U.S. patent application number 12/628243 was filed with the patent office on 2010-03-25 for benzothiazole derivatives with activity as adenosine receptor ligands.
Invention is credited to Alexander Alanine, Alexander Flohr, Aubry Kern Miller, Roger David Norcross, Claus Riemer.
Application Number | 20100075959 12/628243 |
Document ID | / |
Family ID | 8169041 |
Filed Date | 2010-03-25 |
United States Patent
Application |
20100075959 |
Kind Code |
A1 |
Alanine; Alexander ; et
al. |
March 25, 2010 |
BENZOTHIAZOLE DERIVATIVES WITH ACTIVITY AS ADENOSINE RECEPTOR
LIGANDS
Abstract
The present invention relates to substituted benzothiazole
derivatives and to their pharmaceutically acceptable salts useful
for the treatment of diseases related to the adenosine
receptor.
Inventors: |
Alanine; Alexander;
(Schlierbach, FR) ; Flohr; Alexander; (Basle,
CH) ; Miller; Aubry Kern; (San Francisco, CA)
; Norcross; Roger David; (Rheinfelden, CH) ;
Riemer; Claus; (Freiburg, DE) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.;PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
US
|
Family ID: |
8169041 |
Appl. No.: |
12/628243 |
Filed: |
December 1, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11930717 |
Oct 31, 2007 |
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12628243 |
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Current U.S.
Class: |
514/233.8 ;
514/367 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
11/06 20180101; A61K 31/5513 20130101; A61P 25/16 20180101; A61K
31/4439 20130101; A61P 13/12 20180101; A61P 25/24 20180101; A61P
25/28 20180101; C07D 277/82 20130101; A61P 11/00 20180101; A61P
25/00 20180101; A61P 43/00 20180101; A61P 3/10 20180101; A61K
31/541 20130101; A61K 31/5375 20130101; A61K 31/428 20130101; A61K
31/427 20130101; A61P 25/04 20180101; C07D 417/12 20130101; A61P
25/22 20180101; C07D 417/14 20130101; A61K 31/444 20130101; A61P
25/26 20180101; A61P 25/18 20180101; A61K 31/455 20130101; C07D
417/04 20130101; A61P 25/20 20180101; A61P 21/02 20180101 |
Class at
Publication: |
514/233.8 ;
514/367 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/425 20060101 A61K031/425; A61P 25/16 20060101
A61P025/16; A61P 25/00 20060101 A61P025/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 21, 2000 |
EP |
00113219.0 |
Claims
1. A method of treating a person having a disease state treatable
by modulation of the adenosine A.sub.2A receptor comprising
administering to a person in need of such treatment, an effective
amount of a compound of the formula I ##STR00027## wherein R.sup.1
is hydrogen, lower alkyl, lower alkoxy, benzyloxy, cycloalkyloxy,
halogen, hydroxy or trifluoromethyloxy; R.sup.2 and R.sup.3 are
each independently hydrogen, halogen, lower alkyl or lower
alkyloxy; R.sup.4 is hydrogen, lower alkyl, lower alkenyl, halogen,
--C(O)OH, --C(O)-lower alkyl, --C(O)-halogen-lower alkyl,
--CH(OH)-halogen-lower alkyl, --C(O)O-lower alkyl, --NHC(O)-lower
alkyl, --(CH.sub.2).sub.n--OH, or is phenyl, which is optionally
attached to the benzo group via the linker
--(O).sub.m--(CH.sub.2).sub.n-- and is unsubstituted or substituted
by N(R.sup.5)(R.sup.6), halogen, alkoxy or nitro, or is
2,3-dihydro-1H-indolyl, azepan-1-yl, [1,4]oxazepan-4-yl, or is a
five or six membered aromatic or non aromatic heterocycle, which
may be attached to the benzo group via the linker
--(O).sub.m--(CH.sub.2).sub.n or --N.dbd.C(CH.sub.3)-- and is
unsubstituted or substituted by one or two group(s) R.sup.7,
wherein R.sup.7 is defined below; R is (a) phenyl, unsubstituted or
substituted by lower alkyl, halogen-lower alkyl, lower alkoxy,
cyano, nitro, --C(O)H, --C(O)OH or by the following groups
--(CH.sub.2).sub.n--C(O)--N(R.sup.5)--(CH.sub.2).sub.o-lower
alkoxy, --(CH.sub.2).sub.nO-halogen-lower alkyl,
--(CH.sub.2).sub.nO--(CH.sub.2).sub.n+1--O-lower alkyl,
--S(O).sub.2--N(R.sup.5)--(CH.sub.2).sub.n--O-lower alkyl,
--(CH.sub.2).sub.n--OR.sup.5,
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o-lower alkoxy,
--(CH.sub.2).sub.nN[(CH.sub.2).sub.o-lower alkoxy].sub.2,
--(CH.sub.2).sub.nN(R.sup.5)(R.sup.6),
--(CH.sub.2).sub.nN[S(O).sub.2CH.sub.3].sub.2,
--(CH.sub.2).sub.nN[R.sup.5][S(O).sub.2CH.sub.3],
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.oNR.sup.5R.sup.6,
--(CH.sub.2).sub.nN(R.sup.5)-lower alkenyl,
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o-cycloalkyl,
--(CH.sub.2).sub.nN(R.sup.5)--C(O)O-lower alkyl,
--(CH.sub.2).sub.n--S--(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6),
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--S-lower alkyl,
--S(O).sub.2--N(R.sup.5)(R.sup.6),
--(CH.sub.2).sub.nN(R.sup.5)--S(O).sub.2CH.sub.3
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o-phenyl,
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.oOH,
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.oCH(OH)--CF.sub.3,
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--CF.sub.3,
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--O--CH(OH)--C.sub.6H.sub.3-
(OCH.sub.3).sub.2,
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--O--C(O)--C.sub.6H.sub.3(O-
CH.sub.3).sub.2, --N(R.sup.5)--C(O)-morpholin,
--N(R.sup.5)--C(O)--N(R.sup.5)-phenyl, substituted by alkoxy,
--S(O).sub.2-morpholin, or is phenyl, which is unsubstituted or
substituted by --(CR.sup.5R.sup.6).sub.n-five to seven membered
aromatic or non aromatic heterocycle, and wherein the heterocycle
is unsubstituted or further substituted by hydroxy,
--N(R.sup.5)(R.sup.6), lower alkoxy or lower alkyl, or by
--(CH.sub.2).sub.nN(R.sup.5)(CH.sub.2).sub.o-five or six membered
aromatic or non aromatic heterocycle and wherein the heterocycle is
unsubstituted or further substituted by hydroxy,
--N(R.sup.5)(R.sup.6) or lower alkyl, or is b)
--(CH.sub.2).sub.n-five or six membered aromatic or non aromatic
heterocycle, with the exception of the piperazinyl group in case if
n=0, which rings are unsubstituted or substituted by one or two
substituents, selected from the group consisting of
2-oxo-pyrrolidin, piperidinyl, phenyl, --(CH.sub.2).sub.nOH,
halogen, CF.sub.3, .dbd.O, lower alkyl, cycloalkyl,
--(CH.sub.2).sub.n--O-lower alkyl, --(CH.sub.2).sub.nNH.sub.2,
--(CH.sub.2).sub.nCN, --C(O)O-lower alkyl,
--CH.sub.2--O--S(O).sub.2CH.sub.3, --C(O)-lower alkyl,
--C(O)--(CH.sub.2).sub.n-lower alkoxy,
--CH.sub.2--N(R.sup.6)C.sub.6H.sub.4F,
--CH.sub.2--N(R.sup.6)C(O)O-lower alkyl,
--N(R.sup.6)--C(O)--N(R.sup.5)--(CH.sub.2).sub.n--O-lower alkyl, or
by tetrahydrofuran, substituted by 4-Cl-phenyl, or by
piperazin-1-yl, morpholinyl, thiomorpholinyl, thiomorpholin-1-oxo,
pyrrolidin-1-yl or by piperidin-1-yl or is benzopiperidin-1-yl or
benzothien-2-yl, or is c) --(CH.sub.2).sub.n+1-phenyl,
--N(R.sup.5)(CH.sub.2).sub.n-phenyl, unsubstituted or substituted
by lower alkoxy, --O(CH.sub.2).sub.n-phenyl, or
--N(R.sup.5)C(O)-phenyl, or is d) --N(R.sup.5)(CH.sub.2).sub.n-5-
or 6 membered aromatic or non aromatic heterocycle, unsubstituted
or substituted by lower alkyl, --(CH.sub.2).sub.n-5- or 6 membered
aromatic or non aromatic heterocycle or is e)
--(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6), lower alkyl,
--O--(CH.sub.2).sub.n-lower alkoxy, --(CH.sub.2).sub.n-lower
alkoxy, lower alkoxy, cycloalkyl,
--N(R.sup.5)(CH.sub.2).sub.nO-lower alkyl,
--N(R.sup.5)(CH.sub.2).sub.nOH,
--N(R.sup.5)(CH.sub.2).sub.nN(R.sup.5)(R.sup.6), --C(O)O-lower
alkyl, --(CH.sub.2).sub.nOH, --(HC.dbd.CH).sub.nC(O)O-lower alkyl,
octahydro-quinoline, 3,4-dihydro-1H-isoquinoline,
2,3-benzo-1,4-dioxa-8-aza-spiro[4,5]decane or
1,4-dioxa-8-aza-spiro[4,5]decane; X is O, S or two hydrogen atoms;
R.sup.5 and R.sup.6 are each independently hydrogen or lower alkyl,
R.sup.7 is lower alkyl, lower alkoxy, --C(O)-lower alkyl,
--C(O)O-benzyl, --C(O)O-lower alkyl,
--(CH.sub.2).sub.nNR.sup.5R.sup.6, pyridinyl, optionally
substituted by lower alkyl, or is --CH.sub.2N(R.sup.5)--C(O)O-lower
alkyl, --NH--C(phenyl).sub.3, pyrrolidinyl, piperidinyl,
morpholinyl, piperazinyl, unsubstituted or substituted by lower
alkyl; n is 0, 1, 2, 3 or 4; m is 0 or 1; o is 0, 1, 2, 3 or 4; or
a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein the disease is selected from the
group consisting of Parkinson's disease, Alzheimer's disease,
neuroprotection, schizophrenia, anxiety, pain, respiration
deficits, depression, asthma, allergic responses, hypoxia, hypoxia,
ischaemia, seizure, substance abuse, ADHD, and diabetes
mellitus.
3. The method of claim 2, wherein the disease is Parkinson's
disease.
4. The method of claim 1, wherein the compound of formula I has the
formula I-A ##STR00028## wherein R.sup.1 is hydrogen, lower alkyl,
lower alkoxy, benzyloxy, cycloalkyloxy, halogen, hydroxy or
trifluoromethyloxy; R.sup.2 and R.sup.3 are each independently
hydrogen, halogen, lower alkyl or lower alkyloxy; R.sup.4 is
hydrogen, lower alkyl, lower alkenyl, halogen, --C(O)-lower alkyl,
--C(O)-halogen-lower alkyl, --CH(OH)-halogen-lower alkyl,
--C(O)O-lower alkyl, --NHC(O)-lower alkyl, --(CH.sub.2)--OH, or is
phenyl, which is optionally attached to the benzo group via the
linker --(O).sub.m--(CH.sub.2).sub.n-- and is unsubstituted or
substituted by N(R.sup.5)(R.sup.6), halogen or nitro, or is
2,3-dihydro-1H-indolyl, azepan-1-yl, or [1,4]oxazepan-4-yl, or is a
five or six membered aromatic or non aromatic heterocycle, which is
optionally attached to the benzo group via the linker
--(O).sub.m--(CH.sub.2).sub.n or --N.dbd.C(CH.sub.3)-- and is
unsubstituted or substituted by one or two group(s) R.sup.7,
wherein R.sup.7 is defined below; R' is (a) phenyl, optionally
unsubstituted or substituted by halogen-lower alkyl, --C(O)H or by
the following groups
--(CH.sub.2).sub.n--C(O)--N(R.sup.5)--(CH.sub.2)lower alkoxy,
--(CH.sub.2).sub.nO-halogen-lower alkyl,
--(CH.sub.2).sub.nO--(CH.sub.2).sub.n+1O-lower alkyl,
--S(O).sub.2).sub.n--N(R.sup.5)--(CH.sub.2).sub.nO-lower alkyl,
--(CH.sub.2).sub.nOR.sup.5,
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o-lower alkoxy,
--(CH.sub.2).sub.nN[(CH.sub.2).sub.o-lower alkoxy].sub.2,
--(CH.sub.2).sub.nN[S(O).sub.2CH.sub.3].sub.2,
--(CH.sub.2).sub.nN[R.sup.5][S(O).sub.2CH.sub.3],
--(CH.sub.2).sub.nN(R.sup.5)-lower alkenyl,
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o-cycloalkyl,
--(CH.sub.2).sub.nN(R.sup.5)--C(O)O-lower alkyl,
--(CH.sub.2).sub.n--S--(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6),
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--S-lower alkyl,
--(CH.sub.2).sub.nN(R.sup.5)--S(O).sub.2CH.sub.3
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o-phenyl,
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.oOH,
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.oCH(OH)--CF.sub.3,
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--CF.sub.3,
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--O--CH(OH)--C.sub.6H.sub.3-
(OCH.sub.3).sub.2,
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--O--C(O)--C.sub.6H.sub.3(O-
CH.sub.3).sub.2, --N(R.sup.5)--C(O)-morpholin,
--N(R.sup.5)--C(O)--N(R.sup.5)-phenyl, substituted by alkoxy, or
--S(O).sub.2-morpholin, or is phenyl, which is unsubstituted or
substituted by --(CR.sup.5R.sup.6).sub.n-five to seven membered
aromatic or non aromatic heterocycle, and wherein the heterocycle
is unsubstituted or substituted by hydroxy, --N(R.sup.5)(R.sup.6)
or lower alkyl, or by
--(CH.sub.2).sub.nN(R.sup.5)(CH.sub.2).sub.o-five or six membered
aromatic or non aromatic heterocycle and wherein the heterocycle is
unsubstituted or substituted by hydroxy, --N(R.sup.5)(R.sup.6) or
lower alkyl, or is --N(R.sup.5)-phenyl, which is unsubstituted or
substituted by lower alkoxy, or is b) --(CH.sub.2).sub.n-five or
six membered aromatic or non aromatic heterocycle, with the
exception of the piperazinyl group in case if n=0, which rings are
optionally substituted by 2-oxo-pyrrolidin, piperidinyl, phenyl,
--(CH.sub.2).sub.nOH, halogen, CF.sub.3, .dbd.O, lower alkyl,
cycloalkyl, --(CH.sub.2)--O-lower alkyl,
--(CH.sub.2).sub.nNH.sub.2, --(CH.sub.2).sub.nCN, --C(O)O-lower
alkyl, --CH.sub.2--O--S(O).sub.2CH.sub.3, --C(O)-lower alkyl,
--C(O)--(CH.sub.2).sub.n-lower alkoxy,
--CH.sub.2--N(R.sup.6)C.sub.6H.sub.4F,
--CH.sub.2--N(R.sup.6)C(O)O-lower alkyl,
--N(R.sup.6)--C(O)--N(R.sup.5)--(CH.sub.2).sub.n--O-lower alkyl,
-or by tetrahydrofuran, substituted by 4-Cl-phenyl, piperazin-1-yl,
morpholinyl, thiomorpholinyl, thiomorpholin-1-oxo, pyrrolidin-1-yl
or piperidin-1-yl or is benzopiperidin-1-yl or benzothien-2-yl, or
is c) --N(R.sup.5)(CH.sub.2).sub.+1-phenyl, unsubstituted or
substituted by lower alkoxy, --O(CH.sub.2).sub.n-phenyl, or
--N(R.sup.5)C(O)-phenyl, or is d) --N(R.sup.5)(CH.sub.2).sub.n-5-or
6 membered aromatic or non aromatic heterocycle, unsubstituted or
substituted by lower alkyl, --(CH.sub.2).sub.n-5-or 6 membered
aromatic or nonaromatic heterocycle or is e)
--O--(CH.sub.2).sub.n-lower alkoxy, lower alkyl-lower alkoxy,
--N(R.sup.5)(CH.sub.2).sub.nN(R.sup.5)(R.sup.6),
--(CH.sub.2).sub.nOH, --(HC.dbd.CH).sub.nC(O)O-lower alkyl,
octahydro-quinoline, 3,4-dihydro-1H-isoquinoline,
2,3-benzo-1,4-dioxa-8-aza-spiro[4,5]decane or
1,4-dioxa-8-aza-spiro[4,5]decane; X is O, S or two hydrogen atoms;
R.sup.5 and R.sup.6 are each independently hydrogen or lower alkyl,
R.sup.7 is lower alkyl, lower alkoxy, --C(O)-lower alkyl,
--C(O)O-benzyl, --C(O)O-lower alkyl,
--(CH.sub.2).sub.nNR.sup.5R.sup.6, pyridinyl, unsubstituted or
substituted by lower alkyl, or is --CH.sub.2N(R.sup.5)--C(O)O-lower
alkyl, --NH--C(phenyl).sub.3, pyrrolidinyl, piperidinyl,
morpholinyl, or piperazinyl, unsubstituted or substituted by lower
alkyl; n is 0, 1, 2, 3 or 4; m is 0 or 1; o is 0, 1, 2, 3 or 4; or
a pharmaceutically acceptable salt thereof.
5. The method of claim 4, wherein R.sup.1 is lower alkoxy; R.sup.2
and R.sup.3 are hydrogen; R.sup.4 is a five or six membered
aromatic or non aromatic heterocycle, which is optionally attached
to the benzo group via the linker --(O).sub.m--(CH.sub.2) or
--N.dbd.C(CH.sub.3)-- and is unsubstituted or substituted by one or
two group(s) R.sup.7, wherein R.sup.7 is defined below; R' is b)
--(CH.sub.2).sub.n-five or six membered aromatic or non aromatic
heterocycle, with the exception of the piperazinyl group in case if
n=0, which rings are optionally substituted by 2-oxo-pyrrolidin,
piperidinyl, phenyl, --(CH.sub.2).sub.nOH, halogen, CF.sub.3,
.dbd.O, lower alkyl, cycloalkyl, --(CH.sub.2).sub.n--O-lower alkyl,
--(CH.sub.2).sub.nNH.sub.2, --(CH.sub.2).sub.nCN, --C(O)O-lower
alkyl, --CH.sub.2--O--S(O).sub.2CH.sub.3, --C(O)-lower alkyl,
--C(O)--(CH.sub.2).sub.n-lower alkoxy,
--CH.sub.2--N(R.sup.6)C.sub.6H.sub.4F,
--CH.sub.2--N(R.sup.6)C(O)O-lower alkyl,
--N(R.sup.6)--C(O)--N(R.sup.5)--(CH.sub.2)--O-lower alkyl, -or by
tetrahydrofuran, substituted by 4-Cl-phenyl, piperazin-1-yl,
morpholinyl, thiomorpholinyl, thiomorpholin-1-oxo, pyrrolidin-1-yl
or piperidin-1-yl or is benzopiperidin-1-yl or benzothien-2-yl; X
is O; R.sup.5 and R.sup.6 are each independently hydrogen or lower
alkyl; R.sup.7 is lower alkyl, lower alkoxy, --C(O)-lower alkyl,
--C(O)O-benzyl, --C(O)O-lower alkyl,
--(CH.sub.2).sub.nNR.sup.5R.sup.6, pyridinyl, unsubstituted or
substituted by lower alkyl, or is --CH.sub.2N(R.sup.5)--C(O)O-lower
alkyl, --NH--C(phenyl).sub.3, pyrrolidinyl, piperidinyl,
morpholinyl, or piperazinyl, unsubstituted or substituted by lower
alkyl; n is 0, 1, 2, 3 or 4; and m is 0 or 1.
6. The method of claim 5, wherein R.sup.1 is methoxy, R.sup.2 and
R.sup.3 are hydrogen, R.sup.4 is morpholino, X is O, and R' is
4-methyl-4-methoxy-morpholino.
7. The method of claim 6, wherein the disease is Parkinson's
disease.
Description
PRIORITY TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/930,717, filed Oct. 31, 2007, now pending; which is a
division of application Ser. No. 11/219,577, filed Sep. 2, 2005,
now U.S. Pat. No. 7,317,007, issued Jan. 8, 2008, which is a
division of application Ser. No. 10/322,272, filed Dec. 18, 2002,
now U.S. Pat. No. 6,963,000, issued Nov. 8, 2005; which is a
division of U.S. patent application Ser. No. 09/881,252, filed Jun.
14, 2001, now U.S. Pat. No. 6,521,754, issued Feb. 18, 2003. The
entire contents of the above-identified applications are hereby
incorporated by reference.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0002] Ser. No. 10/930,361 filed Aug. 30, 2004 which is now
pending, is a Division of Ser. No. 10/322,272, filed Dec. 18, 2002
which is now pending, which is a Division of Ser. No. 09/881,252,
filed Jun. 14, 2001 which is now U.S. Pat. No. 6,521,754 issued
Feb. 18, 2003.
[0003] Ser. No. 10/310,508 filed Dec. 5, 2002 which is now U.S.
Pat. No. 6,835,732 issued Dec. 28, 2004 which is a Division of Ser.
No. 09/881,252, filed Jun. 14, 2001 which is now U.S. Pat. No.
6,521,754 issued Feb. 18, 2003, all of which relate to the instant
application.
FIELD OF INVENTION
[0004] The present invention is related to benzothiazole compounds,
and more particularly to benzothiazole derivatives showing activity
as adenosine receptor ligands.
BACKGROUND
[0005] Adenosine modulates a wide range of physiological functions
by interacting with specific cell surface receptors. The potential
of adenosine receptors as drug targets was first reviewed in 1982.
Adenosine is related both structurally and metabolically to the
bioactive nucleotides adenosine triphosphate (ATP), adenosine
diphosphate (ADP), adenosine monophosphate (AMP) and cyclic
adenosine monophosphate (cAMP); to the biochemical methylating
agent S-adenosyl-L-methione (SAM); and structurally to the
coenzymes NAD, FAD and coenzym A; and to RNA. Together adenosine
and these related compounds are important in the regulation of many
aspects of cellular metabolism and in the modulation of different
central nervous system activities.
[0006] The receptors for adenosine have been classified as A.sub.1,
A.sub.2A, A.sub.2B and A.sub.3 receptors, belonging to the family
of G protein-coupled receptors. Activation of adenosine receptors
by adenosine initiates signal transduction mechanism. These
mechanisms are dependent on the receptor associated G protein. Each
of the adenosine receptor subtyps has been classically
characterised by the adenylate cyclase effector system, which
utilises cAMP as a second messenger. The A.sub.1 and A.sub.3
receptors, coupled with G.sub.i proteins inhibit adenylate cyclase,
leading to a decrease in cellular cAMP levels, while A.sub.2A and
A.sub.2B receptors couple to G.sub.s proteins and activate
adenylate cyclase, leading to an increase in cellular cAMP levels.
It is known that the A.sub.1 receptor system include the activation
of phospholipase C and modulation of both potassium and calcium ion
channels. The A.sub.3 subtype, in addition to its association with
adenylate cyclase, also stimulates phospholipase C and so activates
calcium ion channels.
[0007] The A.sub.1 receptor (326-328 amino acids) was cloned from
various species (canine, human, rat, dog, chick, bovine,
guinea-pig) with 90-95% sequence identify among the mammalian
species. The A.sub.2A receptor (409-412 amino acids) was cloned
from canine, rat, human, guinea pig and mouse. The A.sub.2B
receptor (332 amino acids) was cloned from human and mouse with 45%
homology of human A.sub.2B with human A.sub.1 and A.sub.2A
receptors. The A.sub.3 receptor (317-320 amino acids) was cloned
from human, rat, dog, rabbit and sheep.
[0008] The A.sub.1 and A.sub.2A receptor subtypes are proposed to
play complementary roles in adenosine's regulation of the energy
supply. Adenosine, which is a metabolic product of ATP, diffuses
from the cell and acts locally to activate adenosine receptors to
decrease the oxygen demand (A.sub.1) or increase the oxygen supply
(A.sub.2A) and so reinstate the balance of energy supply: demand
within the tissue. The actions of both subtypes is to increase the
amount of available oxygen to tissue and to protect cells against
damage caused by a short term imbalance of oxygen. One of the
important functions of endogenous adenosine is preventing damage
during traumas such as hypoxia, ischaemia, hypotension and seizure
activity.
[0009] Furthermore, it is known that the binding of the adenosine
receptor agonist to mast cells expressing the rat A.sub.3 receptor
resulted in increased inositol triphosphate and intracellular
calcium concentrations, which potentiated antigen induced secretion
of inflammatory mediators. Therefore, the A.sub.3 receptor plays a
role in mediating asthmatic attacks and other allergic
responses.
[0010] Adenosine is also a neuromodulator, possessing global
importance in the modulation of molecular mechanisms underlying
many aspects of physiological brain function by mediating central
inhibitory effects. An increase in neurotransmitter release follows
traumas such as hypoxia, ischaemia and seizures. These
neurotransmitters are ultimately responsible for neural
degeneration and neural death, which causes brain damage or death
of the individual. The adenosine A.sub.1 agonists which mimic the
central inhibitory effects of adenosine may therefore be useful as
neuroprotective agents. Adenosine has been proposed as an
endogenous anticonvulsant agent, inhibiting glutamate release from
excitory neurons and inhibiting neuronal firing. Adenosine agonists
therefore may be used as antiepileptic agents. Adenosine
antagonists stimulate the activity of the CNS and have proven to be
effective as cognition enhancers. Selective A.sub.2a-antagonists
have therapeutic potential in the treatment of various forms of
dementia, for example in Alzheimer's disease and are useful as
neuroprotective agents. Adenosine A.sub.2a-receptor antagonists
inhibit the release of dopamine from central synaptic terminals and
stimulate locomotor activity and consequently improve Parkinsonian
symptoms. The central activities of adenosine are also implicated
in the molecular mechanism underlying sedation, hypnosis,
schizophrenia, anxiety, pain, respiration, depression and substance
abuse. Drugs acting at adenosine receptors therefore have
therapeutic potential as sedatives, muscle relaxants,
antipsychotics, anxiolytics, analgesics, respiratory stimulants and
antidepressants, and they may be used in the treatment of ADHD
(attention deficit hyper-activity disorder).
[0011] An important role for adenosine in the cardiovascular system
is as a cardioprotective agent. Levels of endogenous adenosine
increase in response to ischaemia and hypoxia, and protect cardiac
tissue during and after trauma (preconditioning). Adenosine
agonists thus have potential as cardioprotective agents.
[0012] Adenosine modulates many aspects of renal function,
including renin release, glomerular filtration rate and renal blood
flow. Compounds, which antagonise the renal affects of adenosine,
have potential as renal protective agents. Furthermore, adenosine
A.sub.3 and/or A.sub.2B antagonists may be useful in the treatment
of asthma and other allergic responsesor and in the treament of
diabetes mellitus and obesity.
[0013] Numerous documents describe the current knowledge on
adenosine receptors, for example the following publications: [0014]
Bioorganic & Medicinal Chemistry, 6, (1998), 619-641, [0015]
Bioorganic & Medicinal Chemistry, 6, (1998), 707-719, [0016] J.
Med. Chem., (1998), 41, 2835-2845, [0017] J. Med. Chem., (1998),
41, 3186-3201, [0018] J. Med. Chem., (1998), 41, 2126-2133, [0019]
J. Med. Chem., (1999), 42, 706-721, [0020] J. Med. Chem., (1996),
39, 1164-1171, [0021] Arch. Pharm. Med. Chem., 332, 39-41,
(1999).
SUMMARY
[0022] The present invention is a method of treatment of a person
having a disease state treatable by modulation of the adenosine
A.sub.2a receptor by administering to a person in need of such
treatment an effective amount of a compound of the formula
##STR00001##
wherein [0023] R.sup.1 is hydrogen, lower alkyl, lower alkoxy,
benzyloxy, cycloalkyloxy, halogen, hydroxy or trifluoromethyloxy;
[0024] R.sup.2, R.sup.3 are independently from each other hydrogen,
halogen, lower alkyl or lower alkyloxy; [0025] R.sup.4 is hydrogen,
lower alkyl, lower alkenyl, halogen, --C(O)OH, --C(O)-lower alkyl,
--C(O)-halogen-lower alkyl, --CH(OH)-halogen-lower alkyl,
--C(O)O-lower alkyl, --NHC(O)-lower alkyl, --(CH.sub.2).sub.n--OH,
[0026] or is phenyl, which is optionally attached to the benzo
group via the linker --(O).sub.m--(CH.sub.2).sub.n-- and is
unsubstituted or substituted by N(R.sup.5)(R.sup.6), halogen,
alkoxy or nitro, [0027] or is 2,3-dihydro-1H-indolyl, azepan-1-yl,
[1,4]oxazepan-4-yl, or is a five or six membered aromatic or non
aromatic heterocycle, which may be attached to the benzo group via
the linker --(O).sub.m--(CH.sub.2).sub.n or --N.dbd.C(CH.sub.3)--
and is unsubstituted or substituted by one or two group(s) R.sup.7,
wherein R.sup.7 is defined below; [0028] R is [0029] (a) phenyl,
unsubstituted or substituted by lower alkyl, halogen-lower alkyl,
lower alkoxy, cyano, nitro, --C(O)H, --C(O)OH or by the following
groups --(CH.sub.2).sub.n--C(O)--N(R.sup.5)--(CH.sub.2).sub.o-lower
alkoxy, [0030] --(CH.sub.2).sub.nO-halogen-lower alkyl, [0031]
--(CH.sub.2).sub.nO--(CH.sub.2).sub.n+1--O-lower alkyl, [0032]
--S(O).sub.2--N(R.sup.5)--(CH.sub.2).sub.n--O-lower alkyl, [0033]
--(CH.sub.2).sub.n--OR.sup.5, [0034]
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o-lower alkoxy, [0035]
--(CH.sub.2).sub.nN[(CH.sub.2).sub.o-lower alkoxy].sub.2, [0036]
--(CH.sub.2).sub.nN(R.sup.5)(R.sup.6), [0037]
--(CH.sub.2).sub.nN[S(O).sub.2CH.sub.3].sub.2, [0038]
--(CH.sub.2).sub.nN[R.sup.5][S(O).sub.2CH.sub.3], [0039]
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.oNR.sup.5R.sup.6,
[0040] --(CH.sub.2).sub.nN(R.sup.5)-lower alkenyl, [0041]
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o-cycloalkyl, [0042]
--(CH.sub.2).sub.nN(R.sup.5)--C(O)O-lower alkyl, [0043]
--(CH.sub.2).sub.n--S--(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6),
[0044] --(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--S-lower
alkyl, [0045] --S(O).sub.2--N(R.sup.5)(R.sup.6), [0046]
--(CH.sub.2).sub.nN(R.sup.5)--S(O).sub.2CH.sub.3 [0047]
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o-phenyl, [0048]
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--OH, [0049]
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--CH(OH)--CF.sub.3,
[0050] --(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--CF.sub.3,
[0051]
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--O--CH(OH)--C.sub.6H.sub.3-
(OCH.sub.3).sub.2, [0052]
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--O--C(O)--C.sub.6H.sub.3(O-
CH.sub.3).sub.2, [0053] --N(R.sup.5)--C(O)-morpholin, [0054]
N(R.sup.5)--C(O)--N(R.sup.5)-phenyl, substituted by alkoxy, [0055]
--S(O).sub.2-morpholin, [0056] or is phenyl, which is unsubstituted
or substituted by [0057] --(CR.sup.5R.sup.6).sub.n-five to seven
membered aromatic or non aromatic heterocycle, and wherein the
heterocycle is unsubstituted or substituted by hydroxy,
--N(R.sup.5)(R.sup.6), lower alkoxy or lower alkyl, or by
--(CH.sub.2).sub.nN(R.sup.5)(CH.sub.2).sub.o-five or six membered
aromatic or non aromatic heterocycle and wherein the heterocycle is
unsubstituted or substituted by hydroxy, --N(R.sup.5)(R.sup.6) or
lower alkyl, or is [0058] b) --(CH.sub.2).sub.n-five or six
membered aromatic or non aromatic heterocycle, with the exception
of the piperazinyl group in case if n=0, which rings are
unsubstituted or substituted by one or two substituents, selected
from the group consisting of 2-oxo-pyrrolidin, piperidinyl, phenyl,
--(CH.sub.2).sub.nOH, halogen, CF.sub.3, .dbd.O, lower alkyl,
cycloalkyl, --(CH.sub.2).sub.n--O-lower alkyl,
--(CH.sub.2).sub.nNH.sub.2, --(CH.sub.2).sub.nCN, --C(O)O-lower
alkyl, --CH.sub.2--O--S(O).sub.2CH.sub.3, --C(O)-lower alkyl,
--C(O)--(CH.sub.2).sub.n-lower alkoxy,
--CH.sub.2--N(R.sup.6)C.sub.6H.sub.4F,
--CH.sub.2--N(R.sup.6)C(O)O-lower alkyl,
--N(R.sup.6)--C(O)--N(R.sup.5)--(CH.sub.2).sub.n--O-lower alkyl,
-or by tetrahydrofuran, substituted by 4-Cl-phenyl, or by
piperazin-1-yl, morpholinyl, thiomorpholinyl, thiomorpholin-1-oxo,
pyrrolidin-1-yl or by piperidin-1-yl or is benzopiperidin-1-yl or
benzothien-2-yl, or is [0059] c) --(CH.sub.2).sub.n+1-phenyl,
[0060] --N(R.sup.5)(CH.sub.2).sub.n-phenyl, unsubstituted or
substituted by lower alkoxy, [0061] --O(CH.sub.2).sub.n-phenyl, or
--N(R.sup.5)C(O)-phenyl, or is [0062] d)
--N(R.sup.5)(CH.sub.2).sub.n-5- or 6 membered aromatic or non
aromatic heterocycle, unsubstituted or substituted by lower alkyl,
--(CH.sub.2).sub.n-5- or 6 membered aromatic or non aromatic
heterocycle or is [0063] e)
--(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6), lower alkyl,
--O--(CH.sub.2).sub.n-lower alkoxy, --(CH.sub.2).sub.n-lower
alkoxy, lower alkoxy, cycloalkyl,
--N(R.sup.5)(CH.sub.2).sub.nO-lower alkyl,
--N(R.sup.5)(CH.sub.2).sub.nOH,
--N(R.sup.5)(CH.sub.2).sub.nN(R.sup.5)(R.sup.6), --C(O)O-lower
alkyl, --(CH.sub.2).sub.nOH, --(HC.dbd.CH).sub.nC(O)O-lower alkyl,
octahydro-quinoline, 3,4-dihydro-1H-isoquinoline,
2,3-benzo-1,4-dioxa-8-aza-spiro[4,5]decane or
1,4-dioxa-8-aza-spiro[4,5]decane; [0064] X is O, S or two hydrogen
atoms; [0065] R.sup.5, R.sup.6 are independently from each other
hydrogen or lower alkyl, [0066] R.sup.7 is lower alkyl, lower
alkoxy, --C(O)-lower alkyl, --C(O)O-benzyl, --C(O)O-lower alkyl,
[0067] --(CH.sub.2).sub.nNR.sup.5R.sup.6, pyridinyl, unsubstituted
or substituted by lower alkyl, or is [0068]
--CH.sub.2N(R.sup.5)--C(O)O-lower alkyl, --NH--C(phenyl).sub.3,
pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, optionally
substituted by lower alkyl; [0069] n is 0, 1, 2, 3 or 4; [0070] m
is 0 or 1; [0071] is 0, 1, 2, 3 or 4; [0072] and pharmaceutically
acceptable salts thereof for the manufacture of medicaments for the
treatment of diseases related to the adenosine receptor.
