U.S. patent application number 11/995878 was filed with the patent office on 2011-04-14 for pharmaceutical compounds.
This patent application is currently assigned to Orion Corporation. Invention is credited to Marko AHLMARK, Reijo BACKSTROM, Anne LUIRO, Jarmo PYSTYNEN, Eija TIAINEN.
Application Number | 20110086852 11/995878 |
Document ID | / |
Family ID | 37500024 |
Filed Date | 2011-04-14 |
United States Patent
Application |
20110086852 |
Kind Code |
A2 |
AHLMARK; Marko ; et
al. |
April 14, 2011 |
PHARMACEUTICAL COMPOUNDS
Abstract
Compounds of formula (I), wherein R.sub.1-R.sub.4, X, Y and Z
are as defined in claims, exhibit COMT enzyme inhibiting activity
and are thus useful as COMT inhibitors. ##STR1##
Inventors: |
AHLMARK; Marko; (Espoo,
FI) ; BACKSTROM; Reijo; (Helsinki, FI) ;
LUIRO; Anne; (Helsinki, FI) ; PYSTYNEN; Jarmo;
(Espoo, FI) ; TIAINEN; Eija; (Espoo, FI) |
Assignee: |
Orion Corporation
Orionintie 1
Espoo
FI
FI-02200
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20090209532 A1 |
August 20, 2009 |
|
|
Family ID: |
37500024 |
Appl. No.: |
11/995878 |
Filed: |
July 17, 2006 |
PCT Filed: |
July 17, 2006 |
PCT NO: |
PCT/FI2006/000257 |
371 Date: |
November 26, 2008 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60/699,898 |
Jul 18, 2005 |
|
|
|
Current U.S.
Class: |
514/233.5 ;
514/324; 514/338; 514/367; 514/373; 514/416; 514/443; 514/470;
544/146; 546/202; 546/270.1; 548/453; 548/472; 549/466; 549/49 |
Current CPC
Class: |
C07D 277/66 20130101;
C07D 307/89 20130101; C07D 417/04 20130101; C07D 409/06 20130101;
C07D 307/88 20130101; C07D 333/68 20130101; C07D 333/70 20130101;
C07D 275/04 20130101; A61P 43/00 20180101; C07D 277/64 20130101;
C07D 209/46 20130101; C07D 277/84 20130101; C07D 333/62 20130101;
A61P 25/16 20180101 |
Class at
Publication: |
514/233.5 ;
514/324; 514/338; 514/367; 514/373; 514/416; 514/443; 514/470;
544/146; 546/202; 546/270.1; 548/453; 548/472; 549/049;
549/466 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/4535 20060101 A61K031/4535; A61K 31/4439
20060101 A61K031/4439; A61K 31/428 20060101 A61K031/428; A61K
31/4035 20060101 A61K031/4035; A61K 31/381 20060101 A61K031/381;
A61K 31/343 20060101 A61K031/343; C07D 413/02 20060101 C07D413/02;
C07D 409/02 20060101 C07D409/02; C07D 417/02 20060101 C07D417/02;
C07D 275/04 20060101 C07D275/04; C07D 209/46 20060101 C07D209/46;
C07D 333/52 20060101 C07D333/52; C07D 307/87 20060101
C07D307/87 |
Claims
1. A compound of formula I, ##STR8## wherein R.sub.2 is in a
position ortho to R.sub.3 and R.sub.1 is in a position ortho to
R.sub.2 or R.sub.1 is in a position ortho to R.sub.3 and R.sub.4 is
in a position ortho to R.sub.1; R.sub.1 is cyano or nitro; R.sub.2
is hydroxy; R.sub.3 is hydroxy; R.sub.4 is H,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, cyano, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--, halogen or nitro; the dotted
line represents a single or a double bond; two of X, Y or Z are
independently CR.sub.5(R.sub.6).sub.m, N(R.sub.7).sub.n, O or S and
one of X, Y or Z is N(R.sub.7).sub.n, O or S; m is, independently
at each occurrence, 0 or 1; n is, independently at each occurrence,
0, 1 or 2; R.sub.5 is, independently at each occurrence, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, halogen, hydroxy,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.8)alkoxy-(C.dbd.O)--, cyano, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.S)--, (R.sub.8).sub.2N--(C.dbd.S)--,
R.sub.8--(C.dbd.NR.sub.8)--, carboxy, (C.sub.3-C.sub.7)cycloalkyl,
heterocyclyl, aryl, heteroaryl, heterocyclyl-(C.dbd.O)--,
aryl(C.sub.1-C.sub.6)alkyl, (R.sub.8).sub.2N--,
(R.sub.8).sub.2N--(C.sub.1-C.sub.6)alkyl,
(R.sub.8).sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-S--,
R.sub.9--(S.dbd.O)--, R.sub.9--(O.dbd.S.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-S--(C.dbd.O)--,
(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.6)alkyl, aryloxy,
aryloxy(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkoxy,
aryl(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl or
heterocyclyl-(C.dbd.S)--, wherein said (C.sub.3-C.sub.7)cycloalkyl,
heterocyclyl, aryl or heteroaryl as such or as part of another
group is unsubstituted or substituted with 1, 2 or 3 substituent(s)
each independently being (C.sub.1-C.sub.6)alkyl, halogen, hydroxy,
carboxy, (C.sub.1-C.sub.6)alkoxy or (R.sub.8).sub.2N--; R.sub.6 is,
independently at each occurrence, H, (C.sub.1-C.sub.6)alkyl,
halogen, hydroxy, hydroxy(C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)alkoxy; or R.sub.5 and R.sub.6 both attached to
the same carbon ring atom form, together with the carbon ring atom
to which they are attached, a --(C.dbd.O)-- group; or R.sub.5 and
R.sub.6 both attached to the same carbon ring atom form, together
with the carbon ring atom to which they are attached,
C.dbd.C(R.sub.8).sub.2; or R.sub.5 and R.sub.6 both attached to the
same carbon ring atom form, together with the carbon ring atom to
which they are attached, a 5, 6 or 7 membered saturated or
unsaturated carbocyclic ring, wherein said ring is unsubstituted or
substituted with 1 or 2 substituent(s) each independently being
(C.sub.1-C.sub.6)alkyl, halogen, hydroxy, (C.sub.1-C.sub.6)alkoxy
or carboxy; R.sub.7 is, independently at each occurrence, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.1-C.sub.6)alkoxy, aryl or O.sup.-, wherein said
(C.sub.3-C.sub.7)cycloalkyl or aryl is unsubstituted or substituted
with 1, 2 or 3 substituent(s) each independently being
(C.sub.1-C.sub.6)alkyl, halogen, hydroxy, (C.sub.1-C.sub.6)alkoxy
or carboxy; or R.sub.5 and R.sub.5, R.sub.5 and R.sub.7, or R.sub.7
and R.sub.7 attached to adjacent ring atoms form, together with the
ring atoms to which they are attached, a condensed 5, 6 or 7
membered saturated or unsaturated carbocyclic ring or a condensed
5, 6 or 7 membered saturated or unsaturated heterocyclic ring
containing 1 or 2 heteroatom(s) selected from N, O and S, wherein
said carbo- or heterocyclic ring is unsubstituted or substituted
with 1 or 2 substituent(s) each independently being
(C.sub.1-C.sub.6)alkyl, halogen, hydroxy, (C.sub.1-C.sub.6)alkoxy,
carboxy or oxo; R.sub.8 is, independently at each occurrence, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, aryl or
aryl(C.sub.1-C.sub.6)alkyl, wherein said aryl as such or as part of
another group is unsubstituted or substituted with 1 or 2
substituent(s) each independently being (C.sub.1-C.sub.6)alkyl,
halogen, hydroxy, carboxy or (C.sub.1-C.sub.6)alkoxy; R.sub.9 is,
independently at each occurrence, (C.sub.1-C.sub.6)alkyl,
(R.sub.8).sub.2N--, hydroxy or (C.sub.1-C.sub.6)alkoxy; or a
pharmaceutically acceptable salt or ester thereof; with the proviso
that the compound is not
2-benzyl-7-bromo-6-nitro-benzofuran-4,5-diol.
2. A compound as claimed in claim 1, wherein R.sub.2 is in a
position ortho to R.sub.3 and R.sub.1 is in a position ortho to
R.sub.2.
3. A compound as claimed in claim 1, wherein R.sub.1 is in a
position ortho to R.sub.3 and R.sub.4 is in a position ortho to
R.sub.1.
4. A compound as claimed in any one of claims 1 to 3, wherein
R.sub.4 is H, halogen or nitro.
5. A compound as claimed in claim 4, wherein R.sub.4 is H.
6. A compound as claimed in any one of claims 1 to 5, wherein
R.sub.1 is cyano.
7. A compound as claimed in any one of claims 1 to 5, wherein
R.sub.1 is nitro.
8. A compound as claimed in any one of claims 1 to 7, wherein one
of the dotted lines represents a double bond.
9. A compound as claimed in any one of claims 1 to 8, wherein two
of X, Y or Z are CR.sub.5(R.sub.6).sub.m and one of X, Y or Z is
N(R.sub.7).sub.n.
10. A compound as claimed in any one of claims 1 to 8, wherein one
of X, Y or Z is CR.sub.5(R.sub.6).sub.m, one of X, Y or Z is
N(R.sub.7).sub.n, and one of X, Y or Z is S.
11. A compound as claimed in any one of claims 1 to 8, wherein two
of X, Y or Z are CR.sub.5(R.sub.6).sub.m and one of X, Y or Z is
O.
12. A compound as claimed in any one of claims 1 to 8, wherein two
of X, Y or Z are CR.sub.5(R.sub.6).sub.m and one of X, Y or Z is
S.
13. A compound as claimed in any one of claims 1 to 10, wherein
R.sub.7 is, independently at each occurrence, H,
(C.sub.1-C.sub.6)alkyl or aryl, wherein said aryl is unsubstituted
or substituted with 1, 2 or 3 substituent(s) each independently
being halogen.
14. A compound as claimed in any one of claims 1 to 13, wherein
R.sub.5 is, independently at each occurrence, H,
(C.sub.1-C.sub.6)alkyl, halogen, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.8)alkoxy-(C.dbd.O), carboxy, aryl, heteroaryl,
heterocyclyl-(C.dbd.O)-- or (R.sub.8).sub.2N--(C.dbd.O)--, wherein
said heterocyclyl, aryl or heteroaryl as such or as part of another
group is unsubstituted or substituted with 1, 2 or 3 substituent(s)
each independently being (C.sub.1-C.sub.6)alkyl or hydroxy; R.sub.6
is, independently at each occurrence, H; or R.sub.5 and R.sub.6
both attached to the same carbon ring atom form, together with the
carbon ring atom to which they are attached, a --(C.dbd.O)-- group;
R.sub.8 is, independently at each occurrence,
(C.sub.1-C.sub.6)alkyl or aryl, wherein said aryl is unsubstituted
or substituted with 1 or 2 substituent(s) each independently being
carboxy or (C.sub.1-C.sub.6)alkoxy.
15. A compound as claimed in claim 14, wherein m is, independently
at each occurrence, 0; R.sub.5 is, independently at each
occurrence, halogen, (C.sub.1-C.sub.8)alkoxy-(C.dbd.O)--, carboxy,
heterocyclyl-(C.dbd.O)-- or (R.sub.8).sub.2N--(C.dbd.O)--, wherein
said heterocyclyl as part of another group is unsubstituted or
substituted with 1, 2 or 3 substituent(s) each independently being
(C.sub.1-C.sub.6)alkyl or hydroxy; R.sub.8 is, independently at
each occurrence, (C.sub.1-C.sub.6)alkyl or aryl, wherein said aryl
is unsubstituted or substituted with 1 substituent being carboxy or
(C.sub.1-C.sub.6)alkoxy.
16. A compound as claimed in claim 1, wherein the compound is
2-(4-chloro-phenyl)-5,6-dihydroxy-4-nitro-2,3-dihydro-isoindol-1-one,
5,6-dihydroxy-7-nitro-3H-isobenzofuran-1-one,
7-nitro-2-pyridin-4-yl-benzothiazole-5,6-diol, methane sulfonate,
3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid,
3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
ethyl ester,
3-chloro-5,6-dihydroxy-4-nitro-benzo[b]thiophene-2-carboxylic acid,
3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene,
(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-met-
hanone,
3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
diethylamide,
(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-piperidin-1-yl-met-
hanone,
3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
phenylamide,
3-[(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carbonyl)-amino]-b-
enzoic acid,
4-[(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carbonyl-amino]-be-
nzoic acid,
3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
(4-methoxy-phenyl)amide, 2-methyl-7-nitro-benzothiazole-5,6-diol,
(5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone,
5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid,
5,6-dihydroxy-7-nitro-benzofuran-2-carboxylic acid,
5,6-dihydroxy-2-methyl-7-nitro-benzo[d]isothiazol-3-one,
(5,6-dihydroxy-3-methyl-7-nitro-benzo[b]thiophen-2-yl)morpholin-4-yl-meth-
anone, 5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
ethyl ester, 5,6-dihydroxy-4-nitro-isobenzofuran-1,3-dione,
5,6-dihydroxy-4-nitro-3H-isobenzofuran-1-one,
5,6-dihydroxy-4,7-dinitro-3H-isobenzofuran-1-one,
7-nitro-2-phenyl-benzothiazole-5,6-diol,
6,7-dihydroxy-5-nitro-benzo[b]thiophene-2-carboxylic acid methyl
ester, 1-(5,6-dimethoxy-7-nitro-benzo[b]thiophen-2-yl)-nonan-1-one,
(3-chloro-5,6-dihydroxy-4,7-dinitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-
-methanone,
(3,4-chloro-5,6-dihydroxy-7-dinitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-
-methanone,
(3-chloro-5,6-dihydroxy-4-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-met-
hanone,
(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-(2,6-dimeth-
yl-morpholin-4-yl)-methanone,
(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-(4-hydroxy-piperid-
in-1-yl)-methanone,
(3-bromomethyl-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-y-
l-methanone,
5,6-dihydroxy-3-methyl-2-(morpholine-4-carbonyl)-benzo[b]thiophene-4-carb-
onitrile or
(3-chloro-5,6-dihydroxy-7-cyano-benzo[b]thiophen-2-yl)-morpholin-4-yl-met-
hanone.
17. A compound as claimed in any one of claims 1 to 16 for use as a
medicament.
18. Use of a compound as claimed in any one of claims 1 to 16, or a
pharmaceutically acceptable salt or ester thereof, for the
manufacture of a medicament for the treatment of a disease or a
condition where a COMT inhibiting agent is indicated to be
useful.
19. The use as claimed in claim 18, wherein the disease is
Parkinson's disease.
20. A method for the treatment of a disease or condition where a
COMT inhibiting agent is indicated to be useful, which method
comprises administering to a mammal in need of such treatment an
effective amount of at least one compound as claimed in any one of
claims 1 to 16.
21. A method as claimed in claim 20, wherein the disease is
Parkinson's disease.
22. A method as claimed in claim 21, wherein levodopa therapy is
potentiated.
23. A pharmaceutical composition comprising as active ingredient at
least one compound as claimed in any one of claims 1 to 16, or a
pharmaceutically acceptable ester or salt thereof, and a
pharmaceutically acceptable carrier, diluent and/or excipient.
24. A pharmaceutical composition as claimed in claim 23, wherein
the composition comprises further at least one other active
ingredient.
25. A pharmaceutical composition as claimed in claim 23 or 24,
wherein the composition comprises levodopa and carbidopa.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to pharmacologically active
benzofused five-membered heterocycles, or pharmaceutically
acceptable salts and esters thereof, as well as to pharmaceutical
compositions containing them and to their use as inhibitors of
catechol-O-methyltransferase (COMT) enzyme.
BACKGROUND OF THE INVENTION
[0002] It is generally known and accepted in the art that COMT
inhibitors are useful in the treatment of Parkinson's disease. COMT
inhibitors have been shown to be effective in clinical use for the
treatment of Parkinson's disease as an adjunct to levodopa therapy.
In order to achieve a steady plasma concentration of levodopa, it
is desirable that the COMT inhibitor has a good bioavailability and
a long duration of action. However, the commercially available COMT
inhibitors are associated with a rather short duration of action
and their oral bioavailability is limited.
[0003] COMT inhibitors have also been indicated to be useful in the
treatment of, for example, hypertension, heart failure and
depression (cf e.g. U.S. Pat. No. 5,446,194) as well as inhibitors
for the prevention of diabetic vascular dysfunctions (cf. U.S. Pat.
No. 6,207,706). COMT inhibitors have also been disclosed as being
useful for treating or controlling pain (cf. U.S. Pat. No.
6,723,754) as well as for treating restless legs syndrome (RLS),
which is also known as Ekbom's syndrome (cf. WO 2006/051154). RLS
is characterized by an irresistible urge to move the legs
accompanied by other unpleasant sensations deep within the
legs.
[0004] Some compounds with COMT inhibiting activity are known in
the art. For example, catechol derivatives as COMT inhibitors have
been disclosed e.g. in U.S. Pat. No. 5,389,653; U.S. Pat. No.
5,446,194; U.S. Pat. No. 6,150,412; U.S. Pat. No. 6,512,136; WO
01/98250; WO 01/98251; WO 02/02548; U.S. Pat. No. 6,903,114, WO
2004/112729 and WO 2005/058228. Isoflavone derivatives as COMT
inhibitors have been disclosed in U.S. Pat. No. 3,973,608.
[0005] As to known benzofused five-membered heterocycles,
2-benzyl-7-bromo-6-nitro-benzofuran-4,5-diol has been disclosed in
Lyubchanskaya et al. Khimiko-Farmatsevticheskii Zhurnal, 23 (1989)
843.
