterocycloalk(en)yl,
Heteroaryl, Aryl-C.sub.3-8-heterocycloalk(en)yl,
halo-C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl-C.sub.1-6-alk(-
en/yn)yl, NR.sup.5R.sup.6 and
R.sup.7NH--C.sub.1-6-alk(en/yn)yl.
[0074] Typically, R.sup.4 is selected from the group consisting of
halogen, C.sub.1-6-alk(en/yn)yl, C.sub.3-8-heterocycloalk(en)yl,
Heteroaryl, Aryl-C.sub.3-8-heterocycloalk(en)yl, NR.sup.5R.sup.6
and R.sup.7NH--C.sub.1-6-alk(en/yn)yl.
[0075] To further illustrate without limiting the invention, an
embodiment concerns such compounds wherein R.sup.4 is halogen, such
as bromo, chloro or fluoro;
in a further embodiment R.sup.4 is C.sub.1-6-alk(en/yn)yl, such as
methyl; in a further embodiment R.sup.4 is
C.sub.3-8-heterocycloalk(en)yl, such as azepanyl; in a further
embodiment R.sup.4 is Heteroaryl, such as pyrrolyl; in a further
embodiment R.sup.4 is Aryl-C.sub.3-8-heterocycloalk(en)yl wherein
Aryl is optionally substituted, such as phenyl-pyrrolidinyl wherein
phenyl is optionally substituted; in a further embodiment R.sup.4
is NR.sup.5R.sup.6; in a further embodiment R.sup.4 is
R.sup.7NH--C.sub.1-6-alk(en/yn)yl.
[0076] To further illustrate without limiting the invention an
embodiment concerns such compounds of formula I wherein no more
than two of the three substituents R.sup.1, R.sup.2 and R.sup.4 are
identical.
[0077] In a further embodiment of the compound of formula I R.sup.5
and R.sup.6 are independently selected from the group consisting of
Aryl-C.sub.3-8-cycloalk(en)yl,
Aryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl and
Heteroaryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl;
in a further embodiment R.sup.5 or R.sup.6 is selected from the
group consisting of Aryl-C.sub.3-8-cycloalk(en)yl,
Aryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl and
Heteroaryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl and the
remainder of R.sup.5 and R.sup.6 is selected from the group
consisting of hydrogen, Aryl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yl and Heteroaryl-C.sub.1-6-alk(en/yn)yl.
[0078] Typically R.sup.5 and R.sup.6 are independently selected
from the group consisting of hydrogen, Aryl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yl and Heteroaryl-C.sub.1-6-alk(en/yn)yl with
the proviso that R.sup.5 and R.sup.6 are not hydrogen at the same
time.
[0079] To further illustrate without limiting the invention, an
embodiment concerns such compounds wherein R.sup.5 or R.sup.6 is
hydrogen;
in a further embodiment R.sup.5 or R.sup.6 is
Aryl-C.sub.1-6-alk(en/yn)yl, such as phenyl-methyl; in a further
embodiment R.sup.5 or R.sup.6 is C.sub.1-6-alk(en/yn)yl, such as
methyl; in a further embodiment R.sup.5 or R.sup.6 is
Heteroaryl-C.sub.1-6-alk(en/yn)yl, such as thiophenyl-methyl,
pyrimidinyl-methyl or pyridinyl-methyl; in a further embodiment one
of R.sup.5 and R.sup.6 is hydrogen or C.sub.1-6-alk(en/yn)yl such
as methyl and the remainder of R.sup.5 and R.sup.6 is
Aryl-C.sub.1-6-alk(en/yn)yl such as phenyl-methyl or
Heteroaryl-C.sub.1-6-alk(en/yn)yl such as thiophenyl-methyl,
pyrimidinyl-methyl or pyridinyl-methyl.
[0080] In a further embodiment of the compound of formula I R.sup.7
is selected from the group consisting of C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl and
Heteroaryl.
[0081] Typically, R.sup.7 is selected from the group consisting of
Aryl, halo-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.1-6-alk(en/yn)yl and
Heteroaryl.
[0082] To further illustrate without limiting the invention, an
embodiment concerns such compounds wherein R.sup.7 is Aryl, such as
phenyl.
[0083] In further embodiments of the compound of formula I any Aryl
which is mentioned either alone or as a part of a larger
substituent is optionally substituted with one or more substituents
independently selected from the group consisting of
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl,
C.sub.1-6-alkyl-C.sub.3-8-heterocycloalk(en)yl,
C.sub.3-8-Cycloalk(en)yloxy,
C.sub.3-8-Cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy,
halo-C.sub.3-8-cycloalk(en)yloxy,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy,
C.sub.1-6-alk(en/yn)ylamino.
[0084] Typically, any Aryl which is mentioned either alone or as a
part of a larger substituent is optionally substituted with one or
more substituents independently selected from the group consisting
of amino, halogen, cyano, C.sub.1-6-alk(en/yn)yl,
halo-C.sub.1-6-alk(en/yn)yl, hydroxy, C.sub.1-6-alk(en/yn)yloxy,
halo-C.sub.1-6-alk(en/y n)yloxy, di-(C.sub.1-6-alk(en/yn)ylamino,
C.sub.1-6-alk(en/yl)yl-CO--NH-- and
C.sub.1-6-alk(en/yn)yl-sulfonamide; or two adjacent substituents
may together with the Aryl group to which they are attached form a
4-8 membered ring, which optionally contains one or two heteroatoms
and which is optionally substituted with one or more
C.sub.1-6-alk(en/yn)yl groups.
[0085] In further embodiments of the compound of formula I, any
Aryl which is mentioned either alone or as a part of a larger
substituent is unsubstituted;
in further embodiments, any Aryl which is mentioned either alone or
as a part of a larger substituent is monosubstituted; in further
embodiments, any Aryl which is mentioned either alone or as a part
of a larger substituent is disubstituted; in further embodiments
any Aryl which is mentioned either alone or as a part of a larger
substituent is trisubstituted.
[0086] In further embodiments of the compound of formula I, any
Aryl which is mentioned either alone or as a part of a larger
substituent is phenyl which is optionally substituted;
in further embodiments, any phenyl which is mentioned either alone
or as a part of a larger substituent is unsubstituted; in further
embodiments, any phenyl which is mentioned either alone or as a
part of a larger substituent is monosubstituted such as in the
ortho position or in the meta position or in the para position; in
further embodiments, any phenyl which is mentioned either alone or
as a part of a larger substituent is disubstituted such as in the
meta position and in the para position or in both meta positions;
in further embodiments, any phenyl which is mentioned either alone
or as a part of a larger substituent is trisubstituted.
[0087] To further illustrate without limiting the invention,
embodiments concern such compounds wherein any Aryl which is
mentioned either alone or as a part of a larger substituent in any
of substituents R.sup.1 or R.sup.2 is optionally substituted with
one or more substituents independently selected from the group
consisting of amino, halogen such as fluoro or cyano,
C.sub.1-6-alk(en/yn)yl such as methyl, ethenyl or isopropyl,
halo-C.sub.1-6-alk(en/yn)yl such as trifluoromethyl, hydroxy,
C.sub.1-6-alk(en/yn)yloxy such as methoxy,
halo-C.sub.1-6-alk(en/yn)yloxy such as trifluoromethoxy,
di-(C.sub.1-6-alk(en/yn)yl)amino such as dimethylamino,
C.sub.1-6-alk(en/yn)yl-CO--NH-- such as CH.sub.3--CO--NH--,
C.sub.1-6-alk(en/yn)yl-sulfonamide such as methylsulfonamide; or
two adjacent substituents may together with the Aryl group to which
they are attached form a 4-8 membered ring which optionally
contains one or two heteroatoms and which is optionally substituted
with one or more C.sub.1-6-alk(en/yn)yl groups, such two adjacent
substituents may together form e.g. --O--CH.sub.2--CH.sub.2--O-- or
--O--C(CH.sub.3).sub.2--CH.sub.2--.
[0088] To further illustrate without limiting the invention,
embodiments concern such compounds wherein any Aryl Which is
mentioned either alone or as a part of a larger substituent in
R.sup.3 is optionally substituted with one or more halogen atoms
such as fluoro or chloro atoms.
[0089] To further illustrate without limiting the invention,
embodiments concern such compounds wherein any Aryl which is
mentioned either alone or as a part of a larger substituent in
R.sup.5 or R.sup.6 is optionally substituted with one or more
substituents independently selected from the group consisting of
halogen such as fluoro and halo-C.sub.1-6-alk(en/yn) such as
trifluoromethyl.
[0090] To further illustrate without limiting the invention,
embodiments concerns such compounds wherein any Aryl which is
mentioned either alone or as a part of a larger substituent in
R.sup.7 is optionally substituted with one or more substituents
independently selected from the group consisting of halogen such as
fluoro or chloro, C.sub.1-6-alk(en/yn)yl such as methyl,
halo-C.sub.1-6-alk(en/yn)yl such as trifluoromethyl and
C.sub.1-6-alk(en/yn)yloxy such as methoxy.
[0091] In further embodiments of the compound of formula I any
Heteroaryl which is mentioned either alone or as a part of a larger
substituent is optionally substituted with one or more substituents
independently selected from the group consisting of cyano, amino,
halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yloxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy,
C.sub.3-8-cycloalk(en)yl-phenoxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl-phenoxy,
amino-phenoxy, halo-phenoxy, cyano-phenoxy,
halo-C.sub.1-6-alk(en/yn)yl-phenoxy,
halo-C.sub.3-8-cycloalk(en)yl-phenoxy,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl-phenoxy,
C.sub.3-8-heterocycloalk(en)yl-phenoxy,
C.sub.1-6-alkyl-C.sub.3-8-heterocycloalk(en)yl-phenoxy,
hydroxy-phenoxy, C.sub.1-6-alk(en/yn)yloxy-phenoxy,
C.sub.3-8-cycloalk(en)yloxy-phenoxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy-phenoxy,
halo-C.sub.1-6-alk(en/yn)yloxy-phenoxy,
halo-C.sub.3-8-cycloalk(en)yloxy-phenoxy,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy-phenoxy,
C.sub.1-6-alk(en/yn)ylamino-phenoxy,
di-(C.sub.1-6-alk(en/yn/yl)amino-phenoxy,
C.sub.1-6-alk(en/yn)yl-CO--NH-phenoxy and
C.sub.1-6-alk(en/yn)yl-sulfonamide-phenoxy.
[0092] Typically, any Heteroaryl which is mentioned either alone or
as a part of a larger substituent is optionally substituted with
one or more substituents independently selected from the group
consisting of halogen, halo-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yl, Aryl, C.sub.1-6-alk(en/yn)yloxy and
C.sub.1-6-alk(en/yn)yl-phenoxy.
[0093] To further illustrate without limiting the invention,
embodiments of formula I concern such compounds wherein any
Heteroaryl which is mentioned either alone or as a part of a larger
substituent is unsubstituted;
in further embodiments any Heteroaryl which is mentioned either
alone or as a part of a larger substituent is monosubstituted; in
further embodiments any Heteroaryl which is mentioned either alone
or as a part of a larger substituent is disubstituted; in further
embodiments any Heteroaryl which is mentioned either alone or as a
part of a larger substituent is trisubstituted.
[0094] To further illustrate without limiting the invention, an
embodiment concerns such compounds wherein any Heteroaryl which is
mentioned either alone or as a part of a larger substituent in
R.sup.5 or R.sup.6 is optionally substituted with one or more
substituents independently selected from the group consisting of
halogen such as chloro, halo-C.sub.1-6-alk(en/yn)yl such as
trifluoromethyl, C.sub.1-6-alk(en/yn)yl such as methyl, Aryl such
as phenyl, C.sub.1-6-alk(en/yn)yloxy such as methoxy and
C.sub.1-6-alk(en/yn)yl-phenoxy such as methyl-phenoxy.
[0095] To further illustrate without limiting the invention, an
embodiment of formula I relates to a compound having the general
formula XXVI or salts thereof:
##STR00004##
wherein Z, q, R.sup.1, R.sup.2 and Ware as defined above; and
R.sup.8 and R.sup.9 are independently selected from the group
consisting of hydrogen, Aryl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.3-8-cycloalk(en)yl,
Aryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl--C.sub.1-6-alk(en/yn)yl,
Heteroaryl-C.sub.1-6-alk(en/yn)yl,
Heteroaryl-C.sub.3-8-cycloalk(en)yl and
Heteroaryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl with the
proviso that R.sup.8 and R.sup.9 are not hydrogen at the same
time.
[0096] In one embodiment of the compound of formula XXVI R.sup.1
and R.sup.2 are independently selected from the group consisting of
halogen, amino, C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl and
halo-C.sub.1-6-alk(en/yn)yl.
[0097] In one embodiment of the compound of formula XXVI q is
0.
[0098] In one embodiment of the compound of formula XXVI q is
1.
[0099] In one embodiment of the compound of formula XXVI Z is an
oxygen atom.
[0100] In one embodiment of the compound of formula XXVI R.sup.3 is
selected from the group consisting of C.sub.1-8-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
Heteroaryl-C.sub.1-6-alk(en/yn)yl and
amino-C.sub.1-6-alk(en/yn)yl.
[0101] In one embodiment of the compound of formula XXVI any Aryl
which is mentioned either alone or as a part of a larger
substituent is optionally substituted with one or more substituents
independently selected from the group consisting of amino, halogen,
cyano, C.sub.1-6-alk(en/yn)yl, halo-C.sub.1-6-alk(en/yn)yl,
hydroxy, C.sub.1-6-alk(en/yn)yloxy, halo-C.sub.1-6-alk(en/yn)yloxy,
di-(C.sub.1-6-alk(en/yn)yl)amino, C.sub.1-6-alk(en/yn)yl-CO--NH--
and C.sub.1-6-alk(en/yn)yl-sulfonamide; or two adjacent
substituents may together with the Aryl group to which they are
attached form a 41-8 membered ring, which optionally contains one
or two heteroatoms and which is optionally substituted with one or
more C.sub.1-6-alk(en/yn)yl groups.
[0102] In one embodiment of the compound of formula XXVI any
Heteroaryl which is mentioned either alone or as a part of a larger
substituent is optionally substituted with one or more substituents
independently selected from the group consisting of halogen,
halo-C.sub.1-6'' alk(en/yn)yl, C.sub.1-6-alk(en/yn)yl, Aryl,
C.sub.1-6-alk(en/yn)yloxy and C.sub.1-6-alk(en/yn)yl-phenoxy.
[0103] To further illustrate without limiting the invention, an
embodiment of formula I relates to a compound having the general
formula XXVII or salts thereof:
##STR00005##
wherein Z, q, R.sup.1, R.sup.2 and R.sup.3 are as defined above;
and R.sup.10 is selected from the group consisting of halogen,
cyano, C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
Aryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.3-8-heterocycloalk(en)yl, halo-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl and
halo-C.sub.1-6-alk(en/yn)yl-C.sub.3-8-heterocycloalk(en)yl--C.sub.1-6-alk-
(en/yn)yl.
[0104] In one embodiment of the compound of formula XXVII R.sup.1
and R.sup.2 are independently selected from the group consisting of
halogen, amino, C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl and
halo-C.sub.1-6-alk(en/yn)yl.
[0105] In one embodiment of the compound of formula XXVII q is
0.
[0106] In one embodiment of the compound of formula XXVII q is
1.
[0107] In one embodiment of the compound of formula XXVII Z is an
oxygen atom.
[0108] In one embodiment of the compound of formula XXVII R.sup.3
is selected from the group consisting of C.sub.1-8-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
Heteroaryl-C.sub.1-6-alk(en/yn)yl and
amino-C.sub.1-6-alk(en/yn)yl.
[0109] In one embodiment of the compound of formula XXVII R.sup.10
is selected from the group consisting of cyano, halogen, preferably
bromo or chloro and C.sub.1-6-alk(en/yn)yl, preferably methyl.
[0110] In one embodiment of the compound of formula XXVII R.sup.10
is selected from the group consisting of C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl;
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
Aryl-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.3-8-heterocycloalk(en)yl, halo-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl and
halo-C.sub.1-6-alk(en/yn)yl-C.sub.3-8-Heterocycloalk(en)yl-C.sub.1-6-alk(-
en/yn)yl.
[0111] In one embodiment of the compound of formula XXVII any Aryl
which is mentioned either alone or as a part of a larger
substituent is optionally substituted with one or more substituents
independently selected from the group consisting of amino, halogen,
cyano, C.sub.1-6-alk(en/yn)yl, halo-C.sub.1-6-alk(en/yn)yl,
hydroxy, C.sub.1-6-alk(en/yn)yloxy, halo-C.sub.1-6-alk(en/yn)yloxy,
di-(C.sub.1-6-alk(en/yn)yl)amino, C.sub.1-6-alk(en/yn)yl-CO--NH--
and C.sub.1-6-alk(en/yn)yl-sulfonamide; or two adjacent
substituents may together with the Aryl group to which they are
attached form a 4-8 membered ring, which optionally contains one or
two heteroatoms and which is optionally substituted with one or
more C.sub.1-6-alk(en/yn)yl groups.
[0112] In one embodiment of the compound of formula XXVII any
Heteroaryl which is mentioned either alone or as a part of a larger
substituent is optionally substituted with one or more substituents
independently selected from the group consisting of halogen,
halo-C.sub.1-6-alk(en/yn)yl, C.sub.1-6-alk(en/yn)yl, Aryl,
C.sub.1-6-alk(en/yn)yloxy and C.sub.1-6-alk(en/yn)yl-phenoxy.
[0113] To further illustrate without limiting the invention, an
embodiment of formula I relates to a compound having the general
formula XXVIII or salts thereof:
##STR00006##
wherein Z, q, R.sup.1, R.sup.2 and R.sup.3 are as defined above;
and R.sup.11 is R.sup.7NH--C.sub.1-6-alk(en/yn)yl; wherein R.sup.7
is selected from the group consisting of C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl, Aryl,
halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl and
Heteroaryl.
[0114] In one embodiment of the compound of formula XXVIII R.sup.1
and R.sup.2 are independently selected from the group consisting of
halogen, amino, C.sub.1-6-alk(en/yn)yl,
C.sub.3-8-heterocycloalk(en)yl, Aryl, Heteroaryl and
halo-C.sub.1-6-alk(en/yn)yl.
[0115] In one embodiment of the compound of formula XXVIII q is
0.
[0116] In one embodiment of the compound of formula XXVIII q is
1.
[0117] In one embodiment of the compound of formula XXVIII Z is an
oxygen atom.
[0118] In one embodiment of the compound of formula XXVIII R.sup.3
is selected from the group consisting of C.sub.1-8-alk(en/yn)yl,
C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Aryl-C.sub.1-6-alk(en/yn)yl, Aryl-C.sub.3-8-cycloalk(en)yl,
Heteroaryl-C.sub.1-6-alk(en/yn)yl and
amino-C.sub.1-6-alk(en/yn)yl.
[0119] In one embodiment of the compound of formula XXVIII R.sup.7
is Aryl.
[0120] In one embodiment of the compound of formula XXVIII any Aryl
which is mentioned either alone or as a part of a larger
substituent is optionally substituted with one or more substituents
independently selected from the group consisting of amino, halogen,
cyano, C.sub.1-6-alk(en/yn)yl, halo-C.sub.1-6-alk(en/yn)yl,
hydroxy, C.sub.1-6-alk(en/yn)yloxy, alk(en/yn)yloxy,
di-(C.sub.1-4-alk(en/yn)yl)amino, C.sub.1-6-alk(en/yn)yl-CO--NH--
and C.sub.1-6-alk(en/yn)yl-sulfonamide; or two adjacent
substituents may together with the Aryl group to which they are
attached form a 4-8 membered ring, which optionally contains one or
two heteroatoms and which is optionally substituted with one or
more C.sub.1-6-alk(en/yn)yl groups.
[0121] In one embodiment of the compound of formula XXVIII any
Heteroaryl which is mentioned either alone or as a part of a larger
substituent is optionally substituted with one or more substituents
independently selected from the group consisting of halogen,
halo-C.sub.1-6-alk(en/yn)yl, C.sub.1-6-alk(en/yn)yl, Aryl,
C.sub.1-6-alk(en/yn)yloxy and C.sub.1-6-alk(en/yn)yl-phenoxy.