[0073] Some minor subgroups of compounds of the present formula I
are known compounds and have been described, for example in EP 427
963, U.S. Pat. No. 5,099,021, EP 295 656 or DE 19 531 49. These
compounds possess microbicide activity or may be used for lowering
the blood glucose level. Furthermore, WO 00/18767 describes
2-piperazino alkylamino benzoazole, having an affinity to the
dopamine subtype specific ligands and are therefore useful in the
treatment of diseases, related to this receptor. The compounds of
WO 00/18767 are not encompassed from the scope of the present
invention.
[0074] It has surprisingly been found that the compounds of formula
I are adenosine receptor ligands.
[0075] Objects of the present invention are the use of compounds of
formula I or their pharmaceutically acceptable salts for the
manufacture of medicaments for the treatment of diseases, related
to the adenosine A2 receptor, novel compounds of formula I-A per
se, their manufacture, medicaments based on a compound in
accordance with the invention and their production as well as the
use of compounds of formula I in the control or prevention of
illnesses based on the modulation of the adenosine system, such as
Alzheimer's disease, Parkinson's disease, neuroprotection,
schizophrenia, anxiety, pain, respiration deficits, depression,
asthma, allergic responses, hypoxia, ischaemia, seizure and
substance abuse. Furthermore, compounds of the present invention
may be useful as sedatives, muscle relaxants, antipsychotics,
antiepileptics, anticonvulsants and cardiaprotective agents. The
most preferred indications in accordance with the present invention
are those, which base on the A.sub.2A receptor antagonistic
activity and which include disorders of the central nervous system,
for example the treatment or prevention of certain depressive
disorders, neuroprotection and Parkinson's disease as well as ADHD
and diabetes mellitus.
[0076] The present invention includes novel compounds of the
formula
##STR00002## [0077] wherein [0078] R.sup.1 is hydrogen, lower
alkyl, lower alkoxy, benzyloxy, cycloalkyloxy, halogen, hydroxy or
[0079] trifluoromethyloxy; [0080] R.sup.2, R.sup.3 are
independently from each other hydrogen, halogen, lower alkyl or
lower alkyloxy; [0081] R.sup.4 is hydrogen, lower alkyl, lower
alkenyl, halogen, --C(O)-lower alkyl, [0082] --C(O)-halogen-lower
alkyl, --CH(OH)-halogen-lower alkyl, --C(O)O-lower alkyl,
--NHC(O)-lower alkyl, --(CH.sub.2).sub.n--OH, [0083] or is phenyl,
which is optionally attached to the benzo group via the linker
--(O).sub.m--(CH.sub.2).sub.n-- and is unsubstituted or substituted
by N(R.sup.5)(R.sup.6), halogen or nitro, or is
2,3-dihydro-1H-indolyl, azepan-1-yl, [1,4]oxazepan-4-yl, or is
[0084] a five or six membered aromatic or non aromatic heterocycle,
which may be attached to the benzo group via the linker
--(O).sub.m--(CH.sub.2).sub.n or --N.dbd.C(CH.sub.3)-- and is
unsubstituted or substituted by one or two group(s) R.sup.7,
wherein R.sup.7 is defined below; [0085] R' is [0086] (a) phenyl,
optionally unsubstituted or substituted by halogen-lower alkyl,
--C(O)H or by the [0087] following groups [0088]
--(CH.sub.2).sub.n--C(O)--N(R.sup.5)--(CH.sub.2).sub.nlower alkoxy,
[0089] --(CH.sub.2).sub.nO-halogen-lower alkyl, [0090]
--(CH.sub.2).sub.nO--(CH.sub.2).sub.n+1O-lower alkyl, [0091]
--S(O).sub.2--N(R.sup.5)--(CH.sub.2).sub.nO-lower alkyl, [0092]
--(CH.sub.2).sub.nOR.sup.5, [0093]
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o-lower alkoxy, [0094]
--(CH.sub.2).sub.nN[(CH.sub.2).sub.o-lower alkoxy].sub.2, [0095]
--(CH.sub.2).sub.nN[S(O).sub.2CH.sub.3].sub.2, [0096]
--(CH.sub.2).sub.nN[R.sup.5][S(O).sub.2CH.sub.3], [0097]
--(CH.sub.2).sub.nN(R.sup.5)-lower alkenyl, [0098]
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o-cycloalkyl, [0099]
--(CH.sub.2).sub.nN(R.sup.5)--C(O)O-lower alkyl, [0100]
--(CH.sub.2).sub.n--S--(CH.sub.2).sub.n--N(R.sup.5)(R.sup.6),
[0101] --(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--S-lower
alkyl, [0102] --(CH.sub.2).sub.nN(R.sup.5)--S(O).sub.2CH.sub.3
[0103] --(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o-phenyl,
[0104] --(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.oOH, [0105]
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.oCH(OH)--CF.sub.3,
[0106] --(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--CF.sub.3,
[0107]
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--O--CH(OH)--C.sub.6H.sub.3-
(OCH.sub.3).sub.2, [0108]
--(CH.sub.2).sub.nN(R.sup.5)--(CH.sub.2).sub.o--O--C(O)--C.sub.6H.sub.3(O-
CH.sub.3).sub.2, [0109] N(R.sup.5)--C(O)-morpholin, [0110]
N(R.sup.5)--C(O)--N(R.sup.5)-phenyl, substituted by alkoxy,
--S(O).sub.2-morpholin, [0111] or is phenyl, which is unsubstituted
or substituted by [0112] --(CR.sup.5R.sup.6).sub.n-five to seven
membered aromatic or non aromatic heterocycle, and [0113] wherein
the heterocycle is unsubstituted or substituted by hydroxy,
--N(R.sup.5)(R.sup.6) or lower alkyl, or by
--(CH.sub.2).sub.nN(R.sup.5)(CH.sub.2).sub.o-five or six membered
aromatic or non aromatic heterocycle and wherein the heterocycle is
unsubstituted or substituted by hydroxy, [0114]
--N(R.sup.5)(R.sup.6) or lower alkyl, [0115] or is
--N(R.sup.5)-phenyl, which is unsubstituted or substituted by lower
alkoxy, [0116] or is [0117] b) --(CH.sub.2).sub.n-five or six
membered aromatic or non aromatic heterocycle, with the exception
of the piperazinyl group in case if n=0, which rings may be
optionally substituted by 2-oxo-pyrrolidin, piperidinyl, phenyl,
--(CH.sub.2).sub.nOH, halogen, CF.sub.3, .dbd.O, [0118] lower
alkyl, cycloalkyl, --(CH.sub.2).sub.n--O-lower alkyl,
--(CH.sub.2).sub.nNH.sub.2, --(CH.sub.2).sub.nCN, --C(O)O-lower
alkyl, --CH.sub.2--O--S(O).sub.2CH.sub.3, --C(O)-lower alkyl,
--C(O)--(CH.sub.2).sub.n-lower alkoxy,
--CH.sub.2--N(R.sup.6)C.sub.6H.sub.4F,
--CH.sub.2--N(R.sup.6)C(O)O-lower alkyl, [0119]
--N(R.sup.6)--C(O)--N(R.sup.5)--(CH.sub.2).sub.n--O-lower alkyl,
-or by tetrahydrofuran, substituted by 4-Cl-phenyl, or by
piperazin-1-yl, morpholinyl, thiomorpholinyl, thiomorpholin-1-oxo,
pyrrolidin-1-yl or by piperidin-1-yl or is benzopiperidin-1-yl or
benzothien-2-yl, or [0120] is [0121] c)
--N(R.sup.5)(CH.sub.2).sub.n+1-phenyl, unsubstituted or substituted
by lower alkoxy, [0122] --O(CH.sub.2).sub.n-phenyl, or [0123]
--N(R.sup.5)C(O)-phenyl, or [0124] is [0125] d)
--N(R.sup.5)(CH.sub.2).sub.n-5- or 6 membered aromatic or non
aromatic heterocycle, unsubstituted or substituted by lower alkyl,
--(CH.sub.2).sub.n-5- or 6 membered aromatic or nonaromatic
heterocycle [0126] or is [0127] e) --O--(CH.sub.2).sub.n-lower
alkoxy, lower alkyl-lower alkoxy,
--N(R.sup.5)(CH.sub.2).sub.nN(R.sup.5)(R.sup.6),
--(CH.sub.2).sub.nOH, --(HC.dbd.CH).sub.nC(O)O-lower alkyl,
octahydro-quinoline, 3,4-dihydro-1H-isoquinoline,
2,3-benzo-1,4-dioxa-8-aza-spiro[4,5]decane or
1,4-dioxa-8-aza-spiro[4,5]decane. [0128] X is O, S or two hydrogen
atoms; [0129] R.sup.5, R.sup.6 are independently from each other
hydrogen or lower alkyl, [0130] R.sup.7 is lower alkyl, lower
alkoxy, --C(O)-lower alkyl, --C(O)O-benzyl, --C(O)O-lower alkyl,
[0131] --(CH.sub.2).sub.nNR.sup.5R.sup.6, pyridinyl, unsubstituted
or substituted by lower alkyl, or is [0132]
--CH.sub.2N(R.sup.5)--C(O)O-lower alkyl, --NH--C(phenyl).sub.3,
pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, unsubstituted
or substituted by lower alkyl; [0133] n is 0, 1, 2, 3 or 4; [0134]
m is 0 or 1; [0135] is 0, 1, 2, 3 or 4; [0136] or pharmaceutically
acceptable salts thereof.
DETAILED DESCRIPTION
[0137] As used herein, the term "lower alkyl" denotes a saturated
straight- or branched-chain alkyl group containing from 1 to 6
carbon atoms, for example, methyl, ethyl, propyl, isopropyl,
n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred lower
alkyl groups are groups with 1-4 carbon atoms.
[0138] As used herein, the term "lower alkenyl" denotes a
unsaturated straight- or branched-chain alkyl group containing from
2 to 6 carbon atoms, for example, ethylen, propylen, isopropylen,
n-butylen, i-butylen, 2-butylen, t-butylen and the like. Preferred
lower alkyl groups are groups with 2-4 carbon atoms.
[0139] The term "cycloalkyl" denotes a saturated carbocyclic group,
containing 3-6 carbon atoms.
[0140] The term "halogen" denotes chlorine, iodine, fluorine and
bromine.
[0141] The term "lower alkoxy" denotes a group wherein the alkyl
residues are as defined above, and which is attached via an oxygen
atom.
[0142] The term "five or six membered aromatic or non aromatic
heterocycle" denotes the following group: aromatic heterocyclic
groups are, for example pyrrol-1-yl, tetrazolyl, imidazol-1 or
2-yl, pyrazol1-yl, pyridin-1,2,3 or 4-yl, pyrazinyl, pyrimidinyl,
pyridazinyl, isothiazolyl, isoxazolyl, thiazolyl, thienyl or furyl;
Non aromatic heterocyclic groups are, for example, pyrrolidinyl,
imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl,
morpholinyl, thiomorpholinyl, thiomorpholin-1,1-dioxo or
thiomorpholin-1-oxo.
[0143] The term "pharmaceutically acceptable acid addition salts"
embraces salts with inorganic and organic acids, such as
hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid,
citric acid, formic acid, fumaric acid, maleic acid, acetic acid,
succinic acid, tartaric acid, methane-sulfonic acid,
p-toluenesulfonic acid and the like.
[0144] Preferred compounds of formula I are those, wherein R.sup.1
is methoxy, X is oxygen and R.sup.2/R.sup.3 are hydrogen.
[0145] Exemplary preferred are compounds of formula I for the above
mentioned method of treatment, wherein R is an unsubstituted or
substituted five or six membered aromatic heterocycle, for example
the following compounds: [0146]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methyl-isonicotinamide-
, [0147] 5-methyl-thiophene-2-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide, [0148]
5-methyl-furan-2-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide, [0149]
N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-isonicotinamide, [0150]
5-methyl-thiophene-2-carboxylic acid
(4-methoxy-7-pyridin-4-yl-benzothiazol-2-yl)-amide, [0151]
5-methyl-thiophene-2-carboxylic acid
(4-methoxy-7-pyridin-3-yl-benzothiazol-2-yl)-amide, [0152]
5-methyl-thiophene-2-carboxylic acid
[4-methoxy-7-(2-methyl-pyridin-4-yl)-benzothiazol-2-yl]-amide,
[0153] 5-methyl-thiophene-2-carboxylic acid
[7-(3-amino-phenyl)-4-methoxy-benzothiazol-2-yl]-amide, [0154]
N-(4-methoxy-7-thiophen-2-yl-benzothiazol-2-yl)-2-methyl-isonicotinamide,
[0155]
N-[4-methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-2--
methyl-isonicotinamide, [0156]
N-[4-methoxy-7-(2-pyrrolidin-1-yl-thiazol-4-yl)-benzothiazol-2-yl]-2-meth-
yl-isonicotinamide, [0157]
N-{4-methoxy-7-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzothiazol-2--
yl}-2-methyl-isonicotinamide and [0158]
N-[4-methoxy-7-(5-methyl-thiophen-2-yl)-benzothiazol-2-yl]-2-methyl-isoni-
cotinamide.
[0159] Further preferred compounds of formula I for the above
mentioned method of treatment are compounds, wherein R is an
unsubstituted or substituted five or six membered non aromatic
heterocycle, for example the following compounds: [0160]
morpholine-4-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide, [0161]
thiomorpholine-4-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide, [0162] 1-oxo-1l
4-thiomorpholine-4-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide,
morpholine-4-carboxylic acid
{4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-
-yl}-amide, morpholine-4-carboxylic acid
[4-methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-amide,
[0163] morpholine-4-carboxylic acid
{4-methoxy-7-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzothiazol-2-yl-
}-amide, [0164] morpholine-4-carboxylic acid
[4-methoxy-7-(2-piperidin-1-yl-thiazol-4-yl)-benzothiazol-2-yl]-amide,
[0165] morpholine-4-carboxylic acid
[4-methoxy-7-(5-methyl-thiophen-2-yl)-benzothiazol-2-yl]-amide,
[0166]
4-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylcarbamoyl)-piperidine-1-ca-
rboxylic acid tert-butyl ester, [0167]
1-acetyl-piperidine-4-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide, [0168]
4-oxo-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide and [0169]
1-oxo-1.lamda..sup.4-thiomorpholine-4-carboxylic acid
(4-methoxy-7-piperidin-1-yl-benzothiazol-2-yl)-amide.
[0170] Preferred are further compounds, wherein R is methoxy, for
example the following compounds: [0171]
rac-[7-(2-bromo-1-hydroxy-ethyl)-4-methoxy-benzothiazol-2-yl]-carbamic
acid methyl ester, [0172]
{4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl}--
carbamic acid methyl ester, [0173]
[4-methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-carbamic
acid methyl ester, [0174]
[4-methoxy-7-(2-piperidin-1-yl-thiazol-4-yl)-benzothiazol-2-yl]-carbamic
acid methyl ester and [0175]
{4-methoxy-7-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzothiazol-2-yl-
}-carbamic acid methyl ester.
[0176] Preferred compounds of formula I for the above mentioned
method of treatment are those, wherein R is
phenyl, optionally substituted by halogen, CF.sub.3, --CH.sub.2OH,
--CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2NHCH.sub.2CH.sub.2OH, --CH.sub.2NHCH.sub.2-pyridinyl,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.2CH.sub.2SCH.sub.3,
--CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.2SCH.sub.3,
--CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2N(CH.sub.2 CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2NHCH.sub.3, --CH.sub.2SCH.sub.2CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.2OCH.sub.3 or
--CH.sub.2N(CH.sub.3)C(O)OCH.sub.3, for example the following
compounds: [0177]
4-hydroxymethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide-
, [0178]
4-fluoro-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide, [0179]
2-(4-fluoro-benzoylamino)-4-methoxy-benzothiazole-7-carboxylic acid
methyl ester, [0180]
4-[(2-methoxy-ethylamino)-methyl]-N-(4-methoxy-7-phenyl-benzothiazol-2-yl-
)-benzamide, [0181]
4-[(2-hydroxy-ethylamino)-methyl]-N-(4-methoxy-7-phenyl-benzothiazol-2-yl-
)-benzamide, [0182]
N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-{[(pyridin-4-yl-methyl)-amino]-
-methyl}-benzamide, [0183]
N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-{[(pyridin-3-yl-methyl)-amino]-
-methyl}-benzamide, [0184]
4-aminomethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide,
[0185]
N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-[(2-methylsulfanyl-ethylamino)-
-methyl]-benzamide, [0186]
4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-
-benzothiazol-2-yl)-benzamide, [0187]
N-[7-(2-amino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-4-fluoro-benzami-
de, [0188]
4-fluoro-N-{4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl-
]-benzothiazol-2-yl}-benzamide, [0189]
4-fluoro-N-(4-methoxy-7-thiophen-2-yl-benzothiazol-2-yl)-benzamide,
[0190]
4-fluoro-N-{4-methoxy-7-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-
-benzothiazol-2-yl}-benzamide, [0191]
4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-{4-methoxy-7-[2-(6-methyl-p-
yridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl}-benzamide, [0192]
4-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-thiophen-2-yl--
benzothiazol-2-yl)-benzamide, [0193]
4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-[4-methoxy-7-(2-pyridin-2-y-
l-thiazol-4-yl)-benzothiazol-2-yl]-benzamide, [0194]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-trifluoromethyl-benzam-
ide, [0195]
4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide,
[0196] N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide,
[0197]
4-chloro-3-{[ethyl-(2-methoxy-ethyl)-amino]-methyl}-N-(4-methoxy-7-morpho-
lin-4-yl-benzothiazol-2-yl)-benzamide, [0198]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-methylaminomethyl-benz-
amide, [0199]
4-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-methylaminome-
thyl-benzamide, [0200]
4-chloro-3-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morph-
olin-4-yl-benzothiazol-2-yl)-benzamide, [0201]
4-chloro-3-[(2-methoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl--
benzothiazol-2-yl)-benzamide, [0202]
3-[(2-methoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothia-
zol-2-yl)-benzamide, [0203]
3-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-
-benzothiazol-2-yl)-benzamide, [0204]
4-[(2-ethoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiaz-
ol-2-yl)-benzamide, [0205]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benz-
amide, [0206]
4-(2-dimethylamino-ethylsulfanylmethyl)-N-(4-methoxy-7-morpholin-4-yl-ben-
zothiazol-2-yl)-benzamide, [0207]
4-{[(2-ethoxy-ethyl)-ethyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-b-
enzothiazol-2-yl)-benzamide, [0208]
4-{[(2-ethoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl--
benzothiazol-2-yl)-benzamide, [0209]
4-(2-methoxy-ethoxymethyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-y-
l)-benzamide, [0210]
4-methoxymethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamid-
e, [0211]
N-(4-methoxy-7-thiomorpholin-4-yl-benzothiazol-2-yl)-benzamide and
[0212]
[4-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-benzyl]-methy-
l-carbamic acid methyl ester.
[0213] Further preferred compounds of formula I for the above
mentioned method of treatment are those, wherein R is phenyl,
substituted by an unsubstituted or substituted
--(CH.sub.2).sub.n-five to seven membered aromatic or non aromatic
heterocycle, for example the following compounds: [0214]
4-imidazol-1-yl-methyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide-
, [0215]
4-(4-Hydroxy-piperidin-1-yl-methyl)-N-(4-methoxy-7-phenyl-benzoth-
iazol-2-yl)-benzamide, [0216]
4-[1,4]diazepan-1-yl-methyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benz-
amide, [0217]
4-(3(S)-dimethylamino-pyrrolidin-1-yl-methyl)-N-(4-methoxy-7-phenyl-benzo-
thiazol-2-yl)-benzamide, [0218]
N-{4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl-
}-4-pyrrolidin-1-yl-methyl-benzamide, [0219]
N-(4-methoxy-7-thiophen-2-yl-benzothiazol-2-yl)-4-pyrrolidin-1-yl-methyl--
benzamide, [0220]
N-[4-methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-4-pyrroli-
din-1-yl-methyl-benzamide, [0221]
4-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-pyrrolidin-1--
yl-methyl-benzamide, [0222]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-pyrrolidin-1-yl-methyl-
-benzamide, [0223]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-(2-methyl-imidazol-1-y-
l-methyl)-benzamide and [0224]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-(4-methyl-piperazin-1--
yl-methyl)-benzamide.
[0225] Especially preferred are compounds, wherein R.sup.4 is an
unsubstituted or substituted five to seven membered aromatic or non
aromatic heterocycle, which is for example, but not limited to,
morpholine or piperazine.
[0226] Preferred compounds of formula IA are those, wherein R.sup.1
is methoxy, X is oxygen and R.sup.2/R.sup.3 are hydrogen.
[0227] Exemplary preferred are compounds of formula IA, wherein R'
is an unsubstituted or substituted five or six membered aromatic
heterocycle, for example the following compounds: [0228]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methyl-isonicotinamide-
, [0229] 5-methyl-thiophene-2-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide, [0230]
5-methyl-furan-2-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide, [0231]
N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-isonicotinamide, [0232]
5-methyl-thiophene-2-carboxylic acid
(4-methoxy-7-pyridin-4-yl-benzothiazol-2-yl)-amide, [0233]
5-methyl-thiophene-2-carboxylic acid
(4-methoxy-7-pyridin-3-yl-benzothiazol-2-yl)-amide, [0234]
5-methyl-thiophene-2-carboxylic acid
[4-methoxy-7-(2-methyl-pyridin-4-yl)-benzothiazol-2-yl]-amide,
[0235] 5-methyl-thiophene-2-carboxylic acid
[7-(3-amino-phenyl)-4-methoxy-benzothiazol-2-yl]-amide, [0236]
N-(4-methoxy-7-thiophen-2-yl-benzothiazol-2-yl)-2-methyl-isonicotinamide,
[0237]
N-[4-methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-2--
methyl-isonicotinamide, [0238]
N-[4-methoxy-7-(2-pyrrolidin-1-yl-thiazol-4-yl)-benzothiazol-2-yl]-2-meth-
yl-isonicotinamide, [0239]
N-{4-methoxy-7-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzothiazol-2--
yl}-2-methyl-isonicotinamide and [0240]
N-[4-methoxy-7-(5-methyl-thiophen-2-yl)-benzothiazol-2-yl]-2-methyl-isoni-
cotinamide.
[0241] Further preferred compounds of formula IA are compounds,
wherein R is an unsubstituted or substituted five or six membered
non aromatic heterocycle, for example the following compounds:
[0242] morpholine-4-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide,
thiomorpholine-4-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide, [0243] 1-oxo-1l
4-thiomorpholine-4-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide,
[0244] morpholine-4-carboxylic acid
{4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl}--
amide, [0245] morpholine-4-carboxylic acid
[4-methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-amide,
[0246] morpholine-4-carboxylic acid
{4-methoxy-7-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzothiazol-2-yl-
}-amide, [0247] morpholine-4-carboxylic acid
[4-methoxy-7-(2-piperidin-1-yl-thiazol-4-yl)-benzothiazol-2-yl]-amide,
[0248] morpholine-4-carboxylic acid
[4-methoxy-7-(5-methyl-thiophen-2-yl)-benzothiazol-2-yl]-amide,
[0249]
4-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-piperidine-1-c-
arboxylic acid tert-butyl ester, [0250]
1-acetyl-piperidine-4-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide, [0251]
4-oxo-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide and [0252]
1-oxo-1.lamda..sup.4-thiomorpholine-4-carboxylic acid
(4-methoxy-7-piperidin-1-yl-benzothiazol-2-yl)-amide.
[0253] Preferred are further compounds, wherein R is methoxy, for
example the following compounds: [0254]
rac-[7-(2-bromo-1-hydroxy-ethyl)-4-methoxy-benzothiazol-2-yl]-carbamic
acid methyl ester, [0255]
{4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl}--
carbamic acid methyl ester, [0256]
[4-methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-carbamic
acid methyl ester, [0257]
[4-methoxy-7-(2-piperidin-1-yl-thiazol-4-yl)-benzothiazol-2-yl]-carbamic
acid methyl ester and [0258]
{4-methoxy-7-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzothiazol-2-yl-
}-carbamic acid methyl ester.
[0259] Preferred compounds of formula IA are those, wherein R' is
phenyl, unsubstituted or substituted by --CH.sub.2OH,
--CH.sub.2NHCH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2NHCH.sub.2CH.sub.2OH, --CH.sub.2NHCH.sub.2-pyridinyl,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.2CH.sub.2SCH.sub.3,
--CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.2SCH.sub.3,
--CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2N(CH.sub.2 CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2NHCH.sub.3, --CH.sub.2SCH.sub.2CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.2OCH.sub.3 or
--CH.sub.2N(CH.sub.3)C(O)OCH.sub.3, for example the following
compounds: [0260]
4-hydroxymethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide-
, [0261]
4-[(2-methoxy-ethylamino)-methyl]-N-(4-methoxy-7-phenyl-benzothia-
zol-2-yl)-benzamide, [0262]
4-[(2-hydroxy-ethylamino)-methyl]-N-(4-methoxy-7-phenyl-benzothiazol-2-yl-
)-benzamide, [0263]
N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-{[(pyridin-4-ylmethyl)-amino]--
methyl}-benzamide, [0264]
N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-{[(pyridin-3-ylmethyl)-amino]--
methyl}-benzamide, [0265]
4-aminomethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide,
[0266]
N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-[(2-methylsulfanyl-ethylamino)-
-methyl]-benzamide, [0267]
4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-
-benzothiazol-2-yl)-benzamide, [0268]
N-[7-(2-amino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-4-fluoro-benzami-
de, [0269]
4-fluoro-N-{4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl-
]-benzothiazol-2-yl}-benzamide, [0270]
4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-{4-methoxy-7-[2-(6-methyl-p-
yridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl}-benzamide, [0271]
4-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-thiophen-2-yl--
benzothiazol-2-yl)-benzamide, [0272]
4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-[4-methoxy-7-(2-pyridin-2-y-
l-thiazol-4-yl)-benzothiazol-2-yl]-benzamide, [0273]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-trifluoromethyl-benzam-
ide, [0274]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide, [0275]
4-chloro-3-{[ethyl-(2-methoxy-ethyl)-amino]-methyl}-N-(4-methoxy-7-
-morpholin-4-yl-benzothiazol-2-yl)-benzamide, [0276]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-methylaminomethyl-benz-
amide, [0277]
4-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-methylaminome-
thyl-benzamide, [0278]
4-chloro-3-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morph-
olin-4-yl-benzothiazol-2-yl)-benzamide, [0279]
4-chloro-3-[(2-methoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl--
benzothiazol-2-yl)-benzamide, [0280]
3-[(2-methoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothia-
zol-2-yl)-benzamide, [0281]
3-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-
-benzothiazol-2-yl)-benzamide, [0282]
4-[(2-ethoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiaz-
ol-2-yl)-benzamide, [0283]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benz-
amide, [0284]
4-(2-dimethylamino-ethylsulfanylmethyl)-N-(4-methoxy-7-morpholin-4-yl-ben-
zothiazol-2-yl)-benzamide, [0285]
4-{[(2-ethoxy-ethyl)-ethyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-b-
enzothiazol-2-yl)-benzamide, [0286]
4-{[(2-ethoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl--
benzothiazol-2-yl)-benzamide, [0287]
4-(2-methoxy-ethoxymethyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-y-
l)-benzamide, [0288]
4-methoxymethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamid-
e, [0289]
N-(4-methoxy-7-thiomorpholin-4-yl-benzothiazol-2-yl)-benzamide and
[0290]
[4-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-benzyl]-methy-
l-carbamic acid methyl ester.
[0291] Further preferred compounds of formula IA are those, wherein
R' is phenyl, substituted by an unsubstituted or substituted
--(CR.sup.5R.sup.6).sub.n-five to seven membered aromatic or non
aromatic heterocycle, for example the following compounds: [0292]
4-imidazol-1-ylmethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide,
[0293]
4-(4-Hydroxy-piperidin-1-yl-methyl)-N-(4-methoxy-7-phenyl-benzothi-
azol-2-yl)-benzamide, [0294]
4-[1,4]diazepan-1-yl-methyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benz-
amide, [0295]
4-(3(S)-dimethylamino-pyrrolidin-1-yl-methyl)-N-(4-methoxy-7-phenyl-benzo-
thiazol-2-yl)-benzamide, [0296]
N-{4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl-
}-4-pyrrolidin-1-yl-methyl-benzamide, [0297]
N-(4-methoxy-7-thiophen-2-yl-benzothiazol-2-yl)-4-pyrrolidin-1-yl-methyl--
benzamide, [0298]
N-[4-methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-4-pyrroli-
din-1-yl-methyl-benzamide, [0299]
4-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-pyrrolidin-1--
yl-methyl-benzamide, [0300]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-pyrrolidin-1-yl-methyl-
-benzamide, [0301]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-(2-methyl-imidazol-1-y-
l-methyl)-benzamide and [0302]
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-(4-methyl-piperazin-1--
yl-methyl)-benzamide.
[0303] Especially preferred are compounds of formula IA, wherein
R.sup.4 is an unsubstituted or substituted five to seven membered
aromatic or non aromatic heterocycle, which is for example
morpholine or piperazine.
[0304] The present compounds of formulas I and I-A and their
pharmaceutically acceptable salts can be prepared by methods known
in the art, for example, by processes described below, which
process comprises [0305] reacting a compound of formula
[0305] ##STR00003## [0306] with a compound of formula
[0306] ##STR00004## [0307] and an amine of the formula
R.sup.5R.sup.6NH or an appropriate cyclic amine to a compound of
formula
[0307] ##STR00005## [0308] or to compounds of formula I-1, wherein
the group --NR.sup.5R.sup.6 is replaced by a cyclic amine, [0309]
wherein R.sup.1-R.sup.6 and X have the significances given above,
or [0310] reacting a compound of formula
[0310] ##STR00006## [0311] with a compound of formula
[0311] ##STR00007## [0312] to a compound of formula I-A, wherein
R.sup.1-R.sup.4, R' and X have the significances given above, or
[0313] reacting a compound of formula
[0313] ##STR00008## [0314] with a compound of formula
[0314] ##STR00009## [0315] to a compound of formula
[0315] ##STR00010## [0316] wherein R.sup.1-R.sup.5 have the
significances given above, or [0317] hydrogenating a compound of
formula I-3 with H.sub.2/Pd/C to give a compound of formula
[0317] ##STR00011## [0318] wherein R.sup.1-R.sup.5 have the
significances given above, or [0319] reacting a compound of formula
I-3 with N-bromosuccinimide/H.sub.2O to give a compound of
formula
[0319] ##STR00012## [0320] wherein R.sup.1-R.sup.5 have the
significances given above, or [0321] oxidizing a compound of
formula I-4 to a compound of formula
[0321] ##STR00013## [0322] wherein R.sup.1-R.sup.5 have the
significances given above, or [0323] reacting a compound of formula
I-5 with a compound of formula
[0323] ##STR00014## [0324] to a compound of formula
[0324] ##STR00015## [0325] wherein R.sup.1-R.sup.5 and R.sup.7 have
the significances given above, or [0326] reacting a compound of
formula I-5 with a compound of formula
[0326] ##STR00016## [0327] to a compound of formula
[0327] ##STR00017## [0328] wherein R.sup.1-R.sup.6 have the
significances given above, or [0329] reacting a compound of formula
I-5 with a compound of formula
[0329] ##STR00018## [0330] to a compound of formula
##STR00019##
[0330] and [0331] cleaving off the boc-group to a compound of
formula
[0331] ##STR00020## [0332] wherein R.sup.1-R.sup.5 have the
significances given above, or [0333] modifying one or more
substituents R.sup.1-R7.sup.6 within the definitions given above,
and [0334] if desired, converting the compounds obtained into
pharmaceutically acceptable acid addition salts.
[0335] All reaction steps described above are carried out in
conventional manner and are described in more detail in the working
examples.
[0336] In accordance with process variant a) a compound of formula
II, for example 2-amino-7-phenyl-4-methoxy-benzothiazol in pyridine
is dissolved in tetrahydrofuran and is then treated with phosgene
in toluene. The reaction mixture is concentrated to half the volume
under reduced pressure and the appropiate amine, for example an
amine of formula R.sup.5R.sup.6NH or a cyclic amine, such as
morpholine or thiomorpholine, are added. The obtained product is
isolated by flash chromatography.
[0337] Reaction variant b) describes the process for preparation of
a compound of formula I, wherein a compound of formula II is
reacting with a compound of formula IV. The reaction is carried out
for about 10 minutes in conventional manner. The obtained compound
is then isolated by flash chromatography.
[0338] The salt formation is effected at room temperatures in
accordance with methods which are known per se and which are
familiar to any person skilled in the art. Not only salts with
inorganic acids, but also salts with organic acids came into
consideration. Hydrochlorides, hydrobromides, sulphates, nitrates,
citrate, acetates, maleates, succinates, methan-sulphonates,
p-toluenesulphonates and the like are examples of such salts.
[0339] In Examples 1-187 and in the following schemes 1 and 2 the
preparation of compounds of formula I is described in more
detail.
[0340] The starting materials are known compounds or may be
prepared according to methods known in the art.
##STR00021##
wherein the numbers 1-6 have the following meaning: [0341] 1
MeO(CO)Cl, base [0342] 2 ICl [0343] 3 R.sup.4--B(OR.sup.5).sub.2 or
R.sup.4--Sn(CH.sub.3).sub.3, Pd-catalyst [0344] 4 KOH [0345] 5
C(X)Cl.sub.2, R.sup.5R.sup.6NH, or R.sup.5NCX [0346] 6 RC(X)Cl,
base
[0347] The definition of substituents is described above.
##STR00022##
wherein the numbers 1-6 have the following meaning [0348] 1
R.sup.4--B(OR.sup.5).sub.2 or R.sup.4--Sn(CH.sub.3).sub.3,
Pd-catalyst [0349] 2 H.sub.2, Pd--C [0350] 3 Ph(CO)NCS [0351] 4
NaOMe [0352] 5 Br.sub.2 [0353] 6 RC(X)Cl, base [0354] and the
definition of the substituents R.sup.1-R.sup.4, R.sup.5, X and R is
given above.
##STR00023##
[0354] The definitions of R.sup.1 to R.sup.5 are given above and
NBS is N-bromosuccinimide.
##STR00024##
[0355] The definitions or R.sup.1 to R.sup.5 and R.sup.7 are given
above.
##STR00025##
[0356] The definitions of R.sup.1 to R.sup.6 are given above.
##STR00026##
[0357] The definitions of R.sup.1 to R.sup.5 are given above.
[0358] The reactions described in schemes 1 to 6 are carried out in
conventional manner.
[0359] The compounds of formulas I and I-A and their
pharmaceutically usable addition salts possess valuable
pharmacological properties. Specifically, it has been found that
the compounds of the present invention are adenosine receptor
ligands and possess a high affinity towards the adenosine A.sub.2A
receptor.
[0360] All of the compounds were investigated in accordance with
the test given hereinafter. [0361] Human adenosine A.sub.2A
receptor
[0362] The human adenosine A.sub.2A receptor was recombinantly
expressed in chinese hamster ovary (CHO) cells using the semliki
forest virus expression system. Cells were harvested, washed twice
by centrifugation, homogenised and again washed by centrifugation.
The final washed membrane pellet was suspended in a Tris (50 mM)
buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl.sub.2 and 10 mM
MgCl.sub.2 (pH 7.4) (buffer A). The [.sup.3H]-SCH-58261 (Dionisotti
et al., 1997, Br J Pharmacol 121, 353; 1 nM) binding assay was
carried out in 96-well plates in the presence of 2.5 .mu.g of
membrane protein, 0.5 mg of Ysi-poly-1-lysine SPA beads and 0.1 U
adenosine deaminase in a final volume of 200 .mu.l of buffer A.
