U.S. patent application number 11/527063 was filed with the patent office on 2007-01-25 for benzothiazolyl derivatives.
Invention is credited to Matthias Heinrich Nettekoven, Stephan Roever.
Application Number | 20070021478 11/527063 |
Document ID | / |
Family ID | 33522251 |
Filed Date | 2007-01-25 |
United States Patent
Application |
20070021478 |
Kind Code |
A1 |
Nettekoven; Matthias Heinrich ;
et al. |
January 25, 2007 |
Benzothiazolyl derivatives
Abstract
The present invention relates to compounds of formula (I)
##STR1## wherein R.sup.1, R.sup.2, R.sup.3 R.sup.3a and R.sup.3b
are as provided in the description, and pharmaceutically acceptable
salts thereof, for use in the treatment and/or prophylaxis of
diseases which are associated with the modulation of CB1 receptors
such as obesity.
Inventors: |
Nettekoven; Matthias Heinrich;
(Grenzach-Wyhlen, DE) ; Roever; Stephan;
(Inzlingen, DE) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.;PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
US
|
Family ID: |
33522251 |
Appl. No.: |
11/527063 |
Filed: |
September 26, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10871952 |
Jun 18, 2004 |
|
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11527063 |
Sep 26, 2006 |
|
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Current U.S.
Class: |
514/367 ;
548/163 |
Current CPC
Class: |
A61P 3/04 20180101; C07D
277/82 20130101 |
Class at
Publication: |
514/367 ;
548/163 |
International
Class: |
A61K 31/427 20070101
A61K031/427; C07D 277/82 20060101 C07D277/82 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 20, 2003 |
EP |
03013403.5 |
Claims
1. A compound of formula (I) ##STR74## wherein R.sup.1 is phenyl,
or phenyl mono-, di- or tri-substituted, independently, by a group
selected from the group consisting of lower alkyl,
halogenated-lower alkoxy and di-lower alkylamino; R.sup.2 is
phenyl, or phenyl mono-, di- or tri-substituted, independently, by
a group selected from the group consisting of halogen,
halogenated-lower alkyl, nitro and cyano; R.sup.3 is hydrogen,
lower alkyl, benzyl, lower alkoxy, halogen, cyano, nitro, amino,
--NHSO.sub.2--R.sup.3a or --NHCO--R.sup.3b; R.sup.3a is lower
alkyl, di-lower alkylamino, benzyl, phenyl or phenyl mono-, di- or
tri-substituted, independently, by lower alkyl; R.sup.3b is benzyl,
phenyl or phenyl mono-, di- or tri-substituted, independently, by
lower alkyl; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R.sup.2 is phenyl
mono-substituted with halogen.
3. The compound according to claim 1, wherein R.sup.3 is hydrogen,
nitro, amino, --NHSO.sub.2--R.sup.3a or --NHCO--R.sup.3b.
4. The compound according to claim 3, wherein R.sup.3 is
hydrogen.
5. The compound according to claim 1, wherein substituent R.sup.3
is at the 6-position of the benzthiazole ring.
6. The compound according to claim 3 in which R.sup.3 is
--NHSO.sub.2--R.sup.3a, wherein R.sup.3a is methyl, n-butyl,
dimethylamino, benzyl, phenyl or phenyl mono-, di- or
tri-substituted methyl.
7. The compound according to claim 3 in which R.sup.3 is
--NHCO--R.sup.3b, wherein R.sup.3b is benzyl or phenyl
mono-substituted by lower alkyl.
