U.S. patent application number 13/618865 was filed with the patent office on 2013-01-17 for n-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds suitable for treating disorders that respond to modulation of the serotonin 5-ht6 receptor.
This patent application is currently assigned to Abbott Laboratories. The applicant listed for this patent is Gisela Backfisch, Anton Bespalov, Juergen Delzer, Karla Drescher, Andreas Haupt, Yanbin Lao, Frauke Pohlki, Ana-Lucia Relo, Liliane Unger, Barbara Vogg, Karsten Wicke, Min Zhang. Invention is credited to Gisela Backfisch, Anton Bespalov, Juergen Delzer, Karla Drescher, Andreas Haupt, Yanbin Lao, Frauke Pohlki, Ana-Lucia Relo, Liliane Unger, Barbara Vogg, Karsten Wicke, Min Zhang.
Application Number | 20130018047 13/618865 |
Document ID | / |
Family ID | 45565274 |
Filed Date | 2013-01-17 |
United States Patent
Application |
20130018047 |
Kind Code |
A1 |
Haupt; Andreas ; et
al. |
January 17, 2013 |
N-PHENYL-(PIPERAZINYL OR HOMOPIPERAZINYL)-BENZENESULFONAMIDE OR
BENZENESULFONYL-PHENYL-(PIPERAZINE OR HOMOPIPERAZINE) COMPOUNDS
SUITABLE FOR TREATING DISORDERS THAT RESPOND TO MODULATION OF THE
SEROTONIN 5-HT6 RECEPTOR
Abstract
The present invention relates to N-phenyl-(piperazinyl or
homopiperazinyl)-benzenesulfonamide or
benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds,
pharmaceutical compositions containing them, and their use in
therapy. The compounds possess valuable therapeutic properties and
are particularly suitable for treating diseases that respond to
modulation of the serotonin 5-HT.sub.6 receptor.
Inventors: |
Haupt; Andreas;
(Ludwigshafen, DE) ; Pohlki; Frauke;
(Ludwigshafen, DE) ; Drescher; Karla;
(Ludwigshafen, DE) ; Wicke; Karsten;
(Ludwigshafen, DE) ; Unger; Liliane;
(Ludwigshafen, DE) ; Relo; Ana-Lucia;
(Ludwigshafen, DE) ; Bespalov; Anton;
(Ludwigshafen, DE) ; Vogg; Barbara; (Ludwigshafen,
DE) ; Backfisch; Gisela; (Ludwigshafen, DE) ;
Delzer; Juergen; (Ludwigshafen, DE) ; Zhang; Min;
(Abbott Park, IL) ; Lao; Yanbin; (Abbott Park,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Haupt; Andreas
Pohlki; Frauke
Drescher; Karla
Wicke; Karsten
Unger; Liliane
Relo; Ana-Lucia
Bespalov; Anton
Vogg; Barbara
Backfisch; Gisela
Delzer; Juergen
Zhang; Min
Lao; Yanbin |
Ludwigshafen
Ludwigshafen
Ludwigshafen
Ludwigshafen
Ludwigshafen
Ludwigshafen
Ludwigshafen
Ludwigshafen
Ludwigshafen
Ludwigshafen
Abbott Park
Abbott Park |
IL
IL |
DE
DE
DE
DE
DE
DE
DE
DE
DE
DE
US
US |
|
|
Assignee: |
Abbott Laboratories
Abbott Park
IL
Abbott GmbH & Co. KG
Wiesbaden
|
Family ID: |
45565274 |
Appl. No.: |
13/618865 |
Filed: |
September 14, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13284204 |
Oct 28, 2011 |
|
|
|
13618865 |
|
|
|
|
12770837 |
Apr 30, 2010 |
8076326 |
|
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13284204 |
|
|
|
|
61174054 |
Apr 30, 2009 |
|
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|
Current U.S.
Class: |
514/218 ;
514/254.11; 514/255.03 |
Current CPC
Class: |
A61P 25/18 20180101;
A61P 25/00 20180101; A61P 25/28 20180101; C07D 317/46 20130101;
C07D 241/04 20130101; C07D 295/096 20130101; C07D 243/08 20130101;
A61P 25/30 20180101 |
Class at
Publication: |
514/218 ;
514/255.03; 514/254.11 |
International
Class: |
A61K 31/495 20060101
A61K031/495; A61K 31/496 20060101 A61K031/496; A61P 25/30 20060101
A61P025/30; A61K 31/551 20060101 A61K031/551 |
Claims
1-30. (canceled)
31. A non-prophylactic method for treating acute or chronic signs,
symptoms and/or malfunctions of an addictive disease, said method
comprising administering an effective amount of a
N-Phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or
benzenesulfonyl-phenyl-(piperazine or homopiperazine) of formula
(I) or (I') ##STR00125## wherein X is a bond or a group N--R.sup.4;
R.sup.1 is hydrogen or methyl; R.sup.2 is hydrogen or methyl;
R.sup.3 is hydrogen, C.sub.1-C.sub.3 alkyl, fluorine,
C.sub.1-C.sub.2 alkoxy or fluorinated C.sub.1-C.sub.2 alkoxy;
R.sup.4 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.4
cycloalkyl, or C.sub.3-C.sub.4 cycloalkyl-CH.sub.2--; R.sup.5 is
hydrogen, fluorine, chlorine, C.sub.1-C.sub.2 alkyl, fluorinated
C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.2 alkoxy or fluorinated
C.sub.1-C.sub.2 alkoxy; R.sup.6 is hydrogen, fluorine or chlorine;
and n is 1 or 2, or a physiologically tolerated acid addition salt
or an N-oxide thereof.
32. The method of claim 31, wherein the addictive disease is caused
by the abuse of a psychotropic substance.
33. The method of claim 32, wherein the psychotropic substance is a
sedative, an anxiolytic, a hypnotic, or a narcotic.
34. The method of claim 32, wherein the psychotropic substance is
an opioid, cocaine, nicotine, alcohol, a substance which interacts
with the GABA chloride channel complex, a sedative, a hypnotic, a
tranquilizer, lysergic acid diethylamide, a cannabinoid, a
psychomotor stimulant, an amphetamine or amphetamine-like
substance, or caffeine.
35. The method of claim 31, wherein the addictive disease is an
addiction to gaming.
36. The method of claim 31, wherein the addictive disease is an
addiction to gambling, a computer or video game addiction, or an
internet addiction.
37. The method of claim 31, wherein X is a group N--R.sup.4.
38. The method of claim 31, wherein n is 1.
39. The method of claim 31, wherein R.sup.3 is methyl or
methoxy.
40. The method of claim 31, wherein R.sup.4 is hydrogen.
41. The method of claim 31, wherein R.sup.5 is methyl, methoxy or
difluoromethoxy.
42. The method of claim 31, wherein R.sup.6 is hydrogen.
43. The method of claim 31, wherein X is a bond or a group
N--R.sup.4; R.sup.1 is hydrogen or methyl; R.sup.2 is hydrogen;
R.sup.3 is hydrogen, C.sub.1-C.sub.2 alkyl, or C.sub.1-C.sub.2
alkoxy; R.sup.4 is hydrogen, methyl, ethyl, n-propyl, isopropyl or
cyclopropylmethyl; R.sup.5 is hydrogen, methyl or methoxy; R.sup.6
is hydrogen; and n is 1 or 2.
44. The method of claim 31, wherein the OCHF.sub.2-radical in
formula I is located on the benzene ring in the ortho-position with
respect to X.
45. The method of claim 31, wherein the OCHF.sub.2-radical in
formula I is located on the benzene ring in the meta-position with
respect to X.
46. The method of claim 31, wherein the OCHF.sub.2-radical in
formula I is located on the benzene ring in the para-position with
respect to X.
47. The method of claim 31, wherein the compound of formula (I) or
(I') is selected from the group consisting of:
N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide-
;
3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-phenyl)-4-methyl-benzenesulfon-
amide;
1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-piperazin-
e;
N-(2-difluoromethoxy-phenyl)-N-methyl-3-(4-methyl-piperazin-1-yl)-benze-
ne-sulfonamide;
N-(2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzene-
-sulfonamide;
N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzene-s-
ulfonamide;
N-(4-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide-
;
N-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-4-methyl-3-piperazin-1-yl-benzene
sulfonamide;
N-cyclopropylmethyl-N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-y-
l-benzenesulfonamide;
N-cyclopropylmethyl-N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-y-
l-benzenesulfonamide;
N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-N-propyl-benzene-s-
ulfonamide;
N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-N-propyl-benzenesu-
lfonamide;
N-(3-difluoromethoxy-phenyl)-N-ethyl-4-methyl-3-piperazin-1-yl--
benzene sulfonamide;
N-(3-difluoromethoxy-phenyl)-4,N-dimethyl-3-piperazin-1-yl-benzenesulfona-
mide;
N-(2-difluoromethoxy-phenyl)-N-ethyl-4-methyl-3-piperazin-1-yl-benze-
ne sulfonamide;
N-(2-difluoromethoxy-phenyl)-N-methyl-4-methyl-3-piperazin-1-yl-benzene
sulfonamide;
N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide-
;
N-(3-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzene-
-sulfonamide;
N-(4-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamid-
e;
3-[1,4]diazepan-1-yl-N-(2-difluoromethoxy-phenyl)-4-methyl-benzenesulfo-
namide;
3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-4-methyl-phenyl)-4-methy-
l-benzenesulfonamide;
N-(2-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesu-
lfonamide;
N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-piperazin-1-yl-
-benzenesulfonamide;
N-(3-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamid-
e;
N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benze-
nesulfonamide;
N-(2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamid-
e;
N-(2-difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzen-
esulfonamide;
N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-y-
l-benzenesulfonamide;
N-(3-difluoromethoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesu-
lfonamide;
N-(3-difluoromethoxy-4-methoxy-phenyl)-N-ethyl-4-methoxy-3-pipe-
razin-1-yl-benzenesulfonamide;
N-(2-difluoromethoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesu-
lfonamide;
N-(3-difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-y-
l-benzenesulfonamide;
N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propy-
l-benzenesulfonamide;
N-(3-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenes-
ulfonamide;
N-(3-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzen-
esulfonamide;
N-(2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenes-
ulfonamide;
N-(2-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzen-
esulfonamide;
N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1--
yl)-benzenesulfonamide;
N-(2-difluoromethoxy-phenyl)-N-isopropyl-4-methyl-3-piperazin-1-yl-benzen-
esulfonamide;
N-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-4-methoxy-3-piperazin-1-yl-benzene-
sulfonamide;
N-(2-difluoromethoxy-phenyl)-3-piperazin-1-yl-benzenesulfonamide;
N-(2-difluoromethoxy-phenyl)-3-(4-methyl-piperazin-1-yl)-benzenesulfonami-
de;
N-(2-difluoromethoxy-phenyl)-N-methyl-3-piperazin-1-yl-benzenesulfonam-
ide;
N-(2-difluoromethoxy-phenyl)-N-methyl-3-(4-methyl-piperazin-1-yl)-ben-
zenesulfonamide;
1-[3-(3-difluoromethoxy-benzenesulfonyl)-phenyl]-piperazine;
1-[3-(3-difluoromethoxy-benzenesulfonyl)-phenyl]-4-methyl-piperazine;
1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methoxy-phenyl]-piperazine;
1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methoxy-phenyl]-4-methyl-piper-
azine;
1-[5-(3-difluoromethoxy-4-methoxy-benzenesulfonyl)-2-methoxy-phenyl-
]-piperazine;
N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethoxy-3-piperazin-1-yl-benzenesu-
lfonamide;
N-(3,4-bis-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-pipera-
zin-1-yl)-benzenesulfonamide;
N-(3,4-bis-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfo-
namide;
N-(5-chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-pipera-
zin-1-yl)-benzenesulfonamide;
N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethyl-3-(4-methyl-piperazin-1-yl)-
-benzenesulfonamide;
N-(5-difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide;
N-(5-chloro-2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl-
)-benzenesulfonamide;
N-(5-chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenes-
ulfonamide;
N-(5-difluoromethoxy-2-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesu-
lfonamide;
N-(5-difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-piperazin-1-y-
l-benzenesulfonamide;
N-(3,4-bis-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulf-
onamide;
N-(5-chloro-2-difluoromethoxy-phenyl)-4-ethyl-3-piperazin-1-yl-be-
nzenesulfonamide;
N-(2-difluoromethoxy-4-methyl-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesul-
fonamide;
N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-((R)-3-methyl-p-
iperazin-1-yl)-benzenesulfonamide;
N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-((S)-3-methyl-piperazin--
1-yl)-benzenesulfonamide;
N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesul-
fonamide;
N-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-3-(4-methyl-pip-
erazin-1-yl)-benzenesulfonamide;
N-(2-difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide;
N-(3-difluoromethoxy-phenyl)-3-piperazin-1-yl-benzenesulfonamide;
N-(2-difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide;
N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide;
N-(5-chloro-2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesu-
lfonamide;
N-(2-difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-piperazin-1-y-
l-benzenesulfonamide;
N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenes-
ulfonamide;
N(2-difluoromethoxy-4-fluoro-phenyl)-4-methyl-3-piperazin-1-yl-benzenesul-
fonamide;
N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-piper-
azin-1-yl)-benzenesulfonamide;
N-(4-difluoromethoxy-3-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenes-
ulfonamide;
N-(5-difluoromethoxy-2-methoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide;
N-(2-difluoromethoxy-5-methoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide;
N-(2-difluoromethoxy-4-fluoro-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl-
)-benzenesulfonamide;
N-(5-difluoromethoxy-2-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenes-
ulfonamide;
N-(2-difluoromethoxy-5-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenes-
ulfonamide;
N-(2-difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-piperazin-1-yl-benzenes-
ulfonamide;
N-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-3-piperazin-1-yl-benzene-
sulfonamide;
N-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-4-methyl-3-piperazin-1-yl-benzenes-
ulfonamide;
N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenes-
ulfonamide;
N-(3-difluoromethoxy-4-methyoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1--
yl)-benzenesulfonamide;
N-(4-difluoromethoxy-3-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl-
)-benzenesulfonamide;
N-(4-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzene-
sulfonamide;
N-(3-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide;
N-(4-difluoromethoxy-3-methoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1--
yl)-benzenesulfonamide;
N-(2-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl-
)-benzenesulfonamide;
N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl-
)-benzenesulfonamide;
N-(4-difluoromethoxy-3-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzene-
sulfonamide;
N-(3-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzene-
sulfonamide;
N-(4-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzen-
esulfonamide;
3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-phenyl)-4-methyl-benzenesulfona-
mide;
3-[1,4]diazepan-1-yl-N-(2-difluoromethoxy-phenyl)-4-methyl-benzenesu-
lfonamide;
3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-4-methyl-phenyl)-4-me-
thyl-benzenesulfonamide;
N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan--
1-yl)-benzenesulfonamide;
N-(2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-ben-
zenesulfonamide;
N-(3-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-ben-
zenesulfonamide;
N-(5-difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-3-piperazin-1-yl
benzenesulfonamide;
N-(5-difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-N-methyl-3-piperaz-
in-1-yl benzenesulfonamide;
N-(5-difluoromethoxy-2-methylphenyl)-4-fluoro-3-piperazin-1-yl
benzenesulfonamide;
N-(5-difluoromethoxy-2-methylphenyl)-4-fluoro-N-methyl-3-piperazin-1-yl
benzenesulfonamide; and the physiologically tolerated acid addition
salts thereof and the N-oxides thereof.
48. The method of claim 31, wherein the compound of formula (I) or
(I') is selected from the group consisting of:
N-(2-difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide;
N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide;
N-(2-difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenes-
ulfonamide;
N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenes-
ulfonamide;
N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethoxy-3-piperazin-1-yl-benzenesu-
lfonamide;
N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-pip-
erazin-1-yl)-benzenesulfonamide;
N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide;
N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenes-
ulfonamide;
N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenes-
ulfonamide;
N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide;
N-(5-Difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-3-piperazin-1-yl
benzenesulfonamide; and the physiologically tolerated acid addition
salts thereof and the N-oxides thereof.
49. The method of claim 31, wherein the compound of formula (I) or
(I') is
N-(2-difluoromethoxy-4-methyl-phenyl)-4-ethoxy-3-piperazin-1-yl-benzen-
esulfonamide, or a physiologically tolerated acid addition salt or
N-oxide thereof.
50. The method of claim 31, wherein the compound of formula (I) or
(I') is
N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benze-
nesulfonamide, or a physiologically tolerated acid addition salt or
N-oxide thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation-in-part of U.S. patent application
Ser. No. 12/770,837, filed on Apr. 30, 2010, which claims priority
to U.S. Provisional Patent Application No. 61/174,054, filed on
Apr. 30, 2009, the contents of all of which are herein incorporated
by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to N-phenyl-(piperazinyl or
homopiperazinyl)-benzenesulfonamide or
benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds,
pharmaceutical compositions containing them, and their use in
therapy. The compounds possess valuable therapeutic properties and
are particularly suitable for treating diseases that respond to
modulation of the serotonin 5-HT.sub.6 receptor.
[0003] Serotonin (5-hydroxytryptamine, 5-HT), a monoamine
neurotransmitter and local hormone, is formed by the hydroxylation
and decarboxylation of tryptophan. The greatest concentration is
found in the enterochromaffin cells of the gastrointestinal tract,
the remainder being predominantly present in platelets and in the
Central Nervous System (CNS). 5-HT is implicated in a vast array of
physiological and pathophysiological pathways. In the periphery, it
contracts a number of smooth muscles and induces
endothelium-dependent vasodilation. In the CNS, it is believed to
be involved in a wide range of functions, including the control of
appetite, mood, anxiety, hallucinations, sleep, vomiting and pain
perception.
[0004] Neurons that secrete 5-HT are termed serotonergic. The
function of 5-HT is exerted upon its interaction with specific
(serotonergic) neurons. Until now, seven types of 5-HT receptors
have been identified: 5-HT, (with subtypes 5-HT.sub.1A,
5-HT.sub.1B, 5-HT.sub.1D, 5-HT.sub.1E and 5-HT.sub.1F),
5-HT.sub.2(with subtypes 5-HT.sub.2A, 5-HT.sub.2B and 5-HT.sub.2C),
5-HT.sub.3, 5-HT.sub.4, 5-HT.sub.5 (with subtypes 5-HT.sub.5A and
5-HT.sub.5B), 5-HT.sub.6 and 5-HT.sub.7. Most of these receptors
are coupled to G-proteins that affect the activities of either
adenylate cyclase or phospholipase C.gamma..
[0005] The human 5-HT.sub.6 receptors are positively coupled to
adenylyl cyclase. They are distributed throughout the limbic,
striatal and cortical regions of the brain and show a high affinity
to antipsychotics.
[0006] The modulation of the 5-HT.sub.6 receptor by suitable
substances is expected to improve certain disorders including
cognitive dysfunctions, such as a deficit in memory, cognition and
learning, in particular associated with Alzheimer's disease,
age-related cognitive decline and mild cognitive impairment,
attention deficit disorder/hyperactivity syndrome, personality
disorders, such as schizophrenia, in particular cognitive deficits
related with schizophrenia, affective disorders such as depression,
anxiety and obsessive compulsive disorders, motion or motor
disorders such as Parkinson's disease and epilepsy, migraine, sleep
disorders (including disturbances of the Circadian rhythm), feeding
disorders, such as anorexia and bulimia, certain gastrointestinal
disorders such as Irritable Bowel Syndrome, diseases associated
with neurodegeneration, such as stroke, spinal or head trauma and
head injuries, such as hydrocephalus, addiction diseases and
obesity (see e.g. A. Meneses, Drug News Perspect 14(7) (2001) pp.
396-400 and literature cited therein; J. Pharmacol. Sci. Vol. 101
(Suppl. 1), 2006, p. 124. Modulators of the 5HT.sub.6-receptor such
as PRX-07034 (Epix Pharmaceuticals) have been found in preclinical
and clinical studies to be particular useful in the treatment of
cognitive dysfunctions, in particular associated with Alzheimer's
disease or schizophrenia or in the treatment of obesity (see e.g.
http://www.epixpharma.com/products/prx-07034.asp).
[0007] WO 98/027081, WO 99/02502, WO 00/12623, WO 00/12073, US
2003/0069233, WO 02/08179, WO 02/92585, WO 2006/010629 describe
certain benzenesulfonanilide compounds having 5HT.sub.6 receptor
antagonist activity and suggest the use of these compounds for the
treatment of medical disorders which are susceptible to the
treatment with 5HT.sub.6 receptor antagonists such as certain CNS
disorders, drug abuse, ADHD, obesity and type II diabetes. WO
2004/080986 and WO 03/014097 describe certain diarylsulfone
compounds, suggesting the use of these compounds for the treatment
of medical disorders which are susceptible to the treatment with
5HT.sub.6 receptor antagonists such as certain CNS disorders, drug
abuse, ADHD, obesity and type II diabetes. WO 2008087123 suggests
compounds having 5HT.sub.6 receptor antagonist activity for
preventing relapse into addiction.
[0008] However, there is still an ongoing need for providing
compounds having high affinity for the 5-HT.sub.6 receptor and
which show high selectivity to this receptor. In particular the
compounds should have low affinity to adrenergic receptors, such as
.alpha..sub.1-adrenergic receptor, histamine receptors, such as
H.sub.1-receptor, and dopaminergic receptors, such as
D.sub.2-receptor, in order to avoid or reduce considerable side
effects associated with modulation of these receptors, such as
postural hypotension, reflex tachycardia, potentiation of the
antihypertensive effect of prazosin, terazosin, doxazosin and
labetalol or dizziness associated to the blockade of the
.alpha..sub.1-adrenergic receptor, weight gain, sedation,
drowsiness or potentiation of central depressant drugs associated
to the blockade of the H.sub.1-receptor, or extrapyramidal movement
disorder, such as dystonia, parkinsonism, akathisia, tardive
dyskinesia or rabbit syndrome, or endocrine effects, such as
prolactin elevation (galactorrhea, gynecomastia, menstruyl changes,
sexual dysfunction in males), associated to the blockade of the
D.sub.2-receptor.
[0009] It is one object of the present invention to provide
compounds which have a high affinity for the 5-HT.sub.6 receptor.
It is a further object of the present invention to provide
compounds which selectively bind to the 5-HT.sub.6 receptor.
[0010] The compounds should also have good pharmacological profile,
e.g. a good bioavailability and/or a good metabolic stability.
SUMMARY OF THE INVENTION
[0011] The present invention relates to N-phenyl-(piperazinyl or
homopiperazinyl)-benzenesulfonamides or
benzenesulfonyl-phenyl-(piperazines or homopiperazines) of formula
(I) or (I')
##STR00001## [0012] wherein [0013] X is a bond or a group
N--R.sup.4; [0014] R.sup.1 is hydrogen or methyl; [0015] R.sup.2 is
hydrogen or methyl; [0016] R.sup.3 is hydrogen, C.sub.1-C.sub.3
alkyl (e.g. methyl), fluorine, C.sub.1-C.sub.2 alkoxy (e.g.
methoxy) or fluorinated C.sub.1-C.sub.2 alkoxy; [0017] R.sup.4 is
hydrogen C.sub.1-C.sub.4 alkyl (e.g. methyl, ethyl, n-propyl,
isopropyl), C.sub.3-C.sub.4 cycloalkyl, or
--CH.sub.2--C.sub.3-C.sub.4 cycloalkyl (e.g. cyclopropylmethyl);
[0018] R.sup.5 is hydrogen, fluorine, chlorine, C.sub.1-C.sub.2
alkyl (e.g. methyl), fluorinated C.sub.1-C.sub.2 alkyl,
C.sub.1-C.sub.2 alkoxy (e.g. methoxy) or fluorinated
C.sub.1-C.sub.2 alkoxy; [0019] R.sup.6 is hydrogen, fluorine or
chlorine; and [0020] n is 1 or 2, [0021] and physiologically
tolerated acid addition salts and the N-oxides thereof.
[0022] Said compounds, i.e., the N-phenyl-(piperazinyl or
homopiperazinyl)-benzenesulfonamides or
benzenesulfonyl-phenyl-piperazines or -homopiperazines and their
physiologically tolerated acid addition salts and the N-oxides
thereof, exhibit to a surprising and unexpected degree, a high
binding affinity to the 5-HT.sub.6 receptor and are thus useful as
pharmaceuticals.
[0023] The present invention thus further relates to the compounds
of formula (I) or (I') for use in therapy.
[0024] The present invention also relates to pharmaceutical
compositions which comprise a compound of formula (I) or (I') and,
optionally, a physiologically acceptable carrier and/or an
auxiliary substance.
[0025] In particular, said compounds, i.e., the
N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamides or
benzenesulfonyl-phenyl-(piperazines or homopiperazines) and their
physiologically tolerated acid addition salts and the N-oxides
thereof, are modulators of the 5-HT.sub.6 receptor.
[0026] The present invention thus further relates to the compounds
of formula (I) or (I') for use in modulating the 5-HT.sub.6
receptor.
[0027] The present invention also relates to the use of the
compounds of formula (I) or (I') in the manufacture of a medicament
for modulating the 5-HT.sub.6 receptor and corresponding methods of
modulating the 5-HT.sub.6 receptor.
[0028] Modulators of the 5-HT.sub.6 receptor and in particular
antagonists of the 5-HT.sub.6 receptor are known to be useful in
treating a variety of disorders.
[0029] The present invention thus further relates to the compounds
of formula (I) or (I') for use in treating said disorders.
[0030] The present invention also relates to the use of the
compounds of formula (I) or (I') in the manufacture of a medicament
for treating said disorders and corresponding methods of treating
said disorders.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The disorders diseases which are susceptible to treatment
with a compound of the formula (I) or (I') include, e.g., disorders
and diseases of the central nervous system, in particular cognitive
dysfunctions, such as a deficit in memory, cognition and learning,
in particular associated with Alzheimer's disease, age-related
cognitive decline and mild cognitive impairment, attention deficit
disorder/hyperactivity syndrome (ADHD), personality disorders, such
as schizophrenia, in particular cognitive deficits related with
schizophrenia, affective disorders such as depression, anxiety and
obsessive compulsive disorders, motion or motor disorders such as
Parkinson's disease and epilepsy, migraine, sleep disorders
(including disturbances of the Circadian rhythm), feeding
disorders, such as anorexia and bulimia, certain gastrointestinal
disorders such as Irritable Bowel Syndrome, diseases associated
with neurodegeneration, such as stroke, spinal or head trauma and
head injuries, including hydrocephalus, drug addiction and
obesity.
[0032] Provided the compounds of the formula (I) or (I') of a given
constitution may exist in different spatial arrangements, for
example if they possess one or more centers of asymmetry,
polysubstituted rings or double bonds, or as different tautomers,
the invention also relates to enantiomeric mixtures, in particular
racemates, diastereomeric mixtures and tautomeric mixtures,
preferably, however, the respective essentially pure enantiomers
(ennatiomerically pure), diastereomers and tautomers of the
compounds of formula (I) or (I') and/or of their salts and/or their
N-oxides.
[0033] The invention also relates to physiologically tolerated
salts of the compounds of the formula (I) or (I'), especially acid
addition salts with physiologically tolerated acids. Examples of
suitable physiologically tolerated organic and inorganic acids are
hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric
acid, C.sub.1-C.sub.4-alkylsulfonic acids, such as methanesulfonic
acid, aromatic sulfonic acids, such as benzenesulfonic acid and
toluenesulfonic acid, oxalic acid, maleic acid, fumaric acid,
lactic acid, tartaric acid, adipic acid and benzoic acid. Other
utilizable acids are described in Fortschritte der
Arzneimittelforschung [Advances in drug research], Volume 10, pages
224 ff., Birkhauser Verlag, Basel and Stuttgart, 1966.
[0034] The invention also relates to N-oxides of the compounds of
the formula (I) or (I'), provided that those compounds contain a
basic nitrogen atom, such as the nitrogen atom of the piperazine
moiety.
[0035] The organic moieties mentioned in the above definitions of
the variables are--like the term halogen--collective terms for
individual listings of the individual group members. The prefix
C.sub.n-C.sub.m indicates in each case the possible number of
carbon atoms in the group.
[0036] As used herein, C.sub.1-C.sub.4 alkyl is a straight-chain or
branched alkyl group having 1, 2, 3 or 4 carbon atoms. Examples of
such a group include methyl, ethyl, n-propyl, 1-methylethyl
(isopropyl), n-butyl, 1-methylpropyl (=2-butyl), 2-methylpropyl
(=isobutyl) and 1,1-dimethylethyl (=tert.-butyl).
[0037] As used herein, fluorinated C.sub.1-C.sub.2 alkyl is a
straight-chain alkyl group having 1 or 2 carbon atoms, wherein at
least one hydrogen atom, e.g. 1, 2, 3, 4 or 5 hydrogen atoms, are
replaced by fluorine. Examples of such a group include
fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl
and 1,1,2,2,2-pentafluoroethyl.
[0038] As used herein, C.sub.1-C.sub.2 alkoxy is a straight-chain
alkyl group having 1 or 2 carbon atoms which is bound to the
remainder of the molecule via an oxygen atom, i.e., methoxy and
ethoxy.
[0039] As used herein, fluorinated C.sub.1-C.sub.2 alkoxy is an
alkoxy group as defined above, wherein at least one, e.g. 1, 2, 3,
4 or 5 hydrogen atoms are replaced by fluorine atoms. Examples of
such a group are fluoromethoxy, difluoromethoxy, trifluoromethoxy,
2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and
1,1,2,2-tetrafluoroethoxy.
[0040] As used herein, C.sub.3-C.sub.4-cycloalkyl is a
cycloaliphatic radical having from 3 to 4 carbon atoms, i.e.
cyclopropyl and cyclobutyl.
[0041] With respect to the compounds' capability of modulating the
5-HT.sub.6 receptor, the variables X, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6 and n preferably have the following
meanings which, when taken alone or in combination, represent
particular embodiments of the compounds of the formula (I) or
(I').
[0042] X is a bond or a group N--R.sup.4. A first preferred
embodiment of the invention relates to compounds of the formula I
or I', to their pharmacologically tolerated salts and to the
N-oxides thereof, wherein X is a group N--R.sup.4.
[0043] R.sup.1 is hydrogen or methyl. A second preferred embodiment
of the invention relates to compounds of the formula I or I', to
their pharmacologically tolerated salts and to the N-oxides
thereof, wherein R.sup.1 is hydrogen. Another embodiment of the
invention relates to compounds of the formula I or I', to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein R.sup.1 is methyl.
[0044] R.sup.2 is hydrogen or methyl. A third preferred embodiment
of the invention relates to compounds of the formula I or I', to
their pharmacologically tolerated salts and to the N-oxides
thereof, wherein R.sup.2 is hydrogen.
[0045] Another embodiment of the invention relates to compounds of
the formula I or I', wherein R.sup.2 is methyl. If R.sup.2 is
methyl, the carbon atom that carries R.sup.2 creates a center of
chirality. Thus, a specific embodiment of the invention relates to
compounds of the formula I or I', to their pharmacologically
tolerated salts and to the N-oxides thereof, wherein R.sup.2 is
methyl and wherein the carbon atom that carries R.sup.2 has
S-configuration. Another specific embodiment of the invention
relates to compounds of the formula I or I', to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein R.sup.2 is methyl and wherein the carbon atom that carries
R.sup.2 has R-configuration.
[0046] Likewise preferred are mixtures of compounds of the present
invention, wherein the carbon atom that carries R.sup.2 has
S-configuration or R-configuration, respectively. These mixtures
may contain equal amounts or non-equal amounts of the compound I,
or equal amounts or non-equal amounts of the compound I',
respectively, that have R-configuration with regard to the moiety
CH--R.sup.2 and of the compound I or I' that have S-configuration
with regard to CH--R.sup.2.