[0122] In a further embodiment of the compound of formula I said
compound is selected from the following list of compounds
TABLE-US-00001 Example no. Name 1a Hexanoic acid
(4-bromo-2,6-dimethyl-phenyl)-amide 1b
N-(4-Bromo-2,6-dimethyl-phenyl)-2-(4-fluoro-phenyl)-acetamide 1c
N-(2-Bromo-4,6-dimethyl-phenyl)-2-(4-fluoro-phenyl)-acetamide 1d
N-(2-Bromo-4,6-dimethyl-phenyl)-3,3-dimethyl-butyramide 1e
N-(2-Bromo-4,6-dimethyl-phenyl)-2-cyclopentyl-acetamide 1f
N-(2-Bromo-4,6-dichloro-phenyl)-3,3-dimethyl-butyramide 1g
N-(2-Bromo-4,6-dichloro-phenyl)-2-(4-fluoro-phenyl)-acetamide 1h
N-(2-Bromo-4,6-dichloro-phenyl)-2-cyclopentyl-acetamide 1i
Heptanoic acid (4-bromo-2,6-dimethyl-phenyl)-amide 1j
Cyclohexanecarboxylic acid (4-bromo-2,6-dimethyl-phenyl)-amide 1k
N-(4-Bromo-2,6-dimethyl-phenyl)-2-thiophen-2-yl-acetamide 1l
2-Phenyl-cyclopropanecarboxylic acid (4-bromo-2,6-dimethyl-phenyl)-
amide 1m
N-(4-Bromo-2,6-dimethyl-phenyl)-2-(4-chloro-phenyl)-acetamide 1n
Pentanoic acid (4-bromo-2,6-dimethyl-phenyl)-amide 1o Octanoic acid
(4-bromo-2,6-dimethyl-phenyl)-amide 1p
N-(4-Bromo-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide 1q
2-Bicyclo[2.2.1]hept-2-yl-N-(2,4-difluoro-6-morpholin-4-yl-phenyl)-
acetamide 1r
(S)-2-Amino-N-{2,6-dimethyl-4-[methyl-(4-trifluoromethyl-benzyl)-
amino]-phenyl}-3-methyl-butyramide 1s
(S)-2-Amino-4-methyl-pentanoic acid {2,6-dimethyl-4-[methyl-(4-
trifluoromethyl-benzyl)-amino]-phenyl}-amide 1t
(4-Bromo-2,6-dimethyl-phenyl)-carbamic acid ethyl ester 1u
(4-Bromo-2,6-dimethyl-phenyl)-carbamic acid propyl ester 1v
N-(2-Amino-4-bromo-6-methyl-phenyl)-3,3-dimethyl-butyramide 1w
(R)-2-Amino-4-methylpentanoic acid [2,6-dimethyl-4-(4-
trifluoromethylbenzylamino)-phenyl]-amide 1x
[2-Amino-6-methyl-4-(4-trifluoromethylbenzylamino)-phenyl]-carbamic
acid ethyl ester 2a
2-Cyclopentyl-N-{2,6-dimethyl-4-[2-(4-trifluoromethyl-phenyl)-pyrrolidi-
n- 1-yl]-phenyl}-acetamide 2b
N-(4-Azepan-1-yl-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide 2c
2-Cyclopentyl-N-(2,6-dimethyl-4-pyrrol-1-yl-phenyl)-acetamide 2d
3,3-Dimethyl-N-[2-methyl-6-morpholin-4-yl-4-(4-
trifluoromethylbenzylamino)-phenyl]-butyramide 3a
N-(3'-Amino-3,5-dimethyl-biphenyl-2-yl)-2-(4-fluoro-phenyl)-acetamide
3b
N-(4'-Dimethylamino-3,5-dimethyl-biphenyl-2-yl)-2-(4-fluoro-phenyl)-
acetamide 3c
N-(2,4-Dimethyl-6-quinolin-3-yl-phenyl)-2-(4-fluoro-phenyl)-acetamide
3d
2-(4-Fluoro-phenyl)-N-(4'-hydroxy-3'-methoxy-3,5-dimethyl-biphenyl-2-
yl)-acetamide 3e
2-(4-Fluoro-phenyl)-N-(3'-hydroxy-3,5-dimethyl-biphenyl-2-yl)-acetamide
3f
2-(4-Fluoro-phenyl)-N-(2'-methanesulfonylamino-3,5-dimethyl-biphenyl-2-
yl)-acetamide 3g
N-(4'-Isopropyl-3,5-dimethyl-biphenyl-2-yl)-3,3-dimethyl-butyramide
3h 2-Cyclopentyl-N-(3,5-dimethyl-biphenyl-2-yl)-acetamide 3i
N-(4'-Fluoro-3,5-dimethyl-biphenyl-2-yl)-2-(4-fluoro-phenyl)-acetamide
3j
N-(3,5-Dimethyl-3',5'-bis-trifluoromethyl-biphenyl-2-yl)-2-(4-fluoro-
phenyl)-acetamide 3k
N-(3'-Acetylamino-3,5-dimethyl-biphenyl-2-yl)-2-(4-fluoro-phenyl)-
acetamide 3l
2-(4-Fluoro-phenyl)-N-(2'-methoxy-3,5-dimethyl-biphenyl-2-yl)-acetamide
3m
N-(3,5-Dimethyl-4'-vinyl-biphenyl-2-yl)-2-(4-fluoro-phenyl)-acetamide
3n
N-(3'-Cyano-3,5-dimethyl-biphenyl-2-yl)-2-(4-fluoro-phenyl)-acetamide
3o
N-(3,5-Dimethyl-3'-trifluoromethoxy-biphenyl-2-yl)-2-(4-fluoro-phenyl)-
acetamide 3p
N-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-4,6-dimethyl-phenyl]-2-(4-
fluoro-phenyl)-acetamide 3q
N-[2,4-Dimethyl-6-(2,2,5-trimethyl-2,3-dihydro-benzofuran-7-yl)-phenyl]-
- 2-(4-fluoro-phenyl)-acetamide 4a
N-[2,6-Dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-acetamide
4b
N-{2,6-Dimethyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-
acetamide 4c
{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester 4d
[4-(4-Fluoro-benzylamino)-2,6-dimethyl-phenyl]-carbamic acid propyl
ester 4e
[2,6-Dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic
acid propyl ester 4f
[4-(3-Fluoro-4-trifluoromethyl-benzylamino)-2,6-dimethyl-phenyl]-
carbamic acid propyl ester 4g
{2,6-Dimethyl-4-[(4-methyl-2-phenyl-pyrimidin-5-ylmethyl)-amino]-
phenyl}-carbamic acid propyl ester 4h
{2,6-Dimethyl-4-[(6-p-tolyloxy-pyridin-3-ylmethyl)-amino]-phenyl}-
carbamic acid propyl ester 4i
{4-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-2,6-dimethyl-phenyl}-
carbamic acid propyl ester 4j
{4-[(3-Fluoro-4-trifluoromethyl-benzyl)-methyl-amino]-2,6-dimethyl-
phenyl}-carbamic acid propyl ester 4k
2-Cyclopentyl-N-[2,6-dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-
- acetamide 4l
2-Cyclopentyl-N-{2,6-dimethyl-4-[methyl-(4-trifluoromethyl-benzyl)-
amino]-phenyl}-acetamide 4m
2-Cyclopentyl-N-{2,6-dimethyl-4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-
- amino]-phenyl}-acetamide 4n
N-{2,6-Dimethyl-4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-
phenyl}-3,3-dimethyl-butyramide 4o
N-{2-Bromo-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-6-trifluoromethyl-
phenyl}-3-cyclohexyl-propionamide 4p
N-{2-Chloro-6-methyl-4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-
phenyl}-2-(3-fluoro-phenyl)-acetamide 4q
N-[2-Chloro-6-trifluoromethyl-4-(4-trifluoromethylbenzylamino)-phenyl]-
2-cyclopentylacetamide 5a
{4-[(3-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid ethyl ester 5b
{2,6-Dimethyl-4-[(4-trifluoromethyl-phenylamino)-methyl]-phenyl}-
carbamic acid ethyl ester 5c
2-Cyclopentyl-N-{4-[(3-fluoro-phenylamino)-methyl]-2,6-dimethyl-
phenyl}-acetamide 5d
N-{4-[(3-Chloro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-2-
cyclopentyl-acetamide 5e
2-Cyclopentyl-N-{4-[(3-methoxy-phenylamino)-methyl]-2,6-dimethyl-
phenyl}-acetamide 5f
N-{4-[(4-Chloro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-2-
cyclopentyl-acetamide 5g
2-Cyclopentyl-N-{4-[(3,4-difluoro-phenylamino)-methyl]-2,6-dimethyl-
phenyl}-acetamide 5h
2-Cyclopentyl-N-{2,6-dimethyl-4-[(4-trifluoromethyl-phenylamino)-
methyl]-phenyl}-acetamide 5i
2-Cyclopentyl-N-[2,6-dimethyl-4-(p-tolylamino-methyl)-phenyl]-acetamide
5j
2-Cyclopentyl-N-{2,6-dimethyl-4-[(3-trifluoromethyl-phenylamino)-
methyl]-phenyl}-acetamide 5k
2-Cyclopentyl-N-{4-[(3,5-difluoro-phenylamino)-methyl]-2,6-dimethyl-
phenyl}-acetamide 5l
{4-[(4-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester 5m
{4-[(4-Chloro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester 5n
{2,6-Dimethyl-4-[(4-trifluoromethyl-phenylamino)-methyl]-phenyl}-
carbamic acid propyl ester 5o
{4-[(3,5-Difluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester 5p
{4-[(3-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester 5q
{4-[(4-Methoxyphenylamino)-methyl]-2,6-dimethylphenyl}-carbamic
acid propyl ester 5r Pentanoic acid
{4-[(4-chlorophenylamino)-methyl]-2,6-dimethylphenyl}- amide 5s
2-(4-Chlorophenyl)-N-{4-[(4-chlorophenylamino)-methyl]-2,6-
dimethylphenyl}-acetamide 5t
{2,6-Dimethyl-4-[(4-trifluoromethylphenylamino)-methyl]-phenyl}-
carbamic acid 2-methoxyethyl ester 5u
N-{4-[(5-Chloro-pyridin-2-ylamino)-methyl]-2,6-dimethylphenyl}-2-
cyclopentylacetamide 5v
2-Cyclopentyl-N-{4-[(2,6-dichloro-pyridin-4-ylamino)-methyl]-2,6-
dimethylphenyl}-acetamide 5w
2-Cyclopentyl-N-{2,6-dichloro-4-[(4-fluoro-phenylamino)-methyl]-
phenyl}-acetamide 5x
2-Cyclopentyl-N-{2,6-dichloro-4-[(5-trifluoromethylpyridin-2-ylamino)-
methyl]-phenyl}-acetamide 6a
N-(4-Bromo-2-methyl-6-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide
or a salt thereof. Each of these compounds is considered a specific
embodiment and may be subjected to individual claims.
[0123] The present invention also comprises salts of the compounds
of the invention, typically, pharmaceutically acceptable salts. The
salts of the invention include acid addition salts, metal salts,
ammonium and alkylated ammonium salts.
[0124] The salts of the invention are preferably acid addition
salts. The acid addition salts of the invention are preferably
pharmaceutically acceptable salts of the compounds of the invention
formed with non-toxic acids. Acid addition salts include salts of
inorganic acids as well as organic acids. Examples of suitable
inorganic acids include hydrochloric, hydrobromic, hydroiodic,
phosphoric, sulfuric, sulfamic, nitric acids and the like. Examples
of suitable organic acids include formic, acetic, trichloroacetic,
trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric,
glycolic, itaconic, lactic, methanesulfonic, maleic, malic,
malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic,
methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic,
bismethylene salicylic, ethanedisulfonic, gluconic, citraconic,
aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic,
glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline
acetic acids, as well as the 8-halotheophyllines, for example
8-bromotheophylline and the like. Further examples of
pharmaceutical acceptable inorganic or organic acid addition salts
include the pharmaceutically acceptable salts listed in J. Pharm.
Sci. 1977, 66, 2, which is incorporated herein by reference.
[0125] Also intended as acid addition salts are the hydrates, which
the present compounds, are able to form.
[0126] Examples of metal salts include lithium, sodium, potassium,
magnesium salts and the like.
[0127] Examples of ammonium and alkylated ammonium salts include
ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-,
diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium
salts and the like.
[0128] Further, the compounds of this invention may exist in
unsolvated as well as in solvated forms with pharmaceutically
acceptable solvents such as water, ethanol and the like. In
general, the solvated forms are considered equivalent to the
unsolvated forms for the purposes of this invention.
[0129] The compounds of the present invention may have one or more
asymmetric centre and it is intended that any optical isomers (i.e.
enantiomers or diastereomers), as separated, pure or partially
purified optical isomers and any mixtures thereof including racemic
mixtures, i.e. a mixture of stereoisomers, are included within the
scope of the invention.
[0130] Racemic forms can be resolved into the optical antipodes by
known methods, for example, by separation of diastereomeric salts
thereof with an optically active acid, and liberating the optically
active amine compound by treatment with a base. Another method for
resolving racemates into the optical antipodes is based upon
chromatography on an optically active matrix. Racemic compounds of
the present invention can also be resolved into their optical
antipodes, e.g. by fractional crystallization. The compounds of the
present invention may also be resolved by the formation of
diastereomeric derivatives. Additional methods for the resolution
of optical isomers, known to those skilled in the art, may be used.
Such methods include those discussed by J. Jaques, A. Collet and S.
Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and
Sons, New York (1981). Optically active compounds can also be
prepared from optically active starting materials, or by
stereoselective synthesis.
[0131] Furthermore, when a double bond or a fully or partially
saturated ring system is present in the molecule geometric isomers
may be formed. It is intended that any geometric isomers, as
separated, pure or partially purified geometric isomers or mixtures
thereof are included within the scope of the invention. Likewise,
molecules having a bond with restricted rotation may form geometric
isomers. These are also intended to be included within the scope of
the present invention.
[0132] Furthermore, some of the compounds of the present invention
may exist in different tautomeric forms and it is intended that any
tautomeric forms that the compounds are able to form are included
within the scope of the present invention.
[0133] The invention also encompasses prodrugs of the present
compounds, which on administration undergo chemical conversion by
metabolic processes before becoming pharmacologically active
substances. In general, such prodrugs will be functional
derivatives of the compounds of the general formula I, which are
readily convertible in vivo into the required compound of the
formula I. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
[0134] The invention also encompasses active metabolites of the
present compounds.
[0135] The compounds according to the invention have affinity for
the KCNQ2 receptor subtype with an EC.sub.50 of less than 15000 nM
such as less than 10000 nM as measured by the test "Relative efflux
through the KCNQ2 channel" which is described below. One embodiment
concerns such compounds of formula I having affinity for the KCNQ2
receptor subtype with an EC.sub.50 of less than 2000 nM such as
less than 1500 nM as measured by the test "Relative efflux through
the KCNQ2 channel" which is described below. To further illustrate
without limiting the invention an embodiment concerns such
compounds having affinity for the KCNQ2 receptor subtype with an
EC.sub.50 of less than 200 nM such as less than 150 nM as measured
by the test "Relative efflux through the KCNQ2 channel" which is
described below.
[0136] One embodiment concerns such compounds of formula I having
an ED.sub.50 of less than 15 mg/kg in the test "Maximum
electroshock" which is described below. To further illustrate
without limiting the invention an embodiment concerns such
compounds having an ED.sub.50 of less than 5 mg/kg in the test
"Maximum electroshock" which is described below.
[0137] One embodiment concerns such compounds of formula I having
an ED.sub.50 of less than 5 mg/kg in the "Electrical
seizure-threshold test" and "Chemical seizure-threshold test" which
is described below.
[0138] One embodiment concerns such compounds of formula I having
few or clinically insignificant side effects. Some of the compounds
according to the invention are thus tested in models of the
unwanted sedative, hypothermic and ataxic actions.
[0139] One embodiment concerns such compounds of formula I having a
large therapeutic index between anticonvulsant efficacy and
side-effects such as impairment of locomotor activity or ataxic
effects as measured by performance on a rotating rod. Such
compounds will expectedly be well tolerated in patients permitting
high doses to be used before side effects are seen. Thereby
compliance with the therapy will expectedly be good and
administration of high doses may be permitted making the treatment
more efficacious in patients who would otherwise have side effects
with other medications.
[0140] As already mentioned, the compounds according to the
invention have effect on potassium channels of the KCNQ family, in
particular the KCNQ2 subunit, and they are thus considered useful
for increasing ion flow in a voltage-dependent potassium channel in
a mammal such as a human. The compounds of the invention are
considered applicable in the treatment of a disorder or disease
being responsive to an increased ion flow in a potassium channel
such as the KCNQ family potassium ion channels. Such disorder or
disease is preferably a disorder or disease of the central nervous
system.
[0141] In one aspect, the compounds of the invention may be
administered as the only therapeutically effective compound.
[0142] In another aspect the compounds of the invention may be
administered as a part of a combination therapy, i.e. the compounds
of the invention may be administered in combination with other
therapeutically effective compounds having e.g. anti-convulsive
properties. The effects of such other compounds having
anti-convulsive properties may include but not be limited to
activities on: [0143] ion channels such as sodium, potassium, or
calcium channels [0144] the excitatory amino acid systems e.g.
blockade or modulation of NMDA receptors [0145] the inhibitory
neurotransmitter systems e.g. enhancement of GABA release, or
blockade of GABA-uptake or [0146] membrane stabilisation
effects.
[0147] Current anti-convulsive medications include, but are not
limited to, tiagabine, carbamazepine, sodium valproate,
lamotrigine, gabapentin, pregabalin, ethosuximide, levetiracetam,
phenyloin, topiramate, zonisamide as well as members of the
benzodiazepine and barbiturate class.
[0148] An aspect of the invention provides a compound of formula I
or a salt thereof for use as a medicament.
[0149] In one embodiment, the invention relates to the use of a
compound of formula I or a salt thereof in a method of
treatment.
[0150] An embodiment of the invention provides a pharmaceutical
composition comprising a compound of formula I or a salt thereof
and one or more pharmaceutically acceptable carrier or diluent. The
composition may comprise any of the embodiments of formula I as
described above.
[0151] A further embodiment of the invention relates to the use of
a compound of formula I or a salt thereof for the preparation of a
pharmaceutical composition for the treatment of a disease or
disorder wherein a KCNQ potassium channel opener such as a KCNQ2
potassium channel opener is beneficial. Typically, such disorder or
disease is selected from the group consisting of seizure disorders,
anxiety disorders, neuropathic pain and migraine pain disorders or
neurodegenerative disorders.
[0152] A further embodiment of the invention relates to the use of
a compound of formula I or a salt thereof for the preparation of a
pharmaceutical composition for the treatment of seizure
disorders.
[0153] Typically, the seizure disorders to be treated are selected
from the group consisting of acute seizures, convulsions, status
epilepticus and epilepsy such as epileptic syndromes and epileptic
seizures.
[0154] A further embodiment of the invention relates to the use of
a compound of formula I or a salt thereof for the preparation of a
pharmaceutical composition for the treatment of anxiety
disorders.
[0155] Typically, the anxiety disorders to be treated are selected
from the group consisting of anxiety and disorders and diseases
related to panic attack, agoraphobia, panic disorder with
agoraphobia, panic disorder without agoraphobia, agoraphobia
without history of panic disorder, specific phobia, social phobia
and other specific phobias, obsessive-compulsive disorder,
posttraumatic stress disorder, acute stress disorders, generalized
anxiety disorder, anxiety disorder due to general medical
condition, substance-induced anxiety disorder, separation anxiety
disorder, adjustment disorders, performance anxiety,
hypochondriacal disorders, anxiety disorder due to general medical
condition and substance-induced anxiety disorder and anxiety
disorder not otherwise specified.
[0156] A further embodiment of the invention relates to the use of
a compound of formula I or a salt thereof for the preparation of a
pharmaceutical composition for the treatment of neuropathic pain
and migraine pain disorders.
[0157] Typically, the neuropathic pain and migraine pain disorders
to be treated are selected from the group consisting of allodynia,
hyperalgesic pain, phantom pain, neuropathic pain related to
diabetic neuropathy, neuropathic pain related to trigeminal
neuralgia and neuropathic pain related to migraine.
[0158] A further embodiment of the invention relates to the use of
a compound of formula I or a salt thereof for the preparation of a
pharmaceutical composition for the treatment of neurodegenerative
disorders.
[0159] Typically the neurodegenerative disorders to be treated are
selected from the group consisting of Alzheimer's disease,
Huntington's chorea, multiple sclerosis, amyotrophic lateral
sclerosis, Creutzfeld-Jakob disease, Parkinson's disease,
encephalopathies induced by AIDS or infection by rubella viruses,
herpes viruses, borrelia and unknown pathogens, trauma-induced
neurodegenerations, neuronal hyperexcitation states such as in
medicament withdrawal or intoxication and neurodegenerative
diseases of the peripheral nervous system such as polyneuropathies
and polyneuritides.
[0160] A further embodiment of the invention relates to the use of
a compound of formula I or a salt thereof for the preparation of a
pharmaceutical composition for the treatment of stroke, cocaine
abuse, nicotine withdrawal, ethanol withdrawal or tinnitus.
[0161] The term "treatment" as used herein in connection with a
disease or disorders includes also prevention, inhibition and
amelioration as the case may be.
