U.S. patent application number 11/509989 was filed with the patent office on 2007-03-22 for new compounds.
This patent application is currently assigned to Biovitrum AB, a Sweden corporation. Invention is credited to Gary Johansson, Andrew Mott.
Application Number | 20070066599 11/509989 |
Document ID | / |
Family ID | 27354709 |
Filed Date | 2007-03-22 |
United States Patent
Application |
20070066599 |
Kind Code |
A1 |
Johansson; Gary ; et
al. |
March 22, 2007 |
New compounds
Abstract
The present invention relates to substituted sulfonamide
compounds of the general formula (I), wherein P is sulfonamide or
amide-substituted sulfonic acid, which compounds are potentially
useful for the prophylaxis and treatment of medical conditions
relating to obesity, type II diabetes and/or disorders of the
central nervous system. ##STR1##
Inventors: |
Johansson; Gary; (Uppsala,
SE) ; Mott; Andrew; (Knivsta, SE) |
Correspondence
Address: |
FISH & RICHARDSON PC
P.O. BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Assignee: |
Biovitrum AB, a Sweden
corporation
|
Family ID: |
27354709 |
Appl. No.: |
11/509989 |
Filed: |
August 25, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10167141 |
Jun 11, 2002 |
7144883 |
|
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11509989 |
Aug 25, 2006 |
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Current U.S.
Class: |
514/218 ;
514/253.04; 514/253.05; 514/253.06; 514/255.03; 514/300; 514/319;
540/575; 544/362; 544/363; 544/392; 546/122; 546/148; 546/159;
546/203 |
Current CPC
Class: |
C07D 487/04 20130101;
C07D 241/04 20130101; C07D 307/78 20130101; A61P 25/24 20180101;
C07D 215/38 20130101; C07D 471/04 20130101; A61P 7/00 20180101;
A61P 43/00 20180101; A61P 3/04 20180101; A61K 31/4965 20130101;
C07D 319/18 20130101; C07D 333/34 20130101; C07D 487/08 20130101;
C07D 217/22 20130101; A61P 3/10 20180101; A61P 25/30 20180101; A61P
25/14 20180101; A61P 25/16 20180101; A61P 25/06 20180101; A61P
25/20 20180101; C07D 243/08 20130101; C07D 307/79 20130101; A61P
25/22 20180101; A61P 25/28 20180101; C07D 409/12 20130101; A61P
25/18 20180101; C07D 295/096 20130101; C07D 413/12 20130101; A61K
31/495 20130101; C07D 295/135 20130101; C07D 215/40 20130101; A61P
25/00 20180101 |
Class at
Publication: |
514/218 ;
514/253.04; 514/255.03; 514/300; 514/319; 514/253.06; 514/253.05;
540/575; 544/362; 544/363; 544/392; 546/122; 546/159; 546/148;
546/203 |
International
Class: |
A61K 31/551 20060101
A61K031/551; A61K 31/496 20060101 A61K031/496; A61K 31/495 20060101
A61K031/495; A61K 31/4745 20060101 A61K031/4745; A61K 31/4709
20060101 A61K031/4709; A61K 31/445 20060101 A61K031/445; C07D
471/02 20060101 C07D471/02; C07D 403/02 20060101 C07D403/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 11, 2001 |
SE |
0102048-6 |
Jul 3, 2001 |
SE |
0102386-0 |
Oct 16, 2001 |
SE |
0103437-0 |
Claims
1. A compound of the formula III: ##STR360## or a pharmaceutically
acceptable salt thereof, wherein: P is ##STR361## P and R.sup.3 are
bound to the same ring and are disposed in meta- or para-positions
relative to each other; R.sup.1 is (a) C.sub.1-6 alkyl, (b)
C.sub.1-6 alkoxyalkyl, (c) straight or branched C.sub.1-6
hydroxyalkyl, (d) straight or branched C.sub.1-6 alkylhalides; or
(e) a group Ar; Ar is (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl,
(d) benzyl, (e) cinnamoyl, (f) a 5 to 7-membered, optionally
aromatic, partially saturated or completely saturated, heterocyclic
ring, containing 1 to 4 heteroatoms, selected from oxygen, nitrogen
and sulfur, or (g) a bicyclic ring system comprising at least one
heterocyclic ring according to (f). wherein the group Ar is
substituted in one or more positions with (a) H, X or Y, or (b) a 5
to 7-membered, optionally aromatic, partially saturated or
completely saturated, heterocyclic ring each containing 1 to 4
heteroatoms selected from oxygen, nitrogen or sulfur; R.sup.2 is
(a) H, (b) C.sub.1-6 alkyl, (c) C.sub.1-6 alkoxy, (d) straight or
branched C.sub.1-6 hydroxyalkyl, or (e) straight or branched
C.sub.1-6 alkylhalides; or R.sup.1 and R.sup.2 are linked to form a
group (CH.sub.2).sub.4O; One of R.sup.3 is a group ##STR362## X and
Y are independently (a) H, (b) halogen, (c) C.sub.1-6 alkyl, (d)
--CF.sub.3, (e) hydroxy, (f) C.sub.1-6 alkoxy, (g) C.sub.1-4
alkenyl; (h) phenyl; (i) phenoxy, (j) benzyloxy, (k) benzoyl, (l)
--OCF.sub.3, (m) --CN, (n) straight or branched C.sub.1-6
hydroxyalkyl, (o) straight or branched C.sub.1-6 alkylhalides, (p)
--NH.sub.2, (q) --NHR.sup.4, (r) --NR.sup.4R.sup.5, (s) --NO.sub.2,
(t) --CONR.sup.4R.sup.5, (u) --NHSO.sub.2R.sup.4, (v)
--NR.sup.4COR.sup.5, (x) --SO.sub.2NR.sup.4R.sup.5, (z)
--C(.dbd.O)R.sup.4, (aa) --CO.sub.2R.sup.4, (ab)
--S(O).sub.nR.sup.4; wherein n is 0, 1, 2 or 3; (ac)
--S--(C.sub.1-6)alkyl, or (ad) --SCF.sub.3; R.sup.4 and R.sup.5 are
independently (a) H, (b) C.sub.1-6 alkyl, (c) C.sub.3-7 cycloalkyl,
or (d) Ar, as defined above for R.sup.1; alternatively, R.sup.4 and
R.sup.5 are linked to form a group (CH.sub.2).sub.2O,
(CH.sub.2).sub.4O or (CH.sub.2).sub.3-5; and R.sup.6 is (a) H, or
(b) straight of branched C.sub.1-6 alkyl.
2-6. (canceled)
7. The compound according to claim 1, wherein R.sup.1 is (a)
C.sub.1-6 alkyl, or (e) a group Ar; Ar is (a) phenyl, (b)
1-naphthyl, (c) 2-naphthyl, or (f) a 5 to 7-membered, optionally
aromatic, partially saturated or completely saturated, heterocyclic
ring containing 1 to 4 heteroatoms, selected from oxygen, nitrogen
and sulfur; wherein the group Ar is substituted in one or more
positions with X or Y; wherein X or Y is (a) H, (b) halogen, (c)
C.sub.1-6 alkyl, (d) --CF.sub.3, (f) C.sub.1-6 alkoxy, (g)
C.sub.1-4 alkenyl; (l) --OCF.sub.3, or (n) straight or branched
C.sub.1-6 hydroxyalkyl. R.sup.2 is (a) H, or (b) C.sub.1-3 alkyl,
in particular methyl; or R.sup.1 and R.sup.2 are linked to form a
group (CH.sub.2).sub.4O; and R.sup.3 is ##STR363## wherein R.sup.6
is (a) H, or (b) C.sub.1-6 alkyl, in particular methyl
8. (canceled)
9. The compound according to claim 1, wherein the compound is
selected from the group consisting of:
N-[1-(4-Methyl-1-piperazinyl)-3-isoquinolinyl]benzenesulfonamide,
hydrochloride;
2,4-di-Fluoro-N-[1-(4-methyl-1-piperazinyl)-3-isoquinolinyl]benzenesulfon-
amide, hydrochloride;
4-Bromo-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonami-
de, hydrochloride; 5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic
acid[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide,
hydrochloride;
3-Chloro-2-methyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzen-
esulfonamide, hydrochloride;
3,4-Dichloro-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulf-
onamide, hydrochloride;
4-Methyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonam-
ide, hydrochloride;
3-Methoxy-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfona-
mide, hydrochloride; 5-Chloro-thiophene-2-sulfonic
acid[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide,
hydrochloride;
N-{2-Chloro-4-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-ylsulfamoyl]-phe-
nyl}-acetamide hydrochloride; 2,5-Dichloro-thiophene-3-sulfonic
acid[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide,
hydrochloride;
N-[1-(4-Methyl-piperazin-1-yl)-isoquinolin-3-yl]-3-trifluoromethyl-benzen-
esulfonamide, hydrochloride;
N-[1-(4-Methyl-piperazin-1-yl)-isoquinolin-3-yl]-4-phenoxy-benzenesulfona-
mide, hydrochloride;
5-Bromo-2-methoxy-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzen-
esulfonamide, hydrochloride;
2-Methanesulphonayl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benz-
enesulfonamide, hydrochloride; 3,5-Dimethyl-isoxazole-4-sulfonic
acid[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide,
hydrochloride;
2,4,6-Trimethyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenes-
ulfonamide, hydrochloride; and
3,4-Dimethoxy-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesul-
fonamide, hydrochloride.
10-12. (canceled)
13. A process for the preparation of a compound according to claim
1, wherein P is ##STR364## said method comprising the steps of: (a)
nucleophilic aromatic substitution of the aromatic halogen atom in
1-chloro-3-nitronaphthalene or 1-chloro-4-nitronaphthalene with
aliphatic or aromatic diamines; (b) reduction of the nitro group in
1-diamine-3-nitronaphthalene or 1-diamine-4-nitronaphthalene
obtained in step (a) to form 1-diamine-3-NH.sub.2-naphthalene or
1-diamine-4-NH.sub.2-naphthalene, respectively; and (c) synthesis
of a sulfonamide by reacting 1-diamine-3-NH.sub.2-naphthalene or
1-diamine-4-NH.sub.2-naphthalene obtained in step (b) with a
suitable sulfonyl chloride.
14. The process of claim 13, wherein step (a) is by means of
Palladium catalyzed nucleophilic substitution.
15. A process for the preparation of a compound according to claim
1, wherein P is ##STR365## said method comprising the steps of: (a)
nucleophilic aromatic substitution of the trifluoromethanesulfonate
group in 2-trifluoromethansulfonate-5-nitroquinoline with aliphatic
or aromatic diamines; (b) reduction of the nitro group in
2-diamine-5-nitroquinoline obtained in step (a) to form
2-diamine-5-NH.sub.2-quinoline; and (c) synthesis of a sulfonamide
by reacting 2-diamine-5-NH.sub.2-quinoline obtained in step (b)
with a suitable sulfonyl chloride.
16. A process for the preparation of a compound according to claim
1, wherein P is ##STR366## said method comprising the steps of: (a)
reacting a fluoronaphthalene and chlorosulfonic acid under acidic
conditions, to introduce a sulfonyl chloride group in the para
position to the carbon having the fluoro atom; (b) reacting the
product of step (a) with an aliphatic or aromatic primary amine to
give a sulphonamide; and (c) reaction of the product of step (b)
with a diamine.
17. A pharmaceutical formulation containing a compound according to
claim 1 as active ingredient, in combination with a
pharmaceutically acceptable diluent or carrier.
18. A method for the treatment or prophylaxis of obesity, type II
diabetes, and/or disorders of the central nervous system, which
comprises administering to a mammalin need of such treatment an
effective amount of a compound according to claim 1.
19. A method for reducing body-weight or reducing food intake,
comprising administering to a subject in need thereof an effective
amount of a compound according to claim 1.
20. A method for modulating 5-HT.sub.6 receptor activity,
comprising administering to a subject in need thereof an effective
amount of a compound according to claim 1.
Description
RELATED APPLICATIONS
[0001] This application claims priority to Swedish application
number 0102048-6, filed on Jun. 11, 2001, Swedish application
number 0102386-0, filed on Jul. 3, 2001, and Swedish application
number 0103437-0, filed on Oct. 16, 2001, the contents of which are
incorporated herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to substituted sulfonamide
compounds, to pharmaceutical compositions comprising these
compounds, and to the use of the compounds for the prophylaxis and
treatment of medical conditions relating to obesity, type II
diabetes, and CNS disorders.
BACKGROUND ART
[0003] Obesity is a condition characterized by an increase in body
fat content resulting in excess body weight above accepted norms.
Obesity is the most important nutritional disorder in the western
world and represents a major health problem in all industrialized
countries. This disorder leads to increased mortality due to
increased incidences of diseases such as cardiovascular disease,
digestive disease, respiratory disease, cancer and type II
diabetes. Searching for compounds, which reduce body weight has
been going on for many decades. One line of research has been
activation of serotoninergic systems, either by direct activation
of serotonin receptor subtypes or by inhibiting serotonin reuptake.
The exact receptor subtype profile required is however not
known.
[0004] Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter
of the peripheral and central nervous system, modulates a wide
range of physiological and pathological functions, including
anxiety, sleep regulation, aggression, feeding and depression.
Multiple serotonin receptor subtypes have been identified and
cloned. One of these, the 5-HT.sub.6 receptor, was cloned by
several groups in 1993 (Ruat, M. et al. (1993) Biochem. Biophys.
Res. Commun. 193: 268-276; Sebben, M. et al. (1994) NeuroReport 5:
2553-2557). This receptor is positively coupled to adenylyl cyclase
and displays affinity for antidepressants such as clozapine.
Recently, the effect of 5-HT.sub.6 antagonist and 5-HT.sub.6
antisense oligonucleotides to reduce food intake in rats has been
reported (Bentley, J. C. et al. (1999) Br J Pharmac. Suppl. 126,
P66; Bentley, J. C. et al. (1997) J. Psychopharmacol. Suppl. A64,
255).
[0005] Compounds with enhanced affinity and selectivity for the
5-HT.sub.6 receptor have been identified, e.g. in WO 00/34242 and
by Isaac, M. et al. (2000)
6-Bicyclopiperazinyl-1-arylsulfonylindoles and
6-Bicyclopiperidinyl-1-arylsulfonylindoles derivatives as novel,
potent and selective 5-HT.sub.6 receptor antagonists. Bioorganic
& Medicinal Chemistry Letters 10: 1719-1721 (2000).
INFORMATION DISCLOSURE
[0006] J. Med. Chem. 1970, 13(4), 592-598 describes
N-(4-{[2-(diethylamino)ethyl]amino}-1-naphthyl)amides;
N-{5,6,7,8-Tetrahydro-4-[(3-piperidinopropyl)amino]-1-naphthyl}amides
and related amides and urea derivatives as schistosomicides.
[0007] WO 99/42465 discloses sulphonamides derivatives that bind to
the 5-HT.sub.6 receptor and that can be used for the treatment of
CNS disorders such as anxiety, depression, epilepsy, obsessive
compulsive disorders, cognitive disorders, ADHD, anorexia and
bulimia schizophrenia, drug abuse.
WO 01/32646 A1 discloses compounds that binds to the 5-HT.sub.6
receptor and that are used for the treatment of CNS disorders and
which inter alia may be used for the treatment of eating
disorders.
WO 99/37623 A2 discloses compounds that binds to the 5-HT.sub.6
receptor and that are used for the treatment of CNS disorders and
which inter alia may be used for the treatment of eating
disorders.
WO 99/42465 A3 discloses compounds that binds to the 5-HT.sub.6
receptor and that are used for the treatment of CNS disorders and
which inter alia may be used for the treatment of eating
disorders.
EP 0 815 861 A1 discloses compounds that binds to the 5-HT.sub.6
receptor and that are used for the treatment of CNS disorders.
WO 99/02502 A2 discloses compounds that binds to the 5-HT.sub.6
receptor and that are used for the treatment of CNS disorders and
which inter alia may be used for the treatment of eating
disorders.
WO 98/27081 A1 discloses compounds that binds to the 5-HT.sub.6
receptor and that are used for the treatment of CNS disorders and
which inter alia may be used for the treatment of eating
disorders.
DISCLOSURE OF THE INVENTION
[0008] It has surprisingly been found that the compounds of formula
(I) show affinity for the 5-HT.sub.6 receptor as antagonists at low
nanomolar range. Compounds according to the invention and their
pharmaceutically acceptable salts have 5-HT.sub.6 receptor
antagonist activity and are believed to be of potential use in the
treatment or prophylaxis of obesity and type II diabetes, as well
as in the treatment or prophylaxis of disorders of the central
nervous system such as anxiety, depression, panic attacks, memory
disorders, sleep disorders, migraine, anorexia, bulimia, binge
disorders, obsessive compulsive disorders, psychoses, Alzheimer's
disease, Parkinson's disease, Huntington's chorea and/or
schizophrenia, Attention Deficit Hyperactive Disorders (ADHD), drug
abuse.
Definitions
[0009] Unless otherwise stated or indicated, the term "C.sub.1-6
alkyl" denotes a straight or branched alkyl group having from 1 to
6 carbon atoms. Examples of said lower alkyl include methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and
straight- and branched-chain pentyl and hexyl.
[0010] Unless otherwise stated or indicated, the term "C.sub.1-6
alkoxy" denotes a straight or branched alkoxy group having from 1
to 6 carbon atoms. Examples of said lower alkoxy include methoxy,
ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy,
t-butoxy and straight- and branched-chain pentoxy and hexoxy.
[0011] Unless otherwise stated or indicated, the term "halogen"
shall mean fluorine, chlorine, bromine or iodine.
[0012] The term "C.sub.3-7 cycloalkyl" denotes a cyclic alkyl group
having a ring size from C.sub.3 to C.sub.7. Examples of said
cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, methylcyclohexyl and cycloheptyl.
[0013] The term "heterocyclic" refers to a hydrocarbon ring system
containing 4 to 8 ring members that have at least one heteroatom
(e.g., S, N, or O) as part of the ring. It includes saturated,
unsaturated, aromatic, and nonaromatic heterocycles. Suitable
heterocyclic groups include thienyl, furyl, pyridyl, pyrrolidinyl,
imidazolyl, pyrazolyl, piperidyl, azepinyl, morpholinyl, pyranyl,
dioxanyl, pyridazinyl, pyrimidinyl, and piperazinyl groups
[0014] The term "heteroaryl" refers to a hydrocarbon ring system
having at least one aromatic ring which contains at least one
heteroatom such as O, N, or S. Examples of heteroaryl groups
include furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl,
pyridinyl, pyrimidinyl, quinazolinyl, and indolyl groups.
Compounds of Formula I
[0015] In a first aspect, the present invention provides a compound
having the general formula I: ##STR2## or a pharmaceutically
acceptable salt thereof, wherein: W is N or --(CH)--, provided that
not more than three groups W are N; P is ##STR3## with the proviso
that P and R.sup.3 can only be in meta or para position to each
other; R.sup.1 is (a) C.sub.1-6 alkyl, (b) C.sub.1-6 alkoxyalkyl,
(c) straight or branched C.sub.1-6 hydroxyalkyl, (d) straight or
branched C.sub.1-6 alkylhalides; or (e) a group Ar; Ar is (a)
phenyl, (b) 1-naphthyl, (c) 2-naphthyl, (d) benzyl, (e) cinnamoyl,
(f) a 5 to 7-membered, optionally aromatic, partially saturated or
completely saturated, heterocyclic ring containing 1 to 4
heteroatoms, selected from oxygen, nitrogen and sulfur, or (g) a
bicyclic ring system comprising at least one heterocyclic ring
according to (f). [0016] wherein the group Ar is substituted in one
or more positions with [0017] (a) H, X or Y, or [0018] (b) a 5 to
7-membered, optionally aromatic, partially saturated or completely
saturated, mono- or bi-cyclic heterocyclic ring each containing 1
to 4 heteroatoms selected from oxygen, nitrogen or sulfur; R.sup.2
is (a) H, (b) C.sub.1-6 alkyl, (c) C.sub.1-6 alkoxyalkyl, (d)
straight or branched C.sub.1-6 hydroxyalkyl, or (e) straight or
branched C.sub.1-6 alkylhalides; R.sup.3 is a group ##STR4## X and
Y are independently (a) H, (b) halogen, (c) C.sub.1-6 alkyl, (d)
CF.sub.3, (e) hydroxy, (f) C.sub.1-6 alkoxy, (g) C.sub.1-4 alkenyl;
(h) phenyl; (i) phenoxy, (j) benzyloxy, (k) benzoyl, (l)
--OCF.sub.3, (m) --CN, (n) straight or branched C.sub.1-6
hydroxyalkyl, (o) straight or branched C.sub.1-6 alkylhalides, (p)
--NH.sub.2, (q) --NHR.sup.4, (r) --NR.sup.4R.sup.5, (s) --NO.sub.2,
(t) --CON R.sup.4R.sup.5, (u) --NHSO.sub.2 R.sup.4, (v)
--NR.sup.6COR.sup.5, (x) --SO.sub.2NR.sup.4R.sup.5, (z)
--C(.dbd.O)R.sup.4, (aa) --CO.sub.2 R.sup.4, or (ab) --S(O).sub.n
R.sup.4; wherein n is 0, 1, 2 or 3, (ac) --S--(C.sub.1-6)alkyl (ad)
--SCF.sub.3 R.sup.4 and R.sup.5 are independently (a) H, (b)
C.sub.1-6 alkyl, (c) C.sub.3-7 cycloalkyl, or (d) Ar, as defined
above for R.sup.1; alternatively, R.sup.4 and R.sup.5 are linked to
form a group (CH.sub.2).sub.2O, (CH.sub.2).sub.4O or
(CH.sub.2).sub.3-5; and R.sup.6 is (a) H, or (b) C.sub.1-6
alkyl.
[0019] In one aspect, this invention features a compound of the
formula (I): ##STR5## or a pharmaceutically acceptable salt
thereof, wherein: ring B is ##STR6## in which D is a five-membered
heterocyclic or heteroaryl ring, said ring comprising one or two
atoms selected from the group consisting of nitrogen, sulfur and
oxygen, with the proviso that when D contains an oxygen atom, D is
heteroaryl; W is N or --(CH)--, provided that not more than three
groups W are N in both rings A and B together; P is ##STR7## P and
R.sup.3 are bound to the same ring and are disposed in the meta- or
para-positions relative to each other; R.sup.1 is (a) C.sub.1-6
alkyl, (b) C.sub.1-6 alkoxyalkyl, (c) straight or branched
C.sub.1-6 hydroxyalkyl, (d) straight or branched C.sub.1-6
alkylhalides; or (e) a group Ar; Ar is (a) phenyl, (b) 1-naphthyl,
(c) 2-naphthyl, (d) benzyl, (e) cinnamoyl, (f) a 5 to 7-membered,
optionally aromatic, partially saturated or completely saturated,
heterocyclic ring containing 1 to 4 heteroatoms, selected from
oxygen, nitrogen and sulfur, or (g) a bicyclic ring system
comprising at least one heterocyclic ring according to (f). [0020]
wherein the group Ar is substituted in one or more positions with
[0021] (a) H, X or Y, or [0022] (b) a 5 to 7-membered, optionally
aromatic, partially saturated or completely saturated, heterocyclic
ring each containing 1 to 4 heteroatoms selected from oxygen,
nitrogen or sulfur; R.sup.2 is (a) H, (b) C.sub.1-6 alkyl, (c)
C.sub.1-6 alkoxy, (d) straight or branched C.sub.1-6 hydroxyalkyl,
or (e) straight or branched C.sub.1-6 alkylhalides; or R.sup.1 and
R.sup.2 are linked to form a group (CH.sub.2).sub.4O, which
represents (CH.sub.2)--(CH.sub.2)--O--(CH.sub.2)--(CH.sub.2); One
of R.sup.3 is a group ##STR8## X and Y are independently (a) H, (b)
halogen, (c) C.sub.1-6 alkyl, (d) --CF.sub.3, (e) hydroxy, (f)
C.sub.1-6 alkoxy, (g) C.sub.1-4 alkenyl; (h) phenyl; (i) phenoxy,
(j) benzyloxy, (k) benzoyl, (l) --OCF.sub.3, (m) --CN, (n) straight
or branched C.sub.1-6 hydroxyalkyl, (o) straight or branched
C.sub.1-6 alkylhalides, (p) --NH.sub.2, (q) --NHR.sup.4, (r)
--NR.sup.4R.sup.5, (s) --NO.sub.2, (t) --CONR.sup.4R.sup.5, (u)
--NHSO.sub.2R.sup.4, (v) --NR.sup.4COR.sup.5, (x)
--SO.sub.2NR.sup.4R.sup.5, (z) --C(.dbd.O)R.sup.4, (aa)
--CO.sub.2R.sup.4, or (ab) --S(O).sub.nR.sup.4; wherein n is 0, 1,
2 or 3; (ac) --S--(C.sub.1-6)alkyl (ad) --SCF.sub.3 R.sup.4 and
R.sup.5 are independently (a) H, (b) C.sub.1-6 alkyl, (c) C.sub.3-7
cycloalkyl, or (d) Ar, as defined above for R.sup.1; alternatively,
R.sup.4 and R.sup.5 are linked to form a group (CH.sub.2).sub.2O,
(CH.sub.2).sub.4O or (CH.sub.2).sub.3-5; in which (CH.sub.2).sub.2O
represents (CH.sub.2)--O--(CH.sub.2) and (CH.sub.2).sub.4O
represents (CH.sub.2)--(CH.sub.2)--O--(CH.sub.2)--(CH.sub.2); and
R.sup.6 is (a) H, or (b) straight of branched C.sub.1-6 alkyl.
[0023] In preferred forms, the invention provides naphthalene
compounds of the formula (II), isoquinoline compounds of the
formula (III), quinoline compounds of the formula (IV),
1,7-naphthyridine compounds of the formula (V), and benzofuran,
benzothiophene, or indole compounds of the formula (VI): ##STR9##
wherein R.sup.3, P, X and Y are as defined for formula (I); and
wherein D in formula (VI) is a five-membered heterocyclic or
heteroaryl ring, said ring comprising one or two atoms selected
from the group consisting of nitrogen, sulfur and oxygen, with the
proviso that when D contains an oxygen atom, D is heteroaryl. The
group Y can be attached to any unsubstituted carbon atom in D. When
the heteroaryl ring comprises one or two nitrogen atoms, a group
R.sup.6 could be attached at the secondary nitrogen. Preferred
compounds of the general formulas (I), (II), (III), and (IV), (V),
(VI) are those wherein: R.sup.1 is (a) C.sub.1-6 alkyl, or (e) a
group Ar; Ar is (a) phenyl, (b) 1-naphthyl, (c) 2-naphthyl, or (f)
a 5 to 7-membered, partially or completely saturated, mono- or
bi-cyclic heterocyclic ring each containing 1 to 4 heteroatoms
selected from oxygen, nitrogen or sulfur; wherein the group Ar is
substituted in one or more positions with X or Y; wherein X or Y is
(a) H, (b) halogen, (c) C.sub.1-6 alkyl, (d) --CF.sub.3, (f)
C.sub.1-6 alkoxy, (g) C.sub.1-4 alkenyl; (l) --OCF.sub.3, or (m)
straight or branched C.sub.1-6 hydroxyalkyl (n) phenyloxy (o)
benzyloxy (ab) --S(O).sub.nR.sup.4; wherein n is 0, 1, 2 or 3, (ac)
--S--(C.sub.1-6)alkyl (ad) --SCF.sub.3 (v) --NR.sup.4COR.sup.5, (x)
--SO.sub.2NR.sup.4R.sup.5, (z) --C(.dbd.O)R.sup.4. R.sup.2 is (a)
H, or (b) C.sub.1-3 alkyl, in particular methyl; or R.sup.1 and
R.sup.2 are linked to form a group (CH.sub.2).sub.4O; R.sup.3 is
##STR10##
[0024] wherein R.sup.6 is
[0025] (a) H, or
[0026] (b) C.sub.1-6 alkyl, in particular methyl;
X and Y are H; and/or
D is furanyl.
[0027] Preferred compounds of the formula II are para-substituted
naphthalene compounds wherein P is ##STR11## wherein R.sup.1 and
R.sup.2 are as defined for formula (I); and X and Y are H,
halogens, methyl, methoxy, (cf. Table I). Particularly preferred of
such compounds are those wherein R.sup.1 is phenyl, methylphenyl,
methoxyphenyl, dimethoxyphenyl, 1-naphthyl, 2-naphthyl,
fluoromethylphenyl, chlorophenyl, dichlorophenyl,
fluorochlorophenyl, dichlorothienyl, chlorothienyl,
trifluoromethylphenyl, or methoxymethylphenyl; R.sup.2 is H or
methyl; and R.sup.3 is piperazinyl or homopiperazinyl,
3,5-dimethylpiperazine, 4-piperidine, 4-(4,3)-dihydropyridine,
4-(1,2,3,6)-tetrahydropyridine; R.sup.6 is H, methyl, ethyl,
isopropyl. Further preferred compounds of the formula II are
compounds with a group P and a group R.sup.3 in para-position.
[0028] Further preferred compounds of the formula II are compounds
with a group P and a group R.sup.3 in para-position, wherein P is
##STR12## wherein R.sup.1 and R.sup.2 are as defined for formula
(I) (cf. Table M); and X or Y are H, methyl, ethyl, isopropyl,
methoxy, thiomethyl, 1-naphthyl, phenyloxy, trifluoromethoxy,
trifluorothienyl (cf. Table II). Particularly preferred of such
compounds are those wherein R.sup.1 is phenyl, 1-naphthyl,
phenyloxyphenyl, dimethoxyphenyl, dimethylphenyl,
methylchlorophenyl, isopropylphenyl, fluorophenyl,
1(2H)-3,4-dihydroquinolin, R.sup.2 is H or methyl, R.sup.3 is
piperazinyl, and R.sup.6 is H.
[0029] Preferred compounds of the formula III are isoquinoline
compounds wherein P is ##STR13## and occupies position 3 of the
ring, wherein R.sup.1 and R.sup.2 are as defined for formula (I);
and X or Y are H, methyl, bromo, methoxy, acethylamino (cf. Table
IV). Particularly preferred of such compounds are those wherein
R.sup.1 is phenyl, bromophenyl, methylchlorophenyl, methylphenyl,
methoxyphenyl, trimethylphenyl, dimethoxyphenyl,
bromomethoxyphenyl; R.sup.2 is H or methyl; and R.sup.3 is
methylpiperazinyl.
[0030] Preferred compounds of the formula IV are quinoline
compounds wherein P is ##STR14## and occupies position 5 of the
ring, wherein R.sup.1 and R.sup.2 are as defined for formula (I);
and X, Y is H (cf. Table V). Particularly preferred of such
compounds are those wherein R.sup.1 is phenyl; R.sup.2 is H or
methyl; and R.sup.3 is piperidinyl.