[0047] The term "enantiomerically pure" means that the mixture
contains the respective compound in an entaniomeric excess of at
least 80%, in particular at least 90% (ee).
[0048] R.sup.3 is hydrogen, C.sub.1-C.sub.3 alkyl (e.g. methyl),
fluorine, C.sub.1-C.sub.2 alkoxy (e.g. methoxy or ethoxy) or
fluorinated C.sub.1-C.sub.2 alkoxy.
[0049] Preference is given to compounds of the formula I or I', to
their pharmacologically tolerated salts and to the N-oxides
thereof, wherein R.sup.3 is methyl or methoxy, difluoromethoxy or
trifluoromethoxy, in particular methyl or methoxy, and most
preferably methyl. The invention also relates to compounds of the
formula I or I', to their pharmacologically tolerated salts and to
the N-oxides thereof, wherein R.sup.3 is hydrogen or fluorine, in
particular hydrogen. The invention also relates to compounds of the
formula I or I', to their pharmacologically tolerated salts and to
the N-oxides thereof, wherein R.sup.3 is methoxy or ethoxy.
[0050] R.sup.4 is hydrogen, C.sub.1-C.sub.4 alkyl (e.g. methyl,
ethyl, n-propyl, isopropyl), C.sub.3-C.sub.4 cycloalkyl, or
C.sub.3-C.sub.4 cycloalkyl-CH.sub.2-- (e.g. cyclopropylmethyl).
[0051] Preference is given to compounds of the formula I or I', to
their pharmacologically tolerated salts and to the N-oxides
thereof, wherein R.sup.4 is hydrogen, methyl, ethyl, n-propyl,
isopropyl or cyclopropylmethyl. More preference is given to the
compounds of the present invention, wherein R.sup.4 is
hydrogen.
[0052] R.sup.5 is hydrogen, fluorine, C.sub.1-C.sub.2 alkyl (e.g.
methyl), fluorinated C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.2 alkoxy
(e.g. methoxy) or fluorinated C.sub.1-C.sub.2 alkoxy.
[0053] R.sup.5 is preferably selected from the group consisting of
hydrogen, fluorine, methyl, trifluoromethyl, methoxy,
difluoromethoxy and trifluoromethoxy and more preferably from
hydrogen, methoxy and difluoromethoxy. Likewise, preference is
given to the compounds of the formula I or I', wherein R.sup.5 is
chlorine. In a particular preferred embodiment of the invention,
R.sup.5 is hydrogen. In another particular preferred embodiment of
the invention, R.sup.5 is selected from fluorine, methyl,
trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy and
more preferably from methyl, methoxy and difluoromethoxy. Likewise,
more preference is given to the compounds of the formula I or I',
wherein R.sup.5 is fluorine. Likewise, more preference is given to
the compounds of the formula I or I', wherein R.sup.5 is
chlorine.
[0054] R.sup.6 is hydrogen, fluorine or chlorine, preferably
hydrogen or fluorine. In a particular preferred embodiment of the
invention, R.sup.6 is hydrogen. In another particular embodiment of
the invention R.sup.6 is different from hydrogen, in particular
fluorine. If R.sup.6 is different from hydrogen it is preferably
located in the 5- or 6-position of the benzene ring.
[0055] Preference is given to those compounds of the formula I or
I', to their pharmacologically tolerated salts and to the N-oxides
thereof, wherein R.sup.3 is methyl or methoxy and R.sup.6 is
hydrogen, or R.sup.3 is methyl or methoxy and R.sup.6 is fluorine
being located in the 5- or 6-position of the benzene ring, or both
R.sup.3 and R.sup.6 are hydrogen or R.sup.3 is hydrogen and R.sup.6
is fluorine being located in the 5- or 6-position of the benzene
ring.
[0056] According to a further particular embodiment, R.sup.5 and
R.sup.6 are hydrogen, R.sup.3 is selected from the group consisting
of C.sub.1-C.sub.2 alkyl (e.g. methyl) and C.sub.1-C.sub.2 alkoxy
(e.g. methoxy), and R.sup.4 is selected from the group consisting
of hydrogen, C.sub.1-C.sub.4 alkyl (e.g. methyl, ethyl, n-propyl,
isopropyl), or cyclopropylmethyl.
[0057] n is 1 or 2, thus forming a piperazine or a homopiperazine
moiety. Preference is give to n being 1, i.e. compounds having a
piperazine moiety.
[0058] A particular preferred embodiment Ia of the invention
relates to compounds of the formula I, to their pharmacologically
tolerated salts and to the N-oxides thereof, wherein [0059] R.sup.1
is hydrogen; [0060] R.sup.2 is hydrogen; [0061] R.sup.3 is methyl,
methoxy, difluoromethoxy or trifluoromethoxy, in particular methyl
or methoxy; and [0062] R.sup.4 is hydrogen.
[0063] A further particular preferred embodiment Ib of the
invention relates to compounds of the formula I, to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0064] R.sup.1 is hydrogen; [0065] R.sup.2 is hydrogen;
[0066] R.sup.3 is methyl, methoxy, difluoromethoxy or
trifluoromethoxy, in particular methyl or methoxy; and [0067]
R.sup.4 is methyl.
[0068] A further particular preferred embodiment Ic of the
invention relates to compounds of the formula I, to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0069] R.sup.1 is methyl; [0070] R.sup.2 is hydrogen;
[0071] R.sup.3 is methyl, methoxy, difluoromethoxy or
trifluoromethoxy, in particular methyl or methoxy; and [0072]
R.sup.4 is hydrogen.
[0073] A further particular preferred embodiment Id of the
invention relates to compounds of the formula I, to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0074] R.sup.1 is methyl; [0075] R.sup.2 is hydrogen;
[0076] R.sup.3 is methyl, methoxy, difluoromethoxy or
trifluoromethoxy, in particular methyl or methoxy; and [0077]
R.sup.4 is methyl.
[0078] A further particular preferred embodiment Ia of the
invention relates to compounds of the formula I, to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0079] R.sup.1 is hydrogen; [0080] R.sup.2 is hydrogen;
[0081] R.sup.3 is methoxy or ethoxy; and [0082] R.sup.4 is
hydrogen.
[0083] A further particular preferred embodiment Ia of the
invention relates to compounds of the formula I, to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0084] R.sup.1 is methyl; [0085] R.sup.2 is hydrogen;
[0086] R.sup.3 is methoxy or ethoxy; and [0087] R.sup.4 is
hydrogen.
[0088] A particular preferred embodiment Ie of the invention
relates to compounds of the formula I, to their pharmacologically
tolerated salts and to the N-oxides thereof, wherein [0089] R.sup.1
is hydrogen; [0090] R.sup.2 is hydrogen; [0091] R.sup.3 is hydrogen
or fluorine, in particular hydrogen; and [0092] R.sup.4 is
hydrogen.
[0093] A further particular preferred embodiment If of the
invention relates to compounds of the formula I, to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0094] R.sup.1 is hydrogen; [0095] R.sup.2 is hydrogen;
[0096] R.sup.3 is hydrogen or fluorine, in particular hydrogen; and
[0097] R.sup.4 is methyl.
[0098] A further particular preferred embodiment Ig of the
invention relates to compounds of the formula I, to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0099] R.sup.1 is methyl; [0100] R.sup.2 is hydrogen;
[0101] R.sup.3 is hydrogen or fluorine, in particular hydrogen; and
[0102] R.sup.4 is hydrogen.
[0103] A further particular preferred embodiment Ih of the
invention relates to compounds of the formula I, to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0104] R.sup.1 is methyl; [0105] R.sup.2 is hydrogen;
[0106] R.sup.3 is hydrogen or fluorine, in particular hydrogen; and
[0107] R.sup.4 is methyl.
[0108] A further particular preferred embodiment 1 h of the
invention relates to compounds of the formula I, to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0109] R.sup.1 is hydrogen; [0110] R.sup.2 is hydrogen;
[0111] R.sup.3 is methoxy or ethoxy; and [0112] R.sup.4 is
hydrogen.
[0113] A further particular preferred embodiment 1 h of the
invention relates to compounds of the formula I, to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0114] R.sup.1 is methyl; [0115] R.sup.2 is hydrogen;
[0116] R.sup.3 is methoxy or ethoxy; and [0117] R.sup.4 is
hydrogen.
[0118] Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If,
Ig and Ih, preference is given to those, where the radicals R.sup.5
and R.sup.6 in formula I are both hydrogen.
[0119] Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If,
Ig and Ih, likewise preference is given to those, where the radical
R.sup.5 in formula I is hydrogen and where the radical R.sup.6 in
formula I is fluorine, which is located in the 5-position or in the
6-position of the benzene ring.
[0120] Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If,
Ig and Ih, likewise preference is given to those, where the radical
R.sup.5 in formula I is methoxy and where the radical R.sup.6 in
formula I is hydrogen.
[0121] Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If,
Ig and Ih, likewise preference is given to those, where the radical
R.sup.5 in formula I is methoxy and where the radical R.sup.6 in
formula I is fluorine, which is located in the 5-position or in the
6-position of the benzene ring.
[0122] Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If,
Ig and Ih, likewise preference is given to those, where the radical
R.sup.5 in formula I is difluoromethoxy and where the radical
R.sup.6 in formula I is hydrogen.
[0123] Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If,
Ig and Ih, likewise preference is given to those, where the radical
R.sup.5 in formula I is difluoromethoxy and where the radical
R.sup.6 in formula I is fluorine, which is located in the
5-position or in the 6-position of the benzene ring.
[0124] Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If,
Ig and Ih, likewise preference is given to those, where the radical
R.sup.5 in formula I is chlorine and where the radical R.sup.6 in
formula I is hydrogen.
[0125] Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If,
Ig and Ih, likewise preference is given to those, where the radical
R.sup.5 in formula I is fluorine and where the radical R.sup.6 in
formula I is hydrogen.
[0126] Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If,
Ig and Ih, likewise preference is given to those, where the radical
R.sup.5 in formula I is difluoromethoxy and where the radical
R.sup.6 in formula I is hydrogen.
[0127] Amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If,
Ig and Ih, likewise preference is given to those, where the radical
R.sup.5 in formula I is methyl and where the radical R.sup.6 in
formula I is hydrogen.
[0128] A particular preferred embodiment I'a of the invention
relates to compounds of the formula I', to their pharmacologically
tolerated salts and to the N-oxides thereof, wherein
R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is methyl,
methoxy, difluoromethoxy or trifluoromethoxy, in particular methyl
or methoxy; and R.sup.4 is hydrogen.
[0129] A further particular preferred embodiment I'b of the
invention relates to compounds of the formula I', to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein
R.sup.1 is hydrogen; R.sup.2 is methyl; R.sup.3 is methyl, methoxy,
difluoromethoxy or trifluoromethoxy, in particular methyl or
methoxy; and R.sup.4 is hydrogen.
[0130] A further particular preferred embodiment I'c of the
invention relates to compounds of the formula I', to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein
R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is methyl,
methoxy, difluoromethoxy or trifluoromethoxy, in particular methyl
or methoxy; and R.sup.4 is methyl.
[0131] A further particular preferred embodiment I'd of the
invention relates to compounds of the formula I', to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein
R.sup.1 is hydrogen; R.sup.2 is methyl; R.sup.3 is methyl, methoxy,
difluoromethoxy or trifluoromethoxy, in particular methyl or
methoxy; and R.sup.4 is methyl.
[0132] A particular preferred embodiment I'e of the invention
relates to compounds of the formula I', to their pharmacologically
tolerated salts and to the N-oxides thereof, wherein
R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is hydrogen or
fluorine, in particular hydrogen; and R.sup.4 is hydrogen.
[0133] A further particular preferred embodiment I'f of the
invention relates to compounds of the formula I', to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein
R.sup.1 is hydrogen; R.sup.2 is methyl; R.sup.3 is hydrogen or
fluorine, in particular hydrogen; and R.sup.4 is hydrogen.
[0134] A further particular preferred embodiment I'g of the
invention relates to compounds of the formula I', to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein
R.sup.1 is hydrogen; R.sup.2 is hydrogen; R.sup.3 is hydrogen or
fluorine, in particular hydrogen; and R.sup.4 is methyl.
[0135] A further particular preferred embodiment I'h of the
invention relates to compounds of the formula I', to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein
R.sup.1 is hydrogen; R.sup.2 is methyl; R.sup.3 is hydrogen or
fluorine, in particular hydrogen; and R.sup.4 is methyl.
[0136] Amongst the compounds of embodiments I'a, I'b, I'c, I'd,
I'e, I'g and I'h, preference is given to those, where the radicals
R.sup.5 and R.sup.6 in formula I' are both hydrogen.
[0137] Amongst the compounds of embodiments I'a, I'b, I'c, I'd,
I'e, I'g and I'h, likewise preference is given to those, where the
radical R.sup.5 in formula I is hydrogen and where the radical
R.sup.6 in formula I' is fluorine, which is located in the
5-position or in the 6-position of the benzene ring.
[0138] Amongst the compounds of the formula I, in particular
amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and
Ih, particular preference is given to those, wherein the
OCHF.sub.2-radical is located on the benzene ring in the
meta-position with respect to X. Amongst these compounds,
particular preference is given to those compounds of the formula I,
wherein R.sup.5 is hydrogen. Amongst these compounds, likewise
preference is given to those compounds of the formula I, wherein
R.sup.5 is different from hydrogen and in particular selected from
fluorine, chlorine, methyl, trifluoromethyl, methoxy,
difluoromethoxy and trifluoromethoxy and more preferably from
methyl, methoxy and difluoromethoxy, and located in the
para-position, with respect to X, or in the para-position, with
respect to the OCHF.sub.2-radical.
[0139] Amongst the compounds of the formula I, in particular
amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and
Ih, likewise preference is given to those, wherein the
OCHF.sub.2-radical is located on the benzene ring in the
ortho-position with respect to X. Amongst these compounds,
particular preference is given to those compounds of the formula I,
wherein R.sup.5 is hydrogen. Amongst these compounds, likewise
preference is given to those compounds of the formula I, wherein
R.sup.5 is different from hydrogen and in particular selected from
fluorine, chlorine, methyl, trifluoromethyl, methoxy,
difluoromethoxy and trifluoromethoxy and more preferably from
methyl, methoxy and difluoromethoxy, and located in the
para-position, with respect to X, or in the para-position, with
respect to the OCHF.sub.2-radical.
[0140] Amongst the compounds of the formula I, in particular
amongst the compounds of embodiments Ia, Ib, Ic, Id, Ie, If, Ig and
Ih, likewise preference is given to those, wherein the
OCHF.sub.2-radical is located on the benzene ring in the
para-position with respect to X. Amongst these compounds,
particular preference is given to those compounds of the formula I,
wherein R.sup.5 is hydrogen. Amongst these compounds, likewise
preference is given to those compounds of the formula I, wherein
R.sup.5 is different from hydrogen and in particular selected from
fluorine, chlorine, methyl, trifluoromethyl, methoxy,
difluoromethoxy and trifluoromethoxy and more preferably from
methyl, methoxy and difluoromethoxy, and located in the
meta-position, with respect to X.
[0141] Amongst the compounds of the formula I', in particular
amongst the compounds of embodiments I'a, I'b, I'c, I'd, I'e, and
I'g, particular preference is given to those, wherein X is attached
to the benzene ring in the .alpha.-position with respect to the
1,3-dioxole ring. Amongst these compounds, particular preference is
given to those compounds of the formula I', wherein R.sup.5 is
hydrogen.
[0142] Amongst the compounds of the formula I', in particular
amongst the compounds of embodiments I'a, I'b, I'c, I'd, I'e, and
I'g, particular preference is given to those, wherein X is attached
to the benzene ring in the B-position with respect to the
1,3-dioxole ring. Amongst these compounds, particular preference is
given to those compounds of the formula I', wherein R.sup.5 is
hydrogen.
[0143] A particular preferred embodiment of the invention relates
to compounds of the formula I or I', to their pharmacologically
tolerated salts and to the N-oxides thereof, wherein [0144] X is a
bond or a group N--R.sup.4; [0145] R.sup.1 is hydrogen or methyl;
[0146] R.sup.2 is hydrogen or methyl, in particular hydrogen;
[0147] R.sup.3 is hydrogen, C.sub.1-C.sub.2 alkyl, fluorine,
C.sub.1-C.sub.2 alkoxy or fluorinated C.sub.1-C.sub.2 alkoxy,
preferably hydrogen, methyl, methoxy, difluoromethoxy or
trifluoromethoxy, in particular hydrogen, methyl or methoxy; [0148]
R.sup.4 is hydrogen, methyl, ethyl, n-propyl, isopropyl or
cyclopropylmethyl; [0149] R.sup.5 is hydrogen, fluorine, chlorine,
methyl, trifluoromethyl, methoxy, difluoromethoxy and
trifluoromethoxy and more preferably hydrogen, methyl or methoxy;
[0150] R.sup.6 is hydrogen or fluorine, which is located in the 5-
or 6-position of the benzene ring; and [0151] n is 1 or 2.
[0152] A further particular preferred embodiment of the invention
relates to compounds of the formula I or I', to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0153] X is a bond or a group N--R.sup.4; [0154] R.sup.1 is
hydrogen or methyl, preferably hydrogen; [0155] R.sup.2 is
hydrogen; [0156] R.sup.3 is hydrogen, C.sub.1-C.sub.2 alkyl or
C.sub.1-C.sub.2 alkoxy, preferably hydrogen, methyl or methoxy, in
particular methyl or methoxy; [0157] R.sup.4 is hydrogen, methyl,
ethyl, n-propyl, isopropyl or cyclopropylmethyl, preferably
hydrogen; [0158] R.sup.5 is hydrogen, chlorine, fluorine,
difluoromethoxy, methyl or methoxy, preferably hydrogen, methyl or
methoxy, in particular hydrogen; [0159] R.sup.6 is hydrogen; and
[0160] n is 1 or 2, preferably 1.
[0161] A further particular preferred embodiment of the invention
relates to compounds of the formula I or I', to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0162] X is a group N--R.sup.4; [0163] R.sup.1 is hydrogen;
[0164] R.sup.2 is hydrogen; [0165] R.sup.3 is C.sub.1-C.sub.2 alkyl
or C.sub.1-C.sub.2 alkoxy, preferably methyl or methoxy; [0166]
R.sup.4 is hydrogen; [0167] R.sup.5 is hydrogen; [0168] R.sup.6 is
hydrogen; and [0169] n is 1.
[0170] A further particular preferred embodiment of the invention
relates to compounds of the formula I or I', to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0171] X is a group N--R.sup.4; [0172] R.sup.1 is hydrogen;
[0173] R.sup.2 is hydrogen; [0174] R.sup.3 is C.sub.1-C.sub.2 alkyl
or C.sub.1-C.sub.2 alkoxy, preferably methyl or methoxy; [0175]
R.sup.4 is hydrogen; [0176] R.sup.5 is chlorine; [0177] R.sup.6 is
hydrogen; and [0178] n is 1.
[0179] A further particular preferred embodiment of the invention
relates to compounds of the formula I or I', to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0180] X is a group N--R.sup.4; [0181] R.sup.1 is hydrogen;
[0182] R.sup.2 is hydrogen; [0183] R.sup.3 is C.sub.1-C.sub.2 alkyl
or C.sub.1-C.sub.2 alkoxy, preferably methyl or methoxy; [0184]
R.sup.4 is hydrogen; [0185] R.sup.5 is fluorine; [0186] R.sup.6 is
hydrogen; and [0187] n is 1.
[0188] A further particular preferred embodiment of the invention
relates to compounds of the formula I or I', to their
pharmacologically tolerated salts and to the N-oxides thereof,
wherein [0189] X is a group N--R.sup.4; [0190] R.sup.1 is hydrogen;
[0191] R.sup.2 is hydrogen; [0192] R.sup.3 is C.sub.1-C.sub.2 alkyl
or C.sub.1-C.sub.2 alkoxy, preferably methyl or methoxy; [0193]
R.sup.4 is hydrogen; [0194] R.sup.5 is difluoromethoxy; [0195]
R.sup.6 is hydrogen; and [0196] n is 1.
[0197] Examples of compounds according to the present invention are
the compounds of the formula I, their pharmacologically tolerated
salts and the N-oxides thereof, wherein R.sup.6 is hydrogen, and
the meanings of X, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5
and the position of R.sup.5 and of the moiety OCHF.sub.2 on the
benzene ring is given in the following table A:
##STR00002##
TABLE-US-00001 TABLE A No. n R.sup.1 R.sup.2 R.sup.3 X OCHF.sub.2*
R.sup.5 1. 1 H H OCH.sub.3 NH ortho H 2. 1 H H OCH.sub.3 NH meta H
3. 1 H H OCH.sub.3 NH para H 4. 1 H H OCH.sub.3 NH ortho CH.sub.3
(para to NH) 5. 1 H H OCH.sub.3 NH ortho CH.sub.3 (para to
OCHF.sub.2) 6. 1 H H OCH.sub.3 NH meta OCH.sub.3 (para to NH) 7. 1
H H OCH.sub.3 NH meta OCH.sub.3 (para to OCHF.sub.2) 8. 1 H H
OCH.sub.3 NH meta CH.sub.3 (para to NH) 9. 1 H H OCH.sub.3 NH ortho
Cl (para to NH) 10. 1 H H OCH.sub.3 NH ortho Cl (para to
OCHF.sub.2) 11. 1 H H OCH.sub.3 NH ortho F (para to NH) 12. 1 H H
OCH.sub.3 NH ortho F (para to OCHF.sub.2) 13. 1 H H OCH.sub.3 NH
meta OCHF.sub.2 (para to NH) 14. 1 CH.sub.3 H OCH.sub.3 NH ortho H
15. 1 CH.sub.3 H OCH.sub.3 NH meta H 16. 1 CH.sub.3 H OCH.sub.3 NH
para H 17. 1 CH.sub.3 H OCH.sub.3 NH ortho CH.sub.3 (para to NH)
18. 1 CH.sub.3 H OCH.sub.3 NH ortho CH.sub.3 (para to OCHF.sub.2)
19. 1 CH.sub.3 H OCH.sub.3 NH meta OCH.sub.3 (para to NH) 20. 1
CH.sub.3 H OCH.sub.3 NH meta OCH.sub.3 (para to OCHF.sub.2) 21. 1
CH.sub.3 H OCH.sub.3 NH meta CH.sub.3 (para to NH) 22. 1 CH.sub.3 H
OCH.sub.3 NH ortho Cl (para to NH) 23. 1 CH.sub.3 H OCH.sub.3 NH
ortho Cl (para to OCHF.sub.2) 24. 1 CH.sub.3 H OCH.sub.3 NH ortho F
(para to NH) 25. 1 CH.sub.3 H OCH.sub.3 NH ortho F (para to
OCHF.sub.2) 26. 1 CH.sub.3 H OCH.sub.3 NH meta OCHF.sub.2 (para to
NH) 27. 1 H H OCH.sub.3 NCH.sub.3 ortho H 28. 1 H H OCH.sub.3
NCH.sub.3 meta H 29. 1 H H OCH.sub.3 NCH.sub.3 para H 30. 1 H H
OCH.sub.3 NCH.sub.3 ortho CH.sub.3 (para to X) 31. 1 H H OCH.sub.3
NCH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 32. 1 H H OCH.sub.3
NCH.sub.3 meta OCH.sub.3 (para to X) 33. 1 H H OCH.sub.3 NCH.sub.3
meta OCH.sub.3 (para to OCHF.sub.2) 34. 1 H H OCH.sub.3 NCH.sub.3
meta CH.sub.3 (para to X) 35. 1 H H OCH.sub.3 NCH.sub.3 ortho Cl
(para to X) 36. 1 H H OCH.sub.3 NCH.sub.3 ortho Cl (para to
OCHF.sub.2) 37. 1 H H OCH.sub.3 NCH.sub.3 ortho F (para to X) 38. 1
H H OCH.sub.3 NCH.sub.3 ortho F (para to OCHF.sub.2) 39. 1 H H
OCH.sub.3 NCH.sub.3 meta OCHF.sub.2 (para to X) 40. 1 CH.sub.3 H
OCH.sub.3 NCH.sub.3 ortho H 41. 1 CH.sub.3 H OCH.sub.3 NCH.sub.3
meta H 42. 1 CH.sub.3 H OCH.sub.3 NCH.sub.3 para H 43. 1 CH.sub.3 H
OCH.sub.3 NCH.sub.3 ortho CH.sub.3 (para to X) 44. 1 CH.sub.3 H
OCH.sub.3 NCH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 45. 1
CH.sub.3 H OCH.sub.3 NCH.sub.3 meta OCH.sub.3 (para to X) 46. 1
CH.sub.3 H OCH.sub.3 NCH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2)
47. 1 CH.sub.3 H OCH.sub.3 NCH.sub.3 meta CH.sub.3 (para to X) 48.
1 CH.sub.3 H OCH.sub.3 NCH.sub.3 ortho Cl (para to X) 49. 1
CH.sub.3 H OCH.sub.3 NCH.sub.3 ortho Cl (para to OCHF.sub.2) 50. 1
CH.sub.3 H OCH.sub.3 NCH.sub.3 ortho F (para to X) 51. 1 CH.sub.3 H
OCH.sub.3 NCH.sub.3 ortho F (para to OCHF.sub.2) 52. 1 CH.sub.3 H
OCH.sub.3 NCH.sub.3 meta OCHF.sub.2 (para to X) 53. 1 H H OCH.sub.3
NCH.sub.2CH.sub.3 ortho H 54. 1 H H OCH.sub.3 NCH.sub.2CH.sub.3
meta H 55. 1 H H OCH.sub.3 NCH.sub.2CH.sub.3 para H 56. 1 H H
OCH.sub.3 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to X) 57. 1 H H
OCH.sub.3 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 58.
1 H H OCH.sub.3 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to X) 59. 1
H H OCH.sub.3 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2)
60. 1 H H OCH.sub.3 NCH.sub.2CH.sub.3 meta CH.sub.3 (para to X) 61.
1 CH.sub.3 H OCH.sub.3 NCH.sub.2CH.sub.3 ortho H 62. 1 CH.sub.3 H
OCH.sub.3 NCH.sub.2CH.sub.3 meta H 63. 1 CH.sub.3 H OCH.sub.3
NCH.sub.2CH.sub.3 para H 64. 1 CH.sub.3 H OCH.sub.3
NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to X) 65. 1 CH.sub.3 H
OCH.sub.3 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 66.
1 CH.sub.3 H OCH.sub.3 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to X)
67. 1 CH.sub.3 H OCH.sub.3 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para
to OCHF.sub.2) 68. 1 CH.sub.3 H OCH.sub.3 NCH.sub.2CH.sub.3 meta
CH.sub.3 (para to X) 69. 1 H H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3
ortho H 70. 1 H H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta H 71. 1
H H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 para H 72. 1 H H OCH.sub.3
N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to X) 73. 1 H H
OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to
OCHF.sub.2) 74. 1 H H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta
OCH.sub.3 (para to X) 75. 1 H H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3
meta OCH.sub.3 (para to OCHF.sub.2) 76. 1 H H OCH.sub.3
N(CH.sub.2).sub.2CH.sub.3 meta CH.sub.3 (para to X) 77. 1 CH.sub.3
H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho H 78. 1 CH.sub.3 H
OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta H 79. 1 CH.sub.3 H
OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 para H 80. 1 CH.sub.3 H
OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to X) 81.
1 CH.sub.3 H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3
(para to OCHF.sub.2) 82. 1 CH.sub.3 H OCH.sub.3
N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to X) 83. 1 CH.sub.3
H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to
OCHF.sub.2) 84. 1 CH.sub.3 H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3
meta CH.sub.3 (para to X) 85. 1 H H OCH.sub.3
N(CH.sub.2)-cyclopropyl ortho H 86. 1 H H OCH.sub.3
N(CH.sub.2)-cyclopropyl meta H 87. 1 H H OCH.sub.3
N(CH.sub.2)-cyclopropyl para H 88. 1 H H OCH.sub.3
N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to X) 89. 1 H H
OCH.sub.3 N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to
OCHF.sub.2) 90. 1 H H OCH.sub.3 N(CH.sub.2)-cyclopropyl meta
OCH.sub.3 (para to X) 91. 1 H H OCH.sub.3 N(CH.sub.2)-cyclopropyl
meta OCH.sub.3 (para to OCHF.sub.2) 92. 1 H H OCH.sub.3
N(CH.sub.2)-cyclopropyl meta CH.sub.3 (para to X) 93. 1 CH.sub.3 H
OCH.sub.3 N(CH.sub.2)-cyclopropyl ortho H 94. 1 CH.sub.3 H
OCH.sub.3 N(CH.sub.2)-cyclopropyl meta H 95. 1 CH.sub.3 H OCH.sub.3
N(CH.sub.2)-cyclopropyl para H 96. 1 CH.sub.3 H OCH.sub.3
N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to X) 97. 1 CH.sub.3 H
OCH.sub.3 N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to
OCHF.sub.2) 98. 1 CH.sub.3 H OCH.sub.3 N(CH.sub.2)-cyclopropyl meta
OCH.sub.3 (para to X) 99. 1 CH.sub.3 H OCH.sub.3
N(CH.sub.2)-cyclopropyl meta OCH.sub.3 (para to OCHF.sub.2) 100. 1
CH.sub.3 H OCH.sub.3 N(CH.sub.2)-cyclopropyl meta CH.sub.3 (para to
X) 101. 1 H H OCH.sub.3 bond ortho H 102. 1 H H OCH.sub.3 bond meta
H 103. 1 H H OCH.sub.3 bond para H 104. 1 H H OCH.sub.3 bond ortho
CH.sub.3 (para to X) 105. 1 H H OCH.sub.3 bond ortho CH.sub.3 (para
to OCHF.sub.2) 106. 1 H H OCH.sub.3 bond meta OCH.sub.3 (para to X)
107. 1 H H OCH.sub.3 bond meta OCH.sub.3 (para to OCHF.sub.2) 108.
1 H H OCH.sub.3 bond meta CH.sub.3 (para to X) 109. 1 CH.sub.3 H
OCH.sub.3 bond ortho H 110. 1 CH.sub.3 H OCH.sub.3 bond meta H 111.