Non-specific binding was defined using xanthine amine congener
(XAC; 2 .mu.M). Compounds were tested at 10 concentrations from 10
.mu.M-0.3 nM. All assays were conducted in duplicate and repeated
at least two times. Assay plates were incubated for 1 hour at room
temperature before centrifugation and then bound ligand determined
using a Packard Topcount scintillation counter. IC.sub.50 values
were calculated using a non-linear curve fitting program and Ki
values calculated using the Cheng-Prussoff equation.
[0363] In accordance with the invention, it has been shown that all
of the compounds of formula I have a high affinity toward the
A.sub.2A receptor. The most preferred compounds show an affinity to
the hA2A binding in the scope of a pKi value between 8.5 to
9.3.
[0364] Examples of such compounds are the followings:
TABLE-US-00001 Example No. pKi value 3 8.8 10 9.0 17 9.3 23 8.9 36
9.1 59 9.0 61 8.9 62 9.1 91 8.8 92 8.9 96 8.8 100 9.3 107 8.8 108
8.9 121 9.0 125 9.0 157 8.9 159 8.9 201 8.6 221 8.7 238 8.7 240 8.5
253 8.6 258 8.9 271 8.6 275 8.7 277 8.7 278 8.5 279 8.8 280 8.7 282
8.6 283 9.0 286 8.8 287 8.5 289 8.9 290 8.6 292 8.8 298 8.7 301 8.5
304 8.5 308 9.1 309 8.5 314 8.5 315 8.6 317 8.6 326 8.5 327 8.5 342
8.5 369 9.2
[0365] The compounds of formula I, formula Ia and the
pharmaceutically acceptable salts of the compounds of formula I and
formula Ia can be used as medicaments, e.g. in the form of
pharmaceutical preparations. The pharmaceutical preparations can be
administered orally, e.g. in the form of tablets, coated tablets,
dragees, hard and soft gelatine capsules, solutions, emulsions or
suspensions. The administration can, however, also be effected
rectally, e.g. in the form of suppositories, parenterally, e.g. in
the form of injection solutions.
[0366] The compounds of formula I and formula Ia can be processed
with pharmaceutically inert, inorganic or organic carriers for the
production of pharmaceutical preparations. Lactose, corn starch or
derivatives thereof, talc, stearic acids or its salts and the like
can be used, for example, as such carriers for tablets, coated
tablets, dragees and hard gelatine capsules. Suitable carriers for
soft gelatine capsules are, for example, vegetable oils, waxes,
fats, semi-solid and liquid polyols and the like. Depending on the
nature of the active substance no carriers are, however, usually
required in the case of soft gelatine capsules. Suitable carriers
for the production of solutions and syrups are, for example, water,
polyols, glycerol, vegetable oil and the like. Suitable carriers
for suppositories are, for example, natural or hardened oils,
waxes, fats, semi-liquid or liquid polyols and the like.
[0367] The pharmaceutical preparations can, moreover, contain
preservatives, solubilizers, stabilizers, wetting agents,
emulsifiers, sweeteners, colorants, flavorants, salts for varying
the osmotic pressure, buffers, masking agents or antioxidants. They
can also contain still other therapeutically valuable
substances.
[0368] Medicaments containing a compound of formula I, formula Ia
or a pharmaceutically acceptable salt thereof and a therapeutically
inert carrier are also an object of the present invention, as is a
process for their production, which comprises bringing one or more
compounds of formula I and/or pharmaceutically acceptable acid
addition salts and, if desired, one or more other therapeutically
valuable substances into a galenical administration form together
with one or more therapeutically inert carriers.
[0369] In accordance with the invention compounds of formula I and
formula Ia as well as their pharmaceutically acceptable salts are
useful in the control or prevention of illnesses based on the
adenosine receptor antagonistic activity, such as Alzheimer's
disease, Parkinson's disease, neuroprotection, schizophrenia,
anxiety, pain, respiration deficits, depression, asthma, allergic
responses, hypoxia, ischaemia, seizure and substance abuse.
Furthermore, compounds of the present invention may be useful as
sedatives, muscle relaxants, antipsychotics, antiepileptics,
anticonvulsants and cardioprotective agents and for the production
of corresponding medicaments.
[0370] The most preferred indications in accordance with the
present invention are those, which include disorders of the central
nervous system, for example the treatment or prevention of certain
depressive disorders, neuroprotection and Parkinson's disease.
[0371] The dosage can vary within wide limits and will, of course,
have to be adjusted to the individual requirements in each
particular case. In the case of oral administration the dosage for
adults can vary from about 0.01 mg to about 1000 mg per day of a
compound of formula I, formula Ia or of the corresponding amount of
a pharmaceutically acceptable salt thereof. The daily dosage may be
administered as single dose or in divided doses and, in addition,
the upper limit can also be exceeded when this is found to be
indicated.
EXAMPLE 1
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0372] To a solution of 2-amino-4-methoxy-7-phenyl-benzothiazole
(100 mg, 0.4 mmol) in pyridine (2 ml) was added benzoyl chloride
(55 mg, 0.4 mmol) and the mixture stirred overnight at 20.degree.
C. To this mixture 2N HCl to pH 1 (20 ml) was added then the
mixture was extracted twice with EtOAc (20 ml), washed with
saturated NaHCO.sub.3 solution, dried with Na.sub.2SO.sub.4 and the
solvent evaporated. The crude product was then chromatographed over
SiO.sub.2 (Merck 230-400 mesh) eluting with CH.sub.2Cl.sub.2/MeOH
(98:2), the product fractions were pooled and the solvent
evaporated, to afford the title compound as a white solid (97 mg,
69% yield), MS: m/e=360 (M.sup.+).
Following the General Method of Example 1 the Compounds of Examples
2 to 49 were Prepared
EXAMPLE 2
Furan-2-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide
[0373] Using furan-2-carboxylic acid chloride the title compound
was prepared as a beige solid (41% yield), MS: m/e=251.3
(M+H.sup.+).
EXAMPLE 3
5-Methyl-thiophene-2-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide
[0374] Using 5-methyl-thiophene-carboxylic acid chloride the title
compound was prepared as a beige solid (36% yield), MS: m/e=381.3
(M+H.sup.+).
EXAMPLE 4
Furan-2-carboxylic acid (4,6-difluoro-benzothiazol-2-yl)-amide
[0375] Using 2-amino-4,6-difluoro-benzothiazole and
furan-2-carboxylicacid chloride the title compound was prepared as
a grey solid (81% yield), MS: m/e=280 (M.sup.+).
EXAMPLE 5
5-Methyl-thiophene-2-carboxylic acid
(4,6-difluoro-benzothiazol-2-yl)-amide
[0376] Using 2-amino-4,6-difluoro-benzothiazole and
5-methyl-thiophene-carboxylicacid chloride the title compound was
prepared as a yellow solid (74% yield), MS: m/e=310 (M.sup.+).
EXAMPLE 6
N-(4,6-Difluoro-benzothiazol-2-yl)-benzamide
[0377] Using 2-amino-4,6-difluoro-benzothiazole and benzoyl
chloride the title compound was prepared as a beige solid (82%
yield), MS: m/e=290 (M.sup.+).
EXAMPLE 7
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-acetamide
[0378] Using acetyl chloride the title compound was prepared as a
light brown solid (69% yield), MS: m/e=299.2 (M+H.sup.+).
EXAMPLE 8
4-Cyano-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0379] Using 4-cyano-benzoyl chloride the title compound was
prepared as yellow solid (84% yield), MS: m/e=385.1 (M.sup.+).
EXAMPLE 9
5-Methyl-thiophene-2-carboxylic acid
(4-methoxy-benzothiazol-2-yl)-amide
[0380] Using 2-amino-4-methoxy-benzothiazole and
5-methyl-thiophene-2-carboxylic acid chloride in pyridine the title
compound was obtained as a beige solid (95% yield), MS: m/e=304.1
(M.sup.+).
EXAMPLE 10
5-Methyl-furan-2-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide
[0381] Using 2-amino-4-methoxy-7-phenyl-benzothiazole and freshly
prepared 5-methyl-furan-2-carboxylic acid chloride the title
compound was obtained crude, which was chromatographed over
SiO.sub.2 (Merck 230-400 mesh) eluting with nHexane/EtOAc (4:1), to
afford the pure title compound as a pale yellow solid (67% yield),
MS: m/e=364.0 (M.sup.+).
EXAMPLE 11
Furan-2-carboxylic acid (4-methoxy-benzothiazol-2-yl)-amide
[0382] Using 2-amino-4-methoxy-benzothiazole and furan-2-carboxylic
acid chloride in pyridine the title compound was obtained as a tan
solid (100% yield), MS: m/e=274.1 (M.sup.+).
EXAMPLE 12
N-(4-Methoxy-benzothiazol-2-yl)-benzamide
[0383] Using 2-amino-4-methoxy-benzothiazole and benzoyl chloride
in pyridine the title compound was obtained as a white solid (72%
yield), MS: m/e=284.1 (M.sup.+).
EXAMPLE 13
Benzo[b]thiophene-2-carboxylic acid benzothiazol-2-ylamide
[0384] Using 2-amino-benzothiazole and
benzo[b]thiophene-2-carboxylic acid chloride in pyridine the title
compound was obtained as a light yellow solid (86% yield), MS:
m/e=311.1 (M+H.sup.+).
EXAMPLE 14
3-Methyl-thiophene-2-carboxylic acid benzothiazol-2-ylamide
[0385] Using 2-amino-benzothiazole and
3-methyl-thiophene-2-carboxylic acid chloride in pyridine the title
compound was obtained as a yellow solid (69% yield), MS: m/e=275.1
(M+H.sup.+).
EXAMPLE 15
5-Methyl-thiophene-2-carboxylic acid benzothiazol-2-ylamide
[0386] Using 2-amino-benzothiazole and
5-methyl-thiophene-2-carboxylic acid chloride in pyridine the title
compound was obtained as a yellow solid (87% yield), MS: m/e=275.1
(M+H.sup.+).
EXAMPLE 16
N-Benzothiazol-2-yl-6-chloro-nicotinamide
[0387] Using 2-amino-benzothiazole and
2-chloropyridine-5-carboxylic acid chloride in pyridine the title
compound was obtained as a white solid (97% yield), MS: m/e=290.1
(M+H.sup.+).
EXAMPLE 17
4-Hydroxymethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0388] To a solution of
4-formyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide (194
mg, 0.5 mmol), in THF (40 ml) was added sodium borohydride (19 mg,
0.5 mmol) and the mixture stirred for 2 h at r.t. Water was added
(30 ml) followed by 1N HCl (4 ml) and the mixture agitated. The
aqueous phase was then extracted twice with EtOAc (30 ml), the
combined organic phases were then washed with saturated NaCl
solution, dried with Na.sub.2SO.sub.4 filtered and evaporated. The
crude residue was suspended in ether and ultrasonicated for 10
min., the solid precipitate was filtered off, washed with ether
then dried under vacuum (0.05 mmHg, 50.degree. C.) to afford the
title compound as a light yellow solid (150 mg, 77% yield), MS:
m/e=390.0 (M).
EXAMPLE 18
4-Formyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0389] Using 4-formyl benzoic acid the title compound was obtained
as a light yellow solid (73% yield), MS: m/e=388.1 (M+H.sup.+).
EXAMPLE 19
2-Methoxy-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0390] To a solution of 2-amino-4-methoxy-7-phenyl-benzothiazole
(200 mg, 0.67 mmol) in THF (10 m) was added DMAP (10 mg, 0.08
mmol), triethylamine (163 .quadrature.l, 1.17 mmol) and
2-methoxybenzoyl chloride (136 .mu.l, 1 mmol) in THF (2 ml). The
mixture was then heated to reflux for 2 h, after cooling, it was
partitioned between 1:1 AcOEt/THF (70 ml) and 5% NaHCO.sub.3
solution (40 ml). The organic phase was washed with saturated NaCl
solution (50 ml), dried with Na.sub.2SO.sub.4, filtered and the
solvent removed under reduced pressure. The residue was suspended
in ether (10 ml), filtered, washed with ether then dried under
vacuum (0.05 mmHg, 60.degree. C.), to afford the title compound was
a white solid (260 mg, 85% yield), MS: m/e=390.0 (M).
EXAMPLE 20
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-2-methyl-benzamide
[0391] Using 2-methyl-benzoyl chloride the title compound was
obtained crude, which was chromatographed over SiO.sub.2 (Merck
230-400 mesh) eluting with CH.sub.2Cl.sub.2/EtOAc (1:1), to afford
the pure title compound as a white solid, (88% yield), MS:
m/e=374.1 (M.sup.+).
EXAMPLE 21
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-3-methyl-benzamide
[0392] Using 3-methyl-benzoyl chloride the title compound was
obtained crude, which was chromatographed over SiO.sub.2 (Merck
230-400 mesh) eluting with CH.sub.2Cl.sub.2/EtOAc (1:1), to afford
the pure title compound as a light yellow solid, (80% yield), MS:
m/e=374.0 (M.sup.+).
EXAMPLE 22
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-methyl-benzamide
[0393] Using 4-methyl-benzoyl chloride the title compound was
obtained crude, which was chromatographed over SiO.sub.2 (Merck
230-400 mesh) eluting with CH.sub.2Cl.sub.2/EtOAc (1:1), to afford
the pure title compound as a white solid, (79% yield), MS:
m/e=374.1 (M.sup.+).
EXAMPLE 23
4-Fluoro-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0394] Using 4-fluoro-benzoyl chloride the title compound was
obtained crude, which was chromatographed over SiO.sub.2 (Merck
230-400 mesh) eluting with CH.sub.2Cl.sub.2/EtOAc (1:1), to afford
the pure title compound as a white solid (68% yield), MS: m/e=378.0
(M.sup.+).
EXAMPLE 24
3-Methoxy-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0395] Using 3-methoxy-benzoyl chloride the title compound was
obtained crude, which was chromatographed over SiO.sub.2 (Merck
230-400 mesh) eluting with CH.sub.2Cl.sub.2/EtOAc (1:1), to afford
the pure title compound as a light yellow foam (75% yield), MS:
m/e=390.0 (M.sup.+).
EXAMPLE 25
4-Methoxy-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0396] Using 4-methoxy-benzoyl chloride the title compound was
obtained crude, which was chromatographed over SiO.sub.2 (Merck
230-400 mesh) eluting with CH.sub.2Cl.sub.2/EtOAc (1:1), to afford
the pure title compound as a white foam (79% yield), MS: m/e=390.1
(M.sup.+).
EXAMPLE 26
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-2-phenyl-acetamide
[0397] Using phenylacetyl-chloride chloride the title compound was
obtained crude, which was chromatographed over SiO.sub.2 (Merck
230-400 mesh) eluting with CH.sub.2Cl.sub.2/EtOAc (1:1), to afford
the pure title compound as a white solid (29% yield), MS: m/e=374.1
(M.sup.+).
EXAMPLE 27
3-Methyl-thiophene-2-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide
[0398] Using 3-methyl-thiophene-2-carboxylicacid chloride the title
compound was obtained crude, which was chromatographed over
SiO.sub.2 (Merck 230-400 mesh) eluting with CH.sub.2Cl.sub.2/EtOAc
(1:1), to afford the pure title compound as a white solid (64%
yield), MS: m/e=380.0 (M.sup.+).
EXAMPLE 28
2,5-Dimethyl-furan-3-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide
[0399] Using 2,5-dimethyl-furan-3-carboxylicacid chloride the title
compound was obtained crude, which was chromatographed over
SiO.sub.2 (Merck 230-400 mesh) eluting with CH.sub.2Cl.sub.2/EtOAc
(1:1), to afford the pure title compound as a white solid (73%
yield), MS: m/e=378.1 (M.sup.+).
EXAMPLE 29
3-Cyano-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0400] Using 3-cyano-benzoyl chloride the title compound was
obtained crude, which was chromatographed over SiO.sub.2 (Merck
230-400 mesh) eluting with CH.sub.2Cl.sub.2/EtOAc (1:1), to afford
the pure title compound as a white solid (80% yield), MS: m/e=385.0
(M.sup.+).
EXAMPLE 30
N-(4-Methoxy-7-phenoxy-benzothiazol-2-yl)-benzamide
[0401] Using 4-Methoxy-7-phenoxy-benzothiazol-2-ylamine and benzoyl
chloride the title compound was obtained crude, which was
chromatographed over SiO.sub.2 (Merck 230-400 mesh) eluting with
CH.sub.2Cl.sub.2/EtOAc (1:1), to afford the pure title compound as
a white solid (72% yield), MS: m/e=376.1 (M.sup.+).
EXAMPLE 31
4-Dimethylamino-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0402] Using 4-dimethylamino-benzoyl chloride in pyridine the title
compound was obtained crude, which was chromatographed over
SiO.sub.2 (Merck 230-400 mesh) eluting with CH.sub.2Cl.sub.2/(2N
NH.sub.3 in MeOH) (19:1), to afford the pure title compound as a
beige solid (70% yield), MS: m/e=403.0 (M.sup.+).
EXAMPLE 32
4-Fluoro-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-N-methyl-benzamide
[0403] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-methyl-amine
and 4-fluoro-benzoyl chloride in pyridine the title compound was
obtained crude, which was chromatographed over SiO.sub.2 (Merck
230-400 mesh) eluting with CH.sub.2Cl.sub.2/EtOAc (1:1), to afford
the pure title compound as a beige solid (88% yield), MS: m/e=393.2
(M+H.sup.+).
EXAMPLE 33
2-(4-Fluoro-benzoylamino)-4-methoxy-benzothiazole-7-carboxylic acid
methyl ester
[0404] Using 2-amino-4-methoxy-benzothiazole-7-carboxylic acid
methyl ester and 4-fluoro-benzoyl chloride the title compound was
obtained as a white solid (91% yield), MS: m/e=361.1
(M+H.sup.+).
EXAMPLE 34
N-(7-tert-Butyl-4-methoxy-benzothiazol-2-yl)-4-fluoro-benzamide
[0405] Using 7-tert-butyl-4-methoxy-benzothiazol-2-ylamine and
4-fluoro-benzoyl chloride the title compound was obtained as a
white solid (75% yield), MS: m/e=258.1 (M+H.sup.+).
EXAMPLE 35
N-(7-Acetylamino-4-methoxy-benzothiazol-2-yl)-4-fluoro-benzamide
[0406] Using 7-acetylamino-4-methoxy-benzothiazol-2-ylamine and
4-fluoro-benzoyl chloride the title compound was obtained as a tan
solid (25% yield), MS: m/e=359.1 (M+H.sup.+).
EXAMPLE 36
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-isonicotinamide
[0407] Using pyridine-4-carboxylic acid chloride hydrochloride salt
in pyridine the title compound was obtained crude. After cooling a
solid precipitated from the reaction mixture which was further
triturated with ether (10 ml) then collected on a glass sinter and
further washed with ether (10 ml). The filter cake was then washed
sequentially with 10% Na.sub.2CO.sub.3 (20 ml), water (20 ml)
followed by ether (20 ml) and the resulting product dried under
vacuum (0.05 mmHg, 60.degree. C.) to afford the pure title compound
as a yellow solid (188 mg, 67% yield), MS: m/e=361.0 (M.sup.+).
EXAMPLE 37
4-Fluoro-N-(4-methoxy-7-phenoxy-benzothiazol-2-yl)-benzamide
[0408] Using 4-methoxy-7-phenoxy-benzothiazol-2-ylamine and
4-fluoro-benzoyl chloride the title compound was obtained crude,
which was chromatographed over SiO.sub.2 (Merck 230-400 mesh)
eluting with CH.sub.2Cl.sub.2/EtOAc (1:1), to afford the pure title
compound as a white solid (75% yield), MS: m/e=394.1 (M.sup.+).
EXAMPLE 38
5-Methyl-thiophene-2-carboxylic acid
(4-methoxy-7-phenoxy-benzothiazol-2-yl)-amide
[0409] Using 4-methoxy-7-phenoxy-benzothiazol-2-ylamine and
5-methyl-thiophene-2-carboxylic acid chloride the title compound
was obtained crude, which was chromatographed over SiO.sub.2 (Merck
230-400 mesh) eluting with CH.sub.2Cl.sub.2/EtOAc (1:1), to afford
the pure title compound as a pale yellow solid (76% yield), MS:
m/e=396.0 (M.sup.+).
EXAMPLE 39
4-Fluoro-N-(4-methoxy-7-morpholin-4-ylmethyl-benzothiazol-2-yl)-benzamide
[0410] Using
4-methoxy-7-morpholin-4-ylmethyl-benzothiazol-2-ylamine and
4-fluoro-benzoyl chloride in pyridine the title compound was
obtained as a yellow solid (44% yield), MS: m/e=402.4
(M+H.sup.+).
EXAMPLE 40
5-Methyl-thiophene-2-carboxylic acid
(4-methoxy-7-morpholin-4-ylmethyl-benzothiazol-2-yl)-amide
[0411] Using
4-methoxy-7-morpholin-4-ylmethyl-benzothiazol-2-ylamine and
5-methyl-thiophene-2-carboxylic acid chloride in pyridine the title
compound was obtained as a yellow solid (53% yield), MS: m/e=404.4
(M+H.sup.+).
EXAMPLE 41
4-Fluoro-N-[4-methoxy-7-(1H-tetrazol-5-yl)-benzothiazol-2-yl]-benzamide
[0412] Using 4-methoxy-7-(1H-tetrazol-5-yl)-benzothiazol-2-ylamine
and 4-fluoro-benzoyl chloride in pyridine the title compound was
obtained as a tan solid (70% yield), MS: m/e=371.2 (M+H.sup.+).
EXAMPLE 42
N-Benzothiazol-2-yl-benzamide
[0413] Using 2-amino-benzothiazole and benzoyl chloride in pyridine
the title compound was obtained as a white solid (87% yield), MS:
m/e=255.1 (M+H.sup.+).
EXAMPLE 43
Furan-2-carboxylic acid benzothiazol-2-ylamide
[0414] Using 2-amino-benzothiazole and furan-2-carboxylic acid
chloride in pyridine the title compound was obtained as a white
solid (83% yield), MS: m/e=244 (M.sup.+).
EXAMPLE 44
2-Chloro-N-(4-methyl-2-benzothiazolyl)-nicotinamide
[0415] Using 4-methyl-benzothiazol-2-ylamine and 2-chloronicotinic
acid chloride the title compound was obtained as a yellow solid
(50% yield), MS: m/e=304 (M+H.sup.+).
EXAMPLE 45
2-chloro-N-(4-methoxy-2-benzothiazolyl-nicotinamide
[0416] Using 4-methoxy-benzothiazol-2-ylamine and 2-chloronicotinic
acid chloride the title compound was obtained as a off-white solid
(50% yield). MS: m/e=320 (M+H.sup.+).
EXAMPLE 46
3-(4-Methoxy-benzothiazol-2-ylcarbamoyl)-acrylic acid ethyl
ester
[0417] Using 4-methoxy-benzothiazol-2-ylamine and
3-chlorocarbonyl-acrylic acid methyl ester the title compound was
obtained as a off-white solid (50% yield). MS: m/e=307
(M.sup.+).
EXAMPLE 47
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-oxalamic acid ethyl
ester
[0418] The title compound is described in the following patent
literature and was prepared according to the procedure described
therein. N-(Benzothiazol-2-yl)oxamic acid derivatives. W. Winter,
M. Thiel, A. Roesch and O. H. Wilhelms, German Patent, DE 2656468,
1978. Mp. 138-142.degree. C., MS: m/e=357 (M+H.sup.+).
EXAMPLE 48
4-Dimethylamino-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0419] Using pyridine-2-carboxylic acid, chloride hydrochloride
salt in pyridine the title compound was obtained crude. This
compound was purified further with preparative reversed phase HPLC
using a Nucleosil N-protected column (20 mm.times.50 mm) and
eluting with a gradient of MeCN/water (0.1% TFA), The product
fractions were pooled, evaporated and the residue partitioned
between EtOAc (30 ml) and 10% Na.sub.2CO.sub.3 (30 ml) and the
aqueous phase extracted once with EtOAc (30 ml) The combined
organic phases were then washed with saturated NaCl, dried,
filtered and evaporated to afford the pure title compound as a
beige solid (110 mg, 39% yield), MS: m/e=361.1 (M.sup.+).
EXAMPLE 49
4-Fluoro-N-(7-hydroxymethyl-4-methoxy-benzothiazol-2-yl)benzamide
[0420] To a solution of
2-(4-fluoro-benzoylamino)-4-methoxy-benzothiazole-7-carboxylic acid
methyl ester (1.1 g, 3.05 mmol) in THF (250 ml) uner argon at
5.degree. C. was added a solution of 1N LiAlH.sub.4 in THF (2 ml, 2
mmol) over 5 min., the mixture was stirred for 1 h at 5.degree. C.,
then over 1 h allowed to warm to 20.degree. C. A further 3.5 ml of
1N LiAlH.sub.4/THF was then added dropwise and the mixture stirred
a further 2 h at 20.degree. C. A solution of 5 ml THF/Water (4:1)
was then added cautiously followed by 4N NaOH (2 ml), then water (2
ml) and the mixture stirred vigorously for 15 min. Excess
Na.sub.2SO.sub.4 (50 g) was then added with vigorous stirring, then
the solution was filtered and the solvent evaporated to afford the
title compound as a white solid (0.9 g, 89% yield), MS: m/e=333.2
(M+H.sup.+).
EXAMPLE 50
4-Dipropylsulfamoyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0421] To a suspension of 4-dipropylsulfamoyl-benzoic acid (185 mg,
0.65 mmol) in toluene (10 ml) was added thionylchloride (600 mg, 5
mmol) and the mixture heated to 80.degree. C. for 17 h. After
cooling the solvent was evaporated and the residue was taken up in
THF (20 ml), 2-amino-4-methoxy-7-phenyl-benzothiazole (128 mg, 0.5
mmol), triethylamine (105 .mu.l, 0.75 mmol), and DMAP (6 mg, 0.05
mmol) were then added and the mixture was stirred for 1 hour at
r.t. followed by 1 hour at 60.degree. C. After cooling to r.t. the
reaction mixture was quenched by addition of 10% aq.
Na.sub.2CO.sub.3 solution (30 ml) and EtOAc (30 ml) and vigorous
stirring. After separation of the phases the aqueous phase was
extracted with EtOAc (30 ml) and the combined organic phases were
washed with 10% aq. Na.sub.2CO.sub.3, dried with Na.sub.2SO.sub.4,
filtered and evaporated. The residue was then chromatographed over
SiO.sub.2 (Merck 230-400 mesh) eluting with a gradient of
cyclohexane/EtOAc from (1:4) to 100% EtOAc. After pooling and
evaporation of the product fractions the title compound was
obtained as a white solid (240 mg, 92% yield), MS: m/e=524.2
(M+H.sup.+).
Following the General Method of Example 50 the Compounds of
Examples 51 to 53 Were Prepared
EXAMPLE 51
4-Diethylsulfamoyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0422] Using 4-diethylsulfamoyl-benzoic acid the title compound was
obtained as a light yellow solid (81% yield), MS: m/e=496.2
(M+H.sup.+).
EXAMPLE 52
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-(morpholine-4-sulfonyl-benzamid-
e
[0423] Using 4-(morpholine-4-sulfonyl)-benzoic acid the title
compound was obtained as white amorphous solid (32% yield), MS:
m/e=510.3 (M+H.sup.+).
EXAMPLE 53
4-Ethylsulfamoyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0424] Using 4-ethylsulfamoyl-benzoic acid the title compound was
obtained as pale yellow amorphous solid (20% yield), MS: m/e=466.2
(M-H).sup.-.
EXAMPLE 54
5-Methyl-thiophene-2-carboxylic acid
(7-iodo-4-methoxy-benzothiazol-2-yl)-amide
[0425] Iodination of 5-methyl-thiophene-2-carboxylic acid
(4-methoxy-benzothiazol-2-yl)-amide (5.17 g, 17 mmol) with iodine
monochloride (2.26 ml, 44 mmol), sodium acetate (3.63 g, 44 mmol)
and acetic acid (200 ml) in the same manner as described for
(4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester affords
the product as off-white solid in 93% yield. MS: m/e=430
(M.sup.+).
[0426] (7-Aryl-4-methoxy-benzothiazol-2-yl)-carbamic acid ester,
aryl-carboxylic acid (7-aryl-4-methoxy-benzothiazol-2-yl)-amides
and substituted (4-methoxy-7-aryl-benzothiazol-2-yl)-ureas:
[0427] General procedure A:
(7-Iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid ester or the
respective aryl-carboxylic acid
(7-iodo-4-methoxy-benzothiazol-2-yl)-amide or the respective
(4-methoxy-7-aryl-benzothiazol-2-yl)-urea (1 part), the appropriate
boronic acid (or its ester) (1.5 equivalents), palladium(II)
acetate (0.05 equivalents), potassium phosphate (2.5 equivalents)
and 2-biphenyl-dicyclohexyl phosphine (0.1 equivalents) are
combined in toluene (20 parts) and heated in an atmosphere of argon
to 65.degree. C. for 12 hours. The reaction mixture is evaporated
to dryness and the product isolated by flash chromatography
(silica, eluent ethyl acetate/cyclohexane 2:1).
[0428] General procedure B:
(7-Iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid ester or the
respective aryl-carboxylic acid
(7-iodo-4-methoxy-benzothiazol-2-yl)-amide amide or the respective
(4-methoxy-7-aryl-benzothiazol-2-yl)-urea (1 part), the appropriate
aryltrimethylstannane (1.5 equivalents), triphenylarsine (0.5
equivalents), tris-(dibenzylideneacetone)-dipalladium(0) (0.8
equivalents) and copper(I) iodide (0.8 equivalents) are combined in
dimethylformamide (25 parts) and heated to 80.degree. C. for 12
hours. The reaction mixture is evaporated to dryness and the
product isolated by flash chromatography (silica, eluent ethyl
acetate).
Following the General Method the Compounds of Examples 55 to 62
Were Prepared
EXAMPLE 55
5-Methyl-thiophene-2-carboxylic acid
[7-(2-chloro-phenyl)-4-methoxy-benzothiazol-2-yl]-amide
[0429] 5-Methyl-thiophene-2-carboxylic acid
[7-(2-chloro-phenyl)-4-methoxy-benzothiazol-2-yl]-amide is
synthesized from 5-methyl-thiophene-2-carboxylic acid
(7-iodo-4-methoxy-benzothiazol-2-yl)-amide (100 mg, 0.23 mmol) and
2-chlorophenylboronic acid (54 mg, 0.35 mmol) using the general
procedure A as a light yellow solid in 80% yield. MS: m/e=415
(M+H.sup.+).
EXAMPLE 56
5-Methyl-thiophene-2-carboxylic acid
[4-methoxy-7-(3-nitro-phenyl)-benzothiazol-2-yl]-amide
[0430] 5-Methyl-thiophene-2-carboxylic acid
[7-(3-nitro-phenyl)-4-methoxy-benzothiazol-2-yl]-amide is
synthesized from 5-methyl-thiophene-2-carboxylic acid
(7-iodo-4-methoxy-benzothiazol-2-yl)-amide (155 mg, 0.36 mmol) and
3-nitrophenylboronic acid (135 mg, 0.81 mmol) using the general
procedure A as a light yellow crystals in 42% yield. MS:
m/e=425
EXAMPLE 57
5-Methyl-thiophene-2-carboxylic acid
[7-(3-dimethylamino-phenyl)-4-methoxy-benzothiazol-2-yl]-amide
[0431] 5-Methyl-thiophene-2-carboxylic acid
[7-(3-dimethylamino-phenyl)-4-methoxy-benzothiazol-2-yl]-amide is
synthesized from 5-methyl-thiophene-2-carboxylic acid
(7-iodo-4-methoxy-benzothiazol-2-yl)-amide (100 mg, 0.23 mmol) and
3-dimethylaminophenylboronic acid (58 mg, 0.35 mmol) using the
general procedure A as a light yellow solid in 71% yield. MS:
m/e=424 (M+H.sup.+).
EXAMPLE 58
5-Methyl-thiophene-2-carboxylic acid
(4-methoxy-7-pyridin-4-yl-benzothiazol-2-yl)-amide
[0432] 5-Methyl-thiophene-2-carboxylic acid
(4-methoxy-7-pyridin-4-yl-benzothiazol-2-yl)-amide is synthesized
from 5-methyl-thiophene-2-carboxylic acid
(7-bromo-4-methoxybenzothiazol-2-yl)-amide (192 mg, 0.50 mmol) and
4-pyridylboronic acid (92 mg, 0.75 mmol) using the general
procedure A as a white solid in 6% yield. MS: m/e=381
(M.sup.+).
EXAMPLE 59
5-Methyl-thiophene-2-carboxylic acid
(4-methoxy-7-pyridin-3-yl-benzothiazol-2-yl)-amide
[0433] 5-Methyl-thiophene-2-carboxylic acid
(4-methoxy-7-pyridin-3-yl-benzothiazol-2-yl)-amide is synthesized
from 5-methyl-thiophene-2-carboxylic acid
(7-bromo-4-methoxy-benzothiazol-2-yl)-amide (192 mg, 0.50 mmol) and
4-pyridylboronic acid (123 mg, 1.0 mmol) using the general
procedure A as a white solid in 8% yield. MS: m/e=381
(M.sup.+).
EXAMPLE 60
5-Methyl-thiophene-2-carboxylic acid
(4-methoxy-7-pyridin-2-yl-benzothiazol-2-yl)-amide
[0434] 65-Methyl-thiophene-2-carboxylic acid
(4-methoxy-7-pyridin-2-yl-benzothiazol-2-yl)-amide is synthesized
from 5-methyl-thiophene-2-carboxylic acid
(7-iodo-4-methoxy-benzothiazol-2-yl)-amide (100 mg, 0.23 mmol) and
2-tri-n-butylstannane (130 mg, 0.35 mmol) using the general
procedure B as a white solid in 23% yield. MS: m/e=382
(M+H.sup.+).
EXAMPLE 61
5-Methyl-thiophene-2-carboxylic acid
[4-methoxy-7-(2-methyl-pyridin-4-yl)-benzothiazol-2-yl]-amide
[0435] 5-Methyl-thiophene-2-carboxylic acid
[4-methoxy-7-(2-methyl-pyridin-4-yl)-benzothiazol-2-yl]-amide is
synthesized from 5-methyl-thiophene-2-carboxylic acid
(4-methoxy-7-iodo-benzothiazol-2-yl)-amide (260 mg, 0.60 mmol) and
2-methyl-4-trimethylstannanyl-pyridine (384 mg, 0.90 mmol) using
the general procedure B as a light yellow solid in 50% yield. MS:
m/e=396 (M+H.sup.+).
EXAMPLE 62
5-Methyl-thiophene-2-carboxylic acid
[7-(3-amino-phenyl)-4-methoxy-benzothiazol-2-yl]-amide
[0436] 5-Methyl-thiophene-2-carboxylic acid
[7-(3-amino-phenyl)-4-methoxy-benzothiazol-2-yl]-amide is
synthesized from 5-methyl-thiophene-2-carboxylic acid
(4-methoxy-7-iodo-benzothiazol-2-yl)-amide (300 mg, 0.70 mmol) and
3-trimethylstannanyl-phenylamine (291 mg, 1.14 mmol) using the
general procedure B as a light brown solid in 56% yield. MS:
m/e=396 (M+H.sup.+).
EXAMPLE 63
5-Methyl-thiophene-2-carboxylic acid
(4-hydroxy-7-phenyl-benzothiazol-2-yl)-amide
[0437] A solution of 5-methyl-thiophene-2-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide (630 mg, 1.7 mmol) is
slowly trated with boron tribromide (16 ml, 1.0 M in
dichloromethane) at 0.degree. C. The reaction is slowly warmed to
ambient temperature and stirred for further 72 h. The mixture is
diluted with ethyl acetate and extracted twice with water and once
with brine. After drying over sodium sulfate, the solvent is
removed in vacuo. Flash chromatography (silica, eluent ethyl
acetate/hexane 1:1) and final recrystallization from
tetrahydrofurane/hexane yields 118 mg (19%) of the product as white
solid. MS: m/e=367 (M+H.sup.+).