8. A compound of formula (Ia) ##STR75## or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 is phenyl, or phenyl
mono-, di- or tri-substituted, independently, by a group selected
from the group consisting of halogen, lower alkoxy, lower alkyl,
halogenated-lower alkoxy and di-lower alkylamino; R.sup.2 is
phenyl, or phenyl mono-, di- or tri-substituted, independently, by
a group selected from the group consisting of halogen,
halogenated-lower alkyl, nitro and cyano; R.sup.3 is hydrogen,
lower alkyl, benzyl, lower alkoxy, cyano, nitro, amino,
--NHSO.sub.2--R.sup.3a or --NHCO--R.sup.3b; R.sup.3a is lower
alkyl, di-lower alkylamino, benzyl, phenyl or phenyl mono-, di- or
tri-substituted, independently, by lower alkyl; R.sup.3b is benzyl,
phenyl or phenyl mono-, di- or tri-substituted, independently, by
lower alkyl; provided that when R.sup.3 is hydrogen, R.sup.1 is
selected from the group consisting of 2-halogen-phenyl, 4-lower
alkoxy-phenyl, 3-lower alkyl-phenyl, 4-halogen-2-lower
alkyl-phenyl, 3-halogen-2-lower alkyl-phenyl, 4-halogen-3-lower
alkyl-phenyl, 2-halogen-4-lower alkyl-phenyl, 3-halogen-4-lower
alkyl-phenyl, 2-lower alkoxy-4-lower alkyl-phenyl, 3-lower
alkoxy-4-lower alkyl-phenyl, 4-lower alkoxy-2-lower alkyl-phenyl,
4-lower alkoxy-3-lower alkyl-phenyl, 3-lower alkoxy-2-lower
alkyl-phenyl, phenyl substituted by halogenated-lower alkoxy or
di-lower alkylamino, phenyl substituted by two or three groups
independently selected from halogen, lower alkoxy, halogenated
alkoxy and di-lower alkylamino, phenyl substituted by a lower alkyl
group and one or two groups selected from halogenated alkoxy and
di-lower alkylamino, and phenyl substituted by two lower alkyl
groups and a group selected from halogen, lower alkoxy, halogenated
alkoxy and di-lower alkylamino.
9. The compound of formula (Ia) according to claim 8 or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is lower
alkyl, benzyl, lower alkoxy, cyano, nitro, amino,
--NHSO.sub.2--R.sup.3a or --NHCO--R.sup.3b.
10. The compound of formula (Ia) according to claim 8, selected
from the group consisting of:
2-chloro-N-(4-ethoxy-phenyl)-4-fluoro-N-(6-nitro-benzothiazol-2-yl)-benza-
mide;
2-chloro-N-(4-ethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzamid-
e;
2,4-dichloro-N-(4-ethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzami-
de;
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-b-
enzamide;
N-(6-amino-benzothiazol-2-yl)-2,4-dichloro-N-(3,4-dimethoxy-phe-
nyl)-benzamide;
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-methanesulfonylamino-benzothia-
zol-2-yl)-benzamide;
N-[6-(butane-1-sulfonylamino)-benzothiazol-2-yl]-2,4-dichloro-N-(3,4-dime-
thoxy-phenyl)-benzamide;
N-[6-(dimethylamino-1-sulfonylamino)-benzothiazol-2-yl]-2,4-dichloro-N-(3-
,4-dimethoxy-phenyl)-benzamide;
N-(6-benzenesulfonylamino-benzothiazol-2-yl)-2,4-dichloro-N-(3,4-dimethox-
y-phenyl)-benzamide; and
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-phenylmethanesulfonylamino-ben-
zothiazol-2-yl)-benzamide; or a pharmaceutically acceptable salt
thereof.