[0162] The invention provides compounds showing effect in one or
more of the following tests: [0163] "Relative efflux through the
KCNQ2 channel" [0164] Which is a measure of the potency of the
compound at the target channel [0165] "Maximum electroshock" [0166]
Which is a measure of seizures induced by non-specific CNS
stimulation by electrical means [0167] "Pilocarpine induced
seizures" [0168] Seizures induced by pilocarpine are often
difficult to treat with many existing antiseizure medications and
so reflect a model of "drug resistant seizures" [0169] "Electrical
seizure-threshold tests" and "Chemical seizure-threshold tests"
[0170] These models measure the threshold at which seizures are
initiated, thus being models that detect whether compounds could
delay seizure initiation, [0171] "Amygdala kindling" [0172] Which
is used as a measure of disease progression, as in normal animals
the seizures in this model get more severe as the animal receives
further stimulations.
Pharmaceutical Compositions
[0173] The present invention also relates to a pharmaceutical
composition. The compounds of the invention or salts thereof may be
administered alone or in combination with pharmaceutically
acceptable carriers or diluents, in either single or multiple
doses. The pharmaceutical compositions according to the invention
may be formulated with pharmaceutically acceptable carriers or
diluents as well as any other known adjuvants and excipients in
accordance with conventional techniques such as those disclosed in
Remington: The Science and Practice of Pharmacy, 19 Edition,
Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.
[0174] The pharmaceutical compositions may be specifically
formulated for administration by any suitable route such as the
oral, rectal, nasal, pulmonary, topical (including buccal and
sublingual), transdermal, intracisternal, intraperitoneal, vaginal
and parenteral (including subcutaneous, intramuscular, intrathecal,
intravenous and intradermal) route, the oral route being preferred.
It will be appreciated that the preferred route will depend on the
general condition and age of the subject to be treated, the nature
of the disorder or disease to be treated and the active ingredient
chosen.
[0175] The pharmaceutical compositions formed by combining the
compound of the invention and the pharmaceutical acceptable
carriers are then readily administered in a variety of dosage forms
suitable for the disclosed routes of administration. The
formulations may conveniently be presented in unit dosage form by
methods known in the art of pharmacy.
[0176] The compounds of this invention are generally utilized as
the free substance or as a pharmaceutically acceptable salt
thereof. One example is an acid addition salt of a compound having
the utility of a free base. When a compound of the invention
contains a free base such salts are prepared in a conventional
manner by treating a solution or suspension of a free base of the
invention with a chemical equivalent of a pharmaceutically
acceptable acid. Representative examples are mentioned above.
[0177] Pharmaceutical compositions for oral administration may be
solid or liquid. Solid dosage forms for oral administration include
e.g. capsules, tablets, dragees, pills, lozenges, powders, granules
and tablette e.g. placed in a hard gelatine capsule in powder or
pellet form or e.g. in the form of a troche or lozenge. Where
appropriate, pharmaceutical compositions for oral administration
may be prepared with coatings such as enteric coatings or they can
be formulated so as to provide controlled release of the active
ingredient such as sustained or prolonged release according to
methods well known in the art. Liquid dosage forms for oral
administration include e.g. solutions, emulsions, suspensions,
syrups and elixirs.
[0178] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules
or tablets, each containing a predetermined amount of the active
ingredient, and which may include a suitable excipient.
Furthermore, the orally available formulations may be in the form
of a powder or granules, a solution or suspension in an aqueous or
non-aqueous liquid, or an oil-in-water or water-in-oil liquid
emulsion.
[0179] Suitable pharmaceutical carriers include inert solid
diluents or fillers, sterile aqueous solution and various organic
solvents. Examples of solid carriers are lactose, terra alba,
sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia,
magnesium stearate, stearic acid, lower alkyl ethers of cellulose,
corn starch, potato starch, gums and the like. Examples of liquid
carriers are syrup, peanut oil, olive oil, phospho lipids, fatty
acids, fatty acid amines, polyoxyethylene and water.
[0180] The carrier or diluent may include any sustained release
material known in the art, such as glyceryl monostearate or
glyceryl distearate, alone or mixed with a wax.
[0181] Any adjuvants or additives usually used for such purposes
such as colorings, flavourings, preservatives etc. may be used
provided that they are compatible with the active ingredients.
[0182] The amount of solid carrier may vary but will usually be
from about 25 mg to about 1 g. If a liquid carrier is used, the
preparation may be in the form of a syrup, emulsion, soft gelatine
capsule or sterile injectable liquid such as an aqueous or
non-aqueous liquid suspension or solution.
[0183] Tablets may be prepared by mixing the active ingredient with
ordinary adjuvants or diluents and subsequently compressing the
mixture in a conventional tabletting machine.
[0184] Pharmaceutical compositions for parenteral administration
include sterile aqueous and nonaqueous injectable solutions,
dispersions, suspensions or emulsions as well as sterile powders to
be reconstituted in sterile injectable solutions or dispersions
prior to use. Depot injectable formulations are also contemplated
as being within the scope of the present invention.
[0185] For parenteral administration, solutions of the compound of
the invention in sterile aqueous solution, aqueous propylene
glycol, aqueous vitamin E or sesame or peanut oil may be employed.
Such aqueous solutions should be suitably buffered if necessary and
the liquid diluent first rendered isotonic with sufficient saline
or glucose. The aqueous solutions are particularly suitable for
intravenous, intramuscular, subcutaneous and intraperitoneal
administration. The sterile aqueous media employed are all readily
available by standard techniques known to those skilled in the
art.
[0186] Solutions for injections may be prepared by dissolving the
active ingredient and possible additives in a part of the solvent
for injection, preferably sterile water, adjusting the solution to
the desired volume, sterilizing the solution and filling it in
suitable ampoules or vials. Any suitable additive conventionally
used in the art may be added, such as tonicity agents,
preservatives, antioxidants, etc.
[0187] Other suitable administration forms include suppositories,
sprays, ointments, cremes, gels, inhalants, dermal patches,
implants, etc.
[0188] A typical oral dosage is in the range of from about 0.001 to
about 100 mg/kg body weight per day, preferably from about 0.01 to
about 50 mg/kg body weight per day, and more preferred from about
0.05 to about 10 mg/kg body weight per day administered in one or
more dosages such as 1 to 3 dosages. The exact dosage will depend
upon the frequency and mode of administration, the sex, age, weight
and general condition of the subject treated, the nature and
severity of the disorder or disease treated and any concomitant
diseases to be treated and other factors evident to those skilled
in the art.
[0189] The formulations may conveniently be presented in unit
dosage form by methods known to those skilled in the art. A typical
unit dosage form for oral administration one or more times per day
such as 1 to 3 times per day may contain from 0.01 to about 1000
mg, such as about 0.01 to 100 mg, preferably from about 0.05 to
about 500 mg, and more preferred from about 0.5 mg to about 200
mg.
[0190] For parenteral routes such as intravenous, intrathecal,
intramuscular and similar administration, typically doses are in
the order of about half the dose employed for oral
administration.
[0191] Typical examples of recipes for the formulation of the
invention are as follows: [0192] 1) Tablets containing 5.0 mg of a
compound of the invention calculated as the free base:
TABLE-US-00002 [0192] Compound of the invention 5.0 mg Lactose 60
mg Maize starch 30 mg Hydroxypropylcellulose 2.4 mg
Microcrystalline cellulose 19.2 mg Croscarmellose Sodium Type A 2.4
mg Magnesium stearate 0.84 mg
[0193] 2) Tablets containing 0.5 mg of a compound of the invention
calculated as the free base:
TABLE-US-00003 [0193] Compound of the invention 0.5 mg Lactose 46.9
mg Maize starch 23.5 mg Povidone 1.8 mg Microcrystalline cellulose
14.4 mg Croscarmellose Sodium Type A 1.8 mg Magnesium stearate 0.63
mg
[0194] 3) Syrup containing per millilitre:
TABLE-US-00004 [0194] Compound of the invention 25 mg Sorbitol 500
mg Hydroxypropylcellulose 15 mg Glycerol 50 mg Methyl-paraben 1 mg
Propyl-paraben 0.1 mg Ethanol 0.005 mL Flavour 0.05 mg Saccharin
sodium 0.5 mg Water ad 1 mL
[0195] 4) Solution for injection containing per millilitre:
TABLE-US-00005 [0195] Compound of the invention 0.5 mg Sorbitol 5.1
mg Acetic Acid 0.05 mg Saccharin sodium 0.5 mg Water ad 1 mL
[0196] By the expression a compound of the invention is meant any
one of the embodiments of formula I as described herein.
[0197] In a further aspect the present invention relates to a
method of preparing a compound of the invention as described in the
following.
Methods of Preparation of the Compounds of the Invention
[0198] The compounds of the invention of the general formula I,
wherein q, Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6
and R.sup.7 are as defined above may be prepared by the methods as
represented in the schemes and as described below.
[0199] In the compounds of the general formulae I-XXV,
q, Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 are as defined under formula I.
[0200] Compounds of the general formulae II, III, V, VII, XV, XXI,
XXII, XXIII, XXIV and XXV are either obtained from commercial
sources, or prepared by standard methods known to chemists skilled
in the art.
General Methods
##STR00007##
[0202] Compounds of the general formula I (scheme 1) may be
prepared by reacting compounds of the general formula II with
suitable electrophilic reagents, such as, but not limited to,
suitably substituted carboxylic acid fluorides, carboxylic acid
chlorides, carboxylic acid bromides, carboxylic acid iodides,
carboxylic acid anhydrides, activated esters, chloro formates,
chloro thioformates, and with or without the addition of bases,
such as pyridine, trialkyl amines, potassium carbonate, sodium
hydrogen carbonate, magnesium oxide or lithium-, sodium-, or
potassium alcoholates, in a suitable solvent, such as ethyl
acetate, dioxane, tetrahydrofuran, acetonitrile or diethyl ether,
at suitable temperatures, such as room temperature or reflux
temperature. Activated esters and carboxylic acid anhydrides can be
prepared from suitably substituted carboxylic acids under
conditions known to chemists skilled in the art, as described by F.
Albericio and L. A. Carpino, "Coupling reagents and activation" in
Methods in enzymology: Solid-phase peptide synthesis, pp. 104-126,
Academic Press, New York, 1997. Carboxylic acid halides can be
prepared from suitably substituted carboxylic acids by activation
with reagents such as, but not limited to, thionyl chloride, oxalyl
chloride, phosphorus tribromide or phosphorus triiodide under
conditions well known to chemists skilled in the art.
##STR00008##
[0203] Compounds of the general formula IV (scheme 2) may be
prepared by reacting compounds of the general formula III with
suitable electrophilic reagents as described under scheme 1 for the
preparation of compounds of the general formula I.
[0204] Compounds of the general formula I, wherein R.sup.4 is
C.sub.3-8-heterocycloalk(en)yl, Ar--C.sub.1-6-heterocycloalk(en)yl,
Het or NR.sup.5R.sup.6 (scheme 2), may be prepared by reacting
compounds of the general formula IV with suitably substituted
nitrogen-containing compounds in the presence of a palladium or
copper catalyst, such as bis(dibenzylideneacetone)palladium or
copper(II) trifluoromethanesulfonate with the addition of a
suitable ligand, such as
(2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine or
1,10-phenanthroline in the presence of a base, such as potassium
carbonate or lithium-, sodium-, or potassium alcoholates, in a
suitable solvent, such as toluene or tetrahydrofuran, at suitable
temperatures, such as room temperature or reflux temperature as
described by S. L. Buchwald et al. (M. C. Harris, X. Hang and S. L.
Buchwald, Org. Lett., 2002, 4, 2885 and A. Kiyomori, J. F. Marcoux
and S. L. Buchwald, Tet. Lett., 1999, 40, 2657).
[0205] Additionally, compounds of the general formula I, wherein
R.sup.4 is Ar or Het (scheme 2), can be prepared from compounds of
the general formula IV, by means of cross-coupling reactions known
to chemists skilled in the art, such as Suzuki coupling, Stille
coupling, or other transition metal catalyzed cross-coupling
reactions (D. W. Knight, "Coupling reactions between sp2 carbon
centers" in Comprehensive Organic Synthesis, v. 3, pp. 481-520,
Pergamon Press, 1991).
[0206] Additionally, compounds of the general formula I, wherein
R.sup.4 is C.sub.1-6-alk(en/yn)yl, C.sub.3-8-cycloalk(en)yl,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
halo-C.sub.1-6-alk(en/yn)yl, halo-C.sub.3-8-cycloalk(en)yl,
halo-C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl,
Ar--C.sub.1-6-alk(en/yn)yl, Ar--C.sub.3-8-cycloalk(en)yl or
Ar--C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yl (scheme 2), may
be prepared from compounds of the general formula. IV, by means of
cross-coupling reactions known to chemists skilled in the art, such
as Negishi coupling (E.-I. Negishi, A. O. King and N. Okukado, J.
Org. Chem., 1977, 42, 1821), Sonogashira coupling (K. Sonogashira,
Y. Tohda and N. Hagihara, Tet. Lett., 1975, 16, 4467), or other
transition metal catalyzed cross-coupling reactions such as copper
catalyzed reactions (W. Dohle, D. M. Lindsay and P. Knochel, Org.
Lett., 2001, 3, 2871).
[0207] Additionally, compounds of the general formula I, wherein
R.sup.4 is cyano (scheme 2), may be prepared from compounds of the
general formula IV, by means of nickel-catalyzed cyanation
reactions known to chemists skilled in the art as described by L.
Cassar, J. Organomet. Chem., 1973, 54, C57-C58.
##STR00009##
[0208] Compounds of the general formula VI (scheme 3) may be
prepared by reacting compounds of the general formula V with
suitable electrophilic reagents as described under scheme for the
preparation of compounds of the general formula I.
[0209] Compounds of the general formula I (scheme 3) may be
prepared from compounds of the general formula VI by means of
cross-coupling reactions or cyanation reactions as described under
scheme 2 for the preparation of compounds of the general formula
I.
[0210] Compounds of the general formula I, wherein R.sup.1=R.sup.2
(scheme 3), may be prepared from compounds of the general formula
VI, wherein R.sup.1=R.sup.2=Br, by means of cross-coupling
reactions or cyanation reactions as described under scheme 2 for
the preparation of compounds of the general formula I.
##STR00010##
[0211] Compounds of the general formula VIII (scheme 4) may be
prepared by reacting compounds of the general formula VII with
suitable electrophilic reagents as described under scheme 1 for the
preparation of compounds of the general formula I.
[0212] Compounds of the general formula IX (scheme 4) may be
prepared from compounds of the general formula VIII by nitration
reactions known to chemists skilled in the art, such as reaction
with concentrated nitric acid or sodium nitrite, in a suitable
solvent, such as glacial acetic acid, acetic anhydride,
trifluoroacetic acid or mixtures thereof, at appropriate
temperatures, as described by P. B. D. de la Mare and J. H. Ridd,
"Preparative methods of nitration" in Aromatic substitutions, pp.
48-56. Butterworths Scientific Publications, London, 1959.
[0213] Compounds of the general formula X (scheme 4) may be
prepared from compounds of the general formula IX, by reducing the
nitro group to an amino group, with suitable reducing agents such
as zinc or iron powder in the presence of acid such as acetic acid
or aqueous hydrochloric acid, or by hydrogen gas or ammonium
formiate in the presence of a suitable hydrogenation catalyst such
as palladium on activated carbon in suitable solvents such as
methanol, ethanol or tetrahydrofuran, at suitable temperatures or
under ultrasonic irradiation. Alternatively, tin (II) chloride or
sodium dithionite can be used as reducing agents under conditions
well known to chemists skilled in the art.
[0214] Compounds of the general formula XI (scheme 4) may be
prepared from compounds of the general formula X, by means of
reductive alkylation reactions, known to chemists skilled in the
art, with suitably substituted aldehydes or ketones using reducing
agents, such as sodium borohydride, sodium cyanoborohydride or
hydrogen gas in the presence of a suitable hydrogenation catalyst
such as palladium on activated carbon in a suitable solvent, such
as methanol, ethanol, THF, water, dioxane or mixtures thereof, with
or without addition of catalytic amounts of acid, such as acetic
acid, at suitable temperatures.
[0215] Alternatively, compounds of the general formula X (scheme 4)
may be reacted with suitably substituted aldehydes or ketones in a
suitable solvent, such as methanol, ethanol, THF, dioxane, xylene,
or mixtures thereof, with or without addition of catalytic amounts
of acid, such as acetic acid or acidic ion exchange resin, at
suitable temperatures, to form imines, that can be isolated by
crystallisation or by evaporation of the solvent. The imines can
then be reduced using reducing reagents as described above, to form
compounds of the general formula XI.
[0216] Compounds of the general formula XII (scheme 4) may be
prepared from compounds of the general formula XI, by means of
reductive alkylation reactions or imine formation followed by
reduction as described above.
[0217] Alternatively, compounds of the general formula XII (scheme
4) may be prepared from compounds of the general formula X, by
means of reductive alkylation reactions with a suitably substituted
aldehyde or ketone (to introduce R.sup.5) followed by addition of
another suitably substituted aldehyde or ketone (to introduce
R.sup.6) in the presence of excess reducing agent.
##STR00011##
[0218] Compounds of the general formula XIII (scheme 5) may be
prepared by reacting compounds of the general formula IV with a
suitable base such as isopropylmagnesium chloride or methyl lithium
followed by addition of an alkyl or aryl lithium derivative, such
as tert-butyllithium and quenching with a suitable electrophile,
such as N,N-dimethylformamide at suitable temperatures as described
by L. E, Overman and S. E. Angle. J. Org. Chem., 1985, 50,
4021.
[0219] Compounds of the general formula XIV (scheme 5) may be
prepared from compounds of the general formula XIII, by means of
reductive alkylation reactions, known to chemists skilled in the
art, with suitably substituted amines using reducing agents, such
as sodium borohydride, sodium cyanoborohydride or hydrogen gas in
the presence of a suitable hydrogenation catalyst such as palladium
on activated carbon in a suitable solvent, such as methanol,
ethanol, THF, water, dioxane or mixtures thereof, with or without
addition of catalytic amounts of acid, such as acetic acid, at
suitable temperatures.
[0220] Alternatively, compounds of the general formula XIII (scheme
5) may be reacted with suitably substituted amines in a suitable
solvent, such as methanol, ethanol, THF, dioxane, xylene, or
mixtures thereof, with or without addition of catalytic amounts of
acid, such as acetic acid or acidic ion exchange resin, at suitable
temperatures, to form imines, that can be isolated by
crystallisation or by evaporation of the solvent. The imines can
then be reduced using reducing reagents as described above, to form
compounds of the general formula XIV.
##STR00012##
[0221] Compounds of the general formula XVI (scheme 6) may be
prepared by reacting compounds of the general formula XV with
suitable electrophilic reagents as described under scheme 1 for the
preparation of compounds of the general formula I.
[0222] Compounds of the general formula. XVII (scheme 6) may be
prepared from compounds of the general formula XVI, by reducing the
nitro group as described under scheme 4 for the preparation of
compounds of the general formula X.
[0223] Compounds of the general formula I, wherein R.sup.2 is
4-morpholinyl (scheme 6), may be prepared by reacting compounds of
the general formula XVII with suitably substituted
bis-(2-haloethyl)ethers and with or without the addition of bases,
such as trialkyl amines, potassium carbonate or lithium-, sodium-,
or potassium alcoholates, in a suitable solvent, such as dimethyl
sulfoxide or N,N-dimethylformamide, at suitable temperatures, such
as reflux temperature.
##STR00013##
[0224] Compounds of the general formula XVIII (scheme 7) may be
prepared from compounds of the general formula VII, by means of
nitration in acetic anhydride as described under scheme 4 for the
preparation of compounds of the general formula IX.
[0225] Compounds of the general formula XIX (scheme 7) may be
prepared from compounds of the general formula XVIII, by means of
amide hydrolysis with a suitable strong acid, such as concentrated
hydrochloric acid at suitable temperatures, such as room
temperature or reflux temperature.
[0226] Compounds of the general formula IX (scheme 7) may be
prepared by reacting compounds of the general formula XIX with
suitable electrophilic reagents as described under scheme 1 for the
preparation of compounds of the general formula I.
##STR00014##
[0227] Compounds of the general formula II (scheme 8) may be
prepared from compounds of the general formula XX, by means of
amide hydrolysis with a suitable strong acid as described under
scheme 7 for the preparation of compounds of the general formula
XIX.
##STR00015##
[0228] Compounds of the general formula II, wherein R.sup.4 is Cl,
Br or I (scheme 9), may be prepared from compounds of the general
formula VII, by means of electrophilic aromatic substitution well
known to chemists skilled in the art, with appropriate
electrophiles such as N-chlorosuccinimide, N-bromosuccinimide,
N-iodosuccinimide, chlorine, bromine, iodine or iodochloride in a
suitable solvent such as acetic acid, as described by P. B. D. de
la Mare and J. H. Ridd, "Preparative methods of aromatic
halogenation" in Aromatic substitutions, pp. 105-115, Butterworths
Scientific Publications, London, 1959.