EXAMPLE 64
4-{4-Methoxy-2-[(5-methyl-thiophene-2-carbonyl)-amino]-benzothiazol-7-yl}--
piperazine-1-carboxylic acid benzyl ester
[0438] The title compound was synthesized starting from
N-benzyloxycarbonylpiperazine and 4-bromo-2-nitroanisole as
described for 5-methyl-thiophene-2-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide and obtained
as a white solid in 12% overall yield, MS: m/e=523 (M+H.sup.+).
EXAMPLE 65
5-Methyl-thiophene-2-carboxylic acid
[7-(3-dimethylamino-pyrrolidin-1-yl)-4-methoxy-benzothiazol-2-yl]-amide
[0439] The title compound is synthesized starting from
3-(dimethylamino)pyrrolidine and 4-bromo-2-nitroanisole as
described for 5-methyl-thiophene-2-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide and was
obtained as yellow solid in 10% overall yield, MS: m/e=417
(M+H.sup.+).
EXAMPLE 66
5-Methyl-thiophene-2-carboxylic acid
(5-methoxy-7-phenyl-benzothiazol-2-yl)-amide
[0440] 2-Amino-5-methoxy-7-phenylbenzothiazol (45 mg, 0.18 mmol) is
dissolved in dichloromethane (2 ml) and subsequently treated with
triethylamine (0.073 ml, 0.53 mmol) and
5-methyl-thiophene-2-carbonyl chloride (56 mg, 0.35 mmol). After 6
h, further 0.073 ml, 0.53 mmol) and 5-methyl-thiophene-2-carbonyl
chloride (56 mg, 0.35 mmol) are added and the mixture is stirred
for additional 18 h at ambient. After addition of 0.1M aqueous
sodium hydroxide, the mixture is stirred for additional 16 h. The
organic layer is separated, dried and evaporated to dryness. Flash
chromatography (silica, eluent ethyl acetate/cyclohexane 1:1,
containing 0.5% of 25% aqueous ammonia) affords (10 mg, 5%) of the
product as white solid. MS: m/e=380 (M.sup.+).
EXAMPLE 67
5-Methyl-thiophene-2-carboxylic acid
(4,5-dimethoxy-benzothiazol-2-yl)-amide
[0441] 2-Amino-4,5-dimethoxybanzothiazole (1.1 g, 5.3 mmol) and
N,N-dimethylaminopyridine (47 mg, 0.37 mmol) are dissolved in
pyridine (17 ml) and slowly treated with
5-methyl-thiophene-2-carbonyl chloride (1.5 g, 9.0 mmol). After 48
h at ambient temperature, the solution is evaporated to dryness.
Flash chromatography (silica, eluent diethyl ether/cyclohexane 2:1)
affords the product (618 mg, 35%) as light yellow solid.
EXAMPLE 68
5-Methyl-thiophene-2-carboxylic acid
(4-chloro-benzothiazol-2-yl)-amide
[0442] 2-Amino-4-chlorobenzothiazol (92 mg, 0.50 mmol) is dissolved
in dichloromethane (10 ml) and treated with pyridine (0.060 ml,
0.75 mmol) and 5-methyl-thiophene-2-carbonyl chloride (97 mg, 0.60
mmol). The reaction mixture is stirred at ambient temperature for
18 h and then evaporated to dryness. The residue is redissolved in
ethyl acetate and water, the phases are separated and the organic
layer extracted with brine. After drying with sodium sulfate, the
solvent is removed in vacuo Flash chromatography on silica (eluent
ethyl acetate/cyclohexane 1:4 affords the product as white solid.
(88 mg, 57%). MS: m/e=308 (M.sup.+).
EXAMPLE 69
5-Methyl-thiophene-2-carboxylic acid
(7-bromo-4-methoxy-benzothiazol-2-yl)-amide
[0443] 2-Amino-7-bromo-4-methoxybenzothiazol (2.33 g, 9 mmol) is
dissolved in dichloromethane (100 ml) and at 0.degree. C. treated
with pyridine (2.2 ml, 27 mmol) and 5-methyl-thiophene-2-carbonyl
chloride (2.2 g, 13.5 mmol). The reaction mixture is allowed to
warm to room temperature and after stirring for additional 18 h
quenched with water (100 ml). After separation of the phases, the
aqueous phases are extracted twice with ethyl acetate. The combined
organic layers are then washed with brine, dried and avaporated to
dryness. Flash chromatography on silica (eluent ethyl
acetate/cyclohexane 1:1 to 4:1) and final recrystallization from
ethyl acetate affords the product as off-white solid. (34 mg, 69%).
MS: m/e=384 (M.sup.+).
EXAMPLE 70
5-Methyl-thiophene-2-carboxylic acid
(4-fluoro-benzothiazol-2-yl)-amide
[0444] 2-Amino-4-fluorobenzothiazol (84 mg, 0.50 mmol) is dissolved
in pyridine (3 ml) and treated with 4-dimethylaminopyridine (1 mg)
and 5-methyl-thiophene-2-carbonyl chloride (161 mg, 1.0 mmol).
After stirring for 1 h at ambient temperature, the reaction mixture
was evaporated to dryness. Flash chromatography on silica (eluent
diethyl ether/cyclohexane 1:1 containing 0.5% of 25% aqueous
ammonia) and final recrystallization from ethyl acetate affords the
product as off-white solid. (34 mg, 69%). MS: m/e=292
(M.sup.+).
EXAMPLE 71
5-Methyl-thiophene-2-carboxylic acid
(4-trifluoromethoxy-benzothiazol-2-yl)-amide
[0445] 2-amino-4-trifluoromethoxybenzothiazol (70 mg, 0.30 mmol) is
dissolved in pyridine (3 ml) and treated with
4-dimethylaminopyridine (1 mg) and 5-methyl-thiophene-2-carbonyl
chloride (96 mg, 0.60 mmol). After stirring for 4 h at ambient
temperature, the reaction mixture was evaporated to dryness. Flash
chromatography on silica (eluent ethyl acetate/cyclohexane 1:2)
affords the product as white solid. (42 mg, 39% yield). MS: m/e=358
(M.sup.+).
Following the General Method of Example 1, the Compounds of
Examples 72 to 75 Were Prepared
EXAMPLE 72
5-Methyl-thiophene-2-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0446] Using 5-methyl-thiophene-2-carbonyl chloride and
2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol the title compound
was obtained as a yellow solid in 97% yield. MS: m/e=390
(M+H.sup.+)
EXAMPLE 73
6-Hydroxy-pyridine-2-carboxylic acid
(4-methoxy-benzothiazol-2-yl)-amide
[0447] Using 2-Amino-4-methoxybenzothiazole (450 mg, 2.5 mmol) and
6-hydroxypicolinic acid chloride (1.5 g, 10 mmol) the title
compound was obtained as a beige powder in 5% yield. MS: m/e=301
(M.sup.+).
EXAMPLE 74
5-Methyl-thiophene-2-carboxylic acid
(7-benzyloxy-4-methoxy-benzothiazol-2-yl)-amide
[0448] Using 5-methyl-thiophene-2-carboxylic acid chloride the
title compound was obtained as an off-white solid (51% yield).
M.p.: 228-230.degree. C.
Following the General Method of Example 1, the Compound of Example
75 was Prepared
EXAMPLE 75
6-Chloro-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-nicotinamide
[0449] Using 6-chloro-nicotinyl chloride the title compound was
obtained as a light yellow amorphous solid (79% yield), MS:
m/e=395.1 (M.sup.+).
EXAMPLE 76
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-6-pyrrolidin-1-yl-nicotinamide
[0450] To a solution of
6-chloro-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-nicotinamide (297
mg, 0.75 mmol) in dioxane (10 ml) was added pyrrolidine (266 mg,
3.7 mmol, 5 eq.) and the mixture stirred at 100.degree. C. for 2 h.
After cooling the solvent was evaporated and the residue suspended
in methanol (20 ml) at r.t., the solid was then filtered, washed
with methanol and finally dried under vacuum (0.05 mmHg, 60.degree.
C.) to obtain the title compound as a white solid (230 mg, 71%
yield), MS: m/e=431.4 (M+H.sup.+).
Following the General Method of Example 76, the Compounds of
Examples 77 to 80 Were Prepared
EXAMPLE 77
3,4,5,6-Tetrahydro-2H-[1,2']bipyridinyl-5'-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide
[0451] Using piperidine the title compound was obtained as a light
brown solid (59% yield), MS: m/e=445.3 (M+H.sup.+).
EXAMPLE 78
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-6-morpholin-4-yl)-nicotinamide
[0452] Using morpholine the title compound was obtained as a white
solid (82% yield), MS: m/e=447.2 (M+H.sup.+).
EXAMPLE 79
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-6-(4-methyl-piperazin-1-yl)-nicot-
inamide
[0453] Using N-methylpiperazine the title compound was obtained as
a light brown solid (52% yield), MS: m/e=460.4 (M+H.sup.+).
EXAMPLE 80
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-6-thiomorpholin-4-yl-nicotinamide
hydrochloride salt (1:1)
[0454] Using thiomorpholine the free base of the title compound was
obtained, which was then converted to the hydrochloride salt by
addition of 5N HCl/EtOH, affording the title compound as a white
solid (78% yield), MS: m/e=463.1 (M+H.sup.+).
EXAMPLE 81
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-6-(1-oxo-1l
4-thiomorpholin-4-yl)-nicotinamide hydrochloride salt (1:1)
[0455] To a solution of
N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-6-thiomorpholin-4-yl-nicotinamid-
e hydrochloride salt (250 mg, 0.54 mmol) in chloroform (12 ml) was
added 3-phenyl-2-(phenylsulfonyl)oxaziridine (211 mg, 0.81 mmol)
and the mixture stirred at r.t. for 2 hr. After evaporation of the
solvent, the residue was suspended in CH.sub.2Cl.sub.2,
ultrasonicated, then the precipitate was filtered off, washed with
CH.sub.2Cl.sub.2, followed by ether and finally dried under vacuum
(0.05 mmHg, 60.degree. C.) to obtain the title compound as a light
yellow solid (240 mg., 86% yield), MS: m/e=479.2 (M+H.sup.+).
EXAMPLE 82
4-Bromomethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
[0456] To a solution of 4-bromomethyl-benzoic acid (5.45 g, 25.3
mmol) in toluene (60 ml) was added thionyl chloride (18.25 ml, 25.3
mmol) and the mixture stirred at 80.degree. C. for 16 h. The
toluene and excess thionyl chloride were then evaporated in vacuo
and replaced with THF (100 ml). To this solution was added
2-amino-4-methoxy-7-phenyl-benzothiazole (5 g, 19.5 mmol),
triethylamine (4.1 ml, 29.2 mmol) and DMAP (238 mg, 2 mmol) as
catalyst, then the mixture stirred at 65.degree. C. for 4 h. After
cooling the reaction mixture was partitioned between 10% aq.
Na.sub.2CO.sub.3 (200 ml) and EtOAc (100 ml), the aqueous phase was
extracted further with EtOAc/THF (1:1) (150 ml), then the combined
organic phases were washed with satd. aq. NaCl (100 ml), dried
(Na.sub.2SO.sub.4), filtered and evaporated in vacuo. The residue
was then chromatographed over SiO.sub.2 (Merck 230-400 mesh)
eluting with a gradient of CH.sub.2Cl.sub.2/EtOAc (100%
CH.sub.2Cl.sub.2 to 1:1), the product fractions were pooled and
evaporated in vacuo to affords the title compound as a pale yellow
solid (4.9 g, 55% yield), MS: m/e=452.0 (M.sup.+).
EXAMPLE 83
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-pyrrolidin-1-ylmethyl-benzamide
hydrochloride salt (1:1)
[0457] To a solution of
4-formyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide (300
mg, 0.77 mmol) in THF (60 ml) was added pyrrolidine (82 mg, 1.16
mmol), acetic acid (70 mg, 1.16 mmol) and NaBH(OAc).sub.3 (246 mg,
1.16 mmol). This mixture was stirred for 16 h at r.t., then 5%
NaHCO.sub.3 (30 ml) was added with vigorous stirring and the
mixture extracted twice with EtOAc (50 ml). The organic phases were
washed with saturates NaCl solution then dried, filtered and
evaporated to afford the crude product which was converted to its
hydrochloride salt and purified by reversed phase preparative HPLC
using a Nucleosil (Machery-Nagel) N-protected column (20.times.50
mm) and an MeCN/water (0.1% TFA) gradient. After pooling and
evaporation of the product fractions the title compound was
obtained as a white solid (217 mg, 59% yield), MS: m/e=444.4
(M+H.sup.+).
Following the General Method of Example 83, the Compounds of
Examples 84 to 89 Were Prepared
EXAMPLE 84
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-piperidin-1-ylmethyl-benzamide
hydrochloride salt (1:1)
[0458] Using piperidine the title compound was obtained as a light
yellow solid (78% yield), MS: m/e=458.4 (M+H.sup.+).
EXAMPLE 85
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-morpholin-4-ylmethyl-benzamide
hydrochloride salt (1:1)
[0459] Using morpholine the title compound was obtained as a light
yellow solid (23% yield), MS: m/e=460.5 (M+H.sup.+).
EXAMPLE 86
4-Diethylaminomethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
hydrochloride (1:1)
[0460] Using diethylamine the title compound was obtained as a
white solid (39% yield), MS: m/e=446.3 (M+H.sup.+).
EXAMPLE 87
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-[(methyl-pyridin-3-ylmethyl-ami-
no)-methyl]-benzamide hydrochloride salt (1:2)
[0461] Using 3-(methylaminomethyl)-pyridine the title compound was
obtained as a light yellow solid (15% yield), MS: m/e=495.2
(M+H.sup.+).
EXAMPLE 88
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-(4-methyl-piperazin-1-ylmethyl)-
-benzamide hydrochloride salt (1:2)
[0462] Using N-methyl-piperazine the title compound was obtained as
a white solid (21% yield), MS: m/e=473.3 (M+H.sup.+).
EXAMPLE 89
4-Dimethylaminomethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
hydrochloride salt (1:1)
[0463] Using dimethylamine hydrochloride the title compound was
obtained as a light yellow solid (21% yield), MS: m/e=418.3
(M+H.sup.+).
EXAMPLE 90
4-Ethylaminomethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
hydrochloride salt (1:1)
[0464] To a solution of
4-bromomethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
(300 mg, 0.66 mmol) in THF (2 ml) was added ethylamine (2N in THF)
(3 ml, 6.6 mmol) and the mixture stirred at 20.degree. C. for 18 h.
The reaction mixture was then evaporated to dryness and the residue
treated with an excess of 5N HCl/EtOH (3 ml), the ethanol was then
evaporated and the residue dissolved in DMSO and then subjected to
preparative reversed phase HPLC purification using a C18 ODS-AQ
column (20.times.50 mm), eluting with a gradient of MeCN/water
(0.1% TFA). The product fractions were pooled and evaporated to
afford the title compound as a light yellow solid (238 mg, 79%
yield), MS: m/e=418.3 (M+H.sup.+).
Following the General Method of example 90, the Compounds of
Examples 91 to 126 Were Prepared
EXAMPLE 91
4-[(2-Methoxy-ethylamino)-methyl]-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-
-benzamide hydrochloride salt (1:1)
[0465] Using 2-methoxyethylamine in dioxane at 90.degree. C. the
title compound was obtained as a light yellow solid (66% yield),
MS: m/e=448.3 (M+H.sup.+).
EXAMPLE 92
4-[(2-Hydroxy-ethylamino)-methyl]-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-
-benzamide hydrochloride salt (1:1)
[0466] Using ethanolamine in dioxane at 90.degree. C. the title
compound was obtained as a light yellow solid (68% yield), MS:
m/e=434.4 (M+H.sup.+).
EXAMPLE 93
4-(Benzylamino-methyl)-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
hydrochloride salt (1:1)
[0467] Using benzylamine in dioxane at 90.degree. C. the title
compound was obtained as a white solid (50% yield), MS: m/e=480.3
(M+H.sup.+).
EXAMPLE 94
4-[(Benzyl-methyl-amino)-methyl]-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)--
benzamide hydrochloride salt (1:1)
[0468] Using N-methyl-benzylamine in dioxane at 90.degree. C. the
title compound was obtained as a white solid (74% yield), MS:
m/e=494.3 (M+H.sup.+).
EXAMPLE 95
4-[(3-Imidazol-1-yl-propylamino)-methyl]-N-(4-methoxy-7-phenyl-benzothiazo-
l-2-yl)-benzamide hydrochloride salt (1:2)
[0469] Using 1-(3-aminopropyl)-imidazole in dioxane at 90.degree.
C. the title compound was obtained as a pale yellow solid (58%
yield), MS: m/e=498.2 (M+H.sup.+).
EXAMPLE 96
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-{[(pyridin-4-ylmethyl)-amino]-m-
ethyl}-benzamide hydrochloride salt (1:2)
[0470] Using 4-(aminomethyl)-pyridine in dioxane at 90.degree. C.
the title compound was obtained as a beige solid (33% yield), MS:
m/e=481.2 (M+H.sup.+).
EXAMPLE 97
4-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-phenyl-benzothi-
azol-2-yl)-benzamide hydrochloride salt (1:1)
[0471] Using N-(2-methoxyethyl)-methylamine in dioxane at
90.degree. C. the title compound was obtained as a light yellow
solid (73% yield), MS: m/e=462.3 (M+H.sup.+).
EXAMPLE 98
4-(1,1-Dioxo-4-thiomorpholin-4-ylmethyl)-N-(4-methoxy-7-phenyl-benzothiazo-
l-2-yl-benzamide hydrochloride salt (1:1)
[0472] To a solution of
N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-thiomorpholin-4-ylmethyl-benza-
mide (350 mg, 0.73 mmol) in CH.sub.2Cl.sub.2 (10 ml) was added
3-phenyl-2-(phenylsulfonyl) oxaziridine (288 mg, 1.1 mmol) and the
mixture stirred for 2 h at r.t. The reaction mixture was then
evaporated to dryness, the residue suspended in ether, and the
solid filtered off and washed with ether followed by acetone. This
solid was dissolved in methanol (10 ml) and treated with 5N
HCl/MeOH for 1 h at r.t., the resulting precipitate was filtered
off, washed with methanol and finally dried under vacuum (0.05
mmHg, 60.degree. C.) to afford the title compound as a white solid
(270 mg, 68% yield), MS: m/e=508.3 (M+H.sup.+).
EXAMPLE 99
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-thiomorpholin-4-ylmethyl-benzam-
ide hydrochloride salt (1:1)
[0473] Using thiomorpholine in dioxane at 90.degree. C. the title
compound was obtained as a yellow solid (68% yield), MS: m/e=476.1
(M+H.sup.+).
EXAMPLE 100
4-Imidazol-1-ylmethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
hydrochloride salt (1:1)
[0474] Using imidazole in DMF at 90.degree. C. the title compound
was obtained as a pale yellow solid (92% yield), MS: m/e=441.3
(M+H.sup.+).
EXAMPLE 101
4-(2-Hydroxymethyl-imidazol-1-ylmethyl)-N-(4-methoxy-7-phenyl-benzothiazol-
-2-yl)-benzamide
[0475] Using 2-hydroxymethyl-imidazole in DMF at 90.degree. C. the
title compound was obtained as a pale yellow solid (16% yield), MS:
m/e=471.1 (M+H.sup.+).
EXAMPLE 102
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-(2-methylimidazol-1-ylmethyl)-b-
enzamide
[0476] Using 2-methyl-imidazole in DMF at 90.degree. C. the title
compound was obtained as a white solid (79% yield), MS: m/e=455.5
(M+H.sup.+).
EXAMPLE 103
4-(4,5-Dimethyl-imidazol-1-ylmethyl)-N-(4-methoxy-7-phenyl-benzothiazol-2--
yl)-benzamide
[0477] Using 4,5-dimethyl-imidazole in DMF at 90.degree. C. the
title compound was obtained as a pale yellow solid (67% yield), MS:
m/e=469.2 (M+H.sup.+).
EXAMPLE 104
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-piperazin-1-ylmethyl-benzamide
hydrochloride salt (1:2)
[0478] Using 1-tert-butoxycarbonyl-piperazine in dioxane at
90.degree. C. the title compound was obtained as a pale yellow
solid (80% yield), MS: m/e=459.5 (M+H.sup.+).
EXAMPLE 105
4-Allylaminomethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
hydrochloride salt (1:1)
[0479] Using allylamine in dioxane at 90.degree. C. the title
compound was obtained as a pale yellow solid (65% yield), MS:
m/e=430.5 (M+H.sup.+).
EXAMPLE 106
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-propylaminomethyl-benzamide
hydrochloride salt (1:1)
[0480] Using propylamine in dioxane at 90.degree. C. the title
compound was obtained as a pale yellow solid (63% yield), MS:
m/e=432.4 (M+H.sup.+).
EXAMPLE 107
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-{[(pyridin-3-ylmethyl)-amino]-m-
ethyl}-benzamide hydrochloride salt (1:2)
[0481] Using 3-(aminomethyl)-pyridine in THF at 65.degree. C. the
title compound was obtained as a pale yellow solid (28% yield), MS:
m/e=481.3 (M+H.sup.+).
EXAMPLE 108
4-(4-Hydroxy-piperidin-1-ylmethyl)-N-(4-methoxy-7-phenyl-benzothiazol-2-yl-
)-benzamide hydrochloride salt (1:1)
[0482] Using 4-hydroxy-piperidine in THF at 65.degree. C. the title
compound was obtained as a white solid (61% yield), MS: m/e=474.3
(M+H.sup.+).
EXAMPLE 109
4-(3
(S)-Hydroxy-pyrrolidin-1-ylmethyl)-N-(4-methoxy-7-phenyl-benzothiazol-
-2-yl)-benzamide hydrochloride salt (1:1)
[0483] Using (S)-3-hydroxy-pyrrolidine in THF at 65.degree. C. the
title compound was obtained as a white solid (74% yield), MS:
m/e=460.3 (M+H.sup.+).
EXAMPLE 110
4-[1,4]Diazepan-1-ylmethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzam-
ide hydrochloride salt (1:2)
[0484] Using tert-butyl-1-homopiperazine carboxylate in THF at
65.degree. C. the title compound was obtained as a light yellow
solid (87% yield), MS: m/e=473.2 (M+H.sup.+).
EXAMPLE 111
4-(3(R)-Dimethylamino-pyrrolidin-1-ylmethyl)-N-(4-methoxy-7-phenyl-benzoth-
iazol-2-yl)-benzamide hydrochloride salt (1:2)
[0485] Using (3R)-(+)-3-dimethylamino-pyrrolidine in THF at
65.degree. C. the title compound was obtained as a light brown
solid (51% yield), MS: m/e=487.3 (M+H.sup.+).
EXAMPLE 112
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-[(2-morpholin-4-yl-ethylamino)--
methyl]-benzamide hydrochloride salt (1:2)
[0486] Using 4-(2-aminoethyl)-morpholine in THF at 65.degree. C.
the title compound was obtained as a light yellow solid (44%
yield), MS: m/e=503.3 (M+H.sup.+).
EXAMPLE 113
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-[(2-pyrrolidin-1-yl-ethylamino)-
-methyl]-benzamide hydrochloride salt (1:2)
[0487] Using N-(2-aminoethyl)-pyrrolidine in THF at 65.degree. C.
the title compound was obtained as a light yellow solid (37%
yield), MS: m/e=487.3 (M+H.sup.+).
EXAMPLE 114
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-[(2-piperidin-1-yl-ethylamino)--
methyl]-benzamide hydrochloride salt (1:2)
[0488] Using N-(2-aminoethyl)-piperidine in THF at 65.degree. C.
the title compound was obtained as a light yellow solid (50%
yield), MS: m/e=501.3 (M+H.sup.+).
EXAMPLE 115
4-Cyclobutylaminomethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
hydrochloride salt (1:1)
[0489] Using cyclobutylamine in THF at 65.degree. C. the title
compound was obtained as a white solid (68% yield), MS: m/e=444.3
(M+H.sup.+).
EXAMPLE 116
4-Cyclopentylaminomethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamid-
e hydrochloride salt (1:1)
[0490] Using cyclopentylamine in THF at 65.degree. C. the title
compound was obtained as a light brown solid (46% yield), MS:
m/e=458.4 (M+H.sup.+).
EXAMPLE 117
4-{[(Furan-2-ylmethyl)-amino]-methyl}-N-(4-methoxy-7-phenyl-benzothiazol-2-
-yl)-benzamide hydrochloride salt (1:1)
[0491] Using 2-(aminomethyl)-furan in THF at 65.degree. C. the
title compound was obtained as a beige solid (57% yield), MS:
m/e=470.2 (M+H.sup.+).
EXAMPLE 118
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-{[(thiophen-2-ylmethyl)-amino]--
methyl}-benzamide hydrochloride salt (1:1)
[0492] Using 2-(aminomethyl)-thiophene in THF at 65.degree. C. the
title compound was obtained as a light yellow solid (60% yield),
MS: m/e=486.3 (M+H.sup.+).
EXAMPLE 119
4-Dipropylaminomethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
hydrochloride salt (1:1)
[0493] Using dipropylamine in THF at 65.degree. C. the title
compound was obtained as a white solid (64% yield), MS: m/e=474.3
(M+H.sup.+).
EXAMPLE 120
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-{[methyl-(2-pyridin-2-yl-ethyl)-
-amino]-methyl}-benzamide hydrochloride salt (1:2)
[0494] Using 2-[(2-(methylamino)ethyl]-pyridine in THF at
65.degree. C. the title compound was obtained as a beige solid (46%
yield), MS: m/e=509.3 (M+H.sup.+).
EXAMPLE 121
4-Aminomethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide
hydrochloride salt (1:1)
[0495] Using ammonia (7N in MeOH) in THF at 20.degree. C. the title
compound was obtained (after 4 days) as a white solid (34% yield),
MS: m/e=389.1 (M.sup.+).
EXAMPLE 122
4-[(Cyclopropylmethyl-amino)-methyl]-N-(4-methoxy-7-phenyl-benzothiazol-2--
yl)-benzamide hydrochloride salt (1:1)
[0496] Using aminomethyl-cyclopropane in dioxane at 90.degree. C.
the title compound was obtained as a light yellow solid (69%
yield), MS: m/e=444.3 (M+H.sup.+).
EXAMPLE 123
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-[(2-methylsulfanyl-ethylamino)--
methyl]-benzamide hydrochloride salt (1:2)
[0497] Using 2-(methylthio)-ethylamine in THF at 65.degree. C. the
title compound was obtained as a light yellow solid (74% yield),
MS: m/e=464.2 (M+H.sup.+).
EXAMPLE 124
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-4-thiazolidin-3-ylmethyl-benzamid-
e hydrochlorde salt (1:1)
[0498] Using thiazolidine in THF at 65.degree. C. the title
compound was obtained as a white solid (48% yield), MS: m/e=462.2
(M+H.sup.+).
EXAMPLE 125
4-(3(S)-Dimethylamino-pyrrolidin-1-ylmethyl)-N-(4-methoxy-7-phenyl-benzoth-
iazol-2-yl)-benzamide hydrochloride salt (1:2)
[0499] Using (3S)-(-)-3-(dimethylamino)-pyrrolidine in THF at
65.degree. C. the title compound was obtained as a light brown
solid (56% yield), MS: m/e=487.3 (M+H.sup.+).
EXAMPLE 126
4-[(2-Dimethylamino-ethylamino)-methyl]-N-(4-methoxy-7-phenyl-benzothiazol-
-2-yl)-benzamide hydrochloride salt (1:2)
[0500] Using 2-(dimethylamino)-ethylamine in THF at 65.degree. C.
the title compound was obtained as a light yellow solid (32%
yield), MS: m/e=461.3 (M+H.sup.+).
[0501] Preparation of the
4-(R.sup.1R.sup.2-amino)-N-(4-methoxy-7-aryl-benzothiazol-2-yl)-benzamide-
s:
[0502] General procedure C: The appropriate
2-amino-7-aryl-4-methoxy-benzothiazol is converted with
4-(chloromethyl)benzoyl chloride using the general method of
example 1. The product is then converted neat with the appropriate
amine (10 equivalents) at 100.degree. C. for 24 hours. The reaction
mixture is then dissolved in ethyl acetate, extracted with water
and brine, dried and evaporated in vacuo. Flash chromatography
(silica, eluent dichloromethane containing 1.2 to 2.4% methanol)
affords the product in about 50% yield.
EXAMPLE 127
4-Chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
[0503] and 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol (1.0 g,
3.8 mmol), 4-(chloromethyl)benzoyl chloride (810 mg, 4.2 mmol) and
pyridine (0.36 ml, 4.5 mmol) are reacted in dichloromethane (20 ml)
for 18 h. The reaction is quenched with water (25 ml) and brought
to pH 8.0 with sodium carbonate. The mixture is extracted with
dichloromethane and the combined organic layers are dried and
evaporated to dryness. Flash chromatography (silica, eluent
methylene chloride containing 2.5% methanol) affords the product as
white crystalls in 54% yield. MS: m/e=418 (M+H.sup.+).
Following the General Method the Compounds of Examples 128 to 132
were Prepared
EXAMPLE 128
4-(4-Hydroxy-piperidin-1-yl
methyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
[0504] Conversion of
4-chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
(84 mg, 0.20 mmol) with 4-hydroxypiperazin (200 mg, 2.0 mmol) using
the general procedure C affords the product as white solid in 73%
yield. MS: m/e=483 (M+H.sup.+)
EXAMPLE 129
4-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl--
benzothiazol-2-yl)-benzamide
[0505] Conversion of
4-chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
(84 mg, 0.20 mmol) with N-(2-methoxyethyl)-methylamine (178 mg, 2.0
mmol) using the general procedure C affords the product as white
solid in 55% yield. MS: m/e=471 (M+H.sup.+).
EXAMPLE 130
4-{[(2-Hydroxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl--
benzothiazol-2-yl)-benzamide
[0506] 3,4-Dimethoxy-benzoic acid
2-{[4-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl
carbamoyl)-benzyl]-methyl-amino}-ethyl ester (63 mg, 0.10 mmol) are
heated in aqueous sodium hydroxide (1M, 0.5 ml) and ethanol (2 ml)
to 100.degree. C. for 30 min. The mixture is diluted with water and
extracted twice with ethyl acetate. The combined organic layers are
extracted with saturated aqueous sodium hydrogencarbonate, dried
and evaporated to dryness. Flash chromatography (silica, eluent
methylene chloride containing 5% methanol) affords the product as
white crystals in 48% yield. MS: m/e=457 (M+H.sup.+).
EXAMPLE 131
3,4-Dimethoxy-benzoic acid
2-{[4-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylcarbamoyl)-benzyl]-met-
hyl-amino}-ethyl ester
[0507] Conversion of
4-chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
(84 mg, 0.20 mmol) with 3,4-dimethoxybenzoic acid
2-methylamino-ethyl ester chlorohydrate (96 mg, 0.4 mmol) and
N-ethyl diisopropylamine (0.14 ml, 0.80 mmol) using the general
procedure C affords the product as light yellow solid in 57% yield.
MS: m/e=621 (M+H.sup.+).
EXAMPLE 132
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-piperazin-1-ylmethyl-be-
nzamide
[0508] Conversion of
4-chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
(84 mg, 0.20 mmol) with 1-BOC-piperazine (372 mg, 1.9 mmol) using
the general procedure C and afterwards cleavage of the neat
carbamate in trifluoroacetic acid (1 ml) followed by saturated
aqueous sodium carbonate affords the product as colorless crystals
in 72% yield. MS: m/e=468 (M+H.sup.+).
EXAMPLE 133
N-(7-Benzyloxy-4-methoxy-benzothiazol-2-yl)-4-chloromethyl-benzamide
[0509] Following the general method of example 1 the title compound
was obtained as a light yellow solid (70% yield). MS (EI): me/e=438
(M.sup.+).
EXAMPLE 134
N-(7-Benzyloxy-4-methoxy-benzothiazol-2-yl)-4-(3-dimethylamino-pyrrolidin--
1-ylmethyl)-benzamide hydrochloride
[0510] According to general procedure C the title compound was
obtained as a light brown solid (86% yield). M.p.: 195.degree. C.
(dec.).
Preparation of the
3-(7-aryl-4-methoxy-benzothiazol-2-yl)-1-R.sup.3-1-R.sup.4-ureas
[0511] General procedure D: The appropriate
2-amino-7-aryl-4-methoxy-benzothiazol (1 part) and pyridine (1.2
equivalents) are dissolved in 40 parts tetrahydrofuran and treated
with phosgene (20% in toluene, 1 equivalent) at ambient
temperature. After 60 min, the reaction mixture is concentrated to
half the volume under reduced pressure and the appropriate amine
(1.25 equivalents) and pyridine (1.1 equivalents) are added. After
15 min at ambient temperature, the reaction mixture is evaporated
to dryness. The product is isolated by flash chromatography
(silica, eluent dichloromethane containing 2.5% methanol).
Following the General Method the Compounds of Examples 135 to 137
were Prepared
EXAMPLE 135
Thiomorpholine-4-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0512] Conversion of
2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol (100 mg, 0.377 mg)
with phosgene (20% in toluene, 0.2 ml) and thiomorpholine (0.045
ml, 0.47 mmol) using the general procedure D affords the product as
white solid in 73% yield. MS: m/e=395 (M+H.sup.+).
EXAMPLE 136
Morpholine-4-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0513] Conversion of
2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol (100 mg, 0.377 mg)
with phosgene (20% in toluene, 0.2 ml) and morpholine (0.041 ml,
0.47 mmol) using the general procedure D affords the product as
white solid in 25% yield. MS: m/e=379 (M+H.sup.+).
EXAMPLE 137
3-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(6-methyl-pyri-
din-3-ylmethyl)-urea
[0514] Conversion of
2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol (100 mg, 0.377 mg)
with phosgene (20% in toluene, 0.2 ml) and
methyl-(6-methyl-pyridin-3-ylmethyl)-amine (0.064 ml, 0.47 mmol)
using the general procedure D affords the product as white solid in
25% yield. MS: m/e=429 (M+H.sup.+).
EXAMPLE 138
1-Furan-2-yl-methyl-3-(4-methoxy-benzothiazol-2-yl)-urea
[0515] To a solution of (4-Methoxy-benzothiazol-2-yl)-carbamic acid
tert-butyl ester (80 mg, 0.29 mmol) in dioxane (2 ml) was added
furfurylamine (55 mg, 0.57 mmol) and the mixture heated to
100.degree. C. for 20 h. The reaction mixture was then evaporated
to dryness and the residue recrystallised from ether/nHexane to
afford the title compound as a beige solid (80 mg, 92% yield), MS:
m/e=303 (M.sup.+).
Following the General Method of Example 138, the Compounds of
Examples 139 to 163 were Prepared
EXAMPLE 139
1-Furan-2-yl-methyl-3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-urea
[0516] Using (4-Methoxy-benzothiazol-2-yl)-carbamic acid tert-butyl
ester and furfurylamine the title compound was obtained as a beige
solid (66% yield), MS: m/e=380.3 (M+H.sup.+).
EXAMPLE 140
1-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-3-thiophen-2-yl-methyl-urea
[0517] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and thiophene-2-methylamine the title compound was
obtained as a beige solid (62% yield), MS: m/e=396.3
(M+H.sup.+).
EXAMPLE 141
1-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-3-pyridin-2-yl-methyl-urea
[0518] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and 2-(aminomethyl)-pyridine the title compound
was obtained as a beige solid (18% yield) following purification
using reversed-phase preparative HPLC, C18 ODS-AQ, with an
MeCN/water gradient, MS: m/e=391.2 (M+H.sup.+).