1 CH.sub.3 H OCH.sub.3 bond para H 112. 1 CH.sub.3 H OCH.sub.3 bond
ortho CH.sub.3 (para to X) 113. 1 CH.sub.3 H OCH.sub.3 bond ortho
CH.sub.3 (para to OCHF.sub.2) 114. 1 CH.sub.3 H OCH.sub.3 bond meta
OCH.sub.3 (para to X) 115. 1 CH.sub.3 H OCH.sub.3 bond meta
OCH.sub.3 (para to OCHF.sub.2) 116. 1 CH.sub.3 H OCH.sub.3 bond
meta CH.sub.3 (para to X) 117. 2 H H OCH.sub.3 NH ortho H 118. 2 H
H OCH.sub.3 NH meta H 119. 2 H H OCH.sub.3 NH para H 120. 2 H H
OCH.sub.3 NH ortho CH.sub.3 (para to NH) 121. 2 H H OCH.sub.3 NH
ortho CH.sub.3 (para to OCHF.sub.2) 122. 2 H H OCH.sub.3 NH meta
OCH.sub.3 (para to NH) 123. 2 H H OCH.sub.3 NH meta OCH.sub.3 (para
to OCHF.sub.2) 124. 2 H H OCH.sub.3 NH meta CH.sub.3 (para to NH)
125. 2 H H OCH.sub.3 NH ortho Cl (para to NH) 126. 2 H H OCH.sub.3
NH ortho Cl (para to OCHF.sub.2) 127. 2 H H OCH.sub.3 NH ortho F
(para to NH) 128. 2 H H OCH.sub.3 NH ortho F (para to OCHF.sub.2)
129. 2 H H OCH.sub.3 NH meta OCHF.sub.2 (para to NH) 130. 2
CH.sub.3 H OCH.sub.3 NH ortho H 131. 2 CH.sub.3 H OCH.sub.3 NH meta
H 132. 2 CH.sub.3 H OCH.sub.3 NH para H 133. 2 CH.sub.3 H OCH.sub.3
NH ortho CH.sub.3 (para to NH) 134. 2 CH.sub.3 H OCH.sub.3 NH ortho
CH.sub.3 (para to OCHF.sub.2) 135. 2 CH.sub.3 H OCH.sub.3 NH meta
OCH.sub.3 (para to NH) 136. 2 CH.sub.3 H OCH.sub.3 NH meta
OCH.sub.3 (para to OCHF.sub.2) 137. 2 CH.sub.3 H OCH.sub.3 NH meta
CH.sub.3 (para to NH) 138. 2 CH.sub.3 H OCH.sub.3 NH ortho Cl (para
to NH) 139. 2 CH.sub.3 H OCH.sub.3 NH ortho Cl (para to OCHF.sub.2)
140. 2 CH.sub.3 H OCH.sub.3 NH ortho F (para to NH) 141. 2 CH.sub.3
H OCH.sub.3 NH ortho F (para to OCHF.sub.2) 142. 2 CH.sub.3 H
OCH.sub.3 NH meta OCHF.sub.2 (para to NH) 143. 2 H H OCH.sub.3
NCH.sub.3 ortho H 144. 2 H H OCH.sub.3 NCH.sub.3 meta H 145. 2 H H
OCH.sub.3 NCH.sub.3 para H 146. 2 H H OCH.sub.3 NCH.sub.3 ortho
CH.sub.3 (para to X) 147. 2 H H OCH.sub.3 NCH.sub.3 ortho CH.sub.3
(para to OCHF.sub.2) 148. 2 H H OCH.sub.3 NCH.sub.3 meta OCH.sub.3
(para to X) 149. 2 H H OCH.sub.3 NCH.sub.3 meta OCH.sub.3 (para to
OCHF.sub.2) 150. 2 H H OCH.sub.3 NCH.sub.3 meta CH.sub.3 (para to
X) 151. 2 H H OCH.sub.3 NCH.sub.3 ortho Cl (para to X) 152. 2 H H
OCH.sub.3 NCH.sub.3 ortho Cl (para to OCHF.sub.2) 153. 2 H H
OCH.sub.3 NCH.sub.3 ortho F (para to X) 154. 2 H H OCH.sub.3
NCH.sub.3 ortho F (para to OCHF.sub.2) 155. 2 H H OCH.sub.3
NCH.sub.3 meta OCHF.sub.2 (para to X) 156. 2 CH.sub.3 H OCH.sub.3
NCH.sub.3 ortho H 157. 2 CH.sub.3 H OCH.sub.3 NCH.sub.3 meta H 158.
2 CH.sub.3 H OCH.sub.3 NCH.sub.3 para H 159. 2 CH.sub.3 H OCH.sub.3
NCH.sub.3 ortho CH.sub.3 (para to X) 160. 2 CH.sub.3 H OCH.sub.3
NCH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 161. 2 CH.sub.3 H
OCH.sub.3 NCH.sub.3 meta OCH.sub.3 (para to X) 162. 2 CH.sub.3 H
OCH.sub.3 NCH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2) 163. 2
CH.sub.3 H OCH.sub.3 NCH.sub.3 meta CH.sub.3 (para to X) 164. 2
CH.sub.3 H OCH.sub.3 NCH.sub.3 ortho Cl (para to X) 165. 2 CH.sub.3
H OCH.sub.3 NCH.sub.3 ortho Cl (para to OCHF.sub.2) 166. 2 CH.sub.3
H OCH.sub.3 NCH.sub.3 ortho F (para to X) 167. 2 CH.sub.3 H
OCH.sub.3 NCH.sub.3 ortho F (para to OCHF.sub.2) 168. 2 CH.sub.3 H
OCH.sub.3 NCH.sub.3 meta OCHF.sub.2 (para to X) 169. 2 H H
OCH.sub.3 NCH.sub.2CH.sub.3 ortho H 170. 2 H H OCH.sub.3
NCH.sub.2CH.sub.3 meta H 171. 2 H H OCH.sub.3 NCH.sub.2CH.sub.3
para H 172. 2 H H OCH.sub.3 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para
to X) 173. 2 H H OCH.sub.3 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para
to OCHF.sub.2) 174. 2 H H OCH.sub.3 NCH.sub.2CH.sub.3 meta
OCH.sub.3 (para to X) 175. 2 H H OCH.sub.3 NCH.sub.2CH.sub.3 meta
OCH.sub.3 (para to OCHF.sub.2) 176. 2 H H OCH.sub.3
NCH.sub.2CH.sub.3 meta CH.sub.3 (para to X) 177. 2 CH.sub.3 H
OCH.sub.3 NCH.sub.2CH.sub.3 ortho H 178. 2 CH.sub.3 H OCH.sub.3
NCH.sub.2CH.sub.3 meta H 179. 2 CH.sub.3 H OCH.sub.3
NCH.sub.2CH.sub.3 para H 180. 2 CH.sub.3 H OCH.sub.3
NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to X) 181. 2 CH.sub.3 H
OCH.sub.3 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2)
182. 2 CH.sub.3 H OCH.sub.3 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para
to X) 183. 2 CH.sub.3 H OCH.sub.3 NCH.sub.2CH.sub.3 meta OCH.sub.3
(para to OCHF.sub.2) 184. 2 CH.sub.3 H OCH.sub.3 NCH.sub.2CH.sub.3
meta CH.sub.3 (para to X) 185. 2 H H OCH.sub.3
N(CH.sub.2).sub.2CH.sub.3 ortho H 186. 2 H H OCH.sub.3
N(CH.sub.2).sub.2CH.sub.3 meta H 187. 2 H H OCH.sub.3
N(CH.sub.2).sub.2CH.sub.3 para H 188. 2 H H OCH.sub.3
N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to X) 189. 2 H H
OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to
OCHF.sub.2) 190. 2 H H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta
OCH.sub.3 (para to X) 191. 2 H H OCH.sub.3
N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2) 192.
2 H H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta CH.sub.3 (para to X)
193. 2 CH.sub.3 H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho H 194.
2 CH.sub.3 H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta H 195. 2
CH.sub.3 H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 para H 196. 2
CH.sub.3 H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para
to X) 197. 2 CH.sub.3 H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho
CH.sub.3 (para to OCHF.sub.2) 198. 2 CH.sub.3 H OCH.sub.3
N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to X) 199. 2
CH.sub.3 H OCH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para
to OCHF.sub.2) 200. 2 CH.sub.3 H OCH.sub.3
N(CH.sub.2).sub.2CH.sub.3 meta CH.sub.3 (para to X) 201. 2 H H
OCH.sub.3 N(CH.sub.2)-cyclopropyl ortho H 202. 2 H H OCH.sub.3
N(CH.sub.2)-cyclopropyl meta H 203. 2 H H OCH.sub.3
N(CH.sub.2)-cyclopropyl para H 204. 2 H H OCH.sub.3
N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to X) 205. 2 H H
OCH.sub.3 N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to
OCHF.sub.2) 206. 2 H H OCH.sub.3 N(CH.sub.2)-cyclopropyl meta
OCH.sub.3 (para to X) 207. 2 H H OCH.sub.3 N(CH.sub.2)-cyclopropyl
meta OCH.sub.3 (para to OCHF.sub.2) 208. 2 H H OCH.sub.3
N(CH.sub.2)-cyclopropyl meta CH.sub.3 (para to X) 209. 2 CH.sub.3 H
OCH.sub.3 N(CH.sub.2)-cyclopropyl mrtho H 210. 2 CH.sub.3 H
OCH.sub.3 N(CH.sub.2)-cyclopropyl meta H 211. 2 CH.sub.3 H
OCH.sub.3 N(CH.sub.2)-cyclopropyl para H 212. 2 CH.sub.3 H
OCH.sub.3 N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to X) 213. 2
CH.sub.3 H OCH.sub.3 N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para
to OCHF.sub.2) 214. 2 CH.sub.3 H OCH.sub.3 N(CH.sub.2)-cyclopropyl
meta OCH.sub.3 (para
to X) 215. 2 CH.sub.3 H OCH.sub.3 N(CH.sub.2)-cyclopropyl meta
OCH.sub.3 (para to OCHF.sub.2) 216. 2 CH.sub.3 H OCH.sub.3
N(CH.sub.2)-cyclopropyl meta CH.sub.3 (para to X) 217. 2 H H
OCH.sub.3 bond ortho H 218. 2 H H OCH.sub.3 bond meta H 219. 2 H H
OCH.sub.3 bond para H 220. 2 H H OCH.sub.3 bond ortho CH.sub.3
(para to X) 221. 2 H H OCH.sub.3 bond ortho CH.sub.3 (para to
OCHF.sub.2) 222. 2 H H OCH.sub.3 bond meta OCH.sub.3 (para to X)
223. 2 H H OCH.sub.3 bond meta OCH.sub.3 (para to OCHF.sub.2) 224.
2 H H OCH.sub.3 bond meta CH.sub.3 (para to X) 225. 2 CH.sub.3 H
OCH.sub.3 bond ortho H 226. 2 CH.sub.3 H OCH.sub.3 bond meta H 227.
2 CH.sub.3 H OCH.sub.3 bond para H 228. 2 CH.sub.3 H OCH.sub.3 bond
ortho CH.sub.3 (para to X) 229. 2 CH.sub.3 H OCH.sub.3 bond ortho
CH.sub.3 (para to OCHF.sub.2) 230. 2 CH.sub.3 H OCH.sub.3 bond meta
OCH.sub.3 (para to X) 231. 2 CH.sub.3 H OCH.sub.3 bond meta
OCH.sub.3 (para to OCHF.sub.2) 232. 2 CH.sub.3 H OCH.sub.3 bond
meta CH.sub.3 (para to X) 233. 1 H H OCHF.sub.2 NH ortho H 234. 1 H
H OCHF.sub.2 NH meta H 235. 1 H H OCHF.sub.2 NH para H 236. 1 H H
OCHF.sub.2 NH ortho CH.sub.3 (para to NH) 237. 1 H H OCHF.sub.2 NH
ortho CH.sub.3 (para to OCHF.sub.2) 238. 1 H H OCHF.sub.2 NH meta
OCH.sub.3 (para to NH) 239. 1 H H OCHF.sub.2 NH meta OCH.sub.3
(para to OCHF.sub.2) 240. 1 H H OCHF.sub.2 NH meta CH.sub.3 (para
to NH) 241. 1 H H OCHF.sub.2 NH ortho Cl (para to NH) 242. 1 H H
OCHF.sub.2 NH ortho Cl (para to OCHF.sub.2) 243. 1 H H OCHF.sub.2
NH ortho F (para to NH) 244. 1 H H OCHF.sub.2 NH ortho F (para to
OCHF.sub.2) 245. 1 H H OCHF.sub.2 NH meta OCHF.sub.2 (para to NH)
246. 1 CH.sub.3 H OCHF.sub.2 NH ortho H 247. 1 CH.sub.3 H
OCHF.sub.2 NH meta H 248. 1 CH.sub.3 H OCHF.sub.2 NH para H 249. 1
CH.sub.3 H OCHF.sub.2 NH ortho CH.sub.3 (para to NH) 250. 1
CH.sub.3 H OCHF.sub.2 NH ortho CH.sub.3 (para to OCHF.sub.2) 251. 1
CH.sub.3 H OCHF.sub.2 NH meta OCH.sub.3 (para to NH) 252. 1
CH.sub.3 H OCHF.sub.2 NH meta OCH.sub.3 (para to OCHF.sub.2) 253. 1
CH.sub.3 H OCHF.sub.2 NH meta CH.sub.3 (para to NH) 254. 1 CH.sub.3
H OCHF.sub.2 NH ortho Cl (para to NH) 255. 1 CH.sub.3 H OCHF.sub.2
NH ortho Cl (para to OCHF.sub.2) 256. 1 CH.sub.3 H OCHF.sub.2 NH
ortho F (para to NH) 257. 1 CH.sub.3 H OCHF.sub.2 NH ortho F (para
to OCHF.sub.2) 258. 1 CH.sub.3 H OCHF.sub.2 NH meta OCHF.sub.2
(para to NH) 259. 1 H H OCHF.sub.2 NCH.sub.3 ortho H 260. 1 H H
OCHF.sub.2 NCH.sub.3 meta H 261. 1 H H OCHF.sub.2 NCH.sub.3 para H
262. 1 H H OCHF.sub.2 NCH.sub.3 ortho CH.sub.3 (para to X) 263. 1 H
H OCHF.sub.2 NCH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 264. 1 H
H OCHF.sub.2 NCH.sub.3 meta OCH.sub.3 (para to X) 265. 1 H H
OCHF.sub.2 NCH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2) 266. 1 H H
OCHF.sub.2 NCH.sub.3 meta CH.sub.3 (para to X) 267. 1 H H
OCHF.sub.2 NCH.sub.3 ortho Cl (para to X) 268. 1 H H OCHF.sub.2
NCH.sub.3 ortho Cl (para to OCHF.sub.2) 269. 1 H H OCHF.sub.2
NCH.sub.3 ortho F (para to X) 270. 1 H H OCHF.sub.2 NCH.sub.3 ortho
F (para to OCHF.sub.2) 271. 1 H H OCHF.sub.2 NCH.sub.3 meta
OCHF.sub.2 (para to X) 272. 1 CH.sub.3 H OCHF.sub.2 NCH.sub.3 ortho
H 273. 1 CH.sub.3 H OCHF.sub.2 NCH.sub.3 meta H 274. 1 CH.sub.3 H
OCHF.sub.2 NCH.sub.3 para H 275. 1 CH.sub.3 H OCHF.sub.2 NCH.sub.3
ortho CH.sub.3 (para to X) 276. 1 CH.sub.3 H OCHF.sub.2 NCH.sub.3
ortho CH.sub.3 (para to OCHF.sub.2) 277. 1 CH.sub.3 H OCHF.sub.2
NCH.sub.3 meta OCH.sub.3 (para to X) 278. 1 CH.sub.3 H OCHF.sub.2
NCH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2) 279. 1 CH.sub.3 H
OCHF.sub.2 NCH.sub.3 meta CH.sub.3 (para to X) 280. 1 CH.sub.3 H
OCHF.sub.2 NCH.sub.3 ortho Cl (para to X) 281. 1 CH.sub.3 H
OCHF.sub.2 NCH.sub.3 ortho Cl (para to OCHF.sub.2) 282. 1 CH.sub.3
H OCHF.sub.2 NCH.sub.3 ortho F (para to X) 283. 1 CH.sub.3 H
OCHF.sub.2 NCH.sub.3 ortho F (para to OCHF.sub.2) 284. 1 CH.sub.3 H
OCHF.sub.2 NCH.sub.3 meta OCHF.sub.2 (para to X) 285. 1 H H
OCHF.sub.2 NCH.sub.2CH.sub.3 ortho H 286. 1 H H OCHF.sub.2
NCH.sub.2CH.sub.3 meta H 287. 1 H H OCHF.sub.2 NCH.sub.2CH.sub.3
para H 288. 1 H H OCHF.sub.2 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para
to X) 289. 1 H H OCHF.sub.2 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para
to OCHF.sub.2) 290. 1 H H OCHF.sub.2 NCH.sub.2CH.sub.3 meta
OCH.sub.3 (para to X) 291. 1 H H OCHF.sub.2 NCH.sub.2CH.sub.3 meta
OCH.sub.3 (para to OCHF.sub.2) 292. 1 H H OCHF.sub.2
NCH.sub.2CH.sub.3 meta CH.sub.3 (para to X) 293. 1 CH.sub.3 H
OCHF.sub.2 NCH.sub.2CH.sub.3 ortho H 294. 1 CH.sub.3 H OCHF.sub.2
NCH.sub.2CH.sub.3 meta H 295. 1 CH.sub.3 H OCHF.sub.2
NCH.sub.2CH.sub.3 para H 296. 1 CH.sub.3 H OCHF.sub.2
NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to X) 297. 1 CH.sub.3 H
OCHF.sub.2 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2)
298. 1 CH.sub.3 H OCHF.sub.2 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para
to X) 299. 1 CH.sub.3 H OCHF.sub.2 NCH.sub.2CH.sub.3 meta OCH.sub.3
(para to OCHF.sub.2) 300. 1 CH.sub.3 H OCHF.sub.2 NCH.sub.2CH.sub.3
meta CH.sub.3 (para to X) 301. 1 H H OCHF.sub.2
N(CH.sub.2).sub.2CH.sub.3 ortho H 302. 1 H H OCHF.sub.2
N(CH.sub.2).sub.2CH.sub.3 meta H 303. 1 H H OCHF.sub.2
N(CH.sub.2).sub.2CH.sub.3 para H 304. 1 H H OCHF.sub.2
N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to X) 305. 1 H H
OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to
OCHF.sub.2) 306. 1 H H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 meta
OCH.sub.3 (para to X) 307. 1 H H OCHF.sub.2
N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2) 308.
1 H H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 meta CH.sub.3 (para to
X) 309. 1 CH.sub.3 H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 ortho H
310. 1 CH.sub.3 H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 meta H 311.
1 CH.sub.3 H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 para H 312. 1
CH.sub.3 H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3
(para to X) 313. 1 CH.sub.3 H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3
ortho CH.sub.3 (para to OCHF.sub.2) 314. 1 CH.sub.3 H OCHF.sub.2
N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to X) 315. 1
CH.sub.3 H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3
(para to OCHF.sub.2) 316. 1 CH.sub.3 H OCHF.sub.2
N(CH.sub.2).sub.2CH.sub.3 meta CH.sub.3 (para to X) 317. 1 H H
OCHF.sub.2 N(CH.sub.2)-cyclopropyl ortho H 318. 1 H H OCHF.sub.2
N(CH.sub.2)-cyclopropyl meta H 319. 1 H H OCHF.sub.2
N(CH.sub.2)-cyclopropyl para H 320. 1 H H OCHF.sub.2
N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to X) 321. 1 H H
OCHF.sub.2 N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to
OCHF.sub.2) 322. 1 H H OCHF.sub.2 N(CH.sub.2)-cyclopropyl meta
OCH.sub.3 (para to X) 323. 1 H H OCHF.sub.2 N(CH.sub.2)-cyclopropyl
meta OCH.sub.3 (para to OCHF.sub.2) 324. 1 H H OCHF.sub.2
N(CH.sub.2)-cyclopropyl meta CH.sub.3 (para to X) 325. 1 CH.sub.3 H
OCHF.sub.2 N(CH.sub.2)-cyclopropyl ortho H 326. 1 CH.sub.3 H
OCHF.sub.2 N(CH.sub.2)-cyclopropyl meta H 327. 1 CH.sub.3 H
OCHF.sub.2 N(CH.sub.2)-cyclopropyl para H 328. 1 CH.sub.3 H
OCHF.sub.2 N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to X) 329.
1 CH.sub.3 H OCHF.sub.2 N(CH.sub.2)-cyclopropyl ortho CH.sub.3
(para to OCHF.sub.2) 330. 1 CH.sub.3 H OCHF.sub.2
N(CH.sub.2)-cyclopropyl meta OCH.sub.3 (para to X) 331. 1 CH.sub.3
H OCHF.sub.2 N(CH.sub.2)-cyclopropyl meta OCH.sub.3 (para to
OCHF.sub.2) 332. 1 CH.sub.3 H OCHF.sub.2 N(CH.sub.2)-cyclopropyl
meta CH.sub.3 (para to X) 333. 1 H H OCHF.sub.2 bond ortho H 334. 1
H H OCHF.sub.2 bond meta H 335. 1 H H OCHF.sub.2 bond para H 336. 1
H H OCHF.sub.2 bond ortho CH.sub.3 (para to X) 337. 1 H H
OCHF.sub.2 bond ortho CH.sub.3 (para to OCHF.sub.2) 338. 1 H H
OCHF.sub.2 bond meta OCH.sub.3 (para to X) 339. 1 H H OCHF.sub.2
bond meta OCH.sub.3 (para to OCHF.sub.2) 340. 1 H H OCHF.sub.2 bond
meta CH.sub.3 (para to X) 341. 1 CH.sub.3 H OCHF.sub.2 bond ortho H
342. 1 CH.sub.3 H OCHF.sub.2 bond meta H 343. 1 CH.sub.3 H
OCHF.sub.2 bond para H 344. 1 CH.sub.3 H OCHF.sub.2 bond ortho
CH.sub.3 (para to X) 345. 1 CH.sub.3 H OCHF.sub.2 bond ortho
CH.sub.3 (para to OCHF.sub.2) 346. 1 CH.sub.3 H OCHF.sub.2 bond
meta OCH.sub.3 (para to X) 347. 1 CH.sub.3 H OCHF.sub.2 bond meta
OCH.sub.3 (para to OCHF.sub.2) 348. 1 CH.sub.3 H OCHF.sub.2 bond
meta CH.sub.3 (para to X) 349. 2 H H OCHF.sub.2 NH ortho H 350. 2 H
H OCHF.sub.2 NH meta H 351. 2 H H OCHF.sub.2 NH para H 352. 2 H H
OCHF.sub.2 NH ortho CH.sub.3 (para to NH) 353. 2 H H OCHF.sub.2 NH
ortho CH.sub.3 (para to OCHF.sub.2) 354. 2 H H OCHF.sub.2 NH meta
OCH.sub.3 (para to NH) 355. 2 H H OCHF.sub.2 NH meta OCH.sub.3
(para to OCHF.sub.2) 356. 2 H H OCHF.sub.2 NH meta CH.sub.3 (para
to NH) 357. 2 H H OCHF.sub.2 NH ortho Cl (para to NH) 358. 2 H H
OCHF.sub.2 NH ortho Cl (para to OCHF.sub.2) 359. 2 H H OCHF.sub.2
NH ortho F (para to NH) 360. 2 H H OCHF.sub.2 NH ortho F (para to
OCHF.sub.2) 361. 2 H H OCHF.sub.2 NH meta OCHF.sub.2 (para to NH)
362. 2 CH.sub.3 H OCHF.sub.2 NH ortho H 363. 2 CH.sub.3 H
OCHF.sub.2 NH meta H 364. 2 CH.sub.3 H OCHF.sub.2 NH para H 365. 2
CH.sub.3 H OCHF.sub.2 NH ortho CH.sub.3 (para to NH) 366. 2
CH.sub.3 H OCHF.sub.2 NH ortho CH.sub.3 (para to OCHF.sub.2) 367. 2
CH.sub.3 H OCHF.sub.2 NH meta OCH.sub.3 (para to NH) 368. 2
CH.sub.3 H OCHF.sub.2 NH meta OCH.sub.3 (para to OCHF.sub.2) 369. 2
CH.sub.3 H OCHF.sub.2 NH meta CH.sub.3 (para to NH) 370. 2 CH.sub.3
H OCHF.sub.2 NH ortho Cl (para to NH) 371. 2 CH.sub.3 H OCHF.sub.2
NH ortho Cl (para to OCHF.sub.2) 372. 2 CH.sub.3 H OCHF.sub.2 NH
ortho F (para to NH) 373. 2 CH.sub.3 H OCHF.sub.2 NH ortho F (para
to OCHF.sub.2) 374. 2 CH.sub.3 H OCHF.sub.2 NH meta OCHF.sub.2
(para to NH) 375. 2 H H OCHF.sub.2 NCH.sub.3 ortho H 376. 2 H H
OCHF.sub.2 NCH.sub.3 meta H 377. 2 H H OCHF.sub.2 NCH.sub.3 para H
378. 2 H H OCHF.sub.2 NCH.sub.3 ortho CH.sub.3 (para to X) 379. 2 H
H OCHF.sub.2 NCH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 380. 2 H
H OCHF.sub.2 NCH.sub.3 meta OCH.sub.3 (para to X) 381. 2 H H
OCHF.sub.2 NCH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2) 382. 2 H H
OCHF.sub.2 NCH.sub.3 meta CH.sub.3 (para to X) 383. 2 H H
OCHF.sub.2 NCH.sub.3 ortho Cl (para to X) 384. 2 H H OCHF.sub.2
NCH.sub.3 ortho Cl (para to OCHF.sub.2) 385. 2 H H OCHF.sub.2
NCH.sub.3 ortho F (para to X) 386. 2 H H OCHF.sub.2 NCH.sub.3 ortho
F (para to OCHF.sub.2) 387. 2 H H OCHF.sub.2 NCH.sub.3 meta
OCHF.sub.2 (para to X) 388. 2 CH.sub.3 H OCHF.sub.2 NCH.sub.3 ortho
H 389. 2 CH.sub.3 H OCHF.sub.2 NCH.sub.3 meta H 390. 2 CH.sub.3 H
OCHF.sub.2 NCH.sub.3 para H 391. 2 CH.sub.3 H OCHF.sub.2 NCH.sub.3
ortho CH.sub.3 (para to X) 392. 2 CH.sub.3 H OCHF.sub.2 NCH.sub.3
ortho CH.sub.3 (para to OCHF.sub.2) 393. 2 CH.sub.3 H OCHF.sub.2
NCH.sub.3 meta OCH.sub.3 (para to X) 394. 2 CH.sub.3 H OCHF.sub.2
NCH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2) 395. 2 CH.sub.3 H
OCHF.sub.2 NCH.sub.3 meta CH.sub.3 (para to X) 396. 2 CH.sub.3 H
OCHF.sub.2 NCH.sub.3 ortho Cl (para to X) 397. 2 CH.sub.3 H
OCHF.sub.2 NCH.sub.3 ortho Cl (para to OCHF.sub.2) 398. 2 CH.sub.3
H OCHF.sub.2 NCH.sub.3 ortho F (para to X) 399. 2 CH.sub.3 H
OCHF.sub.2 NCH.sub.3 ortho F (para to OCHF.sub.2) 400. 2 CH.sub.3 H
OCHF.sub.2 NCH.sub.3 meta OCHF.sub.2 (para to X) 401. 2 H H
OCHF.sub.2 NCH.sub.2CH.sub.3 ortho H 402. 2 H H OCHF.sub.2
NCH.sub.2CH.sub.3 meta H 403. 2 H H OCHF.sub.2 NCH.sub.2CH.sub.3
para H 404. 2 H H OCHF.sub.2 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para
to X) 405. 2 H H OCHF.sub.2 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para
to OCHF.sub.2) 406. 2 H H OCHF.sub.2 NCH.sub.2CH.sub.3 meta
OCH.sub.3 (para to X) 407. 2 H H OCHF.sub.2 NCH.sub.2CH.sub.3 meta
OCH.sub.3 (para to OCHF.sub.2) 408. 2 H H OCHF.sub.2
NCH.sub.2CH.sub.3 meta CH.sub.3 (para to X) 409. 2 CH.sub.3 H
OCHF.sub.2 NCH.sub.2CH.sub.3 ortho H 410. 2 CH.sub.3 H OCHF.sub.2
NCH.sub.2CH.sub.3 meta H 411. 2 CH.sub.3 H OCHF.sub.2
NCH.sub.2CH.sub.3 para H 412. 2 CH.sub.3 H OCHF.sub.2
NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to X) 413. 2 CH.sub.3 H
OCHF.sub.2 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2)
414. 2 CH.sub.3 H OCHF.sub.2 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para
to X) 415. 2 CH.sub.3 H OCHF.sub.2 NCH.sub.2CH.sub.3 meta OCH.sub.3
(para to OCHF.sub.2) 416. 2 CH.sub.3 H OCHF.sub.2 NCH.sub.2CH.sub.3
meta CH.sub.3 (para to X) 417. 2 H H OCHF.sub.2
N(CH.sub.2).sub.2CH.sub.3 ortho H 418. 2 H H OCHF.sub.2
N(CH.sub.2).sub.2CH.sub.3 meta H 419. 2 H H OCHF.sub.2
N(CH.sub.2).sub.2CH.sub.3 para H 420. 2 H H OCHF.sub.2
N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to X) 421. 2 H H
OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to
OCHF.sub.2) 422. 2 H H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 meta
OCH.sub.3 (para to X) 423. 2 H H OCHF.sub.2
N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2) 424.
2 H H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 meta CH.sub.3 (para to
X) 425. 2 CH.sub.3 H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 ortho H
426. 2 CH.sub.3 H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 meta H 427.
2 CH.sub.3 H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 para H 428. 2
CH.sub.3 H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3
(para to X) 429. 2 CH.sub.3 H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3
ortho CH.sub.3
(para to OCHF.sub.2) 430. 2 CH.sub.3 H OCHF.sub.2
N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to X) 431. 2
CH.sub.3 H OCHF.sub.2 N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3
(para to OCHF.sub.2) 432. 2 CH.sub.3 H OCHF.sub.2
N(CH.sub.2).sub.2CH.sub.3 meta CH.sub.3 (para to X) 433. 2 H H
OCHF.sub.2 N(CH.sub.2)-cyclopropyl ortho H 434. 2 H H OCHF.sub.2
N(CH.sub.2)-cyclopropyl meta H 435. 2 H H OCHF.sub.2
N(CH.sub.2)-cyclopropyl para H 436. 2 H H OCHF.sub.2
N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to X) 437. 2 H H
OCHF.sub.2 N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to
OCHF.sub.2) 438. 2 H H OCHF.sub.2 N(CH.sub.2)-cyclopropyl meta
OCH.sub.3 (para to X) 439. 2 H H OCHF.sub.2 N(CH.sub.2)-cyclopropyl
meta OCH.sub.3 (para to OCHF.sub.2) 440. 2 H H OCHF.sub.2
N(CH.sub.2)-cyclopropyl meta CH.sub.3 (para to X) 441. 2 CH.sub.3 H
OCHF.sub.2 N(CH.sub.2)-cyclopropyl ortho H 442. 2 CH.sub.3 H
OCHF.sub.2 N(CH.sub.2)-cyclopropyl meta H 443. 2 CH.sub.3 H
OCHF.sub.2 N(CH.sub.2)-cyclopropyl para H 444. 2 CH.sub.3 H
OCHF.sub.2 N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to X) 445.