11. The compound of formula (Ia) according to claim 8, selected
from the group consisting of:
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-[6-(toluene-2-sulfonylamino)-benz-
othiazol-2-yl]-benzamide;
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-phenylacetylamino-benzothiazol-
-2-yl)-benzamide;
2-chloro-N-(3,4-dimethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzamide-
;
N-(6-amino-benzothiazol-2-yl)-2-chloro-N-(3,4-dimethoxy-phenyl)-benzami-
de;
2-chloro-N-(3,4-dimethoxy-phenyl)-N-(6-methanesulfonylamino-benzothia-
zol-2-yl)-benzamide;
N-[6-(butane-1-sulfonylamino)-benzothiazol-2-yl]-2-chloro-N-(3,4-dimethox-
y-phenyl)-benzamide;
N-[6-(dimethylamino-1-sulfonylamino)-benzothiazol-2-yl]-2-chloro-N-(3,4-d-
imethoxy-phenyl)-benzamide;
N-(6-benzenesulfonylamino-benzothiazol-2-yl)-2-chloro-N-(3,4-dimethoxy-ph-
enyl)-benzamide;
2-chloro-N-(3,4-dimethoxy-phenyl)-N-(6-phenylmethanesulfonylamino-benzoth-
iazol-2-yl)-benzamide;
2-chloro-N-(3,4-dimethoxy-phenyl)-N-[6-(toluene-2-sulfonylamino)-benzothi-
azol-2-yl]-benzamide; and
N-(6-(2-methylbenzoylamino)-benzothiazol-2-yl)-2-chloro-N-(3,4-dimethoxy--
phenyl)-benzamide; or a pharmaceutically acceptable salt
thereof.
12. The compound of formula (Ia) according to claim 8, wherein
R.sup.3 is hydrogen, and R.sup.1 is selected from the group
consisting of 3,5-dichlorophenyl, 3,4-dichlorophenyl,
4-chloro-2-methyl-phenyl and 4-chloro-3-methoxyphenyl.
13. The compounds of formula (Ia) according to claim 8, wherein
R.sup.3 is hydrogen, and R.sup.1 is selected from the group
consisting of 4-lower alkoxy-phenyl, 3,4-di-lower alkoxy-phenyl,
3,4,5-tri-lower alkoxy-phenyl and 3-lower alkoxy-4-lower
alkyl-phenyl.
14. The compound of formula (Ia) according to claim 1, wherein
R.sup.3 is hydrogen, and R.sup.1 is phenyl substituted by a group
selected from the group consisting of halogenated-lower alkoxy and
di-lower alkylamino.
15. The compound of formula (Ia) according to claim 8, selected
from the group consisting of:
N-benzothiazol-2-yl-2-chloro-N-(3,5-dichloro-phenyl)-benzamide;
N-benzothiazol-2-yl-2-chloro-N-(3,4-dichloro-phenyl)-benzamide;
N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dichloro-phenyl)-benzamide;
N-benzothiazol-2-yl-2-chloro-N-(4-methoxy-phenyl)-benzamide;
N-benzothiazol-2-yl-2,4-dichloro-N-(4-methoxy-phenyl)-benzamide;
N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-2-methyl-phenyl)-benzamide;
N-benzothiazol-2-yl-2-fluoro-N-(4-methoxy-phenyl)-4-trifluoromethyl-benza-
mide;
N-benzothiazol-2-yl-N-(4-methoxy-phenyl)-2,4-bis-trifluoromethyl-be-
nzamide;
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-methoxy-phenyl)-benza-
mide; and
N-benzothiazol-2-yl-2-chloro-N-(4-methoxy-phenyl)-4-nitro-benza-
mide; or a pharmaceutically acceptable salt thereof.
16. The compound of formula (Ia) according to claim 8, selected
from the group consisting of:
N-benzothiazol-2-yl-4-cyano-N-(4-methoxy-phenyl)-benzamide;
N-benzothiazol-2-yl-N-(4-ethoxy-phenyl)-2-fluoro-4-trifluoromethyl-benzam-
ide;
N-benzothiazol-2-yl-2-chloro-N-(4-ethoxy-phenyl)-4-fluoro-benzamide;
N-benzothiazol-2-yl-2-chloro-N-(4-ethoxy-phenyl)-4-nitro-benzamide;
N-benzothiazol-2-yl-4-cyano-N-(4-ethoxy-phenyl)-benzamide;
N-benzothiazol-2-yl-2-chloro-N-(4-ethoxy-phenyl)-benzamide;
N-benzothiazol-2-yl-2,4-dichloro-N-(4-ethoxy-phenyl)-benzamide;
N-benzothiazol-2-yl-N-(3,4-dimethoxy-phenyl)-2-fluoro-4-trifluoromethyl-b-
enzamide;
N-benzothiazol-2-yl-N-(3,4-dimethoxy-phenyl)-2,4-bis-trifluorom-
ethyl-benzamide; and
N-benzothiazol-2-yl-2-chloro-N-(3,4-dimethoxy-phenyl)-4-fluoro-benzamide;
or a pharmaceutically acceptable salt thereof.