EXAMPLE 142
1-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-3-pyridin-3-ylmethyl-urea
[0519] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and 3-(aminomethyl)-pyridine the title compound
was obtained as a beige solid (18% yield) following purification
using reversed-phase preparative HPLC, C18 ODS-AQ, with a
water/acetonitrile gradient, MS: m/e=391.2 (M+H.sup.+).
EXAMPLE 143
1-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-3-pyridin-4-ylmethyl-urea
[0520] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and 4-(aminomethyl)-pyridine the title compound
was obtained as a beige solid (52% yield), MS: m/e=391.2
(M+H.sup.+).
EXAMPLE 144
3-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-1-methyl-1-pyridin-3-yl-methyl-ur-
ea
[0521] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and 3-(methylaminomethyl)-pyridine the title
compound was obtained as a beige solid (23% yield), MS: m/e=405.4
(M+H.sup.+).
EXAMPLE 145
1-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-3-phenethyl-urea
[0522] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and phenethylamine the title compound was obtained
as a beige solid (77% yield), MS: m/e=404.5 (M+H.sup.+).
EXAMPLE 146
1-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-3-(3-phenyl-propyl)-urea
[0523] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and 3-phenyl-propylamine the title compound was
obtained as a beige solid (71% yield), MS: m/e=417.5
(M+H.sup.+).
EXAMPLE 147
1-(4-Methoxy-benzyl)-3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-urea
[0524] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and 4-methoxy-benzylamine the title compound was
obtained as a beige solid (60% yield), MS: m/e=420.3
(M+H.sup.+).
EXAMPLE 148
3,4-Dihydro-1H-isoquinoline-2-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide
[0525] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and 1,2,3,4-tetrahydroisoquinoline the title
compound was obtained as a beige solid (31% yield) following
purification using reverse-phase prep. HPLC, C18 ODS-AQ, with a
water/acetonitrile gradient, MS: m/e=416.3 (M+H.sup.+).
EXAMPLE 149
1-(2-Dimethylamino-ethyl)-3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-urea
[0526] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and 2-dimethylamino-ethylamine the title compound
was obtained as a beige solid (67% yield), MS: m/e=371.3
(M+H.sup.+).
EXAMPLE 150
1-(2-Hydroxy-ethyl)-3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-urea
[0527] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and ethanolamine the title compound was obtained
as a beige solid (35% yield), MS: m/e=344.3 (M+H.sup.+).
EXAMPLE 151
1-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-3-(2-piperidin-1-yl-ethyl)-urea
[0528] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and 1-(2-aminoethyl)-piperidine the title compound
was obtained as a beige solid (67% yield), MS: m/e=411.4
(M+H.sup.+).
EXAMPLE 152
1-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-3-(2-morpholin-4-yl-ethyl)-urea
[0529] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and 4-(2-aminoethyl)-morpholine the title compound
was obtained as a beige solid (29% yield), MS: m/e=413.4
(M+H.sup.+).
EXAMPLE 153
1-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-3-(2-pyridin-2-yl-ethyl)-urea
[0530] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and 2-(2-aminoethyl)-pyridine the title compound
was obtained as a beige solid (88% yield), MS: m/e=405.4
(M+H.sup.+).
EXAMPLE 154
1-(3-Imidazol-1-yl-propyl)-3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-urea
hydrochloride salt (1:1)
[0531] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and N-(3-aminopropyl)-imidazole the free base was
obtained which was treated with 5N HCl/EtOH followed by
crystallisation from methanol/ether to afford the title compound as
a beige solid (72% yield), MS: m/e=408.3 (M+H.sup.+).
EXAMPLE 155
1-Ethyl-3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-1-pyridin-4-yl-methyl-ure-
a hydrochloride salt (1:1)
[0532] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and 4-(N-ethylaminomethyl)-pyridine the free base
was obtained which was treated with 5N HCl/EtOH followed by
crystallisation from acetonitrile to afford the title compound as a
white solid (64% yield), MS: m/e=419.3 (M+H.sup.+).
EXAMPLE 156
1-(2-Imidazol-1-yl-ethyl)-3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-urea
hydrochloride salt (1:1)
[0533] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and N-(2-aminoethyl)-imidazole the free base was
obtained which was treated with 5N HCl/EtOH followed by
crystallisation from acetonitrile to afford the title compound as a
light brown solid (65% yield), MS: m/e=393.0 (M.sup.+).
EXAMPLE 157
Morpholine-4-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide
[0534] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and morpholine the title compound was obtained as
a white solid, following crystallisation from ether/nHexane (67%
yield), MS: m/e=370.3 (M+H.sup.+)
EXAMPLE 158
Thiomorpholine-4-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide
[0535] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and thiomorpholine the title compound was obtained
as a white solid, following crystallisation from ether/nHexane (88%
yield), MS: m/e=386.2 (M+H.sup.+).
EXAMPLE 159
1-Oxo-1l 4-thiomorpholine-4-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide
[0536] To a solution of thiomorpholine-4-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide (240 mg, 0.62 mmol) in
CH.sub.2Cl.sub.2 (10 ml) was added
3-phenyl-2-(phenylsulfonyl)oxaziridine (244 mg, 0.92 mmol) and the
mixture stirred for 2 h at r.t. The solvent was then reduced to ca.
2 ml and the mixture ultrasonicated for 15 min. with addition of
ether (10 ml). The solid precipitated was filtered off, then dried
under vacuum (0.05 mmHg, 60.degree. C.) to afford the title
compound as a light yellow solid (90% yield), MS: m/e=402.9
(M+H.sup.+).
EXAMPLE 160
1-[2-(1,1-Dioxo-1l
6-thiomorpholin-4-yl)-ethyl]-3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-ure-
a hydrochloride (1:1)
[0537] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester 2-(1,1-Dioxo-thiomorpholin-4-yl)-ethylamine the
free base was obtained, which was converted to the hydrochloride
salt by treatment with 5N HCl/EtOH followed by under vacuum (0.05
mmHg, 60.degree. C.) to afford the title compound as a beige solid
(87% yield), MS: m/e=461.2 (M+H.sup.+).
EXAMPLE 161
3-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-1-methyl-1-(6-methyl-pyridin-3-yl-
-methyl)-urea hydrochloride salt (1:2)
[0538] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and methyl-(6-methyl-pyridin-3-ylmethyl)-amine,
the free base was obtained, which was converted to the
hydrochloride salt by treatment with 5N HCl/EtOH followed by
recrystallisation from acetonitrile then drying under vacuum (0.05
mmHg, 60.degree. C.) to afford the title compound as a white solid
(61% yield), MS: m/e=448.9 (M+H.sup.+).
EXAMPLE 162
3-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-1-methyl-1-pyridin-2-yl-methyl-ur-
ea hydrochloride salt (1:2)
[0539] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester and methyl-pyridin-2-yl-methyl-amine, the free
base was obtained, which was converted to the hydrochloride salt by
treatment with 5N HCl/EtOH followed by recrystallisation from
EtOH/ether then drying under vacuum (0.05 mmHg, 60.degree. C.) to
afford the title compound as a white solid (70% yield), MS:
m/e=494.4 (M+H.sup.+).
EXAMPLE 163
3-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-1-methyl-1-pyridin-4-yl-methyl-ur-
ea hydrochloride salt (1:2)
[0540] Using (4-methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid
tert-butyl ester methyl-pyridin-4-ylmethyl-amine the free base was
obtained, which was converted to the hydrochloride salt by
treatment with 5N HCl/EtOH followed by recrystallisation from
EtOH/ether then drying under vacuum (0.05 mmHg, 60.degree. C.) to
afford the title compound as a white solid (65% yield), MS:
m/e=480.3 (M+H.sup.+).
EXAMPLE 164
3-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-1-methyl-1-(1-oxy-pyridin-3-yl-me-
thyl)-urea
[0541] To an ice cooled solution of
3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-1-methyl-1-pyridin-3-yl-methyl-u-
rea (405 mg, 1 mmol), in CH.sub.2Cl.sub.2 was added
3-chloro-perbenzoic acid
[0542] (MCPBA) (295 mg, 1.2 mmol) and the mixture stirred at
0.degree. C. for 1 h, followed by 1 h at r.t. After this time the
pale red reaction mixture was thoroughly washed with 5% NaHCO.sub.3
solution (50 ml), and the aqueous phase was extracted with
CH.sub.2Cl.sub.2 (2.times.30 ml) then the combined extracts were
dried with Na.sub.2SO.sub.4, filtered and evaporated to affording a
violet solid. This solid was then chromatographed over SiO.sub.2
(Merck 230-400 mesh) eluting with a gradient of
CH.sub.2Cl.sub.2/(2N NH.sub.3/MeOH) (97:3 to 9:1), to afford the
tile compound as a light brown solid (260 mg, 62% yield), MS:
m/e=421.3 (M+H.sup.+)
EXAMPLE 165
1-Benzyl-3-(4-methoxy-benzothiazol-2-yl)-urea
[0543] To a stirred solution of 2-amino-4-methoxy-benzothiazole
(180 mg, 1 mol) in THF (5 ml) was added benzylisocyanate (166 mg,
1.25 mmol) and the mixture heated to 60.degree. C. for 3 h. After
evaporation of the solvent, ether (5 ml) was added and the
suspension ultra-sonicated for 10 min with addition of nHexane (5
ml). This suspension was filtered and washed further with
ether/nHexane (1:1) to afford the title compound, after drying
under vacuum, as a white solid (220 mg, 70% yield), MS: m/e=313
(M.sup.+).
Following the General Method of Example 165, the Compound of
Example 166 was Prepared
EXAMPLE 166
1-Benzyl-3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-urea
[0544] Using 2-amino-4-methoxy-7-phenyl-benzothiazole the title
compound was obtained as a white amorphous solid (92% yield), MS:
m/e=389 (M.sup.+)
EXAMPLE 167
1-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-3-pyridin-3-yl-thiourea
[0545] To a stirred solution of
2-amino-4-methoxy-7-phenyl-benzothiazole (80 mg, 0.3 mmol) in
dioxane (3 ml) was added pyridine-3-isothiocyanate (64 mg, 0.47
mmol) and the mixture heated to 100.degree. C. for 69 h. After
cooling to r.t. the resulting yellow suspension was filtered,
washed with ether (5 ml) and dried under vacuum (0.05 mmHg,
50.degree. C., to afford the title compound as a; light yellow
solid (98 mg, 80% yield), MS: m/e=393.1 (M+H.sup.+).
EXAMPLE 168
1-Benzoyl-3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-thiourea
[0546] To a suspension of 2-amino-4-methoxy-7-phenyl-benzothiazole
(1.52 g, 6 mmol) in dioxane (60 ml) was added benzoylisothiocyanate
(1.45 g, 8.9 mmol) and the mixture heated to 100.degree. C. for 2
h, during which time the suspension dissolved. After cooling the
solvent was removed and the solids suspended in hot acetonitrile
(100 ml) and filtered while warm (50.degree. C.). The solid
collected was washed with acetonitrile (20 ml) then dried under
vacuum (0.05 mmHg), at 60.degree. C. to afford the title compound
as a pale yellow amorphous solid (1.38 g, 55% yield), MS: m/e=419.0
(M.sup.+).
EXAMPLE 169
(4-Methoxy-7-phenyl-benzothiazol-2-yl)-thiourea
[0547] To a solution of
1-benzoyl-3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-thiourea (1.3 g,
3.1 mmol) in methanol (20 ml)/THF (40 ml) was added NaOMe (250 mg,
4.6 mmol) and the mixture stirred for 72 h at r.t. After
evaporation of the solvents water (100 ml) was added with stirring
followed by acetic acid (1 ml) which caused a solid to precipitate.
This solid was collected and on a glass sinter, washed with water
(100 ml), followed by EtOAc (30 ml) then finally cyclohexane (30
ml). After drying the title compound was obtained as a white solid
(850 mg, 87% yield), MS: m/e=316.2 (M+H.sup.+).
EXAMPLE 170
(4-Methoxy-benzothiazol-2-yl)-urea
[0548] A mixture of 2-amino-4-methoxy-benzothiazole (330 mg, 1.83
mmol) and urea (1.1 g, 1.83 mmol) were heated together for 1 h at
170.degree. C., with evolution of ammonia. After allowing to cool
to r.t., water (10 ml) was added and the mixture was vigorously
stirred. The solid was then filtered, washed with water (10 ml)
followed by ethanol (10 ml) and dried at 60.degree. C. under vacuum
(0.05 mmHg). The title product was afforded as an off-white solid
(300 mg, 73% yield), MS: m/e=223 (M.sup.+).
Following the General Method of Example 170, the Compounds of
Examples 171 to 173 were Prepared
EXAMPLE 171
(4-Methoxy-7-phenyl-benzothiazol-2-yl)-urea
[0549] Using 2-amino-4-methoxy-7-phenyl-benzothiazole the title
compound was prepared as white solid (58% yield), MS: m/e=299
(M.sup.+). The preparation of this compound is described in the
following patent literature; N-(Benzothiazol-2-yl)oxamic acid
derivatives. W. Winter, M. Thiel, A. Roesch and O. H. Wilhelms,
German Patent, DE 2656468, 1978.
EXAMPLE 172
(4,6-Difluoro-benzothiazol-2-yl)-urea
[0550] Using 2-amino-4,6-difluoro-benzothiazole the title compound
was prepared as a light yellow solid (42% yield), MS: m/e=229
(M.sup.+).
EXAMPLE 173
(7-Isopropyl-4-methoxy-benzothiazol-2-yl)-urea
[0551] The title compound is described in the following patent
literature and was prepared according to the procedure described
therein; N-(Benzothiazol-2-yl)oxamic acid derivatives. W. Winter,
M. Thiel, A. Roesch and O. H. Wilhelms, German Patent, DE 2656468,
1978.
EXAMPLE 174
(4-Methoxy-7-phenyl-benzothiazol-2-yl)-pyridin-3-ylmethyl-amine
[0552] To a solution of 2-chloro-4-methoxy-7-phenyl-benzothiazole
(150 mg, 0.54 mmol), in dioxane (5 ml) was added
3-(aminomethyl)-pyridine (176 mg, 1.6 mmol) and this mixture was
stirred at 100.degree. C. for 18 h. The solvent was then evaporated
and the mixture taken up in methanol (8 ml) and ultrasonicated for
10 min. to precipitate the product, which was washed with methanol
(5 ml), and dried under vacuum (0.05 mmHg, 60.degree. C.) to afford
the title compound as a white solid (58 mg, 31% yield), MS:
m/e=348.3 (M+H.sup.+). Following the general method of example 174,
the compounds of examples 175 to 184 were prepared
EXAMPLE 175
(4-Methoxy-7-phenyl-benzothiazol-2-yl)-pyridin-4-ylmethyl-amine
[0553] Using 4-(aminomethyl)-pyridine the title compound was
obtained as a pale yellow solid (17% yield), MS: m/e=343.3
(M+H.sup.+).
EXAMPLE 176
(4-Methoxy-7-phenyl-benzothiazol-2-yl)-pyridin-2-ylmethyl-amine
[0554] Using 2-(aminomethyl)-pyridine the title compound was
obtained as a white solid (32% yield), MS: m/e=343.3
(M+H.sup.+).
EXAMPLE 177
Benzyl-(4-methoxy-7-phenyl-benzothiazol-2-yl)-amine
[0555] Using benzylamine the title compound was obtained as a white
solid (54% yield), MS: m/e=347.3 (M+H.sup.+).
EXAMPLE 178
(2-Methoxy-ethyl)-(4-methoxy-7-phenyl-benzothiazol-2-yl)-amine
[0556] Using 2-methoxy-ethylamine the title compound was obtained
as a white solid (56% yield), MS: m/e=315.3 (M+H.sup.+).
EXAMPLE 179
Cyclopropylmethyl-(4-methoxy-7-phenyl-benzothiazol-2-yl)-amine
[0557] Using aminomethyl-cyclopropane the title compound was
obtained as a white solid (68% yield), MS: m/e=311.2
(M+H.sup.+).
EXAMPLE 180
(4-Methoxy-7-phenyl-benzothiazol-2-yl)-(2-pyridin-2-yl-ethyl)-amine
hydrochloride salt (1:2)
[0558] Using 3-(2-aminoethyl)-pyridine the crude product was
obtained which was converted to its hydrochloride salt with excess
5N HCl/EtOH (2.5 eq.) and then purified by reversed phase
preparative HPLC, using a C18 ODS-AQ column, with a water (0.1%
TFA)/acetonitrile gradient. After pooling the product fractions and
evaporation of solvents the title compound was obtained as a white
foam (59% yield), MS: m/e=362.2 (M+H.sup.+).
EXAMPLE 181
N-(4-Methoxy-7-phenyl-benzothiazol-2-yl)-N',N'-dimethyl-ethane-1,2-diamine
hydrochloride salt (1:2)
[0559] Using 2-(dimethylamino)-ethylamine the crude product was
obtained which was converted to its hydrochloride salt with excess
5N HCl/EtOH (2.5 eq.) and then purified by reversed phase
preparative HPLC, using a C18 ODS-AQ column, with a water (0.1%
TFA)/acetonitrile gradient. After pooling the product fractions and
evaporation of solvents the title compound was obtained as a white
foam (80% yield), MS: m/e=328.3 (M+H.sup.+).
EXAMPLE 182
(4-Methoxy-7-phenyl-benzothiazol-2-yl)-(2-morpholin-4-yl-ethyl)-amine
hydrochloride salt (1:2)
[0560] Using 4-(2-aminoethyl)morpholine the crude product was
obtained which was converted to its hydrochloride salt with excess
5N HCl/EtOH (2.5 eq.) and then purified by reversed phase
preparative HPLC, using a C18 ODS-AQ column, with a water (0.1%
TFA)/acetonitrile gradient. After pooling the product fractions and
evaporation of solvents the title compound was obtained as a white
foam (67% yield), MS: m/e=370.3 (M+H.sup.+).
EXAMPLE 183
(4-Methoxy-7-phenyl-benzothiazol-2-yl)-(2-piperidin-1-yl-ethyl)-amine
hydrochloride salt (1:2)
[0561] Using 1-(2-aminoethyl)-piperidine the crude product was
obtained which was converted to its hydrochloride salt with excess
5N HCl/EtOH (2.5 eq.) and then purified by reversed phase
preparative HPLC, using a C18 ODS-AQ column, with a water (0.1%
TFA)/acetonitrile gradient. After pooling the product fractions and
evaporation of solvents the title compound was obtained as a white
foam (57% yield), MS: m/e=368.2 (M+H.sup.+).
EXAMPLE 184
2-(4-Methoxy-7-phenyl-benzothiazol-2-ylamino)-ethanol hydrochloride
salt (1:1)
[0562] Using ethanolamine the crude product was obtained which was
converted to its hydrochloride salt with excess 5N HCl/EtOH (2.5
eq.) and then purified by reversed phase preparative HPLC, using a
C18 ODS-AQ column, with a water (0.1% TFA)/acetonitrile gradient.
After pooling the product fractions and evaporation of solvents the
title compound was obtained as a white foam (60% yield), MS:
m/e=300.4 (M+H.sup.+).
EXAMPLE 185
[4-Methoxy-7-(2-methyl-pyridin-4-yl)-benzothiazol-2-yl]-carbamic
acid methyl ester
[0563] The title compound is synthesized from
(7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester and
2-methyl-4-trimethylstannanyl-pyridine using the general procedure
B as a off-white solid in 20% yield. MS: m/e=329 (M.sup.+).
EXAMPLE 186
(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-carbamic acid methyl
ester
[0564] Carbamate formation using the same procedure as for
(4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester yields the
product as off-white solid in 58% yield. MS: m/e=324
(M+H.sup.+).
EXAMPLE 187
(4-Methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid benzyl
ester
[0565] To a stirred solution of
2-amino-4-methoxy-7-phenyl-benzothiazole (512 mg, 2 mmol) in
pyridine at 90.degree. C. was added benzyl chloroformate (3.3 ml,
23.4 mmol) in three portions over 6 hours. The reaction mixture was
then evaporated to dryness and partioned between CH.sub.2Cl.sub.2
(50 ml) and saturated aqueous NaCl solution (50 ml), the aqueous
phase was separated and extracted further with CH.sub.2Cl.sub.2
(2.times.50 ml) and the combined organic phases dried, filtered and
evaporated. The crude residue was then chromatographed over
SiO.sub.2 (Merck 230-400 mesh) eluting with CH.sub.2Cl.sub.2/EtOAc
(4:1) to afford the title compound as a white foam (620 mg, 79%
yield), MS: m/e=391.2 (M+H.sup.+).
EXAMPLE 188
(4-Methoxy-7-vinyl-benzothiazol-2-yl)-carbamic acid methyl
ester
a) (7-Iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl
ester
[0566] (4-Methoxy-benzothiazol-2-yl)-carbamic acid methyl ester
(31.0 g, 130 mmol) and sodium acetate (32.3 g, 394 mmol) are
dissolved in 400 ml of glacial acetic acid and slowly treated with
iodine monochloride (13.5 ml, 264 mmol) at 0.degree. C. The
reaction mixture is then slowly warmed to room temperature and
stirred for 15 hours. After addition of water (1.3 l), the formed
precipitate is filtered off and washed with water. The filter cake
is then dissolved in a minimal amount of tetrahydrofurane (about
150 ml) and decolorized with 1M aqueous sodium thiosulfate. The
product is precipitated by the addition of water (about 2.0 l),
filtered off and dried at 60.degree. C. for 12 hours. 42.3 g (89%)
white solid. MS: m/e=364 (M.sup.+).
b) (4-Methoxy-7-vinyl-benzothiazol-2-yl)-carbamic acid methyl
ester
[0567] (7-Iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid ester (1
part), vinyltributylstannane (1.0 equivalents) and
tetrakis-(triphenylphosphine)-palladium(0) (0.1 equivalents) are
combined in dioxane (25 parts) containing 2M Na.sub.2CO.sub.3 (4.0
equivalents) and heated to reflux for 24 hours. The reaction
mixture was evaporated, washed with brine and dried over
MgSO.sub.4. After evaporation to dryness the product was isolated
by flash chromatography (silica, eluent ethyl acetate/hexanes) as a
white solid (60%). F.p.: 138-139.degree. C.
EXAMPLE 189
4-Fluoro-N-(4-methoxy-7-vinyl-benzothiazol-2-yl)-benzamide
a) 4-Methoxy-7-vinyl-benzothiazol-2-ylamine
[0568] (4-Methoxy-7-vinyl-benzothiazol-2-yl)-carbamic acid methyl
ester was dissolved in ethyleneglycol/2N KOH (2:1) and stirred at
100.degree. C. for 3 hrs. Then water was added and the mixture was
extracted with CH.sub.2Cl.sub.2, the organic phase was washed with
brine and dried over MgSO.sub.4. After evaporation the residue was
crystallized from CH.sub.2Cl.sub.2. White crystals (64%); F.p.:
155-159.degree. C.
b) 4-Fluoro-N-(4-methoxy-7-vinyl-benzothiazol-2-yl)-benzamide
[0569] Following the general method of example 1 the title compound
was obtained from 4-methoxy-7-vinyl-benzothiazol-2-ylamine and
4-fluoro-benzoic acid chloride as a white solid (85%); F.p.:
198-199.degree. C.
EXAMPLE 190
(4-Methoxy-7-propenyl-benzothiazol-2-yl)-carbamic acid methyl
ester
[0570] Following the general method 188b) the title compound was
obtained from (7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid
methyl ester and tributyl-propenyl-stannane as a yellowish solid
(75%); F.p.: 153-156.degree. C.
EXAMPLE 191
N-(7-Ethyl-4-methoxy-benzothiazol-2-yl)-4-fluoro-benzamide
[0571] 100 mg of
4-fluoro-N-(4-methoxy-7-vinyl-benzothiazol-2-yl)-benzamide (0.3
mmol) were dissolved in methanol (100 ml) and Pd/C (4 mg) were
added. The reaction mixture was hydrogenated for 2 hrs. After
filtering and evaporation of the solvent the crude product was
subjected to column chromatography (silica gel, eluent
MeOH/CH.sub.2Cl.sub.2 1:9). The title compound was obtained in form
of white crystals (79%); F.p.: 165-167.degree. C.
EXAMPLE 192
(7-Acetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl
ester
[0572] According to the method described for example 188b) the
title compound was obtained from
(7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester (1
equivalent) and (1-ethoxy-vinyl)-tributylstannane (1 equivalent) as
a white solid (34%); F.p.: 238-240.degree. C.
EXAMPLE 193
Rac-[7-(1-Hydroxy-ethyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid
methyl ester
[0573] 0.05 g of (7-acetyl-4-methoxy-benzothiazol-2-yl)-carbamic
acid methyl ester (0.00018 Mol) were dissolved in ethanol (30 ml)
and 0.028 g of NaBH.sub.4 (0.00072 Mol) were added. After stirring
at 40.degree. C. for 24 hrs. the reaction mixture was diluted with
water, extracted with CH.sub.2Cl.sub.2, the organic phase washed
with brine and dried over MgSO.sub.4. After chromatography on
silica gel with CH.sub.2Cl.sub.2/MeOH 97:3 the title compound was
obtained as a white solid (38%); F.p.: 179.degree. C. (dec.).
EXAMPLE 194
Intermediate
Rac-[7-(2-Bromo-1-hydroxy-ethyl)-4-methoxy-benzothiazol-2-yl]-carbamic
acid methyl ester
[0574] 1.5 g of (4-methoxy-7-vinyl-benzothiazol-2-yl)-carbamic acid
methyl ester (0.0057 Mol), dissolved in THF (60 ml) were treated
with H.sub.2O (6 ml) and 1.0 g of NBS (0.006 Mol) at room
temperature for 15 min. Then the solvent was removed, the residue
taken up in H.sub.2O (30 ml) and extracted four times with ethyl
acetate (50 ml). The combined organic phases were washed with brine
and dried over MgSO.sub.4. After evaporation the crude product was
subjected to column chromatography (silicagel, ethyl acetate). The
title compound was obtained as a white solid (78%), F.p.:
150-155.degree. C.
EXAMPLE 195
Intermediate
[7-(2-Bromo-1-hydroxy-propyl)-4-methoxy-benzothiazol-2-yl]-carbamic
acid methyl ester
[0575] According to the method described for the example above the
title compound was obtained from
(4-methoxy-7-propenyl-benzothiazol-2-yl)-carbamic acid methyl ester
as a foam and carried on to the next step without further
purification and characterization.
EXAMPLE 196
Intermediate
(7-Bromoacetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl
ester
[0576] 1.6 g of
rac-[7-(2-bromo-1-hydroxy-ethyl)-4-methoxy-benzothiazol-2-yl]-carbamic
acid methyl ester (0.0044 Mol) were dissolved in CHCl.sub.3 (100
ml) and treated with 3.8 g of MnO.sub.2 (0.044 Mol) for 3 hrs. at
70.degree. C. The hot reaction mixture was filtered and
subsequently concentrated. The crude product was crystallized from
Et.sub.2O to yield the title compound as a beige solid (73%); F.p.:
250-260.degree. C. (dec.).
EXAMPLE 197
Intermediate
[7-(2-Bromo-propionyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid
methyl ester
[0577] 5.0 g of
[7-(2-bromo-1-hydroxy-propyl)-4-methoxy-benzothiazol-2-yl]-carbamic
acid methyl ester 0.0133 Mol) were suspended in water (30 ml) and
2.0 g of CrO.sub.3 (0.02 Mol), dissolved in acetic acid (30 ml),
were added. The reaction mixture was heated to 70.degree. C. for 2
hrs. and then evaporated to dryness. The residue was taken up in
sat. NaHCO.sub.3 (200 ml), extracted 4.times. with ethyl acetate
(200 ml each) and the combined organic phases were dried over
MgSO.sub.4. The title compound was obtained as orange crystals
(74%); F.p.: 199-201.degree. C.
EXAMPLE 198
(4-Methoxy-7-thiophen-2-yl-benzothiazol-2-yl)-carbamic acid methyl
ester
[0578] Following the method described for
(4-methoxy-7-vinyl-benzothiazol-2-yl)-carbamic acid methyl ester
(Example 188b) the title compound was obtained from
(7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester and
2-tributylstannyl-thiophen as a yellowish solid (41%);
160-165.degree. C.
EXAMPLE 199
[4-Methoxy-7-(5-methyl-thiophen-2-yl)-benzothiazol-2-yl]-carbamic
acid methyl ester
[0579] Following the method described for
(4-methoxy-7-vinyl-benzothiazol-2-yl)-carbamic acid methyl ester
(Example 188b) the title compound was obtained from
(7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester and
2-tributylstannyl-5-methylthiophen as a yellowish solid (40%);
267-274.degree. C. (dec.).
EXAMPLE 200
[4-Methoxy-7-(2-methyl-thiazol-4-yl)-benzothiazol-2-yl]-carbamic
acid methyl ester
[0580] 1.3 g of
(7-bromoacetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl
ester (0.0036 Mol) and 0.27 g of thioacetamide (0.0036 Mol) were
dissolved in dioxane (30 ml) and stirred for 4 hrs. at 70.degree.
C. After evaporation of half of the solvent water (40 ml) was added
and the pH adjust to 7 with sat. NaHCO.sub.3. A solid precipitated,
which was isolated and then subjected to column chromatography on
silicagel using ethyl acetate as eluent. The title product was
isolated as an off-white solid (27%); F.p.: 186-188.degree. C.
EXAMPLE 201
{4-Methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl}-c-
arbamic acid methyl ester
[0581] According to the method described above the title compound
was obtained from
(7-bromoacetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl
ester and 2-methylpyridine-5-thiocaboxamide as a yellowish solid
(73%); F.p.: 240-242.degree. C.
EXAMPLE 202
[4-Methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-carbamic
acid methyl ester
[0582] According to the method described above the title compound
was obtained from
(7-bromoacetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl
ester and pyridine-2-thiocaboxamide as a dark red solid (63%);
F.p.: 207.degree. C.
EXAMPLE 203
{7-[2-(tert-Butoxycarbonylamino-methyl)-thiazol-4-yl]-4-methoxy-benzothiaz-
ol-2-yl}-carbamic acid methyl ester
[0583] According to the method described above the title compound
was obtained from
(7-bromoacetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl
ester and thiocarbamoylmethyl-carbamic acid tert-butyl ester as a
white solid (26%); MS (ISP): m/e=451 (M+H.sup.+)
EXAMPLE 204
[7-(2-Aminomethyl-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-carbamic
acid methyl ester hydrochloride (1:1)
[0584] 0.075 g of
{7-[2-(tert-butoxycarbonylamino-methyl)-thiazol-4-yl]-4-methoxy-benzothia-
zol-2-yl}-carbamic acid methyl ester (0.00017 Mol) were stirred in
2 ml of 2.5 M HCl/MeOH for 4 hrs. Upon cooling to room temperature
a precipitate formed, which was filtered off, washed with hexane
and dried. The title compound was obtained as a white solid (70%),
F.p.: 220-230.degree. C.
EXAMPLE 205
[7-(2-Dimethylaminomethyl-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-carba-
mic acid methyl ester
[0585] According to the method described for
[4-methoxy-7-(2-methyl-thiazol-4-yl)-benzothiazol-2-yl]-carbamic
acid methyl ester the title compound was obtained from
(7-bromoacetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl
ester and dimethylamino-thioacetamide as an off-white solid (11%);
F.p.: 185-189.degree. C. (dec.).
EXAMPLE 206
[7-(2,5-Dimethyl-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-carbamic
acid methyl ester
[0586] According to the method described above the title compound
was obtained from
[7-(2-bromo-propionyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid
methyl ester and thioacetamide as an off-white solid (42%); F.p.:
180-181.degree. C. (dec.).
EXAMPLE 207
{4-Methoxy-7-[2-(trityl-amino)-thiazol-4-yl]-benzothiazol-2-yl}-carbamic
acid methyl ester
[0587] According to the method described above the title compound
was obtained from
[7-(2-bromo-acetyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid
methyl ester and trityl-thiourea as an off-white solid (53%); F.p.:
135-140.degree. C.
EXAMPLE 208
[7-(2-Amino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-carbamic
acid methyl ester
[0588] 0.070 g of
{4-methoxy-7-[2-(trityl-amino)-thiazol-4-yl]-benzothiazol-2-yl}-carbamic
acid methyl ester (0.00012 Mol) were heated to reflux in 2 ml of
2.5 M HCl/MeOH for 4 hrs. After cooling to room temperature the pH
was adjusted to 7 upon drop wise addition of sat. NaHCO.sub.3. A
precipitate formed, which was filtered off, washed with ethyl
acetate and dried.
[0589] The title compound was obtained as a white solid (23%),
F.p.: 293-296.degree. C. (dec.).
EXAMPLE 209
[7-(2-Dimethylamino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-carbamic
acid methyl ester
[0590] According to the method described above the title compound
was obtained from
[7-(2-bromo-acetyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid
methyl ester, N,N-dimethyl-thiourea and triethylamine as an
off-white solid (86%); F.p.: 185-195.degree. C.
EXAMPLE 210
[4-Methoxy-7-(2-pyrrolidin-1-yl-thiazol-4-yl)-benzothiazol-2-yl]-carbamic
acid methyl ester
[0591] According to the method described for the example described
above the title compound was obtained from
[7-(2-bromo-acetyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid
methyl ester and 1-pyrrolidine-carbothioamide as an off-white solid
(16%); F.p.: 199.degree. C.
EXAMPLE 211
[4-Methoxy-7-(2-piperidin-1-yl-thiazol-4-yl)-benzothiazol-2-yl]-carbamic
acid methyl ester
[0592] According to the method described above the title compound
was obtained from
[7-(2-bromo-acetyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid
methyl ester and 1-piperidine-carbothioamide as an off-white solid
(71%); F.p.: 209-211.degree. C.
EXAMPLE 212
[4-Methoxy-7-(2-morpholin-4-yl-thiazol-4-yl)-benzothiazol-2-yl]-carbamic
acid methyl ester
[0593] According to the method described above the title compound
was obtained from
[7-(2-bromo-acetyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid
methyl ester and 1-morpholine-carbothioamide as a yellowish solid
(41%); MS (ISP): m/e=407 (M+H.sup.+).
EXAMPLE 213
{4-Methoxy-7-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzothiazol-2-yl}-
-carbamic acid methyl ester
[0594] According to the method described above the title compound
was obtained from
[7-(2-bromo-acetyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid
methyl ester and 4-methyl-1-piperazinethiocarboxamide as a brownish
solid (41%); F.p.: 143.degree. C.
EXAMPLE 214
[7-(2-tert-Butoxycarbonylamino-1H-imidazol-4-yl)-4-methoxy-benzothiazol-2--
yl]-carbamic acid methyl ester
[0595] 0.25 g of
(7-bromoacetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl
ester (0.0007 Mol) and 0.33 g of tert-butoxycarbonylguanidine
(0.0021 Mol) were heated to reflux in acetonitril (3 ml) for 3 hrs.
After evaporation of the solvent the residue was triturated with
water (10 ml) and filtered. The filtrate was evaporated and the
residue subjected to column chromatography (silicagel,
ethyl-acetate/hexanes 1:1) to yield the title compound as a white
solid (17%); F.p.: 255-265.degree. C.
EXAMPLE 215
[7-(2-Amino-1H-imidazol-4-yl)-4-methoxy-benzothiazol-2-yl]-carbamic
acid methyl ester
[0596] 0.04 g of
[7-(2-tert-butoxycarbonylamino-1H-imidazol-4-yl)-4-methoxy-benzothiazol-2-
-yl]-carbamic acid methyl ester (0.0001 Mol) were heated to
60.degree. C. in HCl/MeOH (2.5 M, 2 ml). After evaporation of the
solvent the residue was dissolved in water (5 ml) and the pH was
adjusted to 8 with sat. NaHCO.sub.3. The water was evaporated and
the residue triturated in ethyl acetate where a precipitation
formed. This was isolated and dried to yield the title compound as
a grey solid (16%); F.p.: 225-235.degree. C.