2 CH.sub.3 H OCHF.sub.2 N(CH.sub.2)-cyclopropyl ortho CH.sub.3
(para to OCHF.sub.2) 446. 2 CH.sub.3 H OCHF.sub.2
N(CH.sub.2)-cyclopropyl meta OCH.sub.3 (para to X) 447. 2 CH.sub.3
H OCHF.sub.2 N(CH.sub.2)-cyclopropyl meta OCH.sub.3 (para to
OCHF.sub.2) 448. 2 CH.sub.3 H OCHF.sub.2 N(CH.sub.2)-cyclopropyl
meta CH.sub.3 (para to X) 449. 2 H H OCHF.sub.2 bond ortho H 450. 2
H H OCHF.sub.2 bond meta H 451. 2 H H OCHF.sub.2 bond para H 452. 2
H H OCHF.sub.2 bond ortho CH.sub.3 (para to X) 453. 2 H H
OCHF.sub.2 bond ortho CH.sub.3 (para to OCHF.sub.2) 454. 2 H H
OCHF.sub.2 bond meta OCH.sub.3 (para to X) 455. 2 H H OCHF.sub.2
bond meta OCH.sub.3 (para to OCHF.sub.2) 456. 2 H H OCHF.sub.2 bond
meta CH.sub.3 (para to X) 457. 2 CH.sub.3 H OCHF.sub.2 bond ortho H
458. 2 CH.sub.3 H OCHF.sub.2 bond meta H 459. 2 CH.sub.3 H
OCHF.sub.2 bond para H 460. 2 CH.sub.3 H OCHF.sub.2 bond ortho
CH.sub.3 (para to X) 461. 2 CH.sub.3 H OCHF.sub.2 bond ortho
CH.sub.3 (para to OCHF.sub.2) 462. 2 CH.sub.3 H OCHF.sub.2 bond
meta OCH.sub.3 (para to X) 463. 2 CH.sub.3 H OCHF.sub.2 bond meta
OCH.sub.3 (para to OCHF.sub.2) 464. 2 CH.sub.3 H OCHF.sub.2 bond
meta CH.sub.3 (para to X) 465. 1 H H CH.sub.3 NH ortho H 466. 1 H H
CH.sub.3 NH meta H 467. 1 H H CH.sub.3 NH para H 468. 1 H H
CH.sub.3 NH ortho CH.sub.3 (para to NH) 469. 1 H H CH.sub.3 NH
ortho CH.sub.3 (para to OCHF.sub.2) 470. 1 H H CH.sub.3 NH meta
OCH.sub.3 (para to NH) 471. 1 H H CH.sub.3 NH meta OCH.sub.3 (para
to OCHF.sub.2) 472. 1 H H CH.sub.3 NH meta CH.sub.3 (para to NH)
473. 1 H H CH.sub.3 NH ortho Cl (para to NH) 474. 1 H H CH.sub.3 NH
ortho Cl (para to OCHF.sub.2) 475. 1 H H CH.sub.3 NH ortho F (para
to NH) 476. 1 H H CH.sub.3 NH ortho F (para to OCHF.sub.2) 477. 1 H
H CH.sub.3 NH meta OCHF.sub.2 (para to NH) 478. 1 CH.sub.3 H
CH.sub.3 NH ortho H 479. 1 CH.sub.3 H CH.sub.3 NH meta H 480. 1
CH.sub.3 H CH.sub.3 NH para H 481. 1 CH.sub.3 H CH.sub.3 NH ortho
CH.sub.3 (para to NH) 482. 1 CH.sub.3 H CH.sub.3 NH ortho CH.sub.3
(para to OCHF.sub.2) 483. 1 CH.sub.3 H CH.sub.3 NH meta OCH.sub.3
(para to NH) 484. 1 CH.sub.3 H CH.sub.3 NH meta OCH.sub.3 (para to
OCHF.sub.2) 485. 1 CH.sub.3 H CH.sub.3 NH meta CH.sub.3 (para to
NH) 486. 1 CH.sub.3 H CH.sub.3 NH ortho Cl (para to NH) 487. 1
CH.sub.3 H CH.sub.3 NH ortho Cl (para to OCHF.sub.2) 488. 1
CH.sub.3 H CH.sub.3 NH ortho F (para to NH) 489. 1 CH.sub.3 H
CH.sub.3 NH ortho F (para to OCHF.sub.2) 490. 1 CH.sub.3 H CH.sub.3
NH meta OCHF.sub.2 (para to NH) 491. 1 H H CH.sub.3 NCH.sub.3 ortho
H 492. 1 H H CH.sub.3 NCH.sub.3 meta H 493. 1 H H CH.sub.3
NCH.sub.3 para H 494. 1 H H CH.sub.3 NCH.sub.3 ortho CH.sub.3 (para
to X) 495. 1 H H CH.sub.3 NCH.sub.3 ortho CH.sub.3 (para to
OCHF.sub.2) 496. 1 H H CH.sub.3 NCH.sub.3 meta OCH.sub.3 (para to
X) 497. 1 H H CH.sub.3 NCH.sub.3 meta OCH.sub.3 (para to
OCHF.sub.2) 498. 1 H H CH.sub.3 NCH.sub.3 meta CH.sub.3 (para to X)
499. 1 H H CH.sub.3 NCH.sub.3 ortho Cl (para to X) 500. 1 H H
CH.sub.3 NCH.sub.3 ortho Cl (para to OCHF.sub.2) 501. 1 H H
CH.sub.3 NCH.sub.3 ortho F (para to X) 502. 1 H H CH.sub.3
NCH.sub.3 ortho F (para to OCHF.sub.2) 503. 1 H H CH.sub.3
NCH.sub.3 meta OCHF.sub.2 (para to X) 504. 1 CH.sub.3 H CH.sub.3
NCH.sub.3 ortho H 505. 1 CH.sub.3 H CH.sub.3 NCH.sub.3 meta H 506.
1 CH.sub.3 H CH.sub.3 NCH.sub.3 para H 507. 1 CH.sub.3 H CH.sub.3
NCH.sub.3 ortho CH.sub.3 (para to X) 508. 1 CH.sub.3 H CH.sub.3
NCH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 509. 1 CH.sub.3 H
CH.sub.3 NCH.sub.3 meta OCH.sub.3 (para to X) 510. 1 CH.sub.3 H
CH.sub.3 NCH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2) 511. 1
CH.sub.3 H CH.sub.3 NCH.sub.3 meta CH.sub.3 (para to X) 512. 1
CH.sub.3 H CH.sub.3 NCH.sub.3 ortho Cl (para to X) 513. 1 CH.sub.3
H CH.sub.3 NCH.sub.3 ortho Cl (para to OCHF.sub.2) 514. 1 CH.sub.3
H CH.sub.3 NCH.sub.3 ortho F (para to X) 515. 1 CH.sub.3 H CH.sub.3
NCH.sub.3 ortho F (para to OCHF.sub.2) 516. 1 CH.sub.3 H CH.sub.3
NCH.sub.3 meta OCHF.sub.2 (para to X) 517. 1 H H CH.sub.3
NCH.sub.2CH.sub.3 ortho H 518. 1 H H CH.sub.3 NCH.sub.2CH.sub.3
meta H 519. 1 H H CH.sub.3 NCH.sub.2CH.sub.3 para H 520. 1 H H
CH.sub.3 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to X) 521. 1 H H
CH.sub.3 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 522.
1 H H CH.sub.3 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to X) 523. 1
H H CH.sub.3 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2)
524. 1 H H CH.sub.3 NCH.sub.2CH.sub.3 meta CH.sub.3 (para to X)
525. 1 CH.sub.3 H CH.sub.3 NCH.sub.2CH.sub.3 ortho H 526. 1
CH.sub.3 H CH.sub.3 NCH.sub.2CH.sub.3 meta H 527. 1 CH.sub.3 H
CH.sub.3 NCH.sub.2CH.sub.3 para H 528. 1 CH.sub.3 H CH.sub.3
NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to X) 529. 1 CH.sub.3 H
CH.sub.3 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 530.
1 CH.sub.3 H CH.sub.3 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to X)
531. 1 CH.sub.3 H CH.sub.3 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para
to OCHF.sub.2) 532. 1 CH.sub.3 H CH.sub.3 NCH.sub.2CH.sub.3 meta
CH.sub.3 (para to X) 533. 1 H H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3
ortho H 534. 1 H H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta H 535. 1
H H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 para H 536. 1 H H CH.sub.3
N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to X) 537. 1 H H
CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to
OCHF.sub.2) 538. 1 H H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta
OCH.sub.3 (para to X) 539. 1 H H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3
meta OCH.sub.3 (para to OCHF.sub.2) 540. 1 H H CH.sub.3
N(CH.sub.2).sub.2CH.sub.3 meta CH.sub.3 (para to X) 541. 1 CH.sub.3
H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho H 542. 1 CH.sub.3 H
CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta H 543. 1 CH.sub.3 H
CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 para H 544. 1 CH.sub.3 H
CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to X) 545.
1 CH.sub.3 H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3
(para to OCHF.sub.2) 546. 1 CH.sub.3 H CH.sub.3
N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to X) 547. 1
CH.sub.3 H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para
to OCHF.sub.2) 548. 1 CH.sub.3 H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3
meta CH.sub.3 (para to X) 549. 1 H H CH.sub.3
N(CH.sub.2)-cyclopropyl ortho H 550. 1 H H CH.sub.3
N(CH.sub.2)-cyclopropyl meta H 551. 1 H H CH.sub.3
N(CH.sub.2)-cyclopropyl para H 552. 1 H H CH.sub.3
N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to X) 553. 1 H H
CH.sub.3 N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to
OCHF.sub.2) 554. 1 H H CH.sub.3 N(CH.sub.2)-cyclopropyl meta
OCH.sub.3 (para to X) 555. 1 H H CH.sub.3 N(CH.sub.2)-cyclopropyl
meta OCH.sub.3 (para to OCHF.sub.2) 556. 1 H H CH.sub.3
N(CH.sub.2)-cyclopropyl meta CH.sub.3 (para to X) 557. 1 CH.sub.3 H
CH.sub.3 N(CH.sub.2)-cyclopropyl ortho H 558. 1 CH.sub.3 H CH.sub.3
N(CH.sub.2)-cyclopropyl meta H 559. 1 CH.sub.3 H CH.sub.3
N(CH.sub.2)-cyclopropyl para H 560. 1 CH.sub.3 H CH.sub.3
N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to X) 561. 1 CH.sub.3
H CH.sub.3 N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to
OCHF.sub.2) 562. 1 CH.sub.3 H CH.sub.3 N(CH.sub.2)-cyclopropyl meta
OCH.sub.3 (para to X) 563. 1 CH.sub.3 H CH.sub.3
N(CH.sub.2)-cyclopropyl meta OCH.sub.3 (para to OCHF.sub.2) 564. 1
CH.sub.3 H CH.sub.3 N(CH.sub.2)-cyclopropyl meta CH.sub.3 (para to
X) 565. 1 H H CH.sub.3 bond ortho H 566. 1 H H CH.sub.3 bond meta H
567. 1 H H CH.sub.3 bond para H 568. 1 H H CH.sub.3 bond ortho
CH.sub.3 (para to X) 569. 1 H H CH.sub.3 bond ortho CH.sub.3 (para
to OCHF.sub.2) 570. 1 H H CH.sub.3 bond meta OCH.sub.3 (para to X)
571. 1 H H CH.sub.3 bond meta OCH.sub.3 (para to OCHF.sub.2) 572. 1
H H CH.sub.3 bond meta CH.sub.3 (para to X) 573. 1 CH.sub.3 H
CH.sub.3 bond ortho H 574. 1 CH.sub.3 H CH.sub.3 bond meta H 575. 1
CH.sub.3 H CH.sub.3 bond para H 576. 1 CH.sub.3 H CH.sub.3 bond
ortho CH.sub.3 (para to X) 577. 1 CH.sub.3 H CH.sub.3 bond ortho
CH.sub.3 (para to OCHF.sub.2) 578. 1 CH.sub.3 H CH.sub.3 bond meta
OCH.sub.3 (para to X) 579. 1 CH.sub.3 H CH.sub.3 bond meta
OCH.sub.3 (para to OCHF.sub.2) 580. 1 CH.sub.3 H CH.sub.3 bond meta
CH.sub.3 (para to X) 581. 2 H H CH.sub.3 NH ortho H 582. 2 H H
CH.sub.3 NH meta H 583. 2 H H CH.sub.3 NH para H 584. 2 H H
CH.sub.3 NH ortho CH.sub.3 (para to NH) 585. 2 H H CH.sub.3 NH
ortho CH.sub.3 (para to OCHF.sub.2) 586. 2 H H CH.sub.3 NH meta
OCH.sub.3 (para to NH) 587. 2 H H CH.sub.3 NH meta OCH.sub.3 (para
to OCHF.sub.2) 588. 2 H H CH.sub.3 NH meta CH.sub.3 (para to NH)
589. 2 H H CH.sub.3 NH ortho Cl (para to NH) 590. 2 H H CH.sub.3 NH
ortho Cl (para to OCHF.sub.2) 591. 2 H H CH.sub.3 NH ortho F (para
to NH) 592. 2 H H CH.sub.3 NH ortho F (para to OCHF.sub.2) 593. 2 H
H CH.sub.3 NH meta OCHF.sub.2 (para to NH) 594. 2 CH.sub.3 H
CH.sub.3 NH ortho H 595. 2 CH.sub.3 H CH.sub.3 NH meta H 596. 2
CH.sub.3 H CH.sub.3 NH para H 597. 2 CH.sub.3 H CH.sub.3 NH ortho
CH.sub.3 (para to NH) 598. 2 CH.sub.3 H CH.sub.3 NH ortho CH.sub.3
(para to OCHF.sub.2) 599. 2 CH.sub.3 H CH.sub.3 NH meta OCH.sub.3
(para to NH) 600. 2 CH.sub.3 H CH.sub.3 NH meta OCH.sub.3 (para to
OCHF.sub.2) 601. 2 CH.sub.3 H CH.sub.3 NH meta CH.sub.3 (para to
NH) 602. 2 CH.sub.3 H CH.sub.3 NH ortho Cl (para to NH) 603. 2
CH.sub.3 H CH.sub.3 NH ortho Cl (para to OCHF.sub.2) 604. 2
CH.sub.3 H CH.sub.3 NH ortho F (para to NH) 605. 2 CH.sub.3 H
CH.sub.3 NH ortho F (para to OCHF.sub.2) 606. 2 CH.sub.3 H CH.sub.3
NH meta OCHF.sub.2 (para to NH) 607. 2 H H CH.sub.3 NCH.sub.3 ortho
H 608. 2 H H CH.sub.3 NCH.sub.3 meta H 609. 2 H H CH.sub.3
NCH.sub.3 para H 610. 2 H H CH.sub.3 NCH.sub.3 ortho CH.sub.3 (para
to X) 611. 2 H H CH.sub.3 NCH.sub.3 ortho CH.sub.3 (para to
OCHF.sub.2) 612. 2 H H CH.sub.3 NCH.sub.3 meta OCH.sub.3 (para to
X) 613. 2 H H CH.sub.3 NCH.sub.3 meta OCH.sub.3 (para to
OCHF.sub.2) 614. 2 H H CH.sub.3 NCH.sub.3 meta CH.sub.3 (para to X)
615. 2 H H CH.sub.3 NCH.sub.3 ortho Cl (para to X) 616. 2 H H
CH.sub.3 NCH.sub.3 ortho Cl (para to OCHF.sub.2) 617. 2 H H
CH.sub.3 NCH.sub.3 ortho F (para to X) 618. 2 H H CH.sub.3
NCH.sub.3 ortho F (para to OCHF.sub.2) 619. 2 H H CH.sub.3
NCH.sub.3 meta OCHF.sub.2 (para to X) 620. 2 CH.sub.3 H CH.sub.3
NCH.sub.3 ortho H 621. 2 CH.sub.3 H CH.sub.3 NCH.sub.3 meta H 622.
2 CH.sub.3 H CH.sub.3 NCH.sub.3 para H 623. 2 CH.sub.3 H CH.sub.3
NCH.sub.3 ortho CH.sub.3 (para to X) 624. 2 CH.sub.3 H CH.sub.3
NCH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 625. 2 CH.sub.3 H
CH.sub.3 NCH.sub.3 meta OCH.sub.3 (para to X) 626. 2 CH.sub.3 H
CH.sub.3 NCH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2) 627. 2
CH.sub.3 H CH.sub.3 NCH.sub.3 meta CH.sub.3 (para to X) 628. 2
CH.sub.3 H CH.sub.3 NCH.sub.3 ortho Cl (para to X) 629. 2 CH.sub.3
H CH.sub.3 NCH.sub.3 ortho Cl (para to OCHF.sub.2) 630. 2 CH.sub.3
H CH.sub.3 NCH.sub.3 ortho F (para to X) 631. 2 CH.sub.3 H CH.sub.3
NCH.sub.3 ortho F (para to OCHF.sub.2) 632. 2 CH.sub.3 H CH.sub.3
NCH.sub.3 meta OCHF.sub.2 (para to X) 633. 2 H H CH.sub.3
NCH.sub.2CH.sub.3 ortho H 634. 2 H H CH.sub.3 NCH.sub.2CH.sub.3
meta H 635. 2 H H CH.sub.3 NCH.sub.2CH.sub.3 para H 636. 2 H H
CH.sub.3 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to X) 637. 2 H H
CH.sub.3 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 638.
2 H H CH.sub.3 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to X) 639. 2
H H CH.sub.3 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2)
640. 2 H H CH.sub.3 NCH.sub.2CH.sub.3 meta CH.sub.3 (para to X)
641. 2 CH.sub.3 H CH.sub.3 NCH.sub.2CH.sub.3 ortho H 642. 2
CH.sub.3 H CH.sub.3 NCH.sub.2CH.sub.3 meta H 643. 2 CH.sub.3 H
CH.sub.3 NCH.sub.2CH.sub.3 para H 644. 2 CH.sub.3 H CH.sub.3
NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to X) 645. 2 CH.sub.3 H
CH.sub.3 NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 646.
2 CH.sub.3 H CH.sub.3 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to X)
647. 2 CH.sub.3 H CH.sub.3 NCH.sub.2CH.sub.3 meta OCH.sub.3 (para
to OCHF.sub.2) 648. 2 CH.sub.3 H CH.sub.3 NCH.sub.2CH.sub.3 meta
CH.sub.3 (para to X) 649. 2 H H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3
ortho H 650. 2 H H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta H 651. 2
H H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 para H
652. 2 H H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para
to X) 653. 2 H H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3
(para to OCHF.sub.2) 654. 2 H H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3
meta OCH.sub.3 (para to X) 655. 2 H H CH.sub.3
N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2) 656.
2 H H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta CH.sub.3 (para to X)
657. 2 CH.sub.3 H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho H 658. 2
CH.sub.3 H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta H 659. 2
CH.sub.3 H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 para H 660. 2
CH.sub.3 H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para
to X) 661. 2 CH.sub.3 H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 ortho
CH.sub.3 (para to OCHF.sub.2) 662. 2 CH.sub.3 H CH.sub.3
N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to X) 663. 2
CH.sub.3 H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para
to OCHF.sub.2) 664. 2 CH.sub.3 H CH.sub.3 N(CH.sub.2).sub.2CH.sub.3
meta CH.sub.3 (para to X) 665. 2 H H CH.sub.3
N(CH.sub.2)-cyclopropyl ortho H 666. 2 H H CH.sub.3
N(CH.sub.2)-cyclopropyl meta H 667. 2 H H CH.sub.3
N(CH.sub.2)-cyclopropyl para H 668. 2 H H CH.sub.3
N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to X) 669. 2 H H
CH.sub.3 N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to
OCHF.sub.2) 670. 2 H H CH.sub.3 N(CH.sub.2)-cyclopropyl meta
OCH.sub.3 (para to X) 671. 2 H H CH.sub.3 N(CH.sub.2)-cyclopropyl
meta OCH.sub.3 (para to OCHF.sub.2) 672. 2 H H CH.sub.3
N(CH.sub.2)-cyclopropyl meta CH.sub.3 (para to X) 673. 2 CH.sub.3 H
CH.sub.3 N(CH.sub.2)-cyclopropyl ortho H 674. 2 CH.sub.3 H CH.sub.3
N(CH.sub.2)-cyclopropyl meta H 675. 2 CH.sub.3 H CH.sub.3
N(CH.sub.2)-cyclopropyl para H 676. 2 CH.sub.3 H CH.sub.3
N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to X) 677. 2 CH.sub.3
H CH.sub.3 N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to
OCHF.sub.2) 678. 2 CH.sub.3 H CH.sub.3 N(CH.sub.2)-cyclopropyl meta
OCH.sub.3 (para to X) 679. 2 CH.sub.3 H CH.sub.3
N(CH.sub.2)-cyclopropyl meta OCH.sub.3 (para to OCHF.sub.2) 680. 2
CH.sub.3 H CH.sub.3 N(CH.sub.2)-cyclopropyl meta CH.sub.3 (para to
X) 681. 2 H H CH.sub.3 bond ortho H 682. 2 H H CH.sub.3 bond meta H
683. 2 H H CH.sub.3 bond para H 684. 2 H H CH.sub.3 bond ortho
CH.sub.3 (para to X) 685. 2 H H CH.sub.3 bond ortho CH.sub.3 (para
to OCHF.sub.2) 686. 2 H H CH.sub.3 bond meta OCH.sub.3 (para to X)
687. 2 H H CH.sub.3 bond meta OCH.sub.3 (para to OCHF.sub.2) 688. 2
H H CH.sub.3 bond meta CH.sub.3 (para to X) 689. 2 CH.sub.3 H
CH.sub.3 bond ortho H 690. 2 CH.sub.3 H CH.sub.3 bond meta H 691. 2
CH.sub.3 H CH.sub.3 bond para H 692. 2 CH.sub.3 H CH.sub.3 bond
ortho CH.sub.3 (para to X) 693. 2 CH.sub.3 H CH.sub.3 bond ortho
CH.sub.3 (para to OCHF.sub.2) 694. 2 CH.sub.3 H CH.sub.3 bond meta
OCH.sub.3 (para to X) 695. 2 CH.sub.3 H CH.sub.3 bond meta
OCH.sub.3 (para to OCHF.sub.2) 696. 2 CH.sub.3 H CH.sub.3 bond meta
CH.sub.3 (para to X) 697. 1 H H F NH ortho H 698. 1 H H F NH meta H
699. 1 H H F NH para H 700. 1 H H F NH ortho CH.sub.3 (para to NH)
701. 1 H H F NH ortho CH.sub.3 (para to OCHF.sub.2) 702. 1 H H F NH
meta OCH.sub.3 (para to NH) 703. 1 H H F NH meta OCH.sub.3 (para to
OCHF.sub.2) 704. 1 H H F NH meta CH.sub.3 (para to NH) 705. 1 H H F
NH ortho Cl (para to NH) 706. 1 H H F NH ortho Cl (para to
OCHF.sub.2) 707. 1 H H F NH ortho F (para to NH) 708. 1 H H F NH
ortho F (para to OCHF.sub.2) 709. 1 H H F NH meta OCHF.sub.2 (para
to NH) 710. 1 CH.sub.3 H F NH ortho H 711. 1 CH.sub.3 H F NH meta H
712. 1 CH.sub.3 H F NH para H 713. 1 CH.sub.3 H F NH ortho CH.sub.3
(para to NH) 714. 1 CH.sub.3 H F NH ortho CH.sub.3 (para to
OCHF.sub.2) 715. 1 CH.sub.3 H F NH meta OCH.sub.3 (para to NH) 716.
1 CH.sub.3 H F NH meta OCH.sub.3 (para to OCHF.sub.2) 717. 1
CH.sub.3 H F NH meta CH.sub.3 (para to NH) 718. 1 CH.sub.3 H F NH
ortho Cl (para to NH) 719. 1 CH.sub.3 H F NH ortho Cl (para to
OCHF.sub.2) 720. 1 CH.sub.3 H F NH ortho F (para to NH) 721. 1
CH.sub.3 H F NH ortho F (para to OCHF.sub.2) 722. 1 CH.sub.3 H F NH
meta OCHF.sub.2 (para to NH) 723. 1 H H F NCH.sub.3 ortho H 724. 1
H H F NCH.sub.3 meta H 725. 1 H H F NCH.sub.3 para H 726. 1 H H F
NCH.sub.3 ortho CH.sub.3 (para to X) 727. 1 H H F NCH.sub.3 ortho
CH.sub.3 (para to OCHF.sub.2) 728. 1 H H F NCH.sub.3 meta OCH.sub.3
(para to X) 729. 1 H H F NCH.sub.3 meta OCH.sub.3 (para to
OCHF.sub.2) 730. 1 H H F NCH.sub.3 meta CH.sub.3 (para to X) 731. 1
H H F NCH.sub.3 ortho Cl (para to X) 732. 1 H H F NCH.sub.3 ortho
Cl (para to OCHF.sub.2) 733. 1 H H F NCH.sub.3 ortho F (para to X)
734. 1 H H F NCH.sub.3 ortho F (para to OCHF.sub.2) 735. 1 H H F
NCH.sub.3 meta OCHF.sub.2 (para to X) 736. 1 CH.sub.3 H F NCH.sub.3
ortho H 737. 1 CH.sub.3 H F NCH.sub.3 meta H 738. 1 CH.sub.3 H F
NCH.sub.3 para H 739. 1 CH.sub.3 H F NCH.sub.3 ortho CH.sub.3 (para
to X) 740. 1 CH.sub.3 H F NCH.sub.3 ortho CH.sub.3 (para to
OCHF.sub.2) 741. 1 CH.sub.3 H F NCH.sub.3 meta OCH.sub.3 (para to
X) 742. 1 CH.sub.3 H F NCH.sub.3 meta OCH.sub.3 (para to
OCHF.sub.2) 743. 1 CH.sub.3 H F NCH.sub.3 meta CH.sub.3 (para to X)
744. 1 CH.sub.3 H F NCH.sub.3 ortho Cl (para to X) 745. 1 CH.sub.3
H F NCH.sub.3 ortho Cl (para to OCHF.sub.2) 746. 1 CH.sub.3 H F
NCH.sub.3 ortho F (para to X) 747. 1 CH.sub.3 H F NCH.sub.3 ortho F
(para to OCHF.sub.2) 748. 1 CH.sub.3 H F NCH.sub.3 meta OCHF.sub.2
(para to X) 749. 1 H H F NCH.sub.2CH.sub.3 ortho H 750. 1 H H F
NCH.sub.2CH.sub.3 meta H 751. 1 H H F NCH.sub.2CH.sub.3 para H 752.
1 H H F NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to X) 753. 1 H H F
NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 754. 1 H H F
NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to X) 755. 1 H H F
NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2) 756. 1 H H F
NCH.sub.2CH.sub.3 meta CH.sub.3 (para to X) 757. 1 CH.sub.3 H F
NCH.sub.2CH.sub.3 ortho H 758. 1 CH.sub.3 H F NCH.sub.2CH.sub.3
meta H 759. 1 CH.sub.3 H F NCH.sub.2CH.sub.3 para H 760. 1 CH.sub.3
H F NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to X) 761. 1 CH.sub.3 H
F NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 762. 1
CH.sub.3 H F NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to X) 763. 1
CH.sub.3 H F NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2)
764. 1 CH.sub.3 H F NCH.sub.2CH.sub.3 meta CH.sub.3 (para to X)
765. 1 H H F N(CH.sub.2).sub.2CH.sub.3 ortho H 766. 1 H H F
N(CH.sub.2).sub.2CH.sub.3 meta H 767. 1 H H F
N(CH.sub.2).sub.2CH.sub.3 para H 768. 1 H H F
N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to X) 769. 1 H H F
N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 770.
1 H H F N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to X) 771. 1
H H F N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2)
772. 1 H H F N(CH.sub.2).sub.2CH.sub.3 meta CH.sub.3 (para to X)
773. 1 CH.sub.3 H F N(CH.sub.2).sub.2CH.sub.3 ortho H 774. 1
CH.sub.3 H F N(CH.sub.2).sub.2CH.sub.3 meta H 775. 1 CH.sub.3 H F
N(CH.sub.2).sub.2CH.sub.3 para H 776. 1 CH.sub.3 H F
N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to X) 777. 1
CH.sub.3 H F N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to
OCHF.sub.2) 778. 1 CH.sub.3 H F N(CH.sub.2).sub.2CH.sub.3 meta
OCH.sub.3 (para to X) 779. 1 CH.sub.3 H F N(CH.sub.2).sub.2CH.sub.3
meta OCH.sub.3 (para to OCHF.sub.2) 780. 1 CH.sub.3 H F
N(CH.sub.2).sub.2CH.sub.3 meta CH.sub.3 (para to X) 781. 1 H H F
N(CH.sub.2)-cyclopropyl ortho H 782. 1 H H F
N(CH.sub.2)-cyclopropyl meta H 783. 1 H H F N(CH.sub.2)-cyclopropyl
para H 784. 1 H H F N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to
X) 785. 1 H H F N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to
OCHF.sub.2) 786. 1 H H F N(CH.sub.2)-cyclopropyl meta OCH.sub.3
(para to X) 787. 1 H H F N(CH.sub.2)-cyclopropyl meta OCH.sub.3
(para to OCHF.sub.2) 788. 1 H H F N(CH.sub.2)-cyclopropyl meta
CH.sub.3 (para to X) 789. 1 CH.sub.3 H F N(CH.sub.2)-cyclopropyl
ortho H 790. 1 CH.sub.3 H F N(CH.sub.2)-cyclopropyl meta H 791. 1
CH.sub.3 H F N(CH.sub.2)-cyclopropyl para H 792. 1 CH.sub.3 H F
N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to X) 793. 1 CH.sub.3
H F N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to OCHF.sub.2)
794. 1 CH.sub.3 H F N(CH.sub.2)-cyclopropyl meta OCH.sub.3 (para to
X) 795. 1 CH.sub.3 H F N(CH.sub.2)-cyclopropyl meta OCH.sub.3 (para
to OCHF.sub.2) 796. 1 CH.sub.3 H F N(CH.sub.2)-cyclopropyl meta
CH.sub.3 (para to X) 797. 1 H H F bond ortho H 798. 1 H H F bond
meta H 799. 1 H H F bond para H 800. 1 H H F bond ortho CH.sub.3
(para to X) 801. 1 H H F bond ortho CH.sub.3 (para to OCHF.sub.2)
802. 1 H H F bond meta OCH.sub.3 (para to X) 803. 1 H H F bond meta
OCH.sub.3 (para to OCHF.sub.2) 804. 1 H H F bond meta CH.sub.3
(para to X) 805. 1 CH.sub.3 H F bond ortho H 806. 1 CH.sub.3 H F
bond meta H 807. 1 CH.sub.3 H F bond para H 808. 1 CH.sub.3 H F
bond ortho CH.sub.3 (para to X) 809. 1 CH.sub.3 H F bond ortho
CH.sub.3 (para to OCHF.sub.2) 810. 1 CH.sub.3 H F bond meta
OCH.sub.3 (para to X) 811. 1 CH.sub.3 H F bond meta OCH.sub.3 (para
to OCHF.sub.2) 812. 1 CH.sub.3 H F bond meta CH.sub.3 (para to X)
813. 2 H H F NH ortho H 814. 2 H H F NH meta H 815. 2 H H F NH para
H 816. 2 H H F NH ortho CH.sub.3 (para to NH) 817. 2 H H F NH ortho
CH.sub.3 (para to OCHF.sub.2) 818. 2 H H F NH meta OCH.sub.3 (para
to NH) 819. 2 H H F NH meta OCH.sub.3 (para to OCHF.sub.2) 820. 2 H
H F NH meta CH.sub.3 (para to NH) 821. 2 H H F NH ortho Cl (para to
NH) 822. 2 H H F NH ortho Cl (para to OCHF.sub.2) 823. 2 H H F NH
ortho F (para to NH) 824. 2 H H F NH ortho F (para to OCHF.sub.2)
825. 2 H H F NH meta OCHF.sub.2 (para to NH) 826. 2 CH.sub.3 H F NH
ortho H 827. 2 CH.sub.3 H F NH meta H 828. 2 CH.sub.3 H F NH para H
829. 2 CH.sub.3 H F NH ortho CH.sub.3 (para to NH) 830. 2 CH.sub.3
H F NH ortho CH.sub.3 (para to OCHF.sub.2) 831. 2 CH.sub.3 H F NH
meta OCH.sub.3 (para to NH) 832. 2 CH.sub.3 H F NH meta OCH.sub.3
(para to OCHF.sub.2) 833. 2 CH.sub.3 H F NH meta CH.sub.3 (para to
NH) 834. 2 CH.sub.3 H F NH ortho Cl (para to NH) 835. 2 CH.sub.3 H
F NH ortho Cl (para to OCHF.sub.2) 836. 2 CH.sub.3 H F NH ortho F
(para to NH) 837. 2 CH.sub.3 H F NH ortho F (para to OCHF.sub.2)
838. 2 CH.sub.3 H F NH meta OCHF.sub.2 (para to NH) 839. 2 H H F
NCH.sub.3 ortho H 840. 2 H H F NCH.sub.3 meta H 841. 2 H H F
NCH.sub.3 para H 842. 2 H H F NCH.sub.3 ortho CH.sub.3 (para to X)
843. 2 H H F NCH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 844. 2 H
H F NCH.sub.3 meta OCH.sub.3 (para to X) 845. 2 H H F NCH.sub.3
meta OCH.sub.3 (para to OCHF.sub.2) 846. 2 H H F NCH.sub.3 meta
CH.sub.3 (para to X) 847. 2 H H F NCH.sub.3 ortho Cl (para to X)
848. 2 H H F NCH.sub.3 ortho Cl (para to OCHF.sub.2) 849. 2 H H F
NCH.sub.3 ortho F (para to X) 850. 2 H H F NCH.sub.3 ortho F (para
to OCHF.sub.2) 851. 2 H H F NCH.sub.3 meta OCHF.sub.2 (para to X)
852. 2 CH.sub.3 H F NCH.sub.3 ortho H 853. 2 CH.sub.3 H F NCH.sub.3
meta H 854. 2 CH.sub.3 H F NCH.sub.3 para H 855. 2 CH.sub.3 H F
NCH.sub.3 ortho CH.sub.3 (para to X) 856. 2 CH.sub.3 H F NCH.sub.3
ortho CH.sub.3 (para to OCHF.sub.2) 857. 2 CH.sub.3 H F NCH.sub.3
meta OCH.sub.3 (para to X) 858. 2 CH.sub.3 H F NCH.sub.3 meta
OCH.sub.3 (para to OCHF.sub.2) 859. 2 CH.sub.3 H F NCH.sub.3 meta
CH.sub.3 (para to X) 860. 2 CH.sub.3 H F NH ortho Cl (para to X)
861. 2 CH.sub.3 H F NH ortho Cl (para to OCHF.sub.2) 862. 2
CH.sub.3 H F NH ortho F (para to X) 863. 2 CH.sub.3 H F NH ortho F
(para to OCHF.sub.2) 864. 2 CH.sub.3 H F NH meta OCHF.sub.2 (para
to X) 865. 2 H H F NCH.sub.2CH.sub.3 ortho H 866. 2 H H F
NCH.sub.2CH.sub.3 meta H 867. 2 H H F NCH.sub.2CH.sub.3 para H 868.