SUMMARY OF THE INVENTION
[0006] An object of the present invention is to provide further
inhibitors of catechol-O-methyltransferase enzyme that can be used
for the treatment of diseases or conditions wherein inhibition of
COMT is indicated to be useful. Accordingly, an object of the
present invention is to provide further compounds to be used as
COMT inhibiting agents in the treatment of mammals, including
humans and animals. Furthermore, pharmaceutical compositions
containing the present compounds are provided.
[0007] Due to slow elimination via glucuronidation, the COMT
inhibitors of the present invention have an improved
bioavailability and/or a prolonged duration of action.
Additionally, the compounds of the present invention possess
enhanced primary pharmacological properties, i.e. COMT inhibiting
activity. Furthermore, the compounds do not uncouple oxidative
phosphorylation and thus possess a desirable safety profile.
DETAILED DESCRIPTION OF THE INVENTION
[0008] The present invention relates to novel COMT inhibitors
having the general formula I, ##STR2## wherein R.sub.2 is in a
position ortho to R.sub.3 and R.sub.1 is in a position ortho to
R.sub.2 or R.sub.1 is in a position ortho to R.sub.3 and R.sub.4 is
in a position ortho to R.sub.1; R.sub.1 is cyano or nitro; R.sub.2
is hydroxy; R.sub.3 is hydroxy; R.sub.4 is H,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, cyano, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--, halogen or nitro; the dotted
line represents a single or a double bond; two of X, Y or Z are
independently CR.sub.5(R.sub.6).sub.m, N(R.sub.7).sub.n, O or S and
one of X, Y or Z is N(R.sub.7).sub.n, O or S; m is, independently
at each occurrence, 0 or 1; n is, independently at each occurrence,
0, 1 or 2; R.sub.5 is, independently at each occurrence, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, halogen, hydroxy,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl-(C.dbd.O)--,
(C.sub.1-C.sub.8)alkoxy-(C.dbd.O)--, cyano, formyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.S)--, (R.sub.8).sub.2N--(C.dbd.S)--,
R.sub.8--(C.dbd.NR.sub.8)--, carboxy, (C.sub.3-C.sub.7)cycloalkyl,
heterocyclyl, aryl, heteroaryl, heterocyclyl-(C.dbd.O)--,
aryl(C.sub.1-C.sub.6)alkyl, (R.sub.8).sub.2N--,
(R.sub.8).sub.2N--(C.sub.1-C.sub.6)alkyl,
(R.sub.8).sub.2N--(C.dbd.O)--, (C.sub.1-C.sub.6)alkyl-S--,
R.sub.8--(S--O)--, R.sub.9--(O.dbd.S.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--,
(C.sub.1-C.sub.6)alkyl-(C.dbd.O)--O--(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-S--(C.dbd.O)--,
(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.6)allyl, aryloxy,
aryloxy(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkoxy,
aryl(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl or
heterocyclyl-(C.dbd.S)--, wherein said (C.sub.3-C.sub.7)cycloalkyl,
heterocyclyl, aryl or heteroaryl as such or as part of another
group is unsubstituted or substituted with 1, 2 or 3 substituent(s)
each independently being (C.sub.1-C.sub.6)alkyl, halogen, hydroxy,
carboxy, (C.sub.1-C.sub.6)alkoxy or (R.sub.8).sub.2N--; R.sub.6 is,
independently at each occurrence, H, (C.sub.1-C.sub.6)alkyl,
halogen, hydroxy, hydroxy(C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)alkoxy; or R.sub.5 and R.sub.6 both attached to
the same carbon ring atom form, together with the carbon ring atom
to which they are attached, a --(C.dbd.O)-- group; or R.sub.5 and
R.sub.6 both attached to the same carbon ring atom form, together
with the carbon ring atom to which they are attached,
C.dbd.C(R.sub.8).sub.2; or R.sub.5 and R.sub.6 both attached to the
same carbon ring atom form, together with the carbon ring atom to
which they are attached, a 5, 6 or 7 membered saturated or
unsaturated carbocyclic ring, wherein said ring is unsubstituted or
substituted with 1 or 2 substituent(s) each independently being
(C.sub.1-C.sub.6)alkyl, halogen, hydroxy, (C.sub.1-C.sub.6)alkoxy
or carboxy; R.sub.7 is, independently at each occurrence, H,
(C.sub.1-C.sub.6)allyl, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.1-C.sub.6)alkoxy, aryl or O.sup.-, wherein said
(C.sub.3-C.sub.7)cycloalkyl or aryl is unsubstituted or substituted
with 1, 2 or 3 substituent(s) each independently being
(C.sub.1-C.sub.6)alkyl, halogen, hydroxy, (C.sub.1-C.sub.6)alkoxy
or carboxy; or R.sub.5 and R.sub.5, R.sub.5 and R.sub.7, or R.sub.7
and R.sub.7 attached to adjacent ring atoms form, together with the
ring atoms to which they are attached, a condensed 5, 6 or 7
membered saturated or unsaturated carbocyclic ring or a condensed
5, 6 or 7 membered saturated or unsaturated heterocyclic ring
containing 1 or 2 heteroatom(s) selected from N, O and S, wherein
said carbo- or heterocyclic ring is unsubstituted or substituted
with 1 or 2 substituent(s) each independently being
(C.sub.1-C.sub.6)alkyl, halogen, hydroxy, (C.sub.1-C.sub.6)alkoxy,
carboxy or oxo; R.sub.8 is, independently at each occurrence, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, aryl or
aryl(C.sub.1-C.sub.6)alkyl, wherein said aryl as such or as part of
another group is unsubstituted or substituted with 1 or 2
substituent(s) each independently being (C.sub.1-C.sub.6)alkyl,
halogen, hydroxy, carboxy or (C.sub.1-C.sub.6)alkoxy; R.sub.9 is,
independently at each occurrence, (C.sub.1-C.sub.6)alkyl,
(R.sub.8).sub.2N--, hydroxy or (C.sub.1-C.sub.6)alkoxy; or a
pharmaceutically acceptable salt or ester thereof; with the proviso
that the compound is not
2-benzyl-7-bromo-6-nitro-benzofuran-4,5-diol.
[0009] In a possible subgroup of the compounds of formula I,
R.sub.2 is in a position ortho to R.sub.3 and R.sub.1 is in a
position ortho to R.sub.2.
[0010] In another possible subgroup of the compounds of formula I,
R.sub.1 is in a position ortho to R.sub.3 and R.sub.4 is in a
position ortho to R.sub.1.
[0011] In another possible subgroup of the compounds of formula I,
R.sub.4 is H, halogen or nitro, for example, H.
[0012] In another possible subgroup of the compounds of formula I,
R.sub.1 is cyano.
[0013] In another possible subgroup of the compounds of formula I,
R.sub.1 is nitro.
[0014] In yet another possible subgroup of the compounds of formula
I, one of the dotted lines represents a double bond.
[0015] In a further possible subgroup of the compounds of formula
I, two of X, Y or Z are CR.sub.5(R.sub.6).sub.m and one of X, Y or
Z is N.
[0016] In a further possible subgroup of the compounds of formula
I, one of X, Y or Z is CR.sub.5(R.sub.6).sub.m, one of X, Y or Z is
N(R.sub.7).sub.n, and one of X, Y or Z is S.
[0017] In a further possible subgroup of the compounds of formula
I, two of X, Y or Z are CR.sub.5(R.sub.6).sub.m and one of X, Y or
Z is O.
[0018] In a further possible subgroup of the compounds of formula
I, two of X, Y or Z are CR.sub.5(R).sub.m and one of X, Y or Z is
S.
[0019] In another possible subgroup of the compounds of formula I,
R.sub.7 is, independently at each occurrence, H,
(C.sub.1-C.sub.6)alkyl or aryl, wherein said aryl is unsubstituted
or substituted with i, 2 or 3 substituent(s) each independently
being halogen.
[0020] In yet another possible subgroup of the compounds of formula
I, R.sub.5 is, independently at each occurrence, H,
(C.sub.1-C.sub.6)alkyl, halogen, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.8)alkoxy-(C.dbd.O)--, carboxy, aryl, heteroaryl,
heterocyclyl-(C.dbd.O)-- or (R.sub.8).sub.2N--(C.dbd.O)--, wherein
said heterocyclyl, aryl or heteroaryl as such or as part of another
group is unsubstituted or substituted with 1, 2 or 3 substituent(s)
each independently being (C.sub.1-C.sub.6)alkyl or hydroxy, R.sub.6
is, independently at each occurrence, H, or R.sub.5 and R.sub.6
both attached to the same carbon ring atom form, together with the
carbon ring atom to which they are attached, a --(C.dbd.O)-- group,
and R.sub.8 is, independently at each occurrence,
(C.sub.1-C.sub.6)alkyl or aryl, wherein said aryl is unsubstituted
or substituted with 1 or 2 substituent(s) each independently being
carboxy or (C.sub.1-C.sub.6)alkoxy, for example, m is,
independently at each occurrence, 0, R.sub.5 is, independently at
each occurrence, H, halogen, (C.sub.1-C.sub.8)alkoxy-(C.dbd.O)--,
carboxy, heterocyclyl-(C.dbd.O)-- or (R.sub.8).sub.2N--(C.dbd.O)--,
wherein said heterocyclyl as part of another group is unsubstituted
or substituted with 1, 2 or 3 substituent(s) each independently
being (C.sub.1-C.sub.6)alkyl or hydroxy, and R.sub.8 is,
independently at each occurrence, (C.sub.1-C.sub.6)alkyl or aryl,
wherein said aryl is unsubstituted or substituted with 1
substituent being carboxy or (C.sub.1-C.sub.6)alkoxy.
[0021] In a further possible subgroup of the compounds of formula
I, the compound is
2-(4-chloro-phenyl)-5,6-dihydroxy-4-nitro-2,3-dihydro-isoindol-1-one,
5,6-dihydroxy-7-nitro-3H-isobenzofuran-1-one,
7-nitro-2-pyridin-4-yl-benzothiazole-5,6-diol, methane sulfonate,
3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid,
3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
ethyl ester,
3-chloro-5,6-dihydroxy-4-nitro-benzo[b]thiophene-2-carboxylic acid,
3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene,
(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-met-
hanone,
3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
diethylamide,
(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-piperidin-1-yl-met-
hanone,
3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
phenylamide,
3-[(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carbonyl)-amino]-b-
enzoic acid,
4-[(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carbonyl)-amino]-b-
enzoic acid,
3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
(4-methoxy-phenyl)amide, 2-methyl-7-nitro-benzothiazole-5,6-diol,
(5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone,
5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid,
5,6-dihydroxy-7-nitro-benzofuran-2-carboxylic acid,
5,6-dihydroxy-2-methyl-7-nitro-benzo[d]isothiazol-3-one,
(5,6-dihydroxy-3-methyl-7-nitro-benzo[b]thiophen-2-yl)morpholin-4-yl-meth-
anone, 5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
ethyl ester, 5,6-dihydroxy-4-nitro-isobenzofuran-1,3-dione,
5,6-dihydroxy-4-nitro-3H-isobenzofuran-1-one,
5,6-dihydroxy-4,7-dinitro-3H-isobenzofuran-1-one,
7-nitro-2-phenyl-benzothiazole-5,6-diol,
6,7-dihydroxy-5-nitro-benzo[b]thiophene-2-carboxylic acid methyl
ester, 1-(5,6-dimethoxy-7-nitro-benzo[b]thiophen-2-yl)-nonan-1-one,
(3-chloro-5,6-dihydroxy-4,7-dinitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-
-methanone,
(3,4-chloro-5,6-dihydroxy-7-dinitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-
-methanone,
(3-chloro-5,6-dihydroxy-4-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-met-
hanone,
(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-(2,6-dimeth-
yl-morpholin-4-yl)-methanone,
(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-(4-hydroxy-piperid-
in-1-yl)-methanone,
(3-bromomethyl-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-y-
l-methanone,
5,6-dihydroxy-3-methyl-2-(morpholine-4-carbonyl)-benzo[b]thiophene-4-carb-
onitrile or
(3-chloro-5,6-dihydroxy-7-cyano-benzo[b]thiophen-2-yl)-morpholin-4-yl-met-
hanone.
[0022] It is evident to a person skilled in the art that, in the
compounds of formula I, at least one of two bonds represented by a
dotted line and having a common atom represented by X, Y or Z is a
single bond and that the aromatic character of the six-membered
ring is retained.
[0023] Likewise, it is evident to a person skilled in the art that,
in the compounds of formula I, when the substituent R.sub.7 is
O.sup.-, the nitrogen atom, to which said substituent is attached,
is a positively charged quaternary nitrogen atom.
[0024] The terms employed herein have the following meanings:
[0025] The term "cyano", as employed herein, refers to a --CN
group.
[0026] The term "nitro", as employed herein, refers to a --NO.sub.2
group.
[0027] The term "(C.sub.1-C.sub.6)alkyl", as employed herein as
such or as part of another group, refers to a straight or branched
chain saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon
atom(s). Representative examples of (C.sub.1-C.sub.6)alkyl include,
but are not limited to, methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl,
and n-hexyl.
[0028] The term "halo" or "halogen", as employed herein as such or
as part of another group, refers to fluorine, chlorine, bromine or
iodine.
[0029] The term "halo(C.sub.1-C.sub.6)alkyl", as employed herein,
refers to at least one halogen, as defined herein, appended to the
parent molecular moiety through an (C.sub.1-C.sub.6)alkyl group, as
defined herein. Representative examples of
halo(C.sub.1-C.sub.6)alkyl include, but are not limited to,
fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl,
2-chloroethyl, 3-bromopropyl, and 2-chloropropyl.
[0030] The term "formyl", as employed herein, refers to a --CHO
group.
[0031] The term "hydroxy", as employed herein as such or as part of
another group, refers to a --OH group.
[0032] The term "(C.sub.1-C.sub.6)alkoxy", as employed herein as
such or as part of another group, refers to an
(C.sub.1-C.sub.6)alkyl group, as defined herein, appended to the
parent molecular moiety through an oxygen atom. Representative
examples of (C.sub.1-C.sub.6)alkoxy include, but are not limited to
methoxy, ethoxy, n-propoxy, n-butoxy, iso-butoxy, sec-butoxy, and
tert-butoxy.
[0033] The term "(C.sub.1-C.sub.8)alkoxy", as employed herein as
part of another group, refers to a straight or branched chain
saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atom(s) appended to the parent molecular moiety through an oxygen
atom. Representative examples of (C.sub.1-C.sub.8)alkoxy include,
but are not limited to methoxy, ethoxy, n-propoxy, n-butoxy,
iso-butoxy, sec-butoxy, tert-butoxy, and n-octoxy.
[0034] The term "hydroxy(C.sub.1-C.sub.6)alkoxy", as employed
herein as part of another group, refers to at least one hydroxy
group, as defined herein, appended to the parent molecular moiety
through an (C.sub.1-C.sub.6)alkoxy group, as defined herein.
Representative examples of hydroxy(C.sub.1-C.sub.6)alkoxy include,
but are not limited to, hydroxymethoxy, dihydroxymethoxy,
2-hydroxyethoxy, 2-hydroxypropoxy, and
2-hydroxy-1-methylethoxy.
[0035] The term "(C.sub.3-C.sub.7)cycloalkyl", as employed herein
as such or as part of another group, refers to a saturated cyclic
hydrocarbon group containing 3, 4, 5, 6 or 7 carbon atoms.
Representative examples of (C.sub.3-C.sub.7)cycloalkyl include, but
are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl.
[0036] The term "(C.sub.2-C.sub.6)alkenyl", as employed herein,
refers to a straight or branched chain hydrocarbon group having 2,
3, 4, 5 or 6 carbon atoms and containing at least one carbon-carbon
double bond. Representative examples of (C.sub.2-C.sub.6)alkenyl
include, but are not limited to, ethenyl and 2-propenyl.
[0037] The term "aryl", as employed herein as such or as part of
another group, refers to a mono- or bicyclic aromatic carbocyclic
group containing 6 or 10 carbon atoms.
[0038] The term "aryl(C.sub.1-C.sub.6)alkyl", as employed herein,
refers to an aryl group, as defined herein, appended to the parent
molecular moiety through an (C.sub.1-C.sub.6)alkyl group, as
defined herein.
[0039] Representative examples of aryl(C.sub.1-C.sub.6)alkyl
include, but are not limited to, phenylmethyl and
naphth-1-ylmethyl.
[0040] The term "hydroxy(C.sub.1-C.sub.6)alkyl", as employed
herein, refers to at least one hydroxy group, as defined herein,
appended to the parent molecular moiety through an
(C.sub.1-C.sub.6)alkyl group, as defined herein. Representative
examples of hydroxy(C.sub.1-C.sub.6)alkyl include, but are not
limited to, hydroxymethyl, 1-hydroxyethyl, 2,2-dihydroxyethyl,
1-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy-1-methylethyl, and
1-hydroxy-1-methylpropyl.
[0041] The term "heterocyclyl", as employed herein as such or as
part of another group, refers to a 5, 6 or 7 membered saturated
cyclic group containing 1 or 2 heteroatom(s) each independently
selected from N, O, and S. Representative examples of heterocyclyl
include, but are not limited to, pyrrolidinyl, piperidinyl,
piperazinyl, morpholinyl, and azepanyl.
[0042] The term "carboxy", as employed herein, refers to a --COOH
group.
[0043] The term "heteroaryl", as employed herein, refers to a 5, 6
or 7 membered aromatic group containing 1, 2, 3 or 4 heteroatom(s)
each independently selected from N, O, and S. Representative
examples of heteroaryl include, but are not limited to, pyrrolyl,
furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl,
tetrazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
pyridazinyl, pyranyl, and azepinyl.