[0597] The following examples were prepared according to the
general method described for
4-methoxy-7-vinyl-benzothiazol-2-yl-amine (Example 189a) from the
corresponding carbamic acid methyl ester: [0598]
4-Methoxy-7-(2-morpholin-4-yl-thiazol-4-yl)-benzothiazol-2-yl-amine
[0599] Obtained as a white solid (73%); F.p.: 289-292.degree. C.
[0600]
4-Methoxy-7-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzothiazol-2-yl--
amine
[0601] Obtained as a light yellow solid (81%); F.p.: 176.degree. C.
(dec.). [0602]
4-Methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl-am-
ine
[0603] Obtained as an off-white solid (94%); MS (ISP): m/e=355
(M+H.sup.+). [0604]
7-(2-Amino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl-amine
[0605] Obtained as a white solid (56%); MS (ISP): m/e=279
(M+H.sup.+). [0606]
7-(2-Dimethylamino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl-amine
[0607] Obtained as a beige solid (62%); F.p.: 225-238.degree. C.
[0608] 4-Methoxy-7-thiophen-2-yl-benzothiazol-2-yl-amine
[0609] Obtained as a light brown solid (85%); F.p.: 215-219.degree.
C. [0610]
4-Methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl-amine
[0611] Obtained as a light yellow solid (67%); F.p.: 302.degree. C.
(dec.). [0612]
4-Methoxy-7-(2-pyrrolidin-1-yl-thiazol-4-yl)-benzothiazol-2-yl-amine
[0613] Obtained as a light brown solid (99%); F.p.: 270.degree. C.
(dec.). [0614]
4-Methoxy-7-(2-piperidin-1-yl-thiazol-4-yl)-benzothiazol-2-yl-amin-
e
[0615] Obtained as a light brown solid (75%); MS (ISP): m/e=347
(M+H.sup.+). [0616]
4-Methoxy-7-(2-methyl-thiazol-4-yl)-benzothiazol-2-yl-amine
[0617] Obtained as an off-white solid (81%); F.p.: 262-265.degree.
C. [0618]
4-Methoxy-7-(5-methyl-thiophen-2-yl)-benzothiazol-2-yl-amine
[0619] Obtained as an off-white solid (81%); F.p.: 195-205.degree.
C. (dec.). [0620]
7-(2,5-Dimethyl-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl-amine
[0621] Obtained as a yellow solid (5%); F.p.: 201-203.degree.
C.
Following the General Method of Example 1 the Following Examples
were Obtained from Corresponding benzothiazol-2-yl-amines and
4-fluoro-benzoic acid chloride:
EXAMPLE 216
4-Fluoro-N-[4-methoxy-7-(2-morpholin-4-yl-thiazol-4-yl)-benzothiazol-2-yl]-
-benzamide
[0622] Obtained as an off-white solid (53%); F.p.: 225-227.degree.
C.
EXAMPLE 217
N-[7-(2-Amino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-4-fluoro-benzamid-
e
[0623] Obtained as a white solid (85%); F.p.: 262-264.degree.
C.
EXAMPLE 218
4-Fluoro-N-{4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothia-
zol-2-yl}-benzamide
[0624] Obtained as an off-white solid (79%); MS (ISP): m/e=477
(M+H.sup.+).
EXAMPLE 219
N-[7-(2-Dimethylamino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-4-fluoro--
benzamide
[0625] Obtained as a light yellow solid (29%); F.p.:
218-220.degree. C.
EXAMPLE 220
4-Fluoro-N-(4-methoxy-7-thiophen-2-yl-benzothiazol-2-yl)-benzamide
[0626] Obtained as a light yellow solid (72%); F.p.:
242-250.degree. C.
EXAMPLE 221
4-Fluoro-N-{4-methoxy-7-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzoth-
iazol-2-yl}-benzamide
[0627] Obtained as an off-white solid (66%); F.p.: 138.degree. C.
(dec.).
EXAMPLE 222
4-Fluoro-N-[4-methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-b-
enzamide
[0628] Obtained as an off-white solid (92%); F.p.: 150.degree. C.
(dec.).
EXAMPLE 223
4-Fluoro-N-[4-methoxy-7-(2-pyrrolidin-1-yl-thiazol-4-yl)-benzothiazol-2-yl-
]-benzamide
[0629] Obtained as an off-white solid (82%); MS (ISP): m/e=455
(M+H.sup.+).
EXAMPLE 224
4-Fluoro-N-[4-methoxy-7-(2-methyl-thiazol-4-yl)-benzothiazol-2-yl]-benzami-
de
[0630] Obtained as awhite solid (36%); F.p.: 217-219.degree. C.
EXAMPLE 225
4-Fluoro-N-[4-methoxy-7-(5-methyl-thiophen-2-yl)-benzothiazol-2-yl]-benzam-
ide
[0631] Obtained as an off-white solid (70%); F.p.: 192-196.degree.
C. (dec.).
EXAMPLE 226
N-[7-(25-Dimethyl-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-4-fluoro-benz-
amide
[0632] Obtained as an off-white solid (42%); F.p.: 205-206.degree.
C. (dec.).
EXAMPLE 227
4-Chloromethyl-N-[4-methoxy-7-(2-morpholin-4-yl-thiazol-4-yl)-benzothiazol-
-2-yl]-benzamide
[0633] 0.165 g of
4-methoxy-7-(2-morpholin-4-yl-thiazol-4-yl)-benzothiazol-2-ylamine
(0.00047 Mol) were dissolved in dioxane (5 ml) and combined with
0.1 ml of triethylamine (0.0007 Mol), 0.006 g DMAP (0.000047 Mol)
and a solution of 0.116 g of 4-(chloromethyl)benzoylchloride
(0.00062 Mol) in dioxane (1 ml). The reaction mixture was stirred
for 6 hrs. at 70.degree. C. After cooling down to room temperature,
water (10 ml) and sat. NaHCO.sub.3 (10 ml) were added. A
precipitation formed. It was filtered, washed with water and tried.
This crude product was subjected to column chromatography
(silicagel, CH.sub.2Cl.sub.2/MeOH 19:1). The title compound was
obtained as a light yellow solid (65%); F.p.: 166-168.degree.
C.
The Following Examples were Prepared from the Corresponding
7-Substituted 4-methoxy-benzothiazol-2-yl-amines According to the
above Described Method:
EXAMPLE 228
4-Chloromethyl-N-{4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-ben-
zothiazol-2-yl}-benzamide
[0634] Obtained as an off-white solid (68%); F.p.: 230-250.degree.
C.
EXAMPLE 229
4-Chloromethyl-N-{4-methoxy-7-[2-(trityl-amino)-thiazol-4-yl]-benzothiazol-
-2-yl}-benzamide
[0635] Obtained as a white solid (42%); F.p.: 163.degree. C.
(dec.).
EXAMPLE 230
4-Chloromethyl-N-[7-(2-dimethylamino-thiazol-4-yl)-4-methoxy-benzothiazol--
2-yl]-benzamide
[0636] Obtained as a light yellow solid (36%); F.p.:
183-186.degree. C.
EXAMPLE 231
4-Chloromethyl-N-(4-methoxy-7-thiophen-2-yl-benzothiazol-2-yl)-benzamide
[0637] Obtained as a light yellow solid (60%); F.p.:
183-209.degree. C. (dec.).
EXAMPLE 232
4-Chloromethyl-N-[4-methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-
-yl]-benzamide
[0638] Obtained as a light brown solid (79%); F.p.: 195-201.degree.
C.
EXAMPLE 233
4-Chloromethyl-N-[4-methoxy-7-(2-methyl-thiazol-4-yl)-benzothiazol-2-yl]-b-
enzamide
[0639] Obtained as a white solid (72%); F.p.: 140-145.degree.
C.
EXAMPLE 234
4-Chloromethyl-N-[4-methoxy-7-(5-methyl-thiophen-2-yl)-benzothiazol-2-yl]--
benzamide
[0640] Obtained as a yellow solid (93%); F.p.: 130-146.degree.
C.
EXAMPLE 235
4-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-N-[4-methoxy-7-(2-morpholin-4--
yl-thiazol-4-yl)-benzothiazol-2-yl]-benzamide
[0641] 0.035 g N-(2-methoxyethyl)-methylamine (0.00039 Mol) and
0.064 g
(4-chloromethyl-N-[4-methoxy-7-(2-morpholin-4-yl-thiazol-4-yl)-benzothiaz-
ol-2-yl]-benzamide (0.00013 Mol) dissolved in THF (2 ml) were
heated to reflux for 4 hrs. After cooling to room temperature and
evaporation of the solvent the residue was triturated with water (7
ml). A precipitation formed, which was filtered, washed with water
and dried yielding the title product as an off-white solid (79%);
F.p.: 100-110.degree. C.
[0642] The following examples were prepared according to the method
above from N-(2-methoxyethyl)methylamine and the corresponding
7-substituted
4-chloromethyl-N-[4-methoxy-benzothiazol-2-yl]-benzamides:
EXAMPLE 236
4-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-N-{4-methoxy-7-[2-(trityl-amin-
o)-thiazol-4-yl]-benzothiazol-2-yl}-benzamide
[0643] Obtained as a white solid (79%); F.p.: 119-128.degree.
C.
EXAMPLE 237
N-[7-(2-Amino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-4-{[(2-methoxy-et-
hyl)-methyl-amino]-methyl}-benzamide
[0644] g of
4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-{4-methoxy-7-[2-(trityl-ami-
no)-thiazol-4-yl]-benzothiazol-2-yl}-benzamide (0.00014 Mol) were
treated with cc HCl (0.03 ml) in MeOH (1 ml) for 1 h at reflux.
After evaporation of the solvent the residue was taken up in water
(10 ml), treated with sat. NaHCO.sub.3 (10 ml) and extracted
4.times. with ethyl acetate. The combined organic phases were dried
over Na.sub.2SO.sub.4, filtered and concentrated. The residue was
subjected to column chromatography (silicagel, ethyl acetate,
CH.sub.2Cl.sub.2/MeOH 19:1 and 9:1). The title compound was
obtained as a white solid (53%); F.p.: 199-206.degree. C.
EXAMPLE 238
4-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-N-{4-methoxy-7-[2-(6-methyl-py-
ridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl}-benzamide
[0645] Obtained as a light yellow foam (69%); MS (ISP): m/e=560
(M+H.sup.+).
EXAMPLE 239
N-[7-(2-Dimethylamino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-4-{[(2-me-
thoxy-ethyl)-methyl-amino]-methyl}-benzamide
[0646] Obtained as a light yellow solid (47%); F.p.: 85-95.degree.
C.
EXAMPLE 240
4-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-thiophen-2-yl-b-
enzothiazol-2-yl)-benzamide
[0647] Obtained as a light beige solid (44%); F.p.: 58-78.degree.
C.
EXAMPLE 241
4-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-N-[4-methoxy-7-(2-pyridin-2-yl-
-thiazol-4-yl)-benzothiazol-2-yl]-benzamide
[0648] Obtained as a light yellow solid (54%); MS (ISP): m/e=546
(M+H.sup.+).
EXAMPLE 242
4-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-N-[4-methoxy-7-(2-methyl-thiaz-
ol-4-yl)-benzothiazol-2-yl]-benzamide
[0649] Obtained as a white solid (36%); F.p.: 140-145.degree.
C.
EXAMPLE 243
4-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-N-[4-methoxy-7-(5-methyl-thiop-
hen-2-yl)-benzothiazol-2-yl]-benzamide
[0650] Obtained as a light beige solid (73%); F.p.: 83-90.degree.
C.
EXAMPLE 244
N-[4-Methoxy-7-(2-morpholin-4-yl-thiazol-4-yl)-benzothiazol-2-yl]-4-pyrrol-
idin-1-yl-methyl-benzamide
[0651] 0.032 g pyrrolidine (0.00045 Mol) and 0.075 g
(4-chloromethyl-N-[4-methoxy-7-(2-morpholin-4-yl-thiazol-4-yl)-benzothiaz-
ol-2-yl]-benzamide (0.00015 Mol) dissolved in THF (2 ml) were
heated to reflux for 1 h. After cooling to room temperature and
evaporation of the solvent the residue was triturated with water (7
ml). A precipitation formed, which was filtered, washed with water
and dried yielding the title product as an off-white solid (87%);
F.p.: 120-130.degree. C.
The Following Examples were Prepared According to the Method Above
from Pyrrolidine and the Corresponding 7-Substituted
4-chloromethyl-N-[4-methoxy-benzothiazol-2-yl]-benzamides:
EXAMPLE 245
N-{4-Methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl}-
-4-pyrrolidin-1-yl-methyl-benzamide
[0652] Obtained as a light brown solid (58%); F.p.: 230-231.degree.
C.
EXAMPLE 246
N-{4-Methoxy-7-[2-(trityl-amino)-thiazol-4-yl]-benzothiazol-2-yl}-4-pyrrol-
idin-1-yl-methyl-benzamide
[0653] Obtained as a light yellow solid (89%); F.p.:
122-135.degree. C.
EXAMPLE 247
N-[7-(2-Amino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-4-pyrrolidin-1-yl-
-methyl-benzamide hydrochloride (1:1)
[0654] 0.055 g of
N-{4-methoxy-7-[2-(trityl-amino)-thiazol-4-yl]-benzothiazol-2-yl}-4-pyrro-
lidin-1-ylmethyl-benzamide (0.000078 Mol) were dissolved in MeOH
(0.5 ml) and ccHCl (0.015 ml). After refluxing for 1 h the solvent
was evaporated, the residue treated with ethyl acetate, filtered
and isolated. This material was triturated in EtOH whereby crystals
formed, which were washed with Et.sub.2O. After drying the title
compound was obtained as a white solid (62%); F.p.: 228-240.degree.
C.
EXAMPLE 248
N-[7-(2-Dimethylamino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-4-pyrroli-
din-1-yl methyl-benzamide
[0655] Obtained as a light yellow solid (75%); F.p.:
120-136.degree. C.
EXAMPLE 249
N-(4-Methoxy-7-thiophen-2-yl-benzothiazol-2-yl)-4-pyrrolidin-1-yl-methyl-b-
enzamide
[0656] Obtained as a light beige solid (47%); F.p.: 174-190.degree.
C. (dec.).
EXAMPLE 250
N-[4-Methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-4-pyrrolid-
in-1-yl-methyl-benzamide
[0657] Obtained as a light yellow foam (48%); MS (ISP): m/e=528
(M+H.sup.+).
EXAMPLE 251
N-[4-Methoxy-7-(5-methyl-thiophen-2-yl)-benzothiazol-2-yl]-4-pyrrolidin-1--
yl-methyl-benzamide
[0658] Obtained as a light beige solid (67%); F.p.: 140-149.degree.
C. (dec.).
EXAMPLE 252
N-[4-Methoxy-7-(2-methyl-thiazol-4-yl)-benzothiazol-2-yl]-4-pyrrolidin-1-y-
l-methyl-benzamide
[0659] Obtained as a light yellow solid (44%); F.p.:
123-134.degree. C.
EXAMPLE 253
N-(4-Methoxy-7-thiophen-2-yl-benzothiazol-2-yl)-2-methyl-isonicotinamide
[0660] 0.21 g of 4-methoxy-7-thiophen-2-yl-benzothiazol-2-yl-amine
(0.0008 Mol) together with 0.27 ml triethylamine (0.002 Mol), 0.01
g of DMAP and 0.20 g isonicotinic acid chloride (0.001 Mol) were
heated to reflux for 20 hrs. in dioxane (10 ml). After cooling to
room temperature water (20 ml) and sat. NaHCO.sub.3 (15 ml) were
added. A precipitation formed, which was filtered, washed with
water and dried. This crude product was subjected to column
chromatography (silicagel, ethyl acetate) to yield the title
compound as a yellow solid (58%); F.p.: 203-211.degree. C.
(dec.).
The Following Examples were Prepared According to the Method Above
from Isonicotinic Acid Chloride and the Corresponding 7-substituted
4-methoxy-benzothiazol-2-yl-amines:
EXAMPLE 254
N-[4-Methoxy-7-(2-pyridin-2-yl-thiazol-4-yl-benzothiazol-2-yl]-2-methyl-is-
onicotinamide
[0661] Obtained as a light yellow solid (38%); MS (ISP): m/e=460
(M+H.sup.+).
EXAMPLE 255
N-[4-Methoxy-7-(2-pyrrolidin-1-yl-thiazol-4-yl)-benzothiazol-2-yl]-2-methy-
l-isonicotinamide
[0662] Obtained as a yellow solid (9%); F.p.: 195-215.degree.
C.
EXAMPLE 256
N-{4-Methoxy-7-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzothiazol-2-y-
l}-2-methyl-isonicotinamide
[0663] Obtained as a yellow foam (4%); MS (ISP): m/e=481
(M+H.sup.+)
EXAMPLE 257
N-[4-Methoxy-7-(5-methyl-thiophen-2-yl)-benzothiazol-2-yl]-2-methyl-isonic-
otinamide
[0664] Obtained as a light orange foam (65%); MS (ISP): m/e=396
(M+H.sup.+).
EXAMPLE 258
Morpholine-4-carboxylic acid
{4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl}--
amide
[0665] 0.1 g of
4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-ylami-
ne (0.00028 Mol) were dissolved in dioxane (2 ml) and treated with
0.047 ml triethylamine (0.00034 Mol) and 0.164 ml of phosgene (20%
in toluene) (0.00031 Mol). After stirring for 2 hrs. at room
temperature 0.122 ml of morpholine (0.0014 Mol) were added and the
whole mixture was stirred for 16 hrs. at ambient temperature. Upon
addition of water (5 ml) a precipitation formed, which was
filtered, washed with water and dried. This crude material was
triturated with hot MeOH and after cooling to room temperature
filtered. The filtrate was evaporated and the residue subjected to
column chromatography (silicagel, CH.sub.2Cl.sub.2/MeOH+1%
NH.sub.4OH). The title compound was obtained as a light yellow
solid (7%); MS (ISP): m/e=468 (M+H.sup.+)
EXAMPLE 259
Morpholine-4-carboxylic acid
[4-methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-amide
[0666] g of
4-methoxy-7-[2-pyridin-2-yl)-thiazol-4-yl]-benzothiazol-2-yl-amine
(0.00029 Mol) were dissolved in THF (5 ml) and treated with 0.063
ml ethyldiisopropylamine (0.00037 Mol), DMAP (1 mg) and 0.029 mg of
triphosgene (0.0001 Mol). After heating to reflux for 30 min.,
0.0322 ml of morpholine (0.00037 Mol) and another 0.062 ml of
ethyldiisopropylamine were added and the whole mixture was stirred
for 16 hrs. at reflux. After cooling to room temperature water (10
ml) was added and the reaction mixture was extracted with ethyl
acetate (4.times., 15 ml each). The combined organic phases were
dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue
was subjected to column chromatography (silicagel, ethyl
acetate).
[0667] The title compound was obtained as a light yellow solid
(7%); F.p.: 152-178.degree. C. (dec.).
EXAMPLE 260
Morpholine-4-carboxylic acid
[4-methoxy-7-(2-methyl-thiazol-4-yl)-benzothiazol-2-yl]-amide
[0668] 0.07 g of
7-(2-Amino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl-amine (0.00025
Mol) were suspended in dioxane (4 ml) and treated with 0.028 g of
NaH (60% dispersion in oil) (0.0006 Mol) for 1 h at room
temperature. Then 0.11 ml of triethylamine (0.00076 Mol) and 0.07
ml of morpholine-4-carbonylchloride (0.0006 Mol) were added and the
reaction mixture was stirred at room temperature for 3 hrs. Then
water (15 ml) was added and the reaction mixture was extracted with
ethyl acetate (4.times., 20 ml each). The combined organic phases
were dried over Na.sub.2SO.sub.4, filtered and evaporated. The
residue was subjected to column chromatography (silicagel, ethyl
acetate). The title compound was obtained as a light yellow solid
(61%); F.p.: 223-226.degree. C. (dec.).
The Following Examples were Prepared According to the Method Above
from Morpholin-4-carbonylchloride and the corresponding
7-substituted 4-methoxy-benzothiazol-2-ylamines:
EXAMPLE 261
Morpholine-4-carboxylic acid
{4-methoxy-7-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzothiazol-2-yl-
}-amide
[0669] Obtained as a beige solid (40%); F.p.: 150-170.degree.
C.
EXAMPLE 262
Morpholine-4-carboxylic acid
[4-methoxy-7-(2-piperidin-1-yl-thiazol-4-yl)-benzothiazol-2-yl]-amide
[0670] Obtained as a light yellow solid (25%); F.p.:
227-234.degree. C.
EXAMPLE 263
Morpholine-4-carboxylic acid
(4-methoxy-7-thiophen-2-yl-benzothiazol-2-yl)-amide
[0671] Obtained as a light beige solid (37%); F.p.: 175-182.degree.
C. (dec.).
EXAMPLE 264
Morpholine-4-carboxylic acid
[4-methoxy-7-(5-methyl-thiophen-2-yl)-benzothiazol-2-yl]-amide
[0672] Obtained as a light beige solid (59%); F.p.: 173-180.degree.
C. (dec.).
EXAMPLE 265
4-Hydroxy-piperidine-1-carboxylic acid
[4-methoxy-7-(2-methyl-thiazol-4-yl)-benzothiazol-2-yl]-amide
[0673] To a suspension of 0.070 g of
4-methoxy-7-(2-methyl-thiazol-4-yl)-benzothiazol-2-ylamine (0.00025
Mol) in THF (4 ml) at room temperature were added 0.054 ml
N-ethyl-diisopropylamine (0.00031 Mol) and 0.001 g DMAP. 0.025 g of
triphosgene (0.000085 Mol) were added and the whole mixture was
heated to 70.degree. C. for 1 hr. Then another 0.054 ml
N-ethyl-diisopropylamine (0.00031 Mol) and 0.031 g of
4-hydroxy-piperidin (0.00031 Mol) were added and the reaction
mixture was stirred at 70.degree. C. for 1.5 hrs. Upon cooling to
room temperature a precipitation formed, which was filtered and
washed with THF. The filtrate was evaporated and the residue was
subjected to column chromatography (silicagel,
CH.sub.2Cl.sub.2/MeOH 9:1). The title product was obtained as a
white solid (11%); F.p.: 145-150.degree. C.
[0674] The following example was prepared according to the above
described methode from
4-methoxy-7-(5-methyl-thiophene-2-yl)-benzothiazol-2-yl-amine:
EXAMPLE 266
4-Hydroxy-piperidine-1-carboxylic acid
[4-methoxy-7-(5-methyl-thiophen-2-yl)-benzothiazol-2-yl]-amide
[0675] Obtained as a yellow solid (10%); F.p.: 197-204.degree. C.
(dec.).
[0676] The following example was prepared according to the method
described above from N-methyl-piperazine and
4-methoxy-7-(2-methyl-thiazol-4-yl)-benzothiazol-2-ylamine:
EXAMPLE 267
4-Methyl-piperazine-1-carboxylic acid
[4-methoxy-7-(2-methyl-thiazol-4-yl)-benzothiazol-2-yl]-amide
[0677] Obtained as a white solid (8%); F.p.: 179-181.degree. C.
EXAMPLE 268
{2-[4-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-ylcarbamoyl)-phenyl]-ethy-
l}-methyl-carbamic acid tert-butyl ester
[0678] Using [2-(4-chlorocarbonyl-phenyl)-ethyl]-methyl-carbamic
acid tert-butyl ester the title compound was prepared using the
general method of example 1 as white solid (16%), MS: m/e=527
(M+H.sup.+).
EXAMPLE 269
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-(1,1,2,2-tetrafluoro-et-
hoxy)-benzamide
[0679] Using 4-(1,1,2,2-tetrafluoro-ethoxy)-benzoyl chloride the
title compound was prepared using the general method of example 1
as light yellow solid (35%), MS: m/e=486 (M+H.sup.+).
EXAMPLE 270
4-[(2-Methoxy-ethyl)-methyl-sulfamoyl]-N-(4-methoxy-7-morpholin-4-yl-benzo-
thiazol-2-yl)-benzamide
[0680] Using (2-methoxy-ethyl)-methyl-sulfamic acid chloride the
title compound was prepared using the general method of example 1
as red solid (44%), MS: m/e=521 (M+H.sup.+).
EXAMPLE 271
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-trifluoromethyl-benzami-
de
[0681] Using 4-(trifluoromethyl)-benzoyl chloride the title
compound was prepared using the general method of example 1 as
white solid (58%), MS: m/e=438 (M+H.sup.+).
EXAMPLE 272
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-trifluoromethoxy-benzam-
ide
[0682] Using 3-(trifluoro-methoxy)-benzoyl chloride the title
compound was prepared using the general method of example 1 as
light yellow solid (84%), MS: m/e=454 (M+H.sup.+).
EXAMPLE 273
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-trifluoromethoxy-benzam-
ide
[0683] Using 4-(trifluoro-methoxy)-benzoyl chloride the title
compound was prepared using the general method of example 1 as
yellow solid (77%), MS: m/e=453 (M.sup.+).
EXAMPLE 274
4-Ethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
[0684] Using 4-ethyl-benzoyl chloride the title compound was
prepared using the general method of example 1 as white solid
(21%), MS: m/e=397 (M+H.sup.+).
EXAMPLE 275
4-Fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
[0685] Using 4-fluoro-benzoyl chloride the title compound was
prepared using the general method of example 1 as white solid
(64%), MS: m/e=388 (M+H.sup.+).
EXAMPLE 276
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methyl-isonicotinamide
[0686] Using 2-methyl-isonicotinyl chloride the title compound was
prepared using the general method of example 1 as white solid
(72%), MS: m/e=385 (M+H.sup.+).
EXAMPLE 277
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
[0687] Using benzoyl chloride the title compound was prepared using
the general method of example 1 as white solid (85%), MS: m/e=370
(M+H.sup.+).
The Following Compounds are Described According to the General
Procedure C in Example 126:
EXAMPLE 278
4-Chloro-3-{[ethyl-(2-methoxy-ethyl)-amino]-methyl}-N-(4-methoxy-7-morphol-
in-4-yl-benzothiazol-2-yl)-benzamide
[0688] Using 4-chloro-3-chloromethyl-benzoyl chloride and
ethyl-(2-methoxy-ethyl)-amine the title compound was prepared using
the general procedure C as off-white solid (69%), MS: m/e=519
(M+H.sup.+).
EXAMPLE 279
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-methylaminomethyl-benza-
mide
[0689] Using 3-chloromethyl-benzoyl chloride and methylamine the
title compound was prepared using the general procedure C as white
solid (44%), MS: m/e=413 (M+H.sup.+).
EXAMPLE 280
4-Chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-methylaminomet-
hyl-benzamide
[0690] Using 4-chloro-3-chloromethyl-benzoyl chloride and
methylamine the title compound was prepared using the general
procedure C as light yellow solid (69%), MS: m/e=447
(M+H.sup.+).
EXAMPLE 281
4-Chloro-3-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpho-
lin-4-yl-benzothiazol-2-yl)-benzamide
[0691] Using 4-chloro-3-chloromethyl-benzoyl chloride and
(2-methoxy-ethyl)-methyl-amine the title compound was prepared
using the general procedure C as off-white solid (54%), MS: m/e=505
(M+H.sup.+).
EXAMPLE 282
4-Chloro-3-[(2-methoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-b-
enzothiazol-2-yl)-benzamide
[0692] Using 4-chloro-3-chloromethyl-benzoyl chloride and
2-methoxy-ethylamine the title compound was prepared using the
general procedure C as off-white solid (69%), MS: m/e=491
(M+H.sup.+)
EXAMPLE 283
4-Chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-pyrrolidin-1-y-
lmethyl-benzamide
[0693] Using 4-chloro-3-chloromethyl-benzoyl chloride and
pyrrolidine the title compound was prepared using the general
procedure C as light yellow solid (72%), MS: m/e=487
(M+H.sup.+).
EXAMPLE 284
1-[4-(4-Benzyloxy-7-morpholin-4-yl-benzothiazol-2-ylcarbamoyl)-benzyl]-pyr-
idinium; chloride
[0694] Using 4-benzyloxy-7-morpholin-4-yl-benzothiazol-2-ylamine,
4-chloromethyl-benzoyl chloride and pyridine the title compound was
prepared using the general procedure C as white solid (80%), MS:
m/e=538 (M.sup.+).
EXAMPLE 285
3-Fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-pyrrolidin-1-y-
lmethyl-benzamide
[0695] Using 4-chloromethyl-3-fluoro-benzoyl chloride and
pyrrolidine the title compound was prepared using the general
procedure C as yellow solid (25%), MS: m/e=471 (M+H.sup.+).
EXAMPLE 286
3-[(2-Methoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiaz-
ol-2-yl)-benzamide
[0696] Using 3-chloromethyl-benzoyl chloride and
2-methoxy-ethylamine the title compound was prepared using the
general procedure C as light yellow solid (68%), MS: m/e=457
(M+H.sup.+)
EXAMPLE 287
3-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl--
benzothiazol-2-yl)-benzamide
[0697] Using 3-chloromethyl-benzoyl chloride and
(2-methoxy-ethyl)-methyl-amine the title compound was prepared
using the general procedure C as yellow solid (75%), MS: m/e=471
(M+H.sup.+).
EXAMPLE 288
1-[4-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-ylcarbamoyl)-benzyl]-pyrid-
inium; chloride
[0698] Using 4-chloromethyl-benzoyl chloride and pyridine the title
compound was prepared using the general procedure C as white solid
(33%), MS: m/e=462 (M.sup.+).
EXAMPLE 289
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-pyrrolidin-1-ylmethyl-b-
enzamide
[0699] Using 3-chloromethyl-benzoyl chloride and pyrrolidine the
title compound was prepared using the general procedure C as light
yellow solid (65%), MS: m/e=454 (M+H.sup.+).
EXAMPLE 290
4-[(2-Ethoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazo-
l-2-yl)-benzamide
[0700] Using 4-chloromethyl-benzoyl chloride and
2-ethoxy-ethylamine the title compound was prepared using the
general procedure C as white solid (18%), MS: m/e=471
(M+H.sup.+).
EXAMPLE 291
[R]-N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-(3-methoxy-pyrrolid-
in-1-yl-methyl)-benzamide
[0701] Using 4-chloromethyl-benzoyl chloride and
[R]-3-methoxy-pyrrolidine the title compound was prepared using the
general procedure C as light yellow solid (18%), MS: m/e=483
(M+H.sup.+)
EXAMPLE 292
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benza-
mide
[0702] Using 4-chloromethyl-benzoyl chloride and methylamine the
title compound was prepared using the general procedure C as light
yellow solid (63%), MS: m/e=413 (M+H.sup.+).
EXAMPLE 293
[S]-N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-(3-methoxy-pyrrolid-
in-1-ylmethyl)-benzamide
[0703] Using 4-chloromethyl-benzoyl chloride and
[S]-3-methoxy-pyrrolidine the title compound was prepared using the
general procedure C as light brown solid (13%), MS: m/e=483
(M+H.sup.+)
EXAMPLE 294
4-Azetidin-1-ylmethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-ben-
zamide
[0704] Using 4-chloromethyl-benzoyl chloride and azetidine the
title compound was prepared using the general procedure C as light
yellow solid (33%), MS: m/e=439 (M+H.sup.+).
EXAMPLE 295
4-[1-(2-Methoxy-ethylamino)-ethyl]-N-(4-methoxy-7-morpholin-4-yl-benzothia-
zol-2-yl)-benzamide
[0705] Using 4-(1-chloro-ethyl)-benzoyl chloride and
2-methoxy-ethylamine the title compound was prepared using the
general procedure C as yellow solid (52%), MS: m/e=471
(M+H.sup.+).
EXAMPLE 296
4-{1-[(2-Methoxy-ethyl)-methyl-amino]-ethyl}-N-(4-methoxy-7-morpholin-4-yl-
-benzothiazol-2-yl)-benzamide
[0706] Using 4-(1-chloro-ethyl)-benzoyl chloride and
(2-methoxy-ethyl)-methyl-amine the title compound was prepared
using the general procedure C as yellow solid (91%), MS: m/e=485
(M+H.sup.+)
EXAMPLE 297
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-(1-pyrrolidin-1-yl-ethy-
l)-benzamide
[0707] Using 4-(1-chloro-ethyl)-benzoyl chloride and pyrrolidine
the title compound was prepared using the general procedure C as
yellow solid (68%), MS: m/e=467 (M+H.sup.+).
EXAMPLE 298
4-(2-Dimethylamino-ethylsulfanylmethyl)-N-(4-methoxy-7-morpholin-4-yl-benz-
othiazol-2-yl)-benzamide
[0708] Using 4-chloromethyl-benzoyl chloride and
2-dimethylamino-ethanethiol the title compound was prepared using
the general procedure C as yellow solid (52%), MS: m/e=487
(M+H.sup.+).
EXAMPLE 299
(rac)
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-{[methyl-(4,4,4-t-
rifluoro-3-hydroxy-butyl)-amino]-methyl}-benzamide
[0709] Using 4-chloromethyl-benzoyl chloride and
(rac)-1,1,1-trifluoro-4-methylamino-butan-2-ol the title compound
was prepared using the general procedure C as white solid (89%),
MS: m/e=539 (M+H).
EXAMPLE 300
4-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-b-
enzothiazol-2-yl)-benzamide
[0710] Using 4-chloromethyl-benzoyl chloride and
(2-methoxy-ethyl)-ethyl-amine the title compound was prepared using
the general procedure C as light brown solid (62%), MS: m/e=485
(M+H.sup.+).
EXAMPLE 301
4-{[(2-Ethoxy-ethyl)-ethyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-be-
nzothiazol-2-yl)-benzamide
[0711] Using 4-chloromethyl-benzoyl chloride and
(2-ethoxy-ethyl)-ethyl-amine the title compound was prepared using
the general procedure C as light brown solid (66%), MS: m/e=499
(M+H.sup.+)
EXAMPLE 302
3-Fluoro-4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpho-
lin-4-yl-benzothiazol-2-yl)-benzamide
[0712] Using 3-fluoro-4-chloromethyl-benzoyl chloride and
(2-methoxy-ethyl)-methyl-amine the title compound was prepared
using the general procedure C as light brown solid (52%), MS:
m/e=489 (M+H.sup.+).
EXAMPLE 303
4-{[Bis-(2-ethoxy-ethyl)-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-benz-
othiazol-2-yl)-benzamide
[0713] Using 4-chloromethyl-benzoyl chloride and
bis-(2-ethoxy-ethyl)-amine the title compound was prepared using
the general procedure C as light brown solid (49%), MS: m/e=543
(M+H.sup.+).
EXAMPLE 304
4-{[(2-Ethoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-b-
enzothiazol-2-yl)-benzamide
[0714] Using 4-chloromethyl-benzoyl chloride and
(2-ethoxy-ethyl)-methyl-amine the title compound was prepared using
the general procedure C as white solid (78%), MS: m/e=485
(M+H.sup.+).
EXAMPLE 305
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-(4-methoxy-piperidin-1--
yl-methyl)-benzamide
[0715] Using 4-chloromethyl-benzoyl chloride and
4-methoxy-piperidine the title compound was prepared using the
general procedure C as white solid (33%), MS: m/e=497
(M+H.sup.+).
EXAMPLE 306
4-Diethylaminomethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benz-
amide
[0716] Using 4-chloromethyl-benzoyl chloride and diethylamine the
title compound was prepared using the general procedure C as light
yellow solid (64%), MS: m/e=456 (M+H.sup.+).