[0031] Preferred compounds of the formula V are 1,7-naphthyridine
compounds wherein P is ##STR15## and occupies position 8 of the
ring, wherein R.sup.1 and R.sup.2 are as defined for formula (I);
and X and Y are halogen, methoxy (cf. Table V). Particularly
preferred of such compounds are those wherein R.sup.1 is phenyl,
dimethoxyphenyl, 1-naphthyl; R.sup.2 is H or methyl; and R.sup.3 is
piperidinyl;
[0032] Preferred compounds of the formula VI are benzofuran
compounds wherein P is ##STR16## and occupies position 5 of the
ring, wherein R.sup.1 and R.sup.2 are as defined for formula (I)
and wherein D in formula (VI) is a five-membered heterocyclic or
heteroaryl ring, said ring comprising one or two atoms selected
from the group consisting of nitrogen, sulfur and oxygen, with the
proviso that when D contains an oxygen atom, D is heteroaryl. The
group Y can be attached to any unsubstituted carbon atom in D. When
the heteroaryl ring comprises one or two nitrogen atoms, a group
R.sup.6 could be attached at the secondary nitrogen; and X and Y
are halogen, methoxy (cf. Table V). Particularly preferred of such
compounds are those wherein R.sup.1 is phenyl, dichlorophenyl,
bromophenyl, dichloromethylphenyl, 1-naphthyl, phenyl,
methylphenyl, fluorophenyl, thiophenyl, chlorothiophenyl; R.sup.2
is H or methyl; and R.sup.3 is piperidinyl or N-methylpiperidinyl.
Para-substituted naphthalene compounds of the formula II wherein P
is ##STR17##
[0033] and X, Y are H: TABLE-US-00001 TABLE I ##STR18## Compound
name R.sup.1 R.sup.3 R.sup.2 1
N-(4-Methylphenyl)-4-(1-piperazinyl)-1- naphthalenesulfonamide,
hydrochloride ##STR19## ##STR20## H 2
N-(2,4-Dimethoxyphenyl)-4-(1-piperazinyl)-1-
naphthalenesulfonamide, hydrochloride ##STR21## ##STR22## H 3
N-(3,4-di-Fluorophenyl)-4-(4-methyl-1,4-diazepan-1-
yl)-1-naphthalenesulfonamide, hydrochloride ##STR23## ##STR24## H 4
N-(3-Fluorophenyl)-4-(4-methyl-1,4-diazepan-1-yl)-1-
naphthalenesulfonamide, hydrochloride ##STR25## ##STR26## H 5
4-(4-Ethyl-1-piperazinyl)-N-phenyl-1- naphthalenesulfonamide,
hydrochloride ##STR27## ##STR28## H 6
4-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl-N-(4-
methylphenyl)-1-naphthalenesulfonamide, hydrochloride ##STR29##
##STR30## H 7 N-(3,4-Dimethoxyphenyl)-4-hexahydropyrrolo`1,2-
a]pyrazin-2(1H)-yl-1-naphthalenesulfonamide, hydrochloride
##STR31## ##STR32## H 8
4-(4-Ethyl-1-piperazinyl)-N-(4-methylphenyl)-1-
naphthalenesulfonamide, hydrochloride ##STR33## ##STR34## H 9
N-(3,4-Dimethoxyphenyl)-4-(3-methyl-1-piperazinyl)-
1-naphthalenesulfonamide, hydrochloride ##STR35## ##STR36## H 10
N-(4-Methylphenyl)-4-(4-methyl-1-piperazinyl)-1-
naphthalenesulfonamide, hydrochloride ##STR37## ##STR38## H 11
N-[4-(2,5-Diazabicyclo[2.2.1]hept-2-yl)-1-naphthyl]-4-
methylbenzenesulfonamide, hydrochloride ##STR39## ##STR40## H 12
N-(4-Methylphenyl)-4-(3-methyl-1-piperazinyl)-1-
naphthalenesulfonamide, hydrochloride ##STR41## ##STR42## H 13
N-(2-Naphthyl)-4-(1-piperazinyl)-1- naphthalenesulfonamide,
hydrochloride ##STR43## ##STR44## H 14
N-Methyl-N-(4-methylphenyl)-4-(1-piperazinyl)-1-
naphthalenesulfonamide, hydrochloride ##STR45## ##STR46##
--CH.sub.3 15 4-(1,4-Diazepan-1-yl)-N-(4-methylphenyl)-1-
naphthalenesulfonamide, hydrochloride ##STR47## ##STR48## H 16
4-(1,4-Diazepan-1-yl)-N-(2-methoxy-4-methylphenyl)-
1-naphthalenesulfonamide, hydrochloride ##STR49## ##STR50## H 17
N-(2-Methoxy-4-methylphenyl)-4-(3,5-trimethyl-1-
piperazinyl)-1-naphthalenesulfonamide, hydrochloride ##STR51##
##STR52## H 18 4-(4-Isopropyl-1-piperazinyl)-N-(4-methylphenyl)-1-
naphthalenesulfonamide, hydrochloride ##STR53## ##STR54## H 19
4-Bromo-N-(4-piperazin-1-yl-naphthalen- 1-yl)-benzenesulfonamide,
hydrochloride ##STR55## ##STR56## H 20
2,5-di-Chloro-N-[4-(1-piperazinyl)-1- naphthyl]benzenesulfonamide,
hydrochloride ##STR57## ##STR58## H 21
2-Chloro-4-fluoro-N-[4-(1-piperazinyl)-1-
naphthyl]benzenesulfonamide, hydrochloride ##STR59## ##STR60## H 22
2,3-di-Chloro-N-[4-(1-piperazinyl)-1- naphthyl]benzenesulfonamide,
hydrochloride ##STR61## ##STR62## H 23
2,4-di-Chloro-5-methyl-N-[4-(1-piperazinyl)-1-
naphthyl]benzenesulfonamide, hydrochloride ##STR63## ##STR64## H 24
3-tri-Fluoromethyl-N-[4-(1-piperazinyl)-1-
naphthyl]benzenesulfonamide, hydrochloride ##STR65## ##STR66## H 25
2-tri-Fluoromethyl-N-[4-(1-piperazinyl)-1-
naphthyl]benzenesulfonamide, hydrochloride ##STR67## ##STR68## H 26
4-Bromo-N-methyl-N-(4-piperazin-1-yl-
naphthalen-1-yl)-benzenesulfonamide, hydrochloride. ##STR69##
##STR70## CH.sub.3 27 Naphthalene-1-sulfonic acid
(4-piperazin-1-yl- naphthalen-1-yl)-amide, hydrochloride ##STR71##
##STR72## H 28 2,5-Dichloro-thiophene-3-sulfonic acid
(4-piperazin-1- yl-naphthalen-1-yl)-amide, hydrochloride ##STR73##
##STR74## H 29 4-Methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-
benzenesulfonamide, hydrochloride ##STR75## ##STR76## H 30
4-Chloro-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide,
hydrochloride ##STR77## ##STR78## H 31
2-Chloro-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide,
hydrochloride ##STR79## ##STR80## H 32
N-(4-Piperazin-1-yl-naphthalen-1-yl)-4-trifluoromethyl-
benzenesulfonamide, hydrochloride ##STR81## ##STR82## H 33
4-Fluoro-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide,
hydrochloride ##STR83## ##STR84## H 34
5-Fluoro-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-
yl)-benzenesulfonamide, hydrochloride ##STR85## ##STR86## H 35
4-Phenoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide,
hydrochloride ##STR87## ##STR88## H 36
2-Bromo-4-iodo-N-(4-piperazin-1-yl-naphthalen-1-yl)-
benzenesulfonamide, hydrochloride ##STR89## ##STR90## H 37
Thiophene-2-sulfonic acid (4-piperazin-1-yl-naphthalen-
1-yl)-amide, hydrochloride ##STR91## ##STR92## H 38
5-Chloro-thiophene-2-sulfonic acid (4-piperazin-1-yl-
naphthalen-1-yl)-amide, hydrochloride ##STR93## ##STR94## H 39
3-Methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide,
hydrochloride ##STR95## ##STR96## H 40
4-Butyl-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide
hydrochloride ##STR97## ##STR98## H 41
2,4,6-Trimethyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-
benzenesulfonamide hydrochloride ##STR99## ##STR100## H 42
2,4,5-Trichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-
benzenesulfonamide, hydrochloride ##STR101## ##STR102## H 43
4-Iodo-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide,
hydrochloride ##STR103## ##STR104## H 44
2-Methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide,
hydrochloride ##STR105## ##STR106## H 45
3,4-Dichloro-N-(4-piperazin-1-yl-naphthalen-
1-yl)-benzenesulfonamide, hydrochloride ##STR107## ##STR108## H 46
5-Bromo-2-methoxy-N-(4-piperazin-1-yl-naphthalen-1-
yl)-benzenesulfonamide, hydrochloride ##STR109## ##STR110## H 47
2-Bromo-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide,
hydrochloride ##STR111## ##STR112## H 48
3-Chloro-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-
yl)-benzenesulfonamide, hydrochloride ##STR113## ##STR114## H 49
2,6-Dichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-
benzenesulfonamide, hydrochloride ##STR115## ##STR116## H 50
3-Methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)- benzenesulfonamide,
hydrochloride ##STR117## ##STR118## H 51
3-Chloro-4-methyl-N-(4-piperazin-1-yl-naphthalen-1-
yl)-benzenesulfonamide, hydrochloride ##STR119## ##STR120## H 52
4-Bromo-2-fluoro-N-(4-piperazin-1-yl-naphthalen-1-
yl)-benzenesulfonamide, hydrochloride ##STR121## ##STR122## H 53
2,4-Dichloro-6-methyl-N-(4-piperazin-1-yl-naphthalen-
1-yl)-benzenesulfonamide, hydrochloride ##STR123## ##STR124## H 54
4-Bromo-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-
yl)-benzenesulfonamide, hydrochloride ##STR125## ##STR126## H 55
4,5-Dichloro-thiophene-2-sulfonic acid (4-piperazin-1-
yl-naphthalen-1-yl)-amide, hydrochloride ##STR127## ##STR128## H 56
N-Methyl-N-(4-bromo-2-methylphenyl)-4-(1-
pyperazinyl)-1-napthalenesulphonamide, hydrochloride ##STR129##
##STR130## CH.sub.3 57 N-Methyl-N-(5-fluoro-2-methylphenyl)-4-(1-
pyperazinyl)-1-napthalenesulphonamide, hydrochloride ##STR131##
##STR132## CH.sub.3 58
N-Methyl-N-(2-methylphenyl)-4-(1-pyperazinyl)-1-
napthalenesulphonamide, hydrochloride ##STR133## ##STR134##
CH.sub.3 59 N-Methyl-N-(3-chloro-2-methylphenyl)-4-(1-
pyperazinyl)-1-napthalenesulphonamide, hydrochloride ##STR135##
##STR136## CH.sub.3 60 2,5-di-Chlorothiophen-3-yl-N-Methyl-N-(2,5-
dichlorothiophen-3-yl)-4-(1-pyperazinyl)-1- napthalenesulphonamide,
hydrochloride ##STR137## ##STR138## CH.sub.3 61
N-Methyl-N-(1-naphthyl)-4-(1-pyperazinyl)-1-
napthalenesulphonamide, hydrochloride ##STR139## ##STR140##
CH.sub.3 62 N-Methyl-N-(1-naphthyl)-4-(1-pyperazinyl)-1-
napthalenesulphonamide, hydrochloride ##STR141## ##STR142##
CH.sub.3 63 N-Methyl-N-(4-chlorophenyl)-4-(1-pyperazinyl)-1-
napthalenesulphonamide, hydrochloride ##STR143## ##STR144##
CH.sub.3 64 N-Methyl-N-(4-methoxyphenyl)-4-(1-pyperazinyl)-1-
napthalenesulphonamide, hydrochloride ##STR145## ##STR146##
CH.sub.3 65 5-Fluoro-2-methyl-N-{4-[(2R,5S)-2,5-dimethyl-1-
]piperazin-1-yl-1-naphthyl}benzenesulfonamide, hydrochloride
##STR147## ##STR148## H 66
5-Fluoro-2-methyl-N-[4-(1,2,3,6-tetrahydropyridin-4-
yl)-1-naphthyl]benzenesulfonamide, hydrochloride ##STR149##
##STR150## H
3-Substituted naphthalene compounds of the formula II wherein P is
##STR151##
[0034] and X, Y are H: TABLE-US-00002 TABLE II ##STR152## Compound
name R.sup.1 R.sup.3 R.sup.2 67 N-[4-(4-Methyl-1-piperazinyl)-2-
naphthyl]benzenesulfonamide, hydrochloride ##STR153## ##STR154##
H
5-Substituted naphthalene compounds of the formula II wherein P is
##STR155##
[0035] and X, Y and R.sup.4 are H: TABLE-US-00003 TABLE III
##STR156## Compound name R.sup.1 R.sup.3 R.sup.2 68
4-Piperazin-1-yl-naphthalene-1-sulfonic acid phenylamide,
hydrochloride ##STR157## ##STR158## H 69
4-Piperazin-1-yl-naphthalene-1-sulfonic acid (2-methoxy-phenyl)-
amide, hydrochloride ##STR159## ##STR160## H 70
4-(cis-3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid
(2-methoxy-phenyl)-amide, hydrochloride ##STR161## ##STR162## H 71
4-(cis-3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid
(3-chloro-phenyl)-amide, hydrochloride ##STR163## ##STR164## H 72
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-chloro-
phenyl)-amide, hydrochloride ##STR165## ##STR166## H 73
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid phenylamide,
hydrochloride ##STR167## ##STR168## H 74
4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-chloro-phenyl)-
amide, hydrochloride ##STR169## ##STR170## H 75
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(2-methylsulfanyl-phenyl)-amide, hydrochloride ##STR171##
##STR172## H 76 4-Piperazin-1-yl-naphthalene-1-sulfonic acid
methyl-naphthalen- 1-yl-amide, hydrochloride ##STR173## ##STR174##
H 77 4-Piperazin-1-yl-naphthalene-1-sulfonic acid (2,3-dihydro-
benzo[1,4]dioxin-6-yl)-methyl-amide, hydrochloride ##STR175##
##STR176## CH.sub.3 78 4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(2,3-dihydro- benzo[1,4]dioxin-6-yl)-amide, hydrochloride
##STR177## ##STR178## H 79 4-Piperazin-1-yl-naphthalene-1-sulfonic
acid methyl-(2- methylsulfanyl-phenyl)-amide, hydrochloride
##STR179## ##STR180## CH.sub.3 80
4-Piperazin-1-yl-naphthalene-1-sulfonic acid methyl-(3-
trifluoromethyl-phenyl)-amide, hydrochloride ##STR181## ##STR182##
CH.sub.3 81 4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(3-chloro-4-methyl- phenyl)-methyl-amide, hydrochloride ##STR183##
##STR184## CH.sub.3 82 4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(3-ethyl-phenyl)- methyl-amide, hydrochloride ##STR185## ##STR186##
CH.sub.3 83 4-(3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic
acid (2- isopropyl-phenyl)-amide, hydrochloride ##STR187##
##STR188## H 84 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid
(2-isopropyl- phenyl)-amide, hydrochloride ##STR189## ##STR190## H
85 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-ethyl-
phenyl)-amide, hydrochloride ##STR191## ##STR192## H 86
N-(2-Fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,
hydrochloride ##STR193## ##STR194## H 87
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-
trifluoromethyl-phenyl)-amide, hydrochloride ##STR195## ##STR196##
H 88 N-(2,4-di-Fluorophenyl)-4-piperazin-1-ylnaphthalene-1-
sulfonamide, hydrochloride ##STR197## ##STR198## H 89
4-Piperazin-1-yl-naphthalene-1-sulfonic acid (2-trifluoromethoxy-
phenyl)-amide, hydrochloride ##STR199## ##STR200## H 90
4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-trifluoromethoxy-
phenyl)-amide, hydrochloride ##STR201## ##STR202## H 91
4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-trifluoromethoxy-
phenyl)-amide, hydrochloride ##STR203## ##STR204## H 92
4-Piperazin-1-yl-naphthalene-1-sulfonic acid (2-chloro-5-methyl-
phenyl)-amide, hydrochloride ##STR205## ##STR206## H 93
4-Piperazin-1-yl-naphthalene-1-sulfonic acid (4-isopropyl-
phenyl)-amide, hydrochloride ##STR207## ##STR208## H 94
N-(3,5-di-Fluorophenyl)-4-piperazin-1-ylnaphthalene-1- sulfonamide,
hydrochloride ##STR209## ##STR210## H 95
1-[4-(3,4-Dihydroquinolin-1(2H)-ylsulfonyl)-1- naphthyl]piperazine,
hydrochloride ##STR211## ##STR212## H 96
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-nitro-
phenyl)-amide, hydrochloride ##STR213## ##STR214## H 97
4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-nitro-phenyl)-
amide, hydrochloride ##STR215## ##STR216## H 98
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (3-nitro-
phenyl)-methyl-amide, hydrochloride ##STR217## ##STR218## CH.sub.3
99 N-(4-methylphenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,
hydrochloride ##STR219## ##STR220## H 100
N-(3-chloro-4-methylphenyl)-4-piperazin-1-ylnaphthalene-1-
sulfonamide, hydrochloride ##STR221## ##STR222## H 101
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (2,3-dimethyl-
phenyl)-methyl-amide, hydrochloride ##STR223## ##STR224## CH.sub.3
102 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (4-isopropyl-
phenyl)-amide, hydrochloride ##STR225## ##STR226## H 103
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (4-isopropyl-
phenyl)-methyl-amide, hydrochloride ##STR227## ##STR228## CH.sub.3
104 4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (2,4-dimethyl-
phenyl)-amide, hydrochloride ##STR229## ##STR230## H 105
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid (2-chloro-5-
methyl-phenyl)-amide, hydrochloride ##STR231## ##STR232## H 106
4-Piperazin-1-yl-naphthalene-1-sulfonic acid (2,5-dimethoxy-
phenyl)-amide, hydrochloride ##STR233## ##STR234## H 107
4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-acetyl-phenyl)-
amide, hydrochloride ##STR235## ##STR236## H 108
4-Piperazin-1-yl-naphthalene-1-sulfonic acid (2,4-dimethyl-
phenyl)-amide, hydrochloride ##STR237## ##STR238## H 109
4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-trifluoromethyl-
phenyl)-amide, hydrochloride ##STR239## ##STR240## H 110
4-Piperazin-1-yl-naphthalene-1-sulfonic acid biphenyl-2-ylamide,
hydrochloride ##STR241## ##STR242## H 111
4-Piperazin-1-yl-naphthalene-1-sulfonic acid (3-benzyloxy-
phenyl)-amide, hydrochloride ##STR243## ##STR244## H 112
N-(4-fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,
hydrochloride ##STR245## ##STR246## H 113
N-(3-Ethylphenyl)-4-piperazin.1.ylnaphthalene-1-sulphonamine,
hydrochloride ##STR247## ##STR248## H 114
4-Piperazinyl-N-[3-(trifluoromethyl)phenyl]naphthalene-1-
sulfonamide, hydrochloride ##STR249## ##STR250## H 115
4-Piperazinyl-N-[3-benzoylphenyl]naphthalene-1-sulfonamide,
hydrochloride ##STR251## ##STR252## H 116
4-Piperazinyl-N-[3-(4-bromo-1-methyl-1H-pyrazol-3-
yl)phenyl]naphthalene-1-sulfonamide, hydrochloride ##STR253##
##STR254## H 117
4-Piperazinyl-N-[3-biphenylphenyl]naphthalene-1-sulfonamide,
hydrochloride ##STR255## ##STR256## H
Meta-substituted isoquinoline compounds of the formula III wherein
P is ##STR257##
[0036] and X, Y are H: TABLE-US-00004 TABLE IV ##STR258## Compound
name R.sup.1 R.sup.3 R.sup.2 118 N-[-(4-methyl-1-piperazinyl)-3-
isoquinolinyl]benzenesulfonamide, hydrochloride ##STR259##
##STR260## H 119 2,4-di-Fluoro-N-[1-(4-methyl-1-piperazinyl)-3-
isoquinolinyl]benzenesulfonamide, hydrochloride ##STR261##
##STR262## H 120 4-Bromo-N-[1-(4-methyl-piperazin-1-
yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride ##STR263##
##STR264## H 121 5-Chloro-3-methyl-benzo[b]thiophene- 2-sulfonic
acid [1-(4-methyl-piperazin-1-yl)- isoquinolin-3-yl]-amide,
hydrochloride ##STR265## ##STR266## H 122
3-Chloro-2-methyl-N-[1-(4-methyl-piperazin-
1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride
##STR267## ##STR268## H 123 3,4-Dichloro-N-[1-(4-methyl-piperazin-
1-yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride
##STR269## ##STR270## H 124 4-Methyl-N-[1-(4-methyl-piperazin-1-
yl)-isoquinolin-3-yl]-benzenesulfonamide, hydrochloride ##STR271##
##STR272## H 125 3-Methoxy-N-[1-(4-methyl-piperazin-1-yl)-
isoquinolin-3-yl]-benzenesulfonamide, hydrochloride ##STR273##
##STR274## H 126 5-Chloro-thiophene-2-sulfonic acid
[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide, hydrochloride
##STR275## ##STR276## H 127 N-{2-Chloro-4-[1-(4-methyl-piperazin-
1-yl)-isoquinolin-3-ylsulfamoyl]-phenyl}-acetamide hydrochloride
##STR277## ##STR278## H 128 2,5-Dichloro-thiophene-3-sulfonic acid
[1-(4-methyl- piperazin-1-yl)-isoquinolin-3-yl]-amide,
hydrochloride ##STR279## ##STR280## H 129
N-[1-(4-Methyl-piperazin-1-yl)-isoquinolin-3-yl]-3-
trifluoromethyl-benzenesulfonamide, hydrochloride ##STR281##
##STR282## H 130
N-[1-(4-Methyl-piperazin-1-yl)-isoquinolin-3-yl]-4-
phenoxy-benzenesulfonamide, hydrochloride ##STR283## ##STR284## H
131 5-Bromo-2-methoxy-N-[1-(4-methyl-piperazin-1-yl)-
isoquinolin-3-yl]-benzenesulfonamide, hydrochloride ##STR285##
##STR286## H 132
2-Methanesulphonayl-N-[1-(4-methyl-piperazin-1-yl)-
isoquinolin-3-yl]-benzenesulfonamide, hydrochloride ##STR287##
##STR288## H 133 3,5-Dimethyl-isoxazole-4-sulfonic acid
[1-(4-methyl- piperazin-1-yl)-isoquinolin-3-yl]-amide,
hydrochloride ##STR289## ##STR290## H 134
2,4,6-Trimethyl-N-[1-(4-methyl-piperazin-1-yl)-
isoquinolin-3-yl]-benzenesulfonamide, hydrochloride ##STR291##
##STR292## H 135 3,4-Dimethoxy-N-[1-(4-methyl-piperazin-1-yl)-
isoquinolin-3-yl]-benzenesulfonamide, hydrochloride ##STR293##
##STR294## H
5-Substituted quinoline compounds of the formula IV wherein P is
##STR295##
[0037] and X, Y are H: TABLE-US-00005 TABLE V ##STR296## Compound
name R.sup.1 R.sup.3 R.sup.2 136
N-(8-{[2-(di-Methylamino)ethyl]amino}-5-quinolinyl)
benzenesulfonamide, hydrochloride ##STR297## ##STR298## H
1.7-Naphthyridine compounds of the formula V wherein P is
##STR299##
[0038] R.sup.2 and X, Y are H: TABLE-US-00006 TABLE VI ##STR300##
Compound name R1 R3 137
4-Methyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-
yl)benzenesulfonamide, trifluoroacetic acid ##STR301## ##STR302##
138 4-Bromo-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)
benzenesulfonamide, trifluoroacetic acid ##STR303## ##STR304## 139
N-(8-Piperazin-1-yl-1,7-naphthyridin-6-yl)naphthalene-1-
sulfonamide, trifluoroacetic acid ##STR305## ##STR306## 140
N-(8-Piperazin-1-yl-1,7-naphthyridin-6-yl)butane-1-sulfonamide,
trifluoroacetic acid ##STR307## ##STR308## 141
3-Trifluoromethyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-
yl)benzenesulfonamide, trifluoroacetic acid ##STR309## ##STR310##
142 3,4-Dimethoxy-N-(8-piperazin-1-yl-1,7-naphthyridin-6-
yl)benzenesulfonamide, trifluoroacetic acid ##STR311## ##STR312##
143 2,4-Dichloro-N-(8-piperazin-1-yl-1,7-naphthyridin-6-
yl)benzenesulfonamide, trifluoroacetic acid ##STR313## ##STR314##
144
N-(8-Piperazin-1-yl-1,7-naphthyridin-6-yl)thiophene-2-sulfonamide,
trifluoroacetic acid ##STR315## ##STR316## 145
1-Phenyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-
yl)methanesulfonamide, trifluoroacetic acid ##STR317##
##STR318##
5-Substituted benzofuran compounds of the formula VI wherein P is
##STR319##
[0039] R.sup.2 and X, Y are H: TABLE-US-00007 TABLE VII ##STR320##
Compound name R1 R3 146
3-Cyanophenyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-
benzenesulfonamide, hydrochloride ##STR321## ##STR322## 147
4-Phenoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)- benzenesulfonamide,
hydrochloride ##STR323## ##STR324## 148
1-Naphthyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-
benzenesulfonamide, hydrochloride ##STR325## ##STR326## 149
N-(7-Piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,
hydrochloride ##STR327## ##STR328## 150
5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid (7-
piperazin-1-yl-benzofuran-5-yl)-amide, hydrochloride ##STR329##
##STR330## 151 N-[7-(4-Methylpiperazin-1-yl)-1-benzofuran-5-yl]-
benzenesulfonamide, hydrochloride ##STR331## ##STR332## 152
4-Methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)- benzenesulfonamide,
hydrochloride ##STR333## ##STR334## 153
3,4-Dimethoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-
benzenesulfonamide, hydrochloride ##STR335## ##STR336## 154
4-Bromo-N-(7-piperazin-1-yl-benzofuran-5-yl)- benzenesulfonamide,
hydrochloride ##STR337## ##STR338## 155
2,3-Dichloro-N-(7-piperazin-1-yl-benzofuran-5-yl)-
benzenesulfonamide, hydrochloride ##STR339## ##STR340## 156
2,4-Dichloro-5-methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-
benzenesulfonamide, hydrochloride ##STR341## ##STR342## 157
4-Methoxy-N-(7-piperazm-1-yl-benzofuran-5-yl)- benzenesulfonamide,
hydrochloride ##STR343## ##STR344## 158
4-Chloro-N-(7-piperazin-1-yl-benzofuran-5-yl)- benzenesulfonamide,
hydrochloride ##STR345## ##STR346## 159
N-(7-Piperazin-1-yl-benzofuran-5-yl)-4-trifluoromethyl-
benzenesulfonamide, hydrochloride ##STR347## ##STR348## 160
5-Fluoro-2-methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-
benzenesulfonamide, hydrochloride ##STR349## ##STR350## 161
5-Chloro-thiophene-2-sulfonic acid (7-piperazin-1-yl-
benzofuran-5-yl)-amide, hydrochloride ##STR351## ##STR352##
Methods for Preparation
[0040] The compounds according to the invention (Tables I, II, IV,
V, VI) can be prepared starting from halo-nitro substituted
bicyclic aromatic rings by base (potassium carbonate) catalyzed
aromatic nucleophilic substitution of a halogen in the desired
position of the central bicyclic ring with the diamine of choice
(R.sup.3). Reduction of a nitro group properly positioned on the
central bicyclic ring by Raney-Ni catalyzed reaction leads to the
aniline that is substituted further by sulfonylation with the
alkyl- or aryl-sulfonylchloride of choice (R.sup.1--SO.sub.2--Cl).
Scheme 1 and Scheme 3
[0041] The compounds according to the invention (Tables III) can be
prepared starting from fluoro substituted bicyclic aromatic rings
in which the sulfonylchloride functionality is introduced by acid
catalyzed sulfonylation. The sulfonyl group is reacted further with
anilines of choice (R.sup.1--NH.sub.2). The diamine group (R.sup.3)
is introduced by base catalyzed aromatic nucleophilic substitution.
Scheme 2
[0042] The compounds according to the invention (Tables VII) can be
prepared starting from iodo substituted bicyclic aromatic rings.
The diamine group (R.sup.3) is introduced by Palladium catalysed
nucleophilic substitution. Reduction of a nitro group properly
positioned on the central bicyclic ring by Raney-Ni catalyzed
reaction leads to the aniline that is substituted further by
sulfonylation with the alkyl- or aryl-sulfonylchloride of choice
(R.sup.1--SO.sub.2--Cl). Scheme 4
[0043] The chemicals used in the above-described synthetic route
may include, for example, solvents, reagents, catalysts, protecting
group and deprotecting group reagents. The methods described above
may also additionally include steps, either before or after the
steps described specifically herein, to add or remove suitable
protecting groups in order to ultimately allow synthesis of the
compounds of formula (I). In addition, various synthetic steps may
be performed in an alternate sequence or order to give the desired
compounds. Synthetic chemistry transformations and protecting group
methodologies (protection and deprotection) useful in synthesizing
applicable compounds are known in the art and include, for example,
those described in R. Larock, Comprehensive Organic
Transformations, VCH Publishers (1989); T. W. Greene and P. G. M.
Wuts, Protective Groups in Organic Synthesis, 2.sup.nd Ed., John
Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's
Reagents for Organic Synthesis, John Wiley and Sons (1994); and L.
Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John
Wiley and Sons (1995) and subsequent editions thereof.
[0044] Depending on the process conditions, the end products of the
formula (I) are obtained either in neutral or salt form. Both the
free base and the salts of these end products are within the scope
of the invention.
[0045] Acid addition salts of the new compounds may in a manner
known per se be transformed into the free base using basic agents
such as alkali or by ion exchange. The free base obtained may also
form salts with organic or inorganic acids.
[0046] In the preparation of acid addition salts, preferably such
acids are used which form suitably therapeutically acceptable
salts. Examples of such acids are hydrohalogen acids, sulfuric
acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic
or heterocyclic carboxyl or sulfonic acids, such as formic acid,
acetic acid, propionic acid, succinic acid, glycolic acid, lactic
acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic
acid, hydroxymaleic acid, pyruvic acid, p-hydroxybensoic acid,
embonic acid, methanesulfonic acid, ethanesulfonic acid,
hydroxyethanesulfonic acid, halogenbensenesulfonic acid,
toluenesulfonic acid, mandelic acid or naphthalenesulfonic
acid.