[0044] The term "(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl", as
employed herein as such or as part of another group, refers to at
least one (C.sub.1-C.sub.6)alkoxy group, as defined herein,
appended to the parent molecular moiety through an
(C.sub.1-C.sub.6)alkyl group, as defined herein. Representative
examples of (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl include,
but are not limited to, methoxymethyl, propoxymethyl,
2-ethoxyethyl, 2,2-dimethoxyethyl, 1-methyl-2-propoxyethyl and
4-methoxybutyl.
[0045] The term "aryl(C.sub.1-C.sub.6)alkoxy", as employed herein
as such or as part of another group, refers to an aryl group, as
defined herein, appended to the parent molecular moiety through an
(C.sub.1-C.sub.6)alkoxy group, as defined herein. Representative
examples of aryl(C.sub.1-C.sub.6)alkoxy include, but are not
limited to, phenylmethoxy, 2-phenylethoxy, and
2-naphth-2-ylethoxy.
[0046] The term "oxo", as employed herein, refers to a .dbd.O
group.
[0047] Pharmaceutically acceptable salts, e.g. metal salts and acid
addition salts, with both organic and inorganic acids, are well
known in the field of pharmaceuticals. Representative examples of
pharmaceutically acceptable metal salts include, but are not
limited to, lithium, sodium, potassium, calcium, magnesium,
aluminum and zinc salts. Representative examples of
pharmaceutically acceptable acid addition salts include, but are
not limited to, chlorides, bromides, sulfates, nitrates,
phosphates, sulfonates, methane sulfonates, formates, tartrates,
maleates, citrates, benzoates, salicylates, and ascorbates.
[0048] Pharmaceutically acceptable esters, when applicable, may be
prepared by known methods using pharmaceutically acceptable acids
that are conventional in the field of pharmaceuticals and that
retain the pharmacological properties of the free form.
Non-limiting examples of these esters include esters of aliphatic
or aromatic alcohols, e.g. methyl, ethyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl
esters.
[0049] The invention includes within its scope all the possible
geometric isomers, e.g. Z and E isomers (cis and trans isomers), of
the compounds as well as all the possible optical isomers, e.g.
diastereomers and enantiomers, of the compounds. Furthermore, the
invention includes in its scope both the individual isomers and any
mixtures thereof, e.g. racemic mixtures. The individual isomers may
be obtained using the corresponding isomeric forms of the starting
material or they may be separated after the preparation of the end
compound according to conventional separation methods. For the
separation of optical isomers, e.g. enantiomers, from the mixture
thereof conventional resolution methods, e.g. fractional
crystallization, may be used.
[0050] The compounds of formula I can be prepared by a variety of
synthetic routes analogously to or according to methods known in
the literature using suitable starting materials.
[0051] Benzofuran derivatives can be prepared, for example,
according to reaction scheme 1: ##STR3##
[0052] In scheme 1 the methoxy substituents are in a position ortho
to each other, R.sub.4 is as defined above and in a position ortho
to either the acyl substituent or the hydroxy substituent in
formula II, and R.sub.5 is as defined above. An acylphenol compound
is alkylated with a functionalized haloderivative at room
temperature in the presence of a suitable base in a suitable
solvent, e.g. potassium carbonate in N,N-dimethylformamide or
sodium hydride in tetrahydrofuran. The activated methylene group is
condensed with the carbonyl by using a suitable base, e.g. sodium
ethanolate. In addition to the carbethoxy group, the methylene
group can be activated with any methylene activating group like
nitro, cyano, acyl, aryl, aryloxy, alkylthio, or arylthio. The
carbethoxy group can then be converted to other functional groups,
if desired.
[0053] The preparation of benzofuran derivatives is further
exemplified in Example 18.
[0054] 2,3-Dihydro-isoindol-1-one derivatives can be prepared, for
example, according to reaction scheme 2: ##STR4##
[0055] In scheme 2 the methoxy substituents are in a position ortho
to each other, R.sub.4 is as defined above and in a position ortho
to either the methoxycarbonyl substituent or the
CBrR.sub.5R.sub.6-substituent in formula V, and R.sub.5, R.sub.6,
and R.sub.7 are as defined above. The ring is formed by refluxing a
compound of formula V with an amine in a suitable solvent, e.g.
toluene.
[0056] The preparation of 2,3-dihydro-isoindol-1-one derivatives is
further exemplified in Example 1.
[0057] Benzothiazole derivatives can be prepared, for example,
according to scheme 3: ##STR5##
[0058] In scheme 3 the methoxy substituents are in a position ortho
to each other, R.sub.4 is as defined above and in a 4- or
7-position in formula VIII, and R.sub.5 is, for example, aryl or
heteroaryl. The ring is formed by refluxing an aniline with an
aldehyde and elementary sulfur in a suitable solvent, e.g. dimethyl
acetamide.
[0059] The preparation of benzothiazole derivatives is further
exemplified in Examples 3, 15 and 25.
[0060] Benzo[b]thiophene derivatives can be prepared, for example,
according to reaction scheme 4: ##STR6##
[0061] In scheme 4 the methoxy substituents are in a position ortho
to each other, R.sub.4 is as defined above and in a 4- or
7-position in formula XI, and R.sub.5' is, for example,
(C.sub.1-C.sub.8)alkoxy, N-containing heterocyclyl or
(R.sub.8).sub.2N--, wherein R.sub.8 is as defined above. A
benzaldehyde is condensed with malonic acid in a suitable solvent,
e.g. pyridine, resulting in an acrylic acid derivative. The ring is
formed by reacting the acid with thionyl chloride in a suitable
solvent, e.g. chlorobenzene or toluene.
[0062] Another route for preparing benzo[b]thiophene derivatives is
illustrated in scheme 5: ##STR7##
[0063] In scheme 5 the methoxy substituents are in a position ortho
to each other. A benzaldehyde is condensed with rhodanine XII in a
suitable solvent, e.g. a carboxylic acid such as acetic acid,
resulting in intermediate XIII. With the aid of a suitable base,
e.g. sodium hydroxide, the intermediate is converted into a
2-mercapto-acrylic acid derivative. The ring is formed by treating
the mercapto compound with, for example, iodine in a suitable
solvent, e.g. tetrahydrofuran. The carboxy group can then be
converted to other functional groups, if desired.
[0064] The preparation of benzo[b]thiophene derivatives is further
exemplified in Examples 4-14, 16-17, 20-21, and 26-35.
[0065] The dealkylation of the resulting dialkoxy intermediates as
well as the insertion of the substituent R.sub.1 being cyano or
nitro is described in the specific compound examples.
[0066] It is obvious for a person skilled in the art that any
starting material or intermediate in the reactions described above
can be protected, if necessary, in a manner well known in the
chemical field. Any protected functionality can subsequently be
deprotected in a manner known in the art.
[0067] The synthetic routes described above are meant to illustrate
the preparation of the compounds of formula I and the preparation
is by no means limited thereto, i.e. there are also other possible
synthetic methods which are within the general knowledge of a
person skilled in the art.
[0068] The compounds of formula I may be converted, if desired,
into their pharmaceutically acceptable salt or ester form using
methods well known in the art.
[0069] The present invention will be explained in more detail by
the following examples. The examples are meant for illustrating
purposes only and do not limit the scope of the invention defined
in the claims.
Example 1
2-(4-Chloro-phenyl)-5,6-dihydroxy-4-nitro-2,3-dihydro-isoindol-1-one
2-(4-Chloro-phenyl)-5,6-dimethoxy-2,3-dihydro-isoindol-1-one
[0070] A solution of 2-bromomethyl-4,5-dimethoxy-benzoic acid
methyl ester (2.9 g), 4-chloroaniline (1.28 g) and triethylamine
(1.4 ml) was refluxed in toluene for six hours. The reaction
mixture was stirred in an ice bath, filtered and washed with 1 M
hydrochloric acid and water.
[0071] Yield: 0.74 g
[0072] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.85 (s, 3H, CH.sub.3O),
3.88 (s, 3H, CH.sub.3O), 4.89 (s, 2H, CH.sub.2), 7.23 (s, 1H, ArH),
7.24 (s, 1H, ArH), 7.48 (d, 2H, J=8.9 Hz), 7.91 (d, 2H, J=8.9
Hz).
2-(4-Chloro-phenyl)-5,6-dihydroxy-2,3-dihydro-isoindol-1-one
[0073] 2-(4-Chloro-phenyl)-5,6-dimethoxy-2,3-dihydro-isoindol-1-one
(0.74 g) was demethylated with 4 eq of boron tribromide as
described in Example 8.
[0074] Yield: 0.79 g (raw material used as such in the next
step)
[0075] .sup.1H NMR (DMSO-d.sub.6): .delta.=4.80 (s, 2H, CH.sub.2),
6.77 (s, 1H, ArH), 6.82 (s, 1H, ArH), 7.48 (d, 2H, J=9.1 Hz), 7.91
(d, 2H, J=9.1 Hz).
Acetic acid
6-acetoxy-2-(4-chloro-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl
ester
[0076] 2-(4-Chloro-phenyl)-5,6-dihydroxy-2,3-dihydro-isoindol-1-one
(0.79 g of raw material) and acetic anhydride (10 ml) was stirred
in 80.degree. C. with one drop of sulfuric acid as a catalyst for
one hour. The mixture was poured into ice water, filtered and
recrystallized from acetic acid.
[0077] Yield: 0.5 g
[0078] .sup.1H NMR (DMSO-d): .delta.=2.29 (s, 3H, CH.sub.3COO),
2.34 (s, 3H, CH.sub.3COO), 5.04 (s, 2H, CH.sub.2), 7.51 (d, 2H,
J=8.8 Hz), 7.62 (s, 1H, ArH), 7.70 (s, 1H, ArH), 7.92 (d, 2H, J=8.8
Hz).
Acetic acid
2-(4-chloro-phenyl)-6-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl
ester
[0079] A solution of acetic acid
6-acetoxy-2-(4-chloro-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl
ester (0.5 g) in dry N,N-dimethylformamide (15 ml) was treated with
morpholine (0.13 ml) at 0-5.degree. C. and stirred then for an hour
at room temperature. The reaction was poured into ice water and
filtered.
[0080] Yield: 0.34 g
[0081] .sup.1H NMR (DMSO-d.sub.6): .delta.=2.29 (s, 3H,
CH.sub.3COO), 4.92 (s, 2H, CH.sub.2), 7.14 (s, 1H, ArH), 7.43 (s,
1H, ArH), 7.48 (d, 2H, J=8.9 Hz), 7.90 (d, 2H, J=8.9 Hz).
Acetic acid
2-(4-chloro-phenyl)-6-hydroxy-7-nitro-3-oxo-2,3-dihydro-1H-isoindol-5-yl
ester
[0082] A suspension of acetic acid
2-(4-chloro-phenyl)-6-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl
ester (0.34 g) in acetic acid (7 ml) was treated with 2 M nitric
acid in dichloromethane (0.6 ml). After an hour the reaction
mixture was filtered.
[0083] Yield: 0.24 g (raw material used as such in the next
step)
[0084] .sup.1H NMR (DMSO-d.sub.6): .delta.=2.35 (s, 3H,
CH.sub.3COO), 5.25 (s, 2H, CH.sub.2), 7.50 (d, 2H, J=8.8 Hz), 7.89
(s, 1H, ArH), 7.93 (d, 2H, J=8.8 Hz).
2-(4-Chloro-phenyl)-5,6-dihydroxy-4-nitro-2,3-dihydro-isoindol-1-one
[0085] Acetic acid
2-(4-chloro-phenyl)-6-hydroxy-7-nitro-3-oxo-2,3-dihydro-1H-isoindol-5-yl
ester (0.24 g raw material) was refluxed in methanol (15 ml) with
three drops of concentrated hydrochloric acid for six hours. The
reaction mixture was cooled and filtered.
[0086] Yield: 80 mg
[0087] .sup.1H NMR (DMSO-d.sub.6): .delta.=5.13 (s, 2H, CH.sub.2),
7.34 (s, 1H, ArH), 7.48 (d, 2H, J=8.7 Hz), 7.91 (d, 2H, J=8.7 Hz),
10.4-11.5 (b, 2H, OH).
Example 2
5,6-Dihydroxy-7-nitro-3H-isobenzofuran-1-one
5,6-Dihydroxy-7-nitro-3H-isobenzofuran-1-one
[0088] To a solution of 5,6-dihydroxy-3H-isobenzofuran-1-one (0.4
g) in sulfuric acid at -30.degree. C. was added 5 M nitric acid in
sulfuric acid (0.55 ml). The reaction mixture was let to warm up to
room temperature and then poured into ice water. The product was
filtered and recrystallized from acetic acid.
[0089] Yield: 0.2 g
[0090] .sup.1H NMR (DMSO-d.sub.6): .delta.=5.26 (s, 2H, CH2), 7.14
(s, 1H, ArH), 10.6 (b, 1H, OH), 11.75 (b, 1H, OH).
Example 3
7-Nitro-2-pyridin-4-yl-benzothiazole-5,6-diol, methane
sulfonate
5,6-Dimethoxy-2-pyridin-4-yl-benzothiazole
[0091] A solution of 3,4-dimethoxyaniline (6 g) and sulfur (5 g)
were refluxed in 4-picolin (15 ml) for five hours. The cool
reaction mixture was poured into methanol, kept over ice bath for
minutes and filtered. The product was washed with methanol and
carbon disulfide.
[0092] Yield: 6.14 g
[0093] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.88 (s, 3H, CH.sub.3O),
3.89 (s, 3H, CH.sub.3O), 7.67 (s, 1H, ArH), 7.76 (s, 1H, ArH), 7.94
(d, 2H, J=6.4 Hz), 8.75 (d, 2H, J=6.4 Hz).
5,6-Dimethoxy-4-nitro-2-pyridin-4-yl-benzothiazole
[0094] To a solution of 5,6-dimethoxy-2-pyridin-4-yl-benzothiazole
(1.1 g) in sulfuric acid (10 ml) was added potassium nitrate (0.5
g). After 60 minutes in room temperature the mixture was poured
into ice water and filtered. Recrystallization from acetone yielded
the pure product.
[0095] Yield: 0.8 g
[0096] .sup.1H NMR (DMSO-d.sub.6): .delta.=4.05 (s, 3H, CH.sub.3O),
4.07 (s, 3H, CH.sub.3O), 8.07 (d, 2H, J=6 Hz), 8.25 (s, 1H, ArH),
8.81 (d, 2H, J=6 Hz).
7-Nitro-2-pyridin-4-yl-benzothiazole-5,6-diol, methane
sulfonate
[0097] A solution of
5,6-dimethoxy-4-nitro-2-pyridin-4-yl-benzothiazole (0.4 g) was
refluxed in 48% HBr (14.5 ml) for two hours. The crystals were
filtered, taken in methanesulfonic acid (2 ml) by warming and
diluted with methanol. After stirring in ice bath the salt was
filtered.
[0098] Yield: 0.44 g
[0099] Melting point: >350.degree. C.
[0100] .sup.1H NMR (DMSO-d.sub.6): .delta.=2.37 (s, 3H,
CH.sub.3SO.sub.3--), 7.83 (s, 1H, ArH), 8.42 (d, 2H, J=6.3 Hz),
8.94 (d, 2H, J=6.3 Hz).
Example 4
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic
acid
3-(3,4-Dimethoxy-phenyl)acrylic acid
[0101] 3,4-Dimethoxybenzaldehyde (5 g), malonic acid (4.7 g),
piperidine (0.5 ml) and pyridine (15 ml) were refluxed for six
hours. The reaction mixture was poured into ice-cold water and
acidified with 6M hydrochloric acid. The resultant solid was
filtered, washed with water and dried under vacuum.
[0102] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.80 (d, 6H), 6.44 (d,
1H), 7.20 (q, 1H), 7.31 (d, 1H), 7.4 (d, 1H), 12 (br, 1H).
3-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid methyl
ester
[0103] 3-(3,4-Dimethoxy-phenyl)acrylic acid (1.0 g) was slurried in
chlorobenzene (25 ml) and then thionyl chloride (1.5 ml) was added.
The suspension was stirred at room temperature and after 30 min
pyridine (0.1 ml) was added. The reaction mixture was refluxed for
24 hours. The resultant solid was filtered and dissolved in
chlorobenzene (20 ml) and methanol (20 ml). The reaction mixture
was refluxed for one hour and then cooled. The solid was filtered,
washed with methanol and dried under vacuum.
[0104] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.88 (s, 3H), 3.89 (s,
3H), 3.90 (s, 3H), 7.29 (s, 1H), 7.29 (s, 1H), 7.68 (s, 1H).
3-Chloro-5,6-dihydroxy-benzo[b]thiophene-2-carboxylic acid
[0105] 3-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid
methyl ester (0.2 g) was suspended in dichloromethane (10 ml) under
nitrogen, cooled to -20.degree. C. and boron tribromide (0.4 ml)
was added. The resultant mixture was stirred at -20.degree. C. for
30 min and then in cool overnight. The mixture was poured into
ice-cold water, extracted into ethyl acetate and evaporated to
dryness. The product was used for the next step without any
purification.
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic
acid
[0106] 3-Chloro-5,6-dihydroxy-benzo[b]thiophene-2-carboxylic acid
was dissolved in ethyl acetate and a solution of nitric acid in
dichloromethane (2M, 0.38 ml) was gradually added at 20.degree. C.
The solution was stirred 10 min at room temperature and then it was
poured into ice-cold water and extracted with ethyl acetate. The
organic extracts were combined, dried and evaporated to dryness.
The residue was recrystallized from acetic acid.
[0107] Yield: 94 mg
[0108] Melting point: 298-300.degree. C.
[0109] .sup.1H NMR (DMSO-d.sub.6): .delta.=7.49 (s, 1H), 13-14 (br,
1H).
Example 5
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
ethyl ester
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
ethyl ester
[0110]
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
(70 mg) from Example 4, ethanol (2 ml) and thionyl chloride (0.16
ml) were refluxed for 4 hours. Ethanol was evaporated. The residue
was heated with absolute ethanol and the hot mixture was filtered.