EXAMPLE 307
4-[(2-Methoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiaz-
ol-2-yl)-benzamide
[0717] Using 4-chloromethyl-benzoyl chloride and
2-methoxy-ethylamine the title compound was prepared using the
general procedure C as white solid (64%), MS: m/e=457
(M+H.sup.+).
EXAMPLE 308
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-(2-methyl-imidazol-1-yl-
-methyl)-benzamide
[0718] Using 4-chloromethyl-benzoyl chloride and
2-methyl-1H-imidazole the title compound was prepared using the
general procedure C as white solid (87%), MS: m/e=464
(M+H.sup.+).
EXAMPLE 309
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl-methyl)-benzamide
[0719] Using 4-chloromethyl-benzoyl chloride and
1-methyl-piperazine the title compound was prepared using the
general procedure C as white solid (78%), MS: m/e=482
(M+H.sup.+).
EXAMPLE 310
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-pyrrolidin-1-yl-methyl--
benzamide
[0720] Using 4-chloromethyl-benzoyl chloride and pyrrolidine the
title compound was prepared using the general procedure C as white
solid (81%), MS: m/e=454 (M+H.sup.+).
EXAMPLE 311
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-morpholin-4-yl-methyl-b-
enzamide
[0721] Using 4-chloromethyl-benzoyl chloride and morpholine the
title compound was prepared using the general procedure C as white
solid (83%), MS: m/e=469 (M+H.sup.+).
EXAMPLE 312
N-(4-Benzyloxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-{[(2-methoxy-ethyl)-m-
ethyl-amino]-methyl}-benzamide
[0722] Using
N-(4-benzyloxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-chloromethyl-benzami-
de and (2-methoxy-ethyl)-methyl-amine the title compound was
prepared using the general procedure C as white solid (69%), MS:
m/e=547 (M+H.sup.+).
EXAMPLE 313
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-{[methyl-(3,3,3-trifluo-
ro-propyl)-amino]-methyl}-benzamide; hydrochloride
[0723]
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethy-
l-benzamide (100 mg, 0.24 mmol), triethylamine (35 mg, 0.34 mmol),
potassium iodide (0.4 mg, 0.02 mmol) and
3,3,3-trifluoro-propylamine (48 mg, 0.27 mmol) were dissolved in
ethanol (1 ml) and dioxane (0.5 ml). The reaction vessel is sealed
and heated to 90.degree. C. for 18 h. Workup and purification as
described in the general procedure C afforded the title compound as
light brown solid (28%), MS: m/e=509 (M+H.sup.+).
EXAMPLE 314
4-(2-Methoxy-ethoxymethyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-
)-benzamide
[0724]
4-Chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-ben-
zamide (200 mg, 0.48 mmol) and sodium hydride (42 mg 55% dispersion
in mineral oil, 0.96 mmol) were dissolved in 2-methoxy-ethanol (3.8
ml, 48 mmol) and stirred at ambient temperature for 18 h. Workup
and purification as described in the general procedure C afforded
the title compound as white solid (70%), MS: m/e=458
(M+H.sup.+).
EXAMPLE 315
4-Methoxymethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
[0725]
4-Chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-ben-
zamide (200 mg, 0.48 mmol) were suspended in THF (5 ml) and sodium
methoxide (0.27 ml 5.4 M in MeOH, 1.4 mmol) were added at 0.degree.
C. The mixture was stirred at ambient temperature for 18 h. Workup
and purification as described in the general procedure C afforded
the title compound as light yellow solid (41%), MS: m/e=414
(M+H.sup.+).
EXAMPLE 316
N-[4-Methoxy-7-(1-oxo-1.lamda..sup.4-thiomorpholin-4-yl)-benzothiazol-2-yl-
]-benzamide
[0726] To a solution of
N-(4-methoxy-7-thiomorpholin-4-yl-benzothiazol-2-yl)-benzamide (80
mg, 0.21 mmol) in [1,4]dioxane (3 ml) was added sodium periodate
(89 mg, 0.42 mmol) and the mixture stirred for 20 h at ambient
temperature. To this mixture water (10 ml) and dichloromethane (10
ml) were added, the phases were separated and the aqueous layer
extracted twice with dichloromethane. The combined organic extracts
were dryed with Na.sub.2SO.sub.4 and the solvent evaporated.
Recrystallization from hot THF afforded the title compound as white
solid (21%), MS: m/e=402 (M+H.sup.+).
EXAMPLE 317
N-(4-Methoxy-7-thiomorpholin-4-yl-benzothiazol-2-yl)-benzamide
[0727] Following the general method of example 403 the title
compound was synthesized from
3-(2-methoxy-5-thiomorpholin-4-yl-phenyl)-thiourea (synthesized
from 4-bromo-1-methoxy-2-nitro-benzene and thiomorpholine as
described for
1-benzoyl-3-(2-methoxy-5-morpholin-4-yl-phenyl)-thiourea) as a
white solid (15%), MS: m/e=386 (M+H.sup.+).
EXAMPLE 318
5-Methyl-thiophene-2-carboxylic acid
(4-methoxy-7-piperazin-1-yl-benzothiazol-2-yl)-amide
[0728] To a solution of
4-{4-methoxy-2-[(5-methyl-thiophene-2-carbonyl)-amino]-benzothiazol-7-yl}-
-piperazine-1-carboxylic acid benzyl ester (300 mg, 0.57 mmol) in
dichloromethane (5 ml) were added boron trifluoride diethyl
etherate (0.72 ml, 5.7 mmol) and ethane thiol (1.2 ml, 17 mmol) and
the mixture stirred for 36 h. The volatile components are
evaporated and the residue codistilled twice with toluene. The
residue was dissolved in dichloromethane (25 ml), extracted with 1N
aqueous sodium carbonate and the organic phase dried with
Na.sub.2SO.sub.4. Removal of the solvent and flash chromatography
(silica, eluent CH.sub.2Cl.sub.2/MeOH/aqu. NH.sub.4OH 100:10:1)
afforded the title compound as light yellow solid (58%), MS:
m/e=389 (M+H.sup.+).
EXAMPLE 319
5-Methyl-thiophene-2-carboxylic acid
[7-(4-acetyl-piperazin-1-yl)-4-methoxy-benzothiazol-2-yl]-amide
[0729] 5-Methyl-thiophene-2-carboxylic acid
(4-methoxy-7-piperazin-1-yl-benzothiazol-2-yl)-amide (100 mg, 0.26
mmol) were suspended in DMF (2 ml) and treated with acetyl chloride
(22 .mu.l, 0.30 mmol) and pyridine (27 .mu.l, 0.34 mmol) and the
mixture stirred for 5 h at ambient temperature. Workup and
purification as described in the general procedure C afforded the
product as a white solid (55%), MS: m/e=431 (M+H.sup.+).
EXAMPLE 320
4-{4-Methoxy-2-[(5-methyl-thiophene-2-carbonyl)-amino]-benzothiazol-7-yl}--
piperazine-1-carboxylic acid methyl ester
[0730] Using methyl chloroformate the tilte compound was
synthesized as described for example 319 and obtained as white
solid (26%), MS: m/e=447(M+H.sup.+).
EXAMPLE 321
5-Methyl-thiophene-2-carboxylic acid
[4-methoxy-7-(4-methyl-piperazin-1-yl)-benzothiazol-2-yl]-amide
[0731] To a solution of 5-methyl-thiophene-2-carboxylic acid
(4-methoxy-7-piperazin-1-yl-benzothiazol-2-yl)-amide (100 mg, 0.26
mmol) in methanol (8 ml) were added formic acid (100 .mu.l, 2.6
mmol) and formaldehyde (23 .mu.l, 0.31 mmol) and the mixture
refluxed for 18 h. Workup and purification as described for
5-methyl-thiophene-2-carboxylic acid
(4-methoxy-7-piperazin-1-yl-benzothiazol-2-yl)-amide afforded the
product as light yellow powder (34%), MS: m/e=403(M+H.sup.+).
EXAMPLE 322
5-Methyl-thiophene-2-carboxylic acid
[7-(2,3-dihydro-1H-indol-6-yl)-4-methoxy-benzothiazol-2-yl]-amide
[0732] The title compound was prepared from
5-methyl-thiophene-2-carboxylic acid
(7-iodo-4-methoxy-benzothiazol-2-yl)-amide (100 mg, 0.23 mmol) and
6-iodo-2,3-dihydro-1H-indole using the general procedure B in
Example 54 as light brown crystals (26%), MS:
m/e=422(M+H.sup.+)
Intermediate
4-(4-Benzyloxy-3-nitro-phenyl)-morpholine
[0733] The title compound was prepared using morpholine and
1-benzyloxy-4-bromo-2-nitro-benzene (prepared from
4-bromo-2-nitro-anisol and benzyl bromide) using the general method
of example "4-(4-methoxy-3-nitro-phenyl)-morpholine" as yellow
solid (58%), MS: m/e=315(M+H.sup.+).
Intermediate
2-Amino-4-morpholin-4-yl-phenol
[0734] Catalytic hydrogenation of
4-(4-benzyloxy-3-nitro-phenyl)-morpholine (5 g, 16 mmol) in
dichloromethane (500 ml) and ethanol (500 ml) using palladium on
carbon (500 mg, 10%) afforded the title compound as a grey solid
(96%), MS: m/e=194(M.sup.+).
EXAMPLE 323
N-(4-Hydroxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
[0735] The title compound was prepared using
2-amino-4-morpholin-4-yl-phenol as described for
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide and
obtained as a light brown solid in 14% overall yield, MS:
m/e=356(M+H.sup.+).
EXAMPLE 324
5-Methyl-thiophene-2-carboxylic acid
[7-(3-dimethylamino-pyrrolidin-1-yl)-4-methoxy-benzothiazol-2-yl]-amide
[0736] Using 5-methyl-thiophene-2-carbonyl chloride and
7-(3-dimethylamino-pyrrolidin-1-yl)-4-methoxy-benzothiazol-2-yl-amine
the title compound was prepared using the general method of example
1 as yellow solid (90%), MS: m/e=417 (M+H.sup.+). Intermediate
7-(3-Dimethylamino-pyrrolidin-1-yl)-4-methoxy-benzothiazol-2-yl-amine
[0737] Following the general method of example 403 the title
compound was synthesized from
[5-(3-dimethylamino-pyrrolidin-1-yl)-2-methoxy-phenyl]-thiourea
(synthesized from 4-bromo-1-methoxy-2-nitro-benzene and
dimethyl-pyrrolidin-3-yl-amine as described for
(2-methoxy-5-morpholin-4-yl-phenyl)-thiourea) as a white solid
(25%), MS: m/e=293 (M+H.sup.+).
EXAMPLE 325
Tetrahydro-pyran-4-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0738] To a solution of
2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol (100 mg, 0.4 mmol)
in tetrahydrofurane (2 ml) were subsequently added
N-ethyl-diisopropylamine (194 .mu.l, 1.1 mmol) and
tetrahydropyran-4-carbonyl chloride (77 mg, 0.52 mmol, dissolved in
0.5 ml tetrahydrofurane) and the mixture refluxed for 3 h. The
mixture was then cooled to 0.degree. C., methanol (0.4 ml) was
added and the mixture slowly warmed to 20.degree. C. Then the
mixture was evaporated to dryness, dichloromethane was added (3 ml)
and extracted with saturated aqueous sodium carbonate. After back
extraction of the aqueous phase with two portions of
dichloromethane (3 ml), the combined organic phases were dryed with
Na.sub.2SO.sub.4 and the solvent evaporated. The crude product was
then chromatographed over SiO.sub.2, eluting with
CH.sub.2Cl.sub.2/MeOH 98:2, the product fractions were pooled and
the solvent evaporated, to afford the title compound as a beige
powder (142 mg, 76% yield), MS: m/e=378(M+H.sup.+).
Following the General Method of Example 325 the Following Examples
were Prepared
EXAMPLE 326
4-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-ylcarbamoyl-piperidine-1-carb-
oxylic acid tert-butyl ester
[0739] Using 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol and
4-chlorocarbonyl-piperidine-1-carboxylic acid tert-butyl ester the
title compound was obtained as a white solid (3%), MS:
m/e=477(M+H.sup.+).
EXAMPLE 327
1-Acetyl-piperidine-4-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0740] Using 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol and
1-acetyl-piperidine-4-carbonyl chloride the title compound was
obtained as a white solid (22%), MS: m/e=419(M+H.sup.+).
EXAMPLE 328
Piperidine-4-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0741]
4-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-ylcarbamoyl)-piperidin-
e-1-carboxylic acid tert-butyl ester (95 mg, 0.2 mmol) were
dissolved in trifluoroacetic acid (0.8 ml). After 1 h at room
temperature, the mixture was evaporated to dryness. Purification as
described for tetrahydro-pyran-4-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide afforded the
title compound as a white solid (77%), MS: m/e=377(M+H.sup.+).
[0742] General procedure E (ureas): The appropriate substituted
2-amino-benzothiazol (1 part, typically 500 mg) is dissolved in
CH.sub.2Cl.sub.2 (100 parts) and treated with pyridine (3 parts)
and phenyl chloroformate (1.25 parts). After stirring for 30 min at
room temperature the mixture is refluxed for 2 h when the
appropriate amine (5 equivalents) is added. After refluxing for 18
h, the mixture is evaporated to dryness, dissolved in
CH.sub.2Cl.sub.2 and extracted with aqueous sodium carbonate, after
back extraction of the aqueous phase with CH.sub.2Cl.sub.2 the
combined organic layers were dried with Na.sub.2SO.sub.4, and
evaporated to dryness. The product is isolated by flash
chromatography (silica, eluent dichloromethane containing 2.5%
methanol). Following the general method E the compounds of examples
329 to 367 and Example 370 were prepared
EXAMPLE 329
4-[(4-Fluoro-phenylamino)-methyl]-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0743] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and
4-[(4-fluoro-phenylamino)-methyl]-piperidine the title compound was
obtained as off-white solid (25%). MS: m/e=522 (M+H.sup.+).
EXAMPLE 330
4-Hydroxymethyl-4-phenyl-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0744] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and
4-hydroxymethyl-4-phenyl-piperidine the title compound was obtained
as light yellow solid (50%). MS: m/e=483 (M+H.sup.+).
EXAMPLE 331
[1-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-piperidin-4-yl-
methyl]-carbamic acid methyl ester
[0745] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
piperidin-4-ylmethyl-carbamic acid methyl ester the title compound
was obtained as white solid (81%). MS: m/e=464 (M+H.sup.+).
EXAMPLE 332
4-Ethyl-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0746] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and
4-ethyl-piperidine the title compound was obtained as white solid
(26%). MS: m/e=406 (M+H.sup.+).
EXAMPLE 333
4-(2-Oxo-pyrrolidin-1-ylmethyl)-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0747] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
4-(2-oxo-pyrrolidin-1-ylmethyl)-piperidine the title compound was
obtained as white solid (29%). MS: m/e=474 (M+H.sup.+).
EXAMPLE 334
4-(2-Methoxy-ethyl)-piperazine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0748] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
4-(2-methoxy-ethyl)-piperazine the title compound was obtained as
off-white solid (79%). MS: m/e=437 (M+H.sup.+).
EXAMPLE 335
4-Cyanomethyl-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0749] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
4-cyanomethyl-piperidine the title compound was obtained as white
solid (46%). MS: m/e=416 (M+H.sup.+).
EXAMPLE 336
[1-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl]-piperidin-4-yl-
methyl-carbamic acid tert-butyl ester
[0750] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
piperidin-4-ylmethyl-carbamic acid tert-butyl ester the title
compound was obtained as white solid (11%). MS: m/e=506
(M+H.sup.+).
EXAMPLE 337
4-[2-(4-Chloro-phenyl)-tetrahydro-furan-2-yl]-piperidine-1-carboxylic
acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0751] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
4-[2-(4-chloro-phenyl)-tetrahydro-furan-2-yl]-piperidine the title
compound was obtained as white solid (43%). MS: m/e=557
(M+H.sup.+).
EXAMPLE 338
4-(2-Hydroxy-ethyl)-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0752] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
4-(2-hydroxy-ethyl)-piperidine the title compound was obtained as
white solid (64%). MS: m/e=421 (M+H.sup.+).
EXAMPLE 339
1-(2-Methoxy-ethyl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-met-
hyl-urea
[0753] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
(2-methoxy-ethyl)-methyl-amine the title compound was obtained as
white solid (65%). MS: m/e=381 (M+H.sup.+).
EXAMPLE 340
4-Methoxyacetyl-piperazine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0754] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
4-methoxyacetyl-piperazine the title compound was obtained as beige
solid (84%). MS: m/e=450 (M+H.sup.+).
EXAMPLE 341
4-Methyl-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0755] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
4-methyl-piperidine the title compound was obtained as white solid
(47%). MS: m/e=391 (M+H.sup.+).
EXAMPLE 342
4-Oxo-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0756] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
piperidin-4-one the title compound was obtained as white solid
(38%). MS: m/e=391 (M+H.sup.+).
EXAMPLE 343
4-Cyclopropyl-4-hydroxy-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0757] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
4-cyclopropyl-4-hydroxy-piperidine the title compound was obtained
as white solid (27%). MS: m/e=434 (M+H.sup.+).
EXAMPLE 344
1,1-Dioxo-1.lamda..sup.6-thiomorpholine-4-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0758] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
thiomorpholine 1,1-dioxide the title compound was obtained as white
solid (50%). MS: m/e=427 (M+H.sup.+).
EXAMPLE 345
4-Hydroxymethyl-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0759] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and
4-hydroxymethyl-piperidine the title compound was obtained as white
solid (31%). MS: m/e=407 (M+H.sup.+).
EXAMPLE 346
Octahydro-quinoline-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0760] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
octahydro-quinoline the title compound was obtained as white solid
(79%). MS: m/e=432 (M+H.sup.+).
EXAMPLE 347
2,3-Benzo-1,4-dioxa-8-aza-spiro[4,5]decane-8-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0761] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
2,3-benzo-1,4-dioxa-8-aza-spiro[4,5]decane the title compound was
obtained as white solid (63%). MS: m/e=483 (M+H.sup.+).
EXAMPLE 348
4-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-piperazine-1-ca-
rboxylic acid methyl ester
[0762] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
piperazine-1-carboxylic acid methyl ester the title compound was
obtained as white solid (90%). MS: m/e=436 (M+H.sup.+)
EXAMPLE 349
Octahydro-isoquinoline-2-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0763] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
octahydro-isoquinoline the title compound was obtained as white
solid (53%). MS: m/e=432 (M+H.sup.+).
EXAMPLE 350
3-Methyl-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0764] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
3-methyl-piperidine the title compound was obtained as white solid
(50%). MS: m/e=391 (M+H.sup.+).
EXAMPLE 351
3-Hydroxymethyl-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0765] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and
3-hydroxymethyl-piperidine the title compound was obtained as white
solid (69%). MS: m/e=436 (M+H.sup.+).
EXAMPLE 352
3,4-Benzo-1-oxa-8-aza-spiro[4,5]decane-8-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amide
[0766] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
3,4-benzo-1-oxa-8-aza-spiro[4,5]decane the title compound was
obtained as light yellow solid (67%). MS: m/e=481 (M+H.sup.+)
EXAMPLE 353
4-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-piperazine-1-ca-
rboxylic acid tert-butyl ester
[0767] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
piperazine-1-carboxylic acid tert-butyl ester the title compound
was obtained as light yellow solid (66%). MS: m/e=478
(M+H.sup.+).
EXAMPLE 354
4-Hydroxy-4-phenyl-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0768] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
4-hydroxy-4-phenyl-piperidine the title compound was obtained as
light yellow solid (36%). MS: m/e=469 (M+H.sup.+).
EXAMPLE 355
4-Methyl-piperazine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0769] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
4-methyl-piperazine the title compound was obtained as beige solid
(20%). MS: m/e=392 (M+H.sup.+).
EXAMPLE 356
4-Trifluoromethyl-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0770] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
4-trifluoromethyl-piperidine the title compound was obtained as
white solid (16%). MS: m/e=445 (M+H.sup.+).
EXAMPLE 357
[1,4']Bipiperidinyl-1'-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0771] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
[1,4']bipiperidinyl the title compound was obtained as white solid
(35%). MS: m/e=461 (M+H.sup.+).
EXAMPLE 358
3-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-(4-methoxy-phenyl)-1-me-
thyl-urea
[0772] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
4-methoxy-phenyl)-methyl-amine the title compound was obtained as
light yellow solid (40%). MS: m/e=430 (M+H.sup.+).
EXAMPLE 359
1,4-Dioxa-8-aza-spiro[4,5]decane-8-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0773] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
1,4-dioxa-8-aza-spiro[4,5]decane the title compound was obtained as
beige solid (28%). MS: m/e=435 (M+H.sup.+).
EXAMPLE 360
3,4-Dihydro-1H-isoquinoline-2-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0774] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
1,2,3,4-tetrahydro-isoquinoline the title compound was obtained as
orange solid (63%). MS: m/e=425 (M+H.sup.+).
EXAMPLE 361
3-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-phenyl-urea
[0775] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
methyl-phenyl-amine the title compound was obtained as white solid
(19%). MS: m/e=399 (M+H.sup.+).
EXAMPLE 362
4-Hydroxy-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0776] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
piperidin-4-ol the title compound was obtained as yellow solid
(50%). MS: m/e=393 (M+H.sup.+).
EXAMPLE 363
4-Methoxy-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0777] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
4-methoxy-piperidine the title compound was obtained as yellow
solid (33%). MS: m/e=407 (M+H.sup.+).
EXAMPLE 364
1-Oxo-1.lamda..sup.4-thiomorpholine-4-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0778] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
thiomorpholine 1-oxide the title compound was obtained as white
solid (87%). MS: m/e=411 (M+H.sup.+).
EXAMPLE 365
Methanesulfonic acid
1-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylcarbamoyl)-piperidin-4-yl--
methyl ester
[0779] 4-Hydroxymethyl-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide (300 mg, 0.43
mmol) and N-ethyldiisopropylamine (95 .mu.l, 0.56 mmol) were
dissolved in CH.sub.2Cl.sub.2 (10 ml), methanesulfonyl chloride (36
.mu.l, 0.47 mmol) was added and the mixture stirred at ambient
temperature for 3 days. Purification as described in the general
procedure E afforded the product as a white solid (34%). MS:
m/e=466 (M+H.sup.+).
EXAMPLE 366
Piperazine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0780] Following the general method for piperidine-4-carboxylic
acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide the title
compound was prepared from
4-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-piperazine-1-c-
arboxylic acid tert-butyl ester as a light yellow solid (99%). MS:
m/e=378 (M+H.sup.+).
EXAMPLE 367
4-Aminomethyl-piperidine-1-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0781] Following the general method for piperidine-4-carboxylic
acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide the title
compound was prepared from
[1-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-piperidin-4-y-
lmethyl]-carbamic acid tert-butyl ester as a white solid (50%). MS:
m/e=(M+H.sup.+).
EXAMPLE 368
(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-carbamic acid
2-methoxy-ethyl ester
[0782] 4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine (300 mg,
1.1 mmol) and N-ethyldiisopropylamine (0.56 ml, 3.4 mmol) were
dissolved in tetrahydrofurane (11 ml) and 2-methoxyethyl
chloroformate (0.19 ml, 1.4 mmol) were added over 5 min. Then the
mixture was heated to 70.degree. C. for 3 h. The mixture was cooled
to room temperature, water added and extracted twice with ethyl
acetate. The combined organic phases were dried with
Na.sub.2SO.sub.4 and evaporated to dryness. The title compound was
obtained as off-white solid (52%). MS: m/e=368 (M+H.sup.+).
EXAMPLE 369
[4-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-ylcarbamoyl)-benzyl]-methyl--
carbamic acid methyl ester
[0783]
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethy-
l-benzamide (100 mg, 0.24 mmol), pyridine (29 .mu.l, 0.36 mmol) and
methyl chloroformate (24 .mu.l, 0.32 mmol) were dissolved in
dichloromethanel (5 ml) and stirred at ambient temperature for 18
h. Workup and purification as described in the general procedure C
afforded the title compound as light yellow solid (66%), MS:
m/e=471 (M+H.sup.+).
EXAMPLE 370
1-Oxo-1.lamda..sup.4-thiomorpholine-4-carboxylic acid
(4-methoxy-7-piperidin-1-yl-benzothiazol-2-yl)-amide
hydrochloride
[0784] Using 4-methoxy-7-piperidin-1-yl-benzothiazol-2-ylamine and
thiomorpholine 1-oxide the title compound was obtained as white
solid in accordance with general procedure E (80%). MS: m/e=409
(M+H.sup.+).
EXAMPLE 371
N-(4-Ethoxy-7-piperidin-1-yl-benzothiazol-2-yl)-4-fluoro-benzamide
[0785] The title compound was prepared starting from
4-bromo-1-ethoxy-2-nitro-benzene and piperidine as described for
4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
(Example 275) and obtained as a yellow solid in 10% overall yield,
MS: m/e=400 (M+H.sup.+).
EXAMPLE 372
4-Fluoro-N-(4-isopropoxy-7-piperidin-1-yl-benzothiazol-2-yl)-benzamide
[0786] The title compound was prepared starting from
4-bromo-1-isopropoxy-2-nitro-benzene and piperidine as described
for
4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
(Example 275) and obtained as a light brown solid in 10% overall
yield, MS: m/e=414 (M+H.sup.+).
EXAMPLE 373
4-Fluoro-N-(4-methoxy-7-pyrrolidin-1-yl-benzothiazol-2-yl)-benzamide
[0787] The title compound was prepared starting from
4-bromo-1-methoxy-2-nitro-benzene and pyrrolidine as described for
4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
(Example 275) and obtained as a light brown solid in about 10%
overall yield, MS: m/e=372 (M+H.sup.+).
EXAMPLE 374
4-Fluoro-N-(4-methoxy-7-[1,4]oxazepan-4-yl-benzothiazol-2-yl)-benzamide
[0788] The title compound was prepared strarting from
4-bromo-1-methoxy-2-nitro-benzene and [1.4]Oxazepane as described
for
4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
(Example 275) and obtained as a light yellow solid in about 10%
overall yield, MS: m/e=402 (M+H.sup.+).
EXAMPLE 375
Morpholine-4-carboxylic acid
[4-methoxy-7-(4-methoxy-piperidin-1-yl)-benzothiazol-2-yl]-amide
[0789] The title compound was prepared starting from
4-bromo-1-methoxy-2-nitro-benzene and 4-methoxy-piperidine as
described for morpholine-4-carboxylic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide (Example 136)
and obtained as a light yellow solid in about 10% overall yield,
MS: m/e=407 (M+H.sup.+).
EXAMPLE 376
N-(7-Azepan-1-yl-4-methoxy-benzothiazol-2-yl)-4-nitro-benzamide
[0790] The title compound was prepared using
4-bromo-1-methoxy-2-nitro-benzene, azepane and 4-nitro-benzoyl
chloride as described for
4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
(Example 275) and obtained as a light yellow solid in about 10%
overall yield, MS: m/e=427 (M+H.sup.+).
EXAMPLE 377
Morpholine-4-carboxylic acid
(4-methoxy-7-thiophen-3-yl-benzothiazol-2-yl)-amide
[0791] The title compound was prepared starting from
4-bromo-1-methoxy-2-nitro-benzene and
trimethyl-thiophen-3-yl-stannane as described for
morpholine-4-carboxylic acid
(4-methoxy-7-phenyl-benzothiazol-2-yl)-amide (Example 157) and
obtained as a light yellow solid in about 10% overall yield, MS:
m/e=376 (M+H.sup.+).
EXAMPLE 378
4-Fluoro-N-[4-methoxy-7-(2-methyl-imidazol-1-yl)-benzothiazol-2-yl]-benzam-
ide
[0792]
N-(7-Acetylamino-4-methoxy-benzothiazol-2-yl)-4-fluoro-benzamide
(100 mg, 0.28 mmol) and Lawessons reagent (135 mg, 0.33 mmol) were
dissolved in THF (10 ml) and stirred at ambient temperature for 18
h. Removal of the solvent and flash chromatography (silica, eluent
CH.sub.2Cl.sub.2/2N aqu. NH.sub.3 in MeOH 99:1 to 19:1) afforded a
yellow solid which was dissolved in acetone (10 ml) and treated
with iodomethane (19.8 mg, 1.4 mmol). After 3 h at ambient
temperature the solvent was removed and after dissolution in
ethanol (10 ml), aminoacetaldehyde dimethyl acetal (15 mg, 1.4
mmol) were added and the mixture stirred for 18 h at room
temperature. The solvent was removed and the residue refluxed for
24 h in ethanol (10 ml) and conc. sulfuric acid (1 ml). The mixture
was diluted with water (50 ml) and the pH adjusted to 8 with sodium
carbonate. It was extracted three times with dichloromethane. The
combined organic extracts were dryed with sodium sulfate and the
solvebt removed. Flash chromatography (silica, eluent
CH.sub.2Cl.sub.2/2N aqu. NH.sub.3 in MeOH 96:4 to 9:1) afforded the
title compound as brown solid, MS: m/e=383 (M+H.sup.+).
EXAMPLE 379
2-Chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-6-methyl-isonico-
tinamide
[0793] To a stirred suspension of
4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine (13.3 g, 50.1
mmol) in THF (700 ml) was added N-ethyldiisopropylamine (21.3 ml,
125 mmol). The mixture was then cooled to 5.degree. C. and a
solution of 2-chloro-6-methyl-isonicotinoyl chloride (10.5 g, 55.1
mmol) in dichloromethane (350 ml) was added dropwise over 2 hours.
The reaction mixture was then stirred overnight at 20.degree. C. To
this mixture was added methanol (40 ml) and stirring continued for
ten minutes. The mixture was then concentrated in vacuo and the
residue partitioned between ethyl acetate and saturated sodium
bicarbonate solution. The organic phases were then dried over
Na.sub.2SO.sub.4 and the solvent evaporated. The crude product was
then chromatographed over SiO.sub.2 (Merck 230-400 mesh) eluting
with CH.sub.2Cl.sub.2/MeOH (98:2), the product fractions were
pooled and the solvent evaporated, to afford the title compound as
a brown solid (16.0 g, 76% yield), MS: m/e=421
(M{.sup.37Cl}+H.sup.+), 419 (M{.sup.35Cl}+H.sup.+).
Following General Procedure E the Compounds of Examples 380 and 381
were Prepared
EXAMPLE 380
(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-urea
[0794] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
ammonia the title compound was obtained as a white solid (20%), MS:
m/e=309 (M+H.sup.+).
EXAMPLE 381
(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-carbamic acid phenyl
ester
[0795] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
without adding an amine the title compound was obtained as a white
foam (75%), MS: m/e=386 (M+H.sup.+).
Following the General Method of Example 379 the Following Compound
was Prepared
EXAMPLE 382
2-Chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
[0796] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
2-chloro-isonicotinoyl chloride the title compound was obtained as
a brown solid (59%), MS: m/e=407 (M{.sup.37Cl}+H.sup.+), 405
(M{.sup.35Cl}+H.sup.+).
EXAMPLE 383
2-Iodo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-6-methyl-isonicoti-
namide
[0797] To a stirred suspension of
2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-6-methyl-isonic-
otinamide (1.00 g, 2.39 mmol) in ethyl methyl ketone (10 ml) and
dioxane (20 ml) were added sodium iodide (2.0 g, 13.3 mmol) and
hydriodic acid (0.95 ml, 7.2 mmol, 57% aqueous). The mixture was
then heated at 100.degree. C. for 96 hours. The mixture was then
concentrated in vacuo and the residue resuspended in
dichloromethane and washed sequentially with saturated sodium
bicarbonate solution, 0.1 M sodium thiosulfate solution, and
saturated brine. The organic phase was then dried over
Na.sub.2SO.sub.4 and the solvent evaporated. The crude product was
then chromatographed over SiO.sub.2 (Merck 230-400 mesh) eluting
with CH.sub.2Cl.sub.2/MeOH (99:1 then 98:2), the product fractions
were pooled and the solvent evaporated, to afford the title
compound as a brown solid (80 mg, 7% yield), MS: m/e=511
(M+H.sup.+)
Following General Procedure E the Compounds of Examples 384 and 385
were Prepared
EXAMPLE 384
1-Benzyl-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea
[0798] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
N-benzylmethylamine the title compound was obtained as an off-white
solid (94%), MS: m/e=413 (M+H.sup.+)
EXAMPLE 385
3-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-phenethyl-urea
[0799] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and
N-methyl-2-phenylethylamine the title compound was obtained as an
off-white solid (53%), MS: m/e=427 (M+H.sup.+).
Following the General Method of Example 379 the Compounds of
Examples 386 to 391 were Prepared
EXAMPLE 386
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-phenyl-acetamide
[0800] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
phenylacetyl chloride the title compound was obtained as a light
yellow solid (37%), MS: m/e=384 (M+H.sup.+).
EXAMPLE 387
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-propionamide
[0801] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
propionyl chloride the title compound was obtained as a light
yellow solid (5%), MS: m/e=322 (M+H.sup.+).
EXAMPLE 388
2-Methoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-acetamide
[0802] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
methoxyacetyl chloride the title compound was obtained as a light
yellow solid (37%), MS: m/e=338 (M+H.sup.+).
EXAMPLE 389
[0803] Pentanoic acid
(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide
[0804] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
valeroyl chloride the title compound was obtained as a light yellow
solid (48%), MS: m/e=350 (M+H.sup.+).
EXAMPLE 390
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isobutyramide
[0805] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
isobutyryl chloride the title compound was obtained as a light
yellow solid (8%), MS: m/e=336 (M+H.sup.+).
EXAMPLE 391
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-phenyl-propionamide
[0806] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
3-phenylpropionyl chloride the title compound was obtained as a
light yellow solid (3%), MS: m/e=398 (M+H.sup.+).
[0807] Following General Procedure E the compounds of examples 392
to 396 were prepared
EXAMPLE 392
1-Benzyl-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-urea
[0808] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
benzylamine the title compound was obtained as an off-white solid
(99%), MS: m/e=399 (M+H.sup.+).
EXAMPLE 393
1-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-phenethyl-urea
[0809] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
2-phenylethylamine the title compound was obtained as an off-white
solid (87%), MS: m/e=413 (M+H.sup.+).
EXAMPLE 394
1-(2-Methoxy-ethyl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-urea
[0810] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
2-methoxyethylamine the title compound was obtained as an off-white
solid (80%), MS: m/e=367 (M+H.sup.+)
EXAMPLE 395
1-(2-Dimethylamino-ethyl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-
-1-methyl-urea
[0811] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
N,N,N'-trimethylethylenediamine the title compound was obtained as
an off-white solid (61%), MS: m/e=394 (M+H.sup.+).
EXAMPLE 396
1-(2-Dimethylamino-ethyl)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-
-urea
[0812] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
2-dimethylamino-ethylamine the title compound was obtained as an
off-white solid (79%), MS: m/e=380 (M+H.sup.+).
Following the General Method of Example 379 the Compound of Example
397 was Prepared
EXAMPLE 397
4-Dimethylamino-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-butyramid-
e
[0813] Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and
4-dimethylamino-butyryl chloride the title compound was obtained as
a light yellow solid (10%), MS: m/e=379 (M+H.sup.+)
[0814] Preparation of intermediates for examples 1 to 187
EXAMPLE 398
(7-Iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester
[0815] (4-Methoxy-benzothiazol-2-yl)-carbamic acid methyl ester
(31.0 g, 130 mmol) and sodium acetate (32.3 g, 394 mmol) are
dissolved in 400 ml of glacial acetic acid and slowly treated with
iodine monochloride (13.5 ml, 264 mmol) at 0.degree. C. The
reaction mixture is then slowly warmed to room temperature and
stirred for 15 hours. After addition of water (1.3 l), the formed
precipitate is filtered off and washed with water. The filter cake
is then dissolved in a minimal amount of tetrahydrofurane (about
150 ml) and decolorized with 1M aqueous sodium thiosulfate. The
product is precipitated by the addition of water (about 2.0 l),
filtered off and dried at 60.degree. C. for 12 hours. 42.3 g (89%)
white solid. MS: m/e=364 (M.sup.+).