[0229] Alternatively, compounds of the general formula II, wherein
R.sup.2 is Cl, Br or I (scheme 9) may be prepared from compounds of
the general formula XXII, by means of electrophilic aromatic
substitution as described above.
##STR00016##
[0230] Compounds of the general formula XXIII (scheme 10) may be
prepared from compounds of the general formula XXII, by means of
nitration reactions as described under scheme 4 for the preparation
of compounds of the general formula IX.
[0231] Compounds of the general formula II (scheme 10) may be
prepared from compounds of the general formula XXIII, by reducing
the nitro group as described under scheme 4 for the preparation of
compounds of the general formula X.
##STR00017##
[0232] Compounds of the general formula XXIII, wherein R.sup.2 is
C.sub.1-6-alk(en/yn)yloxy, C.sub.3-8-cycloalk(en)yloxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy,
C.sub.3-8-heterocycloalk(en)yloxy or C.sub.3-8-heterocycloalk(en)yl
(scheme 11), may be prepared from compounds of the general formula
XXIV, by means of nucleophilic aromatic substitution, with a
suitable nucleophile such as alcohols, phenols, amines or anilines
in their neutral or deprotonated form, and with or without the
addition of bases, such as pyridine, trialkyl amines, potassium
carbonate, magnesium oxide or lithium-, sodium-, or potassium
alcoholates, in a suitable solvent, such as dimethyl sulfoxide or
N,N-dimethylformamide, at suitable temperatures, such as room
temperature or reflux temperature.
##STR00018##
[0233] Compounds of the general formula XXIII, wherein R.sup.4 is
C.sub.1-6-alk(en/yn)yloxy, C.sub.3-8-cycloalk(en)yloxy,
C.sub.3-8-cycloalk(en)yl-C.sub.1-6-alk(en/yn)yloxy,
C.sub.3-8-heterocycloalk(en)yloxy or C.sub.3-8-heterocycloalk(en)yl
(scheme 12), may be prepared from compounds of the general formula
XXV, by means of nucleophilic aromatic substitution as described
under scheme 11 for the preparation of compounds of the general
formula XXIII.
[0234] Additionally, for further variation of R.sup.1, R.sup.2, Ar
and Het-groups, compounds containing a methoxy-group, can be
demethylated by methods known to chemists skilled in the art, such
as treatment with boron tribromide in a suitable solvent, such as
dichloromethane, at suitable temperatures, such as 0.degree. C. or
room temperature. The resulting phenols can then be alkylated or
arylated by methods known to chemists skilled in the art. Such
methods include: (a) the reaction with electrophiles, such as alkyl
chlorides, alkyl bromides, alkyl iodides, benzyl chlorides, benzyl
bromides, benzyl iodides, carbonic acid chlorides, carbonic acid
bromides, or carbonic acid anhydrides in the presence of suitable
bases, such as potassium carbonate, in a suitable solvent, such as
tetrahydrofuran, N,N-dimethylformamide, or 1,2-dichloroethane, at
suitable temperatures, such as room temperature or reflux
temperature; (b) the reaction with alkyl, benzylic, or
heteroarylalkyl alcohols under conditions known as the Mitsunohu
reaction (O. Mitsunobu, Synthesis 1981, 1).
[0235] Compounds containing functional groups, such as hydroxy and
amino groups, not compatible with suggested reaction conditions,
can be protected and deprotected by methods known to chemists
skilled in the art, as described by T. W. Greene and P. G. M. Wuts,
Protective groups in organic synthesis, 2.sup.nd edition, Wiley
Interscience, 1991. In particular, amino groups can be protected by
groups such as, but not limited to, ten-butoxycarbonyl,
trifluoroacetyl, fluorenylmethyloxycarbonyl or masked as a nitro
group, and hydroxy groups can be protected as, but not limited to,
methyl-, ten-butyl-, trialkylsilyl-, allyl- or trityl ethers.
[0236] Alkynes prepared by Sonogashira reactions may be reduced to
alkenes or alkanes by reduction with hydrogen gas or ammonium
formiate in the presence of a suitable hydrogenation catalyst such
as palladium on activated carbon or platinum on activated carbon in
suitable solvents such as methanol, ethanol or tetrahydrofuran, at
suitable temperatures as described by S. Siegel, "Heterogeneous
catalytic hydrogenation of C.dbd.C and alkenes" in Comprehensive
Organic Synthesis, v. 8, pp. 417-442, Pergamon Press, 1991.
[0237] Suitably substituted aryl halides can be converted to
boronic acids or boronic esters by methods known to chemists
skilled in the art as described by W. Gerrard, The chemistry of
boron, Academic Press, New York, 1961 and T. Ishiyama, M. Murata,
N. Miyaura, J. Org. Chem., 1995, 60, 7508.
[0238] Suitably substituted carboxylic acids can be converted to
aldehydes by methods known to chemists skilled in the art as
described by R. A. W. Johnstone, "Reduction of carboxylic acids to
aldehydes by metal hydrides" in Comprehensive Organic Synthesis, v.
8, pp. 259-281, Pergamon Press, 1991.
[0239] Suitably substituted carboxylic acids can be converted to
alcohols by methods known to chemists skilled in the art as
described by A. G. M. Barrett, "Reduction of carboxylic acid
derivatives to alcohols, ethers and amines" in Comprehensive
Organic Synthesis, v. 8, pp. 235-257, Pergamon Press, 1991.
[0240] Suitably substituted alcohols can be converted to aldehydes
by methods known to chemists skilled in the art as described by T.
V. Lee, "Oxidation adjacent to oxygen of alcohols by activated DMSO
methods" in Comprehensive Organic Synthesis, v. 7, pp. 291-303,
Pergamon Press, 1991.
Preparation of Intermediates
[0241] Analytical LC-MS data were obtained on a PE Sciex API 150EX
instrument equipped with atmospheric pressure photo ionisation and
a Shimadzu LC-8A/SLC-10A LC system. Column: 30.times.4.6 mm Waters
Symmetry C18 column with 3.5 .mu.m particle size; Solventsystem:
A=water/trifluoroacetic acid (100:0.05) and
B=water/acetonitrile/trifluoroacetic acid (5:95:0.03); Method:
Linear gradient elution with 90% A to 100% B in 4 minutes and with
a flow rate of 2 mL/minute. Purity was determined by integration of
the UV (254 nm) and ELSD trace. The retention times (t.sub.R) are
expressed in minutes.
[0242] Preparative LC-MS-purification was performed on the same
instrument with atmospheric pressure chemical ionisation. Column:
50.times.20 mm YMC ODS-A with 5 .mu.m particle size; Method: Linear
gradient elution with 80% A to 100% B in 7 minutes and with a flow
rate of 22.7 mL/minute. Fraction collection was performed by
split-flow MS detection.
[0243] Analytical LC-MS-TOF (TOF=time of (light) data were obtained
on a micromass LCT 4-ways MUX equipped with a Waters 2488/Sedex 754
detector system. Column: 30.times.4.6 mm Waters Symmetry C18 column
with 3.5 .mu.m particle size; Solventsystem:
A=water/trifluoroacetic acid (100:0.05) and
B=water/acetonitrile/trifluoroacetic acid (5:95:0.03); Method:
Linear gradient elution with 90% A to 100% B in 4 minutes and with
a flow rate of 2 mL/minute. Purity was determined by integration of
the UV (254 nm) and ELSD trace. The retention times (t.sub.R) are
expressed in minutes.
[0244] GC-MS data were obtained on a Varian CP 3800
gaschromatograph fitted with a Phenomenex column (Zebron ZB-5,
length: 15 metres, internal diameter: 0.25 mm) coupled to a Varian
Saturn 2000 iontrap mass spectrometer. Method: Duration 15 minutes,
column flow 1.4 mL/minute (carrier gas was helium), oven gradient:
0-1 minute, 60.degree. C.; 1-13 minutes, 60-300.degree. C.; 13-15
minutes, 300.degree. C.
[0245] .sup.1H NMR spectra were recorded at 500.13 MHz on a Bruker
Avance DRX 500 instrument. Deuterated chloroform (99.8% D) or
dimethyl sulfoxide (99.8% D) were used as solvents. TMS was used as
internal reference standard. Chemical shift values are expressed in
ppm-values. The following abbreviations are used for multiplicity
of NMR signals: s=singlet, d=doublet, t=triplet, q=quartet,
qui=quintet, h=heptet, dd=double doublet, ddd=double double
doublet, dt=double triplet, dq=double quartet, tt=triplet of
triplets, m=multiplet and b=broad singlet.
Preparation of Intermediates
(4-Formyl-2,6-dimethyl-phenyl) acid ethyl ester
[0246] To (4-bromo-2,6-dimethyl-phenyl)-carbamic acid ethyl ester
(It, 1.0 g) dissolved in dry tetrahydrofuran (25 mL) under argon
was added isopropylmagnesium chloride (2 M in tetrahydrofuran, 1.9
mL) over 5 minutes and then stirred for 30 minutes. The reaction
mixture was cooled to -78.degree. C. and tert-butyllithium (1.7 M
in heptane, 4.5 mL) was added dropwise while keeping the internal
temperature below -65.degree. C. The temperature of the reaction
was raised to -10.degree. C. after complete addition, and then
cooled to -78.degree. C. again followed by addition of
N,N-dimethylformamide (0.6 mL). The reaction was stirred for 30
minutes at -78.degree. C., 30 minutes at 25.degree. C. and then
poured onto crushed ice mixed with acetic acid (25 mL). The mixture
was stirred for 30 minutes, extracted with ethyl acetate
(3.times.100 mL), dried over magnesium sulfate, and concentrated in
vacuo. The crude product was subjected to flash chromatography to
furnish 0.60 g (73% yield) of the title compound as a white solid.
LC-MS (m/z) 222 (MH.sup.+); t.sub.R=2.14, (UV, ELSD) 86%, 99%.
.sup.1H NMR (500 MHz, CDCl.sub.3): 1.30 (t, 3H), 2.34 (s, 6H), 4.21
(q, 2H), 6.28 (b, 1H), 7.59 (s, 2H), 9.92 (s, 1H).
[0247] The following compounds were prepared analogously:
(4-Formyl-2,6-dimethyl-phenyl)-carbamic acid propyl ester
[0248] Yield: 60%. LC-MS (m/z) 236 (MH.sup.+); t.sub.R=2.42, (UV,
ELSD) 96%, 99%. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 0.92 (t, 3H),
1.63 (m, 2H), 2.25 (s, 6H), 4.02 (t, 2H), 7.62 (s, 2H), 9.02 (b,
1H), 9.91 (s, 1H).
2-Cyclopentyl-N-(4-formyl-2,6-dimethyl-phenyl)-acetamide
[0249] Yield: 66%. LC-MS (m/z) 260 (MH.sup.+); t.sub.R=2.52, (UV,
ELSD) 97%, 97%. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 1.23 (m, 2H),
1.53 (m, 2H), 1.63 (m, 2H), 1.79 (m, 2H), 2.22 (s, 6H), 2.27 (m,
1H), 2.35 (d, 2H), 7.61 (s, 2H), 9.46 (s, 1H), 9.91 (s, 1H).
Pentanoic acid (4-formyl-2,6-dimethyl-phenyl)-amide
[0250] Yield: 94%. LC-MS (m/z) 234 (MH.sup.+); t.sub.R=2.27, (UV,
ELSD) 95%, 99%. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 0.92 (t, 3H),
1.45 (m, 2H), 1.63 (m, 2H), 2.20 (s, 6H), 2.35 (t, 2H), 7.60 (s,
2H), 9.45 (s, 1H), 9.90 (s, 1H).
2-(4-(Chloro-phenyl)-N-(4-dimethyl-2,6-dimethyl-phenyl)-acetamide
[0251] Yield: 53%. LC-MS (m/z) 302 (MH.sup.+); t.sub.R=2.72, (UV,
ELSD) 96%, 95%. .sup.1H NMR (500 MHz. DMSO-d.sub.6): 2.17 (s, 6H),
3.70 (s, 2H), 7.40 (m, 4H), 7.60 (s, 2H), 9.75 (s, 1H), 9.90 (s,
1H).
(4-Formyl-2,6-dimethyl-phenyl)-carbamic acid 2-methoxy-ethyl
ester
[0252] Yield: 47%. LC-MS (m/z) 252 (MH.sup.+); t.sub.R=1.81, (UV,
ELSD) 93%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 2.35 (m, 6H),
3.35 (m, 3H), 3.65 (m, 2H), 4.35 (m, 2H), 6.35 (broad s, 1H), 7.60
(s, 2H), 9.95 (s, 1H).
2-Cyclopentyl-N-(2,6-dichloro-4-formyl-phenyl)-acetamide
[0253] Yield: 85%. LC-MS (m/z) 300 (MH.sup.+); t.sub.R=2.89, (UV,
ELSD) 96%, 98%. .sup.1H NMR (500 MHz, CDCl.sub.3): 1.25 (m, 2H),
1.63 (m, 4H), 1.95 (m, 2H), 2.45 (m, 1H), 2.50 (d, 2H), 7.17
(broad, 1H), 7.83 (s, 2H), 9.90 (s, 1H).
(4-Bromo-2,6-dimethyl-phenyl)-carbamic acid 2-methoxy-ethyl
ester
[0254] 4-Bromo-2,6-dimethyl-aniline (20) g) and chloroformic acid
2-methoxyethyl ester (1.52 g) were dissolved in acetonitrile (25
mL) and heated to 130.degree. C. for 15 minutes in a sealed
microwave process vial. Water (25 mL) was added to the reaction
mixture, and the product was collected by filtration and washed
with water (25 mL) and heptane (25 mL) to furnish 2.48 g (82%
yield) of the title compound as a white solid. LC-MS (m/z) 304
(MH.sup.+); t.sub.R=2.93, (UV, ELSD) 96%, 97%. .sup.1H NMR (500
MHz, CDCl.sub.3): 2.36 (m, 6H), 3.40 (m, 3H), 3.60 (m, 2H), 4.35
(m, 2H), 6.55 (broad s, 1H), 7.45 (s, 2H).
N-(4-Bromo-2,6-dichloro-phenyl)-2-cyclopentyl-acetamide
[0255] 4-Bromo-2,6-dichloroaniline (12.1 g) and cyclopentylacetyl
chloride (8.1 g) were dissolved in tetrahydrofuran (100 mL) and
sodium carbonate (6.4 g) is added, followed by heating to reflux
for 6 hours. The reaction mixture was cooled to ambient temperature
and filtered and diluted with water (250 ml). After extraction, the
combined organic phase was concentrated in vacuo to furnish 14.0 g
(80% yield) of the title compound as a white solid. LC-MS (m/z) 352
(MH.sup.+); t.sub.R=3.47, (UV, ELSD) 96%, 99%. .sup.1H NMR (500
MHz, DMSO-d.sub.6): 1.12 (m, 2H), 1.50 (m, 4H), 1.80 (m, 2H), 2.15
(m, 1H), 2.50 (d, 2H), 5.70 (broad s, 1H), 7.45 (s, 2H).
N-(2,6-Dimethyl-4-nitro-phenyl)-acetamide
[0256] 2,6-Dimethylaniline (30.2 g) was added slowly to acetic
anhydride (200 mL) cooled to 0.degree. C. over 10 minutes. After 30
minutes, acetic acid (40 mL) and fuming nitric acid (15 mL) were
added to the reaction mixture and the cooling was removed. The
reaction mixture was filtered after 1 hour and the crystals were
washed with water and dried in vacuo to furnish 5.20 g (30% yield)
of the title compound as a yellow solid. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): 2.10 (s, 3H), 2.26 (s, 6H), 7.98 (s, 2H), 9.61 (s,
1H).
N-(4-Amino-2,6-dimethyl-phenyl)-acetamide
[0257] Zinc dust (30 g) was added in portions over 10 minutes to
N-(2,6-dimethyl-4-nitro-phenyl)-acetamide (5.09 g) in
tetrahydrofuran (200 mL) and acetic acid (60 mL) cooled to
0.degree. C. The reaction mixture was filtered after 30 minutes
through silica (50 g), which was washed with methanol/ethyl acetate
(20:80, 100 mL). The organic phase was washed with saturated
aqueous sodium bicarbonate (100 mL) and treated with heptane until
the title compound precipitated, which was collected, washed with
heptane and dried in vacuo to furnish 1.20 g (28% yield) of the
title compound as a pale red solid. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): 1.95 (s, 3H), 1.96 (s, 6H), 4.82 (s, 2H), 6.23 (s,
2H), 8.79 (s, 1H).
2,6-Dimethyl-4-nitro phenylamine
[0258] Concentrated hydrochloric acid (17.5 mL) was added to
N-(2,6-dimethyl-4-nitro-phenyl)-acetamide (5.05 g) and heated to
140.degree. C. for 30 minutes in a sealed microwave process vial.
The reaction mixture was neutralized with solid sodium carbonate in
water and the precipitated product was collected by filtration and
washed with water (100 mL) to furnish 3.93 g (97% yield) of the
title compound as a yellow solid. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): 2.15 (s, 6H), 6.15 (b, 2H), 7.79 (s, 2H).
2-Cyclopentyl-N-(2,6-dimethyl-4-nitro-phenyl)-acetamide
[0259] 2,6-Dimethyl-4-nitro-phenylamine (0.98 g) and
cyclopentylacetyl chloride (0.99 mL) were dissolved in acetonitrile
(10 mL) and heated to 150.degree. C. for 5 minutes in a sealed
microwave process vial. Water (10 mL) was added to the reaction
mixture, and the product was collected by filtration and washed
with water (20 mL) and heptane (20 mL) to furnish 1.45 g (89%
yield) of the title compound as a yellow solid. .sup.1H NMR (500
MHz, DMSO-d.sub.6): 1.24 (m, 2H), 1.54 (m, 2H), 1.63 (m, 2H), 1.79
(m, 2H), 2.25 (s, 6H), 2.27 (m, 1H), 2.36 (d, 2H), 7.98 (s, 2H),
9.56 (s, 1H).
[0260] The following compound was prepared analogously:
N-(2,6-Dimethyl-4-nitro-phenyl)-3,3-dimethyl-butyramide
[0261] Yield: 96%. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 1.07 (s,
9H), 2.26 (s, 2H), 2.27 (s, 6H), 7.98 (s, 2H), 9.52 (s, 1H).
N-(2-Chloro-6-methyl-4-nitro-phenyl)-2-(4-fluoro-phenyl)-acetamide
[0262] LC-MS (m/z) 323 (MH.sup.+); t.sub.R=2.85, (UV, ELSD) 57%,
98%
N-(2-Chloro-4-nitro-6-trifluoromethyl-phenyl)-2-cyclopentyl-acetamide
[0263] LC-MS (m/z) 351 (ME); t.sub.R=3.10, (UV, ELSD) 97%, 98%.
.sup.1H NMR (500 MHz, CDCl.sub.3): 1.20 (m, 2H), 1.60 (m, 4H), 1.90
(m, 2H), 2.35 (m, 1H), 2.50 (d, 2H), 7.1 (broad, 1H), 8.45 (d, 1H),
8.55 (d, 1H).
N-(4-Amino-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide
[0264] Zinc dust (10 g) was added in portions over 10 minutes to
2-cyclopentyl-N-(2,6-dimethyl-4-nitro-phenyl)-acetamide (1.45 g) in
tetrahydrofuran (40 mL) and acetic acid (10 mL) cooled to 0.degree.
C. The reaction mixture was stirred 2 hours at 25.degree. C.,
neutralized with solid sodium carbonate and filtered through silica
(50 g), which was washed with ethyl acetate (200 mL). The organic
phase was concentrated in vacuo to furnish 1.15 g (89% yield) of
the title compound as a light orange solid. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): 1.20 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 1.75 (m,
2H), 1.96 (s, 6H), 2.22 (m, 1H), 2.23 (d, 2H), 4.81 (b, 2H), 6.23
(s, 2H), 8.74 (s, 1H).
[0265] The following compound was prepared analogously:
N-(4-Amino-2,6-dimethyl-phenyl)-3,3-dimethyl-butyramide
[0266] Yield: 96%. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 1.04 (s,
9H), 1.98 (s, 6H), 2.13 (s, 2H), 4.81 (b, 2H), 6.24 (s, 2H), 8.69
(s, 1H).
N-(4-Amino-2-chloro-6-methyl-phenyl)-2-(4-fluoro-phenyl)-acetamide
[0267] LC-MS (m/z) 293 (MH.sup.+); t.sub.R=1.77, (UV, ELSD) 98%,
99%.