The product was dried under vacuum.
[0111] Yield: 34 mg
[0112] Melting point: 215.degree. C.
[0113] .sup.1H NMR (DMSO-d.sub.6): .delta.=1.36 (t, 3H), 4.36 (q,
2H) 7.50 (s, 1H).
Example 6
3-Chloro-5,6-dihydroxy-4-nitro-benzo[b]thiophene-2-carboxylic
acid
3-Chloro-5-benzyloxy-6-methoxy-benzo[b]thiophene-2-carboxylic acid
methyl ester
[0114] 3-(3-Benzyloxy-4-methoxy-phenyl)acrylic acid was converted
to 3-chloro-5-benzyloxy-6-methoxy-benzo[b]thiophene-2-carboxylic
acid methyl ester by repeating the method of Example 4, except that
3-(3-benzyloxy-4-methoxy-phenyl)acrylic acid was used instead of
3-(3,4-dimethoxy-phenyl)acrylic acid. The product was a mixture of
two compounds and it was used for the next step without any
purification.
3-Chloro-5-hydroxy-6-methoxy-benzo[b]thiophene-2-carboxylic acid
methyl ester
[0115]
3-Chloro-5-benzyloxy-6-methoxy-benzo[b]thiophene-2-carboxylic acid
methyl ester (0.7 g), acetic acid (17.5 ml) and concentrated
hydrochloride acid (2.1 ml) was refluxed for six hours. The mixture
was cooled and evaporated to dryness. The resultant mixture was
extracted first into diethyl ether and then into a solution of 1M
sodium hydroxide. The water phase was acidified with 6M
hydrochloric acid. The solution was stirred in cool for two hours
and filtered. The solid was washed with water and dried under
vacuum. The product was a mixture of two compounds and it was used
for the next step without any purification.
3-Chloro-5-hydroxy-6-methoxy-benzo[b]thiophene-2-carboxylic
acid
[0116] 3-Chloro-5-hydroxy-6-methoxy-benzo[b]thiophene-2-carboxylic
acid methyl ester (0.5 g) was dissolved in methanol (10 ml) and 5M
sodium hydroxide (10 ml) added to. The solution refluxed for two
hours. Methanol was evaporated and the resultant solution was
acidified with 2M hydrochloric acid. The resultant solid was dried
under vacuum. The product was used for the next step without any
purification.
3-Chloro-5-hydroxy-6-methoxy-4-nitro-benzo[b]thiophene-2-carboxylic
acid
[0117] 3-Chloro-5-hydroxy-6-methoxy-benzo[b]thiophene-2-carboxylic
acid (0.28 g) was dissolved in ethyl acetate and a solution of
nitric acid in dichloromethane (2M, 0.75 ml) was gradually added at
20.degree. C. into. The solution was stirred at room temperature
for 10 min and then it was poured into ice-cold water and extracted
with ethyl acetate and evaporated to dryness.
[0118] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.98 (s, 3H), 7.90 (s,
1H) 10.9 (br, 1H), 13.4-14.4 (br, 1H).
3-Chloro-5,6-dihydroxy-4-nitro-benzo[b]thiophene-2-carboxylic
acid
[0119] To the solution of
3-chloro-5-hydroxy-6-methoxy-4-nitro-benzo[b]thiophene-2-carboxylic
acid (0.2 g), pyridine (6.3 ml) in ethyl acetate (5 ml) was
gradually added aluminum trichloride (0.32 g). The reaction mixture
was refluxed at 90.degree. C. for two hours. To the warm reaction
(60.degree. C.) solution was added the mixture of concentrated
hydrochloric acid and ice (1:1). The product was extracted into
ethyl acetate, dried and evaporated. The residue was treated with
diethyl ether and the resultant solid was filtered.
[0120] Yield: 32 mg
[0121] Melting point: 215-219.degree. C.
[0122] .sup.1H NMR (DMSO-d.sub.6): .delta.=7.54 (s, 1H), 10-12 (br,
2H), 13.5-14 (br, 1H)
Example 7
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene
3-Chloro-6-benzyloxy-5-methoxy-benzo[b]thiophene-2-carboxylic acid
methyl ester
[0123] 3-(4-Benzyloxy-3-methoxy-phenyl)acrylic acid was converted
to 3-chloro-6-benzyloxy-5-methoxy-benzo[b]thiophene-2-carboxylic
acid methyl ester by repeating the method of Example 4, except that
3-(4-benzyloxy-3-methoxy-phenyl)acrylic acid was used instead of
3-(3,4-dimethoxy-phenyl)acrylic acid.
[0124] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.88 (s, 3H), 3.90 (s,
3H), 5.20 (s, 2H) 7.32-7.50 (m, 5H), 7.81 (s, 1H).
3-Chloro-6-hydroxy-5-methoxy-benzo[b]thiophene
[0125]
3-Chloro-6-benzyloxy-5-methoxy-benzo[b]thiophene-2-carboxylic acid
methyl ester (1.33 g), methanol (27 ml) and 5M sodium hydroxide (27
ml) were refluxed for 2.5 hours. Methanol was evaporated and the
resultant solid was filtered. The solid was dissolved in water and
acidified with concentrated hydrochloric acid. The mixture was
stirred in an ice-water bath, filtered and dried in vacuum. The
resultant solid, copper (0.17 g) and quinoline (10.6 ml) were
heated at 210.degree. C. for one hour. To the cooled mixture was
added 10% hydrochloric acid (26 ml) and dissolved in ethyl acetate.
The solution was washed with 10% sodium carbonate and 1M
hydrochloric acid and then it was evaporated to dryness. The
residue, acetic acid (24 ml) and concentrate hydrochloric acid (3.2
ml) were refluxed 5 hours. The solution was evaporated to dryness.
The residue was dissolved in diethyl ether and then extracted with
1M sodium hydroxide. The water phase was acidified with 6M
hydrochloric acid and extracted into ethyl acetate. The solution
was dried, evaporated to dryness and then triturated with diethyl
ether and filtered.
[0126] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.89 (s, 3H), 7.17 (s,
1H), 7.35 (s, 1H) 7.56 (s, 1H), 9.52 (s, 1H).
3-Chloro-6-hydroxy-5-methoxy-7-nitro-benzo[b]thiophene
[0127] 3-Chloro-6-hydroxy-5-methoxy-benzo[b]thiophene (0.39 g) was
dissolved in ethyl acetate (26 ml). To the solution was gradually
added a solution of nitric acid in dichloromethane (2M, 0.9 ml) at
room temperature. The solution was stirred at room temperature for
10 min and then it was poured into ice-cold water and extracted
with ethyl acetate and evaporated to dryness. The product was
purified by column chromatography using toluene-ethyl
acetate-acetic acid 8:1:1 as the eluent.
[0128] .sup.1H NMR (DMSO-d.sub.6): .delta.=4.02 (s, 3H), 7.58 (s,
1H), 7.87 (s, 1H).
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene
[0129] To the solution of
3-chloro-6-hydroxy-5-methoxy-7-nitro-benzo[b]thiophene (0.13 g) and
pyridine (3.3 ml) was gradually added aluminum trichloride (0.09
g). The reaction mixture was heated at 90.degree. C. for 2 hours.
To the warm reaction (60.degree. C.) mixture was added the mixture
of ice and concentrated hydrochloric acid (1:1). The product was
filtered, washed with 1M hydrochloric acid and water and dried
under vacuum.
[0130] Yield: 110 mg
[0131] Melting point: 182-184.degree. C.
[0132] .sup.1H NMR (DMSO-d.sub.6): .delta.=7.49 (s, 1H), 7.83 (s,
1H) 10-12 (br, 2H).
Example 8
(3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-meth-
anone
(3-Chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone
[0133] 3-(3,4-Dimethoxy-phenyl)acrylic acid was converted to
(3-chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone
by repeating the method of Example 4, except that morpholine was
used instead of methanol.
[0134] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.53 (min, 4H), 3.64 (m,
4H), 3.85 (s, 3H), 3.88 (s, 3H), 7.21 (s, 1H), 7.67 (s, 1H).
(3-Chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone
[0135]
(3-Chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-meth-
anone (8.6 g) was suspended in dichloromethane (50 ml) under
nitrogen, cooled to -20.degree. C. and treated dropwise with 1M
boron tribromide (100 ml) in dichloromethane. The resultant
suspension was stirred at -20.degree. C. for 30 min and then in
cool overnight. The mixture was poured into ice-cold water and
stirred for 30 min at room temperature. The product was filtered
and washed with water.
[0136] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.40 (br, 4H), 3.62 (br,
4H), 7.11 (s, 1H), 7.32 (s, 1H), 9.5-10.0 (br, 2H).
(3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-meth-
anone
[0137]
(3-Chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-meth-
anone (7.7 g) was dissolved in ethyl acetate (500 ml) and a
solution of nitric acid in dichloromethane (2M, 13.6 ml) was
gradually added at 20.degree. C. into. The solution was stirred 30
min at room temperature and then it was poured into ice-cold water
and the resultant solid was filtered and dried in vacuum. The
product was recrystallized from acetic acid.
[0138] Yield: 4.8 g
[0139] Melting point: 259.degree. C.
[0140] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.53 (br, 4H), 3.62 (br,
4H), 7.51 (s, 1H), 10-11 (br, 2H).
Example 9
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
diethylamide
5,6-Diacetoxy-3-chloro-7-nitro-benzo[b]thiophene-2-carboxylic
acid
[0141]
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
(0.32 g) from Example 4, acetanhydride (1.6 ml) and concentrated
sulphuric acid (2 drops) were warmed at 50-60.degree. C. for one
hour. The reaction mixture was poured into ice-cold water and
stirred in cold. The product was filtered, washed with cold water
and dried in vacuum.
[0142] .sup.1H NMR (DMSO-d.sub.6): .delta.=2.41 (s, 3H), 2.48 (s,
3H), 13.5-14.5 (br, 1H)
5,6-Diacetoxy-3-chloro-7-nitro-benzo[b]thiophene-2-carboxylic acid
diethylamide
[0143] To the solution of
5,6-diacetoxy-3-chloro-7-nitro-benzo[b]thiophene-2-carboxylic acid
(0.39 g) in toluene (3.9 ml) was added thionyl chloride (0.11 ml)
and N,N-dimethylformamide (one drop). The solution was warmed at
80.degree. C. for one hour and then it was evaporated to dryness
and dried under vacuum. The residue was dissolved in
dichloromethane (3.9 ml) and the solution of diethylamine (0.12 ml)
and N,N-diisopropylamine (0.5 ml) in dichloromethane (3.9 ml) was
added. The reaction solution was stirred at room temperature for
three hours. It was evaporated to dryness and methanol (5 ml) and
concentrated hydrochloric acid (1 ml) were added into the residue.
The product was extracted with dichloromethane and after that it
was washed with water and the solution of sodium bicarbonate. The
solution was dried and evaporated. The product was used for the
next step without any purification.
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
diethylamide
[0144]
5,6-Diacetoxy-3-chloro-7-nitro-benzo[b]thiophene-2-carboxylic acid
diethylamide (0.32 g) was dissolved in methanol (16 ml) and a
solution of potassium carbonate (0.61 g) in water (3 ml) was added
to the reaction solution. It was stirred at room temperature for
one hour.
[0145] Methanol was evaporated and the residue was kept in cool and
filtered. The solid was washed with water and recrystallized from
methanol.
[0146] Yield: 138 mg
[0147] Melting point: 202-205.degree. C.
[0148] .sup.1H NMR (DMSO-d.sub.6): .delta.=1.14 (b, 6H), 3.41 (b,
4H), 7.49 (s, 1H), 10-12 (br, 2H).
Example 10
(3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-piperidin-1-yl-meth-
anone
(3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-piperidin-1-yl-meth-
anone
[0149] The title compound was prepared from the product of Example
4 by repeating the method of Example 9, except that piperidine was
used instead of diethylamine.
[0150] Yield: 192 mg
[0151] Melting point: 254-256.degree. C.
[0152] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.55-1.62 (m, 10H), 7.48
(s, 1H), 10-11 (br, 2H).
Example 11
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
phenylamide
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
phenylamide
[0153] The title compound was prepared from the product of Example
4 by repeating the method of Example 9, except that aniline was
used instead of diethylamine.
[0154] Yield: 100 mg
[0155] Melting point: 288.degree. C.
[0156] .sup.1H NMR (DMSO-d.sub.6): .delta.=7.15 (t, 1H), 7.38 (t,
2H), 7.52 (s, 1H), 7.70 (d, 1H), 10.37 (s, 1H).
Example 12
3-[(3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carbonyl)-amino]-be-
nzoic acid
3-[(3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carbonyl)-amino]-be-
nzoic acid
[0157] The title compound was prepared from the product of Example
4 by repeating the method of Example 9, except that 3-amino-benzoic
acid was used instead of diethylamine.
[0158] Yield: 53 mg
[0159] Melting point: 293-294.degree. C.
[0160] .sup.1H NMR (DMSO-d.sub.6): .delta. 7.50 (d, 1H), 7.53 (d,
1H), 7.72 (d, 1H), 7.95 (d, 1H), 8.36 (s, 1H), 10.58 (s, 1H).
Example 13
4-[(3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carbonyl)-amino]-be-
nzoic acid
4-[(3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carbonyl)-amino]-be-
nzoic acid
[0161] The title compound was prepared from the product of Example
4 by repeating the method of Example 9, except that 4-amino-benzoic
acid was used instead of diethylamine.
[0162] Yield: 110 mg
[0163] Melting point: 298-300.degree. C.
[0164] .sup.1H NMR (DMSO-d.sub.6): .delta.=7.55 (s, 1H), 7.84 (d,
2H), 7.96 (d, 2H), 10.70 (s, 1H).
Example 14
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
(4-methoxy-phenyl)amide
3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
(4-methoxy-phenyl)amide
[0165] The title compound was prepared from the product of Example
4 by repeating the method of Example 9, except that
4-methoxy-aniline was used instead of diethylamine.
[0166] Yield: 94 mg
[0167] Melting point: >350.degree. C.
[0168] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.74 (s, 3H), 6.88 (s,
1H), 6.92 (d, 2H), 7.62 (d, 2H), 8.46 (br, 2H), 9.82 (br, 1H).
Example 15
2-Methyl-7-nitro-benzothiazole-5,6-diol
1-Bromo-4,5-dimethoxy-2-nitro-benzene
[0169] To the solution of 4-bromoveratrole (20 g) in acetic acid
(50 ml) was added 2M nitric acid (48 ml). It was stirred at room
temperature for 30 min and then the reaction solution was poured
into water. The resultant solid was filtered, washed with water and
dried in vacuum.
[0170] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.85 (s, 3H), 3.90 (s,
3H), 7.38 (s, 1H), 7.67 (s, 1H).
5,6-Dimethoxy-2-methyl-benzothiazole
[0171] 1-Bromo-4,5-dimethoxy-2-nitro-benzene (10 g) was suspended
into ethanol (50 ml). To the reaction mixture was added the
suspension of sodium sulfide (5 g) and sulfur (0.65 g) in ethanol
(12 ml). The reaction mixture was refluxed 1.5 hour and then the
resultant solid was filtered and washed with hot water and ethanol.
The dry solid was slurried with acetic acid (60 ml) and
acetanhydridi (35 ml). To the suspension was gradually added zinc
(16.6 g) and the suspension was stirred at room temperature for 15
min before filtering off. The residue was evaporated to dryness.
The product was purified by column chromatography using
toluene-ethyl acetate-acetic acid 8:1:1 as the eluent.
[0172] .sup.1H NMR (DMSO-d.sub.6): .delta.=2.72 (s, 3H), 3.81 (s,
3H), 3.82 (s, 3H), 7.44 (s, 1H), 7.56 (s, 1H).
2-Methyl-benzothiazole-5,6-diol
[0173] 5,6-Dimethoxy-2-methyl-benzothiazole (3.9 g) was refluxed
with 47% hydrobromic acid (40 ml) for four hours. The solid was
filtered and dried under vacuum.
[0174] .sup.1H NMR (DMSO-d.sub.6): .delta.=2.66 (s, 3H), 7.21 (s,
1H), 7.33 (s, 1H), 9.23 (s, 2H)
2-Methyl-7-nitro-benzothiazole-5,6-diol
[0175] 2-Methyl-benzothiazole-5,6-diol was dissolved in ethyl
acetate and a solution of nitric acid in dichloromethane (2M, 0.38
ml) was gradually added at 20.degree. C. into. The solution was
stirred 10 min at room temperature and then it was poured into ice
water and extracted into ethyl acetate and evaporated. The product
was purified by column chromatography using toluene-ethyl
acetate-acetic acid 8:1:1 as the eluent.
[0176] Yield: 75 mg
[0177] Melting point: 219.degree. C.
[0178] .sup.1H NMR (DMSO-d.sub.6): .delta.=2.73 (s, 3H), 7.63 (s,
1H), 10.1-10.9 (br, 2H).
Example 16
(5,6-Dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone
5-[1-(4-Benzyloxy-3-methoxy-phenyl)-meth-(Z)-ylidene]-2-thioxo
thiazolidin-4-one
[0179] 4-Benzyloxy-3-methoxy-benzaldehyde (29 g) was dissolved in
acetic acid (16 g) and then rhodanine (16 g) and sodium acetate (36
g) added into. The solution was refluxed for one hour. The reaction
solution was poured into water. The solid was filtered, washed with
water and dried under vacuum.
[0180] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.83 (s, 3H), 5.17 (s,
2H), 7.15-7.22 (q, 3H), 7.33-7.46 (m, 5H), 7.60 (s, 1H), 13.0-14.0
(br, 1H).