17. The compound of formula (la) according to claim 8, selected
from the group consisting of:
N-benzothiazol-2-yl-2-chloro-N-(4-dimethylamino-phenyl)-4-fluoro-benzamid-
e;
N-benzothiazol-2-yl-2-chloro-N-(4-dimethylamino-phenyl)-benzamide;
N-benzothiazol-2-yl-2-chloro-N-(4-diethylamino-phenyl)-4-nitro-benzamide;
and
N-benzothiazol-2-yl-2,4-dichloro-N-(4-diethylamino-phenyl)-benzamide-
; or a pharmaceutically acceptable salt thereof.
18. The compound of formula (Ia) according to claim 8, selected
from the group consisting of:
N-benzothiazol-2-yl-2-chloro-N-(4-trifluoromethoxy-phenyl)-benzamide;
N-benzothiazol-2-yl-2,4-dichloro-N-(4-trifluoromethoxy-phenyl)-benzamide;
and
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-trifluoromethoxy-phenyl)--
benzamide; or a pharmaceutically acceptable salt thereof.
19. The compound of formula (I) in accordance with claim 1,
selected from the group consisting of:
N-benzothiazol-2-yl-2-chloro-N-(4-dimethylamino-phenyl)-4-fluoro-benzamid-
e;
N-benzothiazol-2-yl-2-chloro-N-(4-dimethylamino-phenyl)-benzamide;
N-benzothiazol-2-yl-2-chloro-N-(4-diethylamino-phenyl)-4-nitro-benzamide;
and
N-benzothiazol-2-yl-2,4-dichloro-N-(4-diethylamino-phenyl)-benzamide-
; or a pharmaceutically acceptable salt thereof.
20. The compound of formula (I) in accordance with claim 1,
selected from the group consisting of:
N-benzothiazol-2-yl-2-chloro-N-(4-trifluoromethoxy-phenyl)-benzamide;
N-benzothiazol-2-yl-2,4-dichloro-N-(4-trifluoromethoxy-phenyl)-benzamide;
and
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-trifluoromethoxy-phenyl)--
benzamide; or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a compound of formula
(I) ##STR76## wherein R.sup.1 is phenyl, or phenyl mono-, di- or
tri-substituted, independently, by a group selected from the group
consisting of halogen, lower alkoxy, lower alkyl, halogenated-lower
alkoxy and di-lower alkylamino; R.sup.2 is phenyl, or phenyl mono-,
di- or tri-substituted, independently, by a group selected from the
group consisting of halogen, halogenated-lower alkyl, nitro and
cyano; R.sup.3 is hydrogen, lower alkyl, benzyl, lower alkoxy,
halogen, cyano, nitro, amino, --NHSO.sub.2--R.sup.3a or
--NHCO--R.sup.3b; R.sup.3a is lower alkyl, di-lower alkylamino,
benzyl, phenyl or phenyl mono-, di- or tri-substituted,
independently, by lower alkyl; R.sup.3b is benzyl, phenyl or phenyl
mono-, di- or tri-substituted, independently, by lower alkyl; or a
pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable carrier.
22. A method for the treatment of obesity in a patient in need
thereof, comprising administering to said patient a compound
according to claim 1 or a pharmaceutically acceptable salt thereof
in an amount of from about 1 mg to 1000 mg.