N-(4-Amino-2-chloro-6-trifluoromethyl-phenyl)-2-cyclopentyl-acetamide
[0268] LC-MS (m/z) 321 (MH.sup.+); t.sub.R=2.52, (UV, ELSD) 92%,
96%. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 1.15 (m, 2H), 1.55 (m,
4H), 1.75 (m, 2H), 2.20 (m, 2H), 2.40 (m, 1H), 5.80 (s, 2H), 6.85
(d, 1H), 6.95 (d, 1H), 9.20 (s, 1H).
N-(4-Bromo-2-methyl-6-nitro-phenyl)-3,3-dimethyl-butyramide
[0269] 4-Bromo-2-methyl-6-nitro-phenylamine (2.22 g) and
tart-butylacetyl chloride (1.30 g) were mixed in acetonitrile (3
mL) and heated to 140.degree. C. for 40 minutes in a sealed
microwave process vial. Water (5 mL) was added and the product was
collected by filtration and washed with water and heptane to
furnish 2.80 g (86% yield) of the title compound as a yellow solid.
LC-MS (m/z) 329 (MH.sup.+); t.sub.R=3.07, (UV, ELSD) 96%, 99%.
.sup.1H NMR (500 MHz, DMSO-d.sub.6): 1.01 (s, 9H), 2.21 (s, 2H),
2.29 (s, 3H), 7.87 (d, 1H) 7.95 (d, 1H), 9.77 (s, 1H).
2,6,N'-Trimethyl-N'-(4-trifluoromethyl-benzyl)-benzene-1,4-diamine
[0270] Concentrated aqueous hydrochloric acid (2 mL) was added to
N-{2,6-dimethyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-aceta-
mide (0.20 g) and heated to 130.degree. C. for 80 minutes in a
sealed microwave process vial. The crude mixture was poured onto
solid potassium hydroxide (2 g) mixed with ice. The product was
extracted with 1,2-dichloroethane (100 mL), and the organic phase
was filtered through solid sodium carbonate (5 g), dried over
magnesium sulfate and concentrated in vacuo to furnish 0.10 g (57%
yield) of the title compound as a pale brown oil. LC-MS (m/z) 309
(MH.sup.+); t.sub.R=2.11, (UV, ELSD) 99%, 98%. .sup.1H NMR (500
MHz, DMSO-d.sub.6): 2.03 (s, 6H), 2.76 (s, 3H), 3.94 (b, 2H), 4.41
(s, 2H), 6.39 (s, 2H), 7.42 (d, 2H), 7.65 (d, 2H).
(2,6-Dimethyl-phenyl)-carbamic acid propyl ester
[0271] 2,6-Dimethyl-aniline (3.0 mL) and propyl chloroformate (4.1
mL) were dissolved in acetonitrile (15 mL) and heated to
150.degree. C. for 10 minutes in a sealed microwave process vial.
The reaction mixture was concentrated in vacuo to furnish 4.79 g
(95% yield) of the title compound as a brown solid. The crude
product was used without further purification. .sup.1H NMR (500
MHz, CDCl.sub.3): 0.98 (t, 3H), 1.70 (m, 2H), 2.26 (s, 6H), 4.10
(t, 2H), 6.02 (s, 1H), 7.07 (m, 3H).
(2,6-Dimethyl-4-nitro-phenyl)-carbamic acid propyl ester
[0272] To a solution of concentrated nitric acid (6.4 mL) in water
(30 mL) was added (2,6-dimethyl-phenyl)-carbamic acid propyl ester
(2.72 g), acetic acid (30 mL) and sodium nitrite (1.0 g). The
reaction mixture was refluxed for 16 hours, water (200 mL) was
added and the mixture was cooled to 0.degree. C. The product was
collected by filtration and dried in vacuo to furnish 1.40 g (42%
yield) of the title compound as a yellow solid. The crude product
was used without further purification. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): 0.92 (t, 3H), 1.63 (m, 2H), 2.29 (s, 6H), 4.04 (t,
2H), 7.98 (s, 2H), 9.11 (b, 1H).
(4-Amino-2,6-dimethyl-phenyl)-carbamic acid propyl ester
[0273] Aqueous hydrochloric acid (0 M, 8.3 mL) was added slowly to
a mixture of zinc dust (4.9 g) and
(2,6-dimethyl-4-nitro-phenyl)-carbamic acid propyl ester (1.26 g)
in tetrahydrofuran (50 mL) cooled to 0.degree. C. The reaction
mixture was then stirred for 5 hours at 25.degree. C., and the pH
adjusted to 10 with 25% aqueous ammonia. The product was extracted
with ethyl acetate (3.times.50 mL), the combined organic phases
were dried over magnesium sulfate and concentrated in vacuo to
furnish 1.1 g (99% yield) of the title compound as a dark oil. The
crude product was used without further purification. .sup.1H NMR
(500 MHz, DMSO-d.sub.6): 0.91 (t, 3H), 1.60 (m, 2H), 1.99 (s, 6H),
3.95 (t, 2H), 4.82 (s, 2H), 6.23 (s, 2H), 8.14 (s, 1H).
4-(3,5-Difluoro-2-nitro-phenyl)-morpholine
[0274] 2,4,6-Trifluoronitrobenzene (4.95 g) and potassium carbonate
(4.63 g) were mixed in dry dimethyl sulfoxide (40 mL) and cooled to
10.degree. C. under argon. Morpholine (2.56 mL) was added and the
reaction mixture was allowed to warm to 25.degree. C. and stirred
under argon for 16 hours. The reaction mixture was concentrated in
vacuo, brine (50 mL) was added and the product was extracted with
ethyl acetate (3.times.50 mL), the combined organic phases were
dried over magnesium sulfate and concentrated in vacuo. The crude
material was purified by flash chromatography to furnish 3.69 g
(54% yield) of the title compound as a yellow oil. .sup.1H NMR (500
MHz, DMSO-d.sub.6): 3.02 (t, 4H), 3.66 (t, 4H), 7.08 (dt, 1H), 7.22
(m, 1H).
2,4-Difluoro-6-morpholin-4-yl-phenylamine
[0275] Concentrated hydrochloric acid (6.3 mL) was added slowly to
a mixture of zinc dust (4.9 g) and
4-(3,5-difluoro-2-nitro-phenyl)-morpholine (3.69 g) in
tetrahydrofuran (40 mL) cooled to 0.degree. C. The reaction mixture
was then stirred for 1 hour at 0.degree. C. and 2 hours at
25.degree. C. The reaction mixture was filtered through Celite (10
g), concentrated in vacuo and purified by flash chromatography to
furnish 1.76 g (54% yield) of the title compound as an orange
solid. GC-MS (m/z) 215 (M.sup.+); t.sub.R=5.11. .sup.1H NMR (500
MHz. DMSO-d.sub.6): 2.81 (t, 4H), 3.76 (t, 4H), 4.52 (s, 2H), 6.66
(dt, 1H), 6.82 (m, 1H).
2-Bromo-4-nitro-6-trifluoromethyl-phenylamine
[0276] Bromine (0.60 mL) dissolved in acetic acid (11 mL) was added
dropwise to a solution of 4-nitro-2-trifluoromethyl-phenylamine
(2.4 g) in acetic acid (12 mL). The reaction mixture was heated to
120.degree. C. for 21/2 hours, poured into water (400 mL) and
filtered. The collected solid was washed with water (200 mL) and
dried in vacuo to furnish 3.03 g (91% yield) of the title compound
as a yellow solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 7.08 (s,
2H), 8.23 (d, 1H), 8.51 (d, 1H).
N-(2-Bromo-4-nitro-6-trifluoromethyl-phenyl)-3-cyclohexyl-propionamide
[0277] 2-Bromo-4-nitro-6-trifluoromethyl-phenylamine (2.0 g) and
cyclohexylpropionyl chloride (1.30 mL) were mixed in acetonitrile
(10 mL) and heated to 150.degree. C. for 10 minutes in a sealed
microwave process vial. The reaction was cooled to 0.degree. C.,
the product filtered off and washed with cold acetonitrile (50 mL)
affording 0.97 g (33% yield) of the title compound as a yellow
solid. The crude product was used without further purification.
LC-MS (m/z) 424 (MH.sup.+); t.sub.R=3.53, (UV, ELSD) 95%, 99%.
.sup.1H NMR (500 MHz, DMSO-d.sub.6): 0.88 (m, 2H), 1.17 (m, 3H),
1.28 (m, 1H), 1.51 (m, 2H), 1.68 (m, 5H), 2.38 (t, 2H), 8.45 (d,
1H), 8.82 (d, 1H), 10.17 (s, 1H).
N-(4-Amino-2-bromo-6-trifluoromethyl-phenyl)-3-cyclohexyl-propionamide
[0278] Acetic acid (3.70 mL) was added slowly to a mixture of zinc
dust (7.88 g) and
N-(2-bromo-4-nitro-6-trifluoromethyl-phenyl)-3-cyclohexyl-propionamide
(1.99 g) in tetrahydrofuran (40 mL). The reaction mixture was then
stirred for 11/2 hours at 25.degree. C. The reaction mixture was
filtered, diluted with saturated aqueous sodium bicarbonate (400
mL) and extracted with ethyl acetate (3.times.100 mL). The combined
organic phases were washed with water (100 mL), brine (100 mL),
dried over sodium sulfate and concentrated in vacuo to furnish 1.85
g (100% yield) of the title compound as a yellow solid. LC-MS (m/z)
394 (MH.sup.+); t.sub.R=3.22, (UV, ELSD) 92%, 99%. .sup.1H NMR (500
MHz, DMSO-d.sub.6): 0.86 (q, 2H), 1.17 (m, 3H), 1.26 (m, 1H), 1.46
(q, 2H), 1.67 (m, 5H), 2.40 (t, 2H), 5.83 (s, 2H), 6.88 (d, 1H),
7.07 (d, 1H), 9.27 (s, 1H).
[2-Methyl-6-nitro-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic
acid ethyl ester
[0279] (4-Amino-2-methyl-6-nitro-phenyl)-carbamic acid ethyl ester
(0.50 g) and 4-trifluoromethyl-benzaldehyde (0.29 mL) were
dissolved in ethanol (10 mL) and refluxed for 16 h. The reaction
mixture was poured into water (75 mL) and the precipitate collected
by filtration. Sodium cyanoborohydride (0.3 g) and acetic acid (0.5
mL) were added to the precipitate dispersed in methanol (10 mL) and
stirred for 60 minutes. The reaction mixture was filtered, water
(50 mL) was added and the organic solvent was removed in vacuo. The
product was allowed to precipitate at 25.degree. C. and collected
by filtration and washed with water (100 mL) to furnish 0.47 g (75%
yield) of the title compound as a yellow solid. LC-MS (m/z) 398
(MH.sup.+); t.sub.R=3.18, (UV, ELSD) 86%, 94%. .sup.1H NMR (500
MHz, DMSO-d.sub.6): 1.20 (t, 3H), 2.10 (s, 3H), 4.05 (m, 2H), 4.45
(m, 2H), 6.75 (m, 1H), 6.90 (m, 1H), 7.55 (m, 2H), 7.73 (m, 2H),
8.75 (s, 1H).
(4-Amino-3,5-dimethyl-phenyl)-(4-trifluoromethyl-benzyl)-carbamic
acid tert-butyl ester
[0280] To
(3,5-Dimethyl-4-nitro-phenyl)-(4-trifluoromethyl-benzyl)-carbami- c
acid tert-butyl ester (9.5 g) in ethanol (150 mL) was added zinc
dust (22 g) and acetic acid (13 mL). The reaction mixture was
stirred 3 hours and then filtered. The solution was concentrated in
vacuo, redissolved in ethyl acetate (100 mL) and extracted with
water (2.times.50 mL). The organic phase was dried (MgSO.sub.4),
filtered and concentrated in vacuo to give the title compound as an
off white compound. Yield, 6.5 g (78%). LC-MS (m/z) 395 (MH.sup.+);
t.sub.R=3.06, (UV, ELSD) 89%, 96%. .sup.1H NMR (500 MHz,
CDCl.sub.3): 1.40 (s, 9H), 2.10 (s, 6H), 3.50 (broad, 2H), 4.75 (s,
2H), 6.70 (s, 2H), 7.35 (d, 2H), 7.55 (d, 2H).
(3,5-Dimethyl-4-nitro-phenyl)-(4-trifluoromethyl-benzyl)-carbamic
acid tort-butyl ester
[0281] To
(3,5-Dimethyl-4-nitro-phenyl)-(4-trifluoromethyl-benzyl)-amine (7.7
g) in acetonitrile (150 mL) was added 4-dimethylaminopyridine (1.45
g), triethylamine (4.95 mL) and di-tert-butyl dicarbonate (5.71 g).
The reaction mixture was stirred for 12 hours, and purified by
flash chromatography to furnish 9.6 g (95% yield) of the title
compound as a white solid. LC-MS (m/z) 299 (MH.sup.+);
t.sub.R=3.09, (UV, ELSD) 100%, 99%. .sup.1H NMR (500 MHz,
CDCl.sub.3): 0.93 (t, 3H), 1.39 (m, 4H), 1.76 (qui, 2H), 2.20 (s,
6H), 2.40 (t, 2H), 6.57 (b, 1H), 7.23 (s, 2H).
(3,5-Dimethyl-4-nitro-phenyl)-(4-trifluoromethyl-benzyl)-amine
[0282] 3,5-Dimethyl-4-nitro-phenylamine (3.95 g) and
4-trifluoromethyl-benzaldehyde (4.87 mL) were dissolved in ethanol
(50 mL) and refluxed for 16 h. The reaction mixture was poured into
water (75 mL) and the precipitate collected by filtration. Sodium
cyanoborohydride (3.1 g) and acetic acid (7.0 mL) were added to the
precipitate dispersed in methanol (130 mL) and stirred for 60
minutes. The reaction mixture was filtered, water (350 mL) was
added and the organic solvent was removed in vacuo. The product was
allowed to precipitate at 25.degree. C. and collected by filtration
and washed with water (300 mL) to furnish 6.7 g (85% yield) of the
title compound as a yellow solid. LC-MS (m/z) 325 (MH.sup.+);
t.sub.R=2.00, (UV, ELSD) 92%, 93%. .sup.1H NMR (500 MHz,
CDCl.sub.3): 2.30 (s, 6H), 4.45 (broad, 3H), 6.25 (s, 2H), 7.45 (d,
2H), 7.60 (d, 2H).
2-Chloro-4-nitro-6-trifluoromethylaniline
[0283] 4-Nitro-2-trifluoromethylaniline (15 g) and
N-chlorosuccinimide (10.7 g) dissolved in acetonitril (100 ml) was
heated to 150.degree. C. for 15 minutes in a sealed microwave
process vial. The reaction mixture was cooled to ambient
temperature and poured into 5% sodium hydroxide (500 ml) and
ethylacetate (400 ml). After separation the organic phase was dried
(MgSO.sub.4), filtered and concentrated in vacuo, followed by
purification by flash chromatography to furnish 17.0 g (97% yield)
of the title compound as a yellow solid. LC-MS (m/z) 240
(MH.sup.+); t.sub.R=4.76, (UV, ELSD) 97%, 96%. NMR (500 MHz,
DMSO-d.sub.6): 7.15 (s, 2H), 8.15 (d, 1H), 8.40 (d, 1H).
[0284] The following compound was prepared analogously:
2-Chloro-6-methyl-4-nitro-phenylamine
[0285] LC-MS (m/z) 186 (MH.sup.+); t.sub.R=6.40, (UV, ELSD) 97%,
98%. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 2.20 (s, 3H), 6.55 (s,
2H), 7.90 (d, 1H), 8.00 (d, 1H).
Compounds of the Invention
[0286] Acid addition salts of the compounds of the invention may
easily be formed by methods known to the person skilled in the
art.
Example 1
1a Hexanoic acid (4-bromo-2,6-dimethyl-phenyl)-amide
[0287] 4-Bromo-2,6-dimethyl-aniline (0.50 g) and hexanoyl chloride
(0.45 mL) were dissolved in acetonitrile (4 mL) and heated to
150.degree. C. for 10 minutes in a sealed microwave process vial.
The reaction mixture was concentrated in vacuo and purified by
flash chromatography to furnish 0.37 g (50% yield) of the title
compound as a white solid. LC-MS (m/z) 299 (MH.sup.+);
t.sub.R=3.09, (UV, ELSD) 100%, 99%. .sup.1H NMR (500 MHz,
CDCl.sub.3): 0.93 (t, 3H), 1.39 (m, 4H), 1.76 (qui, 2H), 2.20 (s,
6H), 2.40 (t, 2H), 6.57 (b, 1H), 7.23 (s, 2H).
[0288] The following compound was prepared analogously:
1b
N-(4-Bromo-2,6-dimethyl-phenyl)-2-(4-fluoro-phenyl)-acetamide
[0289] Yield: 24%. LC-MS (m/z) 337 (MH.sup.+); t.sub.R=3.04, (UV,
ELSD) 97%, 98%, .sup.1H NMR (500 MHz, DMSO-d.sub.6): 2.05 (s, 6H),
3.63 (s, 2H), 7.16 (t, 2H), 7.27 (1, 2H), 7.38 (t, 2H), 9.46 (s,
1H).
1c
N-(2-Bromo-4,6-dimethyl-phenyl)-2-(4-fluoro-phenyl)-acetamide
[0290] 2-Bromo-4,6-dimethyl-aniline (600 mg) and
(4-fluoro-phenyl)-acetyl chloride (543 mg) were dissolved in
acetonitrile (6 mL) and heated to 150.degree. C. for 10 minutes in
a sealed microwave process vial. The reaction was cooled to
0.degree. C., the product filtered off and washed with cold
acetonitrile (50 mL) affording 665 mg (66% yield) of the title
compound as a white solid. LC-MS (m/z) 337 (MH.sup.+);
t.sub.R=2.93, (UV, ELSD) 90%, 98%. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): 2.05 (s, 6H), 2.25 (s, 3H), 3.63 (s, 2H), 7.05 (b,
1H), 7.15 (dt, 2H), 7.32 (b, 1H), 7.40 (dt, 2H), 9.67 (s, 1H).
[0291] The following compounds were prepared analogously:
1d N-(2-Bromo-4,6-dimethyl-phenyl)-3,3-dimethyl-butyramide
[0292] Yield: 98%. LC-MS (m/z) 299 (MH.sup.+); t.sub.R=3.06, (UV,
ELSD) 77%, 97%.
1e N-(2-Bromo-4,6-dimethyl-phenyl)-2-cyclopentyl-acetamide
[0293] Yield: 75%. LC-MS (m/z) 311 (MH.sup.+); t.sub.R=3.08, (UV,
ELSD) 77%, 99%.
1f N-(2-Bromo-4,6-dichloro-phenyl)-3,3-dimethyl-butyramide
[0294] Yield: 70%. LC-MS (m/z) 340 (MH.sup.+); t.sub.R=3.17, (UV,
ELSD) 82%, 98%.
1g
N-(2-Bromo-4,6-dichloro-phenyl)-2-(4-fluoro-phenyl)-acetamide
[0295] Yield: 80%. LC-MS (m/z) 378 (MH.sup.+); t.sub.R=3.07, (UV,
ELSD) 99%, 98%.
1h N-(2-Bromo-4,6-dichloro-phenyl)-2-cyclopentyl-acetamide
[0296] Yield: 66%. LC-MS (m/z) 352 (MH.sup.+); t.sub.R=3.18, (UV,
ELSD) 94%, 99%.
1i Heptanoic acid (4-bromo-2,6-dimethyl-phenyl)-amide
[0297] Heptanoyl chloride (16 mg) was added to
4-bromo-2,6-dimethyl-aniline (20 mg) dissolved in acetonitrile and
heated to 70.degree. C. for 16 hours. The reaction mixture was
concentrated in vacuo, redissolved in dimethyl sulfoxide/methanol
(1:1, 0.5 mL) and subjected to preparative LC-MS purification to
furnish 10 mg (33% yield) of the title compound as an oil. LC-MS
(m/z) 313 (MH.sup.+); t.sub.R=3.33, (UV, ELSD) 93%, 100%.
[0298] The following compounds were prepared analogously:
1j Cyclohexanecarboxylic acid
(4-bromo-2,6-dimethyl-phenyl)-amide
[0299] Yield: 22%. LC-MS (m/z) 311 (MH.sup.+); t.sub.R=3.06, (UV,
ELSD) 97%, 100%.
1k N-(4-Bromo-2,6-dimethyl-phenyl)-2-thiophen-2-yl-acetamide
[0300] Yield: 14%. LC-MS (m/z) 325 (MH.sup.+); t.sub.R=2.85, (UV,
ELSD) 97%, 100%.
1l 2-Phenyl-cyclopropanecarboxylic acid
(4-bromo-2,6-dimethyl-phenyl)-amide
[0301] Yield: 15%. LC-MS (m/z) 345 (MH.sup.+); t.sub.R=3.22, (UV,
ELSD) 97%, 100%.