EXAMPLE 399
(4-Methoxy-benzothiazol-2-yl)-carbamic acid methyl ester
[0816] 2-Amino-4-methoxybenzothiazol (23.6 g, 131 mmol) and
pyridine (12.6 ml, 157 mmol) in dichloromethane (230 ml) are slowly
treated with methyl chloroformate (10.6 ml, 137 mmol) at 0.degree.
C. After 10 minutes, further methyl chloroformate (1.0 ml, 13 mmol)
and pyridine (1.0 ml, 12 mmol) are added. After 10 minutes, the
mixture is poured into 200 ml 1M aqueous hydrochloric acid, the
organic layer is separated, diluted with dichloromethane (250 ml)
and washed with brine (50 ml). The organic phase is dried and the
solvent evaporated in vacuo. 31.0 g (99.4%) white solid. MS:
m/e=238 (M+H.sup.+).
EXAMPLE 400
(4-Methoxy-7-phenyl-benzothiazol-2-yl)-carbamic acid tert-butyl
ester
[0817] To a suspension of 2-amino-4-methoxy-7-phenyl-benzothiazole
(1.0 g, 3.9 mmol) in THF (50 ml) was added
di(tert-butoxycarbonyl)-anhydride (BOC).sub.2O and DMAP (47 mg,
0.04 mmol) and the mixture stirred for 1 h a r.t., followed by 3 h
at 60.degree. C. After cooling the solvent was evaporated and the
residue chromatographed over SiO.sub.2 (Merck 230-400 mesh) eluting
with a gradient of cyclohexane/EtOAc (10% to 50% EtOAc), after
pooling the product fractions and evaporation of the solvents the
title compound was obtained as a white foam (1.1 g, 79% yield), MS:
m/e=356 (M.sup.+).
EXAMPLE 401
(4-Methoxy-benzothiazol-2-yl)-carbamic acid tert-butyl ester
[0818] Using 2-amino-4-methoxy-benzothiazole the title compound was
obtained as a white solid (60% yield), MS: m/e=281.2
(M+H.sup.+).
EXAMPLE 402
2-Amino-4-methoxy-7-phenyl-benzothiazole
[0819] The title compound was prepared from
3-amino-4-methoxy-biphenyl, according to the patent literature
N-(Benzothiazol-2-yl)oxamic acid derivatives. W. Winter, M. Thiel,
A. Roesch and O. H. Wilhelms, German Patent, DE 2656468, 1978. and
is obtained as a white solid, MS: m/e=256 (M.sup.+), mp.
207-208.degree. C.
EXAMPLE 403
4-Methoxy-7-phenoxy-benzothiazol-2-yl-amine
[0820] To a suspension of 2-methoxy-5-phenoxy-phenyl)-thiourea
(8.25 g, 30 mmol) in CHCl.sub.3 (70 ml) was added bromine (4.8 g,
30 mmol) in CHCl.sub.3 (10 ml) dropwise over 10 min. The mixture
was then heated to reflux for 3 h, then cooled to r.t., the solvent
was evaporated and the residue crystallised from MeOH/ether (1:4).
The filter cake was then further washed with saturated aqueous
NaHSO.sub.3 solution/water (1:1), (100 ml), water (200 ml), 1N NaOH
(60 ml), then water (100 ml), and finally ether (100 ml). The solid
material thus obtained was dried under vacuum (0.05 mmHg,
60.degree. C.) to afford the title compound as a white solid (6.7
g, 82% yield), MS: m/e=272.1 (M.sup.+).
Following the General Method of Example 403, the Compounds of
Examples 404 to 409 were Prepared
EXAMPLE 404
2-Amino-4-methoxy-benzothiazole-7-carboxylic acid methyl ester
[0821] Using 4-methoxy-3-thioureido-benzoic acid methyl ester the
title compound was obtained as a white solid (55% yield), MS:
m/e=239.2 (M+H.sup.+).
EXAMPLE 405
7-Bromo-4-methoxy-benzothiazole-2-yl-amine
[0822] Using (5-bromo-2-methoxy-phenyl)-thiourea the title compound
was obtained as a white solid (46% yield), MS: m/e=258
(M.sup.+).
EXAMPLE 406
7-tert-Butyl-4-methoxy-benzothiazole-2-yl-amine
[0823] Using (5-tert-butyl-2-methoxy-phenyl)-thiourea the title
compound was obtained as a white solid (79% yield), MS: m/e=238.1
(M.sup.+).
EXAMPLE 407
7-Acetylamino-4-methoxy-benzothiazole-2-yl-amine
[0824] Using (5-acetylamino-2-methoxy-phenyl)-thiourea the title
compound was obtained as a purple solid (49% yield), MS: m/e=238.2
(M+H.sup.+.)
EXAMPLE 408
4-methoxy-7-(1H-tetrazol-5-yl)-benzothiazol-2-yl-amine
[0825] Using 2-methoxy-5-(1H-tetrazol-5-yl)-phenyl]-thiourea the
title compound was obtained as a tan solid (54% yield), MS:
m/e=248.2 (M.sup.+)
EXAMPLE 409
(4-Methoxy-7-phenyl-benzothiazol-2-yl)-methyl-amine
[0826] Using (4-methoxy-biphenyl-3-yl)-thiourea the title compound
was obtained as a white solid (71% yield), MS: m/e=270.1
(M.sup.+).
EXAMPLE 410
5-Methoxy-7-phenyl-benzothiazol-2-yl-amine
[0827] (5-Methoxy-biphenyl-3-yl)-thiourea (109 mg, 0.42 mmol) in
chloroform (2 ml) are treated with bromine (22 .mu.l) and the
mixture heated to 61.degree. C. for 5 hours. After removal of the
volatile components in vacuo, the product (93 g, 86%) is isolated
by flash chromatography (silica, eluent ethyl acetate/cyclohexane
2:1 to 5:1) as beige solid. The regiochemistry of the cyclization
was checked by transfer-NOE measurements. MS: m/e=256
(M.sup.+).
EXAMPLE 411
2-Amino-4,5-dimethoxybanzothiazol
[0828] 2-Amino-4,5-dimethoxybanzothiazol is synthesized starting
from 2,3-dimethoxyaniline (1.0 g, 6.5 mmol) in the same manner as
described for 5-methoxy-7-phenyl-benzothiazol-2-yl-amine in 72%
total yield over three steps. MS: m/e=210 (M.sup.+).
EXAMPLE 412
6-Bromo-4-trifluoromethoxy-benzothiazol-2-yl-amine
[0829] 4-Bromo-2-trifluoromethoxy)aniline (768 mg, 3 mmol) and
potassium thiocyanate (875 mg, 9 mmol) are dissolved in acetic acid
(5 ml) and at 0.degree. C., bromine (0.19 ml, 3.6 mmol) are slowly
added. After stirring for 1 h, acetic acid (2 ml) are added and the
mixture heated to 100.degree. C. for 3 h. After cooling to room
temperature, aqueous sodium hydroxide (10M, 25 ml) is added and the
mixture extracted three times with ethyl acetate. The combined
organic layers were washed with brine, dried and the solvent
removed in vacuo. Flash chromatography (silica, eluent ethyl
acetate/cyclohexane 1:4) and final recrystallization from ethyl
acetate/cyclohexane affords the product as white solid. 170 mg
(18%). MS: m/e=315 (M+H.sup.+).
EXAMPLE 413
4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine
[0830] (2-Methoxy-5-morpholin-4-yl-phenyl)-thiourea (5.0 g, 19
mmol) in chloroform (130 ml) are treated with bromine (960 .mu.l)
and the mixture refluxed for 18 hours. After removal of the
volatile components in vacuo, the product is recrystallized from
THF (2.8 g, 57%). MS: m/e=266 (M.sup.+).
EXAMPLE 414
7-Benzyloxy-4-methoxy-benzothiazole-2-yl-amine
[0831] Synthesized starting from
(5-Benzyloxy-2-methoxy-phenyl)-thiourea in the same manner as
described for 5-methoxy-7-phenyl-benzothiazol-2-yl-amine in 82%
yield as a beige solid. Mp: 165.degree. C. (dec.).
EXAMPLE 415
4-Trifluoromethoxy-benzothiazol-2-yl-amine
[0832] 6-Bromo-4-trifluoromethoxy-benzothiazol-2-ylamine (157 mg,
0.50 mg), triethylamine (0.21 ml, 1.5 mmol) and palladium on carbon
(10%, 15 mg) are suspended in ethanol (12 ml) and hydrogenated at
atmospheric pressure for 96 h. The catalyst was filtered off and
the solution evaporated to dryness. The residue was dissolved in
ethyl acetate, washed three times with water, dried and the solvent
removed in vacuo. The product is obtained as brown solid (85 mg,
73%). MS: m/e=235 (M+H.sup.+).
EXAMPLE 416
2-Amino-4-methoxy-benzothiazole-7-carbaldehyde
[0833] Using (5-Formyl-2-methoxy-phenyl)-thiourea the title
compound was synthesised as described for
4-methoxy-7-phenoxy-benzothiazol-2-yl-amine and obtained as a beige
solid (70% yield), MS: m/e=208.0 (M.sup.+).
EXAMPLE 417
4-Methoxy-7-morpholin-4-ylmethyl-benzothiazol-2-yl-amine
[0834] To a suspension of
2-amino-4-methoxy-benzothiazole-7-carbaldehyde (440 mg, 2.1 mmol)
in THF (100 ml) was added morpholine (276 mg, 3.2 mmol), acetic
acid (190 mg, 3.2 mmol) followed by NaBH(OAc).sub.3 (672 mg, 3.2
mmol). This mixture was stirred vigorously at 20.degree. C. for 48
hours, after which time water (50 ml) and 5% NaHCO.sub.3 solution
(50 ml) were added and the mixture agitated vigorously. After
separating the organic and aqueous layers, the aqueous phase was
extracted with EtOAc (50 ml) and the combined organic phase was
washed with saturated NaCl solution (100 ml) then dried with
Na.sub.2SO.sub.4, filtered and evaporated. The solid residue was
suspended in ether (20 ml) and filtered then the filter cake was
washed with ether (10 ml), and dried under vacuum (0.05 mmHg,
50.degree. C.) to afford the title compound as a yellow solid (430
mg, 73% yield), MS: m/e=280.2 (M.sup.+).
EXAMPLE 418
2-Chloro-4-methoxy-7-phenyl-benzothiazole
[0835] To a suspension of 2-amino-4-methoxy-7-phenyl-benzothiazole
(5.1 g, 20 mmol) in ethylene glycol (75 ml) were added hydrazine
monohydrate (4 g, 80 mmol) and hydrazine dihydrochloride (4.2 g, 40
mmol) and the suspension was heated for 18 h at 140.degree. C.
After cooling to r.t. the suspension was filtered, then the filter
cake was washed with water (200 ml) followed by ether (100 ml), and
dried under vacuum (0.05 mmHg, 70.degree. C.) to afford
2-hydrazino-4-methoxy-7-phenyl-benzothiazole as a white solid (5.2
g, 96% yield). The 2-hydrazine-4-methoxy-7-phenyl-benzothiazole
(4.5 g, 16.6 mmol) was then added in portions over 20 min. to
stirred neat thionyl chloride (12 ml, 165 mmol), the mixture was
then heated to 50.degree. C. for 2 h to complete the reaction. The
reaction mixture was then cooled and poured on to ice/water (300
ml) and stirred for 20 min. at 0-10.degree. C. The whole mixture
was then filtered and the filter cake was washed with water (100
ml). The filter cake was then dissolved in CH.sub.2Cl.sub.2 (250
ml) and washed with saturated NaCl solution. The organic phase was
dried with Na.sub.2SO.sub.4 filtered and evaporated to afford a red
oil which was chromatographed over SiO.sub.2 (Merck 230-400 mesh)
eluting with CH.sub.2Cl.sub.2. The product fractions were pooled
and evaporated to afford the title compound as a brown solid (4.24
g, 93% yield), MS: m/e=275.0
[0836] Lit: Synth. Commun., 1992, 2769-80.
EXAMPLE 419
4-(Morpholine-4-sulfonyl)-benzoic acid
[0837] To a solution of 4-(chlorosulfonyl)-benzoic acid (0.5 g, 2.2
mmol) in THF (20 ml) was added morpholine (0.434 ml, 5 mmol)
dropwise over 5 min, and this mixture stirred at r.t. for 1 h.
Water (50 ml) was then added and the mixture agitated, the phases
were separated and the aqueous phase extracted with EtOAc
(2.times.50 ml). The combined organic phases were washed with satd.
aq. NaCl solution, dried, filtered and evaporated. The residue was
chromatographed over SiO.sub.2 (Merck 230-400 mesh) eluting with a
CHCl.sub.3/(acetone+10% HCO.sub.2H) (9:1), the product fractions
were pooled, evaporated and dried in vacuo (0.05 mmHg, 50.degree.
C.) to afford the title compound as a beige solid (270 mg, 20%
yield), MS: m/e=271 (M.sup.+).
Following the General Method of Example 419, the Compounds of
Examples 420 to 422 were Prepared
EXAMPLE 420
4-Dipropylsulfamoyl-benzoic acid
[0838] Using dipropylamine the title compound was obtained as a
beige solid, MS: m/e=285
EXAMPLE 421
4-Ethylsulfamoyl-benzoic acid
[0839] Using ethylamine the title compound was obtained as a white
solid (85% yield), MS: m/e=228.1 (M-H).sup.-.
EXAMPLE 422
4-Diethylsulfamoyl-benzoic acid
[0840] Using diethylamine the title compound was obtained as a
white solid (44% yield), MS: m/e=257 (M.sup.+).
EXAMPLE 423
2-(1,1-Dioxo-thiomorpholin-4-yl)-ethylamine
[0841] The title compound was prepared according to the following
patent literature: W. R. Baker, S. A. Boyd, A. K. L Fung, H. H
Stein, J. F. Denissen, C. W. Hutchins and S. H. Rosenberg, WO
9203429 (1992).
EXAMPLE 424
Methyl-(6-methyl-pyridin-3-ylmethyl)-amine
[0842] To a suspension of LiAlH.sub.4 in THF (120 ml) at 10.degree.
C. was added a solution of methyl-6-methyl nicotinate (12 g, 79
mmol) in THF (80 ml) dropwise with cooling over 45 min. After
stirring 1.5 h at 20.degree. C., a mixture of THF/water (4:1) 60 ml
was added to the reaction over 30 min. at 0.degree. C.,
Na.sub.2SO.sub.4 (50 g) was then added directly to the reaction
mixture which was stirred vigorously, then filtered and the THF
evaporated in vacuo. The residue was chromatographed over SiO.sub.2
(Merck 230-400 mesh) eluting with a gradient of
CH.sub.2Cl.sub.2/MeOH (97:3 to 9:1), affording a colourless oil
(7.5 g, 77% yield). This material was dissolved in CHCl.sub.3 (100
ml) and treated dropwise with thionyl chloride (17.2 ml, 237 mmol)
stirred at 5.degree. C. to 20.degree. C. over 16 h. The solvents
were then removed in vacuo and the residue partitioned between
CH.sub.2C.sub.2 (100 ml) and aq. 5% NaHCO.sub.3 (100 ml), the
aqueous phase was further extracted with CH.sub.2Cl.sub.2
(2.times.50 ml) and the combined extracts washed with satd. aq.
NaCl solution (1.times.50 ml), then dried and the solvent
evaporated in vacuo. The resulting red oil was dissolved in EtOH
(80 ml) cooled to 0.degree. C. and treated with 33%
methylamine/EtOH (50 ml) dropwise over 1 h, then the mixture was
stirred to 20.degree. C. over 3 h. After evaporation of all the
solvents the residue was partitioned between CH.sub.2Cl.sub.2 and
water (100 ml ea.), the aqueous phase was further extracted with
CH.sub.2Cl.sub.2 (2.times.100 ml), dried (Na.sub.2SO.sub.4),
filtered and the solvent evaporated in vacuo. The brown oily
residue was then distilled under high vacuum (0.1 mm Hg,
68-70.degree. C.) over a Vigreux column to afford the title
compound as a pale yellow liquid (6.03 g, 75% yield), MS: m/e=136.1
(M.sup.+).
[0843] Lit: J. Med. Chem., 1996, 5053-63.
Following the General Method of Example 424, the Compounds of
Examples 425 to 4266 were Prepared
EXAMPLE 425
Methyl-pyridin-2-yl-methyl-amine
[0844] Using 2-chloromethyl-pyridine hydrochloride salt and 33%
methylamine/EtOH the title compound was obtained as a colourless
liquid (0.1 mm Hg, 47-48.degree. C.) (20% yield), MS: m/e=93.1
(M--NHCH.sub.3).
EXAMPLE 426
Methyl-pyridin-4-ylmethyl-amine
[0845] Using 4-chloromethyl-pyridine hydrochloride salt and 33%
methylamine/EtOH the title compound was obtained as a colourless
liquid (0.1 mm Hg, 60-62.degree. C.) (79% yield), MS: m/e=122.1
(M.sup.+).
[0846] Preparation of Intermediates for Examples 188 to 208
EXAMPLE 427
2-Methoxy-5-phenoxy-phenyl)-thiourea
[0847] To a solution of 2-methoxy-5-phenoxy-aniline (9.9 g, 46
mmol) in acetone (60 ml) was added benzoylisothiocyanate (9 g, 55
mmol) and the mixture heated to reflux (56.degree. C.) for 4 h.
After cooling to r.t., the solvent was evaporated and the oily
orange residue was precipitated from ether (20 ml) under
ultrasonication, the solid was then washed on the filter with
ether/nHexane (1:3) (50 ml). The solid thus obtained was further
dried under vacuum (0.05 mmHg, 50.degree. C.) to afford the
benzoylated thiourea as a beige solid (17.2 g, 99%, yield). Fresh
sodium methoxide (14.5 g, 38 mmol) was then added to a suspension
of the benzoylated thiourea (14.5 g, 38 mmol) in methanol (70 ml)
and this mixture stirred for 1 h at r.t. Water was then added (210
ml) and the precipitated solid was collected, then washed on the
filter with water (100 ml), followed by ether (100 ml), then dried
under vacuum (0.05 mmHg, 50.degree. C.) to afford the title
compound as a white solid (8.5 g, 81% yield), MS: m/e=274.1
(M.sup.+).
Following the General Method of Example 427 the Compounds of
Examples 428 to 433 were Prepared
EXAMPLE 428
(5-tert-Butyl-2-methoxy-phenyl)-thiourea
[0848] Using 4-tert-butyl-2-methoxy-aniline the title compound was
obtained as a white solid (79% yield), MS: m/e=238.1 (M.sup.+).
EXAMPLE 429
(5-Acetylamino-2-methoxy-phenyl)-thiourea
[0849] Using 3-amino-4-methoxyacetanilide the title compound was
obtained as a grey solid (69% yield), MS: m/e=240.3
(M+H.sup.+).
EXAMPLE 430
4-Methoxy-3-thioureido-benzoic acid methyl ester
[0850] Using 3-Amino-4-methoxy-benzoic acid methyl ester the title
compound was obtained as a tan solid (78% yield), MS: m/e=240.0
(M.sup.+).
EXAMPLE 431
(5-Bromo-2-methoxy-phenyl)-thiourea
[0851] Using 5-bromo-2-methoxy-aniline the title compound was
obtained as a white solid (88% yield), MS: m/e=260 (M.sup.+).
EXAMPLE 432
2-methoxy-5-(1H-tetrazol-5-yl)-phenyl]-thiourea
[0852] Using 2-methoxy-5-(1H-tetrazol-5-yl)-aniline the title
compound was obtained as a tan solid (92% yield), MS: m/e=250.1
(M.sup.+).
EXAMPLE 433
1-(4-Methoxy-biphenyl-3-yl)-3-methyl-thiourea
[0853] Using 4-methoxy-biphenyl-3-ylamine and
N-methyl-isothiocyanate the title compound was directly obtained as
a white solid (96% yield), MS: m/e=273.2 (M+H.sup.+).
EXAMPLE 434
(5-Methoxy-biphenyl-3-yl)-thiourea
[0854] 1-Benzoyl-3-(5-methoxy-biphenyl-3-yl)-thiourea (183 mg, 0.51
mmol) in methanol (5 ml) are treated with sodium methoxide (5.4M in
methanol, 0.14 ml) and the formed precipitate is filtered off.
Washing with methanol yields the product (115 mg, 88%) as off-white
powder. MS: m/e=258 (M.sup.+).
EXAMPLE 435
1-Benzoyl-3-(5-methoxy-biphenyl-3-yl)-thiourea
[0855] 5-Methoxy-biphenyl-3-ylamine (129 mg, 0.65 mmol) are
dissolved in acetone (5 ml) and slowly treated with a solution of
benzoyl isothiocyanate (0.096 ml, 0.71 mmol) in acetone (2 ml).
After stirring at ambient temperature for 18 h, the solvent is
removed in vacuo and the residue crystallized from hexane. The
product (203 mg, 86%) is obtained as colorless crystals. Mp
149.degree. C.
EXAMPLE 436
(2-Methoxy-5-morpholin-4-yl-phenyl)-thiourea
[0856] 1-Benzoyl-3-(2-methoxy-5-morpholin-4-yl-phenyl)-thiourea
(8.0 g, 21 mmol), suspended in methanol (260 ml), are treated with
6 ml sodium methanolate (5.4M in methanol) and the mixture stirred
until a white precipitate forms. The mixture is concentrated in
vacuo, the crystals are isolated by filtration and washed with
methanol and hexane (5.0 g 86%). MS: m/e=268 (M.sup.+).
EXAMPLE 437
1-Benzoyl-3-(2-methoxy-5-morpholin-4-yl-phenyl)-thiourea
[0857] To a solution of 2-methoxy-5-morpholin-4-yl-phenylamine (4.6
g, 22 mmol) in acetone (140 ml) is added a solution of benzoyl
isothiocyanate (3.4 ml, 25 mmol) in acetone (80 ml) and the
reaction mixture is stirred for further 30 min at ambient
temperature. After removal of the volatile components in vacuo, the
product is isolated by flash chromatography (silica, eluent ethyl
acetate/n-hexane 1:4, then 1:2) as a yellow solid (8.0 g, 97%). MS:
m/e=272 (M.sup.+).
EXAMPLE 438
(5-Benzyloxy-2-methoxy-phenyl)-thiourea
[0858] Synthesized from 5-benzyloxy-2-methoxy-aniline as described
for example 427 in 80% overall yield. Obtained as white crystals.
M.p. 130.degree. C. (dec.).
EXAMPLE 439
(5-Formyl-2-methoxy-phenyl)-thiourea
[0859] To a solution of 2-(4-methoxy-3-nitro-phenyl)-[1,3]dioxolane
(13 g, 57.7 mmol) in MeOH (400 ml) was added Adams
catalyst-Pt(O.sub.2) (700 mg) and the mixture stirred vigorously
under an atmosphere of hydrogen at 20.degree. C. until 41 of
hydrogen had been taken up. The catalyst was then filtered off and
methanol evaporated and replaced with acetone (150 ml). Benzoyl
isothiocyanate was then added dropwise (8.5 ml, 63.5 mmol) over 15
min at r.t. and the mixture then heated to reflux for 1.5 h. After
cooling the solvent was evaporated and the residue was
chromatographed over SiO.sub.2 (Merck 230-400 mesh) eluting with
CH.sub.2Cl.sub.2 affording a yellow oil (10 g). This oil was taken
up in MeOH (150 ml) and sodium methoxide was added (3.7 g, 69 mmol)
and the mixture stirred at 20.degree. C. for 1 h. Following this
the solvent was evaporated and the residue dissolved in THF (200
ml) and 2N HCl (100 ml) was added and the mixture stirred for 30
min. EtOAc (200 ml) was then added and the aqueous phase separated
and extracted with EtOAc/THF (1:1) (200 ml). The combined organic
phases were washed with satd. aq. NaCl solution (2.times.200 ml),
dried, filtered and the solvent evaporated. The solid residue was
suspended in ether (100 ml) and filtered off, washed with ether (50
ml) and dried under vacuum (0.05 mmHg, 50.degree. C.) to afford the
title compound as a yellow solid (4.7 g, 39% yield). MS: m/e=210.1
(M.sup.+).
EXAMPLE 440
2-(4-Methoxy-3-nitro-phenyl)-[1,3]dioxolane
[0860] To a solution of 4-methoxy-3-nitro-benzaldehyde (11.2 g,
61.8 mmol) in toluene (300 ml) was added ethylene glycol (5.2 ml,
92.7 mmol) and Amberlyst A15 resin acid catalyst (0.6 g). This
mixture was stirred vigorously at reflux for 16 h. in a Dean-Stark
apparatus. Upon cooling the Amberlyst resin was filtered off and
the filtrate washed with satd. aq. NaCl solution (3.times.150 ml),
then dried with Na.sub.2SO.sub.4, filtered and evaporated to afford
the title compound as an orange oil (14 g, 100% yield), MS:
m/e=224.1 (M-H).sup.-.
EXAMPLE 441
2-Methoxy-5-(1H-tetrazol-5-yl)-aniline
[0861] To a solution of 4-methoxy-3-nitro-benzonitrile (2.5 g, 1.4
mmol) in toluene (20 ml) was added sodium azide (1.3 g, 1.8 mmol)
and triethylamine hydrochloride (1.5 g, 1.8 mmol), and this mixture
stirred at 100.degree. C. from 48 h. Water was then added (200 ml)
and the mixture agitated, the aqueous phase was further washed with
water (2.times.30 ml). The organic phase was then adjusted to pH 2
and the solid which precipitated was filtered off and washed
further with water (100 ml) then dried in vacuo (0.05 mmHg,
60.degree. C.) to afford the crude tetrazole. This material was
then directly dissolved in MeOH (80 ml), Pd/C (10%) (250 mg) was
added and the mixture stirred under 1 atm of hydrogen at 20.degree.
C. for ca. 1 h until the theoretical amount of hydrogen (ca. 880
ml) had been taken up. The catalyst was then filtered off and the
solvent evaporated to afford the title compound as a white solid
(2.2 g, 82% yield), MS: m/e=191.1
[0862] Lit: Synthesis 1998, p 910.
EXAMPLE 442
1-Iodo-3-methoxy-5-nitro-benzene
[0863] 1-Iodo-3,5-dinitrobenzene (1.8 g, 6.1 mmol) are dissolved in
methanol (12 ml) and treated with a solution of sodium methoxide in
methanol (5.4M, 1.2 ml). The mixture is then stirred at 65.degree.
C. for 52 h. After cooling to ambient temperature, water (50 ml) is
added and the mixture extracted three times with ethyl acetate (50
ml). The combined organic layers are extracted with brine (100 ml),
dried and evaporated to dryness. Flash chromatography (silica,
eluent ethyl acetate/cyclohexane 1:1) affords the product (1.7 g,
99%) as light yellow solid. MS: m/e=279 (M.sup.+).
EXAMPLE 443
5-Methoxy-biphenyl-3-yl-amine
[0864] 3-Methoxy-5-nitro-biphenyl (176 mg, 0.77 mmol) are
hydrogenated in ethanol (5 ml) using palladium on carbon (10%, 17
mg) at atmospheric pressure for 2 h. The catalyst is filtered off
and the solvent removed in vacuo. Flash chromatography (silica,
eluent ethyl acetate/cyclohexane 1:1) affords the product (139 mg,
91%) as a brown oil. MS: m/e=199 (M.sup.+).
EXAMPLE 444
2-Methoxy-5-morpholin-4-yl-phenylamine
[0865] 4-(4-Methoxy-3-nitro-phenyl)-morpholine (6 g) is
hydrogenated in dichloromethane (100 ml) and methanol (600 ml)
using palladium on carbon (10%, 600 mg) for 12 hours. The catalyst
is removed by filtration and the solution evaporated in vacuo.
Purification by flash chromatography (silica, eluent ethyl
acetate/n-hexane 1:1, then) affords the product as off-white solid
(4.6 g, 88%). MS: m/e=209 (M+H.sup.+).
EXAMPLE 445
4-(4-Methoxy-3-nitro-phenyl)-morpholine
[0866] 4-Bromo-2-nitroanisol (8.5 g, 36 mmol), morpholine (3.8 ml,
44 mmol), potassium phosphate (11 g, 51 mmol),
2-biphenyl-dicyclohexyl phosphine (960 mg, 2.7 mmol) and
palladium(II) acetate (411 mg, 1.8 mmol) are dissolved in
dimethoxyethane (80 ml) and stirred at 80.degree. C. for 96 hours.
The mixture is then cooled to room temperature, diluted with ethyl
acetate (50 ml) and filtrated through dicalite. Flash
chromatography on silica (eluent dichloromethane/methanol 99:1)
affords the product as red solid (6.0 g, 69%). MS: m/e=238
EXAMPLE 446
3-Methoxy-5-nitro-biphenyl
[0867] 1-Iodo-3-methoxy-5-nitro-benzene (279 mg, 1 mmol),
phenylboronic acid (146 mg, 1.2 mmol), potassium carbonate (2M, 1.0
ml) and tetrakis(triphenylphosphino)palladium(0) are dissolved in
ethanol (0.5 ml) and toluene (10 ml) and the mixture heated to
90.degree. C. for 24 h. The volatile components are removed in
vacuo and the residue codistilled twice with toluene. Flash
chromatography (silica, eluent dichloromethane/cyclohexane 1:2)
affords the product (185 mg, 81%) as light brown solid. MS: m/e=229
(M.sup.+).
EXAMPLE 447
5-Bromo-2-methoxy-aniline
[0868] A solution of 4-bromo-2-nitro-anisole (7.7 g, 33.1 mmol),
triethylamine (4.6 ml, 33.1 mmol) and Raney Nickel catalyst (4 g)
was vigorously stirred in ethanol (300 ml) under an atmosphere of
hydrogen for 1 h at 20.degree. C. After this time the theoretical
amount of hydrogen had been absorbed (2.5 l), so the catalyst was
filtered off and the solvent evaporated to afford the title
compound as a light yellow solid (7 g, 104% yield), MS: m/e=201
(M.sup.+).
Intermediates for the Preparation of Benzylic Amines:
EXAMPLE 448
4-Chloromethyl-N-(4-hydroxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
[0869]
N-(4-Benzyloxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-chloromethyl-b-
enzamide (1.0 g, 2.0 mmol) were dissolved in CH.sub.2Cl.sub.2 (10
ml) and treated at -78.degree. C. with tetrabutyl ammonium iodide
(0.95 g, 2.6 mmol) and a solution of boron trichloride in
CH.sub.2Cl.sub.2 (1M, 7.4 ml). After subsequent warming to
0.degree. and stirring for additional 2 h, ice (2 g) and then water
(10 ml) and methanol (2 ml) were added and the phases separated.
The aqueous phases were extracted twice with CH.sub.2Cl.sub.2/MeOH,
the combined organic layers were dried with Na.sub.2SO.sub.4 and
evaporated to dryness. Recrystallization from CH.sub.2Cl.sub.2/MeOH
afforded the title compound as an off-white solid (18%). MS:
m/e=403 ([M-H.sup.+].sup.-).
EXAMPLE 449
4-(1-Bromo-ethyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzami-
de
[0870] Following the general method of example 1 the title compound
was obtained as a yellow solid (63%). MS: m/e=478 (M+H.sup.+).
EXAMPLE 450
3-Chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide
[0871] Following the general method of example 1 the title compound
was obtained as a light yellow solid (59%). MS: m/e=418
(M+H.sup.+).
EXAMPLE 451
4-Chloromethyl-3-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-b-
enzamide
[0872] Following the general method of example 1 the title compound
was obtained as a light brown solid (99%). MS: m/e=436
(M+H.sup.+).
EXAMPLE 452
4-Chloro-3-chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-b-
enzamide
[0873] Following the general method of example 1 the title compound
was obtained only in 75% purity (68%) and used in the subsequent
steps without further purification. MS: m/e=452 (M+H.sup.+).
EXAMPLE 453
4-[(2-Methoxy-ethyl)-methyl-sulfamoyl]-benzoic acid
[0874] 4-Chloro-sulfonyl-benzoic acid (100 mg, 0.45 mmol) were
dissolved in (2-methoxyethyl)-methyl-amine (1.0 g, 11.2 mmol) and
heated to 50.degree. C. for 18 h. Removal of the volatile
components in vacuo and flash chromatography (silica, eluent
CH.sub.2Cl.sub.2/MeOH/H.sub.2O/AcOH 90:10:1:1) afforded the product
as white solid (65%). MS: m/e=272 ([M-H].sup.-).
Intermediates for the Preparation of Benzylic Amines for 2-OBn:
EXAMPLE 454
4-Benzyloxy-7-morpholin-4-yl-benzothiazol-2-yl-amine
[0875] Using 2-benzyloxy-5-morpholin-4-yl-phenyl)-thiourea
following the general method of example 403 the title compound was
obtained as off-white solid (69%). MS: m/e=342 (M+H.sup.+).
EXAMPLE 455
N-(4-Benzyloxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-chloromethyl-benzamid-
e
[0876] Following the general method of example 1 the title compound
was obtained as a pale yellow solid (81%). MS: m/e=494
(M+H.sup.+).
Intermediates for the Preparation of Benzylic Amines for Changed
7-Position:
EXAMPLE 456
4-Methoxy-7-thiomorpholin-4-yl-benzothiazol-2-yl-amine
[0877] Using 2-methoxy-5-thiomorpholin-4-yl-phenyl)-thiourea
following the general method of example 403 the title compound was
obtained as light brown solid (31%). MS: m/e=282 (M+H.sup.+).
EXAMPLE 457
[4-Methoxy-7-(2-methyl-pyridin-4-yl)-benzothiazol-2-yl]-carbamic
acid methyl ester
[0878] Using the general procedure B the title compound was
prepared from 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine
and 2-methyl-4-trimethylstannanyl-pyridine as a white solid (8%).
MS: m/e=329 (M.sup.+).
EXAMPLE 458
4-Methoxy-7-(2-methyl-pyridin-4-yl)-benzothiazol-2-yl-amine
[0879]
[4-Methoxy-7-(2-methyl-pyridin-4-yl)-benzothiazol-2-yl]-carbamic
acid methyl ester (100 mg, 0.24 mmol) were dissolved in
ethyleneglycol (3.0 ml) and treated with potassium hydroxide (528
mg, 1.1 mmol) and heated to 100.degree. C. for 6.5 h. The reaction
mixture was cooled to room temperature, diluted with water,
neutralized with 1N HCl and extracted four times with ethyl
acetate. The organic layers were combined and washed with water and
saturated aqueous NaCl. The organic phases were then dried and the
solvent removed in vacuo. The product was obtained as a light brown
solid (83%). MS: m/e=272 (M+H.sup.+).
EXAMPLE A
Tablet Formulation (Wet Granulation)
TABLE-US-00002 [0880] mg/tablet Item Ingredients 5 mg 25 mg 100 mg
500 mg 1. Compound of formula I 5 25 100 500 2. Lactose Anhydrous
DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline
Cellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167
167 831
Manufacturing Procedure
[0881] 1. Mix items 1, 2, 3 and 4 and granulate with purified
water. 2. Dry the granules at 50.degree. C. 3. Pass the granules
through suitable milling equipment. 4. Add item 5 and mix for three
minutes; compress on a suitable press.
EXAMPLE B
Capsule Formulation
TABLE-US-00003 [0882] mg/capsule Item Ingredients 5 mg 25 mg 100 mg
500 mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159
123 148 -- 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5.
Magnesium Stearate 1 2 2 5 Total 200 200 300 600
Manufacturing Procedure
[0883] 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes. 3. Fill into a suitable
capsule.
* * * * *