[0047] Throughout the specification and the appended claims, a
given chemical formula or name shall encompass all stereo and
optical isomers and racemates thereof where such isomers exist. All
diastereomeric forms possible (pure enantiomers, tautomers, racemic
mixtures and unequal mixtures of two enantiomers) are within the
scope of the invention. Such compounds can also occur as cis- or
trans-, E- or Z-double bond isomer forms. All isomeric forms are
contemplated.
[0048] Pharmaceutical formulations are usually prepared by mixing
the active substance, or a pharmaceutically acceptable salt
thereof, with conventional pharmaceutical excipients. The
formulations can be further prepared by known methods such as
granulation, compression, microencapsulation, spray coating,
etc.
[0049] This invention relates to a method of treatment or
prophylaxis of obesity, type II diabetes, and/or disorders of the
central nervous system. The method includes administering to a
subject (e.g., a mammal, a human, a horse, a dog, or a cat) in need
thereof an effective amount of one or more compounds of the formula
(I) described above.
[0050] This invention also features a method for reducing
body-weight (e.g., treating body-weight disorders) or reducing food
intake. The method includes administering to a subject in need
thereof an effective amount of a compound of the formula (I). As
used herein, the term "body weight disorders" refers to the
disorders caused by an imbalance between energy intake and energy
expenditure, resulting in abnormal body (e.g., excessive) weights.
Such body weight disorders include obesity.
[0051] Also within the scope of this invention is a method for
modulating (e.g., inhibiting) 5-HT.sub.6 receptor activity. The
method includes administering to a subject in need thereof an
effective amount of a compound of the formula (I).
[0052] The methods delineated herein can also include the step of
identifying that the subject is in need of treatment of obesity,
type II diabetes, or disorders of the central nervous system, or in
need of reducing body-weight or reducing food intake.
[0053] "An effective amount" refers to an amount of a compound
which confers a therapeutic effect on the treated subject. The
therapeutic effect may be objective (i.e., measurable by some test
or marker) or subjective (i.e., subject gives an indication of or
feels an effect). For clinical use, the compounds of the invention
are formulated into pharmaceutical formulations for oral, rectal,
parenteral or other mode of administration. Usually the amount of
active compounds is between 0.1-95% by weight of the preparation,
preferably between 0.2-20% by weight in preparations for parenteral
use and preferably between 1 and 50% by weight in preparations for
oral administration.
[0054] The typical daily dose of the active substance varies within
a wide range and will depend on various factors such as, for
example, the individual requirement of each patient and the route
of administration. In general, oral and parenteral dosages will be
in the range of 5 to 1000 mg per day of active substance,
preferably 50 to 150 mg per day.
[0055] The specific examples below are to be construed as merely
illustrative, and not limitative of the remainder of the disclosure
in any way whatsoever. Without further elaboration, it is believed
that one skilled in the art can, based on the description herein,
utilize the present invention to its fullest extent. All
publications cited herein are hereby incorporated by reference in
their entirety.
EXAMPLES
[0056] Synthesis of Examples and Intermediates in Table I
##STR353## In scheme 1, the following symbols are used: (i)
K.sub.2CO.sub.3, DMF, diamine of choice; (ii) H.sub.2, Raney-Ni or
Pd/C, THF:Ethanol; (iii) (BOC).sub.2O, NaOH; (iv)
R.sup.1--SO.sub.2--Cl, Py, CH.sub.2Cl.sub.2; (v) HCl in diethyl
ether; (vi) alkylhalides. TfO=trifluoromethanesulfonate. General
Method A Reduction of nitronapthalenes Derivatives to naphthylamine
Derivatives
[0057] To a solution of nitronapthalenes derivatives (1 eq) in
EtOH:THF (4:1) was added Raney-Ni (.about.1.0 mL suspension in
EtOH) followed by hydrazine monohydrate (6 eq). The mixtures are
stirred vigorously for 3 hours and then filtered through celite
pretreated with water. The filtrate was concentrated, followed by
the addition of toluene. Purifications are performed by flash
column chromatography (SiO.sub.2, CHCl.sub.3/MeOH/NH.sub.3 9:1:0.4%
and 2 parts of light petroleum) to obtain the free base of
napthylamine derivatives.
General Method B
Reaction of 4-nitro-chloronaphthalenes with diamines
[0058] Diamines (1.2 eq) are added to a suspension of
chloronaphthalenes derivatives (1 eq) and K.sub.2CO.sub.3 (3.5) in
DMF. The suspensions are stirred at 65.degree. C. for 16 hours
followed by filtration. Elimination of volatiles to give a crude
residue. The residues are purified by flash chromatography
(SiO.sub.2, CHCl.sub.3.fwdarw.CHCl.sub.3/10% MeOH/0.4% aq.
NH.sub.3) to give the corresponding products as free bases.
[0059] (a) Intermediates for Preparation of Compounds in Tables I,
II, IV and V According to Scheme 1
Intermediate 1
[0060] 1-Methyl-4-(4-nitro-1-naphthyl)-1,4-diazepane--To a
suspension of 1-chloro-4-nitronaphthalene (1.0 g, 4.82 mmol) and
K.sub.2CO.sub.3 (2.0 g, 14.46 mmol) in DMF (10 mL) was added
1-methyl-1,4-diazepane (0.66 g, 5.78 mmol). The suspension was
stirred at 65.degree. C. for 16 hours followed by filtration.
Elimination of volatiles to give a crude residue. The residue was
purified by flash chromatography (SiO.sub.2,
CHCl.sub.3.fwdarw.CHCl.sub.3/10% MeOH/0.4% aq. NH.sub.3) to give
0.79 g (57%) of the free base: .sup.1H NMR (CDCl.sub.3) .delta.
8.85-8.75 (m, 1H), 8.35-8.25 (m, 1H), 8.20-8.12 (m, 1H), 7.70-7.60
(m, 1H), 7.55-7.45 (m, 1H), 6.97-6.90 (m, 1H), 3.70-3.55 (m, 4H),
2.83-2.71 (m, 4H), 2.44 (s, 3H), 2.09-1.97 (m, 2H); .sup.13C NMR
(CDCl.sub.3) .delta. 157.47, 139.13, 129.26, 127.82, 127.66,
126.53, 125.69, 125.40, 123.94, 111.22, 58.37, 57.37, 55.44, 54.71,
46.97, 27.88; MS (posES-FIA) m/z=found 285.1463, calc 285.1477.
Intermediate 2
[0061] 4-(4-Methyl-1,4-diazepan-1-yl)-1-naphthylamine--To a
solution of 1-methyl-4-(4-nitro-1-naphthyl)-1,4-diazepane (0.793 g,
2.78 mmol) in 40 mL of EtOH:THF (4:1) was added Raney-Ni
(.about.1.0 mL suspension in EtOH) followed by hydrazine
monohydrate (0.696 g, 13.9 mmol). The mixture was stirred
vigorously for 3 hours and then filtered through celite pretreated
with water. The filtrate was concentrated, followed by the addition
of toluene. Purification by flash column chromatography (SiO.sub.2,
CHCl.sub.3/MeOH/NH.sub.3 9:1:0.4% and 2 parts of light petroleum)
gave 0.441 g (62%) of the free base: .sup.1H NMR (CDCl.sub.3)
.delta. 8.37-8.29 (m, 1H), 7.85-7.76 (m, 1H), 7.55-7.40 (m, 2H),
7.07-7.01 (m, 1H), 6.75-6.68 (m, 1H), 3.96 (br s, 2H), 3.36-3.20
(m, 4H), 2.95-2.76 (m, 4H), 2.48 (s, 3H), 2.10-1.95 (m, 2H); MS
(posESI) m/z=256 (M+H).
Intermediate 3
[0062] 1-Ethyl-4-(4-nitro-1-naphthyl)piperazine--To a mixture of
1-chloro-4-nitronaphthalene (0.794 g, 3.82 mmol), and
K.sub.2CO.sub.3 (0.791 g, 5.73 mmol) in DMF (3 mL) was added
N-ethyl piperazine (0.486 mL, 3.82 mmol). The mixture was heated in
a microwave oven at 100 W for 1 minute. The reaction mixture was
allowed to coot down and the procedure was repeated 5 times. The
mixture was filtered and concentrated. The crude product was
purified by column chromatography (SiO.sub.2,
CHCl.sub.3.fwdarw.CHCl.sub.3/MeOH/NH.sub.3 9:1:0.4%) to give 0.950
g (87%) of a reddish brown solid: .sup.1H NMR (CDCl.sub.3) .delta.;
8.75-8.70 (m, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.24-8.20 (m, 1H),
7.72-7.66 (m, 1H), 7.60-7.54 (m, 1H), 7.02 (d, J=8.4 Hz, 1H),
3.32-3.24 (m, 4H), 2.85-2.70 (m, 4H), 2.54 (q, J=7.3 Hz, 2H), 1.17
(tr, J=7.3 Hz, 3); MS (posEI) m/z 385 (M.sup.+).
Intermediate 4
[0063] (cis)-3,5-Dimethyl-1-(4-nitro-1-naphthyl)piperazine--This
compound was prepared from 1-chloro-4-nitronaphthalene (0.481 g,
2.32 mmol) and cis-2,6-dimethylpiperazine (0.481 g, 2.32 mmol) by
the method described above, yield 0.554 g (84%) of the pure product
as a reddish brown solid; .sup.1H NMR (CDCl.sub.3) .delta.;
8.76-8.71 (m, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.23-8.14 (m, 1H),
7.72-7.66 (m, 1H), 7.61-7.55 (m, 1H), 7.0 (d, J=8.4 Hz, 1H),
3.45-3.37 (m, 2H), 3.35-3.25 (m, 2H), 2.55-2.47 (m, 2H), 1.17-1.4
(m, 6H); MS (posEI) m/z 385 (M.sup.+).
Intermediate 5
[0064] 3-Methyl-1-(4-nitro-1-naphthyl)piperazine--This compound was
prepared from 1-chloro-4-nitronaphthalene (0.395 g, 1.90 mmol) and
2-methylpiperazine (0.395 g, 1.90 mmol) by the method described
above: yield 0.470 g (84%) of the pure product as a solid; .sup.1H
NMR (CDCl.sub.3) .delta. 8.75-8.70 (m, 1H), 8.29 (d, J=8.55 Hz,
1H), 8.24-8.20 (m, 1H), 7.72-7.65 (m, 1H), 7.61-7.55 (m, 1H), 7.00
(d, J=8.55 Hz, 1H), 3.46-3.37 (m, 2H), 3.31-3.15 (m, 3H), 2.95-2.89
(m, 1H), 2.61-2.53 (m, 1H), 1.15 (d, J=6.4 Hz, 3H)); MS (EI) m/z
271 (M.sup.+).
Intermediate 6
[0065] 2-(4-Nitro-1-naphthyl)octahydropyrrolo[1,2-a]pyrazine--This
compound was prepared from 1-chloro-4-nitronaphthalene (0.306 g,
1.47 mmol) and octahydropyrrolo[1,2-a]pyrazine (0.185 g, 1.47 mmol)
by the method described above, yield 0.332 g (76%) of the pure
product as a yellow oil; .sup.1H NMR (CDCl.sub.3) .delta. 8.75-8.71
(m, 1H), 8.29 (d, J=8.5 Hz, 1H), 8.23-8.20 (m, 1H), 7.72-7.67 (m,
1H), 7.60-7.55 (m, 1H), 7.05 (d, J=8.5 Hz, 1H), 3.64-3.59 (m, 1H),
3.54-3.48 (m, 1H), 3.27-3.10 (m, 3H), 2.90-2.80 (m, 1H), 2.70-2.65
(m, 1H), 2.60-2.30 (m, 2H), 2.00-1.80 (m, 3H), 1.65-1.50 (m, 1H);
MS (posESI) m/z 298 (M+H).
Intermediate 7
[0066] 1-(4-Nitro-1-naphthyl)-1,4-diazepane--To a solution of
1-chloro-4-nitronaphthalene is (0.971 g, 4.68 mmol) and
K.sub.2CO.sub.3 (0.973 g, 7.10 mmol) in CH.sub.3CN (5.0 mL) was
added homopiperazine (0.711 g, 7.10 mmol). The reaction mixture was
heated in a closed sealed vessel at 120.degree. C. in a microwave
oven for 10 min. The suspension was filtered and concentrated.
Purification by column chromatography (SiO.sub.2,
CHCl.sub.3.fwdarw.CHCl.sub.3/MeOH 9:1) gave 0.952 g of the pure
product; .sup.1H NMR (CDCl.sub.3) .delta. 8.80-8.74 (m, 1H), 8.29
(d, J=8.5 Hz, 1H), 8.25-8.19 (m, 1H), 7.71-7.63 (m, 1H), 7.57-7.49
(m, 1H), 7.03 (d, J=8.5 Hz, 1H), 3.57-3.48 (m, 4H), 3.18-3.10 (m,
4H), 2.10-1.95 (m, 2H); MS (posEI) m/z 272 (M.sup.+).
Intermediate 8
[0067] tert-Butyl
4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate--1-Chloro-4-nitronaphthale-
ne (2.7 g, 13 mmol), tert-butyl-1-piperazinecarboxylate (2.4 g, 13
mmol) and potassium carbonate (2 g) were heated together in DMSO
(100 mL) at 90.degree. C. overnight. The solution was allowed to
cool to room temperature and poured into water (500 mL). The
product was collected by filtration and recrystallised from
methanol/water to yield 2.8 g (60%) of the title compound; mp
158.2.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta. 1.52 (s, 9H),
3.2 (br, 4H), 3.75 (br, 4H), 7.04 (d, J=8.53 Hz, 1H), 7.62 (t,
J=7.02 Hz, 1H), 7.73 (t, J=7.02 Hz, 1H), 8.25 (d, J=8.53 Hz, 1H),
8.3 (d, J=8.54 Hz, 1H), 8.73 (d, J=8.53 Hz, 1H).
Intermediate 9
[0068] 1-tert-Butyl
4-(4-{bis[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxy-
late--tert-Butyl 4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate (1
g, 2.8 mmol) in ethanol (200 mL) was hydrogenated at atmospheric
pressure over Pd/C (10%, 0.2 g) for 3 hours after which time the
uptake of hydrogen ceased. The solution was filtered and
evaporated. The residue was dissolved in toluene (100 mL) and
evaporated to give an off white solid. The solid was dissolved in
acetonitrile (50 mL) containing 4-dimethylaminopyridine (0.73 g).
Toluene sulfonyl chloride (1.14 g, 6 mmol) was added and the
mixture stirred at 35.degree. C. overnight. Brine was added and the
product extracted into ethyl acetate (2.times.100 mL). The organic
extracts were dried over MgSO.sub.4 and evaporated to give a pale
brown solid which was re-crystallized from ethanol. Yield 1.04 g
(58%) of a white solid. Mp 176-178; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.40 (s, 9H), 2.36 (s, 6H), 3.0 (br, 4H), 3.6
(br, 4H), 6.81 (AB, J=8.03 Hz, 1H), 6.89 (AB, J=8.03 Hz, 1H), 7.17
(m, 1H), 7.19 (d, J=7.53 Hz, 4H), 7.32 (m, 1H), 7.45 (d, J=8.53 Hz,
1H), 7.70 (d, J=8.54 Hz, 4H), 8.03 (d, J=8.03 Hz, 1H).
Intermediate 10
[0069] 1-tert-Butyl
4-(4-{[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylat-
e--1-tert-Butyl
4-(4-{bis[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxy-
late (1 g, 1.6 mmol) was dissolved in ethanol (50 mL). Potassium
hydroxide (85%, 0.54 g) was added and the solution refluxed for 12
hours. The solution was poured into water (100 mL) and acidified
with acetic acid (0.6 mL). The product precipitated and was
collected by filtration, washed with water and dried. Yield 0.81 g;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.36 (s, 9H), 2.22 (s,
3H), 2.8 (br, 4H), 3.5 (br, 4H), 6.47 (s, 1H), 6.79 (d, J=8.03 Hz,
1H), 7.03 (d, J=8.03 Hz, 2H), 7.07 (d, J=8.03 Hz, 1H), 7.3 (m, 2H),
7.47 (d, J=8.53 Hz, 2H), 7.69 (1, J=9.04 Hz, 1H), 8.03 (d, J=7.02
Hz, 1H).
Intermediate 11
[0070] 1-tert-Butyl
4-(4-{methyl[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarb-
oxylate--1-tert-Butyl
4-(4-{[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylat-
e (0.1 g, 0.2 mmol) was dissolved in DMSO (5 mL) and potassium
carbonate (0.2 g) and methyl iodide (0.1 g) were added. The mixture
was stirred and heated at 85.degree. C. for 15 hours. The solution
was poured into water (50 mL) and the product collected by
filtration, washed with water and dried. Yield 0.078 g (78%) of a
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.60 (s,
9H), 2.56 (s, 3H), 3.1 (br, 4H), 3.36 (s, 3H), 3.7 (br, 4H), 6.90
(AB, J=8.03 Hz, 1H), 6.97 (AB, J=8.03 Hz, 1H), 7.41 (d, J=8.03 Hz,
2H), 7.6 (m, 2H), 7.75 (d, J=8.29 Hz, 2H), 8.3 (m, 2H).
Intermediate 12
[0071] 5-Nitro-8-quinolinyl trifluoromethanesulfonate--To a
solution of 5-nitro-8-quinolinol (1.89 g, 9.40 mmol) and Et.sub.3N
(6.60 mL, 4.70 mmol) in CH.sub.2Cl.sub.2 (125 mL) was added
N-phenyl-trifluoromethanesulfonimide (5.06 g, 14.1 mmol). The
mixture was stirred at room temperature for 16 hours and then more
of added N-phenyl-trifluoromethanesulfonimide (1.0 equiv.) was
added and the mixture was stirred from another 16 hours. The
reaction mixture was washed with 10% aqueous NaHCO.sub.3, dried
with K.sub.2CO.sub.3, filtered and concentrated. The crude residue
was triturated in MeOH to give 1.2 g (40%) of the pure product:
.sup.1H NMR (CDCl.sub.3) .delta. 9.20-9.18 (m, 1H), 9.11-9.07 (m,
1H), 8.48-8.45 (m, 1H), 7.83-7.79 (m, 1H), 7.76-7.72 (m, 1H); MS
(posEI-DIP) m/z 321 (M+H).
Intermediate 13
[0072] 8-(4-Methyl-1-piperazinyl)-5-nitroquinoline--To a suspension
of 5-nitro-8-quinolinyl trifluoromethanesulfonate (0.50 g, 1.56
mmol) and K.sub.2CO.sub.3 (0.43 g, 3.12 mmol) in CH.sub.3CN (6.0
mL) was added 1-methylpiperazine (0.19 mL, 1.71 mmol). The
suspension was stirred at room temperature for 16 hours. The
mixture was filtered and concentrated. Purification via flash
column chromatography (SiO.sub.2, CHCl.sub.3/MeOH/NH.sub.3
9:1:0.4%) gave 0.509 g of the pure product: reversed phase
HPLC>95% purity; MS (posESI) m/z 273 (M+H).
Intermediate 14
[0073]
tert-Butyl(2R,6S)-2,6-dimethyl-4-(4-nitro-1-naphthyl)-1-piperazine-
carboxylate--To a solution of
cis-3,5-dimethyl-1-(4-nitro-1-naphthyl)piperazine (0.565 g, 1.98
mmol) and NaOH (0.198 g, 4.95 mmol) in THF:water (20 mL, 1:1) was
added di-tert-butyl dicarbonate (1.30 g, 5.94 mmol) in THF (4 mL).
The reaction mixture was stirred at room temperature for 4 hours
followed by the addition of 3.0 equiv. of di-tert-butyl dicarbonate
and 2.5 equiv. of NaOH. The mixture was stirred at room temperature
for another 3 days. The mixture was concentrated and extracted with
CHCl.sub.3 (3.times.20 mL). The combined organic phases were dried
with K.sub.2CO.sub.3, filtered and concentrated. The crude residue
was purified by column chromatography on silica using CHCl.sub.3 as
eluent gave 0.200 g (26%) of the pure product as a solid brown
solid: MS (posESI) m/z 386 (M+H).
Intermediate 15
[0074]
tert-Butyl-2-methyl-4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate
was prepared from 3-methyl-1-(4-nitro-1-naphthyl)piperazine (0.436
g, 1.61 mmol) by the method described above: yield 0.552 g (92%) of
the pure product as a yellow oil; .sup.1H NMR (CDCl.sub.3) .delta.
8.73-8.70 (m, 1H), 8.34-8.30 (m, 1H), 8.28 (d, J=8.5 Hz, 1H),
7.74-7.69 (m, 1H), 7.63-7.58 (m, 1H), 7.02 (d, J=8.5 Hz, 1H),
4.50-4.442 (m, 1H), 4.10-4.03 (m, 1H), 3.52-3.39 (m, 2H), 3.32-3.27
(m, 1H), 3.08-3.03 (m, 1H), 2.89-2.82 (m, 1H), 1.53 (s, 3H), 1.51
(s, 9H); MS (posESI) m/z 372 (M+H).
EXAMPLES OF COMPOUNDS ACCORDING TO THE INVENTION
Example 1
4-Methyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,
hydrochloride
[0075] 1-tert-Butyl
4-(4-{[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxylat-
e (intermediate 10) (0.4 g, 0.8 mmol) was dissolved in THF (20 mL)
and treated with a 1N solution of HCl in diethyl ether (30 mL) for
twelve hours. The product was collected as a pale pink solid. Yield
0.2 g (60%). mp 181.degree. C. (dec); .sup.1H NMR (DMSO-d.sub.6)
.delta. 2.80 (s, 3H), 3.1 (br, 4H), 3.3 (br, 4H), 7.00 (q, J=8.06
Hz, 2H), 7.27 (ab, J=8.30 Hz, 2 H), 7.4-7.5 (m, 2H), 7.53 (ab,
J=8.30 Hz, 2H), 7.99 (d, J=8.06 Hz, 1H), 8.07 (d, J=7.57 Hz, 1H),
9.2 (br, 2H); MS (ESI+) for C21 H23 N3 O2 S Found m/z 381.1499
M.sup.+ Calc. 381.1611.
Example 2
3,4-Dimethoxy-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,
hydrochloride
[0076] tert-Butyl 4-(4-nitro-1-naphthyl)-1-piperazinecarboxylate (1
g, 2.8 mmol) in ethanol (200 mL) was hydrogenated at atmospheric
pressure over Pd/C (10%, 0.2 g) for 3 hours after which time the
uptake of hydrogen ceased. The solution was filtered and
evaporated. The residue was dissolved in toluene (100 mL) and
evaporated to give an off white solid. The solid was dissolved in
acetonitrile (50 mL) containing 4-dimethylaminopyridine (0.73 g).
This solution was divided into three portions. To one portion was
added 3,4-dimethoxybenzene sulfonyl chloride (0.24 g). The mixture
was stirred for 4 hours at 40.degree. C. under nitrogen. Ethyl
acetate (50 mL) was added and the solution washed with brine
(2.times.100 mL). The organic phase was separated, dried over
MgSO.sub.4 and evaporation. Purification by flash chromatography
(SiO.sub.2, Petrol:Ethyl acetate 1:1) afforded the butoxycarbonyl
protected product which was dissolved in methanol (2 mL) and
treated with a 1N solution of HCl in ethyl acetate (25 mL) for
three hours. The product was precipitated with ether (200 mL) and
collected as a pale pink solid, 45 mg (12%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 3.17 (br, 4H), 3.35 (br, 4H), 3.63 (s, 3H),
3.78 (s, 3H), 7.03 (d, J=8.55 Hz, 1H), 7.07 (ab, J=13.92, 8.06 Hz,
2H), 7.24 (dd, J=8.30, 2.19 Hz, 1H), 7.46 (m, 1H), 7.51 (m, 1H),
8.05 (d, J=7.57 Hz, 1H), 8.12 (d, J=7.56 Hz, 1H), 9.2 (br, 2H),
9.93 (s, 1H); MS (ESI+) for C22 H25 N3 O4 S m/z 427
(M+H).sup.+.
Example 3
3,4-di-Fluoro-N-[4-(4-methyl-1,4-diazepan-1-yl)-1-naphthyl]benzenesulfonam-
ide, hydrochloride
[0077] To a solution of (intermediate 2)
4-(4-methyl-1,4-diazepan-1-yl)-1-naphthylamine (0.173 g, 0.676
mmol) and pyridine (0.450 mL, 4.73 mmol) in CH.sub.2Cl.sub.2 (3 mL)
was added a solution of 2,4-Di-fluorobenzenesulfonyl chloride
(0.158 g, 0.743 mmol) in CH.sub.2Cl.sub.2 (2 mL). The mixture was
stirred at room temperature for 16 hours and then concentrated. The
crude mixture was purified by column chromatography (SiO.sub.2,
CHCl.sub.3/MeOH/NH.sub.3 9:1:0.4%). The free base was converted to
its HCl-salt and recrystallized from MeOH and ether to give 0.227 g
(79%) of the salt: .sup.1H NMR (DMSO-d6) .delta. 11.23 (br s, 1H),
10.49 (s, 1H), 8.21-8.17 (m, 1H), 7.72-7.65 (m, 1H), 7.55-7.46 (m,
3H), 7.19-7.10 (m, 3H), 3.65-3.35 (m, 6H), 3.30-3.15 (m, 2H),
2.85-2.82 (m, 3H), 2.33-2.10 (m, 2H); MS (posES-FIA) m/z 432
(M+H).
Example 4
3-Fluoro-N-[4-(4-methyl-1,4-diazepan-1-yl)-1-naphthyl]benzenesulfonamide,
hydrochloride
[0078] To a solution of (intermediate 3 after reduction according
to Method A) 4-(4-methyl-1,4-diazepan-1-yl)-1-naphthylamine (0.173
g, 0.676 mmol) and pyridine (450 .mu.L, 4.73 mmol) in
CH.sub.2Cl.sub.2 (3.0 mL) was added 3-fluorobenzenesulfonyl
chloride (0.145 g, 0.743 mmol) in CH.sub.2Cl.sub.2 (1.0 mL). The
solution was stirred at room temperature for 16 hours and the
volatiles were evaporated. The crude product was purified by column
chromatography (SiO.sub.2, CHCl.sub.3/MeOH/NH.sub.3 9:1:0.4%) to
give 240 mg of the product as solid that was triturated with
MeOH/ether to give 0.180 g (64%) of the free base which was
converted to its HCl-salt: .sup.1H NMR (DMSO-d6) .delta. 11.07 (br
s, 1H), 10.28 (br s, 1H), 8.20-8.16 (m, 1H), 7.98-7.94 (m, 1H),
7.60-7.40 (m, 6H), 7.16-7.12 (m, 1H), 7.06-7.02 (m, 1H), 3.65-3.30
(m, partly obscured by solvent signal, HDO, 6H), 3.26-3.18 (m, 2H),
2.84 (s, 3H), 2.30-2.05 (m, 2H); MS (posES-FIA) m/z=414 (M+H).
Example 5
N-[4-(4-Ethyl-1-piperazinyl)-1-naphthyl]benzenesulfonamide,
hydrochloride
[0079] The title compound was prepared from (intermediate 3 after
reduction according to Method A)
4-(4-ethyl-1-piperazinyl)-1-naphthylamine (0.241 g, 0.945 mmol) and
benzenesulfonyl chloride (0.121 mL, 0.945 mmol) by the method
described above to yield HCl-salt 0.210 g (51%); .sup.1H NMR
(CD.sub.3OD) .delta. 8.19-8.15 (m, 1H), 7.94-7.90 (m, 1H),
7.70-7.66 (m, 2H), 7.56-7.46 (m, 2H), 7.44-7.36 (m, 3H), 7.19 (d,
J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 3.75-3.40 (m, 6H), 3.34 (q,
J=7.6 Hz, 2H), 3.25-3.10 (m, 2H), 1.43 (tr, J=7.6 Hz, 3H);
MS(posEI) m/z 387 (M.sup.+).
Example 6
N-(4-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl-1-naphthyl)-4-methylbenzenesu-
lfonamide, hydrochloride
[0080] To a solution of (intermediate 6)
2-(4-nitro-1-naphthyl)octahydropyrrolo[1,2-a]pyrazine (0.160 g,
0.54 mmol) in 10 mL THF:EtOH (20 mL, 1:4) was added Raney-Ni (1.0
mL suspension in EtOH) followed by hydrazine hydrate (0.135 g, 2.70
mmol). The mixture was stirred vigorously at room temperature for
16 hours and then filtered through celite pretreated with water.
The filtrate was concentrated and the residue was dissolved in
CH.sub.2Cl.sub.2 (3 mL) and pyridine (0.35 mL, 3.78 mmol) and
p-toluensulfonyl chloride (0.13 g, 0.54 mmol) were added to the
solution. The reaction mixture was stirred at room temperature for
16 hours and then concentrated. The crude product was purified by
column chromatography chromatography (SiO.sub.2,
CHCl.sub.3/MeOH/NH.sub.3 9:1:0.4%) to give 0.217 g (95%) of the
free base which was converted to its HCl-salt: .sup.1H NMR
(CD.sub.3OD) .delta. 8.21-8.14 (m, 1H), 7.97-7.93 (m, 1H),
7.58-7.47 (m, 3H), 7.43-7.37 (m, 1H), 7.25-7.10 (m, 4H), 4.12-4.02
(m, 1H), 3.80-3.0 (m, partly obscured by solvent signal, 8H),
2.45-2.10 (m, 3H), 2.35 (s, 3H), 1.87-1.75 (m, 1H); MS (posEI) m/z
421 (M.sup.+).
Example 7
N-(4-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl-1-naphthyl)-3,4-dimethoxybenz-
enesulfonamide, hydrochloride
[0081] The title compound was prepared from (intermediate 6)
2-(4-nitro-1-naphthyl)octahydropyrrolo[1,2-a]pyrazine (0.133 g,
0.447 mmol) by the method described above: yield 0.160 g (76%) of
the pure product as the free base which was converted to its
HCl-salt; .sup.1H NMR (CD.sub.3OD) .delta. 8.20-8.16 (m, 1H),
7.96-7.92 (m, 1H), 7.54-7.48 (m, 1H), 7.43-7.38 (m, 1H), 7.30-7.26
(m, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.09-7.07
(m, 1H), 6.95-6.92 (m, 1H), 3.83 (s, 3H), 3.82-3.0 (m, partly
obscured by solvent signal, 10H), 3.62 (s, 3H), 2.50-2.10 (m, 2H);
MS (posEI) m/z 467 (M.sup.+).
Example 8
N-[4-(4-Ethyl-1-piperazinyl)-1-naphthyl]-4-methylbenzenesulfonamide,
hydrochloride
[0082] To a solution of (intermediate 3 after reduction according
to Method A) 4-(4-ethyl-1-piperazinyl)-1-naphthylamine 0.241 g,
0.945 mmol) and pyridine (0.534 mL, 0.945 mmol) in CH.sub.2Cl.sub.2
(3.0 mL) was added p-toluenesulfonyl chloride (0.180 g, 0.945 mmol)
in CH.sub.2Cl.sub.2 (2.0 mL). The mixture was stirred at room
temperature for 16 hours followed by the addition of
CH.sub.2Cl.sub.2 (15 mL). The reaction mixture was washed with
saturated aqueous NaHCO.sub.3, dried with Na.sub.2SO.sub.4,
filtered and concentrated. The crude residue was purified by column
chromatography (SiO.sub.2.