2 H H F NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to X) 869. 2 H H F
NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 870. 2 H H F
NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to X) 871. 2 H H F
NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2) 872. 2 H H F
NCH.sub.2CH.sub.3 meta CH.sub.3 (para to X) 873. 2 CH.sub.3 H F
NCH.sub.2CH.sub.3 ortho H 874. 2 CH.sub.3 H F NCH.sub.2CH.sub.3
meta H 875. 2 CH.sub.3 H F NCH.sub.2CH.sub.3 para H 876. 2 CH.sub.3
H F NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to X) 877. 2 CH.sub.3 H
F NCH.sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 878. 2
CH.sub.3 H F NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to X) 879. 2
CH.sub.3 H F NCH.sub.2CH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2)
880. 2 CH.sub.3 H F NCH.sub.2CH.sub.3 meta CH.sub.3 (para to X)
881. 2 H H F N(CH.sub.2).sub.2CH.sub.3 ortho H 882. 2 H H F
N(CH.sub.2).sub.2CH.sub.3 meta H
883. 2 H H F N(CH.sub.2).sub.2CH.sub.3 para H 884. 2 H H F
N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to X) 885. 2 H H F
N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to OCHF.sub.2) 886.
2 H H F N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to X) 887. 2
H H F N(CH.sub.2).sub.2CH.sub.3 meta OCH.sub.3 (para to OCHF.sub.2)
888. 2 H H F N(CH.sub.2).sub.2CH.sub.3 meta CH.sub.3 (para to X)
889. 2 CH.sub.3 H F N(CH.sub.2).sub.2CH.sub.3 ortho H 890. 2
CH.sub.3 H F N(CH.sub.2).sub.2CH.sub.3 meta H 891. 2 CH.sub.3 H F
N(CH.sub.2).sub.2CH.sub.3 para H 892. 2 CH.sub.3 H F
N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to X) 893. 2
CH.sub.3 H F N(CH.sub.2).sub.2CH.sub.3 ortho CH.sub.3 (para to
OCHF.sub.2) 894. 2 CH.sub.3 H F N(CH.sub.2).sub.2CH.sub.3 meta
OCH.sub.3 (para to X) 895. 2 CH.sub.3 H F N(CH.sub.2).sub.2CH.sub.3
meta OCH.sub.3 (para to OCHF.sub.2) 896. 2 CH.sub.3 H F
N(CH.sub.2).sub.2CH.sub.3 meta CH.sub.3 (para to X) 897. 2 H H F
N(CH.sub.2)-cyclopropyl ortho H 898. 2 H H F
N(CH.sub.2)-cyclopropyl meta H 899. 2 H H F N(CH.sub.2)-cyclopropyl
para H 900. 2 H H F N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to
X) 901. 2 H H F N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to
OCHF.sub.2) 902. 2 H H F N(CH.sub.2)-cyclopropyl Meta OCH.sub.3
(para to X) 903. 2 H H F N(CH.sub.2)-cyclopropyl meta OCH.sub.3
(para to OCHF.sub.2) 904. 2 H H F N(CH.sub.2)-cyclopropyl meta
CH.sub.3 (para to X) 905. 2 CH.sub.3 H F N(CH.sub.2)-cyclopropyl
ortho H 906. 2 CH.sub.3 H F N(CH.sub.2)-cyclopropyl meta H 907. 2
CH.sub.3 H F N(CH.sub.2)-cyclopropyl para H 908. 2 CH.sub.3 H F
N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to X) 909. 2 CH.sub.3
H F N(CH.sub.2)-cyclopropyl ortho CH.sub.3 (para to OCHF.sub.2)
910. 2 CH.sub.3 H F N(CH.sub.2)-cyclopropyl meta OCH.sub.3 (para to
X) 911. 2 CH.sub.3 H F N(CH.sub.2)-cyclopropyl meta OCH.sub.3 (para
to OCHF.sub.2) 912. 2 CH.sub.3 H F N(CH.sub.2)-cyclopropyl meta
CH.sub.3 (para to X) 913. 2 H H F bond ortho H 914. 2 H H F bond
meta H 915. 2 H H F bond para H 916. 2 H H F bond ortho CH.sub.3
(para to X) 917. 2 H H F bond ortho CH.sub.3 (para to OCHF.sub.2)
918. 2 H H F bond meta OCH.sub.3 (para to X) 919. 2 H H F bond meta
OCH.sub.3 (para to OCHF.sub.2) 920. 2 H H F bond meta CH.sub.3
(para to X) 921. 2 CH.sub.3 H F bond ortho H 922. 2 CH.sub.3 H F
bond meta H 923. 2 CH.sub.3 H F bond para H 924. 2 CH.sub.3 H F
bond ortho CH.sub.3 (para to X) 925. 2 CH.sub.3 H F bond ortho
CH.sub.3 (para to OCHF.sub.2) 926. 2 CH.sub.3 H F bond meta
OCH.sub.3 (para to X) 927. 2 CH.sub.3 H F bond meta OCH.sub.3 (para
to OCHF.sub.2) 928. 2 CH.sub.3 H F bond meta CH.sub.3 (para to X)
929. 1 H H C.sub.2H.sub.5 NH ortho H 930. 1 H H C.sub.2H.sub.5 NH
meta H 931. 1 H H C.sub.2H.sub.5 NH para H 932. 1 H H
C.sub.2H.sub.5 NH ortho CH.sub.3 (para to NH) 933. 1 H H
C.sub.2H.sub.5 NH ortho CH.sub.3 (para to OCHF.sub.2) 934. 1 H H
C.sub.2H.sub.5 NH meta OCH.sub.3 (para to NH) 935. 1 H H
C.sub.2H.sub.5 NH meta OCH.sub.3 (para to OCHF.sub.2) 936. 1 H H
C.sub.2H.sub.5 NH meta CH.sub.3 (para to NH) 937. 1 H H
C.sub.2H.sub.5 NH ortho Cl (para to NH) 938. 1 H H C.sub.2H.sub.5
NH ortho Cl (para to OCHF.sub.2) 939. 1 H H C.sub.2H.sub.5 NH ortho
F (para to NH) 940. 1 H H C.sub.2H.sub.5 NH ortho F (para to
OCHF.sub.2) 941. 1 H H C.sub.2H.sub.5 NH meta OCHF.sub.2 (para to
NH) 942. 1 CH.sub.3 H C.sub.2H.sub.5 NH ortho H 943. 1 CH.sub.3 H
C.sub.2H.sub.5 NH meta H 944. 1 CH.sub.3 H C.sub.2H.sub.5 NH para H
945. 1 CH.sub.3 H C.sub.2H.sub.5 NH ortho CH.sub.3 (para to NH)
946. 1 CH.sub.3 H C.sub.2H.sub.5 NH ortho CH.sub.3 (para to
OCHF.sub.2) 947. 1 CH.sub.3 H C.sub.2H.sub.5 NH meta OCH.sub.3
(para to NH) 948. 1 CH.sub.3 H C.sub.2H.sub.5 NH meta OCH.sub.3
(para to OCHF.sub.2) 949. 1 CH.sub.3 H C.sub.2H.sub.5 NH meta
CH.sub.3 (para to NH) 950. 1 CH.sub.3 H C.sub.2H.sub.5 NH ortho Cl
(para to NH) 951. 1 CH.sub.3 H C.sub.2H.sub.5 NH ortho Cl (para to
OCHF.sub.2) 952. 1 CH.sub.3 H C.sub.2H.sub.5 NH ortho F (para to
NH) 953. 1 CH.sub.3 H C.sub.2H.sub.5 NH ortho F (para to
OCHF.sub.2) 954. 1 CH.sub.3 H C.sub.2H.sub.5 NH meta OCHF.sub.2
(para to NH) *Position of OCHF.sub.2 versus X
[0198] Examples of compounds according to the present invention are
the compounds of the formula I', their pharmacologically tolerated
salts and the N-oxides thereof, wherein R.sup.5 and R.sup.6 are
hydrogen, and the meanings of X, R.sup.1, R.sup.2, R.sup.3, R.sup.4
and n and the position of X is given in the following table B:
##STR00003##
TABLE-US-00002 TABLE B Position of X vs. difluoro- n R.sup.1
R.sup.2 R.sup.3 X dioxolan 955. 1 H H OCH.sub.3 NH ortho 956. 1 H H
OCH.sub.3 NH meta 957. 1 CH.sub.3 H OCH.sub.3 NH ortho 958. 1
CH.sub.3 H OCH.sub.3 NH meta 959. 2 H H OCH.sub.3 NH ortho 960. 2 H
H OCH.sub.3 NH meta 961. 2 CH.sub.3 H OCH.sub.3 NH ortho 962. 2
CH.sub.3 H OCH.sub.3 NH meta 963. 1 H H OCH.sub.3 NCH.sub.3 ortho
964. 1 H H OCH.sub.3 NCH.sub.3 meta 965. 1 CH.sub.3 H OCH.sub.3
NCH.sub.3 ortho 966. 1 CH.sub.3 H OCH.sub.3 NCH.sub.3 meta 967. 2 H
H OCH.sub.3 NCH.sub.3 ortho 968. 2 H H OCH.sub.3 NCH.sub.3 meta
969. 2 CH.sub.3 H OCH.sub.3 NCH.sub.3 ortho 970. 2 CH.sub.3 H
OCH.sub.3 NCH.sub.3 meta 971. 1 H H OCH.sub.3 NCH.sub.2CH.sub.3
ortho 972. 1 H H OCH.sub.3 NCH.sub.2CH.sub.3 meta 973. 1 CH.sub.3 H
OCH.sub.3 NCH.sub.2CH.sub.3 ortho 974. 1 CH.sub.3 H OCH.sub.3
NCH.sub.2CH.sub.3 meta 975. 2 H H OCH.sub.3 NCH.sub.2CH.sub.3 ortho
976. 2 H H OCH.sub.3 NCH.sub.2CH.sub.3 meta 977. 2 CH.sub.3 H
OCH.sub.3 NCH.sub.2CH.sub.3 ortho 978. 2 CH.sub.3 H OCH.sub.3
NCH.sub.2CH.sub.3 meta 979. 1 H H OCH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 ortho 980. 1 H H OCH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 meta 981. 1 CH.sub.3 H OCH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 ortho 982. 1 CH.sub.3 H OCH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 meta 983. 2 H H OCH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 ortho 984. 2 H H OCH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 meta 985. 2 CH.sub.3 H OCH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 ortho 986. 2 CH.sub.3 H OCH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 meta 987. 1 H H OCH.sub.3 Bond meta 988.
1 CH.sub.3 H OCH.sub.3 Bond ortho 989. 1 CH.sub.3 H OCH.sub.3 Bond
meta 990. 2 H H OCH.sub.3 Bond ortho 991. 2 H H OCH.sub.3 Bond meta
992. 2 CH.sub.3 H OCH.sub.3 Bond ortho 993. 2 CH.sub.3 H OCH.sub.3
Bond meta 994. 1 H H OCHF.sub.2 NCH.sub.3 ortho 995. 1 H H
OCHF.sub.2 NCH.sub.3 meta 996. 1 CH.sub.3 H OCHF.sub.2 NCH.sub.3
ortho 997. 1 CH.sub.3 H OCHF.sub.2 NCH.sub.3 meta 998. 2 H H
OCHF.sub.2 NCH.sub.3 ortho 999. 2 H H OCHF.sub.2 NCH.sub.3 meta
1000. 2 CH.sub.3 H OCHF.sub.2 NCH.sub.3 ortho 1001. 2 CH.sub.3 H
OCHF.sub.2 NCH.sub.3 meta 1002. 1 H H OCHF.sub.2 NCH.sub.2CH.sub.3
ortho 1003. 1 H H OCHF.sub.2 NCH.sub.2CH.sub.3 meta 1004. 1
CH.sub.3 H OCHF.sub.2 NCH.sub.2CH.sub.3 ortho 1005. 1 CH.sub.3 H
OCHF.sub.2 NCH.sub.2CH.sub.3 meta 1006. 2 H H OCHF.sub.2
NCH.sub.2CH.sub.3 ortho 1007. 2 H H OCHF.sub.2 NCH.sub.2CH.sub.3
meta 1008. 2 CH.sub.3 H OCHF.sub.2 NCH.sub.2CH.sub.3 ortho 1009. 2
CH.sub.3 H OCHF.sub.2 NCH.sub.2CH.sub.3 meta 1010. 1 H H OCHF.sub.2
NCH.sub.2CH.sub.2CH.sub.3 ortho 1011. 1 H H OCHF.sub.2
NCH.sub.2CH.sub.2CH.sub.3 meta 1012. 1 CH.sub.3 H OCHF.sub.2
NCH.sub.2CH.sub.2CH.sub.3 ortho 1013. 1 CH.sub.3 H OCHF.sub.2
NCH.sub.2CH.sub.2CH.sub.3 meta 1014. 2 H H OCHF.sub.2
NCH.sub.2CH.sub.2CH.sub.3 ortho 1015. 2 H H OCHF.sub.2
NCH.sub.2CH.sub.2CH.sub.3 meta 1016. 2 CH.sub.3 H OCHF.sub.2
NCH.sub.2CH.sub.2CH.sub.3 ortho 1017. 2 CH.sub.3 H OCHF.sub.2
NCH.sub.2CH.sub.2CH.sub.3 meta 1018. 1 H H OCHF.sub.2 Bond meta
1019. 1 CH.sub.3 H OCHF.sub.2 Bond ortho 1020. 1 CH.sub.3 H
OCHF.sub.2 Bond meta 1021. 2 H H OCHF.sub.2 Bond ortho 1022. 2 H H
OCHF.sub.2 Bond meta 1023. 2 CH.sub.3 H OCHF.sub.2 Bond ortho 1024.
2 CH.sub.3 H OCHF.sub.2 Bond meta 1025. 1 H H CH.sub.3 NCH.sub.3
ortho 1026. 1 H H CH.sub.3 NCH.sub.3 meta 1027. 1 CH.sub.3 H
CH.sub.3 NCH.sub.3 ortho 1028. 1 CH.sub.3 H CH.sub.3 NCH.sub.3 meta
1029. 2 H H CH.sub.3 NCH.sub.3 ortho 1030. 2 H H CH.sub.3 NCH.sub.3
meta 1031. 2 CH.sub.3 H CH.sub.3 NCH.sub.3 ortho 1032. 2 CH.sub.3 H
CH.sub.3 NCH.sub.3 meta 1033. 1 H H CH.sub.3 NCH.sub.2CH.sub.3
ortho 1034. 1 H H CH.sub.3 NCH.sub.2CH.sub.3 meta 1035. 1 CH.sub.3
H CH.sub.3 NCH.sub.2CH.sub.3 ortho 1036. 1 CH.sub.3 H CH.sub.3
NCH.sub.2CH.sub.3 meta 1037. 2 H H CH.sub.3 NCH.sub.2CH.sub.3 ortho
1038. 2 H H CH.sub.3 NCH.sub.2CH.sub.3 meta 1039. 2 CH.sub.3 H
CH.sub.3 NCH.sub.2CH.sub.3 ortho 1040. 2 CH.sub.3 H CH.sub.3
NCH.sub.2CH.sub.3 meta 1041. 1 H H CH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 ortho 1042. 1 H H CH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 meta 1043. 1 CH.sub.3 H CH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 ortho 1044. 1 CH.sub.3 H CH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 meta 1045. 2 H H CH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 ortho 1046. 2 H H CH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 meta 1047. 2 CH.sub.3 H CH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 ortho 1048. 2 CH.sub.3 H CH.sub.3
NCH.sub.2CH.sub.2CH.sub.3 meta 1049. 1 H H CH.sub.3 Bond meta 1050.
1 CH.sub.3 H CH.sub.3 Bond ortho 1051. 1 CH.sub.3 H CH.sub.3 Bond
meta 1052. 2 H H CH.sub.3 Bond ortho 1053. 2 H H CH.sub.3 Bond meta
1054. 2 CH.sub.3 H CH.sub.3 Bond ortho 1055. 2 CH.sub.3 H CH.sub.3
Bond meta 1056. 1 H H F NCH.sub.3 ortho 1057. 1 H H F NCH.sub.3
meta 1058. 1 CH.sub.3 H F NCH.sub.3 ortho 1059. 1 CH.sub.3 H F
NCH.sub.3 meta 1060. 2 H H F NCH.sub.3 ortho 1061. 2 H H F
NCH.sub.3 meta 1062. 2 CH.sub.3 H F NCH.sub.3 ortho 1063. 2
CH.sub.3 H F NCH.sub.3 meta 1064. 1 H H F NCH.sub.2CH.sub.3 ortho
1065. 1 H H F NCH.sub.2CH.sub.3 meta 1066. 1 CH.sub.3 H F
NCH.sub.2CH.sub.3 ortho 1067. 1 CH.sub.3 H F NCH.sub.2CH.sub.3 meta
1068. 2 H H F NCH.sub.2CH.sub.3 ortho 1069. 2 H H F
NCH.sub.2CH.sub.3 meta 1070. 2 CH.sub.3 H F NCH.sub.2CH.sub.3 ortho
1071. 2 CH.sub.3 H F NCH.sub.2CH.sub.3 meta 1072. 1 H H F
NCH.sub.2CH.sub.2CH.sub.3 ortho 1073. 1 H H F
NCH.sub.2CH.sub.2CH.sub.3 meta 1074. 1 CH.sub.3 H F
NCH.sub.2CH.sub.2CH.sub.3 ortho 1075. 1 CH.sub.3 H F
NCH.sub.2CH.sub.2CH.sub.3 meta 1076. 2 H H F
NCH.sub.2CH.sub.2CH.sub.3 ortho 1077. 2 H H F
NCH.sub.2CH.sub.2CH.sub.3 meta 1078. 2 CH.sub.3 H F
NCH.sub.2CH.sub.2CH.sub.3 ortho 1079. 2 CH.sub.3 H F
NCH.sub.2CH.sub.2CH.sub.3 meta 1080. 1 H H F Bond meta 1081. 1
CH.sub.3 H F Bond ortho 1082. 1 CH.sub.3 H F Bond meta 1083. 2 H H
F Bond ortho 1084. 2 H H F Bond meta 1085. 2 CH.sub.3 H F Bond
ortho 1086. 2 CH.sub.3 H F Bond meta
[0199] Table C:
[0200] Further examples are compounds of the formula I, where
R.sup.6 is hydrogen, n, R.sup.1, R.sup.3, X and R.sup.5 are as
defined in the rows of Table A, wherein R.sup.2 is methyl instead
of hydrogen (compounds 1061 to 1988) and the physiologically
tolerated acid addition salts or the N-oxides thereof.
[0201] Table D:
[0202] Further examples are compounds of the formula I', where
R.sup.5 and R.sup.6 are hydrogen, n, R.sup.1, R.sup.3 and X are as
defined in the rows of Table B, wherein R.sup.2 is methyl instead
of hydrogen (compounds 1989 to 2120) and the physiologically
tolerated acid addition salts or the N-oxides thereof.
[0203] The compounds I and I'according to the invention are
prepared in analogy with methods known from the literature. An
important approach to the compounds according to the invention is
offered by the reaction of a 1-(piperazin-1-yl) or
1-(homopiperazin-1-yl) compound II where R.sup.3 is e.g. methyl or
methoxy with chlorosulfonic acid and subsequent reaction of the
intermediate sulfonyl chloride with an aniline derivative IV as
depicted in scheme 1 or with a 2,2-difluorobenzo[1,3]dioxolane
derivative IVa as depicted in scheme 1a.
##STR00004##
##STR00005##
[0204] In schemes 1 and 1a, n, R.sup.2 and R.sup.3 are as defined
herein. R.sup.a is a nitrogen protecting group or methyl. Suitable
N-protecting groups are described, for example, in P. J. Kocienski
"Protecting Groups", 2.sup.nd ed., Georg Thieme Verlag, Stuttgart
2000, pp 186-237 and in the literature cited therein. Preferred
examples of N-protecting groups are e.g. oxycarbonyl groups such as
C.sub.1-C.sub.6-alkoxycarbonyl, e.g. methoxycarbonyl,
ethoxycarbonyl and Boc (tert-butoxycarbonyl) and other oxycarbonyl
groups such as benzyloxycarbonyl (Cbz), allyloxycarbonyl,
9-fluorenylmethoxycarbonyl (Fmoc) and
2-trimethylsilylethoxycarbonyl (Teoc), or 2-propenyl (allyl).
Especially preferred for introduction of a sulfonylchloride group
is the trifluoroacetyl group as a protecting group for the
piperazine or homopiperazine nitrogen. X.sup.1 is a
nucleophilically displaceable leaving group, in particular a
halogen atom and, especially, chlorine or bromine.
[0205] Sulfone compounds of the present invention where X is a bond
can be prepared according to schemes 2 and 3, either from compounds
VII (which in itself can be prepared from aniline compounds VI
where the NH.sub.2 group is transformed into a group X.sup.2 which
can either be e.g. iodine or bromine, via a Sandmeyer reaction) by
reaction with a thiophenol compound VIIIa and subsequent oxidation
of the sulfide (scheme 2) with suitable oxidizing agents such as
oxone or peracids, or by reaction of a compound VII with the salt
of a sulfinic acid derivative VIIIb (usually the sodium salt)
without the further need for an oxidative step (scheme 3; e.g.
Synlett, 2003, 361 Cacchi et al.).
[0206] In schemes 2 and 3, n, R.sup.2 and R.sup.3 are as defined
herein. R.sup.a is a nitrogen protecting group or methyl.
##STR00006##
##STR00007##
[0207] Compounds of formula (IX) can be prepared by the
palladium-catalyzed reaction of the sulfinic acid salt VII Ib with
compounds VII, wherein X.sup.2 is bromine or iodine. A suitable
palladium catalyst is tris(dibenzylideneacetone)dipalladium(0)
(Pd.sub.2(dba).sub.3). The sulfone (IX) is usually prepared in the
presence of Xantphos, a rigid bidendate ligand. The reaction is
also usually carried out in the presence of n-tetrabutylammonium
chloride. Sulfinate compounds VIIIb are either commercially
available or can e.g. be prepared from the corresponding sulfonyl
chlorides by reaction with sodium sulfite under basic
conditions.
[0208] Compounds VIIa, wherein R.sup.3 is as defined above, can
also be prepared from suitable aniline compounds by reaction with a
suitably protected bis(2-chloroethyl)-amine where R.sup.a can e.g.
be the p-tolyl-sulfonyl group.
##STR00008##
[0209] Compounds of the formulae V and Va, wherein R.sup.a is a
nitrogen protecting group, in particular trifluoroacetyl, a
C.sub.1-C.sub.6-alkoxycarbonyl group such as methoxycarbonyl,
ethoxycarbonyl and Boc (tert-butoxycarbonyl), are novel and thus
form also part of the present invention.
[0210] Compounds of the formula V, wherein R.sup.a is methyl
correspond to compounds I, wherein R.sup.1 is methyl. Compounds of
the formula Va, wherein R.sup.a is methyl correspond to compounds
I', wherein R.sup.1 is methyl.
[0211] The reaction depicted in schemes 1 and 1a takes place under
the reaction conditions which are customary for preparing
arylsulfonamide compounds or arylsulfonic esters, respectively, and
which are described, for example, in J. March, Advanced Organic
Chemistry, 3.sup.rd edition, John Wiley & Sons, New York, 1985
p 444 and the literature cited therein, European J. Org. Chem. 2002
(13), pp. 2094-2108, Tetrahedron 2001, 57 (27) pp. 5885-5895,
Bioorganic and Medicinal Chemistry Letters, 2000, 10(8), pp.
835-838 and Synthesis 2000 (1), pp. 103-108.
[0212] The reaction customarily takes place in an inert solvent,
for example in an ether, such as diethyl ether, diisopropyl ether,
methyl tert-butyl ether or tetrahydrofuran, a halohydrocarbon, such
as dichloromethane, an aliphatic or cycloaliphatic hydrocarbon,
such as pentane, hexane or cyclohexane, or an aromatic hydrocarbon,
such as toluene, xylene, cumene and the like, or in a mixture of
the abovementioned solvents. The reaction of compound III with
compound IV (or compound IVa) is customarily carried out in the
presence of an auxiliary base. Suitable bases are inorganic bases,
such as sodium carbonate or potassium carbonate, or sodium hydrogen
carbonate or potassium hydrogen carbonate, and organic bases, for
example trialkylamines, such as triethylamine, or pyridine
compounds, such as pyridine, lutidine, 4-dimethylamino-pyridine and
the like. The latter compounds can at the same time serve as
solvents. The auxiliary base is customarily employed in at least
equimolar quantities, based on the amine compound II.
[0213] The reaction of compound III with compound IV or IVa,
respectively yields compound V or Va, respectively, which, in case
R.sup.a is an N-protecting group, is deprotected to yield the
compound of the general formula I or I', wherein R.sup.1 is
hydrogen. Deprotection of the compound V or Va, respectively, can
be achieved by standard methods, e.g. by the methods as described
in P. J. Kocienski "Protecting Groups", 2.sup.nd ed., Georg Thieme
Verlag, Stuttgart 2000, pp 186-237 and in the literature cited
therein.
[0214] Customary methods can then be used to react these compounds
with a methylating agent such as methyl iodide or dimethyl sulfate
resulting in a compound of the formula I or I', respectively, in
which R.sup.1 is methyl. The reaction conditions which are required
for this methylating reaction are disclosed, for example, in WO
02/083652, Tetrahedron 2000, 56(38) pp. 7553-7560 and Synlett. 2000
(4), pp. 475-480.
[0215] For preparing a compound of formula I or I', respectively,
in which R.sup.1 is methyl, it is likewise possible to react a
compound of formula I or I', in which R.sup.1 is hydrogen, with
formaldehyde in the presence of a reducing agent in a sense of a
reductive amination. Suitable reducing agents are borohydrides such
as sodium borohydride, sodium cyanoborohydride, sodium
triacetoxyborohydride or borane-pyridine. The reductive amination
is usually carried out in an organic solvent such as
dichloromethane, 1,2-dichloroethane, tetrahydrofuran or
acetonitrile.
[0216] Reaction of the compound V or Va with an alkylating agent
yields a compound of the formula V' or V'a, respectively, wherein
n, R.sup.a, R.sup.2 and R.sup.3 are as defined above. In the
compound of the formula V' or V'a, respectively, the sulfonamide
hydrogen is replaced by C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.4
cycloalkyl, or C.sub.3-C.sub.4 cycloalkyl-CH.sub.2--.
[0217] It is possible to react the compound V or Va with a
methylating agent such as methyl iodide or dimethyl sulfate to
yield a compound of the formula Vc or Vd, respectively, wherein n,
R.sup.a, R.sup.2 and R.sup.3 are as defined above.
##STR00009##
[0218] If R.sup.a in formulae Vc or Vd is an N-protecting group,
compound Vc or Vd, respectively is deprotected to yield the
compound of the general formula I, wherein R.sup.1 is hydrogen.
Deprotection of the compound Vc or Vd can be achieved by standard
methods, e.g. by the methods as described in P. J. Kocienski
"Protecting Groups", 2.sup.nd ed., Georg Thieme Verlag, Stuttgart
2000, pp 186-237 and in the literature cited therein.
[0219] Compounds V and IX where R.sup.a is methyl can best be
prepared by reaction of compounds V and IX where R.sup.a is
hydrogen with formaldehyde under reducing conditions as described
above.
[0220] The compounds of the general formula VI are known per se or
can be prepared in the manner shown in scheme 4.
##STR00010##
[0221] In scheme 4, n, R.sup.a, R.sup.2 and R.sup.3 are as defined
herein.
[0222] In step i) of scheme 4, the compound X is subjected to a
nitration under standard conditions thereby yielding compound XI.
Reaction conditions can be taken e.g. from U.S. Pat. No. 6,599,904
or from the working examples of the present application.
[0223] In step ii) of scheme 4, the NH-group of compound XI is
protected, either by a conventional N-protecting group as defined
above or by introducing a methyl group via a methylating agent such
as methyl bromide, methyl iodide or dimethyl sulfate. Introduction
of an N-protecting group into compound XI can be achieved by
standard methods, e.g. by the methods as described in P. J.
Kocienski "Protecting Groups", 2nd ed., Georg Thieme Verlag,
Stuttgart 2000, pp 186-237 and in the literature cited therein.
Methylation of compound XI is likewise achieved by standard methods
of Organic chemistry.
[0224] In step iii), the nitro group in compound XII is reduced to
the NH.sub.2 group to yield compound VI. The reaction conditions
which are required for step iii) correspond to the customary
conditions for reducing aromatic nitro groups which have been
described extensively in the literature (see, for example, J.
March, Advanced Organic Chemistry, 3rd ed., J. Wiley & Sons,
New-York, 1985, p. 1183 and the literature cited in this
reference). The reduction can be achieved, for example, by reacting
the nitro compound XII with a metal such as iron, zinc or tin under
acidic reaction conditions, i.e. using nascent hydrogen, or using a
complex hydride such as lithium aluminum hydride or sodium
borohydride, preferably in the presence of transition metal
compounds of nickel or cobalt such as
NiCl.sub.2(P(phenyl).sub.3).sub.2, or CoCl.sub.2, (see Ono et al.
Chem. Ind. (London), 1983 p. 480), or using NaBH.sub.2S.sub.3 (see
Lalancette et al. Can. J. Chem. 49, 1971, p. 2990), with it being
possible to carry out these reductions, depending on the given
reagent, in substance or in a solvent or diluent. Alternatively,
the reduction of XII to VI can be carried out with hydrogen in the
presence of a transition metal catalyst, e.g. using hydrogen in the
presence of catalysts based on platinum, palladium, nickel,
ruthenium or rhodium. The catalysts can contain the transition
metal in elemental form or in the form of a complex compound, of a
salt or of an oxide of the transition metal, with it being
possible, for the purpose of modifying the activity, to use
customary coligands, e.g. organic phosphine compounds, such as
triphenylphosphine, tricyclohexylphosphine or tri-n-butylphosphines
or phosphites. The catalyst is customarily employed in quantities
of from 0.001 to 1 mol per mol of compound XII, calculated as
catalyst metal. In a preferred variant, the reduction is effected
using tin(II) chloride in analogy with the methods described in
Bioorganic and Medicinal Chemistry Letters, 2002, 12(15), pp.