(Z)-3-(4-Benzyloxy-3-methoxy-phenyl)-2-mercapto-acrylic acid
[0181]
5-[1-(4-Benzyloxy-3-methoxy-phenyl)-meth-(Z)-ylidene]-2-thioxo
thiazolidin-4-one (38 g) and 2.5M NaOH were warmed at 80.degree. C.
for one hour. Next the solution was cooled to 10.degree. C. and
poured slowly into 6M HCl-solution (200 ml). The reaction mixture
was stirred at room temperature for one hour. The solid was
filtered, washed with water and dried under vacuum.
[0182] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.80 (s, 3H), 5.14 (s,
2H), 7.14-7.16 (d, 1H), 7.26-7.46 (m, 6H), 7.70 (s, 1H).
6-Hydroxy-5-methoxy-benzo[b]thiophene-2-carboxylic acid
[0183] (Z)-3-(4-Benzyloxy-3-methoxy-phenyl)-2-mercapto-acrylic acid
(21 g) and iodine (21 g) in tetrahydrofuran (300 ml) was stirred in
60.degree. C. for 15 hours. Then it was poured into water (1 l) and
120 g sodium bisulfite was added. The product was extracted into
ethylacetate and then it extracted into sodium bicarbonate. The
water phase was acified by concentrated hydrochloric acid and
stirred in room temperature for one hour. The solid was filtered,
washed with water and dried under vacuum.
[0184] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.83 (s, 3H), 7.29 (s,
1H), 7.45 (s, 1H), 7.89 (s, 1H), 9.70 (br, 1H), 12.8-13.3 (br,
1H).
6-Hydroxy-5-methoxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
[0185] 6-Hydroxy-5-methoxy-benzo[b]thiophene-2-carboxylic acid (3.2
g) was dissolved in ethyl acetate (200 ml) and a solution of nitric
acid in dichloromethane (2M, 7.7 ml) was gradually added at
0.degree. C. into. The solution was stirred 30 min at room
temperature and then it was poured into ice-cold water and
filtered. The solid was washed with ethyl acetate and dried under
vacuum.
[0186] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.96 (s, 3H), 7.95 (s,
1H), 8.05 (s, 1H), 11.5-12.0 (br, 1H), 12.8-13.6 (br, 1H).
(6-Hydroxy-5-methoxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-methano-
ne
[0187] 6-Hydroxy-5-methoxy-7-nitro-benzo[b]thiophene-2-carboxylic
acid (2.7 g) was dissolved in toluene (45 ml). Thionyl chloride
(1.2 ml) and N,N-dimethylformamide (4 drops) were added. The
solution was stirred at 80.degree. C. for two hours and after that
it was evaporated. The residue was dissolved into dichloromethane
(45 ml) and morpholine (1.4 ml) and triethylamine (1.2 ml) added.
The reaction solution was stirred at room temperature overnight.
The solution of water and 2M HCl was added to the solution. The
solid was washed with water and dried under vacuum.
[0188] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.67 (b, 4H), 3.69 (b,
4H), 3.95 (s, 3H), 7.73 (s, 1H), 7.87 (s, 1H), 11.0-11.8 (br,
1H).
(5,6-Dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone
[0189]
(6-Hydroxy-5-methoxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-
-methanone (1.0 g) was dissolved in ethyl acetate (11 ml) and
pyridine (14 ml) added into. Next aluminum trichloride (0.47 g) was
gradually added into the solution. The reaction mixture was
refluxed for 2 hours at 110.degree. C. To the warm reaction
(60.degree. C.) solution was added the mixture of ice and
concentrated hydrochloric acid (1:1) and then it was stirred at
room temperature for one hour. The solid was filtered, washed with
water and treated with diethyl ether.
[0190] Yield: 114 mg
[0191] Melting point: 266.degree. C.
[0192] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.65 (b, 4H), 3.68 (b,
4H), 7.64 (s, 1H), 7.72 (s, 1H), 10-11 (br, 2H).
Example 17
5,6-Dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
4-Benzyloxy-3-ethoxy-benzaldehyde
[0193] To the solution of 3-ethoxy-4-hydroxy-benzaldehyde (83 g) in
N,N-dimethylformamide (400 ml) was gradually added 10 M sodium
hydroxide (55 ml) and then benzyl chloride (60 ml) was added at a
temperature under 40.degree. C. The mixture was stirred at room
temperature for a half an hour and for 2 hours at 60.degree. C. The
solution was poured into ice-cold water (2 l) and extracted with
diethyl ether. The organic phase was washed with water and 5M
sodium hydroxide and then it was dried and evaporated. The product
was recrystallized from toluene-heptane.
[0194] .sup.1H NMR (DMSO-d.sub.6): .delta.=1.34 (t, 3H), 4.12 (q,
2H), 5.24 (s, 2H), 7.26 (d, 1H), 7.34-7.53 (m, 7H), 9.83 (s,
1H).
4-Benzyloxy-5-ethoxy-2-nitro-benzaldehyde
[0195] 4-Benzyloxy-3-ethoxy-benzaldehyde (20 g) was dissolved in
dichloromethane (100 ml) and a solution of nitric acid in
dichloromethane (2M, 200 ml) was gradually added at a temperature
under 30.degree. C. The solution was stirred at room temperature
for 10 min and then it was poured into ice-cold water. The organic
phase was washed with 1M sodium hydroxide and water and then it was
dried and evaporated.
[0196] .sup.1H NMR (DMSO-d.sub.6): .delta.=1.37 (t, 3H), 4.25 (q,
2H), 5.34 (s, 2H), 7.36-7.49 (m, 5H), 7.82 (s, 1H), 10.19 (s,
1H)
5-Ethoxy-4-hydroxy-2-nitro-benzaldehyde
[0197] 4-Benzyloxy-5-ethoxy-2-nitro-benzaldehyde (23 g) was
dissolved in acetic acid (93 ml) and concentrated hydrochloric acid
(10 ml). The reaction solution was refluxed for 24 hours. Then the
solution was evaporated to dryness and the residue was dissolved in
diethyl ether.
[0198] The product was extracted into 1M sodium hydroxide and
acidified with 6M hydrochloric acid. The resultant solid was
filtered and dried under vacuum.
[0199] .sup.1H NMR (DMSO-d.sub.6): .delta.=1.37 (t, 3H), 4.20 (q,
2H), 7.33 (s, 1H), 7.57 (s, 1H), 10.15 (s, 1H), 10.6-11.2 (br,
1H).
5-Ethoxy-4-hydroxy-2,3-dinitro-benzaldehyde
[0200] 5-Ethoxy-4-hydroxy-2-nitro-benzaldehyde (1.6 g) was
dissolved in dichloromethane (30 ml) and a solution of nitric acid
in dichloromethane (2M, 13 ml) was gradually added at a temperature
under 30.degree. C. The solution was stirred at room temperature
for 10 min and then it was poured into ice-cold water. The organic
phase was washed with water and then it was dried and
evaporated.
[0201] .sup.1H NMR (DMSO-d.sub.6): .delta.=1.41 (t, 3H), 4.32 (q,
2H), 7.56 (s, 1H), 9.93 (s, 1H).
4,5-Diethoxy-2,3-dinitro-benzaldehyde
[0202] 5-Ethoxy-4-hydroxy-2,3-dinitro-benzaldehyde (3.77 g),
N,N-dimethylformamide (35 ml), K.sub.2CO.sub.3 (3.877 g) and ethyl
bromide (50 ml) were refluxed 24 hours. To the reaction solution
was added diethyl ether (100 ml) and then it was washed with water
and 1M sodium hydroxide. The solution was dried and evaporated.
[0203] .sup.1H NMR (DMSO-d.sub.6): .delta.=1.26 (t, 3H), 1.43 (t,
3H), 4.36 (m, 6H), 7.70 (s, 1H), 10.05 (s, 1H).
5,6-Diethoxy-7-nitro-benzo[b]thiophene-2-carboxylic acid methyl
ester
[0204] 4,5-Diethoxy-2,3-dinitro-benzaldehyde (1.53 g) was dissolved
into N,N-dimethylformamide (6 ml) and then methylthioglycolate
(1.36 ml) was added. Triethylamine (2.6 ml) was added in cold to
the reaction solution. The mixture was stirred overnight. The solid
was filtered and washed with N,N-dimethylformamide.
[0205] .sup.1H NMR (DMSO-d.sub.6): .delta.=1.39 (t, 3H), 1.44 (t,
3H), 4.24 (t, 3H), 4.28 (q, 3H), 8.08 (s, 1H), 8.19 (s, 1H).
5,6-Dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
[0206] 5,6-Diethoxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
methyl ester (160 mg), hydrobromic acid (8 ml) and acetic acid (8
ml) was refluxed for 6 hours and stirred at room temperature
overnight. The solid was filtered and washed with a solution of
acetic acid and hydrobromic acid (1:1) and water. The product was
recrystallized from acetonitrile.
[0207] Yield: 90 mg
[0208] .sup.1H NMR (DMSO-d.sub.6): .delta.=7.71 (s, 1H), 8.05 (s,
1H), 10-11 (br, 2H), 13-13.5 (br, 1H).
Example 18
5,6-Dihydroxy-7-nitro-benzofuran-2-carboxylic acid
2,4-Dihydroxy-5-methoxybenzaldehyde
[0209] 2,4,5-Trimethoxybenzaldehyde (20 g) was dissolved in
dichloromethane (20 ml) and aluminum chloride (34.1 g) was added in
small portions. The resulting mixture was stirred at room
temperature for 5 hours and then poured in acidic ice water. The
dichloromethane layer was separated and the water phase extracted
with ethyl acetate. The combined organic layers were extracted with
1 N NaOH. The water phase was acidified with HCl and the
precipitate was filtered. The product was recrystallized from
toluene.
[0210] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=3.74 (s, 3H),
6.41 (s, 1H), 7.12 (s, 1H), 9.96 (s, 1H), 10.4 (br, 1H), 10.52 (br,
1H).
4-Benzyloxy-2-hydroxy-5-methoxybenzaldehyde
[0211] 2,4-Dihydroxy-5-methoxybenzaldehyde (6.0 g), benzyl bromide
(9.7 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (8.6 g) in
N,N-dimethylformamide (30 ml) were heated at 100.degree. C. under
nitrogen for 5 hours. After cooling to room temperature, 1 N NaOH
was added and the mixture washed with ethyl acetate. The water
phase was acidified with HCl and the precipitate was filtered.
[0212] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=3.74 (s, 3H),
5.16 (s, 2H), 6.65 (s, 1H), 7.17 (s, 1H), 7.36-7.47 (m, 5H), 10.02
(s, 1H), 10.68 (s, 1H).
(5-Benzyloxy-2-formyl-4-methoxyphenoxy)acetic acid ethyl ester
[0213] 4-Benzyloxy-2-hydroxy-5-methoxybenzaldehyde (2.9 g), ethyl
bromoacetate (2.3 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.1 g)
in N,N-dimethylformamide (30 ml) were heated at 100.degree. C.
under nitrogen for 5 hours. After cooling to room temperature,
water was added and the mixture extracted with ethyl acetate. Ethyl
acetate was washed with 1 N NaOH and 1 N HCl, dried with
Na.sub.2SO.sub.4 and evaporated to dryness.
[0214] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=1.20 (t, 3H,
J=7.2 Hz), 3.76 (s, 3H), 4.15 (q, 2H, J=7.2 Hz), 4.98 (s, 2H), 5.21
(s, 2H), 6.97 (s, 1H), 7.19 (s, 1H), 7.36-7.47 (m, 5H), 10.29 (s,
1H).
6-Benzyloxy-5-methoxybenzofuran-2-carboxylic acid ethyl ester
[0215] (5-Benzyloxy-2-formyl-4-methoxyphenoxy)acetic acid ethyl
ester (1.5 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 g) and
acetic acid (0.026 g) in N,N-dimethylformamide (8 ml) were stirred
at 100.degree. C. under nitrogen for 5 hours. After cooling to room
temperature the mixture was poured in ice water and the precipitate
was filtered.
[0216] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=1.32 (t, 31,
J=7.1 Hz), 3.82 (s, 3H), 4.37 (q, 2H, J=7.1 Hz), 5.18 (s, 2H), 7.25
(s, 1H), 7.33-7.50 (m, 6H), 7.62 (d, 1H, J=0.8 Hz).
6-Hydroxy-5-methoxy-benzofuran-2-carboxylic acid ethyl ester
[0217] 6-Benzyloxy-5-methoxybenzofuran-2-carboxylic acid ethyl
ester (7.3 g), acetic acid (45 ml) and conc. HCl (24 ml) were
stirred at 50.degree. C. for 0.5 hour. Water was added and pH
adjusted to 3 with NaOH. The mixture was extracted with ethyl
acetate. Ethyl acetate was dried with Na.sub.2SO.sub.4 and
evaporated to dryness. The product was recrystallized from
toluene.
[0218] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=1.32 (t, 3H,
J=7.1 Hz), 3.82 (s, 3H), 4.31 (q, 2H, J=7.1 Hz), 7.07 (d, 1H, J=0.9
Hz), 7.20 (s, 1H), 7.58 (d, 1H, J=0.9 Hz).
6-Hydroxy-5-methoxy-7-nitro-benzofuran-2-carboxylic acid ethyl
ester
[0219] 6-Hydroxy-5-methoxybenzofuran-2-carboxylic acid ethyl ester
(1.5 g) was dissolved to dichloromethane (30 ml) and the solution
cooled to -20.degree. C. 1 M HNO.sub.3 in dichloromethane (6.4 ml)
was added and after 10 minutes the mixture poured in ice water. The
dichloromethane layer was separated and the water phase extracted
with ethyl acetate. The combined organic phases were dried with
Na.sub.2SO.sub.4 and evaporated to dryness.
[0220] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=1.33 (t, 3H,
J=7.1 Hz), 3.94 (s, 3H, 4.35 (q, 2H, J=7.1 Hz), 7.57 (s, 1H), 7.74
(s, 1H), 11.3 (br, 1H).
5,6-Dihydroxy-7-nitro-benzofuran-2-carboxylic acid
[0221] 6-Hydroxy-5-methoxy-7-nitro-benzo fan-2-carboxylic acid
ethyl ester (0.25 g) was dissolved to dichloromethane and cooled to
-5.degree. C. 1 M boron tribromide solution in dichloromethane (4.5
ml) was added and the mixture stirred at 0.degree. C. for 24 hours.
The mixture was poured in ice water and the dichloromethane layer
separated. The water phase was extracted with ethyl acetate. The
combined organic phases were dried with Na.sub.2SO.sub.4 and
evaporated to dryness. The product was purified by reverse phase
column chromatography using methanol (1%) in dichloromethane as an
eluent.
[0222] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.=7.37 (s, 1H),
7.53 (s, 1H).
Example 19
5,6-Dihydroxy-2-methyl-7-nitro-benzo[d]isothiazol-3-one
2-Mercapto-4,5-dimethoxybenzoic acid
[0223] To a solution of 2-amino-4,5-dimethoxybenzoic acid (10.2 g)
in HCl (9 ml cons. HCl and ml water) was added a solution of
NaNO.sub.2 (3.6 g in 20 ml of water) at 5.degree. C. and stirred
for 2 hours. The diazonium solution was filtered and the filtrate
was added to a cold solution of Na.sub.2S.sub.2 prepared from
sodium sulphide nonahydrate (11.6 g in 20 ml of water) and sulphur
(1.5 g) in NaOH solution (1.8 g in 20 ml of water). The mixture was
stirred at room temperature overnight, filtered and acidified with
concentrated HCl. The precipitate was filtered. The product was a
mixture of 2-mercapto-4,5-dimethoxy-benzoic acid and dimerized
product 4,4',5,5'-tetramethoxy-2,2'-dithiobis(benzoic acid) and was
used for next step without purification.
[0224] .sup.1H NMR (400 M z, DMSO-d.sub.6): .delta.=monomer 3.65
(s, 3H), 3.72 (s, 3H), 7.29 (s, 1H), 7.36 (s, 1H), dimerized
product 3.59 (s, 6H), 3.78 (s, 6H), 7.24 (s, 2H), 7.48 (s, 2H).
2-Chlorosulfenyl-4,5-dimethoxybenzoyl chloride
[0225] 2-Mercapto-4,5-dimethoxybenzoic acid (12.8 g), toluene (50
ml) and thionyl chloride (100 ml) were heated at 80.degree. C. for
3 hours. The solvent and excess SOCl.sub.2 were evaporated. Toluene
was added to the residue and the mixture was evaporated again to
dryness. The residue was suspended in toluene (50 ml), sulfuryl
chloride (14.3 ml) was added, and the mixture heated at 65.degree.
C. for 2 hours. The mixture was evaporated to dryness and the
residue used for next step without purification.
[0226] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=3.84 (s, 3H),
3.89 (s, 3H), 7.32 (s, 1H), 7.79 (s, 1H).
5,6-Dimethoxy-2-methylbenzo[d]isothiazol-3-one
[0227] 2-Chlorosulfenyl-4,5-dimethoxybenzoyl chloride (5.0 g) was
dissolved in pyridine (30 ml) and methylamine hydrochloride (6.0 g)
was added. The mixture was stirred at room temperature for 2 days.
Ethyl acetate was added and the mixture was washed with 1 N HCl and
water. Ethyl acetate was dried with Na.sub.2SO.sub.4 and evaporated
to dryness. The crude product was purified by flash chromatography
eluting with heptane-ethyl acetate (1:9).
[0228] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=3.30 (s, 3H),
3.83 (s, 3H), 3.85 (s, 3H), 7.26 (s, 1H), 7.53 (s, 1H).