CHCl.sub.3.fwdarw.CHCl.sub.3/MeOH/NH.sub.3 9:1:0.4%) to give a
solid which was converted to its HCl-salt: yield HCl-salt 0.372 g
(88%); .sup.1H NMR (CD.sub.3OD) .delta. 8.20-8.15 (m, 1H),
7.97-7.93 (m, 1H), 7.58-7.54 (m, 2H), 7.53-7.47 (m, 1H), 7.43-7.37
(m, 1H), 7.25-7.20 (m, 2H), 7.18 (d, J=8.0 Hz, 1H), 7.10 (d, J=8.0
Hz, 1H), 3.80-3.10 (m, partly obscured by solvent signal, 10H),
2.35 (s, 3H), 1.43 (tr, J=7.3 Hz, 3H); MS (posEI) m/z 409
(M.sup.+).
Example 9
3,4-Dimethoxy-N-[4-(3-methyl-1-piperazinyl)-1-naphthyl]benzenesulfonamide,
hydrochloride
[0083] The title compound was prepared from (intermediate 8 after
reduction according to Method A) tert-butyl
4-(4-amino-1-naphthyl)-2-methyl-1-piperazinecarboxylate (0.189 g,
0.55 mmol) and 3,4-dimethoxybenzenesulfonyl chloride (0.130 g, 0.55
mmol) by the method described above: yield HCl-salt 0.068 g (26%);
.sup.1H NMR (CD.sub.3OD)
Example 10
4-Methyl-N-[4-(4-methyl-1-piperizinyl)-1-naphthyl]-1-benzenesulfonamide,
hydrochloride
[0084] To a solution of 4-(4-methyl-1-piperazinyl)-1-naphthylamine
(prepared according to methods A and B) (0.099 g, 0.409 mmol) and
pyridine (231 .mu.L, 2.86 mmol) in CH.sub.2Cl.sub.2 (3.0 mL) was
added 4-methylbenzenesulfonyl chloride (0.078 g, 0.409 mmol) in
CH.sub.2Cl.sub.2 (1.0 mL). The solution was stirred at room
temperature for 16 hours and then washed with saturated aqueous
NaHCO.sub.3, dried with Na.sub.2SO.sub.4, filtered and
concentrated. The crude product was purified via column
chromatography (SiO.sub.2,
CHCl.sub.3.fwdarw.CHCl.sub.3/MeOH/NH.sub.3 9:1:0.4%) to give the
pure base which was converted to its HCl-salt: yield 110 mg (62%);
.sup.1H NMR (DMSO-d6) .delta. 10.86 (br s, 1H), 10.02 (s, 1H),
8.11-8.03 (m, 2H), 7.60-7.56 (m, 2H), 7.55-7.44 (m, 2H), 7.33-7.30
(m, 2H), 7.09-7.06 (m, 1H), 7.04-7.01 (m, 1H), 3.55-3.32 (m, 6H),
3.19-3.10 (m, 2H), 2.86 (s, 3H), 2.34 (s, 3H); MS (posES-FIA)
m/z=395.1665 (M+H)(calc 395.1667).
Example 11
4-Methyl-N-[4-(5-methyl-2,5-diazabicyclo[2,2,1]hept-2-yl]-naphtyl]benzenes-
ulfonamide, hydrochloride
[0085] To a solution of
4-(5-methyl-2,5-diazabicyclo[2,2,1]hept-2-yl)-1-naphtylamine (0.210
g, 0.829 mmol) (prepared according to methods A and B), pyridine
(468 .mu.L, 5.80 mmol) in CH.sub.2Cl.sub.2 (3.0 mL) was added
4-methylbenzenesulfonyl chloride (0.158 g, 0.829 mmol) in
CH.sub.2Cl.sub.2 (1.0 mL). The solution was stirred at room
temperature for 16 hours and then concentrated. The crude product
was purified via column chromatography (SiO.sub.2,
CHCl.sub.3.fwdarw.CHCl.sub.3/MeOH/NH.sub.3 9:1:0.4%) to give the
pure base which was converted to its HCl-salt: yield 160 mg (43%);
.sup.1H NMR (DMSO-d6) .delta. 10.78 (br s, 1H), 9.90-9.88 (m, 1H),
8.02-7.98 (m, 2H), 7.58-7.55 (m, 2H), 7.49-7.41 (m, 2H), 7.33-7.30
(m, 2H), 7.06-7.03 (m, 1H), 6.93-6.90 (m, 1H), 4.38-4.30 (m, 3H),
3.65-3.60 (m, 3H), 2.90-2.87 (m, 1H), 2.86-2.83 (m, 3H), 2.36 (br
s, 2H), 2.35 (s, 3H); MS (posES-FIA) m/z=407.1655 (M+H)(calc
407.1667).
Example 12
4-Methyl-N-[4-(3-methyl-1-piperazinyl)-1-naphthyl]benzenesulfonamide,
hydrochloride
[0086] To a solution of (intermediate 8 after resuction according
to Method A) tert-butyl
4-(4-amino-1-naphthyl)-2-methyl-1-piperazinecarboxylate (0189 g,
0.55 mmol) and pyridine (0.311 mL, 3.85 mmol) in CH.sub.2Cl.sub.2
(3 mL) was added tolouenesulfonyl chloride (0.105 g, 0.55 mmol).
The mixture was stirred at room temperature for 16 hours and then
concentrated. The crude residue was purified by column
chromatography (SiO.sub.2, EtOAc:pentane 3:7). The pure
intermediate was dissolved in small amount of MeOH and de-protected
using ether saturated with HCl-gas. The precipitate was collected
by filtration and triturated with MeOH and ether: yield HCl-salt
0.047 g (19%); .sup.1H NMR (CDCl.sub.3) .delta. 8.28-8.20 (m, 1H),
7.85-7.79 (m, 1H), 7.65-7.55 (m, 1H), 7.50-7.10 (m, partly obscured
by solvent signal, 5H), 6.95-6.85 (m, 1H), 6.51 (br s, 1H),
4.50-4.25 (m, 1H), 4.05-3.85 (m, 1H), 3.52-3.33 (m, 1H), 3.28-3.05
(m, 2H), 2.97-2.85 (m, 1H), 2.82-2.67 (m, 1H), 2.85 (s, 3H),
1.52-1.47 (m, partly obscured by H.sub.2O signal, 3H); MS (pos-ES)
m/z=395 (M+H).
Example 13
2-N-[4-(1-piperazinyl)-1-naphthyl]naphthalenesulfonamide,
hydrochloride
[0087] To another portion of the solution of the reduced nitro
compound was added 2-naphthalenesulfonyl chloride (0.23 g). The
mixture was stirred for 4 hours at 40.degree. C. under nitrogen and
worked up as above. The product obtained was identified as
1-tert-butyl
4-(4-{bis[(2-naphthalene)sulfonyl]amino}-1-naphthyl)-1-piperazinecarboxyl-
ate. This bis sulfonamide was refluxed for 3 hours in ethanol (10
mL) containing NaOH (0.1 g). This solution was added to a solution
of HCl in ethyl acetate (1N, 100 mL) and stirred overnight. The
solution was evaporated to give the crude product which was
purified by preparative hplc (CH.sub.3CN:H.sub.2O 10% to 50%
gradient). Yield 47 mg. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
3.05 (br, 4H), 3.3 (br, 4H), 7.0 (s, 2H), 7.2-7.5 (m, 2H), 7.55 (t,
J=7.9 Hz, 1H), 7.62 (t, J=6.9 Hz, 1H), 7.76 (m, 1H), 7.9-8.1 (m,
5H), 8.21 (s, 1H), 8.7 (br, 2H)
Example 14
N,4-Dimethyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,
hydrochloride
[0088] 1-tert-Butyl
4-(4-{methyl[(4-methylphenyl)sulfonyl]amino}-1-naphthyl)-1-piperazinecarb-
oxylate (intermediate 14 after reduction according to Method A) (75
mg, 0.15 mmol) was dissolved in methanol (5 mL) and treated with 1N
HCl in ether (20 mL). After stirring overnight, the product
precipitated and was collected by filtration, washed with ether and
dried. Yield 60 mg (92%) of an off white solid.
Example 15
N-[4-(1,4-Diazepan-1-yl)-1-napthyl]-4-methylbenzenesulfonamide,
hydrochloride
[0089] To a solution of (intermediate 7 after reduction according
to Method A) 4-(1,4-diazepan-1-yl)-1-naphtylamine (0.399 g, 1.17
mmol), pyridine (661 .mu.L, 8.19 mmol) and Et.sub.3N (329 .mu.L,
2.34 mmol in CH.sub.2Cl.sub.2 (3.0 mL) was added
4-methylbenzenesulfonyl chloride (0.223 g, 1.17 mmol) in
CH.sub.2Cl.sub.2 (1.0 mL). The solution was stirred at room
temperature for 16 hours and then concentrated. The crude product
was purified via column chromatography (SiO.sub.2,
CHCl.sub.3.fwdarw.CHCl.sub.3/MeOH/NH.sub.3 9:1:0.4%) to give 0.360
g of the boc-protected compound. De-protection was accomplished by
dissolving the intermediate in MeOH and then adding HCl-gas
dissolved in ether. The precipitate was collected by filtration to
give 0.143 g (28%) of the pure compound as the HCl-salt: .sup.1H
NMR (DMSO-d6) .delta. 10.00 (s, 1H), 9.28 (br s, 1H), 8.20-8.16 (m,
1H), 8.04-7.99 (m, 1H), 7.60-7.55 (m, 2H), 7.54-7.49 (m, 1H),
7.47-7.42 (m, 1H), 7.33-7.29 (m, 2H), 7.12 (d, J=8.16 Hz, 1H), 7.01
(d, J=8.16 Hz, 1H), 3.42-3.31 (m, 6H), 3.20.3.16 (m, 2H), 2.34 (s,
3H), 2.14-2.08 (m, 2); MS (posES-FIA) m/z=395.1667 (M+H) (calc
395.1667)
Example 16
N-[4-(1,4-Diazepan-1-yl)-1-napthyl]-2-methoxy-4-methylbenzenesulfonamide,
hydrochloride
[0090] To a solution of (intermediate 7 after reduction according
to Method A) 4-(1,4-diazepan-1-yl)-1-napthylamine (0.399 g, 1.17
mmol), pyridine (661 .mu.L, 8.19 mmol) and Et.sub.3N (329 .mu.L,
2.34 mmol in CH.sub.2Cl.sub.2 (3.0 mL) was added
2-methoxy-4-methylbenzenesulfonyl chloride (0.258 g, 1.17 mmol) in
CH.sub.2Cl.sub.2 (1.0 mL). The solution was stirred at room
temperature for 16 hours and then concentrated. The crude product
was dissolved in EtOH and powdered KOH was added to the solution.
The mixture was stirred at 70.degree. C. for 16 hours. The
suspension was concentrated and water was added. The solution was
neutralized with 1N HCl and extracted with CH.sub.2Cl.sub.2
(2.times.20 mL). The combined organic phases were washed with
brine, dried with Na.sub.2SO.sub.4, and concentrated. Column
chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2.fwdarw.CH.sub.2Cl.sub.2/MeOH (95:5) gave 0.432 g
of a reddish brown solid. De-protection of the intermediate using
MeOH ether saturated with HCl-gas gave brown solid which was
collected by filtration. The product was re-crystallized from
MeOH/ether to give 109 mg (20%) of product as its HCl-salt: .sup.1H
NMR (DMSO-d6) .delta. 9.74 (s, 1H), 9.36 (br s, 2H), 8.20-8.14 (m,
2H), 7.55-7.45 (m, 3H), 7.44-7.42 (m, 1H), 7.16-7.09 (m, 2H),
7.02-7.00 (m, 1H), 6.75-6.74 8 m, 1H), 3.85 (s, 3H), 3.42-3.27 (m,
6H), 3.18-3.14 (m, 2H), 2.31-(s, 3H), 2.14-2.07 (m, 2H); MS
(posES-FIA) m/z=425.1768 (M+H)(calc 425.1774)
Example 17
N-(2-Methoxy-4-methylphenyl)-4-(3,5-trimethyl-1-piperazinyl)-1-naphthalene-
sulfonamide, hydrochloride
[0091] To a solution of (intermediate-4 after reduction according
to Method A) 4-(2,6-dimethyl-1-piperazinyl)-1-naphthylamine (0.203
g, 0.563 mmol) and pyridine (322 .mu.L, 3.99 mmol) in DCM (3.0 mL)
was added 4-methylbenzenesulfonyl chloride (0.107 g, 0.563 mmol) in
DCM (1.0 mL). The solution was stirred at room temperature for 16
hours and then washed with saturated aqueous NaHCO.sub.3, dried
with Na.sub.2SO.sub.4, filtered and concentrated. The crude
intermediate was purified via column chromatography on silica using
CHCl.sub.3/CHCl.sub.3+10% MeOH+0.4% NH.sub.3 to give 0.230 g of the
boc-protected intermediate. Removal of the boc-group was
accomplished by dissolving the intermediate in MeOH and then adding
ether saturated with HCl-gas. The crude product was dissolved in
DCM and then purified via column chromatography on silica using
CHCl.sub.3/CHCl.sub.3+10% MeOH+0.4% NH.sub.3 to give 156 mg (67%)
of the pure base which was converted to its HCl-salt: 1H NMR
(DMSO-d6) .delta. 10.01 (s, 1H), 9.86-9.78 (m, 1H), 9.14-9.00 (m,
1H), 8.13-8.10 (m, 1H), 8.05-8.02 (m, 1H), 7.58-7.55 (m, 2),
7.53-7.49 (m, 1H), 7.48-7.43 (m, 1H), 7.33-7.29 (m, 2H), 7.06 (d,
J=7.85 Hz, 1H), 7.02 (d, J=8.17 Hz, 1H), 3.65-3.55 (m, 2H),
3.35-3.27 (m, 2H), 2.86-2.79 (m, 2H), 2.34 (s, 3H), 1.31 (d, J=6.60
Hz, 6H); MS (posES-FIA) m/z=409.1838 (M+H)(calc 407.1824)
Example 18
N-[4-(4-Isopropyl-1-piperizinyl)-1-naphthyl]-4-methylbenzenesulfonamide,
hydrochloride
[0092] To a solution of
4-(4-isopropyl-1-piperazinyl)-1-naphthylamine (0.209 g, 0.776 mmol)
(prepared according to Methods A and B) and pyridine (438 .mu.L,
5.43 mmol) in CH.sub.2Cl.sub.2 (3.0 mL) was added
4-methylbenzenesulfonyl chloride (0.163 g, 0.850 mmol) in
CH.sub.2Cl.sub.2 (1.0 mL). The solution was stirred at room
temperature for 16 hours and the solid was collected by filtration
as the HCl-salt to yield 0.236 g (66%); .sup.1H NMR (DMSO-d6)
.delta. 10.65 (br s, 1H), 9.95 (br s, 1H), 8.10-8.05 (m, 1H),
8.02-7.94 (m, 1H), 7.56-7.49 (m, 2H), 7.48-7.37 (m, 2H), 7.28-7.22
(m, 2H), 7.02-6.94 (m, 2H), 3.53-3.40 (m, 3H), 3.37-3.15 (m, 8H),
2.28 (s, 3H), 1.32-1.28 (m, 6H); MS (posES-FIA) m/z=423.1972
(M+H)(calc 423.1980).
Example 19
4-Bromo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0093] .sup.1H NMR (DMSO-d6) .delta.; 10.21 (s, 1H), 9.12 (brs,
2H), 8.12 (d, J=8.48 Hz, 1H), 7.97 (d, J=8.16 Hz., 1H), 7.75-7.70
(m, 2H), 7.61-7.57 (m, 2H), 7.54-7.49 (m, 1H), 7.48-7.43 (m, 1H),
7.10-7.01 (M, 2 h), 3.38-3.31 (M, 4H), 3.23-3.10 (M, 4H), MS
(posESI) m/z=446 (M+H).
Example 20
2,5-Dichloro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,
hydrochloride
[0094] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.2 (br, 4H),
3.4 (br, 4H), 7.09 (s, 2H), 7.54 (m, 2H), 7.70 (m, 3H), 8.10 (m,
2H); MS (ESI+) for C20 H19 C12 N3 O2 S m/z 436 (M+H).sup.+.
Example 21
2-Chloro-4-fluoro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,
hydrochloride
[0095] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.1 (br, 4H),
3.4 (br, 4H), 7.01 (AB, J=8.03 Hz, 1H), 7.04 (AB, J=8.03 Hz, 1H),
7.27 (dt, J=3.01, 8.53 Hz, 1H), 7.5 (m, 2H), 7.68 (dd, J=2.51, 9.03
Hz, 1H), 7.85 (dd, J=6.52, 9.03 Hz, 1H), 8.10 (d, J=7.03 Hz, 1H),
8.20 (d, J=7.03 Hz, 1H); MS (ESI+) for C20 H19 Cl F N3 O2 S m/z 420
(M+H).sup.+.
Example 22
2,3-Dichloro-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,
hydrochloride
[0096] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.1 (br, 4H),
3.4 (br, 4H), 7.01 (AB, J=8.03 Hz, 1H), 7.03 (AB, J=8.03 Hz, 1H),
7.42 (t, J=7.78 Hz, 1H), 7.50 (m, 2H), 7.81 (dd, J=1.51, 8.03 Hz,
1H), 7.85 (dd, J=1.51, 8.03 Hz, 1H), 8.10 (dd, J=6.52, 2.0 Hz, 1H),
8.20 (dd, J=7.53, 2.01 Hz, 1H); MS (ESI+) for C20 H19 C12 N3 O2 S
m/z 436 (M+H).sup.+.
Example 23
2,4-Dichloro,5-methyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,
hydrochloride
[0097] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 2.27 (s, 3H),
3.15 (br, 4H), 3.4 (br, 4H), 7.07 (s, 2H), 7.54 (m, 2H), 7.79 (s,
1H), 7.85 (s, 1H), 8.13 (m, 1H), 8.19 (m, 1H); MS (ESI+) for C21
H21 C12 N3 O2 S m/z 450 (M+H).sup.+.
Example 24
3-Trifluoromethyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,
hydrochloride
[0098] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.2 (br, 4H),
3.4 (br, 4H), 7.05 (AB, J=8.03 Hz, 1H), 7.10 (AB, J=8.03 Hz, 1H),
7.40 (t, J=7.53 Hz, 1H), 7.50 (t, J=7.53 Hz, 1H), 7.76 (t, J=8.03
Hz, 1H), 7.81 (s, 1H), 7.88 (d, J=8.53 Hz, 1H), 7.95 (d, J=8.03 Hz,
1H), 7.99 (d, J=8.03 Hz, 1H), 8.12 (d, J=8.54 Hz, 1H); MS (ESI+)
for C21 H20 F3 N3 O2 S m/z 436 (M+H).sup.+.
Example 25
2-Trifluoromethyl-N-[4-(1-piperazinyl)-1-naphthyl]benzenesulfonamide,
hydrochloride
[0099] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.0 (br, 4H),
3.4 (br, 4H), 6.93 (s, 2H), 7.36 (m, 1H), 7.41 (m, 1H), 7.64 (m,
2H), 7.85 (dd, J=2.01, 7.53 Hz, 1H), 7.90 (dd, J=2.01, 7.03 Hz,
1H), 8.02 (d, J=8.54 Hz, 2H).
Example 26
4-Bromo-N-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0100] .sup.1H NMR (DMSO-d6) .delta.; 9.12 (brs, 2H), 8.22-8.07 (m,
2H), 7.89 (d, J=8.44 Hz, 2H), 7.74-7.58 (m, 4H), 7.10 (d, J=7.91
Hz, 1H), 6.89 (d, 8.18 Hz, 1H), 3.50 (s, 3H), 3.43-3.27 (m,
obscured in part by solvent signal), MS (posESI) m/z=460 (M+H).
Example 27
Naphthalene-1-sulfonic acid
(4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride
[0101] .sup.1H NMR (DMSO-d6) .delta.; 9.00 (brs, 1H), 8.77-8.71 (m,
1H), 8.18 (d, J=8.44 Hz, 1H), 8.10-8.02 (m, 2H), 8.01-7.96 (m, 1H),
7.90 (d, J=8.18 Hz, 1H), 7.73-7.62 (m, 2H), 7.56-7.49 (m, 1H),
7.47-7.39 (m, 1H), 7.31-7.23 (m, 1H), 7.02-6.94 (m, 2H), 3.40-3.25
(m, obscured by solvent signal), 3.19-3.05 (m, 4H), MS (posESI)
m/z=418 (M+H).
Example 28
2,5-Dichloro-thiophene-3-sulfonic acid
(4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride
[0102] .sup.1H NMR (DMSO-d6) .delta.; 10.52 (brs, 1H), 9.02 (brs,
2H), 8.19-8.12 (m, 1H), 8.01-7.94 (m, 1H), 7.60-7.47 (m, 2H),
7.23-7.12 (m, 3H), 3.43-3.28 (m, obscured in part by solvent
signal), 3.25-3.10 (m, m, 4H), MS (posESI) m/z=442 (M+H).
Example 29
4-Methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0103] .sup.1H NMR (DMSO-d6) .delta.; 9.96 (s, 1H), 9.13 (brs, 1H),
8.15-8.08 (m, 1H), 8.06-7.99 (m, 1H), 7.65-7.57 (m, 2H), 7.55-7.42
(m, 2H), 7.12-6.97 (m, 4H), 3.43-3.29 (m, 4H), 3.24-3.10 (m, 4H),
MS (posESI) m/z=398 (M+H).
Example 30
4-Chloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0104] .sup.1H NMR (DMSO-d6) .delta.; 10.25 (brs, 1H), 9.03 (brs,
1H), 8.16-8.09 (m, 1H), 8.00-7.94 (m, 1H), 7.71-7.41 (m, 6H),
7.13-7.01 (m, 2H), 3.40-3.26 (m, obscured in part by solvent
signal), 3.24-3.08 (m, 4H), MS (posESI) m/z=402 (M+H).
Example 31
2-Chloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0105] .sup.1H NMR (CDCl.sub.3) .delta.; 8.24-8.12 (m, 2H),
7.90-7.83 (m, 1H), 7.60-7.43 (m, 3H), 7.32-7.27 (m, obscured in
part by solvent signal, 1H), 7.09 (s, 1H), 7.04 (d, J=8.44 Hz, 1H),
6.87-6.79 (m, 1H), 3.90-3.40 (m, 4H), 3.12-2.80 (m, 4H), MS
(posESI) m/z=402 (M+H).
Example 32
N-(4-Piperazin-1-yl-naphthalen-1-yl)-4-trifluoromethyl-benzenesulfonamide,
hydrochloride
[0106] .sup.1H NMR (DMSO-d6) .delta.; 10.40 (brs, 1H), 9.03 (brs,
1H), 8.12 (d, J=7.65 Hz, 1H), 7.95-7.83 (m, 5H), 7.55-7.39 (m, 2H),
7.13-7.02 (m, 2H), 3.40-3.30 (m, obscured in part by solvent
signal), 3.23-3.09 (m, 4H), MS (posESI) m/z=436 (M+H).
Example 33
4-Fluoro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0107] .sup.1H NMR (DMSO-d6) .delta.; 10.17 (brs, 1H), 9.18 (brs,
2H), 8.15-8.08 (m, 1H), 7.99-7.92 (m, 1H), 7.77-7.66 (m, 2H),
7.55-7.30 (m, 4H), 7.11-7.01 (m, 2H), 3.40-3.30 (m, obscured by
solvent signal,), 3.25-3.10 (m, 4H), MS (posESI) m/z=386 (M+H).
Example 34
5-Fluoro-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0108] .sup.1H NMR (DMSO-d6) .delta.; 10.27 (brs, 1H), 9.19 (brs,
2H), 8.16-8.10 (m, 1H), 8.03-7.96 (m, 1H), 7.58-7.33 (m, 5H),
7.12-6.98 (m, 2H), 3.40-3.30 (m, obscured by solvent signal)
3.24-3.10 (m, 4H), MS (posESI) m/z=400 (M+H).
Example 35
4-Phenoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0109] .sup.1H NMR (DMSO-d6) .delta.; 10.08 (s, 1H), 9.11 (brs,
2H), 8.18-8.07 (m, 1H), 7.98-7.89 (m, 1H), 7.67-7.60 (m, 2H),
7.57-7.40 (m, 4H), 7.28-7.20 (m, 1H), 7.11 (s, 2H), 7.07-6.98 (m,
1H), 7.11 (s, 2H), 7.07-6.98 (m, 4H), 3.40-3.30 (m, obscured by
solvent signal), 3.24-3.10 (m, 4H), MS (posESI) m/z=460 (M+H).
Example 36
2-Bromo-4-iodo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0110] .sup.1H NMR (DMSO-d6) .delta.; 10.45 (brs, 1H), 9.01 (brs,
2H), 8.28 (d, J=1.58 Hz, 1H), 8.18-8.09 (m, 2H), 7.88-7.83 (m, 1H),
7.59-7.50 (m, 3H), 7.07 (s, 2H), 3.40-3.30 (m, obscured by solvent
signal), 3.23-3.10 (m, 4H), MS (posESI) m/z=572 (M+H).
Example 37
Thiophene-2-sulfonic acid (4-piperazin-1-yl-naphthalen-1-yl)-amide,
hydrochloride
[0111] .sup.1H NMR (DMSO-d6) .delta.; 10.30 (s, 1H), 9.12 (brs,
1H), 8.17-8.09 (m, 1H), 8.00-7.92 (m, 1H), 7.89-7.85 (m, 1H),
7.56-7.38 (m, 3H), 7.18-7.06 (m, 3H), 3.40-3.30 (m, obscured by
solvent signal), 3.25-3.15 (m, 4H), MS (posESI) m/z=374 (M+H).
Example 38
5-Chloro-thiophene-2-sulfonic acid
(4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride
[0112] .sup.1H NMR (DMSO-d6) .delta.; 10.43 (brs, 1H), 9.11 (brs,
2H), 8.19-8.111 (m, 1H), 8.02-7.95 (m, 2H), 7.29 (d, J=3.95 Hz,
1H), 7.21-7.12 (m, 3H), 3.40-3.30 (m, obscured by solvent signal),
3.25-3.15 (m, 4H), MS (posESI) m/z=408 (M+H).
Example 39
3-Methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0113] .sup.1H NMR (DMSO-d6) .delta.; 8.14-8.07 (m, 1H), 8.04-7.97
(m, 1H), 7.55-7.35 (m, 6H), 7.07-6.97 (m, 2H), 3.30-2.98 (m,
obscured in part by solvent signal, 8H), 2.29 (s, 3H), MS (posESI)
m/z=442 (M+H).
Example 40
4-Butyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide
hydrochloride
[0114] .sup.1H NMR (DMSO-d6) .delta.; 10.05 (s, 1H), 9.20 (brs,
2H), 8.11 (d, J=7.91 Hz, 1H), 7.93 (d, J=8.18 Hz, 1H), 7.62-7.26
(m, 5H), 7.07 (s, 2H), 3.40-3.30 (m, obscured by solvent signal),
3.25-3.15 (m, 4H), 2.66-2.55 (m, obscured in part by solvent
signal, 2H), 1.58-1.15 (m, 2H), 1.32-1.15 (m, 2H), 0.92-0.83 (m,
3H), MS (posESI) m/z=427 (M+H).
Example 41
2,4,6-Trimethyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0115] .sup.1H NMR (DMSO-d6) .delta.; 9.92 (brs, 1H), 9.01 (brs,
2H), 8.15-8.09 (m, 1H), 8.05-7.98 (m, 1H), 7.55-7.42 (m, 2H),
7.09-6.94 (m, 4H), 3.40-3.30 (m, obscured by solvent signal),
3.25-3.15 (m, 4H) 2.85 (s, 6H), 2.22 (s, 3H), MS (posESI) m/z=410
(M+H).
Example 42
2,4,5-Trichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0116] .sup.1H NMR (DMSO-d6) .delta.; 10.68 (brs, 1H), 9.06 (brs,
1H), 8.22-8.08 (m, 2H), 8.18 (s, 1H), 7.88 (s, 1H), 7.61-7.52 (m,
2H), 7.09 (s, 2H), 3.40-3.30 (m, obscured by solvent signal),
3.25-3.15 (m, 4H); MS (posESI) m/z=470 (M+H).
Example 43
4-Iodo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0117] .sup.1H NMR (DMSO-d6) .delta.; 10.22 (s, 1H), 9.06 (brs,
2H), 8.16-8.09 (m, 1H), 8.02-7.87 (m, 3H), 7.58-7.39 (m, 4H),
7.18-6.98 (m, 2H), 3.40-3.30 (m, 4H), 3.25-3.10 (m, 4H), MS
(posESI) m/z=494 (M+H).
Example 44
2-Methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0118] .sup.1H NMR (DMSO-d6) .delta.; 10.13 (s, 1H), 9.15 (brs,
2H), 8.15-8.08 (m, 1H), 8.07-7.63 (m, 1H), 7.70-7.63 (m, 1H),
7.61-7.23 (m, 2H), 3.41-3.27 (m, 4H), 3.24-3.09 (m, 4H), 2.55 (s,
obscured in part by solvent signal, 3H), MS (posESI) m/z=382
(M+H).
Example 45
3,4-Dichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0119] MS (posESI) m/z=436 (M+H)
Example 46
5-Bromo-2-methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0120] .sup.1H NMR (DMSO-d6) .delta.; 10.13 (s, 1H), 9.10 (brs,
2H), 8.16-8.07 (m, 2H), 7.78-7.71 (m, 1H), 7.59 (d, J=2.64 Hz, 1H),
7.57-7.46 (m, 2H), 7.22-7.06 (m, 3H), 3.19 (s, 3H), 3.40-3.30 (m,
obscured by solvent signal), 3.24-3.09 (m, 4H), MS (posESI) m/z=476
(M+H).
Example 47
2-Bromo-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0121] .sup.1H NMR (DMSO-d6) .delta.; 9.37 (brs, 1H), 8.22-8.07 (m,
2H), 7.89-7.79 (m, 2H), 7.57-7.40 (m, 4H), 7.05 (s, 2H), 3.40-3.30
(m, obscured by solvent signal), 3.24-3.09 (m, 4H), MS (posESI)
m/z=446 (M+H).