23. The method according to claim 22, wherein the amount is from
about 1 mg to 100 mg.
Description
PRIORITY TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/871,952, filed Jun. 18, 2004, now pending; which claims the
benefit of European Application No. 03013403.5, filed Jun. 20,
2003. The entire contents of the above-identified applications are
hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Two different subtypes of cannabinoid receptors (CB.sub.1
amd CB.sub.2) have been isolated and both belong to the G protein
coupled receptor superfamily. An alternative spliced form of
CB.sub.1, CB.sub.1A, has also been described, but it did not
exhibit different properties in terms of ligand binding and
receptor activation than CB.sub.1 (D. Shire, C. Carrillon, M.
Kaghad, B. Calandra, M. Rinaldi-Carmona, G. Le Fur, D. Caput, P.
Ferrara, J. Biol. Chem. 270 (8) (1995) 3726-31). The CB.sub.1
receptor is mainly located in the brain, whereas the CB.sub.2
receptor is predominately distributed in the periphery and
primarily localized in spleen and cells of the immune system (S.
Munro, K. L. Thomas, M. Abu-Shaar, Nature 365 (1993) 61-65).
Therefore in order to avoid side effects a CB.sub.1-selective
compound is desirable.
[0003] .DELTA..sup.9-tetrahydrocannabinol (.DELTA..sup.9-THC) is
the principal psychoactive compound in the Indian hemp (Y. Gaoni,
R. Mechoulam, J. Am. Chem. Soc., 86 (1964) 1646), canabis savita
(marijuanan), which is used in medicine since ages (R. Mechoulam
(Ed.) in "Cannabinoids as therapeutic Agents", 1986, pp. 1-20, CRC
Press). .DELTA..sup.9-THC is a non-selective CB.sub.1/.sub.2
receptor agonist and is available in the USA as dronabinol
(marinol.RTM.) for the alleviation of cancer chemotherapy-induced
emesis (CIE) and the reversal of body weight loss experienced by
AIDS patients through appetite stimulation. In the UK Nabolinone
(LY-109514, Cesamet.RTM.), a synthetic analogue of
.DELTA..sup.9-THC, is used for CIE (R. G. Pertwee, Pharmaceut. Sci.
3 (11) (1997) 539-545, E. M. Williamson, F. J. Evans, Drugs 60 (6)
(2000) 1303-1314). Anandamide (arachidonylethanolamide) was
identified as the endogenous ligand (agonist) for the CB.sub.1
receptor (R. G. Pertwee, Curr. Med. Chem., 6 (8) (1999) 635-664; W.
A. Devane, L. Hanus, A. Breuer, R. G. Pertwee, L. A. Stevenson, G.
Griffin, D. Gibson, A. Mandelbaum, A. Etinger, R. Mechoulam,
Science 258 (1992) 1946-9). Anandamide and 2-arachidonoylglycerol
(2-AG) modulate at the presynaptic nerve teminal negatively
adenylate cyclase and voltage-sensitive Ca.sup.21 channels and
activate the inwardly rectifying K.sup.+ channel (V. Di Marzo, D.
Melck, T. Bisogno, L. De Petrocellis, Trends in Neuroscience 21
(12) (1998) 521-8), thereby affecting neurotransmitter release
and/or action, which decreases the release of neurotransmitter (A.
C. Porter, C. C. Felder, Pharmacol. Ther., 90 (1) (2001)
45-60).
[0004] Anandamide as .DELTA..sup.9-THC also increases feeding
through CB.sub.1 receptor-mediated mechanism. CB.sub.1 receptor
selective antagonists block the increase in feeding associated with
administration of anandamide (C. M. Williams, T. C. Kirkham,
Psychopharmacology 143 (3) (1999) 315-317; C. C. Felder, E. M.