1917-1919 and J. Med. Chem. 2002, 45(21), pp. 4679-4688. The
reaction of XII with tin(II) chloride is preferably carried out in
an inert organic solvent, preferably an alcohol such as methanol,
ethanol, isopropanol or butanol.
[0225] If not indicated otherwise, the above-described reactions
are generally carried out in a solvent at temperatures between room
temperature and the boiling temperature of the solvent employed.
Alternatively, the activation energy which is required for the
reaction can be introduced into the reaction mixture using
microwaves, something which has proved to be of value, in
particular, in the case of the reactions catalyzed by transition
metals (with regard to reactions using microwaves, see Tetrahedron
2001, 57, p. 9199 ff. p. 9225 ff. and also, in a general manner,
"Microwaves in Organic Synthesis", Andre Loupy (Ed.), Wiley-VCH
2002.
[0226] The acid addition salts of compounds I and I' are prepared
in a customary manner by mixing the free base with a corresponding
acid, where appropriate in solution in an organic solvent, for
example acetonitrile, a lower alcohol, such as methanol, ethanol or
propanol, an ether, such as diethyl ether, methyl tert-butyl ether
or diisopropyl ether, a ketone, such as acetone or methyl ethyl
ketone, an ester, such as ethyl acetate, mixtures thereof as well
as mixtures thereof with water.
[0227] The compounds of the present invention can be a 5-HT.sub.6
receptor agonist, including partial agonistic activity, or a
5-HT.sub.6 receptor antagonist, including inverse agonist
activity.
[0228] The compounds of formulae I and I'according to the present
invention, as well as their salts and their N-oxides, have a
surprisingly high affinity for 5-HT.sub.6 receptors. The high
affinity of the compounds according to the invention for 5-HT.sub.6
receptors is reflected in very low in-vitro receptor binding
constants (K.sub.i(5-HT.sub.6) values) of as a rule less than 500,
100 or 50 nM (nmol/l), preferably of less than 10 nM and, in
particular of less than 5 nM. The displacement of .sup.3H-LSD can,
for example, be used in receptor binding studies for determining
binding affinities to 5-HT.sub.6 receptors.
[0229] Furthermore the compounds of formulae I and I', as well as
their salts and their N-oxides, are highly selective 5-HT.sub.6
receptor ligands which, because of their low affinity for other
receptors such as dopamine receptors, adrenergic receptors,
muscarinic receptors, histamine receptors, opiate receptors, in
particular dopamine D.sub.2, .alpha..sub.1-adrenergic and histamine
H.sub.1 receptors, give rise to fewer side-effects than other, less
selective 5-HT.sub.6 ligands.
[0230] For instance the 5-HT.sub.6/D.sub.2,
5-HT.sub.6/.alpha..sub.1-adrenergic or 5-HT.sub.6/H.sub.1
selectivities of the compounds according to the present invention,
i.e. the ratios K.sub.i(D.sub.2)/K.sub.i(5-HT.sub.6),
K.sub.i(.alpha..sub.1-adrenergic)/K.sub.i(5-HT.sub.6) or
K.sub.i(H.sub.1)/K.sub.i(5-HT.sub.6) of the receptor binding
constants, is as a rule at least 25, preferably at least 50, even
better at least 100.
[0231] The displacement of [.sup.3H]SCH23390 or
[.sup.125I]spiperone can be used, for example, for carrying out
receptor binding studies on D.sub.1, D.sub.2 and D.sub.4
receptors.
[0232] Furthermore the compounds of the present invention because
of their structural features are susceptible to display an enhanced
brain penetration than other known 5-HT.sub.6 receptor ligands.
[0233] Because of their binding profile, the compounds of the
present invention can be used for treating diseases which respond
to 5-HT.sub.6 receptor ligands (or which are susceptible to
treatment with a 5-HT.sub.6 receptor ligand), i.e. they are
effective for treating those medical disorders or diseases in which
exerting an influence on (modulating) the 5-HT.sub.6 receptors
leads to an improvement in the clinical picture or to the disease
being cured. Examples of these diseases are disorders or diseases
of the central nervous system.
[0234] Disorders or diseases of the central nervous system are
understood as meaning disorders which affect the spinal cord and,
in particular, the brain. Within the meaning of the invention, the
term "disorder" denotes disturbances and/or anomalies which are as
a rule regarded as being pathological conditions or functions and
which can manifest themselves in the form of particular signs,
symptoms and/or malfunctions. While the treatment according to the
invention can be directed toward individual disorders, i.e.
anomalies or pathological conditions, it is also possible for
several anomalies, which may be causatively linked to each other,
to be combined into patterns, i.e. syndromes, which can be treated
in accordance with the invention.
[0235] The disorders which can be treated in accordance with the
invention are in particular disorders which respond to a modulation
of the 5-HT.sub.6 receptor. They include cognitive dysfunctions,
such as a deficit in memory, cognition and learning, in particular
associated with Alzheimer's disease, age-related cognitive decline
and mild cognitive impairment, attention deficit
disorder/hyperactivity syndrome, personality disorders, such as
schizophrenia, in particular cognitive deficits related with
schizophrenia, affective disorders such as depression, anxiety and
obsessive compulsive disorders, motion or motor disorders such as
Parkinson's disease and epilepsy, migraine, sleep disorders
(including disturbances of the Circadian rhythm), feeding
disorders, such as anorexia and bulimia, certain gastrointestinal
disorders such as Irritable Bowel Syndrome, diseases associated
with neurodegeneration, such as stroke, spinal or head trauma and
head injuries, such as hydrocephalus, addiction diseases including
e.g. drug addiction and obesity.
[0236] The addiction diseases include psychic disorders and
behavioral disturbances which are caused by the abuse of
psychotropic substances, including certain pharmaceuticals, such as
sedative, anxiolytica, hypnotics or narcotics (hereinafter also
referred to as drug addiction), and also other addiction diseases,
such as addiction to gaming (gambling; impulse control disorders
not elsewhere classified). Examples of addictive substances are:
opioids (e.g. morphine, heroin and codeine), cocaine; nicotine;
alcohol; substances which interact with the GABA chloride channel
complex, sedatives, hypnotics and tranquilizers, for example
benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as
3,4-methylenedioxy-N-methylamphetamine (ecstasy); amphetamine and
amphetamine-like substances such as methylphenidate and other
stimulants including caffeine. Addictive substances which come
particularly into consideration are opioids, cocaine, amphetamine
or amphetamine-like substances, hallucinogens, NMDA-receptor
antagonists such phencyclidine and related cyclidines,
dextrometorphan, dextrorphan, ibogaine, ketimine and tiletamine,
cannabis, nicotine and alcohol. Other addiction diseases include
gaming (gambling), including problem gambling (compulsive gambling,
ludomania), computer or video game addiction and internet
addiction.
[0237] With regard to the treatment of addiction diseases,
particular preference is given to those compounds according to the
present invention which themselves do not possess any psychotropic
effect. This can also be observed in a test using rats, which,
after having been administered compounds which can be used in
accordance with the invention, reduce their self administration of
psychotropic substances, for example cocaine or alcohol.
[0238] According to another aspect of the present invention, the
compounds according to the invention are suitable for treating
disorders whose causes can at least partially be attributed to an
anomalous activity of 5-HT.sub.6 receptors.
[0239] According to another aspect of the present invention, the
treatment is directed, in particular, toward those disorders which
can be influenced, within the sense of an expedient medicinal
treatment, by the binding of preferably exogeneously administered
binding partners (ligands) to 5-HT.sub.6 receptors.
[0240] The diseases which can be treated with the compounds
according to the invention are frequently characterized by
progressive development, i.e. the above-described conditions change
over the course of time; as a rule, the severity increases and
conditions may possibly merge into each other or other conditions
may appear in addition to those which already exist.
[0241] The compounds of the present invention can be used to treat
a large number of signs, symptoms and/or malfunctions which are
connected with the disorders of the central nervous system and, in
particular, the abovementioned conditions. These signs, symptoms
and/or malfunctions include, for example, a disturbed relationship
to reality, lack of insight and ability to meet customary social
norms or the demands made by life, changes in temperament, changes
in individual drives, such as hunger, sleep, thirst, etc., and in
mood, disturbances in the ability to observe and combine, changes
in personality, in particular emotional lability, hallucinations,
ego-disturbances, distractedness, ambivalence, autism,
depersonalization and false perceptions, delusional ideas, chanting
speech, lack of synkinesia, short-step gait, flexed posture of
trunk and limbs, tremor, poverty of facial expression, monotonous
speech, depressions, apathy, impeded spontaneity and decisiveness,
impoverished association ability, anxiety, nervous agitation,
stammering, social phobia, panic disturbances, withdrawal symptoms
in association with dependency, maniform syndromes, states of
excitation and confusion, dysphoria, dyskinetic syndromes and tic
disorders, e.g. Huntington's chorea and Gilles-de-la-Tourette's
syndrome, vertigo syndromes, e.g. peripheral positional, rotational
and oscillatory vertigo, melancholia, hysteria, hypochondria and
the like.
[0242] Within the meaning of the invention, a treatment also
includes a preventive treatment (prophylaxis), in particular as
relapse prophylaxis or phase prophylaxis, as well as the treatment
of acute or chronic signs, symptoms and/or malfunctions. The
treatment can be orientated symptomatically, for example as the
suppression of symptoms. It can be effected over a short period, be
orientated over the medium term or can be a long-term treatment,
for example within the context of a maintenance therapy.
[0243] The compounds according to the invention are preferentially
suitable for treating diseases of the central nervous system, more
preferably for treating cognitive dysfunctions and in particular,
for treating cognitive dysfunctions associated with schizophrenia
or with Alzheimer's disease.
[0244] According to another aspect of the invention the compounds
of the present invention are particularly suitable for treating
addiction diseases caused for instance by the abuse of psychotropic
substances, such as pharmaceuticals, narcotics, nicotine or
alcohol, including psychic disorders and behavioral disturbances
related thereto. The compounds of the present invention are
likewise particularly suitable for treating addiction diseases
which are not caused by the abuse of psychotropic substances, such
as gaming (gambling), including problem gambling (compulsive
gambling, ludomania), computer or video game addiction and internet
addiction. With regard to addiction diseases, the compound of the
present invention can be used for the therapy during addiction and
also for preventing relapse into addiction.
[0245] According to another aspect of the invention the compounds
of formulae (I) and (I)', their salts and their N-oxides are
particularly suitable for treating nutritional disorders, such as
obesity, as well as diseases related thereto, such as
cardiovascular diseases, digestive diseases, respiratory diseases,
cancer or type 2 diabetes.
[0246] Within the context of the treatment, the use according to
the invention of the described compounds involves a method. In this
method, an effective quantity of one or more compounds, as a rule
formulated in accordance with pharmaceutical and veterinary
practice, is administered to the individual to be treated,
preferably a mammal, in particular a human being, productive animal
or domestic animal. Whether such a treatment is indicated, and in
which form it is to take place, depends on the individual case and
is subject to medical assessment (diagnosis) which takes into
consideration signs, symptoms and/or malfunctions which are
present, the risks of developing particular signs, symptoms and/or
malfunctions, and other factors.
[0247] As a rule, the treatment is effected by means of single or
repeated daily administration, where appropriate together, or
alternating, with other active compounds or active
compound-containing preparations such that a daily dose of
preferably from about 0.1 to 1000 mg/kg of bodyweight, in the case
of oral administration, or of from about 0.1 to 100 mg/kg of
bodyweight, in the case of parenteral administration, is supplied
to an individual to be treated.
[0248] The invention also relates to the production of
pharmaceutical compositions for treating an individual, preferably
a mammal, in particular a human being, productive animal or
domestic animal. Thus, the compounds of formulae I or I', their
salts and/or their N-oxides are customarily administered in the
form of pharmaceutical compositions which comprise a
pharmaceutically acceptable excipient together with at least one
compound according to the invention and, where appropriate, other
active compounds. These compositions can, for example, be
administered orally, rectally, transdermally, subcutaneously,
intravenously, intramuscularly or intranasally.
[0249] Examples of suitable pharmaceutical formulations are solid
medicinal forms, such as powders, granules, tablets, in particular
film tablets, lozenges, sachets, cachets, sugar-coated tablets,
capsules, such as hard gelatin capsules and soft gelatin capsules,
suppositories or vaginal medicinal forms, semisolid medicinal
forms, such as ointments, creams, hydrogels, pastes or plasters,
and also liquid medicinal forms, such as solutions, emulsions, in
particular oil-in-water emulsions, suspensions, for example
lotions, injection preparations and infusion preparations, and
eyedrops and eardrops.
[0250] Implanted release devices can also be used for administering
inhibitors according to the invention. In addition, it is also
possible to use liposomes or microspheres.
[0251] When producing the compositions, the compounds according to
the invention are optionally mixed or diluted with one or more
excipients. Excipients can be solid, semisolid or liquid materials
which serve as vehicles, carriers or medium for the active
compound.
[0252] Suitable excipients are listed in the specialist medicinal
monographs. In addition, the formulations can comprise
pharmaceutically acceptable carriers or customary auxiliary
substances, such as glidants; wetting agents; emulsifying and
suspending agents; preservatives; antioxidants; antiirritants;
chelating agents; coating auxiliaries; emulsion stabilizers; film
formers; gel formers; odor masking agents; taste corrigents; resin;
hydrocolloids; solvents; solubilizers; neutralizing agents;
diffusion accelerators; pigments; quaternary ammonium compounds;
refatting and overfatting agents; raw materials for ointments,
creams or oils; silicone derivatives; spreading auxiliaries;
stabilizers; sterilants; suppository bases; tablet auxiliaries,
such as binders, fillers, glidants, disintegrants or coatings;
propellants; drying agents; opacifiers; thickeners; waxes;
plasticizers and white mineral oils. A formulation in this regard
is based on specialist knowledge as described, for example, in
Fiedler, H. P., Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and
angrenzende Gebiete [Encyclopedia of auxiliary substances for
pharmacy, cosmetics and related fields], 4.sup.th edition,
Aulendorf: ECV-Editio-Kantor-Verlag, 1996.
[0253] The following examples serve to explain the present
invention without limiting its scope.
[0254] The compounds were either characterized via proton-NMR in
d.sub.6-dimethylsulfoxid or d-chloroform on a 400 MHz or 500 MHz
NMR instrument (Bruker AVANCE), or by mass spectrometry, generally
recorded via HPLC-MS in a fast gradient on C18-material
(electrospray-ionisation (ESI) mode), or melting point.
[0255] The magnetic nuclear resonance spectral properties (NMR)
refer to the chemical shifts (.delta.) expressed in parts per
million (ppm). The relative area of the shifts in the .sup.1H NMR
spectrum corresponds to the number of hydrogen atoms for a
particular functional type in the molecule. The nature of the
shift, as regards multiplicity, is indicated as singlet (s), broad
singlet (s. br.), doublet (d), broad doublet (d br.), triplet (t),
broad triplet (t br.), quartet (q), quintet (quint.) and multiplet
(m).
I. Preparation of the Intermediate Compounds V and IX
I.1 Preparation of the Intermediate Compounds V
Preparation Example 1
N-(3-Difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-pipera-
zin-1-yl]-benzenesulfonamide
##STR00011##
[0256] 1.1
2,2,2-Trifluoro-1-(4-o-tolyl-piperazin-1-yl)-ethanone
##STR00012##
[0258] 29.9 g of 2,2,2-trifluoroacetic anhydride (104 mmol) were
dissolved in 150 mL of dichloromethane, cooled to -20.degree. C.,
and 20 g of 1-o-tolylpiperazine-1,4-diium chloride (80
mmol)--dissolved in 150 mL of dichloromethane--added dropwise.
After stirring for 16 h at room temperature, 400 ml of ice water
were added, the organic phase separated, washed twice with water,
and the pH adjusted to neutral with 1% aqueous sodium bicarbonate
solution. The organic phase was washed with saturated aqueous
sodium chloride, dried over sodium sulphate, filtered and the
solvent evaporated to yield 21.5 g of product which crystallized
upon cooling.
1.2
4-Methyl-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonyl
chloride
##STR00013##
[0260] To a solution of 2 g of
2,2,2-trifluoro-1-(4-o-tolyl-piperazin-1-yl)-ethanone (7.35 mmol)
in 5 mL of dichloromethane at -5.degree. C. were slowly added 19.7
g of chlorosulfonic acid (169 mmol). After stirring for 2 h at
-5.degree. C., the reaction mixture continued stirring for 16 h,
thereby slowly allowed to warm to room temperature. After cooling
to 0.degree. C., the reaction mixture was slowly added to a
water/ice mixture. The aqueous phase was extracted five times with
dichloromethane, the combined organic phases washed with aqueous
sodium bicarbonate solution and saturated sodium chloride solution.
The organic layer was dried over magnesium sulphate, filtered, and
the solvent evaporated to yield 2.2 g of product as a white
solid.
1.3
N-(3-Difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-pi-
perazin-1-yl]-benzenesulfonamide
##STR00014##
[0262] 0.429 g of 3-(difluoromethoxy)-aniline (2.7 mmol) were
dissolved in 5 mL of pyridine. 1 g of
4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonylchl-
oride (2.7 mmol) were added slowly at room temperature. After
stirring for 16 h at room temperature, the reaction mixture was
evaporated several times after addition of toluene. The residue was
dissolved in dichloromethane and washed several times with 5%
aqueous ammonium chloride. The organic phase was then washed with
saturated aqueous sodium chloride, dried over sodium sulphate,
filtered, and the solvent evaporated. The crude product was
purified via silica gel chromatography using
dichloromethane/methanol (0-5%) to yield 0.63 g of product.
[0263] For the preparation of the intermediate compounds V' or V'a,
respectively, i.e. compounds of the formula V or V', respectively,
wherein the sulphonamide hydrogen (R.sup.4.dbd.H) is replaced by
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.4 cycloalkyl, or
C.sub.3-C.sub.4 cycloalkyl-CH.sub.2-- (compounds V or V',
respectively, with R.sup.4.dbd.C.sub.1-C.sub.4 alkyl,
C.sub.3-C.sub.4 cycloalkyl, or C.sub.3-C.sub.4
cycloalkyl-CH.sub.2--), where R.sup.4 is e.g. a methyl group, the
corresponding trifluoroacetyl group has to be removed by reaction
under basic conditions, followed by reprotection with
tert.butyl-dicarbonate, reaction of this Boc-protected intermediate
V with sodium hydride and an alkylating agent, e.g. in case that
R.sup.4 is methyl, methyl iodide. The N-methylated derivative can
then be deprotected at the piperazine or homopiperazine moiety
under standard acidic conditions to yield final products.
Preparation Example 2
N-(3-Difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-[1,4]d-
iazepan-1-yl]-benzenesulfonamide
##STR00015##
[0265] The compound can be prepared as described for PREPARATION
EXAMPLE 1 starting from commercially available
1-o-tolyl-[1,4]diazepane.
1.2 Preparation of Intermediate Compounds IX
Preparation Example 3
1-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-4-(toluene-4-sul-
fonyl)-piperazine
##STR00016##
[0266] 3.1
1-(5-Iodo-2-methyl-phenyl)-4-(toluene-4-sulfonyl)-piperazine
##STR00017##
[0268] 9.97 g of N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide
(30.3 mmol) and 5.03 g of potassium iodide (30.3 mmol) in 75 mL of
cyclohexanol were stirred for 1 h at 80.degree. C. After addition
of 7.7 g of sodium carbonate (72.7 mmol) and 5.65 g of
5-iodo-2-methyl-aniline (24.2 mmol), stirring continued for 8 h at
160.degree. C. At room temperature, the mixture was filtered,
washed with dichloromethane, and the filtrate evaporated to
dryness. The residue was dissolved in dichloromethane, filtered,
and the solvent evaporated. The remaining residue was trituated
with n-heptane and the crystalline product filtered off, washed
several times with n-heptane and dried in vacuo to yield 10.7 g of
product.
3.2
1-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-4-(toluene-4-
-sulfonyl)-piperazine
##STR00018##
[0270] 0.521 g of
1-(5-Iodo-2-methyl-phenyl)-4-(toluene-4-sulfonyl)-piperazine (1.14
mmol), 0.315 g of sodium 3-(difluoromethoxy)benzenesulfinate (1.37
mmol), 0.558 g of cesium carbonate (1.713 mmol), 0.026 g of
Pd(dba).sub.3 (0.029 mmol), 0.033 g of Xantphos (0.059 mmol) and
0.381 g of tetrabutylammonium chloride (1.37 mmol) were stirred for
8 h in 10 mL of toluene. The reaction mixture was filtered and the
solvent evaporated. The crude product was purified via silica gel
chromatography with toluene/methanol 20:1 (2.5% triethylamine),
fractions containing the product combined and the solvents
evaporated to yield 0.386 g of product.
II. Preparation of the compounds I
Example 1
N-(3-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide
hydrochloride
##STR00019##
[0272] 0.63 g of
N-(3-Difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-piper-
azin-1-yl]-benzenesulfonamide (1.28 mmol) were dissolved in 90 ml
of methanol, 2.77 ml of 6N aqueous sodium hydroxide (16.6 mmol)
added and the reaction stirred at 67.degree. C. for 10 min. 150 mL
of water were added, the aqueous layer extracted with ethyl
acetate, and the organic phase washed with saturated aqueous sodium
chloride, dried over sodium sulfate, filtered and the solvent
evaporated. The residue was converted to the hydrochloride salt by
addition of HCl in diethyl ether. Evaporation to dryness followed
by dissolution of the remaining white solid in water and
lyophilisation of the aqueous phase yielded 0.535 g of product.
[0273] ESI-MS: 398.1 [M+H].sup.+
[0274] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.45 (s,
1H), 9.0 (broad, 2H), 7.3-7.45 (m, 3H), 7.25 (m, 1H), 7.15 (t, 1H),
6.95 (d, 1H), 6.9 (s, 1H), 6.85 (d, 1H), 3.25 (broad, 4H), 3.0
(broad, 4H), 2.25 (s, 3H).
Example 2
3-[1,4]Diazepan-1-yl-N-(3-difluoromethoxy-phenyl)-4-methyl-benzenesulfonam-
ide hydrochloride
##STR00020##
[0276] The product was obtained as described for Example 1 by
reaction of
N-(3-difluoromethoxy-phenyl)-4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-[1,4]-
diazepan-1-yl]-benzenesulfonamide with aqueous sodium
hydroxide.
[0277] ESI-MS: 412.1 [M+H].sup.+
[0278] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.5 (s,
1H), 9.55 (s, broad, 2H), 7.45 (s, 1H), 7.0-7.4 (several m, 4H),
7.0 (d, 1H), 6.95 (s, 1H), 6.8 (d, 1H), 4.0 (s, broad, 2H), 3.2
(broad, 6H), 3.0 (m, 2H), 2.25 (s, 3H).
Example 3
1-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-piperazine
hydrochloride
##STR00021##
[0280] 0.75 g of 4-hydroxy-benzoic acid (7.06 mmol) and 2.485 mL of
32% HBr in acetic acid (72.4 mmol) were mixed under stirring and
the suspension cooled to 0.degree. C. 0.379 g of
1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-4-(toluene-4-su-
lfonyl)-piperazine (0.706 mmol) dissolved in 5 mL of acetic acid
were added and the reaction mixture stirred for 16 h. Additional 30
equivalents of HBr in acetic acid were added, stirred for 18 h, and
the reaction added slowly to ice water. The pH was adjusted to
neutral conditions with addition of aqueous ammonia, the aqueous
layer extracted three times with dichloromethane, the combined
organic layers dried over magnesium sulphate, filtered and the
solvent evaporated. The crude product was purified via silica gel
chromatography using toluene/methanol 5:1 (2.5% triethylamine), the
solvents evaporated and the residue redissolved in a small amount
of ethyl acetate. The hydrochloride was precipitated by addition of
2 N hydrochlorid acid in diethyl ether yielding 0.059 g of
product.
[0281] ESI-MS: 383.1 [M+H].sup.+
[0282] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.5 (s
broad, 2H), 7.8 (d, 1H), 7.7 (s, 1H), 7.65 (m, 1H), 7.6 (d, 1H),
7.5 (m, 2H), 7.45 (d, 1H), 7.4 (t, 1H), 3.2 (broad, 4H), 3.1
(broad, 4H), 2.3 (s, 3H).
[0283] The compounds of Examples 4 to 49 can be prepared in a
manner analogous to the preparations described above.
Example 4
N-(2-Difluoromethoxy-phenyl)-N-methyl-3-(4-methyl-piperazin-1-yl)-benzene--
sulfonamide hydrochloride
##STR00022##
[0285] ESI-MS: 412.1 [M+H].sup.+
[0286] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 6.9-7.5
(several m, 9H), 3.5 (broad, 8H), 3.1 (s, 3H), 2.75 (s, 3H).
Example 5
N-(2-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzene--
sulfonamide hydrochloride
##STR00023##
[0288] ESI-MS: 412.1 [M+H].sup.+
[0289] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 11.4
(broad, 1H), 9.9 (s, 1H), 7.4 (s, 1H), 7.05-7.35 (several m, 6H),
6.95 (t, 1H), 3.45 (broad, 2H), 3.2 (broad, 2H), 3.1 (broad, 4H),
2.8 (s, 3H), 2.3 (s, 3H).
Example 6
N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzene-su-
lfonamide hydrochloride
##STR00024##
[0291] ESI-MS: 412.1 [M+H].sup.+
[0292] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.7
(broad, 3H), 7.45 (s, 1H), 7.38 (d, 1H), 7.32 (d, 1H), 7.15 (d,
1H), 7.05 (t, 1H), 6.95 (s, 1H), 6.9 (d, 1H), 3.2 (broad, 4H), 3.0
(broad, 4H), 2.25 (s, 3H), 2.05 (s, 3H).
Example 7
N-(4-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide
hydrochloride
##STR00025##
[0294] ESI-MS: 398.1 [M+H].sup.+
[0295] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.35
(broad, 1H), 9.55 (broad, 2H), 7.25-7.45 (several m, 3H), 7.15 (t,
1H), 7.15 (d, 2H), 7.05 (d, 2H), 3.2 (broad, 4H), 3.05 (broad, 4H),
2.25 (s, 3H).
Example 8
N-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-4-methyl-3-piperazin-1-yl-benzenesu-
lfonamide hydrochloride
##STR00026##
[0297] ESI-MS: 412.1 [M+H].sup.+
[0298] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.6
(broad, 1H), 7.25-7.45 (several m, 3H), 7.2 (d, 1H), 7.1 (m, 1H),
6.9 (d, 1H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.3 (broad,
3H).
Example 9
N-Cyclopropylmethyl-N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-
-benzenesulfonamide hydrochloride
##STR00027##
[0300] ESI-MS: 452.2 [M+H].sup.+
[0301] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.55
(broad, 2H), 7.05-7.5 (several m, 7H), 7.1 (t, 1H), 3.35 (m, 2H),
3.2 (broad, 4H), 3.05 (broad, 4H), 2.3 (broad, 3H), 0.75 (m, 1H),
0.3 (m, 2H), -0.05 (m, 2H).
Example 10
N-Cyclopropylmethyl-N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-
-benzenesulfonamide hydrochloride
##STR00028##
[0303] ESI-MS: 452.2 [M+H].sup.+
[0304] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.6
(broad, 2H), 6.8-7.55 (several m, 8H), 3.4 (m broad, 2H), 3.2
(broad, 4H), 3.05 (broad, 4H), 2.35 (broad, 3H), 0.75 (m broad,
1H), 0.35 (m broad, 2H), 0.0 (m broad, 2H).
Example 11
N-(2-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-N-propyl-benzene-su-
lfonamide hydrochloride
##STR00029##
[0306] ESI-MS: 440.1 [M+H].sup.+
[0307] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.55
(broad, 2H), 7.4 (m, 2H), 7.3 (d, 1H), 7.25 (d, 2H), 7.1 (t, 1H),
7.1 (m, 2H), 3.4 (m, 2H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.3
(s, 3H), 1.3 (m, 2H), 0.8 (t, 3H).
Example 12
N-(3-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-N-propyl-benzenesul-
fonamide hydrochloride
##STR00030##
[0309] ESI-MS: 440.1 [M+H].sup.+
[0310] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.4
(broad, 2H), 7.4 (m, 2H), 7.3 (t, 1H), 7.25 (d, 1H), 7.15 (d, 1H),
6.95 (s, 1H), 6.95 (d, 1H), 6.85 (s, 1H), 3.45 (t, 2H), 3.2 (broad,
4H), 3.0 (broad, 4H), 2.35 (s, 3H), 1.3 (m, 2H), 0.8 (t, 3H).
Example 13
N-(3-Difluoromethoxy-phenyl)-N-ethyl-4-methyl-3-piperazin-1-yl-benzene
sulfonamide hydrochloride
##STR00031##
[0312] ESI-MS: 426.1 [M+H].sup.+
[0313] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.35
(broad, 2H), 7.4 (m, 2H), 7.25 (t, 1H), 7.25 (d, 1H), 7.2 (d, 1H),
7.0 (s, 1H), 6.95 (d, 1H), 6.85 (s, 1H), 3.55 (m, 2H), 3.2 (broad,
4H), 3.0 (broad, 4H), 2.35 (s, 3H), 0.95 (t, 3H).
Example 14
N-(3-Difluoromethoxy-phenyl)-4,N-dimethyl-3-piperazin-1-yl-benzenesulfonam-
ide hydrochloride
##STR00032##
[0315] ESI-MS: 412.1 [M+H].sup.+
[0316] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.5
(broad, 2H), 7.4 (m, 2H), 7.3 (t, 1H), 7.2 (d, 1H), 7.1 (d, 1H),
7.0 (d, 1H), 6.95 (s, 1H), 6.9 (s, 1H), 3.55 (m, 2H), 3.2 (broad,
4H), 3.1 (s, 3H), 2.95 (broad, 4H), 2.35 (s, 3H).
Example 15
N-(2-Difluoromethoxy-phenyl)-N-ethyl-4-methyl-3-piperazin-1-yl-benzene
sulfonamide hydrochloride
##STR00033##
[0318] ESI-MS: 426.1 [M+H].sup.+
[0319] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.55
(broad, 2H), 7.4 (m, 2H), 7.35 (d, 1H), 7.25 (m, 2H), 7.15 (t, 1H),
7.15 (d, 1H), 7.1 (d, 1H), 3.5 (m, 2H), 3.2 (broad, 4H), 3.05
(broad, 4H), 2.35 (s, 3H), 0.95 (t, 3H).
Example 16
N-(2-Difluoromethoxy-phenyl)-N-methyl-4-methyl-3-piperazin-1-yl-benzene
sulfonamide hydrochloride
##STR00034##
[0321] ESI-MS: 412.1 [M+H].sup.+
[0322] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.7
(broad, 2H), 7.4 (m, 2H), 7.3 (d, 1H), 7.2 (m, 2H), 7.1 (t, 1H),
7.1 (m, 2H), 3.2 (broad, 4H), 3.05 (broad, 4H), 3.05 (s, 3H), 2.3
(s, 3H).
Example 17
N-(2-Difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide
hydrochloride
##STR00035##
[0324] ESI-MS: 398.1 [M+H].sup.+
[0325] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.85 (s,
1H), 9.1 (broad, 2H), 7.3-7.4 (m, 3H), 7.25 (d, 1H), 7.1-7.2 (m,
3H), 6.9 (t, 1H), 3.25 (broad, 4H), 3.0 (broad, 4H), 2.3 (s,
3H).
Example 18
N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzene-s-
ulfonamide hydrochloride
##STR00036##
[0327] ESI-MS: 428.1 [M+H].sup.+
[0328] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 7.3 (d,
1H), 7.2 (s, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 6.8-7.2 (t, 1H), 6.9
(s, 1H), 6.8 (d, 1H), 3.8 (s, 3H), 2.8 (s, 8H, 2.1 (s, 3H).