5,6-Dihydroxy-2-methylbenzo[d]isothiazol-3-one
[0229] To a suspension of
5,6-dimethoxy-2-methylbenzo[d]isothiazol-3-one (0.35 g) in
dichloromethane (30 ml) boron tribromide (3.1 ml, 1 M solution in
dichloromethane) was added at -40.degree. C. The mixture was
allowed to warm to -10.degree. C. Next day methanol (30 ml) was
added and the mixture was evaporated to dryness. To the residue
sodium sulfite solution (9 ml, 5% in water) and brine (9 ml) were
added. After stirring at 0.degree. C. the precipitate was
filtered.
[0230] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=3.24 (s, 3H),
7.13 (s, 1H), 7.20 (s, 3H), 9.53 (br, 1H), 10.0 (br, 1H).
Acetic acid
6-acetoxy-2-methyl-3-oxo-2,3-dihydro-benzo[d]isothiazol-5-yl
ester
[0231] 5,6-Dihydroxy-2-methylbenzo[d]isothiazol-3-one (0.23 g) was
suspended in N,N-dimethylformamide and triethylamine (0.47 g) and
acetic acid anhydride (0.24 g) were added at 0.degree. C. After
stirring at room temperature for one hour the mixture was poured to
ice water and the precipitate was filtered.
[0232] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=2.31 (s, 3H),
2.34 (s, 3H), 3.35 (s, 3H), 7.76 (s, 1H), 7.94 (s, 1H).
Acetic acid
6-hydroxy-2-methyl-3-oxo-2,3-dihydro-benzo[d]isothiazol-5-yl
ester
[0233] To a solution of acetic acid
6-acetoxy-2-methyl-3-oxo-2,3-dihydro-benzo[d]isothiazol-5-yl ester
(0.21 g) in dimethylformamide morpholine (0.070 g) was added at
0.degree. C. The mixture was stirred at 0.degree. C. for one hour
and then poured to ice water. The precipitated product was
filtered.
[0234] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=2.27 (s, 3H),
3.27 (s, 3H), 7.44 (s, 1H), 7.47 (s, 1H), 10.72 (s, 1H).
Acetic acid
6-hydroxy-2-methyl-7-nitro-3-oxo-2,3-dihydro-benzo[d]isothiazol-5-yl
ester
[0235] To a solution of acetic acid
6-hydroxy-2-methyl-3-oxo-2,3-dihydro-benzo[d]isothiazol-5-yl ester
(0.055 g) in acetic acid at 10.degree. C. nitric acid (100% 0.015
g) was added and stirring was continued at room temperature for 15
minutes. The mixture was poured into ice water and extracted with
ethyl acetate. Ethyl acetate was dried and evaporated to
dryness.
[0236] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=2.29 (s, 3H),
3.29 (s, 3H), 7.73 (s, 1H).
5,6-Dihydroxy-2-methyl-7-nitro-benzo[d]isothiazol-3-one
[0237] Acetic acid
6-hydroxy-2-methyl-7-nitro-3-oxo-2,3-dihydro-benzo[d]isothiazol-5-yl
ester (0.046 g) in methanol-HCl (14:1, 7 ml) was heated at
60.degree. C. for 3 hours. The mixture was evaporated to dryness.
The crude product was purified by flash chromatography using ethyl
acetate as an eluent and followed by crystallization from
isopropanol-methanol.
[0238] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=3.30 (s, 3H),
7.49 (s, 1H).
Example 20
(5,6-Dihydroxy-3-methyl-7-nitro-benzo[b]thiophen-2-yl)morpholin-4-yl-metha-
none
[0239]
(5,6-Dimethoxy-3-methylbenzo[b]thiophen-2-yl)morpholin-4-yl-methan-
one
[0240]
(3-Chloro-5,6-dimethoxybenzo[b]thiophen-2-yl)morpholin-4-yl-methan-
one (3.0 g) from Example 8, trimethylaluminum (3.2 g) and
[1,3-bis(diphenylphosphino)propane]dichloronickel (II) (1.2 g) in
1,2-dimethoxyethane (100 ml) were refluxed under argon for 10
hours. To the cold mixture ethanol (50 ml), water and HCl were
added respectively and the mixture was extracted with ethyl
acetate. Ethyl acetate was dried and evaporated to dryness. The
crude product was purified by flash chromatography eluting with
heptane-ethyl acetate (5:5).
[0241] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=2.34 (s, 3H),
3.52 (br, 4H), 3.61 (br, 4H), 3.83 (s, 3H), 3.85 (s, 3H), 7.26 (s,
1H), 7.54 (s, 1H).
(5,6-Dihydroxy-3-methylbenzo[b]thiophen-2-yl)morpholin-4-yl-methanone
[0242] To a solution of
(5,6-dimethoxy-3-methylbenzo[b]thiophen-2-yl)morpholin-4-yl-methanone
(0.80 g) in dichloromethane (8 ml) boron tribromide (5.2 ml, 2 M
solution in dichloromethane) was added at 0.degree. C. The mixture
was allowed to warm to room temperature. After 2 hours at room
temperature methanol (16 ml) was added and solvents were
evaporated. To the residue sodium sulfite solution (16 ml, 5% in
water) was added and after stirring for 0.5 hour the precipitate
was filtered.
[0243] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=2.24 (s, 3H),
3.51 (br, 4H), 3.59 (br, 4H), 7.07 (s, 1H), 7.21 (s, 1H), 9.20 (s,
1H), 9.42 (s, 1H).
(5,6-Dihydroxy-3-methyl-7-nitro-benzo[b]thiophen-2-yl)morpholin-4-yl-metha-
none
[0244]
(5,6-Dihydroxy-3-methylbenzo[b]thiophen-2-yl)morpholin-4-yl-methan-
one (0.10 g) was dissolved to ethyl acetate (60 ml). Nitric acid (2
eq, 2 M solution in dichloromethane) was added in small portions at
55.degree. C. 15 minutes after last addition the mixture was
cooled, washed with water, dried with Na.sub.2SO.sub.4 and
concentrated to small volume. The precipitated product was
filtered.
[0245] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=2.31 (s, 3H),
3.53 (br, 4H), 3.61 (br, 4H), 7.54 (s, 1H), 10.5 (br, 2H).
Example 21
5,6-Dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid ethyl
ester
5,6-Dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid ethyl
ester
[0246] 5,6-Dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
(50 mg, 0.20 mmol) from Example 17 and thionyl chloride (130 .mu.l)
in ethanol (2 ml) were refluxed for 1.5 hours, evaporated to
dryness and recrystallized from ethanol.
[0247] Yield: 46 mg
[0248] .sup.1H NMR (DMSO-d.sub.6): .delta.=8.13 (1H, s), 7.72 (1H,
s), 4.34 (2H, q), 1.34 (3H, t).
Example 22
5,6-Dihydroxy-4-nitro-isobenzofuran-1,3-dione
5,6-Dimethoxy-3H-isobenzofuran-1-one
[0249] A mixture of 3,4-dimethoxy-benzoic acid (10 g) in 37% HCl
(150 ml) and formaldehyde (25 ml, 37 wt. % solution in water) was
heated to 90.degree. C. for 43/4 hours, and then insoluble material
was removed by filtration. The filtrate was quenched with water
(200 ml) and extracted three times with ethyl acetate (200 ml). The
combined organic layers were washed with aqueous NaOH (40 ml, 2.5
M) and water (100 ml). The organic solvent was dried over anhydrous
Na.sub.2SO.sub.4, filtered and evaporated to dryness
[0250] Yield: 8.9 g
[0251] .sup.1H NMR (DMSO-d.sub.6): .delta.=7.27 (1H, s), 7.24 (1H,
s), 5.28 (2H, s), 3.88 (3H, s), 3.84 (3H, s).
4,5-Dimethoxy-phthalic acid
[0252] To a mixture of 5,6-dimethoxy-3H-isobenzofuran-1-one (4.5 g)
and 7% aqueous NaOH (47 ml) was added KMnO.sub.4 (4.0 g) diluted in
water (125 ml). The mixture was stirred at room temperature for 4
days. Insoluble material was removed by filtration. The filtrate
was cooled with ice-water bath and acidified with concentrated HCl.
The acidic solution was extracted three times with ethyl acetate
(300 ml). The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4 and evaporated.
[0253] Yield: 4.8 g
[0254] .sup.1H NMR (DMSO-d.sub.6): .delta.7.19 (2H, s), 3.83 (6H,
s).
5,6-Dimethoxy-4-nitro-isobenzofuran-1,3-dione
[0255] 4,5-Dimethoxy-phthalic acid (1.0 g) was cooled in ice-water
bath. A cooled mixture of sulfuric acid (3.0 ml) and fuming nitric
acid (3.0 ml) was added dropwise. The mixture was stirred for 10
minutes and left standing for 10 minutes. A mixture of brine and
ice was added (1:1). The solid was filtered off, washed with water
and recrystallized from ethanol.
[0256] Yield: 0.46 g
[0257] .sup.1H NMR (DMSO-d.sub.6): .delta.8.19 (1H, s), 4.11 (3H,
s), 4.05 (3H, s).
5-Hydroxy-6-methoxy-4-nitro-isobenzofuran-1,3-dione
[0258] 5,6-Dimethoxy-4-nitro-isobenzofuran-1,3-dione (346 mg), 48%
hydrogen bromide (1.5 ml), Acetic acid (15 ml) and benzyl
triethylammonium bromide (37 mg) were heated at 140.degree. C. for
3 hours. The acetic acid and water was removed in vacuo. The
remainder was filtered through silica gel using a mixture of
toluene, ethyl acetate and methanol (8:1:1) as eluent. Appropriate
fractions were collected and evaporated.
[0259] Yield: 275 mg
[0260] .sup.1H NMR (DMSO-d.sub.6): .delta.7.44 (1H, s), 3.85 (3H,
s).
5,6-Dihydroxy-4-nitro-isobenzofuran-1,3-dione
[0261] 5-Hydroxy-6-methoxy-4-nitro-isobenzofuran-1,3-dione (115
mg), aluminum chloride (80 mg) was mixed with ethyl acetate (3 ml).
Pyridine (155 .mu.l) in ethyl acetate (2 ml) was added dropwise.
The resulting mixture was stirred at room temperature for 0.5
hours, heated to reflux for 3 hours, and then quenched with water
(0.5 ml) and cone. HCl (0.5 ml) at 60.degree. C. Ethyl acetate and
water was removed in vacuo. The remainder was mixed with brine (2
ml) and extracted two times with ethyl acetate (15 ml). The
combined organic layers were dried over anhydrous Na.sub.2SO.sub.4,
filtrated, evaporated and triturated with diethyl ether.
[0262] Yield: 55 mg
[0263] .sup.1H NMR (DMSO-d.sub.6): .delta.=7.42 (1H, s).
Example 23
5,6-Dihydroxy-4-nitro-3H-isobenzofuran-1-one
5,6-Dihydroxy-3H-isobenzofuran-1-one
[0264] 5,6-Dimethoxy-3H-isobenzofuran-1-one (2.91 g) was dissolved
in dichloromethane (150 ml) followed by cooling to -50.degree. C.
Boron tribromide (34.9 ml, 1.0M solution in dichloromethane) was
added dropwise under nitrogen atmosphere. The mixture was slowly
allowed to warm overnight to room temperature and continued
stirring for 3 hours. The reaction was quenched with methanol
followed by evaporation to dryness. The remainder was mixed with 5%
aqueous Na.sub.2SO.sub.3 (20 ml) and brine (20 ml) and
filtrated.
[0265] Yield: 2.31 g
[0266] .sup.1H NMR (DMSO-d.sub.6): .delta.10.22 (1H, bs), 9.70 (1H,
bs), 7.09 (1H, s), 6.93 (1H, s), 5.17 (2H, s).
Acetic acid 6-acetoxy-3-oxo-1,3-dihydro-isobenzofuran-5-yl ester
(8)
[0267] 5,6-Dihydroxy-3H-isobenzofuran-1-one (2.26 g), acetic
anhydride (25 ml) and pyridine (2.31 ml) were stirred for 5 hours
at room temperature. Acetic anhydride was removed in vacuo and the
remainder was mixed with water (20 ml), filtrated and washed with
water. Yield: 3.35 g
[0268] .sup.1H NMR (DMSO-d.sub.6): .delta.7.81 (1H, s), 7.64 (1H,
s), 5.42 (2H, s), 2.34 (3H, s), 2.32 (3H, s).
Acetic acid 6-hydroxy-3-oxo-1,3-dihydro-isobenzofuran-5-yl
ester
[0269] Acetic acid 6-acetoxy-3-oxo-1,3-dihydro-isobenzofuran-5-yl
ester (5.0 g) was dissolved in N,N-dimethylformamide (100 ml)
followed by addition of morpholine (1.78 ml). The solution was
stirred at room temperature overnight followed by concentration in
reduced pressure. Ethyl acetate (200 ml) was added to the
remainder. The organic phase was washed two times with a mixture of
aqueous HCl (50 ml, 2M) and brine (50 ml). The organic solvent was
dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to
dryness.
[0270] Yield: 3.96 g
[0271] .sup.1H NMR (DMSO-d.sub.6): .delta.11.01 (1H, bs), 7.51 (1H,
s), 7.12 (1H, s), 5.29 (2H, s), 2.28 (3H, s).
Acetic acid 6-hydroxy-7-nitro-3-oxo-1,3-dihydro-isobenzofuran-5-yl
ester
[0272] Acetic acid 6-hydroxy-3-oxo-1,3-dihydro-isobenzofuran-5-yl
ester (3.8 g) was mixed with acetic acid (150 ml) followed by
addition of 65% nitric acid (2.5 ml). After dissolution the mixture
was stirred at room temperature for 2 hours followed by removal of
the acetic acid and water in vacuo. The remainder was filtered
through silica gel using a mixture of toluene, ethyl acetate and
methanol (8:1:1) as eluent. Appropriate fractions were collected
and evaporated to dryness.
[0273] Yield: 4.1 g
[0274] .sup.1H NMR (DMSO-d.sub.6): .delta.7.91 (1H, s), 5.59 (2H,
s), 2.33 (3H, s).
5,6-Dihydroxy-4-nitro-3H-isobenzofuran-1-one
[0275] Acetic acid
6-hydroxy-7-nitro-3-oxo-1,3-dihydro-isobenzofuran-5-yl ester (4.1
g) was suspended in methanol (150 ml) and 37% HCl (20 ml) followed
by stirring at room temperature for 3 days. The precipitate was
filtered and washed with methanol.
[0276] Yield: 2.25 g
[0277] .sup.1H NMR (DMSO-d.sub.6): .delta.7.32 (1H, s), 5.50 (2H,
s).
Example 24
5,6-Dihydroxy-4,7-dinitro-3H-isobenzofuran-1-one
5,6-Dimethoxy-4,7-dinitro-3H-isobenzofuran-1-one
[0278] 5,6-Dimethoxy-3H-isobenzofuran-1-one (582 mg) was cooled in
ice-water bath. A cooled mixture of sulfuric acid (2 ml) and fuming
nitric acid (2 ml) was added dropwise. The mixture was stirred for
15 minutes and left standing for 45 minutes. The reaction was
quenched with ice. The aqueous phase was extracted three times with
ethyl acetate (30 ml) and washed with brine (15 ml). The organic
solvent was dried over anhydrous Na.sub.2SO.sub.4, filtered and
evaporated to dryness.
[0279] Yield: 586 mg
[0280] .sup.1H NMR (DMSO-d.sub.6): .delta.5.67 (2H, s), 4.12 (3H,
s), 4.00 (3H, s).
5-Hydroxy-6-methoxy-4,7-dinitro-3H-isobenzofuran-1-one
[0281] 5,6-Dimethoxy-4,7-dinitro-3H-isobenzofuran-1-one (450 mg),
acetic acid (15 ml) and 37% aqueous HCl (3 ml) were refluxed for
7.25 hours. The acetic acid and water were evaporated in vacuo. The
residue was purified by column chromatography (toluene-ethyl
acetate-methanol 8:1:1).
[0282] Yield: 215 mg
[0283] .sup.1H NMR (DMSO-d.sub.6): .delta.5.48 (2H, s), 3.86 (3H,
s).
5,6-Dihydroxy-4,7-dinitro-3H-isobenzofuran-1-one
[0284] 5-Hydroxy-6-methoxy-4,7-dinitro-3H-isobenzofuran-1-one (210
mg) was dissolved in ethyl acetate (2.5 ml) followed by addition of
aluminum chloride (132 mg) in nitrogen atmosphere. Pyridine (265
.mu.l, 3.28 mmol) was added dropwise. The resulting mixture was
heated to reflux for 2 hours, and then quenched with water (0.5 ml)
and cone. HCl (0.5 ml) at 75.degree. C. Ethyl acetate (15 ml) was
added and phases were separated. The aqueous layer was extracted
once with ethyl acetate (15 ml). The combined organic layers were
dried over anhydrous Na.sub.2SO.sub.4. The product was filtrated,
evaporated to dryness and recrystallized from heptane-toluene-ethyl
acetate.
[0285] Yield: 76 mg
[0286] .sup.1H NMR (DMSO-d.sub.6): .delta.5.41 (2H, s).
Example 25
7-Nitro-2-phenyl-benzothiazole-5,6-diol
Catechol cyclohexylidene ketal
[0287] Catechol (55 g), cyclohexanone (65 ml), p-toluenesulfonic
acid monohydrate (0.50 ml) and toluene (500 ml) were refluxed at
Dean-Stark apparatus for 4.5 hours. The reaction mixture was washed
with NaOH-solution and water, dried and evaporated to dryness.
[0288] Yield: 90 g
[0289] .sup.1H NMR (DMSO-d.sub.6): .delta.1.46 (m, 2H), 1.65 (m,
4H), 1.85 (t, 4H, J 6.2), 6.75-6.85 (m, 4H)
4-Nitrocatechol cyclohexylidene ketal
[0290] To a solution of catechol cyclohexylidene ketal (87.3 g) in
methylene chloride (900 ml) was added a solution of nitric acid in
methylene chloride (2 M, 250 ml) at a rate to keep the temperature
at about 25.degree. C. with the use of a water bath. The product
mixture was washed with sodium hydroxide (1 M, 500 ml). The organic
phase was separated, dried and evaporated.