Example 48
3-Chloro-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0122] .sup.1H NMR (DMSO-d6) .delta.; 9.11 (brs, 1H), 8.17-8.09 (m,
1H),), 8.04-7.96 (m, 1H), 7.73-7.67 (m, 2H), 7.58-7.46 (m, 2H),
7.36-7.27 (m, 1H), 7.11-6.99 (m, 2H), 3.40-3.30 (m, obscured by
solvent signal), 3.24-3.09 (m, 4H), 2.57 (s, 3H), MS (posESI)
m/z=416 (M+H).
Example 49
2,6-Dichloro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0123] .sup.1H NMR (DMSO-d6) .delta.; 10.60 (s, 1H), 9.08 (brs,
1H), 8.18-8.06 (m, 2H), 7.66-7.44 (m, 5H), 7.09 (s, 2H), 3.40-3.30
(m, obscured by solvent signal), 3.24-3.09 (m, 4H), MS (posESI)
m/z=436 (M+H).
Example 50
3-Methoxy-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0124] .sup.1H NMR (DMSO-d6) .delta.; 10.13 (s, 1H), 9.07 (brs,
2H), 8.15-8.08 (m, 1H), 8.02-7.95 (m, 1H), 7.56-7.36 (m, 3H),
7.28-7.22 (m, 1H), 7.19-7.02 (m, 4H), 3.69 (s, 3H), 3.40-3.30 (m,
4H), 3.24-3.10 (m, 4H), MS (posESI) m/z=398 (M+H).
Example 51
3-Chloro-4-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0125] .sup.1H NMR (DMSO-d6) .delta.; 10.20 (brs, 1H), 9.12 (brs,
2H), 8.16-8.10 (m, 1H), 8.04-7.97 (m, 1H), 7.65-7.61 (m, 1H),
7.58-7.43 (m, 4H), 7.12-6.99 (m, 2H), 3.40-3.30 (m, obscured by
solvent signal), 3.24-3.09 (m, 4H), 2.36 (s, 3H), MS (posESI)
m/z=416 (M+H).
Example 52
4-Bromo-2-fluoro-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0126] .sup.1H NMR (DMSO-d6) .delta.; 10.59 (s, 1H), 9.17 (brs,
2H), 8.17-8.09 (m, 1H), 8.08-7.99 (m, 1H), 7.87-7.80 (m, 1H),
7.59-7.46 (m, 4H), 7.16-7.07 (m, 2H), 3.42-3.28 (, 4H), 3.24-3.08
(m, 4H), MS (posESI) m/z=464 (M+H).
Example 53
2,4-Dichloro-6-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonam-
ide, hydrochloride
[0127] .sup.1H NMR (DMSO-d6) .delta.; 9.08 (brs, 2H), 8.18-8.04 (m,
2H), 7.73-7.69 (m, 1H), 7.60-7.42 (m, 3H), 7.14-7.04 (m, 2H),
3.40-3.30 (m, obscured by solvent signal), 3.24-3.09 (m, 4H), 2.80
(s, 3H), MS (posESI) m/z=450 (M+H).
Example 54
4-Bromo-2-methyl-N-(4-piperazin-1-yl-naphthalen-1-yl)-benzenesulfonamide,
hydrochloride
[0128] .sup.1H NMR (DMSO-d6) .delta.; 10.24 (brs, 1H), 9.12 (brs,
2H), 8.17-8.10 (m, 1H), 8.05-7.98 (m, 1H), 7.68-7.65 (m, 1H),
7.58-7.46 (m, 4H), 7.10-6.96 (m, 2H), 3.40-3.30 (m, obscured by
solvent signal), 3.24-3.09 (m, 4H), 2.53 (s, obscured in part by
solvent signal, 3H), MS (posESI) m/z=450 (M+H).
Example 55
4,5-Dichloro-thiophene-2-sulfonic acid
(4-piperazin-1-yl-naphthalen-1-yl)-amide, hydrochloride
[0129] .sup.1H NMR (DMSO-d6) .delta.; 8.97 (brs, 2H), 8.19-8.12 (m,
1H), 8.01-7.94 (m, 1H), 7.60-7.47 (m, 2 h), 7.50 (S, 1H), 7.25-7.14
(m, 2H), 3.40-3.30 (m, obscured by solvent signal), 3.24-3.09 (m,
4H), MS (posESI) m/z=442 (M+H).
Example 56
N-Methyl-N-(4-bromo-2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphona-
mide, hydrochloride
[0130] .sup.1H NMR (DMSO) .delta. 9.39 (br s, 2H), 8.23-8.13 (m,
1H), 8.09-7.99 (m, 1H), 7.75-7.56 (m, 5H), 7.13-7.02 (m, 2H),
3.41-3.18 (m, 8H), 3.26 (s, 3H), 2.25 (s, 3H); MS m/z (M+1)
475.
Example 57
N-Methyl-N-(5-fluoro-2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphon-
amide, hydrochloride
[0131] .sup.1H NMR (DMSO) .delta. 9.21 (br s, 2H), 8.23-8.14 (m,
1H), 8.04-7.97 (m, 1H), 7.64-7.45 (m, 5H), 7.13-7.03 (m, 2H),
3.43-3.17 (m, 8H), 3.29 (s, 3H), 2.21 (s, 3H); MS m/z (M+1)
414.
Example 58
N-Methyl-N-(2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,
hydrochloride
[0132] .sup.1H NMR (CD.sub.3OD) .delta. 8.26-8.19 (m, 1H),
8.11-8.05 (m, 1H), 7.87-7.81 (m, 1H), 7.62-7.49 (m, 3H), 7.40-7.32
(m, 2H), 7.13-7.03 (m, 2H), 3.57-3.49 (m, 4H), 3.34-3.30 (m, 7H),
2.30 (s, 3H); MS m/z (M+1) 396.
Example 59
N-Methyl-N-(3-chloro-2-methylphenyl)-4-(1-pyperazinyl)-1-napthalenesulphon-
amide, hydrochloride
[0133] .sup.1H NMR (DMSO) .delta. 9.52 (br s, 2H), 8.23-8.14 (m,
1H), 8.04-7.96 (m, 1H), 7.88-7.76 (m, 2H), 7.64-7.54 (m, 2H),
7.49-7.39 (m, 1H), 7.17-7.05 (m, 2H), 3.42-3.16 (m, 8H), 3.27 (s,
3H), 2.34 (s, 3H); MS m/z (M+1) 430.
Example 60
2,5-Dichlorothiophen-3-yl-Methyl-N-(2,5-dichlorothiophen-3-yl)-4-(1-pypera-
zinyl)-1-napthalenesulphonamide, hydrochloride
[0134] .sup.1H NMR (DMSO) .delta. 9.49 (br s, 1H), 8.24-8.13 (m,
1H), 8.07-7.98 (m, 1H), 7.67-7.55 (m, 2H), 7.33 (s, 1H), 7.24-7.07
(m, 2H), 3.44-3.18 (m, 10H); MS m/z (M+1) 456.
Example 61
N-Methyl-N-(1-naphthyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,
hydrochloride
[0135] The compound was prepared
1-tert-butyl-4-(4-{bis[(2-naphthalene)sulfonyl]amino}-1-naphthyl)-1-piper-
azinecarboxylate and potassium carbonate (120 mg, 0.87 mmol) in
acetone (2 ml) was added iodomethane (44 .mu.l, 0.7 mmol) and the
mixture was stirred at room temperature over night. The mixture was
diluted with acetonitrile, filtered and concentrated in vacuo. The
residue was redissolved in DCM (3 ml) and treated with concentrated
TFA (1 ml) at 0.degree. C. for 30 min and then allowed to reach
room temperature. Removal of the solvents in vacuo and purification
by reversed phase HPLC followed by treatment of the residue with an
excess of 1M HCl in diethyl ether, gave the title compound (70 mg,
58%) as a solid. .sup.1H NMR (DMSO) .delta. 9.28 (br s, 2H), 8.44
(s, 1H), 8.24-8.07 (m, 5H), 7.80-7.56 (m, 5H), 7.07-7.00 (m, 1H),
6.88-6.81 (m, 1H), 3.41-3.18 (m, 8H), 3.27 (s, 3H); MS m/z (M+1)
432.
Example 62
N-Methyl-N-(1-naphthyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,
hydrochloride
[0136] .sup.1H NMR (DMSO) .delta. 9.25 (br s, 2H), 8.37-8.28 (m,
2H), 8.22-8.08 (m, 3H), 8.02-7.95 (m, 1H), 7.72-7.46 (m, 5H), 6.97
(s, 2H), 3.42-3.33 (m, 4H), 3.25 (s, 3H), 3.24-3.16 (m, 3H); MS m/z
(M+1) 432.
Example 63
N-Methyl-N-(4-chlorophenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,
hydrochloride
[0137] .sup.1H NMR (DMSO) .delta. 9.41 (br s, 2H), 8.23-8.05 (m,
2H), 7.73 (s, 4H), 7.67-7.56 (m, 2H), 7.13-7.03 (m, 1H), 6.92-6.85
(m, 1H), 3.42-3.19 (m, 8H), 3.22 (s, 3H); MS m/z (M+1) 416.
Example 64
N-Methyl-N-(4-methoxyphenyl)-4-(1-pyperazinyl)-1-napthalenesulphonamide,
hydrochloride
[0138] .sup.1H NMR (DMSO) .delta. 9.45 (br s, 2H), 8.22-8.11 (m,
2H), 7.69-7.57 (m, 4H), 7.21-7.14 (m, 2H), 7.09-7.03 (m, 1H),
6.86-6.81 (m, 1H), 3.87 (s, 3H), 3.41-3.19 (m, 8H), 3.16 (s, 3H);
MS m/z (M+1) 412.
Example 65
5-Fluoro-2-methyl-N-{4-[(2R,5S)-2,5-dimethyl-1-]piperazin-1-yl-1-naphthyl}-
benzenesulfonamide, hydrochloride
[0139] Synthesis of
(2R,5S)-2,5-Dimethyl-1-(4-nitro-1-naphthyl)piperazine--A mixture of
1-chloro-4-nitronaphtalene (400 mg, 1.9 mmol),
(2R,5S)-2,5-dimethylpiperazine (800 mg, 7 mmol) and potassium
carbonate (1 g, 7 mmol) in DMSO (4 ml) was stirred at 100.degree.
C. over night followed by an additional 48 hours at room
temperature. The reaction mixture was diluted with ethyl acetate
and filtered. The filtrate was washed with brine and 2M NaOH
solution and then dried with potassium carbonate. The residue was
purified on a silica column, using 10% methanol in chloroform as an
eluent, to give the title compound (220 mg, 41%) as an oil. .sup.1H
NMR (CDCl.sub.3) .delta. 8.68-8.53 (m, 2H), 8.31-8.26 (m, 1H),
7.76-7.59 (m, 2H), 7.30-7.24 (m, 1H), 3.32-3.87 (m, 4H), 2.96-2.82
(m, 1H), 2.44-2.32 (m, 1H), 1.14-1.04 (m, 3H), 0.99-0.89 (m, 3H);
MS m/z (M+1) 286.
[0140] Synthesis of
tert-Butyl(2R,5S)-2,5-dimethyl-1-(4-nitro-1-naphthyl)piperazine-1-carboxy-
late--To a stirred solution of
(2R,5S)-2,5-Dimethyl-1-(4-nitro-1-naphthyl)piperazine (220 mg, 0.77
mmol) in DCM (2 ml) was added, at 0.degree. C., BOC-anhydride
dissolved in DCM (2 ml). The solution was stirred for 15 min and
was then allowed to reach room temperature. Water was added and the
solution was extracted with DCM. The organic phase was separated
and dried with potassium carbonate to give the title compound (300
mg, 100%) as an oil. .sup.1H NM (CDCl.sub.3) .delta. 8.75-8.67 (m,
1H), 8.30-8.17 (m, 2H), 7.70-7.55 (m, 2H), 6.93-6.86 (m, 1H),
4.60-4.50 (m, 1H), 3.97-3.65 (m, 4H), 2.90-2.73 (m, 1H), 1.49 (s,
9H), 1.41-1.36 (m, 3H), 0.99-0.87 (m, 3H); MS m/z (M+1) 386.
[0141] Synthesis of
5-Fluoro-2-methyl-N-{4-[(2R,5S)-2,5-dimethyl-1-]piperazin-1-yl-1-naphthyl-
}benzenesulfonamide hydrochloride salt--A mixture of
tert-butyl(2R,5S)-2,5-dimethyl-1-(4-nitro-1-naphthyl)piperazine-1-carboxy-
late (300 mg, 0.78 mmol) and 10% Pd on carbon (approx. 0.1 mmol) in
methanol (10 ml) was stirred in an hydrogen atmosphere over night.
The mixture was filtered through a pad of Celite and the solvent
evaporated. The crude aniline was dissolved in DCM (2 ml) and
pyridine (0.5 ml) and 5-fluoro-2-methylbenzenesulfonyl chloride (97
.mu.l, 0.67 mmol) was added slowly to the solution. After stirring
for 2 hours water was added and the solution was extracted with
DCM, the organic phase separated and dried using potassium
carbonate. Removal of the solvents in vacuo gave a residue which
was dissolved in DCM (3 ml) and treated with concentrated TFA (2
ml) at 0.degree. C. The stirred solution was allowed to reach room
temperature after which the solvents where removed in vacuo to
give, after purification by reversed phase HPLC and treatment with
an excess of 1M HCl in diethyl ether, the title compound (30 mg,
9%) as a solid. .sup.1H NMR (CD.sub.3OD) .delta. 0.85 (d, J=6.07
Hz, 3H) 1.31 (d, J=6.60 Hz, 3H) 2.47 (s, 3H) 2.83 (m, 1H) 3.15 (m,
2H) 3.49 (m, 2H) 3.67 (m, 1H) 7.21 (m, 4H) 7.47 (m, 3H) 7.97 (m,
J=7.92 Hz, 1H) 8.44 (d, J=8.44 Hz, 1H) MS m/z 428 (M+1).
Example 66
5-Fluoro-2-methyl-N-[4-(1,2,3,6-tetrahydropyridin-4-yl)-1naphthyl]benzenes-
ulfonamide, hydrochloride
[0142]
5-Fluoro-2-methyl-N-[4-bromo-1-naphthyl]benzenesulfonamide--4-Brom-
o-1-naphthylamine (0.96 g, 4.33 mmol) was dissolved in DCM (10 mL)
before pyridine (1 mL) was added. 5-Fluoro-2-methylbenzenesulfonyl
chloride was added neat and the reaction mixture was stirred for 16
h. HCl (1 M, 1 mL) was added to the reaction mixture. The organic
phase was filtered through a Silica plug using DCM as eluent. The
solvent was evaporated. The obtained crude product was purified by
flash-chromatography using MeOH (10%) in pentane, to give the
desired product as a tar. To increase the purity, the product was
purified by recrystallising (EtOAc/hexanes). This gave the product
with a purity of 95%. .sup.1H NMR (270 MHz, CDCl.sub.3) .delta.
8.22 (d, J=8.98 Hz, 1H), 7.92 (d, J=7.92 Hz, 1H), 7.64-7.51 (m,
4H), 7.25-7.23 (m, 1H), 7.21-7.05 (m, 2H), 6.84 (br.s, 1H, N--H),
2.55 (s, 3H); MS (ESI+) for C17 H13 Br F N O2 S m/z 394.263
(M+H).sup.+.
[0143] MS (ESI-) for C17 H13 Br F N O2 S m/z 394.263 m/z
(M-H).sup.-.
[0144]
5-Fluoro-2-methyl-N-[4-(4-(tert-butoxycarbonyl)-1-hydroxypiperidin-
-1-yl)-1-naphthyl]benzenesulfonamide--5-Fluoro-2-methyl-N-[4-bromo-1-napht-
hyl]benzenesulfonamide (0.32 g, 0.812 mmol) was dissolved in dry
THF (1 m mL) under N.sub.2(g); The reaction flask was cooled to
-78.degree. C. before n-BuLi (1.5 mL, 2.4 mmol) was added. The
reaction mixture turned green. The reaction mixture was stirred for
5 minutes before a solution of tert-butyl
4-oxopiperidine-1-carboxylate (0.34 g, 1.7 mmol) was added during
10 s. The resulting reaction mixture was stirred and slowly
reaching -30.degree. C. after 3 h. Water dissolved in THF was added
and the reaction flask was brought to RT. Brine and EtOAc was
added. The phases were separated and the organic phase was dried
(MgSO4). The obtained crude product was purified by reverse-phase
(using the gradient 40.fwdarw.90). This gave 0.17 g of the desired
product. Purity 95%. .sup.1H NMR (270 MHz, CDCl.sub.3) .delta.
8.91-8.87 (m, 1H), 7.97-7.93 (m, 1H), 7.63-7.59 (m, 1H), 7.53-7.45
(m, 2H), 7.35 (d, J=8.1 Hz, 1H), 7.28-7.21 (m, 1H), 7.16-7.09 (m,
2H), 7.14 (br.s, 1H, N--H), 6.85 (br.s, 1H, O--H), 4.07-3.98 (m,
2H), 3.41-3.31 (m, 2H), 2.59 (s, 3H), 2.17-2.08 (m, 4H), 1.46 (s,
9H); MS (ESI+) for C27 H31 F N2 O5 S m/z 514.615 (M+H).sup.+.
Nothing; MS (ESI-) for C27 H31 F N2 O5 S m/z 514.615 (M-H).sup.-
513.1.
[0145] The final product was obtained as following:
5-Fluoro-2-methyl-N-[4-(4-(tert-butoxycarbonyl)-1-hydroxypiperidin-1-yl)--
1-naphthyl]benzenesulfonamide (0.022 g, 0.043 mmol) was dissolved
in formic acid (5 mL) and stirred at RT for 24 h. HPLC showed
complex reaction mixture. The reaction mixture was stirred at
100.degree. C. for 4 h. One compound was seen on HPLC. The solvent
was evaporated. The crude was transformed to the HCl salt (0.020 g)
for the desired product, purity 98%. .sup.1H NMR (270 MHz,
CD.sub.3OD) .delta. 8.05-7.97 (m, 2H), 7.55-7.43 (m, 3H), 7.33-7.30
(m, 1H), 7.24-7.17 (m, 3H), 5.97 (br.s, 1H), 3.90-3.88 (m, 2H),
3.56-3.52 (m, 2H), 2.73-2.70 (m, 2H), 2.53 (s, 3H); MS (ESI+) for
C22 H21 F N2 O2 S HCl m/z 396.13+35.98 (M+H).sup.+ 397.2; MS (ESI-)
C22 H21 F N2 O2 S HCl m/z 396.13+35.98 (M-H).sup.-. 395.3.
Synthesis of Example in Table II
Example 67
N-[4-(4-Methyl-1-piperazinyl)-2-naphthyl]benzenesulfonamide,
hydrochloride
[0146] To a solution of
1-(4-dimethyl-1-piperazinyl)-3-naphthylamine (0.230 g, 0.951 mmol)
and pyridine (537 .mu.L, 6.66 mmol) in DCM (3.0 mL) was added
benzenesulfonyl chloride (0.168 g, 0.951 mmol) in DCM (1.0 mL). The
reaction mixture was stirred at room temperature for 16 hours and
then and then concentrated. The crude intermediate was first
purified via column chromatography on silica using
CHCl.sub.3/CHCl.sub.3+10% MeOH+0.4% NH.sub.3 and then by
preparative HPLC to give the pure base which was converted to its
HCl-salt (yield 53% as HCl-salt): 1H NMR (DMSO-d6) .delta. 10.76
(br s, 1H), 10.50 (s, 1H), 7.98-7.94 (m, 1H), 7.85-7.81 (m, 2H),
7.76-7.73 (m, 1H), 7.60-7.56 (m, 1H), 7.55-7.51 (m, 2H), 7.30 (d,
J=1.60 Hz, 1H), 6.99 (d, J=1.88 Hz, 1H), 3.58-3.48 (m, 2H),
3.42-3.25 (m, m, partly obscured by HDO signal, 4H), 3.12-3.00 (m,
2H), 2.86 (s, 3H); MS (posES-FIA) m/z=381.15 24 (M+H)(calc
381.1511) Synthesis of Intermediates and Examples in Table III
##STR354## In Scheme 2, the following reagents are used: (i)
Chlorosulphonic acid, trifluoroacetic acid; (ii) R.sup.1--NH.sub.2,
pyridine (1:4); (iii) diamines of choice and DMSO. Intermediate
16
[0147] 4-Fluoro-naphthalene-1-sulfonyl chloride--An emulsion of
1-fluoronaphthalene (4.00 g, 27 mmol) in TFA (19.5 mL) was stirred
on an ice-bath. Chlorosulfonic acid (4.33 mL, 65 mmol) was added
dropwise over 30 min. The ice-bath was removed and the reaction
slurry stirred at rt for 2 h. Pouring the reaction mixture on 29 mL
ice-cold water gave a white precipitate, which was filtered and
washed with cold water. After drying, 4.50 g of white solid (67%):
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.80 (d, 1H), 8.39 (dd,
1H), 8.28 (d, 1H), 7.88 (t, 1H), 7.76 (t, 1H), 7.26 (t, 1H); MS
(EI) 244 (M). Purity (HPLC, Hichrom 200.times.4.6 mm I.D.)
>98%.
General Method C
[0148] 4-Fluoro-naphthalene-1-sulfonic acid phenylamide,
4-fluoro-naphthalene-1-sulfonic acid (2-methoxy-phenyl)-amide and
4-fluoro-naphthalene-1-sulfonic acid (3-chloro-phenyl)-amide--Three
reaction flasks with 4-fluoro-naphthalene-1-sulfonyl chloride (489
mg, 2.00 mmol) in CH.sub.2Cl.sub.2 (2 mL) were treated with aniline
(224 mg, 2.40 mmol), o-anisidine (296 mg, 2.40 mmol) and
m-chloroaniline (306 mg, 2.40 mmol), respectively. Pyridine (0.5
mL) was added and the reaction mixtures stirred for 3 h at rt.
Dilution with ethyl acetate (50 mL) followed by washing with 1 M
HCl (3.times.50 mL), drying (Na.sub.2SO.sub.4) and evaporation gave
586 mg of 4-fluoro-naphthalene-1-sulfonic acid phenylamide (97%),
629 mg of 4-fluoro-naphthalene-1-sulfonic acid
(2-methoxy-phenyl)-amide (95%) and 656 mg of and
4-fluoro-naphthalene-1-sulfonic acid (3-chloro-phenyl)-amide (97%)
as pink to red solids.
Intermediate 17
[0149] 4-Fluoro-naphthalene-1-sulfonic acid phenylamide: .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 8.66 (d, 1H), 8.20 (d, 1H), 8.15
(dd, 1H), 7.74 (t, 1H), 7.66 (t, 1H), 7.03-7.15 (m, 4H), 6.89 (d,
2H), 6.60 (bs, 1H); MS (CI) 299.8 (M-H).sup.+; Purity (HPLC,
Hichrom 200.times.4.6 mm I.D.) >98%.
Intermediate 18
[0150] 4-Fluoro-naphthalene-1-sulfonic-acid
(2-methoxy-phenyl)-amide: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
8.70 (d, 1H), 8.16 (d, 1H), 8.12 (dd, 1H), 7.71 (t, 1H), 7.63 (t,
1H), 7.42 (d, 1H), 7.16 (bs, H), 7.06 (t, 1H), 6.95 (t, 1H), 6.83
(t, 1H), 6.56 (d, 1H), 3.30 (s, 3H); MS (CI) 330.2 (M-H).sup.+;
Purity (HPLC, Hichrom 200.times.4.6 mm I.D.) >98%.
Intermediate 19
[0151] 4-Fluoro-naphthalene-1-sulfonic acid
(3-chloro-phenyl)-amide: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
8.64 (d, 1H), 8.18-8.22 (m, 2H), 7.76 (t, 1H), 7.68 (t, 1H), 7.14
(dd, 1H), 7.06 (t, 1H), 7.02 (d, 1H), 6.97 (t, 1H), 6.78 (d, 1H),
6.67 (bs, 1H); MS (CI) 334.2 (M-H).sup.+; Purity (HPLC, Hichrom
200.times.4.6 mm I.D.) >98%.
General Procedure D
General procedure for preparation of compounds according to
Examples 68-74:
[0152] Solutions of 4-fluoro-naphthalene-1-sulfonic acid
(2-methoxy-phenyl)-amide (60 mg, 0.20 mmol),
4-fluoro-naphthalene-1-sulfonic acid (2-methoxy-phenyl)-amide (66
mg, 0.20 mmol) and 4-fluoro-naphthalene-1-sulfonic acid
(3-chloro-phenyl)-amide (67 mg, 0.20 mmol) in DMSO (2 mL) were
treated with piperazine (86 mg, 1.0 mmol), homopiperazine (100 mg,
1.0 mmol) and cis-2,6-dimethyl piperazine (114 mg, 1.0 mmol) in
eight reaction combinations. The reaction mixtures were stirred at
100.degree. C. for 3 h, diluted with ethyl acetate (50 mL), washed
with sat. Na.sub.2CO.sub.3 (3.times.50 mL), dried
(Na.sub.2SO.sub.4) and evaporated with an excess of HCl in ether,
giving the hydrochlorides. No purification was necessary for
compounds 20-23, while compounds 24-27 were purified with HPLC (YMC
combiprep ODS-AQ, 50.times.20 mm I.D.).
Example 68
4-Piperazin-1-yl-naphthalene-1-sulfonic acid phenylamide,
hydrochloride
[0153] 86 mg (95% yield) of a white solid. .sup.1H NMR (DMSO, 400
MHz) .delta. 9.52 (bs, 1H), 8.72 (d, 1H), 8.20 (d, 1H), 8.15 (d,
1H), 7.71 (t, 1H), 7.64 (t, 1H), 7.20 (d, 1H), 7.13 (t, 2H), 7.01
(d, 2H), 6.90 (t, 1H), 3.35 (bs, 4H), 3.30 (bs, 4H). .sup.13C NMR
(DMSO, 101 MHz) .delta. 153.3, 137.7, 137.6, 130.8, 129.2, 129.0,
128.9, 127.9, 126.5, 124.9, 124.5, 123.3, 118.7, 113.0, 49.1, 42.8;
MS (CI) 368.0 (M+H).sup.+, 366.4 (M-H).sup.-; Purity (HPLC, Hichrom
200.times.4.6 mm I.D.) 90%.
Example 69
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(2-methoxy-phenyl)-amide, hydrochloride
[0154] .sup.1H NMR (DMSO, 400 MHz) .delta. 9.59 (s, 1H), 8.76 (d,
1H), 8.23 (d, 1H), 7.93 (d, 1H), 7.64-7.70 (m, 2H), 7.14-7.19 (m,
2H), 7.05 (t, 1H), 6.82 (t, 1H), 6.76 (d, 1H), 3.39 (bs, 4H), 3.29
(bs, 4H), 3.11 (s, 3H). .sup.13C NMR (DMSO, 101 MHz) .delta. 152.9,
152.5, 130.6, 129.7, 129.3, 127.9, 127.3, 126.5, 126.3, 125.7,
125.3, 125.2, 124.1, 120.2, 112.8, 111.6, 54.9, 49.2, 43.0. MS (CI)
398.2 (M+H).sup.+, 396.2 (M-H).sup.-; Purity (HPLC, Hichrom
200.times.4.6 mm I.D.) 96%.
Example 70
4-(cis-3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid
(2-methoxy-phenyl)-amide, hydrochloride
[0155] .sup.1H NMR (DMSO, 400 MHz) .delta. 9.75-9.81 (m, 1H), 9.60
(s, 1H), 9.03-9.12 (m, 1H), 8.76 (d, 1H), 8.23 (d, 1H), 7.93 (d,
1H), 7.64-7.71 (m, 2H), 7.05 (t, 1H), 6.82 (t, 1H), 6.76 (d, 1H),
3.63-3.71 (m, 2H), 3.47 (d, 2H), 3.13 (s, 3H), 2.89 (t, 2H), 1.32
(d, 6H). .sup.13C NMR (DMSO, 101 MHz) .delta. 152.4, 152.3, 130.6,
129.8, 129.3, 127.9, 127.3, 126.5, 126.3, 125.3, 125.2, 125.1,
124.1, 120.2, 113.0, 111.6, 55.0, 54.9, 51.2, 15.5. MS (CI) 426.2
(M+H).sup.+, 424.4 (M-H).sup.-; Purity (HPLC, Hichrom 200.times.4.6
mm I.D.) 96%.
Example 71
4-(cis-3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid
(3-chloro-phenyl)-amide, hydrochloride
[0156] .sup.1H NMR (MeOD, 400 MHz) .delta. 8.80 (d, 1H), 8.32 (d,
1H), 8.27 (d, 1H), 7.79 (t, 1H), 7.73 (t, 1H), 7.28 (d, 1H), 7.12
(t, 1H), 7.07 (t, 1H), 6.95-7.00 (m, 2H); MS (CI) 430.2
(M+H).sup.+, 428.4 (M-H).sup.-; Purity (HPLC, Hichrom 200.times.4.6
mm I.D.) 98%.
Example 72
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid
(3-chloro-phenyl)-amide, hydrochloride
[0157] .sup.1H NMR (MeOD, 400 MHz) .delta. 8.69 (d, 1H), 8.28 (d,
1H), 8.14 (d, 1H), 7.68 (t, 1H), 7.61 (t, 1H), 7.22 (d, 1H), 7.02
(t, 1H), 6.97 (bs, 1H), 6.86-6.89 (m, 2H), 3.57 (bs, 2H), 3.48 (bs,
4H), 3.33-3.37 (m, 2H), 2.20-2.24 (m, 2H); MS (CI) 416.0
(M+H).sup.+, 414.2 (M-H).sup.-; Purity (HPLC, Hichrom 200.times.4.6
mm I.D.) 88%.
Example 73
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid phenylamide,
hydrochloride
[0158] .sup.1H NMR (MeOD, 400 MHz) .delta. 8,57 (d, 1H), 8.13 (d,
1H), 7.96 (d, 1H), 7.44-7.55 (m, 2H), 7.04 (d, 1H), 6.90 (t, 2H),
6.72-6.82 (m, 3H), 3.39-3.43 (m, 2H), 3.32-3.36 (m, 4H), 3.17-3.21
(m, 2H), 2.05-2.10 (m, 2H); MS (CI) 382.2 (M+H).sup.+, 380.4
(M-H).sup.-; Purity (HPLC, Hichrom 200.times.4.6 mm I.D.) 94%.
Example 74
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(3-chloro-phenyl)-amide, hydrochloride
[0159] .sup.1H NMR (MeOD, 400 MHz) .delta. 8.69 (d, 1H), 8.23 (d,
1H), 8.16 (d, 1H), 7.68 (t, 1H), 7.62 (t,1H), 7.17 (d, 1H), 7.02
(t, 1H), 6.97 (t, 1H), 6.85-6.89 (m, 2H), 3.46-3.50 (m, 4H), 3.33
(bs, 4H); MS (CI) 402.2 (M+H).sup.+, 400.0 (M-H).sup.-; Purity
(HPLC, Hichrom 200.times.4.6 mm I.D.) 98%. ##STR355##
[0160] 4-Fluoro-naphtalene-1-sulfonylchloride was dissolved in DCM.