1m
N-(4-Bromo-2,6-dimethyl-phenyl)-2-(4-chloro-phenyl)-acetamide
[0302] Yield: 49%. LC-MS (m/z) 353 (MH.sup.+); t.sub.R=3.16, (UV,
ELSD) 99%, 100%.
1n Pentanoic acid (4-bromo-2,6-dimethyl-phenyl)-amide
[0303] Yield: 54%. LC-MS (m/z) 285 (MH.sup.+); t.sub.R=2.81, (UV,
ELSD) 99%, 100%.
1o Octanoic acid (4-bromo-2,6-dimethyl-phenyl)-amide
[0304] Yield: 44%. LC-MS (m/z) 327 (MH.sup.+); t.sub.R=3.58, (UV,
ELSD) 100%, 100%.
1p N-(4-Bromo-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide
[0305] 4-Bromo-2,6-dimethyl-aniline (4.3 g) and cyclopentylacetyl
chloride (3.46 g) were mixed in acetonitrile (50 mL) and
tetrahydrofuran (20 mL) and the reaction mixture was heated to
reflux for 1 hour. Potassium carbonate (4.5 g) was added and the
reaction mixture was refluxed for 1 hour and then poured onto
crushed ice and saturated aqueous potassium carbonate (50 mL). The
product was collected by filtration and washed with water (100 mL)
to furnish 6.6 g (100% yield) of the title compound as a solid.
LC-MS (m/z) 311 (MH.sup.+); t.sub.R=3.07, (UV, ELSD) 100%, 100%.
.sup.1H NMR (500 MHz, DMSO-d.sub.6): 1.21 (m, 2H), 1.52 (m, 2H),
1.61 (m, 2H), 1.77 (m, 2H), 2.11 (s, 6H), 2.25 (m, 1H), 2.31 (d,
2H), 7.27 (s, 2H), 9.23 (s, 1H).
1q
2-Bicyclo[2.2.1]-hept-2-yl-N-(2,4-difluoro-6-morpholin-4-yl-phenyl)-ace-
tamide
[0306] Bicyclo[2.2.1]hept-2-yl-acetic acid (0.20 mL),
N,N-diisopropyl-ethylamine (0.50 mL) and
N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-met-
hyl-methanaminium hexafluoro-phosphate N-oxide (0.55 g) were mixed
in dry N,N-dimethylformamide (3 mL) and stirred under argon for 2
minutes. 2,4-Difluoro-6-morpholin-4-yl-phenylamine (0.20 g)
dissolved in dry N,N-dimethylformamide (2 mL) was added to the
reaction mixture, which was stirred at 60.degree. C. under argon
for 16 hours. Ethyl acetate (20 mL) was added and the organic phase
was washed with saturated aqueous ammonium chloride/water (1:1, 20
mL), water (20 mL), brine/water (1:1, 20 mL), dried over magnesium
sulfate, concentrated in vacuo and purified by flash chromatography
to furnish 0.17 g (51% yield) of the title compound as a white
solid. LC-MS (m/z) 351 (MH.sup.+); t.sub.R=2.94, (UV, ELSD) 96%,
99%. NMR (500 MHz, DMSO-d.sub.6): 1.12 (m, 4H), 1.41 (m, 4H), 1.87
(m, 1H), 1.99 (d, 2H), 2.13 (dd, 1H), 2.20 (m, 1H), 2.27 (dd, 1H),
2.88 (t, 4H), 3.70 (t, 4H), 6.72 (m, 1H), 6.89 (dt, 1H), 9.10 (s,
1H).
1r
(S)-2-Amino-N-{2,6-dimethyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-
-phenyl}-3-methyl-butyramide
[0307] Tert-butyloxycarbonyl-L-valine (21.7 mg),
N,N-diisopropyl-ethylamine (35 uL),
N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-met-
hyl-methanaminium hexafluoro-phosphate N-oxide (0.38 g) and
2,6,N'-trimethyl-N'-(4-trifluoromethyl-benzyl)-benzene-1,4-diamine
(15.4 mg) were mixed in dry N,N-dimethylformamide (0.2 mL) and
stirred under argon for 2 hours. Brine (2 mL) was added and the
reaction mixture was extracted with ethyl acetate (2.times.2 mL).
The combined organic phases were dried over sodium sulfate,
concentrated in vacuo and purified by flash chromatography. 15.4 mg
(61% yield) of the N-Boc-protected title compound was isolated and
it was dissolved in trifluoroacetic acid/dichloromethane (1:1, 2
mL) and stirred at 25.degree. C. for 30 minutes. The reaction
mixture was concentrated in vacuo to furnish 18 mg (96% yield) of
the title compound. LC-MS-TOF (m/z) 408 (MH.sup.+); t.sub.R=2.19,
(UV, ELSD) 93%, 98%.
[0308] The following compound was prepared analogously:
1s (S)-2-Amino-4-methyl-pentanoic acid
{2,6-dimethyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-amide
[0309] Yield: 59%. LC-MS-TOF (m/z) 422 (MH.sup.+); t.sub.R=2.34,
(UV, ELSD) 97%, 99%.
1w (R)-2-Amino-4-methylpentanoic acid
[2,6-dimethyl-4-(4-trifluoromethylbenzylamino)-phenyl]-amide
[0310] Yield: 43%. LC-MS-TOF (m/z) 408 (MH.sup.+); t.sub.R=2.14,
(UV, ELSD) 96%, 97%.
1t (4-Bromo-2,6-dimethyl-phenyl)-carbamic acid ethyl ester
[0311] 4-Bromo-2,6-dimethyl-aniline (10 g), ethyl chloroformate
(5.4 g) and potassium carbonate (10.4 g) were mixed in
tetrahydrofuran (100 mL) and heated to reflux for 16 hours, cooled,
filtered and concentrated in vacuo. Heptane (200 mL) was added to
the crude product, which was stirred for 30 minutes at 70.degree.
C. The mixture was filtered and concentrated in vacuo to furnish 12
g (88% yield) of the title compound as a solid. LC-MS (m/z) 273
(MH.sup.+); t.sub.R=2.95, (UV, ELSD) 99%, 99%. .sup.1H NMR (500
MHz, CDCl.sub.3): 1.31 (t, 3H), 2.24 (s, 6H), 4.19 (q, 2H), 5.92
(b, 1H), 7.22 (s, 2H).
1u (4-Bromo-2,6-dimethyl-phenyl)-carbamic acid propyl ester
[0312] 4-Bromo-2,6-dimethyl-aniline (4.3 g) and propyl
chloroformate (2.70 mL) were mixed in acetonitrile (50 mL) and
tetrahydrofuran (20 mL) and the reaction mixture was heated to
reflux for 1 hour. Potassium carbonate (4.5 g) was added and the
reaction mixture was refluxed for 1 hour and then poured onto
crushed ice and saturated aqueous potassium carbonate (50 mL). The
product was collected by filtration and washed with water (100 mL)
to furnish 5.26 g (86% yield) of the title compound as a solid.
LC-MS (m/z) 287 (MH.sup.+); t.sub.R=3.18, (UV, ELSD) 99%, 95%.
.sup.1H NMR (500 MHz, CDCl.sub.3): 0.93 (t, 3H), 1.62 (m, 2H), 2.15
(s, 6H), 4.00 (t, 2H), 7.28 (s, 2H), 8.74 (b, 1H).
1v N-(2-Amino-4-bromo-6-methyl-phenyl)-3,3-dimethyl-butyramide
[0313] Zinc dust (16 g) was added in portions over 2 hours to
N-(4-bromo-2-methyl-6-nitro-phenyl)-3,3-dimethyl-butyramide (2.74
g) in tetrahydrofuran (50 mL) and acetic acid (12 mL) cooled to
0.degree. C., and then stirred 30 minutes at 25.degree. C. The
reaction mixture was poured into a suspension of sodium carbonate
(16 g) in tetrahydrofuran and filtered through silica (50 g), which
was washed with ethyl acetate (100 mL). The organic phase was
concentrated in vacuo to furnish 2.47 g (100% yield) of the title
compound as a pale red solid. LC-MS (m/z) 300 (MH.sup.+);
t.sub.R=2.54, (UV, ELSD) 96%, 99%. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): 1.04 (s, 9H), 2.05 (s, 3H), 2.21 (s, 2H), 4.94 (s,
2H), 6.59 (d, 1H), 6.74 (d, 1H), 8.85 (s, 1H).
1x
[2-Amino-6-methyl-4-(4-trifluoromethylbenzylamino)-phenyl]-carbamic
acid ethyl ester
[0314] To
[2-Methyl-6-nitro-4-(4-trifluoromethyl-benzylamino)-phenyl]-carb-
amic acid ethyl ester (0.45 g) in tetrahydrofuran (5 mL) was added
sodiumdithionite (1.8 g) in water (5 mL). The reaction mixture was
stirred 3 hours at 50.degree. C. The reaction mixture was
concentrated in vacuo and purified by flash chromatography, to
furnish the title compounds as a pale yellow solid. LC-MS (m/z) 368
(MH.sup.+); t.sub.R=2.39, (UV, ELSD) 95%, 99%. .sup.1H NMR (500
MHz. DMSO-d.sub.6): 1.20 (t, 3H), 1.90 (s, 3H), 4.00 (m, 2H), 4.30
(d, 2H), 4.40 (s, 2H), 5.75 (s, 2H), 6.00 (t, 1H), 7.50 (d, 2H),
7.65 (d, 2H), 7.85 (s, 1H).
Example 2
2a
2-Cyclopentyl-N-{2,6-dimethyl-4-[2-(4-trifluoromethyl-phenyl)-pyrrolidi-
n-1-yl]-phenyl}-acetamide
[0315] Bis(dibenzylideneacetone)palladium (3.6 mg) and
(2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (3.7 mg)
were mixed in dry toluene (2 mL) under argon for 5 minutes. To this
mixture were added cesium carbonate (41 mg),
2-[4-(trifluoromethyl)phenyl]pyrrolidine (15 mg) and
N-(4-bromo-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide (1p, 20 mg)
and the reaction was heated to 110.degree. C. in a sealed 4 mL vial
under argon for 48 hours. Aqueous sodium bicarbonate (5 mL) was
added and the mixture was extracted with ethyl acetate (3.times.3
mL). The combined organic phases were dried over magnesium sulfate
and concentrated in vacuo. The crude product was purified by vacuum
liquid chromatography to furnish 7.6 mg (27% yield) of the title
compound as an oil. LC-MS-TOF (WO 445 (MH.sup.+); t.sub.R=3.91,
(UV, ELSD) 98%, 99%.
2b
N-(4-Azepan-1-yl-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide
[0316] Bis(dibenzylideneacetone)palladium (2.8 mg) and
(2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (3.8 mg)
were mixed in dry toluene (2.5 mL) under argon for 5 minutes. To
this mixture were added sodium tert-butoxide (6 mg),
azacycloheptane (7.5 mg) and
N-(4-bromo-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide (1p, 15 mg)
and the reaction was heated to 110.degree. C. in a sealed 4 mL vial
under argon for 48 hours. The reaction mixture was concentrated in
vacuo, sodium hydroxide (2 M, 1.5 mL) was added and the product was
extracted with isopropyl acetate (3.times.1.5 mL). The combined
organic phases were dried over magnesium sulfate, concentrated in
vacuo and purified by flash chromatography to furnish 7.9 mg (50%
yield) of the title compound as an oil. LC-MS-TOF (m/z) 329
(MH.sup.+); t.sub.R=2.08, (UV, ELSD) 90%, 99%.
2c
2-Cyclopentyl-N-(2,6-dimethyl-4-pyrrol-1-yl-phenyl)-acetamide
[0317] Dibenzylideneacetone (1.1 mg) and 1,10-phenanthroline (17
mg) were mixed in dry toluene (1 mL) under argon for 5 minutes,
followed by addition of copper(II) trifluoromethanesulfonate (1.8
mg), cesium carbonate (35 mg), pyrrole (10 mg) and
N-(4-bromo-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide (1p, 30 mg)
and the reaction was heated to 110.degree. C. in a sealed 4 mL vial
under argon for 48 hours. The reaction mixture was concentrated in
mew), sodium hydroxide (2 M, 1.5 mL) was added and the product was
extracted with isopropyl acetate (3.times.1.5 mL). The combined
organic phases were dried over magnesium sulfate, concentrated in
vacuo and redissolved in dimethyl sulfoxide (0.50 mL) of which 0.25
mL was subjected to preparative LC-MS purification to furnish 1.3
mg (9% yield) of the title compound as an oil. LC-MS-TOF (m/z) 297
(MH.sup.+); t.sub.R=3.11, (UV, ELSD) 97%, 99%.
2d
3,3-Dimethyl-N-[2-methyl-6-morpholin-4-yl-4-(4-trifluoromethylbenzylami-
no)-phenyl]-butyramide
[0318]
N-(4-Bromo-2-methyl-6-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramid-
e (0.030 g, 6a), 4-trifluorobenzylmine (0.056 g),
palladium(II)acetate (0.009 g),
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.0028 g) and
potassium tert-butoxide (0.010 g) were dissolved in dry
dimethylformamide (2 mL) and heated to 180.degree. C. for 15
minutes in a sealed microwave process vial. Saturated aqueous
sodium bicarbonate (20 mL) was added and the mixture was extracted
with ethyl acetate (3.times.10 mL), the combined organic phases
were dried over sodium sulfate and concentrated in vacuo. The crude
product was purified by flash chromatography to furnish 0.014 g
(37% yield) of the title compound as a yellow solid. LC-MS (m/z)
464 (MH.sup.+); t.sub.R=3.02, (UV, ELSD) 89%, 99%.
Example 3
3a
N-(3'-Amino-3,5-dimethyl-biphenyl-2-yl)-2-(4-fluoro-phenyl)-acetamide
[0319]
N-(2-Bromo-4,6-dimethyl-phenyl)-2-(4-fluoro-phenyl)-acetamide (1c,
15.1 mg), 3-aminobenzeneboronic acid (30.8 mg), aqueous potassium
carbonate (5 M, 90 uL) and palladium(II) acetate (1 mg) were mixed
in acetone (2 mL) and heated to 125.degree. C. for 15 minutes in a
sealed microwave process vial. The reaction mixture was filtered
through silica (500 mg), concentrated in vacuo, redissolved in
dimethyl sulfoxide (0.5 mL) and subjected to preparative LC-MS
purification to furnish 14.9 mg (95% yield) of the title compound
as an oil. LC-MS (m/z) 349 (MH.sup.+); t.sub.R=1.92, (UV, ELSD)
98%, 99%.
[0320] The following compounds were prepared analogously:
3b
N-(4'-Dimethylamino-3,5-dimethyl-biphenyl-2-yl)-2-(4-fluoro-phenyl)-ace-
tamide
[0321] Yield: 12%. LC-MS (m/z) 377 (WO; t.sub.R=2.00, (UV, ELSD)
99%, 99%.
3c
N-(2,4-Dimethyl-6-quinolin-3-yl-phenyl)-2-(4-fluoro-phenyl)-acetamide
[0322] Yield: 34%. LC-MS (m/z) 384 (MH.sup.+); t.sub.R=1.95, (UV,
ELSD) 97%, 99%.
3d
2-(4-fluoro-phenyl)-N-(4'-hydroxy-3'-methoxy-3,5-dimethyl-biphenyl-2-A--
acetamide
[0323] Yield: 15%. LC-MS (m/z) 380 (MH.sup.+); t.sub.R=2.71 (UV,
ELSD) 91%, 78%.
3e
2-(4-Fluoro-phenyl)-N-(3'-hydroxy-3,5-dimethyl-biphenyl-2-yl)-acetamide
[0324] Yield: 52%. LC-MS (m/z) 350 (MH.sup.+); t.sub.R=2.73, (UV,
ELSD) 94%, 90%.
3f
2-(4-Fluoro-phenyl)-N-(2'-methanesulfonylamino-3,5-dimethyl-biphenyl-2--
yl)-acetamide
[0325] Yield: 22%. LC-MS (m/z) 427 (MH.sup.+); t.sub.R=2.90, (UV,
ELSD) 93%, 99%.
3g
N-(4'-isopropyl-3,5-dimethyl-biphenyl-2-yl)-3,3-dimethyl-butyramide
[0326] Yield: 19%. LC-MS (m/z) 338 (MH.sup.+); t.sub.R=3.81, (UV,
ELSD) 99%, 99%.
3h 2-Cyclopentyl-N-(3,5-dimethyl-biphenyl-2-yl)-acetamide
[0327] Yield: 35%. LC-MS (m/z) 308 (MH.sup.+); t.sub.R=3.32, (UV,
ELSD) 98%, 99%.
3i
N-(4'-Fluoro-3,5-dimethyl-biphenyl-2-yl)-2-(4-fluoro-phenyl)-acetamide
[0328] Yield: 23%. LC-MS (m/z) 352 (MH.sup.+); t.sub.R=3.20, (UV,
ELSD) 99%, 96%.
3j
N-(3,5-Dimethyl-3',5'-bis-trifluoromethyl-biphenyl-2-yl)-2-(4-fluoro-ph-
enyl)-acetamide
[0329] Yield: 9%. LC-MS (m/z) 470 (MH.sup.+); t.sub.R=3.79, (UV,
ELSD) 99%, 99%.
3k
N-(3'-Acetylamino-3,5-dimethyl-biphenyl-2-yl)-2-(4-fluoro-phenyl)-aceta-
mide
[0330] Yield: 23%. LC-MS (m/z) 391 (MH.sup.+); t.sub.R=2.60, (UV,
ELSD) 95%, 99%.
3l
2-(4-Fluoro-phenyl)-N-(2'-methoxy-3,5-dimethyl-biphenyl-2-yl)-acetamide
[0331] Yield: 12%. LC-MS (m/z) 364 (MH.sup.+); t.sub.R=3.20, (UV,
ELSD) 95%, 99%.
3m
N-(3,5-Dimethyl-4'-vinyl-biphenyl-2-yl)2-(4-fluoro-phenyl)-acetamide
[0332] Yield: 20%. LC-MS (m/z) 360 (MH.sup.+); t.sub.R=3.41, (UV,
ELSD) 99%, 99%.
3n
N-(3'-Cyano-3,5-dimethyl-biphenyl-2-yl)-2-(4-fluoro-phenyl)-acetamide
[0333] Yield: 6% LC-MS (m/z) 359 (MH.sup.+); t.sub.R=3.01, (UV,
ELSD) 81%, 95%.
3o
N-(3,5-Dimethyl-3'-trifluoromethoxy-biphenyl-2-yl)-2-(4-fluoro-phenyl)--
acetamide
[0334] Yield: 20%. LC-MS (m/z) 418 (MH.sup.+); t.sub.R=3.55, (UV,
ELSD) 99%, 99%.
3p
N-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-4,6-dimethyl-phenyl]-2-(fluoro-
-phenyl)-acetamide
[0335] Yield: 58%. LC-MS (m/z) 392 (MH.sup.+); t.sub.R=3.06, (UV,
ELSD) 99%, 99%.
3q
N-[2,4-Dimethyl-6-(2,2,5-trimethyl-2,3-dihydro-benzofuran-7-yl)-phenyl]-
-2-(4-fluoro-phenyl)-acetamide
[0336] Yield: 9%. LC-MS (m/Z) 418 (MH.sup.+); t.sub.R=3.80, (UV,
ELSD) 99%, 99%.
Example 4
4a
N-[2,6-Dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-acetamide
[0337] N-(4-Amino-2,6-dimethyl-phenyl)-acetamide (1.2 g) and
4-trifluoromethyl-benzaldehyde (1.3 g) were dissolved in ethanol
(100 mL) and refluxed for 16 h. The reaction mixture was poured
into water (3 L) and the precipitate collected by filtration.
Sodium cyanoborohydride (2 g) and acetic acid (2 mL) were added to
the precipitate dispersed in methanol (50 mL) and stirred for 15
minutes. The reaction mixture was filtered, water (100 mL) was
added and the organic solvent was removed in vacuo. The product was
allowed to precipitate at 25.degree. C. and collected by filtration
and washed with water (200 mL) to furnish 0.68 g (30% yield) of the
title compound as a pale yellow solid. LC-MS (m/z) 337 (MH.sup.+);
t.sub.R=2.39, (UV, ELSD) 99%, 99%. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): 1.95 (s, 3H), 1.96 (s, 6H), 4.34 (d, 2H), 6.18 (t,
1H), 6.25 (s, 2H), 7.55 (d, 2H), 7.69 (d, 2H), 8.81 (s, 1H).
4b
N-{2,6-Dimethyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-ace-
tamide
[0338] To a stirred solution of
N-[2,6-dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-acetamide
(4a, 1.0 g) and formaldehyde (1 mL) in methanol (20 mL) and acetic
acid (1 mL) was slowly added sodium cyanoborohydride (0.30 g).