Example 19
N-(4-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide
hydrochloride
##STR00037##
[0330] ESI-MS: 414.1 [M+H].sup.+
[0331] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.25 (s,
1H), 9.5 (broad, 2H), 7.35 (d, 1H), 7.25 (d, 1H), 7.15 (d, 2H),
7.15 (t, 1H), 7.05 (m, 3H), 3.8 (s, 3H), 3.2 (broad, 8H).
Example 20
3-[1,4]Diazepan-1-yl-N-(2-difluoromethoxy-phenyl)-4-methyl-benzenesulfonam-
ide hydrochloride
##STR00038##
[0333] ESI-MS: 412.1 [M+H].sup.+
[0334] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.8 (s,
1H), 9.4 (s broad, 2H), 7.4 (s, 1H), 7.2-7.3 (m, 3H), 7.1-7.2 (m,
3H), 6.9 (t, 1H), 3.25 (m, 6H), 3.0 (m, 2H), 2.3 (s, 3H), 2.0 (m,
2H).
Example 21
3-[1,4]Diazepan-1-yl-N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-benzen-
esulfonamide hydrochloride
##STR00039##
[0336] ESI-MS: 426.1 [M+H].sup.+
[0337] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.3 (s,
1H), 9.4 (s broad, 2H), 7.4 (s, 1H), 7.3 (m, 2H), 7.15 (d, 1H),
7.05 (t, 1H), 6.95 (m, 1H), 6.85 (m, 1H), 3.2-3.3 (m, 6H), 3.0 (m,
2H), 2.3 (s, 3H), 2.1 (s, 3H), 2.05 (m, 2H).
Example 22
N-(2-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesul-
fonamide
##STR00040##
[0339] ESI-MS: 412.1 [M+H].sup.+
[0340] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.6
(broad, 3H), 7.4 (s, 1H), 7.3 (m, 2H), 7.1 (d, 1H), 6.9-7.0 (m,
2H), 6.9 (t, 1H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.3 (s, 3H),
2.25 (s, 3H).
Example 23
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesul-
fonamide hydrochloride
##STR00041##
[0342] ESI-MS: 412.1 [M+H].sup.+
[0343] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.4-9.9
(broad, 3H), 7.4 (s, 1H), 7.3 (m, 2H), 7.1 (s, 1H), 6.9-7.0 (m,
2H), 6.85 (t, 1H), 3.2 (broad, 4H), 3.05 (broad, 4H), 2.3 (s, 3H),
2.2 (s, 3H).
Example 24
N-(3-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide
hydrochloride
##STR00042##
[0345] ESI-MS: 414.1 [M+H].sup.+
[0346] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.5 (s,
1H), 9.6 (s broad, 2H), 7.4 (d, 1H), 7.3 (s, 1H), 7.25 (m, 1H),
7.15 (t, 1H), 7.1 (d, 1H), 7.0 (m, 1H), 6.95 (s, 1H), 6.8 (d, 1H),
3.8 (s, 3H), 3.1-3.2 (broad, 8H).
Example 25
N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenes-
ulfonamide hydrochloride
##STR00043##
[0348] ESI-MS: 444.1 [M+H].sup.+
[0349] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.05 (s,
1H), 9.3 (s broad, 2H), 7.35 (d, 1H), 7.25 (s, 1H), 6.8-7.1
(several m, 5H), 3.8 (s, 1H), 3.7 (s, 3H), 3.2 (s broad, 4H), 3.15
(s broad, 4H).
Example 26
N-(2-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide
hydrochloride
##STR00044##
[0351] ESI-MS: 414.1 [M+H].sup.+
[0352] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.8 (s,
1H), 9.7 (s broad, 2H), 7.35 (d, 1H), 7.3 (s, 1H), 7.25 (d, 1H),
7.1-7.2 (several m, 3H), 7.05 (d, 1H), 7.0 (t, 1H), 3.8 (s, 3H),
3.2 (broad, 8H).
Example 27
N-(2-Difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesu-
lfonamide hydrochloride
##STR00045##
[0353] 27.1 tea-butyl
4-(5-(N-(2-(difluoromethoxy)phenyl)sulfamoyl)-2-methoxyphenyl)piperazine--
1-carboxylate
[0354] 1 g of
N-(2-(difluoromethoxy)phenyl)-4-methoxy-3-(piperazin-1-yl)benzenesulfonam-
ide (2.419 mmol) were dissolved in 15 mL of tetrahydrofuran. 0.674
mL of triethylamine (4.84 mmol) were added, followed by addition of
0.528 g of di-tert-butyl dicarbonate (2.419 mmol) in 2 mL of
tetrahydrofurane. The reaction mixture was stirred at room
temperature for 16 h. After evaporation of the solvent, the residue
was dissolved in dichloromethane, washed with 5% aqueous citric
acid. The organic phase was washed with saturated aqueous sodium
chloride, dried over sodium sulphate, filtered, and the solvent
evaporated. The crude product containing ca. 25% of the bis-boc
derivative was used without further purification in the next step
(1.2 g).
27.2 tert-butyl
4-(5-(N-(2-(difluoromethoxy)phenyl)methyl-sulfamoyl)-2-methoxyphenyl)pipe-
razine-1-carboxylate
[0355] 0.15 g of tert-butyl
4-(5-(N-(2-(difluoromethoxy)phenyl)sulfamoyl)-2-methoxyphenyl)piperazine--
1-carboxylate (0.219 mmol) were dissolved in 5 mL of
dimethylformamide. 11.4 mg of sodium hydride (0.285 mmol, 60%) were
added and the reaction stirred at 50.degree. C. for 20 min. At room
temperature, 0.018 mL of methyl iodide (0.285 mmol) were added.
Stirring was continued for 16 h at room temperature followed by
addition of additional 0.018 mL of methyl iodide and stirring for
16 h. The solvent was evaporated, the residue dissolved in
dichloromethane and washed with saturated aqueous sodium chloride.
The organic layer was dried over sodium sulfate, filtered and the
solvent evaporated. Purification via silica gel chromatography
(Redisep NP-cartridge) with cyclohexane/ethyl acetate (0-50%)
yielded 0.104 g of the title compound.
[0356] ESI-MS: 528.2 [M+H].sup.+
27.3
N-(2-Difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benz-
enesulfonamide hydrochloride
[0357] 0.104 g tert-butyl
4-(5-(N-(2-(difluoromethoxy)phenyl)methyl-sulfamoyl)-2-methoxyphenyl)pipe-
razine-1-carboxylate (0.197 mmol) were dissolved in 5 mL of
dichloromethane. At room temperature, 0.296 mL of 2 N aqueous
hydrochloric acid (0.591 mmol) were added and the reaction stirred
for 16 h and 2 h at 35.degree. C. After addition of methanol,
stirring continued for 1 h before the solvents were evaporated and
the residue co-destilled several times with diethyl ether to remove
residual hydrochloric acid. The remaining solid was dissolved in
water (pH 4), extracted several times with dichloromethane, and
aqueous layer lyophilized to yield 0.08 g of the title
compound.
[0358] ESI-MS: 428.1 [M+H].sup.+
[0359] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.3 (s
broad 2H), 7.45 (m, 1H), 7.4 (m, 1H), 7.25 (m, 2H), 7.2 (d, 1H),
7.1 (d, 1H), 7.1 (t, 1H), 7.0 (s, 1H), 3.9 (s, 3H), 3.2 (s broad,
4H), 3.15 (s broad, 4H), 3.05 (s, 3H).
[0360] Examples 9, 10, 11, 12, 13, 14, 15, 16, 28, 29, 30, 31, 32,
33, 34, 36, 39, and 43 were prepared as described for Example 27,
using either methyl iodide, ethyl iodide, propyl bromide, isopropyl
bromide or cyclopropyl-methylen-bromide as alkylating reagents.
Example 28
N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-
-benzenesulfonamide hydrochloride
##STR00046##
[0362] ESI-MS: 458.1 [M+H].sup.+
[0363] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.7 (s
broad, 2H), 9.05 (s broad, 1H), 7.2 (m, 1H), 7.25 (m, 2H), 7.05 (t,
1H), 6.95 (m, 1H), 6.9 (s, 1H), 6.8 (s, 1H), 3.9 (s, 3H), 3.85 (s,
3H), 3.2 (broad, 8H), 3.05 (s, 3H).
Example 29
N-(3-Difluoromethoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesul-
fonamide hydrochloride
##STR00047##
[0365] ESI-MS: 442.2 [M+H].sup.+
[0366] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.5 (s
broad, 2H), 7.4 (m, 1H), 7.25 (t, 1H), 7.25 (m, 1H), 7.1-7.2
(several m, 2H), 6.9 (d, 1H), 6.8 (s, 2H), 3.85 (s, 3H), 3.5 (m,
2H), 3.2 (s broad, 4H), 3.15 (s broad, 4H), 0.9 (t, 3H).
Example 30
N-(3-Difluoromethoxy-4-methoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl--
benzenesulfonamide hydrochloride
##STR00048##
[0368] ESI-MS: 472.2 [M+H].sup.+
[0369] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.3 (s
broad, 2H), 7.25 (d, 1H), 7.1-7.2 (m, 2H), 7.0 (t, 1H), 6.95 (m,
1H), 6.9 (s, 1H), 6.8 (s, 1H), 3.9 (s, 3H), 3.85 (s, 3H), 3.5 (m,
2H), 3.2 (s broad, 4H), 3.15 (s broad, 4H), 0.95 (t, 3H).
Example 31
N-(2-Difluoromethoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesul-
fonamide hydrochloride
##STR00049##
[0371] ESI-MS: 442.1 [M+H].sup.+
[0372] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.5 (s,
broad, 2H), 7.45 (m, 1H), 7.35 (m, 1H), 7.2-7.3 (m, 2H), 7.2 (m,
1H), 7.15 (t, 1H), 7.1 (d, 1H), 7.0 (s, 1H), 3.9 (s, 3H), 3.5 (m,
2H), 3.1-3.25 (s broad, 8H), 0.95 (t, 3H).
Example 32
N-(3-Difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesu-
lfonamide hydrochloride
##STR00050##
[0374] ESI-MS: 428.1 [M+H].sup.+
[0375] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.6 (s
broad, 2H), 9.0 (s, broad, 1H), 7.4 (m, 1H), 7.3 (t, 1H), 7.25 (m,
1H), 7.1-7.2 (m, 2H), 7.0 (d, 1H), 6.95 (s, 1H), 6.7 (s, 1H), 3.9
(s, 3H), 3.2 (s broad, 4H), 3.1 (s broad, 4H), 2.5 (m, 3H).
Example 33
N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-
-benzenesulfonamide hydrochloride
##STR00051##
[0377] ESI-MS: 486.2 [M+H].sup.+
[0378] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.3 (s
broad, 2H), 7.25 (d, 1H), 7.15 (m, 2H), 7.0 (t, 1H), 6.95 (d, 1H),
6.85 (d, 1H), 6.75 (s, 1H), 3.9 (s, 3H), 3.8 (s, 3H), 3.4 (t, 2H),
3.2 (broad, 4H), 3.1 (broad, 4H), 1.8 (m, 2H), 0.8 (t, 3H).
Example 34
N-(3-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesu-
lfonamide hydrochloride
##STR00052##
[0380] ESI-MS: 456.2 [M+H].sup.+
[0381] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.55 (s
broad, 2H), 7.4 (m, 1H), 7.25 (d, 2H), 7.15 (m, 2H), 6.95 (d, 1H),
6.85 (s, 1H), 6.8 (s, 1H), 3.85 (s, 3H), 3.45 (t, 2H), 3.2 (broad,
4H), 3.1 (broad, 4H), 1.8 (m, 2H), 0.8 (t, 3H).
Example 35
N-(3-Difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzene-
sulfonamide hydrochloride
##STR00053##
[0383] ESI-MS: 428.1 [M+H].sup.+
[0384] .sup.1H-NMR (CDCl.sub.3, 400 Hz): .delta. [ppm] 7.45 (d,
1H), 7.2 (m, 2H), 6.8-7.0 (several m, 4H), 6.45 (t, 1H), 3.9 (s,
3H), 3.0 (s, 4H), 2.6 (s, 4H), 2.35 (s, 3H).
Example 36
N-(2-Difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesu-
lfonamide hydrochloride
##STR00054##
[0386] ESI-MS: 456.1 [M+H].sup.+
[0387] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.0
(broad, 2H), 7.45 (m, 1H), 7.35 (m, 1H), 6.9-7.3 (several m, 6H),
3.9 (s, 3H), 3.4 (t, 2H), 3.2 (broad, 4H), 3.15 (broad, 4H), 1.3
(m, 2H), 0.8 (t, 3H).
Example 37
N-(2-Difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzene-
sulfonamide hydrochloride
##STR00055##
[0389] ESI-MS: 428.1 [M+H].sup.+
[0390] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.5 (s
broad, 1H), 9.7 (s, 1H), 7.4 (d, 1H), 7.3 (m, 2H), 7.05-7.2
(several m, 4H), 6.95 (t, 1H), 3.85 (s, 3H), 3.45 (m, 4H), 3.2 (m,
2H), 2.95 (m, 2H), 2.8 (d, 3H).
Example 38
N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide hydrochloride
##STR00056##
[0392] ESI-MS: 458.1 [M+H].sup.+
[0393] .sup.1H-NMR (CDCl.sub.3, 400 Hz): .delta. [ppm] 7.35 (m,
2H), 7.0 (m, 1H), 6.9 (s, 1H), 6.8 (m, 2H), 6.5 (t, 1H), 3.9 (s,
3H), 3.8 (s, 3H), 3.2 (broad, 4H), 2.8 (broad, 4H), 2.5 (s, broad,
3H).
Example 39
N-(2-Difluoromethoxy-phenyl)-N-isopropyl-4-methyl-3-piperazin-1-yl-benzene-
sulfonamide hydrochloride
##STR00057##
[0395] ESI-MS: 440.2 [M+H].sup.+
[0396] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.6 (s
broad, 2H), 6.95-7.55 (several m, 8H), 4.3 (m, 1H), 3.2 (broad,
4H), 3.1 (broad, 4H), 2.3 (s, 3H), 1.0 (d, 3H), 0.9 (d, 3H).
Example 40
N-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-4-methoxy-3-piperazin-1-yl-benzenes-
ulfonamide hydrochloride
##STR00058##
[0398] ESI-MS: 428.1 [M+H].sup.+
[0399] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.4 (s,
1H), 9.6 (s broad, 2H), 7.35 (d, 1H), 7.25 (s, 1H), 7.2 (d, 1H),
7.1 (m, 2H), 6.9 (d, 1H), 3.85 (s, 3H), 3.2 (broad, 8H).
Example 41
N-(2-Difluoromethoxy-phenyl)-3-piperazin-1-yl-benzenesulfonamide
hydrochloride
##STR00059##
[0401] ESI-MS: 384.1 [M+H].sup.+
[0402] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.9 (s,
1H), 9.75 (s broad, 2H), 7.4 (m, 2H), 7.25 (m, 2H), 7.1-7.2 (m,
4H), 6.95 (t, 1H), 3.4 (broad, 4H), 3.15 (broad, 4H),
Example 42
N-(2-Difluoromethoxy-phenyl)-3-(4-methyl-piperazin-1-yl)-benzenesulfonamid-
e hydrochloride
##STR00060##
[0404] ESI-MS: 398.1 [M+H].sup.+
[0405] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 11.45 (s
broad, 1H), 9.9 (s broad, 1H), 7.35-7.45 (m, 2H), 7.25 (m, 2H),
7.1-7.2 (m, 4H), 7.0 (t, 1H), 3.0-3.9 (broad, 8H), 2.75 (s,
3H).
Example 43
N-(2-Difluoromethoxy-phenyl)-N-methyl-3-piperazin-1-yl-benzenesulfonamide
hydrochloride
##STR00061##
[0407] ESI-MS: 398.1 [M+H].sup.+
[0408] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.5 (s
broad, 2H), 7.5 (m, 1H), 7.45 (m, 1H), 7.3 (m, 1H), 7.2 (m, 2H),
7.1 (m, 3H), 7.05 (t, 1H), 3.4 (broad, 4H), 3.2 (broad, 4H), 3.1
(s, 3H).
Example 44
N-(2-Difluoromethoxy-phenyl)-N-methyl-3-(4-methyl-piperazin-1-yl)-benzenes-
ulfonamide hydrochloride
##STR00062##
[0410] ESI-MS: 412.1 [M+H].sup.+
[0411] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 11.5
(broad, 1H), 7.55 (m, 1H), 7.5 (m, 1H), 7.45 (d, 1H), 7.25 (m, 2H),
7.05-7.2 (several m, 4H), 3.4 (broad, 8H), 3.1 (s, 3H), 2.8 (s,
3H).
Example 45
1-[3-(3-Difluoromethoxy-benzenesulfonyl)-phenyl]-piperazine
hydrochloride
##STR00063##
[0413] ESI-MS: 369.1 [M+H].sup.+
[0414] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.6 (s
broad, 2H), 7.85 (d, 1H), 7.75 (s, 1H), 7.7 (m, 1H), 7.45-7.55
(several m, 3H), 7.4 (t, 1H), 7.4 (d, 1H), 7.3 (m, 1H), 3.5 (s
broad, 4H), 3.15 (s broad, 4H).
Example 46
1-[3-(3-Difluoromethoxy-benzenesulfonyl)-phenyl]-4-methyl-piperazine
hydrochloride
##STR00064##
[0416] ESI-MS: 383.1 [M+H].sup.+
[0417] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 7.85 (d,
1H), 7.8 (s, 1H), 7.7 (m, 1H), 7.45-7.55 (several m, 3H), 7.4 (d,
1H), 7.4 (t, 1H), 7.3 (d, 1H), 3.95 (d, 2H), 3.65 (d, 2H), 3.25 (m,
2H), 3.15 (m, 2H), 2.8 (d, 3H).
Example 47
1-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methoxy-phenyl]-piperazine
hydrochloride
##STR00065##
[0419] ESI-MS: 399.1 [M+H].sup.+
[0420] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.5 (s
broad, 2H), 7.8 (d, 1H), 7.7 (s, 1H), 7.65 (m, 2H), 7.45 (d, 1H),
7.4 (t, 1H), 7.4 (m, 1H), 7.2 (d, 1H), 3.85 (s, 3H), 3.25 (s broad,
4H), 3.2 (s broad, 4H).
Example 48
1-[5-(3-Difluoromethoxy-benzenesulfonyl)-2-methoxy-phenyl]-4-methyl-pipera-
zine hydrochloride
##STR00066##
[0422] ESI-MS: 413.1 [M+H].sup.+
[0423] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 7.8 (d,
1H), 7.75 (s, 1H), 7.65 (m, 2H), 7.5 (d, 1H), 7.4 (t, 1H), 7.4 (s,
1H), 7.2 (d, 1H), 3.85 (s, 3H), 3.55 (m, 2H), 3.45 (m, 2H),
3.05-3.2 (m, 4H), 2.8 (s, 3H).
Example 49
1-[5-(3-Difluoromethoxy-4-methoxy-benzenesulfonyl)-2-methoxy-phenyl]-piper-
azine hydrochloride
##STR00067##
[0425] ESI-MS: 429.2 [M+H].sup.+
[0426] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.55 (s
broad, 2H), 7.85 (d, 1H), 7.7 (s, 1H), 7.6 (d, 1H), 7.3 (m, 2H),
7.2 (t, 1H), 7.17 (d, 1H), 3.9 (s, 3H), 3.85 (s, 3H), 3.25 (s
broad, 4H), 3.2 (s broad, 4H).
Example 50
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-ethoxy-3-piperazin-1-yl-benzenesul-
fonamide hydrochloride
##STR00068##
[0428] ESI-MS: 442.1 [M+H].sup.+
[0429] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.7
(broad, 1H), 9.0 (broad, 2H), 7.35 (d, 1H), 7.27 (s, 1H), 7.1 (s,
1H), 7.05 (d, 1H), 6.95 (m, 2H), 6.85 (t, 1H), 4.1 (q, 2H), 3.2
(broad, 4H), 3.15 (broad, 4H), 2.2 (s, 3H), 1.35 (t, 3H).
Example 51
N-(3,4-Bis-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-b-
enzenesulfonamide hydrochloride
##STR00069##
[0431] ESI-MS: 494 [M+H].sup.+
Example 52
N-(3,4-Bis-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfon-
amide hydrochloride
##STR00070##
[0433] ESI-MS: 464.1 [M+H].sup.+
[0434] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.6
(broad, 1H), 9.6 (broad, 2H), 7.3-7.45 (m, 3H), 6.9-7.3 (several m,
5H), 3.2 (broad, 4H), 3.05 (broad, 2H), 2.3.
Example 53
N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl-
)-benzenesulfonamide hydrochloride
##STR00071##
[0436] ESI-MS: 462 [M+H].sup.+
[0437] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): 8]ppm] 10.5 (broad, 1H),
10.05 (broad, 1H), 7.4 (d, 1H), 7.35 (s, 1H), 7.32 (s, 1H), 7.23
(d, 1H), 7.18 (d, 1H), 7.1 (d, 1H), 7.0 (t, 1H), 3.85 (s, 3H), 3.5
(broad, 4H), 3.2 (broad, 2H), 3.0 (broad, 2H), 2.8 (s, 3H).
Example 54
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-ethyl-3-(4-methyl-piperazin-1-yl)--
benzenesulfonamide
##STR00072##
[0439] ESI-MS: 440.1 [M+H].sup.+
Example 55
N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl-
)-benzenesulfonamide hydrochloride
##STR00073##
[0441] ESI-MS: 442.1 [M+H].sup.+
[0442] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.6
(broad, 1H), 9.6 (broad, 1H), 7.35 (d, 1H), 7.05-7.25 (several m,
4H), 6.9 (d, 1H), 6.8 (s, 1H), 3.85 (s, 3H), 3.1-3.7 (broad, 8H),
3.4 (s, 3H), 2.0 (s, 3H).
Example 56
N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-
-benzenesulfonamide hydrochloride
##STR00074##
[0444] ESI-MS: 446.1 [M+H].sup.+
[0445] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.4 (very
broad, 2H), 7.48 (s, 1H), 7.4 (m, 2H), 7.33 (s, 1H), 7.23 (d, 1H),
7.18 (d, 1H), 6.98 (t, 1H), 2.95-3.7 (broad, 8H), 2.9 (s, 3H), 2.3
(s, 3H).
Example 57
N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesu-
lfonamide hydrochloride
##STR00075##
[0447] ESI-MS: 448.1 [M+H].sup.+
[0448] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.05 (s,
1H), 9.1 (broad, 2H), 7.4 (d, 1H), 7.32 (m, 2H), 7.22 (d, 1H), 7.17
(d, 1H), 7.10 (d, 1H), 7.0 (t, 1H), 3.85 (s, 3H), 3.2 (broad, 4H),
3.15 (broad, 4H).
Example 58
N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesul-
fonamide hydrochloride
##STR00076##
[0450] ESI-MS: 412.1 [M+H].sup.+
[0451] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 7.2-7.4
(several m, 3H), 7.15 (d, 1H), 7.1 (t, 1H), 6.88 (d, 1H), 6.82 (s,
1H), 3.1 (broad, 4H), 2.9 (broad, 4H), 2.3 (s, 3H), 1.95 (s,
3H).
Example 59
N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesu-
lfonamide hydrochloride
##STR00077##
[0453] ESI-MS: 428.1 [M+H].sup.+
[0454] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.65-9.8
(broad, 3H), 7.3 (d, 1H), 7.2 (s, 1H), 7.18 (d, 1H), 7.12 (t, 1H),
7.1 (d, 1H), 6.9 (d, 1H), 6.75 (s, 1H), 3.8 (s, 3H), 3.15 (broad,
8H), 1.95 (s, 3H).
Example 60
N-(3,4-Bis-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfo-
namide hydrochloride
##STR00078##
[0456] ESI-MS: 480.1 [M+H].sup.+
[0457] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.55 (s,
1H), 9.5 (s, 2H), 7.43 (d, 1H), 7.25 (m, 2H), 6.9-7.15 (m, 5H), 3.9
(s, 3H), 3.2 (broad, 8H).
Example 61
N-(5-Chloro-2-difluoromethoxy-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulf-
onamide hydrochloride
##STR00079##
[0459] ESI-MS: 446 [M+H].sup.+
[0460] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.25
(broad, 1H), 9.55 (broad, 2H), 7.5 (s, 1H), 7.4 (m, 2H), 7.3 (s,
1H), 7.25 (d, 1H), 7.2 (d, 1H), 7.0 (t, 1H), 3.25 (broad, 4H), 3.05
(broad, 4H), 2.7 (q, 2H), 1.2 (t, 3H).
Example 62
N-(2-Difluoromethoxy-4-methyl-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulf-
onamide hydrochloride
##STR00080##
[0462] ESI-MS: 426.1 [M+H].sup.+
[0463] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.5
(broad, 2H), 7.3-7.4 (m, 3H), 7.1 (d, 1H), 6.97 (d, 1H), 6.93 (s,
1H), 6.9 (t, 1H), 3.2 (broad, 4H), 3.0 (broad, 4H), 2.68 (q, 2H),
2.25 (s, 3H), 1.18 (t, 3H).
Example 63
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methyl-3-((R)-3-methyl-piperazin-1-
-yl)-benzenesulfonamide hydrochloride
##STR00081##
[0465] ESI-MS: 426.2 [M+H].sup.+
[0466] .sup.1H NMR (methanol-d.sub.4, 400 Hz): .delta. [ppm]
7.3-7.45 (m, 4H), 6.9-7.05 (m, 2H), 6.4 (t, 1H), 2.7-3.7 (several
m, 7H), 2.4 (s, 3H), 2.3 (s, 3H), 1.4 (d, 3H).
Example 64
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methyl-3-((S)-3-methyl-piperazin-1-
-yl)-benzenesulfonamide hydrochloride
##STR00082##
[0468] ESI-MS: 426.2 [M+H].sup.+
[0469] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.85 (s,
1H), 9.65 (broad, 1H), 9.4 (broad, 1H), 7.4 (s, 1H), 7.35 (s, 2H),
7.1 (s, 1H), 6.95-7.0 (m, 2H), 7.0 (t, 1H), 3.4 (broad, 3H), 3.1
(m, 2H), 2.95 (m, 1H), 2.8 (m, 1H), 2.3 (s, 3H), 2.22 (s, 3H), 1.3
(d, 3H).
Example 65
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulf-
onamide hydrochloride
##STR00083##
[0471] ESI-MS: 426.1 [M+H].sup.+
[0472] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.85
(broad, 1H), 9.6 (broad, 2H), 7.45 (s, 1H), 7.4 (m, 2H), 7.1 (s,
1H), 6.95-7.0 (m, 2H), 6.85 (t, 1H), 3.22 (broad, 4H), 3.02 (broad,
4H), 2.68 (q, 2H), 2.2 (s, 3H), 1.15 (t, 3H).
Example 66
N-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide hydrochloride
##STR00084##
[0474] ESI-MS: 442.1 [M+H].sup.+
[0475] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.1
(broad, 1H), 7.33 (d, 1H), 7.28 (d, 1H), 7.08-7.15 (m, 2H), 7.05
(d, 1H), 6.8 (d, 1H), 3.8 (s, 3H), 2.9 (broad, 4H), 2.45 (broad,
4H), 2.2 (s, 3H).
Example 67
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl-
)-benzenesulfonamide hydrochloride
##STR00085##
[0477] 0.429 g
N-(2-(difluoromethoxy)-5-methylphenyl)-4-methoxy-3-(piperazin-1-yl)benzen-
esulfonamide (1.004 mmol) were dissolved in 5 mL of
dichloromethane. 0.086 mL of acetic acid (1.505 mmol) and 0.319 g
of sodium triacetoxyborohydride (3.01 mmol) were added. After
stirring for 10 min, 0.083 mL of aqueous formaldehyde solution
(3.01 mmol) were added and the reaction stirred for 72 h at room
temperature. The solvents were evaporated and the residue purified
via preparative silica gel chromatography (Super Flash cartridge
(Interchim)) using a dichloromethane (+0.1% triethylamine) and
methanol gradient as eluent. Fractions containing the product were
combined, the solvents evaporated, and the product converted to the
hydrochloride salt by addition of hydrochloric acid in diethyl
ether and subsequent evaporation to dryness (yield 0.169 g of
product).
[0478] ESI-MS: 442.1 [M+H].sup.+
[0479] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.6
(broad, 1H), 7.3 (d, 1H), 7.2 (s, 1H), 7.1 (s, 1H), 6.9-7.05
(several m, 3H), 6.8 (t, 1H), 3.8 (s, 3H), 2.9 (broad, 4H), 2.45
(broad, 4H), 2.2 (two s, 6H).
Example 68
N-(3-Difluoromethoxy-phenyl)-3-piperazin-1-yl-benzenesulfonamide
hydrochloride
##STR00086##
[0481] ESI-MS: 384.1 [M+H].sup.+
[0482] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.6 (s,
1H), 9.85 (broad, 1H), 9.45 (broad, 2H), 7.4 (m, 2H), 7.2-7.35 (m,
3H), 7.2 (t, 1H), 7.0 (m, 1H), 6.95 (s, 1H), 6.85 (d, 1H),
3.15-3.65 (broad, 8H).
Example 69
N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl-
)-benzenesulfonamide hydrochloride
##STR00087##
[0484] ESI-MS: 446.1 [M+H].sup.+
[0485] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.85
(broad, 1H), 9.75 (s, 1H), 7.2-7.35 (m, 3H), 7.0-7.1 (m, 3H), 7.07
(t, 1H), 3.85 (s, 3H), 3.5 (m, 4H), 3.18 (m, 2H), 3.02 (m, 2H),
2.85 (s, 3H).
Example 70
N-(2-Difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl-
)-benzenesulfonamide hydrochloride
##STR00088##
[0487] ESI-MS: 442.1 [M+H].sup.+
[0488] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 11.2
(broad, 1H), 9.6 (s, 1H), 7.3 (m, 2H), 7.12 (d, 1H), 7.05 (d, 1H),
6.9-7.0 (several m, 2H), 6.92 (t, 1H), 3.8 (s, 3H), 3.45 (m, 4H),
3.17 (m, 2H), 3.05 (m, 2H), 2.8 (s, 3H), 2.25 (s, 3H).
Example 71
N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesul-
fonamide hydrochloride
##STR00089##
[0490] ESI-MS: 432.1 [M+H].sup.+
[0491] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.3 (s,
1H), 9.75 (broad, 2H), 7.15-7.5 (several m, 6H), 7.05 (t, 1H), 3.2
(broad, 4H), 3.07 (broad, 4H), 2.3 (s, 3H).
Example 72
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesu-
lfonamide hydrochloride
##STR00090##
[0493] ESI-MS: 428.1 [M+H].sup.+
[0494] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 463.9306
1H-NMR (DMSO-d6, 400 Hz): d [ppm] 9.7 (broad, 1H), 9.6 (broad, 2H),
7.35 (d, 1H), 7.3 (s, 1H), 7.1 (s, 1H), 7.05 (d, 1H), 6.9-7.0 (m,
2H), 6.85 (t, 1H), 3.8 (s, 3H), 3.1-3.25 (broad, 8H) 2.2 (s,
3H).
Example 73
N-(2-Difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesu-
lfonamide hydrochloride
##STR00091##
[0496] ESI-MS: 428.1 [M+H].sup.+
[0497] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 7.3 (d,
1H), 7.2 (s, 1H), 7.15 (d, 1H), 6.95 (d, 1H), 6.9 (d, 1H), 6.85 (t,
1H), 3.8 (s, 3H), 2.8-2.95 (broad, 8H) 2.2 (s, 3H).
Example 74
N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methyl-3-piperazin-1-yl-benzenesul-
fonamide hydrochloride
##STR00092##
[0499] ESI-MS: 416.1 [M+H].sup.+
[0500] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 7.15-7.35
(several m, 4H), 7.1 (t, 1H), 6.8-6.95 (m, 2H), 3.0 (broad, 4H),
2.85 (broad, 4H), 2.2 (s, 3H).