[0291] Yield: 106 g
[0292] .sup.1H NMR (DMSO-d.sub.6): .delta.1.49 (m, 2H), 1.67 (m,
4H), 1.95 (t, 4H, J 6.2), 7.08 (d, 1H, J 8.8 Hz), 7.70 (d, 1H, J
2.4 Hz), 7.86 (dd, 1H, J 2.4 and 8.8).
4-Aminocatechol cyclohexylidene ketal
[0293] 4-Nitrocatechol cyclohexylidene ketal (2 g) was hydrogenated
in ethyl acetate (12 ml) with Pd--C (0.2 g) as a catalyst.
[0294] Yield: 1.77 g
[0295] .sup.1H NMR (DMSO-d.sub.6): .delta.1.45 (m, 2H), 1.60 (m,
4H), 1.79 (m, 4H), 4.62 (br, 2H), 5.94 (dd, 1H, J 3.1 and 12.2 Hz),
6.14 (d, 1H, J 3.1), 6.48 (d, 1H, J 12.2 Hz).
2-Phenyl-benzothiazole-5,6-diol cyclohexylidene ketal
[0296] 4-Aminocatechol cyclohexylidene ketal (1.77 g), benzaldehyde
(0.82 ml) and sulfur (0.55 g) were refluxed in dimethyl acetamide
(8.6 ml) for two hours. The reaction mixture was poured into water
(100 ml) and extracted with ether (100 ml), dried, evaporated and
recrystallized from acetonitrile.
[0297] Yield: 0.93 g
[0298] .sup.1H NMR (DMSO-d.sub.6): .delta.1.49 (m, 2H), 1.69 (m,
4H), 1.94 (m, 4H), 7.50-7.57 (m, 5H), 7.99-8.01 (m, 2H).
7-Nitro-2-phenyl-benzothiazole-5,6-diol cyclohexylidene ketal
[0299] To a solution of the 2-phenyl-benzothiazole-5,6-diol
cyclohexylidene ketal (0.93 g) in acetic acid (25 ml) was added
concentrated nitric acid (1.5 ml). The reaction mixture was
filtered. Water was added to the filtrate and the precipitate was
filtered. The latter product was recrystallized from
acetonitrile.
[0300] Yield: 0.40 g
[0301] .sup.1H NMR (DMSO-d.sub.6): .delta.1.57 (m, 2H), 1.75 (m,
4H), 2.10 (m, 4H), 7.58-7.60 (m, 3H), 7.99 (s, 1H), 8.09-8.11 (m,
2H).
7-Nitro-2-phenyl-benzothiazole-5,6-diol
[0302] 7-Nitro-2-phenyl-benzothiazole-5,6-diol cyclohexylidene
ketal (0.35 g), acetic acid (8.8 ml) and concentrated hydrochloric
acid (3.5 ml) were refluxed for two hours. The product was filtered
and washed with acetic acid.
[0303] Yield: 0.27 g
[0304] Melting point: 221-224.degree. C.
[0305] .sup.1H NMR (DMSO-d.sub.6): .delta.7.55-7.58 (m, 3H), 7.79
(s, 1H), 8.07-8.09 (m, 2H), 10.6 (br, 2H).
Example 26
6,7-Dihydroxy-5-nitro-benzo[b]thiophene-2-carboxylic acid methyl
ester
4-Hydroxy-3-methoxy-5-nitrobenzaldehyde
[0306] To a solution of concentrated nitric acid (900 ml) and water
(900 ml) was added 4-hydroxy-3-methoxybenzaldehyde (300 g) at a
temperature under 10.degree. C. After stirring 1 hour at 0.degree.
C. the precipitate was filtered and washed with water.
[0307] .sup.1H NMR (DMSO-d.sub.6): .delta.3.90 (s, 3H), 7.64 (d,
1H, J 1.8 Hz), 8.09 (d, 1H, J 1.8 Hz), 9.88 (s, 1H).
2-Bromo-3,4-dihydroxy-5-nitrobenzaldehyde
[0308] The product of the previous reaction step, concentrated
hydrobromic acid (2 l) and acetic acid (2 l) were refluxed for 2
days. Water (1 l) and saturated Na.sub.2SO.sub.4-solution (1 l)
were added and the mixture was extracted with ether. The organic
phase was dried with Na.sub.2SO.sub.4 and evaporated to small
volume. The precipitated product was filtered.
[0309] .sup.1H NMR (DMSO-d.sub.6): .delta.7.92 (s, 1H), 10.3 (s,
1H).
2-Bromo-3,4-diethoxy-5-nitrobenzaldehyde
[0310] 2-Bromo-3,4-dihydroxy-5-nitrobenzaldehyde (5.2 g),
ethylbromide (4.5 ml) and N,N-diisopropylethylamine (10.5 ml) in
N,N-dimethylformamide (50 ml) were stirred at 70.degree. C. for 2
days. The mixture was poured into water and extracted with ether.
The organic phase was washed with NaOH-solution, dried with
Na.sub.2SO.sub.4 and evaporated to dryness.
[0311] .sup.1H NMR (DMSO-d.sub.6): .delta.1.33 (t, 3H, J 8.0 Hz),
1.40 (t, 3H, J 8.0 Hz), 4.15 (q, 2H, 8.0 Hz), 4.30 (q, 2H, J 8.0
Hz), 8.09 (s, 1H), 10.2 (s, 1H).
6,7-Diethoxy-5-nitro-benzo[b]thiophene-2-carboxylic acid methyl
ester
[0312] To a solution of 2-bromo-3,4-diethoxy-5-nitrobenzaldehyde
(1.5 g) in N,N dimethylformamide (5 ml) were added methyl
thioglycolate (1.5 g) and triethylamine (2.2 ml) at 0.degree. C.
Stirring was continued at room temperature overnight. 1 M HCl was
added and the product was extracted with ether. The organic phase
was dried with Na.sub.2SO.sub.4 and evaporated. The crude product
was triturated with methanol.
[0313] .sup.1H NMR (DMSO-d.sub.6): .delta.1.34 (t, 3H, J 7.8 Hz),
1.39 (t, 3H, J 7.8 Hz), 3.92 (s, 3H), 4.22 (q, 2H, J 7.8 Hz), 4.31
(q, 2H, J 7.8 Hz), 8.30 (s, 1H), 8.82 (s, 1H).
6,7-Dihydroxy-5-nitro-benzo[b]thiophene-2-carboxylic acid methyl
ester
[0314] 6,7-Diethoxy-5-nitro-benzo[b]thiophene-2-carboxylic acid
methyl ester (0.77 g), zinc chloride (5.0 g) and conc. HCl (1.3 ml)
were mixed and heated at 100.degree. C. for 2 hours. The reaction
mixture was cooled. Water (20 ml) was added and the precipitate was
filtered. The crude product was recrystallized twice from
methanol.
[0315] Melting point: 216-218.degree. C.
[0316] .sup.1H NMR (DMSO-d.sub.6): .delta.3.84 (s, 3H), 8.17 (s,
1H), 8.21 (s, 1H), 10.2 (br, 2H).
Example 27
1-(5,6-Dimethoxy-7-nitro-benzo[b]thiophen-2-yl)-nonan-1-one
1-(5,6-Dimethoxy-7-nitro-benzo[b]thiophen-2-yl)-nonan-1-one
[0317] 5,6-Dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid
(0.1 g) from Example 17, 1-octanol (2 ml) and concentrated
sulphuric acid (one drop) were refluxed at 120.degree. C. for 3
hours. The product was purified by column chromatography using
toluene-ethyl acetate-acetic acid 8:1:1 as the eluent.
[0318] Melting point: 115-117.degree. C.
[0319] Yield: 62.4 mg
[0320] .sup.1H NMR (DMSO-d.sub.6): .delta.=0.83-0.87 (m, 3H),
1.26-1.39 (m, 10H); 1.68-1.73 (m, 2H), 4.26-4.30 (q, 2H), 7.69 (s,
1H), 8.11 (s, 1H).
Example 28
(3-Chloro-5,6-dihydroxy-4,7-dinitro-benzo[b]thiophen-2-yl)-morpholin-4-yl--
methanone
(3-Chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone
[0321] Aluminum chloride (6.62 g) was gradually added into cool
acetonitrile (14.7 ml) at 10.degree. C. and then sodium iodide
(5.57 g) was added. The solution was stirred at room temperature 30
min.
(3-Chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone
(2.1 g) from Example 8 was added. The solution was stirred at
50.degree. C. five hours and at room temperature overnight. 2N HCl
(8.4 ml) was added into the cool reaction solution and then sodium
sulfite (1.58 g) and water (35 ml) were added. The mixture was
stirred at 40.degree. C. 30 min. The product was filtered, washed
with water and dried in vacuum.
[0322] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.52 (m, 4H), 3.63 (m,
4H), 7.11 (1H), 7.32 (1H), 9.63 (1H), 9.70 (1H).
(3-Chloro-5,6-dihydroxy-4,7-dinitro-benzo[b]thiophen-2-yl)-morpholin-4-yl--
methanone
[0323]
(3-Chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-meth-
anone (1.0 g) was slurried in methanesulfonic acid (20 ml) and then
was gradually added potassium nitrate (0.73 g). The reaction
mixture was stirred at room temperature and after 15 min it was
poured into ice water (100 ml). The product was filtered, washed
with water and methanol and dried in vacuum.
[0324] Melting point: 233-235.degree. C.
[0325] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.52 (m, 4H), 3.62 (m,
4H), 9.6-10.4 (br, 2H).
Example 29
(3,4-Chloro-5,6-dihydroxy-7-dinitro-benzo[b]thiophen-2-yl)-morpholin-4-yl--
methanone
(3,4-Chloro-5,6-dihydroxy-7-dinitro-benzo[b]thiophen-2-yl)-morpholin-4-yl--
methanone
[0326]
(3-Chloro-5,6-dihydroxy-7-dinitro-benzo[b]thiophen-2-yl)-morpholin-
-4-yl-methanone (0.5 g) from Example 8, copper(II) chloride (0.9 g)
and lithium chloride (0.3 g) in acetic acid (5 ml) were refluxed
for five hours. Water was added to the reaction mixture. The
resultant solid was filtered, washed with water and dried in
vacuum.
[0327] Melting point: 273-279.degree. C.
[0328] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.64 (m, 8H), 8.8-10.8
(br, 2H).
Example 30
(3-Chloro-5,6-dihydroxy-4-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-meth-
anone
(3-Chloro-5,6-dihydroxy-4-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-meth-
anone
[0329]
(3-Chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-meth-
anone (2.0 g) from Example 28 was slurried in methanesulfonic acid
(40 ml) and then potassium nitrate (0.64 g) was gradually added.
The reaction mixture was stirred at room temperature and after 15
min it was poured into ice water (100 ml). The solid was filtered,
washed with water (50 ml) and dried in vacuum. The resultant solid
was dissolved in DMF (6.2 ml) and then ethanol (18.4 ml) was added.
The product was filtered and washed with methanol (15 ml).
[0330] Melting point: 216.degree. C.
[0331] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.43 (m, 4H), 3.62 (m,
4H), 7.59 (s, 1H), 10.55 (b, 1H), 11.21 (br, 1H).
Example 31
(3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-(2,6-dimethyl-morph-
olin-4-yl)-methanone
(3-Chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-(2,6-dimethyl-morpholin-4-y-
l)-methanone
[0332] 3-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carbonyl chloride
(2.0 g) and 2,6-dimethylmorpholine (1.82 g) was suspended in
tetrahydrofuran (15 ml) and triethylamine (0.96 ml) was added and
stirring continued at room temperature for weekend. Water was
added, pH adjusted to 3 by HCl, and the precipitate filtered.
[0333] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=1.10 (s, 6H),
2.6-4.5 (br, 6H), 3.85 (s, 3H), 3.88 (s, 3H), 7.22 (s, 1H), 7.68
(s, 1H).
(3-Chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-(2,6-dimethyl-morpholin-4-y-
l)-methanone
[0334] Sodium iodide (1.62 g) was added to a solution of aluminum
chloride (2.16 g) in acetonitrile (5 ml). After 30 minutes stirring
(3-chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-(2,6-dimethyl-morpholin-4--
yl)-methanone was added and the mixture was heated at 50.degree. C.
for 12 hours. To the mixture 2 N HCl (4 ml), Na.sub.2SO.sub.3 (0.68
g) and water were added and the mixture was heated at 60.degree. C.
for 30 minutes and then cooled to room temperature. The precipitate
was filtered.
[0335] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=1.09 (s, 6H),
2.6-4.4 (br, 6H), 7.11 (s, 1H), 7.31 (s. 1H), 9.63 (s, 1H), 9.70
(s, 1H).
(3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-(2,6-dimethyl-morph-
olin-4-yl)-methanone
[0336]
(3-Chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-(2,6-dimethyl-morph-
olin-4-yl)-methanone (0.20 g) was dissolved in ethyl acetate and 1
N HNO.sub.3 solution in dichloromethane (0.64 ml) was added.
Stirring was continued for 4 hours. The mixture was concentrated to
smaller volume and the precipitate filtered and washed with water.
The crude product was recrystallized from
N,N-dimethylformamide/ethanol (25:75).
[0337] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=1.09 (s, 6H),
2.6-4.5 (br, 6H), 7.49 (s, 1H).
Example 32
(3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-(4-hydroxy-piperidi-
n-1-yl)-methanone
(3-Chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-(4-hydroxy-piperidin-1-yl)--
methanone
[0338] 3-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carbonyl chloride
(2.0 g) and 4-hydroxy-piperidine (1.60 g) was suspended in
tetrahydrofuran (15 ml) and triethylamine (0.96 ml) was added and
stirring continued at room temperature for two hours. Water was
added, pH adjusted to 3 by HCl and the precipitate filtered.
[0339] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=1.38-1.42 (m,
2H), 1.72-1.85 (m, 2H), 3.2-3.3 (m, 2H), 3.4-4.2 (br, 2H) 3.7-3.8
(m, 1H), 3.85 (s, 3H), 3.88 (s, 3H), 4.81 (d, 1H, J=4.1), 7.21 (s,
1H), 7.67 (s, 1H).
(3-Chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-(4-hydroxy-piperidin-1-yl)--
methanone
[0340] Sodium iodide (1.62 g) was added to a solution of aluminum
chloride (2.52 g) in acetonitrile (7 ml). After 30 minutes stirring
(3-chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-(4-hydroxy-piperidin-1-yl)-
-methanone (0.96 g) was added and the mixture was heated at
50.degree. C. for 12 hours. To the mixture 2 N HCl (4 ml),
Na.sub.2SO.sub.3 (0.68 g) and water were added and the mixture was
heated at 60.degree. C. for 30 minutes and then cooled to room
temperature. The precipitate was filtered.
[0341] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=1.35-1.45 (m,
2H), 1.72-1.82 (m, 2H), 3.18-3.30 (m, 2H), 3.4-4.2 (br, 2H),
3.7-3.8 (m, 1H), 4.80 (d, 1H, J=4.1 Hz), 7.10 (s, 1H), 7.31 (s,
1H), 9.61 (s, 1H), 9.68 (s, 1H).
(3-Chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-(4-hydroxy-piperidi-
n-1-yl)-methanone
[0342] A solution of 1 M HNO.sub.3 in dichloromethane (0.67 ml) was
added to a solution of
(3-chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-(4-hydroxy-piperidin-1-yl)-
-methanone (0.17 g) in ethyl acetate (10 ml). Stirring was
continued at 60.degree. C. for 3 hours and then at room temperature
overnight. The mixture was concentrated to smaller volume and the
precipitate filtered and washed with water. The crude product was
recrystallized from N,N-dimethylformamide/ethanol (25:75).
[0343] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=1.35-1.45 (m,
2H), 1.70-1.85 (br, 2H), 3.1-4.0 (br, 6H), 7.49 (s, 1H).
Example 33
(3-Bromomethyl-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-
-methanone
(3-Bromomethyl-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methano-
ne
[0344]
(5,6-Dimethoxy-3-methylbenzo[b]thiophen-2-yl)morpholin-4-yl-methan-
one (2.0 g) from Example 20, N-bromosuccinimide (1.18 g) and
2,2'-azobis(2-methylpropionitrile) (40 mg) in carbon tetrachloride
(6 ml) was refluxed under argon for 4 hours. The mixture was cooled
and filtered and the filtrate evaporated to dryness. The product
was a mixture of
(4-bromo-5,6-dimethoxy-3-methyl-benzo[b]thiophen-2-yl)-morpholin-4-yl-met-
hanone and
(3-bromomethyl-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-
-yl-methanone. The compounds were separated by flash chromatography
using ethyl acetate/heptane (1:4) as an eluent.
[0345]
(3-Bromomethyl-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-
-methanone: .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=3.53 (br,
4H), 3.64 (br, 4H), 3.84 (s, 3H), 3.86 (s, 3H), 4.91 (s, 2H), 7.45
(s, 1H), 7.61 (s, 1H).
[0346]
(4-Bromo-5,6-dimethoxy-3-methyl-benzo[b]thiophen-2-yl)-morpholin-4-
-yl-methanone: .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=2.56
(s, 3H), 3.51 (br, 4H), 3.57 (br, 4H), 3.76 (s, 3H), 3.89 (s, 3H),
7.73 (s, 1H).
(3-Bromomethyl-5,6-dihydroxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methano-
ne
[0347] A solution of 1 N boron tribromide in dichloromethane (3.4
ml) was added to a solution of
(3-bromomethyl-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methan-
one) (0.46 g) in dichloromethane (10 ml) at -20.degree. C. Stirring
was continued at 0.degree. C. for one hour. Methanol was added and
the mixture was evaporated to dryness. To the residue 5%
Na.sub.2SO.sub.3 solution (5 ml) was added, the mixture acidified
and the precipitate filtered.