The amine (1.2 eq) was added followed by pyridine (3 eq). The
mixture was stirred for 2 h at ambient temperature, diluted with
DCM and washed 2 times with HCl (1M). The organic layer was
filtered through a silica plug to afford the sulfonylamide.
##STR356##
[0161] The sulfonamide and the amine (5 eq) were dissolved in DMSO
and stirred at 100.degree. C. overnight. The DMSO solution was
added dropwise to water to give a precipitate. After
centrifugation, the solvent was decanted and the procedure was
repeated. The residue was dissolved in MeOH and converted to HCl
salt by adding HCl in ether (2 M) and evaporation. ##STR357##
[0162] To a solution of the sulfonamide in acetone, K.sub.2CO.sub.3
(3 eq) was added followed by MeI (1.2 eq). The mixture was stirred
overnight, filtered through a short silica plug and evaporated to
give the methylated sulfonamide.
Example 75
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(2-methylsulfanyl-phenyl)-amide, hydrochloride
[0163] N-(2-methylsulfanyl-phenyl)-4-fluorosulphonamide--Method E;
Yield (84%)
[0164] .sup.1H NMR (CDCl.sub.3) .delta. 8.74-8.70 (m, 1H),
8.29-8.24 (m, 1H), 8.17-8.14 (m, 1H), 8.01 (br. s, 1 H), 7.75-7.60
(m, 2H), 7.50-7.47 (m, 1H), 7.29-7.25 (m, 1H), 7.18-7.10 (m, 2H),
6.98-6.92 (m, 1H), 2.02 (s, 3H); MS (ESI+) for C17 H14 F N O2 S2
m/z 348 (M+H).sup.+.
The final product was prepared according to Method F; Yield 0.77 g
(53%)
[0165] .sup.1H NMR (DMSO-d.sub.6) .delta. 11.13 (s, 1H), 9.42 (br.
s, 2H), 8.69-8.66 (m, 1H), 8.21-8.18 (m, 2H), 7.76-7.62 (m, 2H),
7.42-7.21 (m, 5H), 3.421-3.30 (m, 8H); MS (ESI+) for C21 H23 N3 O2
S2 m/z 414.2 (M+H).sup.+.
Example 76
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
methyl-naphthalen-1-yl-amide, hydrochloride
[0166] N-(1-naphthyl)-4-fluoronaqphthalensulphonamide--Method E;
Yield (83%)
[0167] .sup.1H NMR (CDCl.sub.3) .delta. 8.77-8.74 (m, 1H),
8.18-8.05 (m, 2H), 7.75-7.61 (m, 5H), 7.41-7.35 (m, 1H), 7.30-7.26
(m, 1H), 7.14-7.00 (m, 2H), 6.93 (br. s, 1H); MS (ESI+) for C20 H14
F N O2 S m/z 352 (M+H).sup.+.
[0168] 4-Fluoro-1-naphthalene-1-sulfonic acid
methyl-naphthalen-1-yl-amide--Methylation according to Method G,
Yield (97%)
[0169] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.38-8.35 (m, 1H),
8.23-8.20 (m, 1H), 8.16 (dd, J=8.4, 5.5 Hz, 1H), 7.99-7.91 (m, 3H),
7.79-7.73 (m, 1H), 7.66-7.46 (m, 4H), 7.37-7.31 (m, 1H), 7.03 (dd,
J=7.5, 1.2 Hz, 1H), 3.29 (s, 3H)
[0170] The final product was prepared according to Method F; Yield
(36%)
[0171] .sup.1H NMR (DMSO-d.sub.6) .delta. 9.33 (br. s, 1H), 8.40
(d, J=8.4 Hz, 1H), 8.25 (d, J=7.9 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H),
7.98-7.91 (m, 3H), 7.68-7.62 (m, 1H), 7.58-7.43 (m, 3H), 7.40-7.34
(m, 1H), 7.24 (d, J=8.2 Hz, 1H), 7.13-7.10 (m, 1H), 3.44-3.39 (m,
4H), 3.29 (br. s, 4H), 3.25 (s, 3H); MS (ESI+) for C25 H25 N3 O2 S
m/z 432 (M+H).sup.+.
Example 77
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methyl-amide, hydrochloride
[0172] N-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-4-sulphonamide--Method
E; Yield (96%). .sup.1H NMR (CDCl.sub.3) .delta. 8.66-8.63 (m, 1H),
8.22-8.09 (m, 2H), 7.77-7.63 (m, 2H), 7.10 (dd, J=8.2, 9.5 Hz, 1H),
6.58 (d, J=8.5 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.30 (dd, J=2.6,
8.7 Hz, 1H), 4.14 (s, 4H); MS (ESI+) for C18 H14 F N O4 S m/z 360
(M+H).sup.+.
[0173] 4-Fluoro-Nl-naphthalene-1-sulfonic
acid-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methyl-amide--Methylation
according to Method G; Yield (100%). .sup.1H NMR (DMSO-d.sub.6)
.delta. 8.19-8.13 (m, 2H), 8.09 (dd, J=8.4, 5.5 Hz, 1H), 7.75-7.70
(m, 1H), 7.64-7.58 (m, 1H), 7.50 (dd, J=10.0, 8.4 Hz, 1H), 6.71 (d,
J=8.4 Hz, 1H), 6.55 (d, J=2.6 Hz, 1H), 6.51-6.47 (m, 1H), 4.20-4.15
(m, 4H), 3.10 (s, 3H)
[0174] The final product was prepared according to Method F; the
product precipitates in MeOH; Yield (57%): .sup.1H NMR
(DMSO-d.sub.6) .delta. 9.29 (br. s, 2H), 8.23-8.16 (m, 2H), 8.01
(d, J=8.2 Hz, 1H), 7.64-7.49 (m, 2H), 7.25 (d, J=8.2 Hz, 1H), 6.72
(d, J=8.4 Hz, 1H), 6.56-6.48 (m, 2H), 4.21-4.16 (m, 4H), 3.38-3.31
(m, 4H), 3.08 (s, 3H); MS (ESI+) for C23 H25 N3 O4 S m/z 440
(M+H).sup.+.
Example 78
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide, hydrochloride
[0175] The final product was prepared according to Method F; Yield
(36%); .sup.1H NMR (270 MHz, DMSO-D6) .delta. ppm 3.32 (m, 8H) 4.08
(m, 4H) 6.45 (m, 2H) 6.61 (d, J=8.44 Hz, 1H) 7.20 (d, J=8.18 Hz,
1H) 7.67 (m, 2H) 8.07 (d, J=7.92 Hz, 1H) 8.21 (d, J=8.71 Hz, 1H)
8.67 (d, J=8.44 Hz, 1H) 9.22 (s, 1H) 10.32 (s, 1H); MS (ESI+) for
C22 H23 N3 O4 S m/z 426.2 (M+H).sup.+.
Example 79
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
methyl-(2-methylsulfanyl-phenyl)-amide, hydrochloride
[0176]
4-Fluoro-N-methyl-N-(2-methylsulfanyl-phenyl)-amide--Methylation
according to Method G; Yield (97%); .sup.1H NMR (DMSO-d.sub.6)
.delta. 8.52-8.49 (m, 1H), 8.22-8.19 (m, 1H), 8.16 (dd, J=8.4, 5.5
Hz, 1H), 7.79-7.66 (m, 2H), 7.52 (dd, J=10.0, 8.4 Hz, 1H),
7.37-7.24 (m, 2H), 7.06-7.00 (m, 1H), 6.88 (dd, J=7.9, 1.3 Hz, 1H),
3.10 (s, 3H), 2.28 (s, 3H).
[0177] The final product was prepared according to Method F;
Trituration with MeCN; Yield (65%) .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.27 (br. s, 2H), 8.54-8.50 (m, 1H), 8.27-8.23 (m, 1H),
8.09 (d, J=8.2 Hz, 1H), 7.67-7.56 (m, 2H), 7.38-7.25 (m, 3H),
7.07-6.92 (m, 2H), 3.41-3.33 (m, 8H), 3.06 (s, 3H), 2.30 (s, 3H);
MS (ESI+) for C22 H25 N3 O2 S.sub.2 m/z 428 (M+H).sup.+.
Example 80
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
methyl-(3-trifluoromethyl-phenyl)-amide, hydrochloride
[0178]
N-(3-trifluoromethylphenyl)-4-fluoronaphthalenesulphonamide--Metho-
d E; Yield (90%). .sup.1H NMR (CDCl.sub.3) .delta. 8.65-8.62 (m,
1H), 8.23-8.18 (m, 2H), 7.78-7.65 (m, 2H), 7.31-7.17 (m, 2H),
7.16-7.08 (m, 3H); MS (ESI+) for C17 H11 F4 N O2 S m/z 370
(M+H).sup.+. Methylation according to Method F; Yield (100%);
.sup.1H NMR (DMSO-d.sub.6) .delta. 8.19-8.11 (m, 2H), 8.01-7.98 (m,
1H), 7.73-7.62 (m, 2H), 7.57-7.44 (m, 4H), 7.35 (br. s, 1H), 3.21
(s, 3H).
[0179] The final product was prepared according to Method F;
Trituration with MeCN; Yield 0.07 g (40%). .sup.1H NMR
(DMSO-d.sub.6) .delta. 9.35 (br. s, 2H), 8.21 (d, J=8.2 Hz, 1H),
8.06-8.02 (m, 2H), 7.63-7.42 (m, 5H), 7.28-7.24 (m, 2H), 3.39 (br.
s, 8H), 3.21 (s, 3H), 2.06 (s, 3H); MS (ESI+) for C22 H22 F3 N3 O2
S m/z 450 (M+H).sup.+.
Example 81
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(3-chloro-4-methyl-phenyl)-methyl-amide, hydrochloride
[0180]
N-(3-Chloro-4-methylphenyl)-4-fluoronaphthalenesulphonamide--Metho-
d E; Yield (88%). .sup.1H NMR (DMSO-d.sub.6) .delta. 10.86 (br. s,
1H), 8.74-8.71 (m, 1H), 8.22 (dd, J=8.3, 5.4 Hz, 1H), 8.19-8.16 (m,
1H), 7.89-7.75 (m, 2H), 7.47 (dd, J=10.0, 8.4 Hz, 1H), 7.12-7.09
(m, 1H), 7.00 (d, J=2.2 Hz, 1H), 6.86 (dd, J=8.3, 2.2 Hz, 1H), 2.11
(s, 3H);
[0181] 4-Fluoro-1-naphthalene-1-sulfonic acid
(3-chloro-4-methyl-phenyl)-methyl-amide--Methylation according to
Method G; Yield (100%). .sup.1H NMR (DMSO-d.sub.6) .delta.
8.20-8.07 (m, 3H), 7.76-7.70 (m, 1H), 7.62-7.48 (m, 2H), 7.27-7.24
(m, 1H), 7.13 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.2, 2.4 Hz, 1H), 3.15
(s, 3H), 2.28 (s, 3H);
[0182] The final product was prepared according to Method F; Yield
(28%). .sup.1H NMR (DMSO-d.sub.6) .delta. 9.29 (br. s, 2H),
8.24-8.15 (m, 2H), 8.01 (d, J=8.2 Hz, 1H), 7.65-7.47 (m, 2H), 7.26
(dd, J=8.3, 4.6 Hz, 2H), 7.09-7.08 1H), 7.03-6.99 (m, 1H),
3.38-3.33 (m, 8H), 3.14 (s, 3H), 2.27 (s, 3H);MS (ESI+) for C22 H24
Cl N3 O2 S m/z 430 (M+H).sup.+.
Example 82
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(3-ethyl-phenyl)-methyl-amide, hydrochloride
[0183] N-(3-ethylphenyl)-4-fluoronaphthalenesulphonamide--Method E;
Yield (85%). .sup.1H NMR (CDCl.sub.3) .delta. 8.66 (d, J=8.4 Hz,
1H), 8.20-8.14 (m, 2H), 7.75-7.62 (m, 2H), 7.10 (dd, J=9.5, 8.4 Hz,
1H), 7.02 (t, J=7.8 Hz, 1H), 6.88-6.85 (m, 1H), 6.72-6.68 (m, 3H),
2.45 (q, J=7.7 Hz, 2H), 1.03 (t, J=7.7 Hz, 3H)
[0184] 4-Fluoro-1-yl-naphthalene-1-sulfonic acid
(3-ethyl-phenyl)-methyl-amide--Methylation according to Method G;
Yield (100%); .sup.1H NMR (DMSO-d.sub.6) .delta. 8.18-8.06 (m, 3H),
7.72-7.66 (m, 1H), 7.54-7.48 (m, 2H), 7.21-7.16 (m, 1H), 7.10-7.08
(m, 1H), 6.96-6.92 (m, 1H), 6.81-6.80 (m, 1H), 3.16 (s, 3H), 2.41
(q, J=7.5 Hz, 2H), 0.93 (t, J=7.5 Hz, 3H)
[0185] The final product was prepared according to Method f;
Trituration with MeCN; Yield (49%); .sup.1H NMR (DMSO-d.sub.6)
.delta. 9.21 (br. s, 2H), 8.21 (d, J=8.4 Hz, 1H), 8.13 (d, J=8.7
Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.62-7.57 (m, 1H), 7.47-7.41 (m,
1H), 7.27-7.17 (m, 2H), 7.10-6.95 (m, 2H), 6.8 (br. s, 1H),
3.40-3.29 (m, 8H), 3.15 (s, 3H), 2.43 (q, J=7.6 Hz, 2H), 0.95 (t,
J=7.6 Hz, 2H); MS (ESI+) for C23 H27 N3 O2 S m/z 410
(M+H).sup.+.
Example 83
4-(3,5-Dimethyl-piperazin-1-yl)-naphthalene-1-sulfonic acid
(2-isopropyl-phenyl)-amide, hydrochloride
[0186] The final product was prepared according to Method F; Yield
(35%); .sup.1H NMR (270 MHz, DMSO-D6) .delta. ppm 0.64 (d, J=6.86
Hz, 6H) 1.30 (d, J=6.60 Hz, 6H) 2.92 (m, 3H) 3.53 (m, 4H) 6.86 (d,
J=7.65 Hz, 1H) 6.98 (m, 1H) 7.13 (m, 3H) 7.67 (m, 2H) 7.86 (d,
J=7.92 Hz, 1H) 8.24 (m, 1H) 8.74 (m, 1H) 9.08 (m, 1H) 9.79 (m, 2H);
MS (ESI+) for C25 H31 N3 O2 S m/z 438.01 (M+H).sup.+.
Example 84
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid
(2-isopropyl-phenyl)-amide, hydrochloride
[0187] N-(2 isopropylphenyl)-4-fluoronaphthalensulphonamide--Method
E; Yield (87%) .sup.1H NMR (CDCl.sub.3) .delta. 8.67-8.64 (m, 1H),
8.22-8.18 (m, 1H), 8.12 (dd, J=8.3, 5.4 Hz, 1H), 7.71-7.62 (m, 2H),
7.15-6.97 (m, 5H), 2.84-2.73 (m, 1H), 0.85 (s, 3H), 0.82 (s,
3H)
[0188] The final product was prepared according to Method F; Yield
(22%). .sup.1H NMR (DMSO-d6) .delta. 9.83 (s, 1H), 9.37 (br. s,
2H), 8.74-8.70 (m, 1H), 8.27.8.24 (m, 1H), 7.84 (d, J=7.9 Hz, 1H),
7.68-7.64 (m, 2H), 7.17-7.11 (m, 3H), 7.01-6.87 (m, 2H), 3.82 (br.
s, 6H), 3.51-3.50 (m, 2H), 3.38-3.28 (m, 2H), 3.02-2.93 (m, 1H),
0.65 (s, 3H), 0.63 (s, 3H); MS (ESI+) for C24 H29 N3 O2 S m/z
424.02 (M+H).sup.+.
Example 85
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid
(3-ethyl-phenyl)-amide, hydrochloride
[0189] The final product was prepared according to Method F; Yield
(22%); .sup.1H NMR (DMSO-d.sub.6) .delta. 10.53 (s, 1H), 9.24 (br.
s, 2H), 8.68 (d, J=8.2 Hz, 1H), 8.20 (d, J=7.9 Hz, 1H), 8.14 (d,
J=8.2 Hz, 1H), 7.72-7.60 (m, 2H), 7.22 (d, J=8.2 Hz, 1H), 7.01 (t,
J=7.8 Hz, 1H), 6.83-6.72 (m, 3H), 3.33 (br. s, 6H), 2.39 (q, J=7.7
Hz, 2H), 2.12 (br. s, 2H), 0.98 (t, J=7.5 Hz, 3H); MS (ESI+) for
C23 H27 N3 O2 S m/z 410.03 (M+H).sup.+.
Example 86
N-(2-Fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,
hydrochloride
[0190] N-(2-Fluorophenyl)-4-fluoronaphthalensulphonamide--Method E;
Yield (88%); .sup.1H NMR (DMSO-d.sub.6) .delta. 10.41 (br. s, 1H),
8.76-8.69 (m, 1H), 8.20-8.17 (m, 1H), 8.08 (dd, J=8.0, 5.5 Hz, 1H),
7.82-7.75 (m, 2H), 7.41 (dd, J=10.0, 8.3 Hz, 1H), 7.20-7.01 (m,
4H); MS (ESI-) for C16 H11 F2 N O2 S m/z 318.2 (M-H).sup.-.
[0191] The final product was prepared according to Method F; Yield
(22%); .sup.1H NMR (DMSO-d.sub.6) .delta. 10.41 (s, 1H), 9.35 (m,
2H), 8.72-8.68 (m, 1H), 8.24-8.20 (m, 1H), 8.02 (d, J=7.9 Hz, 1H),
7.72-7.62 (m, 2H), 7.22-7.00 (m, 5H), 4.05 (d, J=1.3 Hz, 4H), 3.36
(s, 4H); MS (ESI+) for C20 H20 F N3 O2 S m/z 386 (M+H).sup.+.
Example 87
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid
(3-trifluoromethyl-phenyl)-amide, hydrochloride
[0192] The final product was prepared according to Method F; Yield
(21%); .sup.1H NMR (DMSO-d6) .delta. 11.1 (s, 1H), 9.32 (br. s,
2H), 8.65 (d, J=8.2 Hz, 1H), 8.19 (t, J=8.6 Hz, 2H), 7.75-7.62 (m,
2H), 7.42-7.22 (m, 4H), 3.88 (br. s, 6H), 3.55-3.53 (m, 2H), 2.11
(m, 2H); MS (ESI+) for C22 H22 F3 N3 O2 S m/z 449.95
(M+H).sup.+.
Example 88
N-(2,4-difluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,
hydrochloride
[0193]
N-(2,4-di-Fluorophenyl)-4-fluoronaphthalensulphonamide--Method E;
Yield (81%); .sup.1H NMR (DMSO-d.sub.6) .delta. 10.44 (s, 1H),
8.73-8.69 (m, 1H), 8.21-8.18 (m, 1H), 8.02 (dd, J=8.4, 5.5 Hz, 1H),
7.85-7.76 (m, 2H), 7.41 (dd, J=10.2, 8.3 Hz, 1H), 7.22-7.11 (m,
2H), 7.01-6.93 (m, 1H); MS (ESI-) for C16 H10 F3 N O2 S m/z 336.2
(M-H).sup.-.
[0194] The final product was prepared according to Method F; Yield
(27%); .sup.1H NMR (DMSO-d6) .delta. 10.33 (s, 1H), 9.28 (br. s,
2H), 8.68-8.65 (m, 1H), 8.25-8.21 (m, 1H), 8.0 (d, J=8.2 Hz, 1H),
7.73-7.62 (m, 2H), 7.21-7.08 (m, 3H), 7.0-6.93 (m, 1H), 3.29 (br.
s, 4H); MS (ESI+) for C20 H19 F2 N3 O2 S m/z 403.94
(M+H).sup.+.
Example 89
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(2-trifluoromethoxy-phenyl)-amide, hydrochloride
[0195]
N-(2-tri-Fluoromethoxyphenyl)-4-fluoronephthylsulphonamide--Method
E; Yield (43%); .sup.1H NMR (DMSO-d.sub.6) .delta. 10.58 (s, 1H),
8.80-8.76 (m, 1H), 8.20-8.17 (m, 1H), 8.08 (dd, J=8.3, 5.4 Hz, 1H),
7.84-7.74 (m, 2H), 7.42 (dd, J=10.2, 8.3 Hz, 1H), 7.32-7.18 (m,
4H).
[0196] The final product was prepared according to Method F; Yield
(48%); .sup.1H NMR (DMSO-d6) .delta. 10.49 (s, 1H), 9.27 (br. s,
2H), 8.75-8.72 (m, 1H), 8.24-8.21 (m, 1H), 8.02 (d, J=7.9 Hz, 1H),
7.71-7.62 (m, 2H), 7.32-7.17 (m, 5H), 3.38 (br. s, 4H), 3.28 (br.
s, 4H); S (ESI+) for C21 H20 F3 N3 O3 S m/z 451.9 (M+H).sup.+.
Example 90
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(3-phenoxy-phenyl)-amide, hydrochloride
[0197] N-(3-phenyloxyphenyl)-4-fluoronephthylsulphonamide--Method
E; Yield 0.64 g (100%); .sup.1H NMR (DMSO-d.sub.6) .delta. 10.80
(br. s, 1H), 8.71-8.68 (m, 1H), 8.19-8.16 (m, 1H), 8.10 (dd, J=8.3,
5.4 Hz, 1H), 7.85-7.74 (m, 2H), 7.45 (dd, J=10.2, 8.3 Hz, 1H),
7.38-7.31 (m, 2'H), 7.18-7.10 (m, 2H), 6.82-6.73 (m, 3H), 6.58-6.55
(m, 2H); MS (ESI-) for C22 H16 F N O3 S m/z 392.2 (M-H).sup.-.
[0198] The final product was prepared according to Method F; Yield
0.08 g (31%); .sup.1H NMR (DMSO-d6) .delta. 10.76 (s, 1H), 9.37
(br. s, 2H), 8.67-8.63 (m, 1H), 8.23-8.20 (m, 1H), 8.02 (d, J=8.2
Hz, 1H), 7.73-7.62 (m, 2H), 7.41-7.35 (m, 2H), 7.20-7.09 (m, 3H),
6.84-6.73 (m, 3H), 6.60-6.52 (m, 2H), 3.47-3.37 (m, 8H); MS (ESI+)
for C26 H25 N3 O3 S m/z 459.95 (M+H).sup.+.
Example 91
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(3-trifluoromethoxy-phenyl)-amide, hydrochloride
[0199]
N-(3-Trifluoromethoxyphenyl)-4-fluoronaphthalensulphonamide--Metho-
d E; Yield (35%); .sup.1H NMR (DMSO-d6) .delta. 11.01 (br.s, 1H),
8.74-8.71 (m, 1H), 8.26 (dd, J=8.3, 5.3 Hz, 1H), 8.16 (d, J=9.0 Hz,
1H), 7.86-7.82 (m, 1H), 7.78-7.74 (m, 1H), 7.46 (dd, J=10.0, 8.5
Hz, 1H), 7.27 (t, J=8.3 Hz, 1H), 7.02-6.90 (m, 3H); MS (ESI-) for
C17 H11 F4 N O3 S m/z 383.8 (M-H).sup.-.
[0200] The final product was prepared according to Method F; Yield
(35%); .sup.1H NMR (DMSO-d6) .delta. 11.07 (s, 1H), 9.63 (br. s,
1H), 9.31 (br. s, 1H), 8.66 (d, J=8.4 Hz, 1H), 8.21-8.18 (m, 2H),
7.75-7.62 (m, 2H), 7.29-7.21 (m, 2H), 7.03-6.86 (m, 3H), 3.32-3.28
(m, 8H); MS (ESI+) for C26 H25 N3 O3 S m/z 451.94 (M+H).sup.+.
Example 92
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(2-chloro-5-methyl-phenyl)-amide, hydrochloride
[0201] The final product was prepared according to method F:
.sup.1H NMR ((DMSO-d6) .delta.; 10.10 (brs, 1H), 9.25 (brs, 2H),
8.76-8.66 (m, 1H), 8.27-8.17 (m, 1H), 8.00-7.94 (m, 1H), 7.71-7.60
(m, 2H), 7.25-7.11 (m, 2H), 7.02 (s, 1H), 6.99-6.92 (m, 1H),
3.40-3.20 (m, obscured by solvent signal) 2.17 (s, 3H), MS (posESI)
m/z=416 (M+H).
Example 93
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(4-isopropyl-phenyl)-amide, hydrochloride
[0202] The final product was prepared according to method F:
.sup.1H NMR ((DMSO-d6) .delta.; 10.52 (s, 1H), 9.26 (brs, 2H),
8.74-8.66 (m, 1H), 8.27-8.11 (m, 2H), 7.76-7.60 (m, 2H), 7.26.7.17
(m, 1H), 7.06-6.89 (m, 4H), 3.40-3.20 (m, obscured by solvent
signal), 2.77-2.61 (m, 1H), 1.05 (d, J=6.87 Hz, 6H), MS (posESI)
m/z=410 (M+H).
Example 94
N-(3,5-Difluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,
hydrochloride
[0203] The final product was prepared according to Method F using
the crude N-(3,5-difluorophenyl)-4-fluoronaphthalene-1-sulfonamide
(50 mg, 0.15 mmol) afforded the title compound (20 mg, 31%) as a
yellow solid. .sup.1H NMR (DMSO) .delta. 11.33 (s, 1H), 9.35 (br s,
2H), 8.69 (m, 1H), 8.30-8.18 (m, 2H), 7.80-7.61 (m, 2H), 7.30-7.21
(m, 1H), 6.84-6.62 (m, 3H), 3.45-3.24 (m, 8H); MS m/z (M+1)
404.
Example 95
1-[4-(3,4-Dihydroquinolin-1(2H)-ylsulfonyl)-1-naphthyl]piperazine,
hydrochloride
[0204] 4-Fluoronaphthalene-1-sulfonyl chloride--To a stirred
solution of 1-fluoronaphthalene (8.0 g, 55 mmol) in concentrated
trifluoroacetic acid (40 ml), chlorosulfonic acid was added slowly
(15 min) at 0.degree. C. The mixture was stirred at room
temperature for an additional 2 hours and then added slowly onto a
stirred ice slurry. The formed precipitate filtered off, washed
with cold water and dried in vacuo to give the title compound (7.3
g) as a white solid.
[0205]
1-[(4-Fluoro-1-naphthyl)sulfonyl]-1,2,3,4-tetrahydroquinoline--Met-
hod E: To a stirred solution of 4-fluoronaphthalene-1-sulfonyl
chloride (200 mg, 0.82 mmol) in DCM (1 ml) was added
1,2,3,4-tetrahydroquinoline (123 .mu.l, 0.98 mmol) followed by
pyridine (0.25 ml). The reaction mixture was stirred over night,
diluted with DCM and washed with 1M HCl (3.times.3 ml). Subsequent
drying of the organic phase using MgSO.sub.4, and removal of the
solvents in vacuo afforded the title compound (280 mg, 100%) as a
white solid. .sup.1H NMR (CDCl.sub.3) .delta. 8.24-8.10 (m, 3H),
7.68-7.62 (m, 1H), 7.58-7.51 (m, 1H), 7.42-7.34 (m, 1H), 7.23-7.04
(m, 3H), 6.96-6.89 (m, 1H), 3.84-3.74 (m, 2H), 2.39-2.28 (m, 2H),
1.63-1.49 (m, 1H); MS m/z (M+1) 342.
[0206] The final product was prepared according to Method F: A
stirred solution of
1-[(4-fluoro-1-naphthyl)sulfonyl]-1,2,3,4-tetrahydroquinoline (50
mg, 0.15 mmol) and piperazine (80 mg, 0.9 mmol) in DMSO (1 ml) was
heated at 95.degree. C. over night. The reaction mixture was
allowed to reach room temperature and was subsequently added
dropwise into water. The formed solid was isolated, re-dissolved in
MeOH and treated with an excess of 1M HCl in diethyl ether. Removal
of the solvents in vacuo afforded the title compound (60 mg, 83%)
as a white solid. .sup.1H NMR (DMSO) .delta. 9.17 (br s, 2H),
8.23-8.06 (m, 3H), 7.61-7.55 (m, 1H), 7.48-7.38 (m, 2H), 7.29-7.23
(m, 1H), 7.19-7.12 (m, 1H), 7.09-6.98 (m, 2H), 3.78-3.71 (m, 2H),
3.44-3.30 (m, 8H), 2.42-2.32 (m, 2H), 1.57-1.48 (m, 2H); MS m/z
(M+1) 408.
Example 96
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid
(3-nitro-phenyl)-amide, hydrochloride
[0207] The final product was prepared according to Method F:
.sup.1H NMR ((DMSO-d6) .delta.; 8.68-8.63 (m, 1H), 8.27-8.13 (m,
2H), 7.78 (s, 1H), 7.72-7.53 (m, 3H), 7.35-7.16 (m, 3H), 3.55-3.40
(m, 6H), 3.34-3.27 (m, obscured in part by solvent signal),
2.22-2.13 (m, 2H), MS (posESI) m/z=427 (M+H).
Example 97
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(3-nitro-phenyl)-amide, hydrochloride
[0208] The final product was prepared according to Method F:
.sup.1H NMR ((DMSO-d6) .delta.; 8.68-8.60 (m, 1H), 8.24-8.13 (m,
2H), 7.77 (s, 1H), 7.71-7.53 (m, 3H), 7.30-7.20 (m, 2H), 7.16-7.10
(m, 1H), 3.45-3.40 (m, 4H), 3.31-3.20 (m, 4H), MS (posESI) m/z=413
(M+H).
Example 98
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid
(3-nitro-phenyl)-methyl-amide, hydrochloride
[0209] The final product was prepared according to Method F:
.sup.1H NMR (DMSO-d6) .delta.; 8.21 (d, J=8.47 Hz, 1H), 8.12 (d,
J=8.79 Hz, 1H), 8.01-7.95 (m, 2H), 7.64 (s, 1H), 7.54-7.39 (m, 3H),
7.34-7.28 (m, 1H), 7.23-7.18 (m, 1H), 3.60-3.30 (m, 8H), 3.17 (s,
3H), 2.24-2.16 (m, 2H), MS (posESI) m/z=441 (M+H).
Example 99
N-(4-Methylphenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,
hydrochloride
[0210] 4-Fluoro-N-(4-methylphenyl)naphthalene-1-sulfonamide--Method
E: Use of 4-methylaniline afforded the title compound (500 mg, 95%)
as an oil by the application of the general procedure A described
above. .sup.1H NMR (CDCl.sub.3) .delta. 8.82-8.75 (m, 1H),
8.22-8.13 (m, 2H), 7.73-7.58 (m, 2H), 7.44 (s, 1H), 7.11-7.02 (m,
1H), 6.93-6.80 (m, 4H), 2.17 (s, 3H); MS m/z (M+1) 316.