Example 75
N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-
-benzenesulfonamide hydrochloride
##STR00093##
[0502] ESI-MS: 426.1 [M+H].sup.+
[0503] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 11.35
(broad, 1H), 10.4 (s, 1H), 7.4 (s, 1H), 7.35 (m, 2H), 7.15 (d, 1H),
7.1 (t, 1H), 7.0 (s, 1H), 6.9 (m, 1H), 3.5 (broad, 2H), 3.2 (broad,
2H), 3.1 (broad, 4H), 2.8 (s, 3H), 2.3 (s, 3H), 2.1 (s, 3H).
Example 76
N-(4-Difluoromethoxy-3-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesu-
lfonamide
##STR00094##
[0505] ESI-MS: 428.1 [M+H].sup.+
[0506] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.4
(broad, 1H), 7.4 (m, 1H), 7.37 (m, 2H), 7.03 (d, 1H), 6.9 (t, 1H),
6.87 (s, 1H), 6.65 (d, 1H), 3.7 (s, 3H), 3.25 (broad, 4H), 3.0
(broad, 4H), 2.25 (s, 3H).
Example 77
N-(5-Difluoromethoxy-2-methoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl-
)-benzenesulfonamide trifluoroacetate
##STR00095##
[0508] ESI-MS: 442.1 [M+H].sup.+
[0509] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.6 (s,
1H), 7.3-7.45 (m, 3H), 7.07 (d, 1H), 7.05 (t, 1H), 6.95 (m, 2H),
3.55 (s, 3H), 3.55 (broad, 2H), 3.2 (broad, 4H), 2.9 (broad, 2H),
2.9 (s, 3H), 2.3 (s, 3H).
Example 78
[0510]
N-(2-Difluoromethoxy-5-methoxy-phenyl)-4-methyl-3-(4-methyl-piperaz-
in-1-yl)-benzenesulfonamide trifluoroacetate
##STR00096##
[0511] ESI-MS: 442.1 [M+H].sup.+
[0512] .sup.1H-NMR (CDCl.sub.3, 400 Hz): .delta. [ppm] 7.5 (d, 1H),
7.37 (s, 1H), 7.2 (d, 1H), 6.93 (m, 2H), 6.6 (d, 1H), 6.2 (t, 1H),
3.8 (s, 3H), 3.67 (m, 2H), 3.2 (m, 2H), 3.1 (m, 2H), 3.0 (m, 2H),
2.9 (s, 3H), 2.3 (s, 3H).
Example 79
N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-
-benzenesulfonamide trifluoroacetate
##STR00097##
[0514] ESI-MS: 430.1 [M+H].sup.+
[0515] .sup.1H-NMR (CDCl.sub.3, 400 Hz): .delta. [ppm] 7.63 (m,
1H), 7.38 (m, 2H), 6.95 (m, 1H), 6.85 (s, 1H), 6.78 (d, 1H), 6.27
(t, 1H), 3.7 (m, 2H), 3.25 (m, 2H), 2.95-3.2 (broad, 4H), 2.9 (s,
3H), 2.3 (s, 3H).
Example 80
[0516]
N-(5-Difluoromethoxy-2-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-be-
nzenesulfonamide trifluoroacetate
##STR00098##
[0517] ESI-MS: 428.1 [M+H].sup.+
[0518] .sup.1H-NMR (CDCl.sub.3, 400 Hz): .delta. [ppm] 9.8 (broad,
2H), 7.52 (d, 1H), 7.38 (s, 2H), 7.1 (s, 1H), 6.8 (m, 1H), 6.7 (m,
1H), 6.45 (t, 1H), 3.7 (s, 3H), 3.35 (broad, 4H), 3.1 (broad, 4H),
2.3 (s, 3H).
Example 81
N-(2-Difluoromethoxy-5-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesu-
lfonamide hydrochloride
##STR00099##
[0520] ESI-MS: 428.1 [M+H].sup.+
[0521] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.7
(broad, 2H), 7.45 (s, 1H), 7.35 (m, 2H), 7.05 (d, 1H), 6.8 (d, 1H),
6.8 (t, 1H), 6.7 (d, 1H), 3.65 (s, 3H), 3.2 (broad, 4H), 3.05
(broad, 4H), 2.3 (s, 3H).
Example 82
N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesu-
lfonamide hydrochloride
##STR00100##
[0523] ESI-MS: 432.1 [M+H].sup.+
[0524] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 7.15-7.35
(several m, 3H), 6.9-7.05 (several m, 3H), 6.85-7.15 (t, 1H), 3.8
(s, 3H), 3.05 (m, 4H), 3.0 (m, 4H).
Example 83
N-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-3-piperazin-1-yl-benzenes-
ulfonamide hydrochloride
##STR00101##
[0526] ESI-MS: 428.1 [M+H].sup.+
[0527] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 7.35 (d,
1H), 7.15-7.2 (m, 2H), 7.05 (s, 1H), 7.0 (d, 1H), 6.85 (d, 1H), 3.8
(s, 3H), 2.85-3.0 (broad, 8H).
Example 84
N-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-4-methyl-3-piperazin-1-yl-benzenesu-
lfonamide hydrochloride
##STR00102##
[0529] ESI-MS: 412.1 [M+H].sup.+
[0530] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.4 (s,
1H), 9.25 (broad, 2H), 7.4 (s, 1H), 7.35 (m, 2H), 7.28 (d, 1H),
7.15 (m, 1H), 6.88 (d, 1H), 3.25 (broad, 4H), 3.05 (broad, 4H), 2.3
(s, 3H).
Example 85
N-(3-Difluoromethoxy-4-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesu-
lfonamide hydrochloride
##STR00103##
[0532] ESI-MS: 428.2 [M+H].sup.+
[0533] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 8.8-10.4
(very broad, 3H), 7.3-7.4 (m, 3H), 7.03 (d, 1H), 6.95 (t, 1H),
6.85-7.0 (m, 2H), 3.75 (s, 3H), 3.2 (broad, 4H), 3.05 (broad, 4H),
2.25 (s, 3H).
Example 86
N-(3-Difluoromethoxy-4-methyoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide hydrochloride
##STR00104##
[0535] ESI-MS: 443.2 [M+H].sup.+
[0536] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 11.3 (very
broad, 1H), 10.15 (s, 1H), 7.4 (s, 1H), 7.3 (m, 2H), 7.05 (d, 1H),
6.95 (m, 2H), 6.95 (t, 1H), 3.7 (s, 3H), 3.05-3.5 (broad, 8H), 2.8
(s, 3H), 2.25 (s, 3H).
Example 87
N-(4-Difluoromethoxy-3-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-
-benzenesulfonamide hydrochloride
##STR00105##
[0538] ESI-MS: 427.1 [M+H].sup.+
[0539] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.3 (s
broad, 1H), 7.3-7.4 (m, 3H), 7.15 (d, 1H), 7.0 (t, 1H), 6.95 (s,
1H), 6.88 (m, 1H), 3.4 (broad, 4H), 3.1 (broad, 4H), 2.8 (s, 3H),
2.25 (s, 3H), 2.1 (s, 3H).
Example 88
N-(4-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenes-
ulfonamide hydrochloride
##STR00106##
[0541] ESI-MS: 413.2 [M+H].sup.+
[0542] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.25 (s
broad, 1H), 7.3-7.4 (m, 3H), 7.1 (dd, 2H), 7.05 (dd, 2H), 7.05 (t,
1H), 3.4 (broad, 4H), 3.1 (broad, 4H), 2.75 (s, 3H), 2.3 (s,
3H).
Example 89
N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl-
)-benzenesulfonamide hydrochloride
##STR00107##
[0544] ESI-MS: 442.2 [M+H].sup.+
[0545] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.2 (s
broad, 1H), 7.4 (d, 1H), 7.3 (s, 2H), 7.15 (d, 1H), 7.08 (m, 1H),
7.03 (t, 1H), 6.95 (s, 1H), 6.9 (d, 1H), 3.8 (s, 3H), 3.0-3.6
(broad, 8H), 2.8 (s, 3H), 2.1 (s, 3H).
Example 90
N-(4-Difluoromethoxy-3-methoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-y-
l)-benzenesulfonamide
##STR00108##
[0547] ESI-MS: 458.1 [M+H].sup.+
[0548] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 7.42 (d,
1H), 7.27 (s, 1H), 7.05 (m, 2H), 6.9 (d, 1H), 6.9 (t, 1H), 6.7 (d,
1H), 3.8 (s, 3H), 3.7 (s, 3H), 3.1 (broad, 4H), 2.9 (broad, 4H),
2.5 (s, 3H).
Example 91
N-(2-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-
-benzenesulfonamide hydrochloride
##STR00109##
[0550] ESI-MS: 427.1 [M+H].sup.+
[0551] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 11.3
(broad, 1H), 9.7 (s broad, 1H), 7.4 (s, 1H), 7.25-7.35 (m, 2H), 7.1
(d, 1H), 6.97 (d, 1H), 6.95 (s, 1H), 6.9 (t, 1H), 3.0-3.5 (broad,
8H), 2.8 (s, 3H), 2.3 (s, 3H), 2.25 (s, 3H).
Example 92
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-
-benzenesulfonamide hydrochloride
##STR00110##
[0553] ESI-MS: 427.5 [M+H].sup.+
[0554] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 11.3
(broad, 1H), 9.8 (s broad, 1H), 7.4 (s, 1H), 7.32 (s, 2H), 7.1 (s,
1H), 7.0 (m, 2H), 6.85 (t, 1H), 6.9 (t, 1H), 3.0-3.5 (broad, 8H),
2.8 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H).
Example 93
N-(4-Difluoromethoxy-3-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenes-
ulfonamide hydrochloride
##STR00111##
[0556] ESI-MS: 444.1 [M+H].sup.+
[0557] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 8.4
(broad, 1H), 7.42 (m, 1H), 7.24 (s, 1H), 7.0-7.15 (m, 2H), 6.85-7.0
(m, 2H), 6.7 (m, 1H), 3.8 (s, 3H), 3.7 (s, 3H), 3.0 (broad,
8H).
Example 94
N-(3-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenes-
ulfonamide hydrochloride
##STR00112##
[0559] ESI-MS: 412.1 [M+H].sup.+
[0560] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.5 (s
broad, 1H), 7.2-7.4 (several m, 3H), 7.15 (t, 1H), 7.0 (d, 1H),
6.92 (s, 1H), 6.82 (d, 1H), 3.0-3.5 (broad, 8H), 2.8 (s, 3H), 2.25
(s, 3H).
Example 95
N-(4-Difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzene-
sulfonamide hydrochloride
##STR00113##
[0562] ESI-MS: 428.1 [M+H].sup.+
[0563] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 11.3
(broad, 1H), 10.2 (s, 1H), 7.38 (d, 1H), 7.3 (s, 1H), 7.15 (dd,
2H), 7.07 (m, 3H), 7.1 (t, 1H), 3.8 (s, 3H), 3.4 (broad, 4H), 3.1
(broad, 4H), 2.8 (s, 3H).
Example 96
3-[1,4]Diazepan-1-yl-N-(3-difluoromethoxy-phenyl)-4-methyl-benzenesulfonam-
ide hydrochloride
##STR00114##
[0565] ESI-MS: 412.1 [M+H].sup.+
[0566] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.53 (s,
1H), 9.55 (s, 2H), 7.45 (s, 1H), 7.2-7.4 (m, 3H), 7.15 (t, 1H), 7.0
(d, 1H), 6.95 (s, 1H), 6.8 (d, 1H), 3.25 (broad, 6H), 3.05 (m, 2H),
2.25 (s, 3H), 2.05 (broad, 2H).
Example 97
3-[1,4]Diazepan-1-yl-N-(2-difluoromethoxy-phenyl)-4-methyl-benzenesulfonam-
ide hydrochloride
##STR00115##
[0568] ESI-MS: 412.1 [M+H].sup.+
[0569] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.8 (s,
1H), 9.4 (s, 2H), 7.4 (s, 1H), 7.2-7.35 (m, 3H), 7.1-7.2 (m, 3H),
6.9 (t, 1H), 3.25 (broad, 6H), 3.05 (m, 2H), 2.3 (s, 3H), 2.05
(broad, 2H).
Example 98
3-[1,4]Diazepan-1-yl-N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-benzen-
esulfonamide hydrochloride
##STR00116##
[0571] ESI-MS: 426.1 [M+H].sup.+
[0572] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 10.3 (s,
1H), 9.45 (s, 2H), 7.4 (s, 1H), 7.3 (s, 2H), 7.15 (d, 1H), 7.05 (t,
1H), 6.95 (s, 1H), 6.87 (d, 1H), 3.25 (broad, 6H), 3.05 (m, 2H),
2.3 (s, 3H), 2.1 (s, 3H), 2.05 (broad, 2H).
Example 99
N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-
-yl)-benzenesulfonamide hydrochloride
##STR00117##
[0574] ESI-MS: 440.2 [M+H].sup.+
Example 100
N-(2-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benz-
enesulfonamide hydrochloride
##STR00118##
[0576] ESI-MS: 426.1 [M+H].sup.+
[0577] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 9.5-11.0
(very broad, 2H), 7.4 (s, 1H), 7.2-7.35 (m, 3H), 7.1-7.2 (m, 3H),
6.93 (t, 1H), 3.4 (broad, 6H), 3.05 (m, 2H), 2.8 (s, 3H), 2.3 (s,
3H), 2.15 (broad, 2H).
Example 101
N-(3-Difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benz-
enesulfonamide hydrochloride
##STR00119##
[0579] ESI-MS: 426.2 [M+H].sup.+
Example 102
N-(5-Difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-3-piperazin-1-yl
benzenesulfonamide
##STR00120##
[0580] Example 103
N-(5-Difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-N-methyl-3-piperazi-
n-1-yl benzenesulfonamide
##STR00121##
[0581] Example 104
N-(5-Difluoromethoxy-2-methylphenyl)-4-fluoro-3-piperazin-1-yl
benzenesulfonamide
##STR00122##
[0582] Example 105
N-(5-Difluoromethoxy-2-methylphenyl)-4-fluoro-N-methyl-3-piperazin-1-yl
benzenesulfonamide
##STR00123##
[0583] Example 106
N-(2-Difluoromethoxy-4-methylphenyl)-4-ethoxy-3-piperazin-1-yl
benzenesulfonamide
##STR00124##
[0585] ESI-MS: 442.1 [M+H].sup.+
[0586] .sup.1H-NMR (DMSO-d.sub.6, 400 Hz): .delta. [ppm] 7.3 (d,
1H), 7.25 (s, 1H), 7.15 (d, 1H), 7.0 (m, 1H), 6.95 (m, 2H), 6.9 (t,
1H), 4.07 (q, 2H), 3.15 (b, 4H), 3.11 (b, 4H), 2.2 (s, 3H), 1.35
(t, 3H).
III. Biological Investigations
[0587] Displacement of Radioligands Binding to the Following Cloned
Human Receptors
[0588] 1. Preparation of Membranes by Ultrasonic Treatment and
Differential Centrifugation
[0589] Cells from stable clonal cell lines expressing the
corresponding receptor (5-HT.sub.6, .alpha..sub.1-adrenergic,
dopamine D.sub.2 or histamine H.sub.1 receptors) were washed with
PBS (w/o Ca.sup.++, Mg.sup.++) and harvested in PBS with 0.02%
EDTA. The cells were collected by centrifugation at 500 g for 10
min. at 4.degree. C., washed with PBS and centrifuged (500 g, 10
min. 4.degree. C.). The pellets were stored at -80.degree. C. until
use. For membrane preparation, the thawed cell pellet was
resuspended in ice-cold sucrose buffer (0.25 M sucrose, 10 mM Hepes
(pH 7.4), 1 mM Phenylmethylsulfonyl fluoride (PMSF) in DMSO, 5
.mu.g/ml Pepstatin-A, 3 mM EDTA, 0.025% Bacitracin) and homogenized
with a Branson Sonifier W-250 (Settings: Timer 4; Output Control 3;
Duty Cycle constant; 2 to 3 cycles). Cell disruption was checked
with the aid of a microscope. Remaining unbroken cells were
pelleted at 1.000 g for 10 min. at 4.degree. C. The sucrose buffer
supernatant was then centrifuged at 60.000 g for 1 h at 4.degree.
C. (Beckman Ultrazentrifuge XL 80). The pellet was resuspended in
30 ml ice-cold Tris buffer (20 mM TRIS (pH 7.4), 5 .mu.g/ml
Pepstatin A, 0.1 mM PMSF, 3 mM EDTA) by pipetting through a 10 ml
serological pipet and centrifuged for 1 h at 4.degree. C. at 60.000
g. A final resuspension was performed in a small volume of ice-cold
Tris buffer (see above) by pressing through a serological pipet
followed by ultrasonic treatment with a Branson Sonifier W-250
(Settings: Timer 1; Output Control 3; Duty Cycle constant; 1
cycle). Protein concentration was determined (BCA-Kit; Pierce) and
aliquots stored at -80.degree. C. or in liquid nitrogen for
long-term storage.
[0590] 2. Receptor Binding Experiments
[0591] All receptor binding experiments were carried out in the
corresponding assay buffer in a total volume of 200 .mu.l in the
presence of various concentrations of test compound (10.sup.-5 M to
10.sup.-9 M, tenfold serial dilution, duplicate determinations).
The assays were terminated by filtration on polyethylenimine (PEI
0.1% or 0.3%) presoaked Packard Unifilter Plates (GF/C or GF/B)
with a Tomtec Machin U 96 well-plate harvester. After the plates
had been dried for 2 h at 55.degree. C. in a drying chamber
scintillation cocktail (BetaPlate Scint; PerkinElmer) was added.
Radioactivity was measured in a Microbeta Trilux two hours after
the addition of the scintillation mixture. Data derived from liquid
scintillation counting were analysed by iterative non-linear
regression analysis with the use of the Statistical Analysis System
(SAS): a program similar to "LIGAND" as described by Munson and
Rodbard (Analytical Biochemistry 107, 220-239 (1980).
[0592] a) 5-HT.sub.6 Receptor Binding Assay
[0593] HEK293 cells stably expressing the h-5-HT.sub.6 receptor
(NCBI Reference Sequence XM 001435) were cultured in RPMI1640
medium supplemented with 25 mM HEPES, 10% fetal calf serum and 1-2
mM glutamine. The membrane preparation was performed as described
in section 1. For these membranes a K.sub.D of 1.95 nM for
[.sup.3H]-LSD (Lysergic Acid Diethylamide; Amersham, TRK1038) was
determined by means of saturation binding experiments. On the day
of the assay, the membranes were thawed, diluted in assay buffer
(50 mM Tris-HCl, 5 mM CaCl.sub.2, 0.1% ascorbic acid, 10 .mu.M
pargyline, pH 7.4) to a concentration of 8 .mu.g protein/assay and
homogenized by gentle vortexing For inhibition studies, 1 nM
[.sup.3H]-Lysergic Acid Diethylamide was incubated in the presence
of various concentrations of test compound in assay buffer.
Non-specific binding was defined with 1 .mu.M methiothepin. The
binding reaction was carried out for 3.5 h at room temperature.
During the incubation, the plates were shaken on a plate shaker at
100 rpm and terminated by filtration on Packard Unifilter GF/C
(0.1% PEI) plates, followed by 2 wash cycles with ice-cold 50 mM
Tris-HCl, 5 mM CaCl.sub.2.
[0594] a) Dopamine D.sub.2 Receptor Binding Assay
[0595] HEK293 cells stably expressing the dopamine D.sub.2 receptor
(NCBI Reference Sequence NM.sub.--000795) were cultured in RPMI1640
medium supplemented with 25 mM HEPES, 10% fetal calf serum and 1-2
mM glutamine. The membrane preparation was performed as described
in section 1. For these membranes a K.sub.D of 0.22 nM for
[.sup.125I]-iodospiperone (PerkinElmer Life Sciences, NEX284) was
determined by means of saturation binding experiments. On the day
of the assay, the membranes were thawed, diluted in assay buffer
(50 mM Tris-HCl, 120 mM NaCl, 5 mM MgCl.sub.2, 5 mM KCl, 1.5 mM
CaCl.sub.2, pH 7.4) to a concentration of 15 .mu.g protein/assay
and homogenized by gentle vortexing. For inhibition studies, 0.01
nM [.sup.125I]-iodospiperone (PerkinElmer Life Sciences, NEX284)
was incubated in the presence of various concentrations of test
compound in assay buffer. Non-specific binding was defined with 1
.mu.M haloperidol. The binding reaction was carried out for 1 h at
room temperature and terminated by filtration on Packard Unifilter
GF/B (0.1% PEI) plates, followed by 6 wash cycles with an ice-cold
7% polyethylenglycol solution.
[0596] b) .alpha..sub.1-Adrenergic Receptor Binding Assay
[0597] CHO-K.sub.1 cells stably expressing the
.alpha..sub.1-adrenergic receptor (NCBI Reference Sequence
NM.sub.--033303) were cultured in RPMI1640 medium supplemented with
25 mM HEPES, 10% fetal calf serum and 1-2 mM glutamine. The
membrane preparation was performed as described in section 1. For
these membranes a K.sub.D of 0.12 nM for [.sup.3H]-prazosine
(PerkinElmer Life Sciences, NET823) was determined by means of
saturation binding experiments. On the day of the assay, the
membranes were thawed, diluted in assay buffer (50 mM Tris-HCl, pH
7.4) to a concentration of 4 .mu.g protein/assay and homogenized by
gentle vortexing. For inhibition studies, 0.1 nM
[.sup.3H]-prazosine (PerkinElmer Life Sciences, NET823) was
incubated in the presence of various concentrations of test
compound in assay buffer. Non-specific binding was defined with 1
.mu.M phentolamine. The binding reaction was carried out for 1 h at
room temperature and terminated by filtration on Packard Unifilter
GF/C (0.1% PEI) plates, followed by 3 wash cycles with ice-cold
assay buffer.
[0598] c) H.sub.1 Receptor Binding Assay
[0599] CHO-K.sub.1 cells stably expressing the histamine H.sub.1
receptor (Euroscreen-ES-390-C, NCBI Reference Sequence
NM.sub.--000861) were cultured in RPMI1640 medium supplemented with
25 mM HEPES, 10% fetal calf serum and 1-2 mM glutamine. The
membrane preparation was performed as described in section 1. For
these membranes a K.sub.D of 0.83 nM for [.sup.3H]-pyrilamine
(PerkinElmer Life Sciences, NET594) was determined by means of
saturation binding experiments. On the day of the assay, the
membranes were thawed, diluted in assay buffer (50 mM
Na.sub.2HPO.sub.4, 50 mM KH.sub.2PO.sub.4, pH 7.4) to a
concentration of 6 .mu.g protein/assay and homogenized by gentle
vortexing. For inhibition studies, 1 nM [.sup.3H]-pyrilamine
(PerkinElmer Life Sciences, NET594) was incubated in the presence
of various concentrations of test compound in assay buffer.
Non-specific binding was defined with 1 .mu.M pyrilamine. The
binding reaction was carried out for 50 minutes at room temperature
and terminated by filtration on Packard Unifilter GF/C (0.3% PEI)
plates, followed by 2 wash cycles with ice-cold assay buffer.
[0600] 3. Data Analysis
[0601] Data derived from liquid scintillation counting were
analyzed by iterative non-linear regression analysis with the use
of the Statistical Analysis System (SAS): a program similar to
"LIGAND" as described by Munson and Rodbard (Anal. Biochem. 1980,
107, 220-239). Fitting was performed according to formulae
described by Feldman (Anal. Biochem. 1972, 48, 317-338). IC.sub.50,
nH and K.sub.i values were expressed as geometrical mean. For
receptors with a low affinity for the test compound, where the
highest tested compound concentration inhibited less than 30% of
specific radioligand binding, K.sub.i-values were determined
according to the equation of Cheng and Prusoff (Biochem. Pharmacol.
1973, 22, 2099-2108) and expressed as greater than (>).
[0602] The results of the receptor binding studies are expressed as
receptor binding constants K.sub.i(5-HT.sub.6), K.sub.i(D.sub.2),
K.sub.i(.alpha..sub.1-adrenergic) and K.sub.i(H.sub.1),
respectively, as described herein before, and given in table I.
[0603] In these tests, the compounds according to the invention
exhibit very good affinities for the 5-HT.sub.6 receptor
(K.sub.1<500 nM or <100 nM or <50 nM or <20 nM and
frequently <10 nM). Furthermore those compounds bind selectively
to the 5-HT.sub.6 receptor, as compared to the affinity for the
D.sub.2, the .alpha..sub.1-adrenergic or the H.sub.1 receptors.
These compounds exhibit little affinities for the D.sub.2,
.alpha..sub.1-adrenergic or H.sub.1 receptors (K.sub.i>500 nM or
>1000 nM and frequently >10000 nM).
[0604] Example 1: Ki (5HT.sub.6)<10 nM
[0605] Example 5: Ki (5HT.sub.6)<50 nM
[0606] Example 6: Ki (5HT.sub.6)<50 nM
[0607] Example 7: Ki (5HT.sub.6)<50 nM
[0608] Example 8: Ki (5HT.sub.6)<500 nM
[0609] Example 9: Ki (5HT.sub.6)<500 nM
[0610] Example 10: Ki (5HT.sub.6)<50 nM
[0611] Example 11: Ki (5HT.sub.6)<500 nM
[0612] Example 12: Ki (5HT.sub.6)<50 nM
[0613] Example 13: Ki (5HT.sub.6)<50 nM
[0614] Example 14: Ki (5HT.sub.6)<100 nM
[0615] Example 15: Ki (5HT.sub.6)<500 nM
[0616] Example 16: Ki (5HT.sub.6)<500 nM
[0617] Example 17: Ki (5HT.sub.6)<10 nM
[0618] Example 18: Ki (5HT.sub.6)<10 nM
[0619] Example 24: Ki (5HT.sub.6)<10 nM
[0620] Example 25: Ki (5HT.sub.6)<10 nM
[0621] Example 26: Ki (5HT.sub.6)<10 nM
[0622] Example 27: Ki (5HT.sub.6)<50 nM
[0623] Example 28: Ki (5HT.sub.6)<50 nM
[0624] Example 29: Ki (5HT.sub.6)<10 nM
[0625] Example 30: Ki (5HT.sub.6)<10 nM
[0626] Example 31: Ki (5HT.sub.6)<50 nM
[0627] Example 32: Ki (5HT.sub.6)<10 nM
[0628] Example 33: Ki (5HT.sub.6)<10 nM
[0629] Example 34: Ki (5HT.sub.6)<10 nM
[0630] Example 35: Ki (5HT.sub.6)<10 nM
[0631] Example 36: Ki (5HT.sub.6)<10 nM
[0632] Example 37: Ki (5HT.sub.6)<10 nM
[0633] Example 38: Ki (5HT.sub.6)<10 nM
[0634] Example 39: Ki (5HT.sub.6)<500 nM
[0635] Example 40: Ki (5HT.sub.6)<50 nM
[0636] Example 41: Ki (5HT.sub.6)<10 nM
[0637] Example 42: Ki (5HT.sub.6)<10 nM
[0638] Example 43: Ki (5HT.sub.6)<500 nM
[0639] Example 45: Ki (5HT.sub.6)<10 nM
[0640] Example 46: Ki (5HT.sub.6)<10 nM
[0641] Example 47: Ki (5HT.sub.6)<10 nM
[0642] Example 48: Ki (5HT.sub.6)<10 nM
[0643] Example 49: Ki (5HT.sub.6)<10 nM
[0644] Example 51: Ki (5HT.sub.6)<10 nM
[0645] Example 52: Ki (5HT.sub.6)<50 nM
[0646] Example 53: Ki (5HT.sub.6)<10 nM
[0647] Example 54: Ki (5HT.sub.6)<10 nM
[0648] Example 55: Ki (5HT.sub.6)<10 nM
[0649] Example 56: Ki (5HT.sub.6)<50 nM
[0650] Example 57: Ki (5HT.sub.6)<10 nM
[0651] Example 58: Ki (5HT.sub.6)<10 nM
[0652] Example 59: Ki (5HT.sub.6)<10 nM
[0653] Example 60: Ki (5HT.sub.6)<10 nM
[0654] Example 61: Ki (5HT.sub.6)<10 nM
[0655] Example 62: Ki (5HT.sub.6)<10 nM
[0656] Example 63: Ki (5HT.sub.6)<10 nM
[0657] Example 64: Ki (5HT.sub.6)<10 nM
[0658] Example 65: Ki (5HT.sub.6)<10 nM
[0659] Example 66: Ki (5HT.sub.6)<10 nM
[0660] Example 67: Ki (5HT.sub.6)<10 nM
[0661] Example 68: Ki (5HT.sub.6)<10 nM
[0662] Example 69: Ki (5HT.sub.6)<10 nM
[0663] Example 70: Ki (5HT.sub.6)<10 nM
[0664] Example 71: Ki (5HT.sub.6)<10 nM
[0665] Example 72: Ki (5HT.sub.6)<10 nM
[0666] Example 73: Ki (5HT.sub.6)<10 nM
[0667] Example 74: Ki (5HT.sub.6)<50 nM
[0668] Example 75: Ki (5HT.sub.6)<50 nM
[0669] Example 76: Ki (5HT.sub.6)<50 nM
[0670] Example 77: Ki (5HT.sub.6)<50 nM
[0671] Example 78: Ki (5HT.sub.6)<50 nM
[0672] Example 79: Ki (5HT.sub.6)<50 nM
[0673] Example 80: Ki (5HT.sub.6)<50 nM
[0674] Example 81: Ki (5HT.sub.6)<50 nM
[0675] Example 82: Ki (5HT.sub.6)<10 nM
[0676] Example 83: Ki (5HT.sub.6)<10 nM
[0677] Example 84: Ki (5HT.sub.6)<50 nM
[0678] Example 85: Ki (5HT.sub.6)<500 nM
[0679] Example 86: Ki (5HT.sub.6)<500 nM
[0680] Example 87: Ki (5HT.sub.6)<50 nM
[0681] Example 88: Ki (5HT.sub.6)<500 nM
[0682] Example 89: Ki (5HT.sub.6)<10 nM
[0683] Example 90: Ki (5HT.sub.6)<50 nM
[0684] Example 91: Ki (5HT.sub.6)<50 nM
[0685] Example 92: Ki (5HT.sub.6)<10 nM
[0686] Example 93: Ki (5HT.sub.6)<10 nM
[0687] Example 94: Ki (5HT.sub.6)<10 nM
[0688] Example 95: Ki (5HT.sub.6)<10 nM
[0689] Example 96: Ki (5HT.sub.6)<50 nM
[0690] Example 97: Ki (5HT.sub.6)<10 nM
[0691] Example 98: Ki (5HT.sub.6)<50 nM
[0692] Example 99: Ki (5HT.sub.6)<500 nM
[0693] Example 100: Ki (5HT.sub.6)<10 nM
[0694] Example 101: Ki (5HT.sub.6)<10 nM
[0695] Example 106: Ki (5HT.sub.6)<10 nM
[0696] 3. Determination of the Metabolic Stability
[0697] The metabolic stability of the compounds of the invention
was determined in the following assay by analyzing the microsomal
half-life. The test substances are incubated in a concentration of
0.5 .mu.M as follows:
[0698] 0.5 .mu.M test substance is preincubated together with liver
microsomes of various species (0.25 mg of protein/ml) in 0.05M
potassium phosphate buffer pH 7.4 in microtiter plates at
37.degree. C. for 5 min. The reaction is started by adding NADPH (1
mg/mL). Aliquots are taken after 0, 5, 10, 15, 20 and 30 min, and
the reaction is stopped with the same volume of acetonitrile and
cooled down. The remaining test compound concentrations are being
determined by liquid chromatography--mass spectrometry analysis.
Intrinsic clearance values are calculated using the elimination
rate constant of test compound depletion.
* * * * *
References