[0348] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=3.52 (br, 4H),
3.61 (br, 4H), 4.78 (s, 2H), 7.26 (s, 1H), 7.28 (s, 1H), 9.39 (s,
1H), 9.56 (s, 1H).
(3-Bromomethyl-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-
-methanone
[0349] A solution of 1 M HNO.sub.3 in dichloromethane (1.02 ml) was
added to a solution of
(3-bromomethyl-5,6-dihydroxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methan-
one (0.35 g) in ethyl acetate (50 ml) and stirring continued at
60.degree. C. for 2 hours. The cooled mixture was washed with
water, dried and evaporated to dryness. The product was
recrystallized from acetone.
[0350] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=3.68 (br, 4H),
3.78 (br, 4H), 4.70 (s, 2H), 5.94 (s, 1H), 7.78 (s, 1H), 11.6 (s,
1H).
Example 34
5,6-Dihydroxy-3-methyl-2-(morpholine-4-carbonyl)-benzo[b]thiophene-4-carbo-
nitrile
5,6-Dimethoxy-3-methyl-2-(morpholine-4-carbonyl)-benzo[b]thiophene-4-carbo-
nitrile
[0351]
(4-Bromo-5,6-dimethoxy-3-methyl-benzo[b]thiophen-2-yl)-morpholin-4-
-yl-methanone (0.42 g) from Example 33 and copper(I) cyanide (2.0
g) in N,N-dimethylfomamide (8 ml) were irradiated in a microwave
oven at 150.degree. C. for 1.5 hours. To the mixture water was
added and the product was extracted into ethyl acetate. Ethyl
acetate was dried and evaporated to dryness.
[0352] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=2.66 (s, 3H),
3.5-3.8 (br, 8H), 3.96 (s, 3H), 4.05 (s, 3H), 7.46 (s, 1H). NOESY
NMR indicated the cyano group at the position 4.
5,6-Dihydroxy-3-methyl-2-(morpholine-4-carbonyl)-benzo[b]thiophene-4-carbo-
nitrile
[0353] A solution of 1 N boron tribromide in dichloromethane (3.4
ml) was added to a solution of
5,6-dimethoxy-3-methyl-2-(morpholine-4-carbonyl)-benzo[b]thiophene-4-carb-
onitrile (0.19 g) in dichloromethane (40 ml) at 0.degree. C. The
mixture was allowed to stay at 6.degree. C. for two days. Methanol
was added and the mixture was evaporated to dryness. To the residue
0.1 N HCl was added and the product was extracted into ethyl
acetate. Ethyl acetate was dried and evaporated to dryness. The
compound was recrystallized from isopropanol.
[0354] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.=2.49 (s, 3H),
3.51 (br, 4H), 3.60 (br, 4H), 7.54 (s, 1H).
Example 35
(3-Chloro-5,6-dihydroxy-7-cyano-benzo[b]thiophen-2-yl)-morpholin-4-yl-meth-
anone
(3-Chloro-6-hydroxy-5-methoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methan-
one
[0355]
(3-Chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-meth-
anone (11.8 g) from Example 8 was slurried in dichloromethane (250
ml) and aluminum chloride (33 g) was gradually added. The reaction
mixture was stirred at room temperature for 24 hours. Then 6M
hydrochloric acid (96 ml) was gradually added. The organic layer
was dried with sodium sulphate, evaporated and dried in vacuum. The
product was a mixture of two compounds and was used for the next
step without any purification.
(7-Bromo-3-chloro-6-hydroxy-5-methoxy-benzo[b]thiophen-2-yl)-morpholin-4-y-
l-methanone
[0356]
(3-Chloro-6-hydroxy-5-methoxy-benzo[b]thiophen-2-yl)-morpholin-4-y-
l-methanone (6.9 g) was slurried in acetic acid. A solution of
bromine (3.51 g) in acetic acid (31 ml) was gradually added. The
reaction mixture was stirred at room temperature and after 15
minutes water (125 ml) was added. The reaction mixture was stirred
at cool for 1.5 hours. The solid was filtered and dried in vacuum.
The product was a mixture of two compounds and was used for the
next step without any purification.
(7-Bromo-3-chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-meth-
anone
[0357]
(7-Bromo-3-chloro-6-hydroxy-5-methoxy-benzo[b]thiophen-2-yl)-morph-
olin-4-yl-methanone (7.0 g) was dissolved in
1-methyl-2-pyrrolidinone (35 ml) and di-isopropylethylamine was
gradually added. The reaction solution was warmed at 80.degree. C.
for 3 hours. Then water (350 ml) was added. The reaction solution
was stirred at room temperature for 30 minutes. The product was
extracted into ethyl acetate. The organic phase was washed with 1M
hydrochloric acid and a solution of sodium sulphate, evaporated and
dried in vacuum. The product was purified by flash chromathography
using heptane-ethyl acetate as an eluent.
[0358] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.46 (br, 4H), 3.64 (br,
4H), 3.84 (s, 3H), 3.97 (s, 3H), 7.39 (s, 1H).
(3-Chloro-7-cyano-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-meth-
anone
[0359]
(7-Bromo-3-chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-
-yl-methanone (0.7 g) and copper(I) cyanide (2.3 g) in
N,N-dimethylformamide were irradiated in a microwave oven at
180.degree. C. for 1.5 hours. To the mixture water (40 ml) and
ethyl acetate (40 ml) were added. The solid was filtered and the
organic phase was evaporated and dried in vacuum. The product was
purified by flash chromathography using heptane-ethyl acetate as an
eluent.
[0360] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.65 (br, 8H), 4.00
(min, 3H), 4.05 (m, 3H), 7.39 (s, 1H).
(3-Chloro-7-cyano-5,6-dihydroxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-meth-
anone
[0361]
(3-Chloro-7-cyano-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-
-yl-methanone (0.05 g) was suspended in dichloromethane under
nitrogen, cooled to -20.degree. C. and treated dropwise with a
solution of 1M boron tribromide in dichloromethane. The suspension
was stirred at -20.degree. C. for 30 minutes and in cool overnight.
The mixture was poured into ice-cold water and stirred at room
temperature for 30 minutes. The product was filtered and purified
by a preparative plate (reverse phase) using a mixture of toluene,
ethyl acetate and acetic acid (8:1:1) as an eluent.
[0362] .sup.1H NMR (DMSO-d.sub.6): .delta.=3.52 (m, 4H), 3.63 (br,
4H), 7.02 (s, 1H).
[0363] As already mentioned hereinbefore, the compounds of formula
I show interesting pharmacological properties, namely they exhibit
an enhanced catechol-O-methyltransferase (COMT) enzyme inhibiting
activity and have an improved bioavailability and/or a prolonged
duration of action due to slow elimination via glucuronidation.
Furthermore, they do not uncouple oxidative phosphorylation. Said
properties are demonstrated with the pharmacological tests
presented below.
Experiment 1
Determination of COMT Inhibiting Activity In Vitro
[0364] The K.sub.i values were determined by measuring the COMT
activity with various drug concentrations using recombinant human
soluble form of COMT (hS-COMT). hS-COMT was preincubated with 25
.mu.M S-adenosyl-L-methionine (SAM) and COMT inhibitor in 100 .mu.M
Na.sub.2HPO.sub.4 buffer (pH 7.4) containing 5 .mu.M MgCl.sub.2 for
5 min at 37.degree. C. The reaction was started by adding the
substrate esculetin (10 .mu.M). The production of O-methylated
esculetin was measured as time-resolved fluorescence (excitation at
355 nm, emission at 460 nm) using a FlexStation fluorometer
(Molecular Probes, USA). The assay was performed on 96-well plates.
The tight binding inhibition constant, K.sub.i, was resolved from
the reaction kinetics observed at varying inhibitor concentrations
using PlateKi software (BioKin, USA).
[0365] The results are shown in Table 1. The results show that the
compounds of formula I are capable of inhibiting COMT activity in
vitro with an efficacy better than or equal to entacapone.
TABLE-US-00001 TABLE 1 COMT inhibiting activity in vitro. Compound
K.sub.i/nM Compound of example 4 0.5 Compound of example 5 1.5
Compound of example 7 1.5 Compound of example 8 0.6 Compound of
example 12 0.6 Compound of example 13 0.2 Compound of example 16
0.9 Compound of example 23 2.0 Entacapone 1.9
Experiment 2
Determination of Metabolic Stability In Vitro
[0366] The metabolic stability was studied by incubating the
compounds together with human liver microsomes (Human Biologics
Inc.) using uridine-5'-diphosphoglucuronic acid (UDPGA, Sigma) as a
cofactor. The incubation was carried out in 100 mM phosphate buffer
(pH 7.4) containing 5 mM MgCl.sub.2. The final test substance
concentration was 100 .mu.M and the microsomal protein amount was
0.4 mg/ml. After 5 min preincubation the reaction was started with
pre-warmed UDPGA, final concentration 5 mM. The mixture was
incubated in Eppendorf tubes for 60 min at 37.degree. C., and the
reaction was terminated either by adding methanol or perchloric
acid/methanol (1:9) mixture. After protein precipitation the
glucuronide formed was separated by high-performance liquid
chromatography (HPLC). The area of the glucuronide in the HPLC
chromatogram was compared to that formed from entacapone in the
same experimental conditions to obtain a relative glucuronidation
value for each compound.
[0367] The results are shown in Table 2. The results show that the
compounds of formula I possess increased metabolic stability
compared to entacapone in respect of glucuronidation.
Glucuronidation has been shown to be the major elimination route of
entacapone and thus the compounds of formula I have an improved
bioavailability and/or a prolonged duration of action.
TABLE-US-00002 TABLE 2 Metabolic stability in vitro (relative
glucuronidation; entacapone = 1.00). Relative Compound
glucuronidation Compound of example 4 <0.01 Compound of example
12 0.03 Compound of example 16 <0.01 Compound of example 23 0.26
Entacapone 1.00
Experiment 3
Determination of Uncoupling of Oxidative Phosphorylation In
Vitro
[0368] Uncoupling of oxidative phosphorylation was studied in
isolated rat liver mitochondria measuring the oxygen consumption by
a fluorescent technique.
[0369] The mitochondrial preparations were made as described in
Nissinen et al. European Journal of Pharmacology, 340 (1997) 287.
Shortly, a rat was decapitated, liver was excised, washed in ice
cold 0.9% NaCl and cut into pieces. The tissue was placed into 40
ml of homogenization buffer containing 2 mM Tris-HCl, 0.25 M
sucrose, 0.1 mM EDTA pH 6.8 (1:4 w/vol) and homogenized with 5-20
strokes (800 rpm) in a medium-fitting Teflon-in-glass Braun
homogenizator. The homogenate was centrifuged at 1000 g for 10 min
at 4.degree. C. The supernatant was collected and centrifuged at
8200 g for 10 min at 4.degree. C. The supernatant was discarded and
the pellet was washed twice with 10 ml of homogenization buffer.
The suspension was centrifuged at 8200 g for 10 min at 4.degree. C.
The supernatant was discarded and the pellet was suspended into 2
ml of homogenization buffer and kept in ice until use (up to 2-6
hours). The protein concentration was measured.
[0370] BD.TM. oxygen Biosensor 96 microwell plates were used for
measuring oxygen consumption of mitochondria. The microwell plate
has an oxygen sensitive fluorescent compound (Tris
1,7-diphenyl-1,10-phenanthroline ruthenium(II) chloride) embedded
in the gas permeable bottom of the well. Oxygen inhibits dye's
fluorescence so the oxygen consumption of mitochondria is detected
as an increase in fluorescence.
[0371] The test compounds were added into the assay plate at
various final concentrations (1, 2.5, 5, 10, 25, 50 .mu.M). A known
uncoupler of mitochondrial oxidative phosphorylation, dinitrophenol
(DNP; 10 .mu.M), was used as a reference compound (cf. Hemker
Biochimica et Biophysica Acta, 81 (1964) 1, Nissinen et al.
European Journal of Pharmacology, 340 (1997) 287). The control
contained only 2% DMSO. A stock solution of mitochondria (0.72 ml=4
mg/protein/ml) was added into 2.28 ml of respiratory buffer
(37.degree. C.) containing 250 mM saccharose, 5 mM
Na.sub.2HPO.sub.4, 2 mM MgCl.sub.2, 1 mM EGTA, 5 mM sodium
succinate and 10 mM MOPS pH 7.0. The measurement was started with
the addition of the mitochondrial suspension (50 .mu.l/well) to the
wells. The plate was stirred for 20 s and the fluorescence in the
wells was measured for 10 min using 9 s interval, excitation at 485
nm, emission at 630 nm and emission cut off at 610 nm. The
photomultiplier tube sensitivity option was set to "low".
[0372] The slope factor of each oxygen consumption measurement was
determined. The means of two replicates were divided by the means
of six control values, and the threshold values of uncoupling were
determined for the compounds. The DNP/Control ratios describe the
activity of mitochondria.
[0373] If a sample/Control slope ratio exceeded 2, it was
interpreted as uncoupling of oxidative phosphorylation. As a
control for assay quality, DNP/Control ratios were calculated,
which gives the activity of mitochondria. Only assays where
DNP/Control ratio was larger than 4 were considered acceptable and
used in tests.
[0374] The results are shown in Table 3. The results show that the
compounds of formula I do not uncouple oxidative phosphorylation.
The compounds of formula I thus possess a desirable safety profile.
TABLE-US-00003 TABLE 3 Uncoupling of oxidative phosphorylation in
vitro. Compound Uncoupling/.mu.M Compound of example 4 >50
Compound of example 12 >50 Compound of example 13 >50
Compound of example 23 >50 DNP 10 Tolcapone 2.6
[0375] The compounds of formula I exhibit COMT inhibiting activity.
The present invention thus provides compounds, or salts or esters
thereof, for use as a medicament. Furthermore, a method for the
treatment of diseases or conditions wherein COMT inhibiting agents
are indicated to be useful is provided. For example, a method for
the treatment of Parkinson's disease, such as potentiation of
levodopa therapy or therapy with another dopamine precursor, is
provided. In said method a therapeutically effective amount of at
least one compound of formula I is administered to a subject in
need of such treatment. The use of the compounds of formula I for
the manufacture of a medicament for the treatment of diseases or
conditions wherein COMT inhibiting agents are indicated to be
useful, e.g. Parkinson's disease, is also provided.
[0376] The compounds of formula I can be administered, for example,
enterally, topically or parenterally by means of any pharmaceutical
formulation useful for said administration and containing at least
one active compound of formula I in pharmaceutically acceptable and
effective amounts together with pharmaceutically acceptable
diluents, carriers and/or excipients known in the art.
[0377] The therapeutic dose to be given to a patient in need of the
treatment will vary depending on the compound being administered,
the age and the sex of the subject being treated, the particular
condition being treated, as well as the route and method of
administration, and is easily determined by a person skilled in the
art. Accordingly, the typical dosage for oral administration is
from 5 .mu.g/kg to 100 mg/kg per day and for parenteral
administration from 0.5 .mu.g/kg to 10 mg/kg for an adult
mammal.
[0378] The compounds according to this invention are given to a
patient as such or in combination with one or more other active
ingredients and/or suitable pharmaceutical excipients. The latter
group comprises conventionally used excipients and formulation
aids, such as fillers, binders, disintegrating agents, lubricants,
solvents, gel forming agents, emulsifiers, stabilizers, colorants
and/or preservatives.
[0379] The compounds of formula I are formulated into dosage forms
using commonly known pharmaceutical manufacturing methods. The
dosage forms can be e.g. tablets, capsules, granules,
suppositories, emulsions, suspensions or solutions. Depending on
the route of administration and the galenic form, the amount of the
active ingredient in a formulation can typically vary between 0.01%
and 100% (w/w).
[0380] For the treatment of Parkinson's disease the compounds of
formula I can be given together with levodopa or another dopamine
precursor, each in its own composition or combined in a single
composition. Also a dopa decarboxylase (DDC) inhibitor, such as
benserazide or carbidopa, and/or a monoamine oxidase type B (MAO-B)
inhibitor, such as lazabemide, rasagiline, safinamide or
selegiline, can be present. The amount of levodopa can be from 50
mg to 400 mg, e.g. from 50 mg to 300 mg, such as from 50 mg to 200
mg. The amount of carbidopa can be from 5 mg to 200 mg, e.g. from 5
mg to 100 mg, such as from 5 mg to 50 mg.
[0381] The DDC inhibitor and the dopamine precursor, such as
levodopa, are typically administered in a ratio of from 1:1 to
1:40, e.g. from 1:4 to 1:10.
[0382] The daily dose of lazabemide is typically from 100 mg to 800
mg, e.g. from 100 mg to 200 mg, divided into 1 to 10 individual
doses, e.g. 1 to 2 individual doses. The daily dose of rasagiline
is typically from 0.1 mg to 5 mg, e.g. from 0.5 mg to 2 mg, divided
into 1 to 10 individual doses, e.g. 1 to 2 individual doses. The
daily dose of safinamide is typically from mg to 600 mg, e.g. from
50 mg to 150 mg, divided into 1 to 10 individual doses, e.g. 1 to 2
individual doses. The daily dose of selegiline is typically from 1
mg to 20 mg, e.g. from 2 mg to 10 mg, divided into 1 to 10
individual doses, e.g. 1 to 2 individual doses.
[0383] A person skilled in the art will appreciate that the
embodiments described in this application can be modified without
departing from the inventive concept. A person skilled in the art
also understands that the invention is not limited to the
particular embodiments disclosed but is intended to also cover
modifications of the embodiments that are within the spirit and
scope of the invention.
* * * * *