[0211] The final product was prepared according to Method E: Use of
4-fluoro-N-(4-methylphenyl)naphthalene-1-sulfonamide afforded the
title compound (200 mg, 30%), after washing with methanol, as a
yellow solid. .sup.1H NMR (DMSO) .delta. 10.46 (s, 1H), 9.30 (br s,
2H), 8.76-8.65 (m, 1H), 8.25-8.06 (m, 2H), 7.78-7.59 (m, 2H),
7.25-7.14 (m, 1H), 6.98-6.83 (4H), 3.41-3.22 (m, 8H), 2.09 (s, 3H);
MS m/z (M+1) 382.
Example 100
N-(3-Chloro-4-methylphenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,
hydrochloride
[0212] The final product was prepared according to Method E: yield
100%, purity 93% .sup.1H NMR (500 MHz, DMSO-D6) .delta. ppm 2.26
(s, 3H), 2.74 (m, 4H), 3.54 (m, 4H), 7.23 (m, 4H), 7.83 (m, 2H),
8.31 (m, 2H), 8.81 (s, 1H), 9.11 (s, 1H, N--H), 10.86 (s, 1H,
N--H); MS (ESI+) for C21 H22 Cl N3 O2 S HCl m/z (M+H).sup.+. 416.1;
MS (ESI-) for C21 H22 Cl N3 O2 S HCl m/z (M-H).sup.-. 414.1.
Example 101
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid
(2,3-dimethyl-phenyl)-methyl-amide, hydrochloride
[0213] The final product was prepared according to Method F:
.sup.1H NMR (DMSO-d6) .delta.; 8.51-8.41 (m, 1H), 8.39-8.30 (m,
1H), 8.11-7.99 (m, 1H), 7.68-7.56 (m, 1H), 7.54-7.42 (m, 1H),
7.35-7.23 (m, 1H), 7.13-7.02 (M, 1H), 6.90-6.78 (m, 1H), 6.62-6.47
(m, 1H), 3.70-3.40 (m, 8H), 3.17 (s, 3H), 2.25 (s, 3H), 2.10 (s,
3H), MS (posESI) m/z=424 (M+H).
Example 102
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid
(4-isopropyl-phenyl)-amide, hydrochloride
[0214] The final product was prepared according to Method F:
.sup.1H NMR ((DMSO-d6) .delta.; 8.74 (d, J=8.16 Hz, 1H), 8.33 (d,
J=8.48 Hz, 1H), 8.15-8.10 (m, 1H), 7.72-7.62 (m, 2H), 7.25-7.21 (m,
1H), 6.99-6.86 (m, 4H), 3.62-3.57 (m, 2H), 3.56-3.50 (m, 4H),
3.41-3.35 (m, 2H), 2.79-2.69 (m, 1H), 2.32-2.22 (m, 2H), 1.14-1.10
(m, 6H), MS (posESI) m/z=424 (M+H).
Example 103
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid
(4-isopropyl-phenyl)-methyl-amide, hydrochloride
[0215] The final product was prepared according to Method F:
.sup.1H NMR (DMSO-d6) .delta.; 8.13-8.07 (m, 1H), 8.01-7.93 (m,
1H), 7.51-7.41 (m, 1H), 7.38-7.15 (m, 2H), 7.00-6.95 (m, 2H),
6.89-6.85 (m, 2H), 3.59-3.28 (m, 8H), 3.09 (s, 3H), 2.81-2.71 (m,
1H), 1.11 (d, J=6.60 Hz, 6H), MS (posESI) m/z=438 (M+H).
Example 104
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid
(2,4-dimethyl-phenyl)-amide, hydrochloride
[0216] The final product was prepared according to Method F:
.sup.1H NMR ((DMSO-d6) .delta.; 8.70-8.61 (m, 1H), 8.30-8.20 (m,
1H), 7.91-7.78 (m, 1H), 7.60-7.51 (m, 2H), 7.14-7.06 (m, 1H),
6.76-6.59 (m, 3H), 3.64-3.40 (m, 6H), 3.35-3.30 (m, obscured in
part by solvent signal), 2.24-2.13 (m, 2H), 2.07 (s, 3H), 1.76 (s,
3H), MS (posESI) m/z=410 (M+H).
Example 105
4-[1,4]Diazepan-1-yl-naphthalene-1-sulfonic acid
(2-chloro-5-methyl-phenyl)-amide, hydrochloride
[0217] The final product was prepared according to Method F:
.sup.1H NMR ((DMSO-d6) .delta.; 8.67-8.61 (m, 1H), 8.24-8.19 (m,
1H), 7.95 (d, J=8.16 Hz, 1H), 7.57-7.56 (m, 2H), 7.21-7.18 (m, 1H),
7.12 (d, J=8.17 Hz, 1H), 6.89 (d, J=8.17 Hz, 1H), 6.78-6.75 (m,
1H), 3.52-3.47 8 m, 2H), 3.45-3.40 (m, 4H), 3.31-3.26 (m, 2H),
2.20-2.10 (m, 2H), 2.14 (s, 3H), MS (posESI) m/z=430 (M+H).
Example 106
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(2,5-dimethoxy-phenyl)-amide, hydrochloride
[0218] The final product was prepared according to Method F:
.sup.1H NMR ((DMSO-d6) .delta.; 8.80-8.72 (m, 1H), 8.27-8.19 (m,
1H), 7.98 (d, J=8.18 Hz, 1H), 7.74-7.60 (m, 2H), 7.17 (d, J=7.91
Hz, 1H), 6.76-6.75 (m, 2H), 6.62-6.55 (m, 1H), 3.60 (s, 3H),
3.40-3.20 (m, obscured by solvent signal), 3.12 (s, 3H), MS
(posESI) m/z=428 (M+H).
Example 107
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(3-acetyl-phenyl)-amide; hydrochloride
[0219] The final product was prepared according to Method F:
.sup.1H NMR ((DMSO-d6) .delta.; 8.79-8.72 (m, 1H), 8.29-8.21 (m,
2H), 7.75-7.62 (m, 2H), 7.59-7.52 (m, 2H), 7.26-7,19 (m, 3H),
3.52-3.44 (m, 4H), 3.39-3.30 (m, obscured by solvent signal), 2.43
(s, 3H), MS (posESI) m/z=410 (M+H).
Example 108
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(2,4-dimethyl-phenyl)-amide, hydrochloride
[0220] The final product was prepared according to Method F:
.sup.1H NMR ((DMSO-d6) .delta.; 8.81-8.72 (m, 1H), 8.34-8.25 (m,
1H), 7.98 (d, J=8.18 hz, 1H), 7.71-7.60 (m, 2H), 7.14 (d, J=8.18
Hz, 1H), 6.81 (s, 1H), 6.76-6.72 (m, 2H), 3.58-3.47 (m, 4H),
3.44-3.30 (m, obscured in part by solvent signal), 2.16 (s, 3H),
1.84 (s, 3H), MS (posESI) m/z=396 (M+H).
Example 109
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(3-trifluoromethyl-phenyl)-amide, hydrochloride
[0221] The final product was prepared according to Method F:
.sup.1H NMR ((DMSO-d6) .delta.; 8.72-8.64 (m, 1H9, 82.7-8.16 (m,
2H), 7.81-7.62 (m, 2H), 7.45-7.19 (m, 5H), 3.40-3.20 (m, obscured
by solvent signal), MS (posESI) m/z=436 (M+H).
Example 110
4-Piperazin-1-yl-naphthalene-1-sulfonic acid biphenyl-2-ylamide,
hydrochloride
[0222] The final product was prepared according to Method F:
.sup.1H NMR ((DMSO-d6) .delta.; 9.71 (s, 1H), 944 (brs, 2H),
8.51-8.42 (m, 1H), 8.24-8.15 (m, 1H), 7.83 (d, J=8.18 Hz, 1H),
7.66-7.49 (m, 2H), 7.29-6.98 (m, 10H), 3.50-3.30 (m, obscured by
solvent signal), MS (posESI) m/z=444 (M+H).
Example 111
4-Piperazin-1-yl-naphthalene-1-sulfonic acid
(3-benzyloxy-phenyl)-amide,
[0223] N-(3-phenyloxyphenyl)-4-fluoronaphthalensulphonamide--Method
E; Yield 9.2 g (47%). .sup.1H NMR (DMSO-d.sub.6) .delta. 10.75 (s,
1H), 8.75 (d, J=8.4 Hz, 1H), 8.23-8.14 (m, 2H), 7.87-7.73 (m, 2H),
7.44 (dd, J=10.2, 8.3 Hz, 1H), 7.34-7.29 (m, 5H), 7.03 (t, J=8.2
Hz, 1H), 6.66-6.56 (m, 3H), 4.93 (s, 2H); MS (ESI+) for C23 H18 F N
O3 S m/z 407 (M+H).sup.+.
[0224] The final product was prepared according to Method F: Yield
0.6 g (78%); .sup.1H NMR (DMSO-d.sub.6) .delta. 10.67 (s, 1H), 9.30
(br. s, 2H), 8.69 (d, J=7.7 Hz, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.13
(d, J=8.2 Hz, 1H), 7.75-7.61 (m, 2H), 7.35-7.30 (m, 5H), 7.19 (d,
J=8.2 Hz, 1H), 7.03 (t, J=8.2 Hz, 1H), 6.68-6.54 (m, 3H), 4.93 (s,
2H), 3.36-3.29 (m, 8H); MS (ESI+) for C27 H27 N3 O3 S m/z 474
(M+H).sup.+.
Example 112
[0225]
N-(4-fluorophenyl)-4-piperazin-1-ylnaphthalene-1-sulfonamide,
hydrochloride4-Fluoro-N-(4-fluorophenyl)naphthalene-1-sulfonamide--Method
E: Use of 4-methoxyaniline afforded the title compound (475 mg,
86%) as an oil by the application of the general procedure A
described above. .sup.1H NMR (CDCl.sub.3) .delta. 8.79-8.71 (m,
1H), 8.23-8.10 (m, 2H), 7.75-7.59 (2H), 7.52-7.45 (m, 1H),
7.15-7.04 (m, 1H), 6.96-6.73 (m, 4H); MS m/z (M+1) 320.
[0226] The final product was prepared according to Method F: Use of
4-fluoro-N-(4-fluorophenyl)naphthalene-1-sulfonamide afforded the
title compound (95 mg, 15%), after recrystallization from methanol,
as a white solid by the application of the general procedure B
described above. .sup.1H NMR (DMSO) .delta. 10.60 (s, 1H), 9.37 (br
s, 2H), 8.73-8.65 (m, 1H), 8.25-8.17 (m, 1H), 8.13-8.06 (m, 1H),
7.76-7.60 (m, 2H), 7.22-7.15 (m, 1H), 7.04-6.95 (m, 4H), 3.43-3.24
(m, 8H); MS m/z (M+1) 386.
Example 113
N-(3-Ethylphenyl)-4-piperazin.1.ylnaphthalene-1-sulphonamine,
hydrochloride
[0227] N-(3-Ethylphenyl)-4-fluoronaphthalene-1-sulfonamide --Method
E: yield 80%, purity 92%. .sup.1H NMR (270 MHz, CDCl.sub.3) .delta.
ppm 1.03 (t, J=7.52 Hz, 3H), 2.45 (q, J=7.65 Hz, 2H), 6.68-6.72 (m,
2H, N--H), 6.87 (d, J=7.13 Hz, 1H), 6.99-7.13 (m, 2H), 7.65-7.72
(m, 2H), 8.13-8.20 (m, 2H), 8.65 (d, J=8.44 Hz, 1H); MS (ESI+) for
C18 H16 F N O2 S m/z 329.393 (M+H).sup.+. 330.0; MS (ESI-) for C18
H16 F N O2 S m/z 329.393 (M-H).sup.-. 328.1
[0228] The final product was prepared according to Method F: yield
61%, purity 98%. .sup.1H NMR (500 MHz, DMSO) .delta. 8.67-8.65 (m,
1H), 8.16-8.10 (m, 2H), 7.66-7.57 (m, 2H), 7.14 (d, J=8.56 Hz, 1H),
6.97-6.94 (m, 1H), 6.78-6.76 (m, 2H), 6-70-6.69 (m, 1H), 3.30-3.28
(m, 2H), 3.22-3.19 (m, 2H), 2.34 (q, J=17 Hz, 2H), 1.94 (tr, J=17
Hz, 3H); MS (ESI+) for C22 H25 N3 O2 S HCl m/z 431.98
(M-HCl+H).sup.+. 396.1; MS (ESI-) for C22 H25 N3 O2 S HCl m/z
(M-HCl-H).sup.-. 394.1
Example 114
4-Piperazinyl-N-[3-(trifluoromethyl)phenyl]naphthalene-1-sulfonamide,
hydrochloride
[0229] The final product was prepared according to Method F: Use of
4-fluoro-N-(3-trifluoromethythiophenyl)naphthalene-1-sulfonamide
afforded the title compound (0.08 g), gave 0.060 g of the desired
product, yield 85%, purity 96%.
[0230] .sup.1H NMR (270 MHz, CD.sub.3OD) .delta. 8.74-8.71 (m, 1H),
8.26-8.19 (m, 2H), 7.75-7.65 (m, 2H), 7.32 (br.s, 1H), 7.23-7.14
(m, 4H), 3.57-3.47 (m, 4H), 3.35-3.30 (m, 4H); MS (ESI+) for C21
H20 F3 N3 O2 S2 HCl m/z 467.09+35.46 (M+H).sup.+ 468.0; MS (ESI+)
for C21 H20 F3 N3 O2 S2 HCl m/z 467.09+35.46 (M-H).sup.- 466.1.
Example 115
4-Piperazinyl-N-[3-benzoylphenyl]naphthalene-1-sulfonamide,
hydrochloride
[0231] The final product was prepared according to Method F: yield
25%, purity 97%. .sup.1H NMR (270 MHz, CD.sub.3OD) .delta.
8.76-8.72 (m, 1H), 8.29-8.26 (m, 1H), 8.17 (d, J=8,1 Hz, 1H),
7.73-7.60 (m, 3H), 7.55-7.44 (m, 4H), 7.34-7.28 (m, 4H), 7.18 (d,
J=8,1 Hz, 1H), 3.54-3.50 (m, 4H), 3.37-3.30 (m, 4H); MS (ESI+) for
C27 H25 N3 O3 S HCl m/z 471.17+35.46 (M+H).sup.+ 472.1; MS (ESI+)+)
for C27 H25 N3 O3 S HCl m/z 471.17+35.46 (M-H).sup.- 470.01.
Example 116
4-piperazinyl-N-[3-(4-bromo-1-methyl-1H-pyrazol-3-yl)phenyl]naphthalene-1--
sulfonamide, hydrochloride
[0232] The final product was prepared according to Method F: yield
81%, purity 96%. .sup.1H NMR (270 MHz, CD.sub.3OD) .delta.
8.78-8.74 (m, 1H), 8.27-8.24 (m, 1H), 8.19 (d, J=8,1 Hz, 1H),
7.75-7.64 (m, 2H), 7.46 (s, 1H), 7.31-7.25 (m 1H), 7.19-7.16 (m,
2H), 7.02-6.96 (m, 2H), 3.57-3.49 (m, 4H), 3.52 (s, 3H), 3.35-3.30
(m, 4H); MS (ESI+) for C24 H24 Br N5 O2 S HCl m/z 525.08+35.46
(M+H).sup.+ 526.0; MS (ESI+) C24 H24 Br N5 O2 S HCl m/z 525.08
+35.46 (M-H).sup.- 524.1.
Example 117
4-Piperazinyl-N-[3-biphenylphenyl]naphthalene-1-sulfonamide,
hydrochloride
[0233] The final product was prepared according to Method F: yield
33%, purity 95%. .sup.1H NMR (270 MHz, CD.sub.3OD) .delta.
8.83-8.80 (m, 1H), 8.26-8.22 (m, 2H), 7.79-7.68 (m, 2H), 7.39-7.35
(m, 5H), 7.23-7.19 (m, 4H), 7.03-6.99 (m, 1H), 3.52-3.47 (m, 4H),
3.35-3.30 (m, 4H); MS (ESI+) for C26 H25 N3 O2 S HCl m/z
443.17+36.45 (M+H).sup.+ 444.1; MS (ESI-) for C26 H25 N3 O2 S HCl
m/z 443.17+36.45 (M-H).sup.- 442.2.
Synthesis of Examples and Intermediates in Table IV
General Method H
Example 118
N-[1-(4-Methyl-1-piperazinyl)-3-isoquinolinyl]benzenesulfonamide,
hydrochloride
[0234] To a solution of
1-(4-methyl-1-piperazinyl)-3-isoquinolinylamine (commercially
available; 0.26 g, 1.07 mmol) and pyridine (0.60 mL, 7.51 mmol) in
CH.sub.2Cl.sub.2 (3.0 mL) was added benzenesulfonyl chloride (151
.mu.L, 1.18 mmol) in CH.sub.2Cl.sub.2 (1 mL). The mixture was
stirred at room temperature for 16 hours and left in the
refrigerator for 24 hours. The precipitate was collected by
filtration to give 0.255 g (57%) of the pure product as the
HCl-salt: .sup.1H NMR (DMSO-d6) .delta. 10.93 (s, 2H), 7.96-7.90
(m, 3H), 7.79-7.75 (m, 1H), 7.64-7.56 (m, 4H), 7.44-7.38 (m, 1H),
7.01 (s, 1H9, 3.70-3.15 (m, partly obscured by solvent signal, 8H),
2.79 (s, 3H); MS (posEI-DIP) m/z 382 (M.sup.+).
Example 119
2,4-di-Fluoro-N-[1-(4-methyl-1-piperazinyl)-3-isoquinolinyl]benzenesulfona-
mide, hydrochloride
[0235] The title compound was prepared from
1-(4-methyl-1-piperazinyl)-3-isoquinolinylamine (commercially
available; 0.209 g, 0.862 mmol) using the method described in the
example that follows: yield 0.152 g (65%); .sup.1H NMR (DMSO-d6)
.delta.; 11.35 (s, 1H), 11.09 (br s, 1H), 8.15-8.04 (m, 1H),
7.97-7.90 (m, 1H), 7.83-7.35 (m, 5H), 6.95 (s, 1H), 3.70-3.10 (m,
8H), 2.85-2.75 (m, 3H); MS (posESI) m/z 419 (M+H).
Example 120
4-Bromo-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonamid-
e, hydrochloride
[0236] .sup.1H NMR (DMSO-d6) .delta.; 11.07 (s, 1H), 10.75 (br s,
1H), 7.98-7.75 (m, 5H), 7.66-7.58 (m, 1H), 7.52 (s, 1H), 7.47-7.37
(m, 1H), 7.00 (brs, 1H), 3.70-3.20 (obscured in part by solvent
signal, 8H), 2.85-2.80 (m, 2H), MS (posESI) m/z=461 (M+H)
Example 121
5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid
[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide,
hydrochloride
[0237] .sup.1H NMR (DMSO-d6) .delta.; 11.47 (br s, 1H), 10.55 (br
s, 1H), 8.14-8.07 (m, 1H), 8.01-7.98 (m, 1H), 7.96-7.98 (m, 1H),
7.82-7.76 (m, 1H), 7.67-7.52 (m, 2H), 7.47-7.39 (m, 1H), 7.06 (s,
1H), 3.80-3.65 (m, 2H), 3.60-3.25 (m, obscured by solvent signal),
2.80-2.73 (m, 3H),), MS (posESI) m/z=487 (M+H)
Example 122
3-Chloro-2-methyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzene-
sulfonamide, hydrochloride
[0238] .sup.1H NMR (DMSO-d6) .delta.; 11.24 (br s, 1H), 10.56 (br
s, 1H), 8.10-8.05 (m, 1H), 7.95-7.89 (m, 1H), 7.80-7.69 (m, 2H),
7.66-7.57 (m, 1H), 7.53-7.35 (m, 2H), 6.94 (s, 1H), 3.70-330 (m,
obscured by solvent signal), 3.29-3.10 (m, 4H), 3.85-2.79 (m,
3H),), MS (posESI) m/z=431(M+H).
Example 123
3,4-Dichloro-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfo-
namide, hydrochloride
[0239] .sup.1H NMR (DMSO-d6) .delta.; 11.17 (s, 1H), 10.50 (br s,
1H), 8.16-8.14 (m, 1H), 7.98-7.93 (m, 1H), 7.91-7.89 (m, 2H),
7.85-7.80 (m, 1H), 7.68-7.60 (m, 1H), 7.49-7.41 (m, 1H), 7.04 (s,
1H), 3.85-3.20 (m, obscured by solvent signal), 2.87-2.83 (m,
3H),), MS (posESI) m/z=451(M+H).
Example 124
4-Methyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonami-
de, hydrochloride
[0240] .sup.1H NMR (DMSO-d6) .delta.; 10.88 (m, brs, 1H), 7.95-7.88
(m, 1H), 7.85-7.74 (m, 3H), 7.65-7.56 (m, 1H), 7.51-7.34 (m, 4H),
7.14-7.09 (m, 1H), 6.99 (s, 1H), 3.75-3.45 (m, obscured by solvent
signal, 4H), 3.35-3.15 (m, 4H), 2.84 (d, J=4.75 Hz, 3H), 2.33 (s,
3H),), MS (posESI) m/z=397(M+H).
Example 125
3-Methoxy-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulfonam-
ide, hydrochloride
[0241] .sup.1H NMR (DMSO-d6) .delta.; 10.93 (brs, 1H), 10.69 (brs,
1H), 7.93 (d, J=8.19 Hz, 1H), 7.79 (d, J=7.92 Hz, 1H), 7.65-7.57
(m, 1H), 7.52-7.37 (m, 4H), 7.24-7.13 (m, 1H), 7.03 (s, 1H), 3.78
(s, 3H), 3.75-3.20 (m, obscured by solvent signal, 8H), 2.81 (d,
J=4.48 Hz, 3H), MS (posESI) m/z=413(M+H).
Example 126
5-Chloro-thiophene-2-sulfonic acid
[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide,
hydrochloride
[0242] .sup.1H NMR (DMSO-d6) .delta.; 7.76-7.21 (m, 1H), 7.01-6.96
(m, 1H), 6.89-6.82 (m, 1H), 6.74-6.71 (m, 1H), 6.70-6.66 (m, 1H),
6.40 (brs, 1H), 6.22 (d, J=3.96 Hz, 1H), 3.20-3.10 (m, 2H),
2.87-2.75 (m, 2H), 2.70-2.50 (m, obscured in part by solvent
signal, 4H), 2.19 (brs, 3H), MS (posESI) m/z=423(M+H).
Example 127
N-{2-Chloro-4-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-ylsulfamoyl]-phen-
yl}-acetamide, hydrochloride
[0243] .sup.1H NMR (DMSO-d6) .delta.; 10.03 (s, 1H), 10.52 (brs,
1H), 7.93 (d, J=8.44 Hz, 1H), 7.78 (d, J=7.92 Hz, 1H), 7.71 (d,
J=2.11 Hz, 1H), 7.65-7.57 (m, 1H), 7.57-7.51 (dd, J=2.11 and 8.44
Hz, 1H), 7.45-7.37 (m, 1H), 6.99 (s, 1H), 6.80 (d, 8.44 Hz, 1H),
m3.82-3.71 (m, 2H), 3.60-3.20 (m, obscured by solvent signal) 2.84
(d, J=4.49 hz, 3H), MS (posESI) m/z=474(M+H).
Example 128
2,5-Dichloro-thiophene-3-sulfonic acid
[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide,
hydrochloride
[0244] .sup.1H NMR (DMSO-d6) .delta.; 794-7.89 (m, 1H), 7.77-7.72
(m, 1H), 7.63-7.56 (m, 1H), 7.46 (s, 1H), 7.44-7.36 (m, 1H),
3.50-3.20 (m, obscured by solvent signal), 2.70-2.50 m, obscured by
solvent signal), 2.32 (brs, 3H), MS (posESI) m/z=457(M+H).
Example 129
N-[1-(4-Methyl-piperazin-1-yl)-isoquinolin-3-yl]-3-trifluoromethyl-benzene-
sulfonamide, hydrochloride
[0245] .sup.1H NMR (DMSO-d6) .delta.; 11.17 (s, 1H), 10.71 (brs,
1H), 8.27-8.17 (m, 2H), 8.07-8.01 (m, 1H), 7.97-7.79 (m, 3H),
7.67-7.60 (m, 1H), 7.48-7.40 (m, 1H), 7.06 (s, 1H), 3.70-3.40 (m,
m, obscured by solvent signal), 3.31-3.14 (m, 4H), 2.82 (d, J=4.75
Hz, 3H), MS (posESI) m/z=451(M+H).
Example 130
N-[1-(4-Methyl-piperazin-1-yl)-isoquinolin-3-yl]-4-phenoxy-benzenesulfonam-
ide, hydrochloride
[0246] .sup.1H NMR (DMSO-d6) .delta.; 10.91 (s, 1H), 10.79 (brs,
1H), 7.98-7.89 (m, 3H), 7.81-7.74 (m, 1H), 7.66-7.55 (m, 1H),
7.49-7.37 (m, 3H), 7.28-7.20 (m, 1H), 7.13-7.06 (m, 4H), 7.00 (s,
1H), 3.77-3.66 (m, 2H), 3.50-3.20 (m, 6H), 2.82 (d, J=4.49 Hz, 3H),
MS (posESI) m/z=475 (M+H).
Example 131
5-Bromo-2-methoxy-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzene-
sulfonamide, hydrochloride
[0247] .sup.1H NMR (DMSO-d6) .delta.; 10.90 (s, 1H), 10.75 (brs,
1H), 7.99 (d, J=2.64 Hz, 1H), 7.91 (m, d, J=8.45 Hz, 1H), 7.80-7.73
(m, 2H), 7.65-7.57 (m, 1H), 7.45-7.37 (m, 1H), 7.14 (d, J=8.47 Hz,
1H), 3.82 (s, 3H), 3.68-3.55 (m, 2H), 3.52-3.38 (m, 2H), 3.35-3.20
(m, 4H), 2.84 (d, J=4.49 Hz, 3H), MS (posESI) m/z=491(M+H).
Example 132
2-Methanesulphonyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzen-
esulfonamide, hydrochloride
[0248] MS (posESI) m/z=461 (M+H).
Example 133
3,5-Dimethyl-isoxazole-4-sulfonic acid
[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-amide,
hydrochloride
[0249] .sup.1H NMR (DMSO-d6) .delta.; 11.17 (s, 1H), 10.54 (s, 1H),
7.99 (d, J=8.45 Hz, 1H), 7.86 (d, J=7.92 Hz, 1H), 7.71-7.63 (m,
1H), 7.53-7.45 (m, 1H), 7.07 (s, 3H), 3.75-3.64 (m, 2H), 3.55-3.45
(m, 2H), 3.35-3.15 (m, 4H), 2.84 (d, J=4.49 Hz, 3H), 2.76 (s, 3H),
2.31 (s, 3H), MS (posESI) m/z=402 (M+H).
Example 134
2,4,6-Trimethyl-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesu-
lfonamide
[0250] .sup.1H NMR (DMSO-d6) .delta.; 10.82 (s, 1H), 10.52 (brs,
1H), 7.92-7.87 (m, 1H), 7.76-7.70 (m, 1H), 7.64-7.56 (m, 1H),
7.43-7.36 (m, 1H), 7.00 (s, 2H), 6.88 (s, 1H), 6.74 (brs, 1H),
3.60-3.10 (m, 8H), 2.81 (d, J=4.75 Hz, 3H), 2.61 (s, 6H), 2.22 (s,
3H), MS (posESI) m/z=425 (M+H).
Example 135
3,4-Dimethoxy-N-[1-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-benzenesulf-
onamide, hydrochloride
[0251] .sup.1H NMR (DMSO-d6) .delta.; 10.75 (brs, 1H), 10.72 (s,
1H), 7.95-7.90 (m, 1H), 7.82-7.76 (m, 1H), 7.65-7.57 (m, 1H),
7.55-7.37 (m, 2H), 7.11 (d, J=8.71 Hz, 1H)m 7.05 (s, 1H), 3.78 (s,
3H), 3.76 (s, 3H), 3.76-3.69 (m, obscured in part by --OMe),
3.51-3.19 (m, 6H), 2.82 (d, J=4.49 Hz, 3H), MS (posESI) m/z=443
(M+H).
Synthesis of Examples in Table V
Example 136
N-[8-(4-Methyl-1-piperazinyl)-5-quinolinyl]benzenesulfonamide,
hydrochloride
[0252] To a solution of 8-(4-methyl-1-piperazinyl)-5-nitroquinoline
(0.379 g, 1.39 mmol) in THF:EtOH 1:4 solvent system was added
Raney-Ni (1.0 mL suspension in EtOH) followed by hydrazine hydrate
(0.348 g, 6.95 mmol). The mixture was stirred vigorously at room
temperature for 16 hours and then filtered through celite
pretreated with water. The filtrate was concentrated, and the
residue was purified by column chromatography (SiO.sub.2,
CHCl.sub.3/MeOH/NH.sub.3 9:1:0.4%) to give 0.337 g of
8-(4-methyl-1-piperazinyl)-5-quinolinylamine. The amine was
dissolved in CH.sub.2Cl.sub.2 (6.0 mL) and pyridine (0.785 mL, 9.73
mmol) and benzenesulfonyl chloride (0.178 mL, 1.39 mmol) was added.
The reaction mixture was stirred at room temperature for 16 hours
and then washed with saturated aqueous NaHCO.sub.3. The organic
phase was dried with Na.sub.2SO.sub.4, filtered and concentrated.
The crude product was purified by column chromatography (SiO.sub.2,
CHCl.sub.3/MeOH/NH.sub.3 9:1:0.4%) to give 0.130 g of the free base
which was converted to its HCl-salt: .sup.1H NMR (DMSO-d6) .delta.;
11.09 (br s, 1H), 10.32 (s, 1H), 8.94-8.89 (m, 1H), 8.55-8.48 (m,
1H), 7.68-7.65 (m, 2H), 7.64-7.57 (m, 2H), 7.54-7.49 (m, 2H),
7.27-7.22 (m, 1H), 7.12-7.08 (m, 1H), 3.95-3.84 (m, 2H), 3.55-3.49
(m, 2H), 3.45-3.35 (m, 2H), 3.26-3.16 (m, 2H), 2.85-2.82 (m, 3); MS
(posESI) m/z 383 (M+H). Synthesis of Examples and Intermediates in
Table VI ##STR358## Intermediate 20
[0253] 3-Cyanomethylpyridine-N-oxide--Hydrogenperoxide (17 ml, 30%
ww) was added to a mixture of 3-cyanomethylpyridine (11 g, 93 mmol)
and glacial acetic acid (55 ml) and heated at 100.degree. C.
overnight. The mixture was diluted with water (70 ml) and MnO.sub.2
(5.0 g) was carefully added and stirred for 5 hours (check peroxide
content with peroxide sticks), and only small amounts of peroxide
was left. The mixture was concentrated in vacuo to 40 ml and
diluted with methanol (40 ml), filtered through a short plug of
silica, and washed with methanol (400 ml). The filtrate were
concentrated and recrystallized from chloroform and hexane to give
the title compound (9.5 g, 76%). .sup.1H NMR (CDCl.sub.3) .delta.