After 15 minutes, the reaction mixture was cooled to 5.degree. C.
for 16 hours to precipitate the product, which was collected by
filtration and washed with water (100 mL) to furnish 0.63 g (60%
yield) of the title compound as a pale yellow solid. LC-MS-TOF
(m/z) 351 (MH.sup.+); t.sub.R=2.58, (UV, ELSD) 99%, 99%. .sup.1H
NMR (500 MHz, DMSO-d.sub.6): 1.97 (s, 3H), 2.02 (s, 6H), 2.97 (s,
3H), 4.63 (s, 2H), 7.41 (d, 2H), 7.68 (d, 2H), 8.88 (s, 1H).
4c
{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester
[0339] (4-Amino-2,6-dimethyl-phenyl)-carbamic acid propyl ester (84
mg) and 5-chloro-thiophene-2-carbaldehyde (48 uL) were dissolved in
methanol (3 mL) and heated to 130.degree. C. for 5 minutes in a
sealed microwave process vial. Sodium cyanoborohydride (95 mg) was
added and the reaction mixture was heated to 130.degree. C. for 5
minutes in a sealed microwave process vial, followed by addition of
water/brine (1:1, 3 mL). The product was extracted with ethyl
acetate (3.times.3 mL) and the combined organic phases were washed
with brine (5 mL), dried over magnesium sulfate and concentrated in
vacuo. The crude product was purified by flash chromatography to
furnish 66 mg (49% yield) of the title compound as an oil. LC-MS
(m/z) 353 (MH.sup.+); t.sub.R=3.06, (UV, ELSD) 87%, 87%.
[0340] The following compounds were prepared analogously:
4d [4-(4-Fluoro-benzylamino)-2,6-dimethyl-phenyl]-carbamic acid
propyl ester
[0341] Yield: 71%. LC-MS (m/z) 331 (MH.sup.+); t.sub.R=2.57, (UV,
ELSD) 97%, 99%. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 0.91 (t, 3H),
1.60 (m, 2H), 2.02 (s, 6H), 3.96 (t, 2H), 4.11 (b, 1H), 4.28 (b,
2H), 6.47 (s, 2H), 7.16 (t, 2H), 7.41 (t, 2H), 8.32 (s, 1H).
4e [2,6-Dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic
acid propyl ester
[0342] Yield: 73%. LC-MS (m/z) 381 (MH.sup.+); t.sub.R=3.17, (UV,
ELSD) 98%, 95%. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 0.91 (t, 3H),
1.59 (m, 2H); 2.00 (s, 6H), 3.95 (t, 2H), 4.37 (s, 2H), 4.48 (b,
1H), 6.36 (s, 2H), 7.57 (d, 2H), 7.68 (d, 2H), 8.25 (s, 1H).
4f
[4-(3-Fluoro-4-trifluoromethyl-benzylamino)-2,6-dimethyl-phenyl]-carbam-
ic acid propyl ester
[0343] Yield: 61%. LC-MS (m/z) 399 (MH.sup.+); t.sub.R=3.46, (UV,
ELSD) 95%, 95%. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 0.91 (1, 3H),
1.59 (m, 2H), 1.99 (s, 6H), 3.57 (s, 2H), 3.95 (t, 2H), 4.35 (b,
1H), 6.26 (s, 2H), 7.37 (d, 1H), 7.42 (d, 1H), 7.73 (t, 1H), 8.19
(s, 1H).
4g
{2,6-Dimethyl-4-[(4-methyl-2-phenyl-pyrimidin-5-ylmethyl)-amino]-phenyl-
}-carbamic acid propyl ester
[0344] (4-Amino-2,6-dimethyl-phenyl)-carbamic acid propyl ester (22
mg) and 4-methyl-2-phenyl-5-pyrimidinecarbaldehyde (20 mg) were
dissolved in methanol (0.5 mL) and heated to 170.degree. C. for 10
minutes in a sealed microwave process vial. Sodium cyanoborohydride
(2 M in methanol, 250 uL) and acetic acid (100 uL) were added and
the reaction mixture was heated to 50.degree. C. for 2 hours.
Aqueous sodium carbonate (10%, 1 mL) was added, the product was
extracted with ethyl acetate (2.times.1 mL), and the combined
organic phases were concentrated in vacuo. The crude product was
redissolved in dimethyl sulfoxide (0.5 mL) of which 0.25 mL was
subjected to preparative LC-MS purification to furnish 6.6 mg (33%
yield) of the title compound as an oil. LC-MS (m/z) 405 (MH.sup.+);
t.sub.R=3.12, (UV, ELSD) 84%, 99%.
[0345] The following compounds were prepared analogously:
4h
{2,6-Dimethyl-4-[(6-p-tolyloxy-pyridin-3-ylmethyl)-amino]-phenyl}-carba-
mic acid propyl ester
[0346] Yield: 25%. LC-MS (m/z) 420 (MH.sup.+); t.sub.R=2.90, (UV,
ELSD) 83%, 99%.
4i
{4-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester
[0347] Yield: 22%. LC-MS (m/z) 344 (MH.sup.+); t.sub.R=2.02, (UV,
ELSD) 66%, 95%.
4j
{4-[(3-Fluoro-4-trifluoromethyl-benzyl)-methyl-amino]-2,6-dimethyl-phen-
yl}-carbamic acid propyl ester
[0348]
[4-(3-Fluoro-4-trifluoromethyl-benzylamino)-2,6-dimethyl-phenyl]-ca-
rbamic acid propyl ester (4f, 22 mg) and formaldehyde (0.1 mL) were
refluxed in methanol (1 mL) for 3 hours. Sodium cyanoborohydride
(35 mg) was added and the reaction mixture was stirred for 16 hours
at 25.degree. C., followed by addition of water (3 mL). The product
was extracted with ethyl acetate (3.times.3 mL) and the combined
organic phases were washed with brine (5 mL), dried over magnesium
sulfate and concentrated in vacuo. The crude product was subjected
to preparative LC-MS purification to furnish 9.7 mg (43% yield) of
the title compound as a solid. LC-MS (m/z) 413 (MH.sup.+);
t.sub.R=3.68, (UV, ELSD) 88%, 96%.
4k
2-Cyclopentyl-N-[2,6-dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-
-acetamide
[0349] N-(4-Amino-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide (207
mg) and 4-trifluoromethyl-benzaldehyde (125 uL) were dissolved in
acetonitrile (2 mL) and heated to 150.degree. C. for 5 minutes in a
sealed microwave process vial. Sodium cyanoborohydride (0.7 M in
methanol, 5 mL) and acetic acid (500 uL) were added and the
reaction mixture was stirred at 25.degree. C. for 16 hours. Aqueous
sodium carbonate (10%, 25 mL) was added, and the product was
collected by filtration to furnish 0.31 g (91% yield) of the title
compound as a white solid. LC-MS (m/z) 405 (MH.sup.+);
t.sub.R=3.19, (UV, ELSD) 97%, 99%. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): 1.19 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 1.75 (m,
2H), 1.96 (s, 6H), 2.22 (m, 3H), 4.34 (d, 21-1), 6.18 (t, 1H), 6.25
(s, 2H), 7.55 (d, 2H), 7.67 (d, 2H), 8.76 (s, 1H).
4l
2-Cyclopentyl-N-{2,6-dimethyl-4-[methyl-(4-trifluoromethyl-benzyl)-amin-
o]-phenyl}-acetamide
[0350] To
2-cyclopentyl-N-[2,6-dimethyl-4-(4-trifluoromethyl-benzylamino)--
phenyl]-acetamide (4k, 150 mg) dissolved in methanol (20 mL) and
acetic acid (2 mL) were added sodium cyanoborohydride (175 mg) and
formaldehyde (200 uL) and the reaction mixture was stirred at
25.degree. C. for 70 minutes. The reaction was quenched with
saturated aqueous sodium bicarbonate and the product collected by
filtration to furnish 151 mg (97% yield) of the title compound as a
white solid. LC-MS (m/z) 419 (MH.sup.+); t.sub.R=3.39, (UV, ELSD)
99%, 99%. .sup.1H NMR (500 MHz. DMSO-d.sub.6): 1.20 (m, 2H), 1.51
(m, 2H), 1.61 (m, 2H), 1.75 (m, 2H), 2.02 (s, 6H), 2.24 (m, 3H),
2.97 (s, 3H), 4.63 (s, 2H), 6.42 (s, 2H), 7.41 (d, 2H), 7.68 (d,
2H), 8.83 (s, 1H).
4m
2-Cyclopentyl-N-{2,6-dimethyl-4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-
-amino]-phenyl}-acetamide
[0351] N-(4-Amino-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide (204
mg) and 6-trifluoromethyl-pyridine-3-carbaldehyde (163 mg) were
dissolved in acetonitrile (3 mL) and heated to 150.degree. C. for
10 minutes in a sealed microwave process vial. The reaction mixture
was concentrated in vacuo, redissolved in methanol (5 mL) followed
by addition of acetic acid (0.5 mL) and sodium cyanoborohydride
(244 mg) and stirred at 25.degree. C. for 16 hours. Aqueous sodium
carbonate (10%, 25 mL) was added, and the product was collected by
filtration to furnish 0.311 g (92% yield) of the title compound as
a white solid. LC-MS (m/z) 406 (MH.sup.+); t.sub.R=2.90, (UV, ELSD)
98%, 99%. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 1.20 (m, 2H), 1.51
(m, 2H), 1.60 (m, 2H), 1.75 (m, 2H), 1.97 (s, 6H), 2.22 (m, 3H),
4.39 (d, 2H), 6.20 (t, 1H), 6.28 (s, 2H), 7.85 (d, 1H), 7.99 (d,
1H), 8.75 (s, 1H), 8.77 (s, 1H).
[0352] The following compound was prepared analogously:
4n
N-{2,6-Dimethyl-4-[(6-trifluoromethylpyridin-3-ylmethyl)-amino]phenyl}--
3,3-dimethyl-butyramide
[0353] Yield: 91%. LC-MS (m/z) 394 (MH.sup.+); t.sub.R=2.87, (UV,
ELSD) 98%, 99%. NMR (500 MHz, DMSO-d.sub.6): 1.03 (s, 9H), 1.99 (s,
6H), 2.13 (s, 2H), 4.39 (d, 2H), 6.21 (t, 1H), 6.29 (s, 2H), 7.85
(d, 1H), 7.99 (d, 1H), 8.73 (s, 1H), 8.75 (s, 1H).
4o
N-{2-Bromo-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-6-trifluoromethyl-p-
henyl}-3-cyclohexyl-propionamide
[0354]
N-(4-Amino-2-bromo-6-trifluoromethyl-phenyl)-3-cyclohexyl-propionam-
ide (1.03 g) and 5-chloro-thiophene-2-carbaldehyde (310 uL) were
dissolved in methanol (16 mL) and heated to 130.degree. C. for 8
minutes in a sealed microwave process vial. Sodium cyanoborohydride
(800 mg) was added and the reaction mixture was heated to
130.degree. C. for 5 minutes in a sealed microwave process vial.
Saturated aqueous sodium bicarbonate (100 mL) was added, the
product was extracted with ethyl acetate (3.times.50 mL) and the
combined organic phases were washed with water (2.times.100 mL) and
brine (100 mL), dried over sodium sulfate and concentrated in
vacuo. The crude product was purified by flash chromatography to
furnish 517 mg (33% yield) of the title compound as a yellow solid.
LC-MS (m/z) 524 (MH.sup.+); t.sub.R=4.09, (UV, ELSD) 99%, 99%.
.sup.1H NMR (500 MHz, DMSO-d.sub.6): 0.86 (q, 2H), 1.15 (m, 3H),
1.26 (m, 1H), 1.46 (q, 2H), 1.65 (m, 5H), 2.24 (t, 2H), 4.89 (d,
2H), 6.94 (d, 1H), 6.95 (d, 1H), 6.98 (d, 1H), 7.04 (t, 1H), 7.13
(d, 1H), 9.32 (s, 1H).
[0355] The following compound was prepared analogously:
4p
N-{2-Chloro-6-methyl-4-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-p-
henyl}-2-(3-fluoro-phenyl)-acetamide
[0356] LC-MS (m/z) 452 (MH.sup.+); t.sub.R=3.06, (UV, ELSD) 96%,
98%. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 1.95 (s, 3H), 3.60 (s,
2H), 4.40 (d, 2H), 6.40 (s, 1H), 6.55 (s, 1H), 6.60 (m, 1H), 7.05
(m, 1H), 7.15 (s, 2H), 7.35 (m, 1H), 7.85 (m, 1H), 8.05 (m, 1H),
8.75 (s, 1H), 935 (s, 1H).
4q
N-[2-Chloro-6-trifluoromethyl-4-(4-trifluoromethylbenzylamino)-phenyl]--
2-cyclopentylacetamide
[0357] LC-MS (m/z) 481 (MH.sup.+); t.sub.R=3.52, (UV, ELSD) 99%,
99%. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 1.15 (m, 2H), 1.45 (m,
2H), 1.55 (m, 2H), 1.75 (m, 2H), 2.15 (m, 1H), 2.20 (m, 2H), 4.55
(d, 2H), 6.90 (m, 2H), 7.15 (m, 1H), 7.55 (d, 2H), 7.75 (d,
2H).
Example 5
5a {4-[(3-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid ethyl ester
[0358] To (4-formyl-2,6-dimethyl-phenyl)-carbamic acid ethyl ester
(230 mg) and 3-fluoroaniline (122 mg) dissolved in dry ethanol (25
mL) was added 3 .ANG. molecular sieves (0.5 g) and the reaction
mixture was refluxed for 16 hours under argon. Upon cooling to
25.degree. C., sodium cyanoborohydride (320 mg) and acetic acid (3
mL) were added and stirred for 1 hour. A second batch of sodium
cyanoborohydride (320 mg) was added and the mixture stirred for 1
additional hour. Saturated aqueous sodium carbonate (5 mL) was
added and the mixture stirred for 1 hour, water (50 mL) was added
and the mixture was extracted with ethyl acetate (3.times.25 mL).
The combined organic phases were dried over magnesium sulfate,
concentrated in vacuo and purified by flash chromatography to
furnish 95 mg (29% yield) of the title compound as a white solid.
LC-MS-TOF (m/z) 317 (Min; t.sub.R=3.37, (UV. ELSD) 99%, 96%.
.sup.1H NMR (500 MHz, CDCl.sub.3): 1.31 (b, 3H), 2.25 (s, 6H), 4.20
(m, 5H), 5.98 (b, 1H), 6.30 (dt, 1H), 6.39 (m, 2H), 7.06 (s, 2H),
7.08 (q, 1H).
[0359] The following compounds were prepared analogously:
5b
{2,6-Dimethyl-4-[(4-trifluoromethyl-phenylamino)-methyl]-phenyl}-carbam-
ic acid ethyl ester
[0360] Yield: 20%. LC-MS-TOF (m/z) 367 (MH.sup.+); t.sub.R=3.62,
(UV, ELSD) 98%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 1.31 (b,
3H), 2.25 (s, 6H), 4.21 (d, 2H), 4.25 (b, 2H), 4.37 (b, 1H), 5.99
(b, 1H), 6.61 (d, 2H), 7.05 (s, 2H), 7.38 (d, 2H).
5c
2-Clopentyl-N-{4-[(3-fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-a-
cetamide
[0361] Yield: 33%. LC-MS (m/z) 355 (MH.sup.+), t.sub.R=3.22, (UV,
ELSD) 99%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 1.25 (m, 2H),
1.59 (m, 2H), 1.67 (m, 2H), 1.91 (m, 2H), 2.20 (s, 6H), 2.36 (m,
1H), 2.40 (d, 2H), 4.14 (b, 1H), 4.18 (b, 2H), 6.29 (dt, 1H), 6.38
(dt, 2H), 6.77 (b, 1H), 7.04 (s, 2H), 7.08 (q, 1H).
[0362] 5d
N-{4-[(3-Chloro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-2-cycl-
opentyl-acetamide
[0363] Yield: 46%. LC-MS (m/z) 371 (MH.sup.+); t.sub.R=3.43, (UV,
ELSD) 99%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 1.24 (m, 2H),
1.58 (m, 2H), 1.66 (m, 2H), 1.90 (m, 2H), 2.19 (s, 6H), 2.35 (m,
1H), 2.38 (d, 2H), 4.11 (b, 1H), 4.16 (b, 2H), 6.46 (dd, 1H), 6.58
(m, 1H), 6.65 (dd, 1H), 6.84 (b, 1H), 7.02 (s, 2H), 7.05 (m,
1H).
5e
2-Cyclopentyl-N-{4-[(3-methoxy-phenylamino)-methyl]-2,6-dimethyl-phenyl-
}-acetamide
[0364] Yield: 32%. LC-MS (m/z) 367 (MH.sup.+); t.sub.R=2.73, (UV,
ELSD) 96%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 1.25 (m, 2H),
1.58 (m, 2H), 1.66 (m, 2H), 1.90 (m, 2H), 2.20 (s, 6H), 2.35 (m,
1H), 2.39 (d, 2H), 3.75 (s, 3H), 3.99 (b, 1H), 4.19 (b, 2H), 6.18
(m, 1H), 6.25 (dq, 2H), 6.76 (b, 1H), 7.06 (s, 2H), 7.07 (m,
1H).
5f
N-{4-[(4-Chloro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-2-cyclopentyl-
-acetamide
[0365] Yield: 25%. LC-MS (m/z) 371 (MH.sup.+); t.sub.R=3.31, (UV,
ELSD) 98%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 1.26 (m, 2H),
1.59 (m, 2H), 1.67 (m, 2H), 1.92 (m, 2H), 2.21 (s, 6H), 2.36 (m,
1H), 2.40 (d, 2H), 4.03 (b, 1H), 4.18 (b, 2H), 6.53 (d, 6.72 (b,
1H), 7.04 (s, 2H), 7.09 (d, 2H).
5g
2-Cyclopentyl-N-{4-[(3,4-difluoro-phenylamino)-methyl]-2,6-dimethyl-phe-
nyl}-acetamide
[0366] Yield: 31%. LC-MS (m/z) 373 (MH.sup.+); t.sub.R=3.27, (UV,
ELSD) 97%, 99%. NMR (500 MHz, CDCl.sub.3): 1.25 (m, 2H), 1.59 (m,
2H), 1.67 (m, 2H), 1.92 (m, 2H), 2.20 (s, 6H), 2.36 (m, 1H), 2.39
(d, 2H), 4.02 (b, 1H), 4.14 (b, 2H), 6.26 (m, 1H), 6.37 (m, 1H),
6.78 (b, 1H), 6.92 (q, 1H), 7.03 (s, 2H).
5h
2-Cyclopentyl-N-{2,6-dimethyl-4-[(4-trifluoromethyl-phenylamino)-methyl-
]-phenyl}-acetamide
[0367] Yield: 22%. LC-MS (m/z) 405 (MH.sup.+); t.sub.R=3.56, (UV,
ELSD) 96%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 1.26 (m, 2H),
1.61 (m, 2H), 1.68 (m, 2H), 1.93 (m, 2H), 2.21 (s, 6H), 2.37 (m,
1H), 2.40 (d, 2H), 4.24 (d, 2H), 4.38 (t, 1H), 6.61 (d, 2H), 6.72
(b, 1H), 7.04 (s, 2H), 7.38 (d, 2H).
5i
2-Cyclopentyl-N-[2,6-dimethyl-4-(p-tolylamino-methyl)-phenyl]-acetamide
[0368] Yield: 10%. LC-MS (m/z) 351 (MH.sup.+); t.sub.R=2.23, (UV,
ELSD) 78%, 91%.
5j
2-Cyclopentyl-N-(2,6-dimethyl-4-[(3-trifluoromethyl-phenylamino)-methyl-
]-phenyl)-acetamide
[0369] Yield: 10%. LC-MS (m/z) 405 (MH.sup.+); t.sub.R=3.60, (UV,
ELSD) 75%, 99%.
5k
2-Cyclopentyl-N-{4-[(3,5-difluoro-phenylamino)-methyl]-2,6-dimethyl-phe-
nyl}-acetamide
[0370] Yield: 10%. LC-MS (m/z) 373 (MH.sup.+); t.sub.R=3.44, (UV,
ELSD) 73%, 99%.
5l {4-[(4-fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester
[0371] Yield: 86%. LC-MS (m/z) 331 (MH.sup.+); t.sub.R=2.53, (UV,
ELSD) 95%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 0.99 (t, 3H),
1.70 (m, 2H), 2.26 (s, 6H), 3.95 (b, 1H), 4.11 (1, 2H), 4.19 (s,
2H), 5.97 (b, 1H), 6.56 (m, 2H), 6.88 (dt, 2H), 7.07 (s, 2H).
5 m
{4-[(4-Chloro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester
[0372] Yield: 64%. LC-MS (m/z) 347 (MH.sup.+); t.sub.R=3.43, (UV,
ELSD) 98%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 0.99 (b, 3H),
1.70 (b, 2H), 2.25 (s, 6H), 4.11 (m, 3H), 4.20 (b, 2H), 5.97 (b,
1H), 6.54 (d, 2H), 7.06 (s, 2H), 7.10 (d, 2H).