8.16 (s, 2H), 7.32 (s, 2H), 3.73 (s, 2H); MS m/z (M+1) 135.
Intermediate 21
[0254]
3-(Cyanomethyl)pyridine-2-carbonitrile--Trimethylsilylcyanide (4.2
ml, 32 mmol) was added to a suspension of
3-cyanomethylpyridine-N-oxide (3.5 g, 26 mmol) in toluene (35 ml)
and after 1 minute dimethylcarbamylchloride (2.4 ml, 26 mmol) was
added and the reaction was stirred overnight at 65.degree. C. EtOAc
and 1N NaOH was added and the mixture was washed with water
(2.times.). The organic phase was dried (MgSO.sub.4) and
evaporated. The crude product was dissolved in ethanol (150 ml) and
stirred overnight, filtered (remove byproduct) and concentrated (25
ml). After 30 min at 0.degree. C. the yellow powder was filtered
and washed with cold ethanol (1.times.) to give, after drying, the
title compound (2.15 g, 57%). .sup.1H NMR (CDCl.sub.3) .delta. 8.71
(m, 1H), 8.03 (d, J=8.03 Hz, 1H), 7.62 (dd, J=8.16, 4.64 Hz, 1H),
4.04 (s, 2H); MS m/z (M-1) 142.
Intermediate 22
[0255]
6-Amino-8-bromo-1,7-naphthyridine--3-(Cyanomethyl)pyridine-2-carbo-
nitrile (4.0 g, 28 mmol) was added carefully to HBr in acetic acid
(33%) (25 ml) at rt. The red suspension was stirred for 1.5 h and
filtered. The red solid was washed with EtOAc (3.times.) and
suspended in water. 1N NaOH was added dropwise until pH-8, and the
suspension was stirred for 45 minutes and filtered. The red solid
was washed with water (2.times.) and dried. The crude product was
suspended in 5% MeOH in CH.sub.2Cl.sub.2 and filtered through a
short plug of silica, washing with 5% MeOH in CH.sub.2Cl.sub.2.
Subsequent concentration in vacuo afforded the title compound (3.85
g, 61%). .sup.1H NMR (DMSO) .delta. 8.58 (dd, J=4.02, 1.51 Hz, 1H),
8.01 (dd, J=8.53, 1.51 Hz, 1H), 7.47 (dd, J=8.53, 4.02 Hz, 1H),
6.58 (s, 1H), 6.48 (s, 2H); MS m/z (M+1) 226.
Intermediate 23
[0256] tert-Butyl
4-(6-amino-1,7-naphthyridin-8-yl)piperazine-1-carboxylate--A
mixture of 6-amino-8-bromo-1,7-naphthyridine (650 mg, 2.9 mmol),
BOC-piperazine (1.1 g, 5.9 mmol), potassium carbonate (2 g, 15
mmol) in DMSO (1 ml) was stirred at 90.degree. C. for 3 days.
Chloroform was added, the mixture was filtered and the filtrate was
washed with brine (3.times.100 ml). The organic phase was dried
using potassium carbonate, filtered and concentrated in vacuo to
give a yellow oil. The oil was triturated with diethyl ether and
then eluted through a short silica plug using chloroform.
Subsequent concentration of the residue in vacuo gave the title
compound (700 mg, 74%) as a yellow oil. .sup.1H NMR (CDCl.sub.3)
.delta. 8.43 (dd, J=4.09, 1.72 Hz, 1H), 7.67 (dd, J=8.31; 1.72 Hz,
1H), 7.25-7.20 (m, 1H), 6.08 (s, 1H), 4.29 (s, 2H), 3.95-3.88 (m,
4H), 3.65-3-57 (m, 4H), 1.46 (s, 9H); MS m/z (M+1) 330.
General Procedure I
[0257] To a stirred solution of tert-butyl
4-(6-amino-1,7-naphthyridin-8-yl)piperazine-1-carboxylate (63 mg,
0.19 mmol) in anhydrous dichloromethane (0.5 ml) and pyridine (0.25
ml) was added p-toluenesulfonyl chloride (36 mg, 0.19 mmol). The
reaction mixture was stirred at room temperature over night and
then concentrated in vacuo. The residue was purified using
reversed-phase preparative HPLC to give the corresponding
tert-butoxycarbonyl protected piperazine intermediate. This was
dissolved in dichloromethane (1.5 ml) and treated with concentrated
TFA (1 ml) at room temperature for 1.5 hours.
Example 137
4-Methyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide,
trifluoroacetic acid
[0258] The title compound was prepared following the general
procedure I (61 mg, 65%) as a yellow solid. .sup.1H NMR
(CD.sub.3OD) .delta. 8.57-8.65 (m, 1H), 8.06-7.98 (m, 1H),
7.86-7.78 (m, 2H), 7.53-7.43 (m, 1H), 7.36-7.26 (m, 2H), 6.88 (s,
1H), 4.18-4.06 (m, 4H), 3.35-3.24 (m, 4H), 2.35 (s, 3H); MS m/z
(M+1) 384.
Example 138
4-Bromo-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide,
trifluoroacetic acid
[0259] The title compound was prepared following the general
procedure I (14 mg, 13%). .sup.1H NMR (CD.sub.3OD) .delta.
8.70-8.63 (m, 1H), 8.14-8.05 (m, 1H), 7.91-7.83 (m, 2H), 7.76-7.67
(m, 2H), 7.57-7.49 (m, 1H), 6.91 (s, 1H), 4.19-4.09 (m, 4H),
3.38-3.28 (m, 4H); MS m/z (M+1) 449.
Example 139
N-(8-Piperazin-1-yl-1,7-naphthyridin-6-yl)naphthalene-1-sulfonamide,
trifluoroacetic acid
[0260] The title compound was prepared following the general
procedure I (66 mg, 65%). .sup.1H NMR (CD.sub.3OD) .delta.
8.82-8.76 (m, 1H), 8.58-8.54 (m, 1H), 8.42-8.37 (m, 1H), 8.13-8.07
(m, 1H), 8.01-7.92 (m, 2H), 7.71-7.54 (m, 3H), 7.47-7.40 (m, 1H),
6.80 (s, 1H), 4.02-3.96 (m, 4H), 3.24-3.18 (m, 4H); MS m/z (M+1)
420.
Example 140
N-(8-Piperazin-1-yl-1,7-naphthyridin-6-yl)butane-1-sulfonamide,
trifluoroacetic acid
[0261] The title compound was prepared following the general
procedure I (48 mg, 55%). .sup.1H NMR (CD.sub.3OD) .delta.
8.71-8.66 (m, 1H), 8.13-8.06 (m, 1H), 7.58-7.51 (m, 1H), 6.83 (s,
1H), 4.33-4.23 (m, 4H), 3.51-3.38 (m, 6H), 1.91-1.72 (m, 2H),
1.53-1.38 (m, 2H), 0.98-0.86 (m, 3H); MS m/z (M+2) 351.
Example 141
3-Trifluoromethyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfona-
mide, trifluoroacetic acid
[0262] The title compound was prepared following the general
procedure I (60 mg, 57%). .sup.1H NMR (CD.sub.3OD) .delta.
8.70-8.63 (m, 1H), 8.28-8.17 (m, 2H), 8.13-8.05 (m, 1H), 7.96-7.87
(m, 1H), 7.80-7.69 (m, 1H), 7.58-7.48 (m, 1H), 6.93 (s, 1H),
4.18-4.07 (m, 4H), 3.39-3.27 (m, 4H); MS m/z (M+1) 438.
Example 142
3,4-Dimethoxy-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide-
, trifluoroacetic acid
[0263] The title compound was prepared following the general
procedure I (65 mg, 63%). .sup.1H NMR (CD.sub.3OD) .delta.
8.68-8.59 (m, 1H), 8.11-8.01 (m, 1H), 7.61-7.40 (m, 3H), 7.04-6.92
(m, 2H), 4.22-4.10 (m, 4H), 3.81 (s, 3H), 3.78 (s, 3H), 3.39-3.27
(m, 4H); MS m/z (M+1) 430.
Example 143
2,4-Dichloro-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)benzenesulfonamide,
trifluoroacetic acid
[0264] The title compound was prepared following the general
procedure I (56 mg, 53%). .sup.1H NMR (CD.sub.3OD) .delta.
8.66-8.61 (m, 1H), 8.25-8.20 (m, 1H), 8.06-8.00 (m, 1H), 7.65-7.61
(m, 1H), 7.57-7.47 (m, 2H), 6.76 (s, 1H), 4.13-4.06 (m, 4H),
3.36-3.28 (m, 4H); MS m/z (M+2) 439.
Example 144
N-(8-Piperazin-1-yl-1,7-naphthyridin-6-yl)thiophene-2-sulfonamide,
trifluoroacetic acid
[0265] The title compound was prepared following the general
procedure I (57 mg, 61%). .sup.1H NMR (CD.sub.3OD).delta. 8.71-8.64
(m, 1H), 8.14-8.05 (m, 1H), 7.76-7.67 (m, 2H), 7.58-7.49 (m, 1H),
7.11-7.O3 (m, 1H), 6.98 (s, 1H), 4.27-4.15 (m, 4H), 3.40-3.28 (m,
4H); MS m/z (M+1) 376.
Example 145
1-Phenyl-N-(8-piperazin-1-yl-1,7-naphthyridin-6-yl)methanesulfonamide,
trifluoroacetic acid
[0266] The title compound was prepared following the general
procedure I (35 mg, 37%). .sup.1H NMR (DMSO) .delta. 8.83 (br s,
1H), 8.52-8.40 (m, 2H), 7.47-7.41 (m, 1H), 7.29-7.10 (m, 6H), 6.87
(s, 1H), 4.52 (s, 2H), 4.39-4.31 (m, 4H), 3.30-3.22 (m, 4H); MS m/z
(M+1) 384. Synthesis of Examples and Intermediates in Table
##STR359## Intermediate 24
[0267] 7-Iodo-5-nitro-1-benzofuran--A mixture of
4-nitro-2,5-diiodophenol (7.68 g, 6.86 mmol), TMS-acetylene (0.67
g, 6.86 mmol) and Cu.sub.2O (0.59 g, 4.12 mmol) in pyridine (120
mL) was heated to 80 C for 48 h. The mixture was filtered through
celite and the solvent was removed. Column chromatography
DCM/heptane 1:1 gave 0.35 g (18%) of product. .sup.1HNMR
(CD.sub.3OD) .delta. 8.60 (d, 1H, j=2.1 Hz), 8.51 (d, 1H, J=2.1
Hz), 7.84 (d, 1H, J=2.1 Hz), 7.04 (d, 1H, J=2.4 Hz); MS (ESI) 289.8
(M+H).sup.+; Purity (HPLC, column X) 93%.
Intermediate 25
[0268] 1-Methyl-4-(5-Nitro-1-benzofuran-7-yl)-piperazine--A mixture
of 7-iodo-5-nitro-1-benzofuran (94.5 mg, 0.327 mmol), Xanthpos (19
mg. 0.032 mmol), Pd.sub.2(dba).sub.3 (7.4 mg, 0.025 mmol) and
NaOt-Bu (44.0 mg, 0.458 mmol), methylpiperazine (39.3 mg, 0.392
mmol) in xylene (3 mL) was heated to 120.degree. C. overnight. The
mixture was diluted with DCM and filtered through silica. The
product was elueed with DCM/MeOH.times.0.4% NH.sub.3. Flash
chromatography (DCM/MeOH.times.0.4% NH.sub.3) gave 60 mg (70%) of
BVT: .sup.1HNMR (CD.sub.3OD) .delta. 8.07 (d, 1H, J=2.1 Hz), 7.70
(d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=2.1 Hz), 6.84 (d, 1H, J=2.1 Hz),
3.44-3.40 (m, 4H), 2.65-2.62 (m, 4H), 2.36 (s, 3H); MS (ESI) 262.0
(M+H).sup.+; Purity (HPLC, column X) 95%.
Intermediate 26
[0269]
tert-Butyl-4-(5-nitro-1-benzofuran-7-yl)-piperazine-1-carboxylate--
-The title compound was prepared according to the same procedure
used for Intermediate 25 using N-tert-butyl-piperazine carboxylate
to afford 240 mg (64%) of a white solid: .sup.1HNMR (CD.sub.3OD)
.delta. 8.08 (d, 1H, J=2.1 Hz), 7.72 (d, 1H, J=2.1 Hz), 7.58 (d,
1H, J=2.1 Hz), 6.86 (d, 1H, J=2.1 Hz), 3.66-3.62 (m, 4H), 3.34-3.31
(m, 4H), 1.46 (s, 9H); MS (ESI) 370.0 (M+Na).sup.+; Purity (HPLC,
column X) 96%.
Intermediate 27
1-Methyl-4-(5-amino-1-benzofuran-7-yl)-piperazine
Intermediate 28
[0270] tert-Butyl
4-(5-amino-1-benzofuran-7-yl)-piperazine-1-carboxylate-1-Methyl-4-(5-Nitr-
o-1-benzofuran-7-yl)-piperazine (1 eq) and tert-butyl
4-(5-nitro-1-benzofuran-7-yl)-piperazine-1-carboxylate (1 eq) were
reduced to aromatic amine with Raney-Ni and hydrazine (10 eq) in
THF/Ethanol (1:4), 3 h at room temperature. The reaction mixture
are filtered through celite pad, the volatiles are evaporated and
the crude is used in the next reactions.
Example 146
3-Cyanophenyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,
hydrochloride
[0271] To a solution of tert-butyl
4-(5-amino-1-benzofuran-7-yl)-piperazine-1-carboxylate (43 mg 0.138
mmol) and pyridine (100 .mu.L, 1.24 mmol) was added
3-cyanobenzenesulfonylchloride (33.4 mg, 0.166 mmol). After 2 h
PS-Trisamin was added and the reaction was stirred overnight. Flash
chromatography (DCM/Heptane/MeOH 5:4:1) gave 24.6 mg of a solid.
The crude product was dissolved in MeOH (2 mL) and HCl/ether 2M (4
mL) was added. After 0.5 h the sample was concentrated to afford 19
mg (36%) of a white solid: .sup.1HNMR (CD.sub.3OD) .delta.
8.02-7.88 (m, 3H), 7.72 (d, 1H, J=2.1 Hz), 7.76-7.61 (m, 1H), 6.92
(d, 1H, J=2.1 Hz), 6.74 (d, 1H, J=2.1 Hz), 6.60 (d, 1H, J=2.1 Hz),
3.52-3.41 (m, 8H); MS (ESI) 381.2 (M+H).sup.+; Purity (HPLC, column
X) 95%.
Example 147
4-Phenoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,
hydrochloride
[0272] The title compound was prepared according to the method used
for the synthesis of Example 146 (21%) of a white solid: .sup.1HNMR
(CD.sub.3OD) .delta. 7.73 (d, 1H, J=2.1 Hz), 7.69-7.64 (m, 2H),
7.43-7.37 (m, 2H), 7.24-7.17 (m, 1H9, 7.04-6.94 (m, 4H), 6.88 (d,
1H, J=2.1 Hz), 6.74 (d, 1H, J=2.1 Hz), 6.70 (d, 1H, J=2.1 Hz),
3.53-3.41 (m, 8H); MS (ESI) 450.1 (M+H).sup.+; Purity (HPLC, column
X) 90%.
Example 148
1-Naphthyl-Phenoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide-
, hydrochloride
[0273] The title compound was prepared according to the method used
for the synthesis of Example 146 (30%) of a white solid: .sup.1HNMR
(CD.sub.3OD) .delta. 8.65 (d, 1H, J=8.8 Hz), 8.03-7.86 (m, 3H),
7.58-7.49 (m, 3H9, 7.36-7.33 (m, 1H), 6.74 (d, 1H, J=2.2 Hz), 6.53
(d, 1H, J=2.2 Hz), 6.30 (d, 1H, J=2.2 Hz), 3.52-3.41 (m, 8H); MS
(ESI) 408.1 (M+H).sup.+; Purity (HPLC) 100%.
Example 149
N-(7-Piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,
hydrochloride
[0274] The title compound was prepared according to the method used
for the synthesis of Example 146 (33%) of a white solid: .sup.1HNMR
(CD.sub.3OD) .delta. 7.72-7.69 (m, 3H), 7.57-7.51 (m, 1H),
7.47-7.41 (m, 2H), 6.92 (d, 1H, J=2.1 Hz), 6.72 (d, 1H, J=2.1 Hz),
6.58 (d, 1H, J=2.1), 3.49-3.39 (m, 8H); MS (ESI) 358.1 (M+H).sup.+;
Purity (HPLC) 96%.
Example 150
5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid
(7-piperazin-1-yl-benzofuran-5-yl)-amide, hydrochloride
[0275] The title compound was prepared according to the method used
for the synthesis of Example 146 (9%) of a white solid: .sup.1HNMR
(CD.sub.3OD) .delta. 7.74-7.73 (m, 2H), 7.62 (d, 1H, J=2.2 Hz),
7.38-7.36 (m, 1H), 6.87 (d, 1H, J=1.8 Hz), 6.64 (d, 1H, J=2.2 Hz),
6.58 (d, 1H, J=1.8 Hz), 3.36-3.28 (m, 8H); MS (ESI) 398.2
(M+H).sup.+; Purity (HPLC'') 98%.
Example 151
N-[7-(4-methylpiperazin-1-yl)-1-benzofuran-5-yl]-benzenesulfonamide,
hydrochloride
[0276] The title compound was prepared according to the method used
for the synthesis of Example 146 using
1-Methyl-4-(5-Nitro-1-benzofuran-7-yl)piperazine (45%) of a white
solid: .sup.1HNMR (CD.sub.3OD) .delta. 7.74-7.283 (m, 6H), 6.82 (d,
1H, J=1.8 Hz), 6.62 (d, 1H, J=2.2 Hz), 6.48 (d, 1H, J=1.8 Hz),
3.82-2.95 (m, 8H), 2.87 (s, 3H); MS (ESI) 372.1 (M+H).sup.+; Purity
(HPLC, column X) 96%.
Example 152
4-Methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,
hydrochloride
[0277] 4-(5-Amino-benzofuran-7-yl)-piperazine-1-carboxylic acid
tert-butyl ester (44 mg, 0.139 mmol) in 3 ml dichloromethane was
added to a tube containing p-toluenesulfonyl chloride (32 mg, 0.167
mmol) together with pyridine (100 .mu.l, 1.25 mmol) and left on a
shaker over weekend. After purification by preparative HPLC, the
resulting Boc-material was treated with HCl in ether and left on a
shaker until the salt had formed. The solution was centrifugated
and the supernatant was removed. Ether was added, then
centrifugated and decanted (repeated three times) to remove the
excess HCl. The remaining ether was finally evaporated in a SpeedV
Ac concentrator to yield 10 mg of title product. HPLC purity=94%,
m/z=372.3 (M+H). .sup.1H NMR (270 MHz, methanol-d4) .delta. ppm
2.35 (s, 3H) 3.45 (m, 8H) 6.63 (d, J=1.85 Hz, 1H) 6.71 (d, J=2.11
Hz, 1H) 6.88 (d, J=1.85 Hz, 1H) 7.25 (m, 2H) 7.58 (m, 2H) 7.71 (d,
J=2.11 Hz, 1H).
Example 153
3,4-Dimethoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,
hydrochloride
[0278] HPLC purity=92%, m/z=418.3 (M+H). 1 H NMR (270 MHz,
methanol-d4) .delta. ppm 3.45 (m, 8H) 3.70 (m, 3H) 3.81 (m, 3H)
6.62 (d, J=1.85 Hz, 1H) 6.73 (d, J=2.38 Hz, 1H) 6.94 (m, 2H) 7.17
(d, J=2.11 Hz, 1H) 7.29 (dd, J=8.44, 2.11 Hz, 1H) 7.72 (d, J=2.38
Hz, 1H).
Example 154
4-Bromo-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,
hydrochloride
[0279] HPLC purity=95%, m/z=436.2 (M+H). 1 H NMR (270 MHz,
methanol-d4) .delta. ppm 3.46 (m, 8H) 6.62 (d, J=1.85 Hz, 1H) 6.74
(d, J=2.38 Hz, 1H) 6.93 (d, J=1.85 Hz, 1H) 7.61 (m, 4H) 7.73(d,
J=2.11 Hz, 1H).
Example 155
2,3-Dichloro-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,
hydrochloride
[0280] HPLC purity=96%, m/z=426.2 (M+H). 1 H NMR (270 MHz,
methanol-d4) .delta. ppm 3.44 (m, 8H) 6.67 (d, J=1.85 Hz, 1H) 6.72
(d, J=2.11 Hz, 1H) 7.01 (d, J=1.85 Hz, 1H) 7.34 (t, J=8.18 Hz, 1H)
7.70 (m, 2H) 7.94 (dd, J=7.92, 1.58 Hz, 1H).
Example 156
2,4-Dichloro-5-methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonam-
ide, hydrochloride
[0281] HPLC purity=96%, m/z=440.2 (M+H). 1 H NMR (270 MHz,
methanol-d4) .delta. ppm 2.30 (s, 3H) 3.46 (m, 8H) 6.69 (d, J=1.85
Hz, 1H) 6.73 (d, J=2.11 Hz, 1H) 7.01 (d, J=1.85 Hz, 1H) 7.60 (s,
1H) 7.71 (d, J=2.11 Hz, 1H) 7.87 (s, 1H).
Example 157
4-Methoxy-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,
hydrochloride
[0282] HPLC purity=93%, m/z=388.3 (M+H). 1 H NMR (270 MHz,
methanol-d4) .delta. ppm 3.45 (m, 8H) 3.79 (s, 3H) 6.72 (d, J=2.11
Hz, 1H) 6.93 (m, 3H) 7.63 (m, 3H) 7.71 (d, J=2.11 Hz, 1H).
Example 158
4-Chloro-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,
hydrochloride
[0283] HPLC purity=97%, m/z=392.3 (M+H). 1 H NMR (270 MHz,
methanol-d4) .delta. ppm 3.46 (m, 8H) 6.63 (d, J=1.85 Hz, 1H) 6.74
(d, J=2.38 Hz, 1H) 7.47 (m, 2H) 7.67 (m, 3H) 7.73 (d, J=2.11 Hz,
1H).
Example 159
N-(7-Piperazin-1-yl-benzofuran-5-yl)-4-trifluoromethyl-benzenesulfonamide,
hydrochloride
[0284] HPLC purity=91%, m/z=426.3 (M+H). 1 H NMR (270 MHz,
methanol-d4) .delta. ppm 3.47 (m, 8H) 6.64 (d, J=1.85 Hz, 1H) 6.74
(d, J=2.11 Hz, 1H) 6.92 (d, J=1.85 Hz, 1H) 7.73 (d, J=2.11 Hz, 1H)
7.84 (m, 4H).
Example 160
5-Fluoro-2-methyl-N-(7-piperazin-1-yl-benzofuran-5-yl)-benzenesulfonamide,
hydrochloride
[0285] HPLC purity=94%, m/z=390.3 (M+H). 1 H NMR (270 MHz,
methanol-d4) .delta. ppm 2.57 (m, 3H) 3.46 (m, 8H) 6.63 (m, 1H)
6.74 (d, J=2.11 Hz, 1H) 6.91 (d, J=1.85 Hz, 1H) 7.20 (m, 1H) 7.34
(m, 1H) 7.56 (dd, J=8.71, 2.64 Hz, 1H) 7.73 (d, J=2.11 Hz, 1H).
Example 161
5-Chloro-thiophene-2-sulfonic acid
(7-piperazin-1-yl-benzofuran-5-yl)-amide, hydrochloride
[0286] HPLC purity=94%, m/z=398.3 (M+H). 1 H NMR (270 MHz,
methanol-d4) .delta. ppm 3.48 (m, 8H) 6.68 (d, J=2.11 Hz, 1H) 6.79
(d, J=2.38 Hz, 1H) 6.97 (d, J=3.96 Hz, 1H) 7.01 (d, J=1.85 Hz, 1H)
7.25 (d, J=3.96 Hz, 1H) 7.76 (d, J=2.38 Hz, 1H).
Biological Tests
The ability of a compound according to the invention to bind a
5-HT.sub.6 receptor, and to be pharmaceutically useful, can be
determined using in vivo and in vitro assays known in the art.
(a) 5-HT.sub.6 Intrinsic Activity Assay
[0287] Antagonists to the 5-HT.sub.6 receptor were characterized by
measuring inhibition of 5-HT induced increase in cAMP in HEK 293
cells expressing the human 5-HT.sub.6 receptor (see Boess et al.
(1997) Neuropharmacology 36: 713-720). Briefly, HEK293/5-HT.sub.6
cells were seeded in polylysine coated 96-well plates at a density
of 25,000/well and grown in DMEM (Dulbecco's Modified Eagle Medium)
(without phenol-red) containing 5% dialyzed Fetal Bovine Serum for
48 h at 37.degree. C. in a 5% CO.sub.2 incubator. The medium was
then aspirated and replaced by 0.1 ml assay medium (Hanks Balance
Salt Solution containing 20 mM HEPES, 1.5 mM isobutylmethylxanthine
and 1 mg/ml bovine serum albumin). After addition of test
substances, 50 .mu.l dissolved in assay medium, the cells were
incubated for 10 min at 37.degree. C. in a 5% CO.sub.2 incubator.
The medium was again aspirated and the cAMP content was determined
using a radioactive cAMP kit (Amersham Pharmacia Biotech, BIOTRAK
RPA559). The potency of antagonists was quantified by determining
the concentration that caused 50% inhibition of 5-HT (at [5-HT]=8
times EC.sub.50) evoked increase in cAMP, using the formula
K.sub.i.dbd.IC.sub.50/(1+[5HT]/EC.sub.50).
[0288] The compounds in accordance with the invention have a
selective affinity to 5-HT.sub.6 receptors with K.sub.i values
between 0.5 nM and 5 .mu.M. The compounds show good selectivity for
5-HT.sub.1a, 5-HT.sub.2a, 5-HT.sub.2a, 5-HT.sub.2b,
5-HT.sub.2c.
(b) In Vivo Assay of Reduction of Food Intake
[0289] For a review on serotonin and food intake, see Blundell, J.
E. and Halford, J. C. G. (1998) Serotonin and Appetite Regulation.
Implications for the Pharmacological Treatment of Obesity. CNS
Drugs 9:473-495.
[0290] Obese (ob/ob) mouse is selected as the primary animal model
for screening as this mutant mouse consumes high amounts of food
resulting in a high signal to noise ratio. To further substantiate
and compare efficacy data, the effect of the compounds on food
consumption is also studied in wild type (C57BL/6J) mice. The
amount of food consumed during 15 hours of infusion of compounds is
recorded.
[0291] Male mice (obese C57BL/6JBom-Lep.sup.ob and lean wild-type
C57B1/6JBom; Bomholtsgaard, Denmark) 8-9 weeks with an average body
weight of 50 g (obese) and 25 g (lean) are used in all the studies.
The animals are housed singly in cages at 23.+-.1.degree. C.,
40-60% humidity and have free access to water and standard
laboratory chow. The 12/12-h light/dark cycle is set to lights off
at 5 p.m. The animals are conditioned for at least one week before
start of study.
[0292] The test compounds are dissolved in solvents suitable for
each specific compound such as cyclodextrin, cyclodextrin/methane
sulfonic acid, polyethylene glycol/methane sulfonic acid, saline.
Fresh solutions are made for each study. Doses of 30, 50 and 100 mg
kg.sup.-1day.sup.-1 are used. The purity of the test compounds is
of analytical grade.
[0293] The animals are weighed at the start of the study and
randomized based on body weight. Alzet osmotic minipumps (Model
2001D; infusion rate 8 .mu.l/h) are used and loaded essentially as
recommended by the Alzet technical information manual (Alza
Scientific Products, 1997; Teeuwes and Yam, 1976). Continuous
subcutaneous infusion with 24 hours duration is used. The minipumps
are either filled with different concentrations of test compounds
dissolved in vehicle or with only vehicle solution and maintained
in vehicle pre-warmed to 37.degree. C. (approx. 1 h). The minipumps
are implanted subcutaneously in the neck/back region under short
acting anesthesia (metofane/enflurane). This surgical procedure
lasts approximately 5 min. It takes about 3 h to reach steady state
delivery of the compound.
[0294] The weight of the food pellets are measured at 5 p.m. and at
8 p.m. for two days before (baseline) and one day after the
implantation of the osmotic minipumps. The weigh-in is performed
with a computer assisted Mettler Toledo PR 5002 balance. Occasional
spillage is corrected for. At the end of the study the animals are
killed by neck dislocation and trunk blood sampled for later
analysis of plasma drug concentrations.
[0295] The plasma sample proteins are precipitated with methanol,
centrifuged and the supernatant is transferred to HPLC vials and
injected into the liquid chromatography/mass spectrometric system.
The mass spectrometer is set for electrospray positive ion mode and
Multiple Reaction Monitoring (MM with the transition m/z 316221). A
linear regression analysis of the standards forced through the
origin is used to calculate the concentrations of the unknown
samples.
[0296] Food consumption for 15 hours is measured for the three
consecutive days and the percentage of basal level values is
derived for each animal from the day before and after treatment.
The values are expressed as mean.+-.SD and .+-.SEM from eight
animals per dose group. Statistical evaluation is performed by
Kruskal-Wallis one-way ANOVA using the percent basal values. If
statistical significance is reached at the level of p<0.05,
Mann-Whitney U-test for statistical comparison between control and
treatment groups is performed.
[0297] The compounds according to the invention show an effect in
the range of 50-200 mg/kg. TABLE-US-00008 TABLE VI In vivo efficacy
data on the effect of the compounds on Food Intake reduction In
vivo efficacy - Food intake (15 h) in ob/ob mouse % Inhibition of
Food Intake Free plasma concentration in ob/ob mice at of the
compounds at steady EXAMPLES 50 mg/Kg/day, 15 h state (Css, u) 48
23.8 0.008 13 24.1 0.035 53 25.7.sup.a ND 34 51.4 0.078 24 46.2
0.0076 19 69.6 0.150 27 68.9 0.008 30 60.1 0.275 29 71 0.33 14
41.sup.b 0.23 .sup.aThe effect on Food Intake reported in the table
was obtained at the dose of 14.8 mg/kg/d .sup.bThe effect on Food
Intake reported in the table was obtained at the dose of 100
mg/kg/d
* * * * *