5n
{2,6-Dimethyl-4-[(4-trifluoromethyl-phenylamino)-methyl]-phenyl}-carbam-
ic acid propyl ester
[0373] Yield: 61%. LC-MS (m/z) 381 (MH.sup.+); t.sub.R=3.56, (UV,
ELSD) 97%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 0.99 (b, 3H),
1.70 (b, 2H), 2.26 (s, 6H), 4.12 (m, 3H), 4.27 (b, 2H), 5.98 (b,
1H), 6.62 (d, 2H), 7.06 (s, 2H), 7.39 (d, 2H).
5o
{4-[(3,5-Difluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester
[0374] Yield: 42%. LC-MS (m/z) 349 (MH.sup.+); t.sub.R=3.39, (UV,
ELSD) 94%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 0.99 (b, 3H),
1.70 (b; 2H), 2.26 (s, 6H), 4.11 (m, 3H), 4.19 (b, 2H), 5.99 (b,
1H), 6.11 (m, 3H), 7.04 (s, 2H).
5p {4-[(3-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic
acid propyl ester
[0375] Yield: 62%. LC-MS (min 331 (MH.sup.+); t.sub.R=3.22, (UV,
ELSD) 96%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 0.99 (b, 3H),
1.70 (b, 2H), 2.26 (s, 6H), 4.11 (m, 3H), 4.21 (b, 2H), 5.97 (b,
1H), 6.31 (m, 1H), 6.38 (m, 1H), 7.06 (s, 2H), 7.09 (m, 1H).
5q {4-[(4-Methoxyphenylamino)-methyl]-2,6-dimethylphenyl}-carbamic
acid propyl ester
[0376] Yield: 41%. LC-MS (m/z) 341 (MH.sup.+); t.sub.R=1.94, (UV,
ELSD) 89%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 1.00 (m, 3H),
1.70 (m, 2H), 2.25 (s, 6H), 3.75 (s, 3H), 3.80 (broad, 1H), 4.10
(broad s, 2H), 4.35 (s, 2H), 5.95 (broad, 1H), 6.60 (d, 2H), 6.80
(d, 2H), 7.10 (s, 2H).
5r Pentanoic acid
{4-[(4-chlorophenylamino)-methyl]-2,6-dimethylphenyl}-amide
[0377] Yield: 64%. LC-MS (m/z) 345 (MH.sup.+); t.sub.R=3.10, (UV,
ELSD) 98%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 1.00 (t, 3H),
1.45 (m, 2H), 1.72 (m, 2H), 2.20 (s, 6H), 2.43 (t, 2H), 4.20 (s,
2H), 6.51 (d, 2H), 6.65 (b, 1H), 7.06 (s, 2H), 7.15 (d, 2H).
5s
2-(4-Chlorophenyl)-N-{4-[(4-chlorophenylamino)-methyl]-2,6-dimethylphen-
yl}-acetamide
[0378] Yield: 43%. LC-MS (m/z) 415 (MH.sup.+); t.sub.R=3.52, (UV,
ELSD) 97%, 98%. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 2.00 (s, 6H),
4.15 (broad, 5H), 6.62 (d, 2H), 7.05 (s, 2H), 7.13 (d, 2H), 7.40
(m, 4H).
5t
{2,6-Dimethyl-4-[(4-trifluoromethylphenylamino)-methyl]-phenyl}-carbami-
c acid 2-methoxyethyl ester
[0379] Yield: 42%. LC-MS (m/z) 397 (MH.sup.+); t.sub.R=3.22, (UV,
ELSD) 97%, 96%. .sup.1H NMR (500 MHz, CDCl.sub.3): 2.25 (s, 6H),
3.40 (b, 3H), 3.65 (b, 2H), 4.27 (s, 2H), 4.35 (b, 3H), 6.10 (b,
1H), 6.60 (d, 2H), 7.05 (s, 2H), 7.40 (d, 2H).
5u
N-{4-[(5-Chloro-pyridin-2-ylamino)-methyl]-2,6-dimethylphenyl}-2-cyclop-
entylacetamide
[0380] Yield: 63%. LC-MS (m/z) 372 (MH.sup.+); t.sub.R=1.93, (UV,
ELSD) 97%, 100%. .sup.1H NMR (500 MHz, CDCl.sub.3): 1.25 (m, 2H),
1.55 (m, 4H), 1.92 (m, 2H), 2.20 (s, 6H), 2.35 (m, 1H), 2.45 (d,
2H), 4.45 (d, 2H), 4.95 (broad t, 1H), 6.35 (d, 1H), 6.75 (s, 1H),
7.05 (s, 2H), 7.35 (d, 1H), 8.05 (s, 1H).
5v
2-Cyclopentyl-N-{4-[(2,6-dichloro-pyridin-4-ylamino)-methyl]-2,6-dimeth-
ylphenyl}-acetamide
[0381] Yield: 47%. LC-MS (m/z) 406 (MH.sup.+); t.sub.R=3.18, (UV,
ELSD) 96%, 96%. .sup.1H NMR (500 MHz, CDCl.sub.3): 1.25 (m, 2H),
1.60 (m, 2H), 1.65 (m, 2H), 1.95 (m, 2H), 2.20 (s, 6H), 2.35 (m,
1H), 2.45 (d, 2H), 4.25 (d, 2H), 4.60 (s, 1H), 6.40 (s, 2H), 6.85
(broad, 1H), 7.10 (s, 2H).
[0382] 5w
2-Cyclopentyl-N-{2,6-dichloro-4-[(4-fluoro-phenylamino)-methyl]p-
henyl}-acetamide
[0383] Yield: 52%. LC-MS (m/z) 395 (MH.sup.+); t.sub.R=3.31, (UV,
ELSD) 96%, 99%. .sup.1H NMR (500 MHz, CDCl.sub.3): 1.25 (m, 2H),
1.63 (m, 4H), 1.95 (m, 2H), 2.35 (m, 1H), 2.45 (d, 2H), 4.05
(broad, 1H), 4.25 (broad, 2H), 6.50 (m, 2H), 6.87 (m, 2H), 7.40 (s,
2H).
5x
2-Cyclopentyl-N-{2,6-dichloro-4-[(5-trifluoromethylpyridin-2-ylamino)-m-
ethyl]-phenyl}-acetamide
[0384] Yield: 47%. LC-MS (m/z) 446 (MH.sup.+); t.sub.R=3.10, (UV,
ELSD) 95%, 98%. .sup.1H NMR (500 MHz, CDCl.sub.3): 1.30 (m, 2H),
1.65 (m, 4H), 1.90 (m, 2H), 2.35 (m, 1H), 2.45 (d, 2H), 4.50
(broad, 1H), 4.65 (broad, 2H), 6.50 (d, 1H), 6.90 (s, 1H), 7.40 (s,
2H), 7.60 (d, 1H), 8.40 (s, 1H).
Example 6
6a
N-(4-Bromo-2-methyl-6-Morpholin-1-yl-phenyl)-3,3-dimethyl-butyramide
[0385] N-(2-Amino-4-bromo-6-methyl-phenyl)-3,3-dimethyl-butyramide
(1v, 1.01 g), N,N-diisopropyl-ethylamine (1.80 mL) and
bis(2-bromoethyl)ether (0.50 mL) were dissolved in dry
N,N-dimethylformamide (5 mL) and heated to 180.degree. C. for 50
minutes in a sealed microwave process vial. Saturated aqueous
sodium bicarbonate (20 mL) was added and the mixture was extracted
with ethyl acetate (3.times.20 mL), the combined organic phases
were dried over sodium sulfate and concentrated in vacuo. The crude
product was purified by flash chromatography to furnish 0.740 g
(60% yield) of the title compound as a white solid. LC-MS (m/z) 370
(MH.sup.+); t.sub.R=3.05, (UV, ELSD) 95%, 99%. .sup.1H NMR (500
MHz, DMSO-d.sub.6): 1.05 (s, 9H), 2.09 (s, 3H), 2.23 (s, 2H), 2.80
(t, 4H), 3.69 (t, 4H), 7.03 (d, 1H), 7.15 (d, 1H), 8.99 (s,
1H).
TABLE-US-00006 TABLE 1 Reagents used for the preparation of
compounds in Example 1-6 Name Supplier CAS no. Cat. no.
(2'-dicyclohexylphosphanyl-biphenyl-2-yl)- STREM 213697-53-1
15-1145 dimethyl-amine (3-acetylaminophenyl)boronic acid Lancaster
78887-39-5 14023 [(2-methylsulfonyl)aminophenyl]boronic acid
Combiblocks 2000 BB-2172-500 pinacol ester 1,10-phenanthroline
Avocado 66-71-7 13163 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid
Maybridge 164014-95-3 CC01312 2,4,6-Trifluoronitrobenzene Aldrich
315-14-0 26,180-7 2,6-dimethylaniline Fluka 87-62-7 39520
2-[4-(trifluoromethyl)phenyl]pyrrolidine Array 2AAX-Q07-0
2-Amino-5-chloropyridine Aldrich 1072-98-6 A4,680-3
2-Amino-5-(trifluoromethyl)pyridine Acros 74784-70-6 RF04702DA
2-Bromo-4,6-dichloroaniline Aldrich 697-86-9 29,769-0
2-Amino-5-nitrobenzotrifluoride Aldrich 121-01-7 19,657-6
2-Bromo-4,6-dimethylaniline Aldrich 41825-73-4 52,886-2
2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2- Aldrich 51,878-6
dioxaborolan-2-yl)phenol 2-methoxyphenylboronic acid Aldrich
5720-06-9 44,523-1 2-Methoxypyridine-5-carboxaldehyde Aldrich
65873-72-5 53,306-8 2-Methyl-4-nitroaniline Aldrich 99-52-5
14,643-9 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Aldrich
214360-76-6 52,256-2 yl)phenol 3-(trifluoromethoxy)benzeneboronic
acid Frontier Scientific 179113-90-7 T3636 3,4-difluoroaniline
Aldrich 3863-11-4 27,023-7 3,5-bis(trifluoromethyl)benzeneboronic
acid Aldrich 73852-19-4 47,107-0 3,5-difluoroaniline Aldrich
372-39-4 26,353-2 3-aminobenzeneboronic acid ABCR 30418-59-8
AV18189 3-chloroaniline Aldrich 108-42-9 C2,240-7
3-cyanophenylboronic acid Aldrich 150255-96-2 51,301-6
3-fluoro-4-trifluoromethylbenzaldehyde ABCR 204339-72-0 AV20008
3-fluoroaniline Fluorochem 372-19-0 1438 3-methoxy-aniline Fluka
536-90-3 10480 3-quinolineboronic acid Frontier Scientific
191162-39-7 Q5061 3-trifluoromethylaniline Fluka 98-16-8 07060
4-(dimethylamino)phenylboronic acid Aldrich 28611-39-4 48,353-2
4-(trifluoromethyl)benzylamine Aldrich 3300-51-4 26,350-8
4-Amino-2,6-dichloropyridine Aldrich 2587-02-2 56,534-2
4-Bromo-2,6,-dichloroaniline Avocado 697-88-1 A14884.14
4-Bromo-2,6-dimethylaniline Aldrich 24596-19-8 19,237-6
4-Bromo-2-methyl-6-nitro-phenylamine Maybridge 77811-44-0 BTB 07466
4-chloroaniline Aldrich 106-47-8 C2,241-5 4-Chlorophenylacetyl
chloride Lancaster 25026-34-0 6317 4-fluoroaniline Fluorochem
371-40-4 F03410 4-fluorobenzaldehyde Aldrich 459-57-4 12,837-6
4-Fluorophenylacetyl chloride Aldrich 459-04-1 46,695-6
4-fluorophenylboronic acid Aldrich 1765-93-1 41,755-6
4-isopropylphenylboronic acid Lancaster 16152-51-5 17459
4-methyl-2-phenyl-5-pyrimidinecarbaldehyde Maybridge 342405-36-1
CC20204 4-methylaniline Fluka 106-49-0 89632
4-nitro-2-trifluoromethyl-phenylamine Aldrich 121-01-7 19,657-6
4-trifluoromethylaniline Aldrich 455-14-1 22,493-6
4-trifluoromethylbenzaldehyde Aldrich 455-19-6 22,494-4
4-vinylphenylboronic acid Aldrich 2156-04-9 41,758-0
5-chloro-2-thiophenecarboxaldehyde Aldrich 7283-96-7 44,323-9
6-(4-methylphenoxy)nicotinaldehyde Bionet Research 5L-355S
6-(trifluoromethyl)pyridine-3-carboxaldehyde Fluorochem 9397
azacycloheptane Aldrich 111-49-9 H1,040-1
Bicyclo[2,2,1]hept-2-yl-acetic acid Aldrich 1007-01-8 12,726-4
Bis-(2-bromoethyl)ether Aldrich 5414-19-7 38,220-5
Bis(dibenzylideneacetone)palladium Acros 32005-36-0 29197-0050
Bromine Aldrich 7726-95-6 20,788-8 cesium carbonate Aldrich
534-17-8 44,190-2 Chloroformic acid 2-methoxyethyl ester Aldrich
628-12-6 59,229-3 copper(II) trifluoromethanesulfonate Aldrich
34946-82-2 28,367-3 Cyclohexanecarbonyl chloride Aldrich 2719-27-9
15,696-5 3-cyclohexylpropionyl chloride Acros 39098-75-4 35071-0250
Cyclopentylacetyl chloride Lancaster 1122-99-2 14562
Dibenzylideneacetone Lancaster 35225-79-7 2181 ethyl chloroformate
Merck 541-41-3 8.00881.2500 Heptanoyl chloride Aldrich 2528-61-2
14,724-9 Hexanoyl chloride Aldrich 142-61-0 29,465-9
isopropylmagnesium chloride (2 M in THF) Aldrich 1068-55-9 23,011-1
Morpholine Aldrich 110-91-8 25,236-0
N-[(Dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin- Fluka
148893-10-1 11373 1-ylmethylene]-N- methylmethanaminium
hexafluorophosphate N-oxide n-Propyl chloroformate Aldrich 109-61-5
24,946-7 Octanoyl chloride Fluka 111-64-8 21700 p-Anisidine Aldrich
104-94-9 A8,825-5 palladium(II) acetate Aldrich 3375-31-3 20,586-9
Pentanoyl chloride Aldrich 638-29-9 15,714-7 phenylboronic acid
Aldrich 98-80-6 P2,000-9 pyrrole Aldrich 109-97-7 13,170-9
tert-butyl lithium (1.7 M in heptane) Aldrich 594-19-4 18,619-8
Tert-butylacetyl chloride Aldrich 7065-46-5 B8,880-2
Tert-butyloxycarbonyl-L-leucine Aldrich 13139-15-6 13,454-6
Tert-butyloxycarbonyl-L-valine Aldrich 13734-41-3 35,972-6
thiophene-2-acetyl chloride Aldrich 39098-97-0 19,599-5
Trans-2-phenyl-1-cyclopropanecarbonyl Aldrich 939-87-7 13,430-9
chloride
In Vitro and In Vivo Testing
[0386] The compounds of the invention have been tested and shown
effect in one or more of the below models:
Relative Efflux Through the KCNQ2 Channel.
[0387] This exemplifies a KCNQ2 screening protocol for evaluating
compounds of the present invention. The assay measures the relative
efflux through the KCNQ2 channel, and was carried out according to
a method described by Tang et al. (Tang, W. et. J. Biomol. Screen,
2001, 6, 325-331) for hERG potassium channels with the
modifications described below.
[0388] An adequate number of CHO cells stably expressing
voltage-gated KCNQ2 channels were plated at a density sufficient to
yield a mono-confluent layer on the day of the experiment. Cells
were seeded on the day before the experiment and loaded with 1
.mu.Ci/ml [.sup.86Rb] over night. On the day of the experiment
cells were washed with a HBSS-containing buffer. Cells were
pre-incubated with drug for 30 minutes and the .sup.86Rb.sup.+
efflux was stimulated by a submaximal concentration of 15 mM KCl in
the continued presence of drug for additional 30 minutes. After a
suitable incubation period, the supernatant was removed and counted
in a liquid scintillation counter (Tricarb). Cells were lysed with
2 mM NaOH and the amount of .sup.86Rb.sup.+ was counted. The
relative efflux was calculated
((CPM.sub.super/(CPM.sub.super+CPM.sub.cell)).sub.Cmpd(CPM.sub.super/(CPM-
.sub.super+CPM.sub.cell).sub.15 mM KCl)*100-100.
[0389] The compounds of the invention have an EC.sub.50 of less
than 20000 nM, in most cases less than 2000 nM and in many cases
less than 200 nM. Accordingly, the compounds of the invention are
considered to be useful in the treatment of diseases associated
with the KCNQ family potassium channels.
Electrophysiological Patch-Clamp Recordings.
[0390] Voltage-activated KCNQ2 currents were recorded from
mammalian CHO cells by use of conventional patch-clamp recordings
techniques in the whole-cell patch-clamp configuration (Hamill O P
et. al. Pflugers Arch 1981; 391: 85-100). CHO cells with stable
expression of voltage-activated KCNQ2 channels were grown under
normal cell culture conditions in CO.sub.2 incubators and used for
electrophysiological recordings 1-7 days after plating. KCNQ2
potassium channels were activated by voltage steps up to +80 mV in
increments of 5-20 mV (or with a ramp protocol) from a membrane
holding potential between -100 mV and -40 mV (Tatulian L et al. J
Neuroscience 2001; 21 (15): 5535-5545). The electrophysiological
effects induced by the compounds were evaluated on various
parameters of the voltage-activated KCNQ2 current. Especially
effects on the activation threshold for the current and on the
maximum induced current were studied.
[0391] Some of the compounds of the invention have been tested in
this test. Melt-ward shift of the activation threshold or an
increase in the maximum induced potassium current is expected to
decrease the activity in neuronal networks and thus make the
compounds useful in diseases with increased neuronal activity--like
epilepsia.
Maximum Electroshock
[0392] The test was conducted in groups of male mice using corneal
electrodes and administering a square wave current of 26 mA for 0.4
seconds in order to induce a convulsion characterised by a tonic
hind limb extension (Wlaz et al. Epilepsy Research 1998, 30,
219-229).
Pilocarpine Induced Seizures
[0393] Pilocarpine induced seizures are induced by intraperitoneal
injection of pilocarpine 250 mg/kg to groups of male mice and
observing for seizure activity resulting in loss of posture within
a period of 30 minutes (Starr et al. Pharmacology Biochemistry and
Behavior 1993, 45, 321-325).
Electrical Seizure-Threshold Test
[0394] A modification of the up-and-down method (Kimball et al.
Radiation Research 1957, 1-12) was used to determine the median
threshold to induce tonic hind-limb extension in response to
corneal electroshock in groups of male mice. The first mouse of
each group received an electroshock at 14 mA, (0.4 s, 50 Hz) and
was observed for seizure activity. If a seizure was observed the
current was reduced by 1 mA for the next mouse, however, if no
seizure was observed then the current was increased by 1 mA. This
procedure was repeated for all 15 mice in the treatment group.
Chemical Seizure-Threshold Test
[0395] The threshold dose of pentylenetetrazole required to induce
a clonic convulsion was measured by timed infusion of
pentylenetetrazole (5 mg/mL at 0.5 mL/minute) into a lateral tail
vein of groups of male mice (Nutt et al. J Pharmacy and
Pharmacology 1986, 38, 697-698).
Amygdala Kindling
[0396] Rats underwent surgery to implantation of tri-polar
electrodes into the dorsolateral amygdala. After surgery the
animals were allowed to recover before the groups of rats received
either varying doses of test compound or the drug's vehicle. The
animals were stimulated with their initial after discharge
threshold+25 .mu.A daily for 3-5 weeks and on each occasion seizure
severity, seizure duration, and duration of electrical after
discharge were noted. (Racine. Electroencephalography and clinical
Neurophysiology 1972, 32, 281-294).
Side Effects
[0397] Central nervous system side-effects were measured by
measuring the time mice would remain on rotarod apparatus (Capacio
et al. Drug and Chemical Toxicology 1992, 15, 177-201); or by
measuring their locomotor activity by counting the number of
infra-red beams crossed in a test cage (Watson et al.
Neuropharmacology 1997, 36, 1369-1375). Hypothermic actions on the
animals core body temperature of the compound were measured by
either rectal probe or implanted radiotelemetry transmitters
capable of measuring temperature (Keeney et al. Physiology and
Behavior 2001, 74, 177-184).
Pharmacokinetics
[0398] The pharmacokinetic properties of the compounds were
determined via. i.v. and p.o. dosing to Sprague Dawley rats, and,
thereafter, drawing blood samples over 20 hours. Plasma
concentrations were determined with LC/MS/MS.
* * * * *