Briley, J. Axelrod, J. T. Simpson, K. Mackie, W. A. Devane, Proc.
Natl. Acad. Sci. U.S.A. 90 (16) (1993) 7656-60) and cause appetite
suppression and weight loss (G. Colombo, R. Agabio, G. Diaz, C.
Lobina, R. Reali, G. L. Gessa, Life Sci. 63 (8) (1998)
L113-PL117).
[0005] Leptin is the primary signal through which the hypothalamus
senses nutritional state and modulates food intake and energy
balance. Following temporary food restriction, CB1 receptor
knockout mice eat less than their wild-type littermates, and the
CB1 antagonist SR141716A reduces food intake in wild-type but not
knockout mice. Furthermore, defective leptin signaling is
associated with elevated hypothalamic, but not cerebellar, levels
of endocannabinoids in obese db/db and ob/ob mice and Zucker rats.
Acute leptin treatment of normal rats and ob/ob mice reduces
anandamide and 2-arachidonoyl glycerol in the hypothalamus. These
findings indicate that endocannabinoids in the hypothalamus may
tonically activate CB1 receptors to maintain food intake and form
part of the neural circuitry regulated by leptin (V. Di Marzo, S.
K. Goparaju, L. Wang, J. Liu, S. Bitkai, Z. Jarai, F. Fezza, G. I.
Miura, R. D. Palmiter, T. Sugiura, G. Kunos, Nature 410 (6830)
822-825).
[0006] SR-141716A, a CB1 selective antagonist/inverse agonist is
undergoing currently phase III clinical trials for the treatment of
obesity. In a double blind placebo-controlled study, at the doses
of 5, 10 and 20 mg daily, SR 141716 significantly reduced body
weight when compared to placebo (F. Barth, M. Rinaldi-Carmona, M.
Arnone, H. Heshmati, G. Le Fur, "Cannabinoid antagonists: From
research tools to potential new drugs." Abstracts of Papers, 222nd
ACS National Meeting, Chicago, Ill., United States, Aug. 26-30,
2001). Other compounds which have been proposed as CB1 receptor
antagonists respectively inverse agonists are aminoalkylindols
(AAI; M. Pacheco, S. R. Childers, R. Arnold, F. Casiano, S. J.
Ward, J. Pharmacol. Exp. Ther. 257 (1) (1991) 170-183), like
6-bromopravadoline (WIN54661; F. M. Casiano, R. Arnold, D. Haycock,
J. Kuster, S. J. Ward, NIDA Res. Monogr. 105 (1991) 295-6) or
6-iodopravadoline (AM630, K. Hosohata, R. M. Quock, R. M; Hosohata,
T. H. Burkey, A. Makriyannis, P. Consroe, W. R. Roeske, H. I.
Yamamura, Life Sci. 61 (1997) 115-118; R. Pertwee, G. Griffin, S.
Fernando, X. Li, A. Hill, A. Makriyannis, Life Sci. 56 (23-24)
(1995) 1949-55). Arylbenzo[b]thiophene and benzo[b]furan (LY320135,
C. C. Felder, K. E. Joyce, E. M. Briley, M. Glass, K. P. Mackie, K.
J. Fahey, G. J. Cullinan, D. C. Hunden, D. W. Johnson, M. O.
Chaney, G. A. Koppel, M. Brownstein, J. Pharmacol. Exp. Ther. 284
(1) (1998) 291-7) as disclosed in WO9602248 or US5596106,
3-alkyl-(5,5-diphenyl)-imidazolidine-diones (M. Kanyonyo, S. J.
Govaerts, E. Hermans, J. H. Poupaert, D. M. Lambert, Bioorg. Med.
Chem. Lett. 9 (15) (1999) 2233-2236.) as well as
3-alkyl-5-arylimidazolidine-diones (F. Ooms, J. Wouters, O. Oscaro.
T. Happaerts, G. Bouchard, P.-A. Carrupt, B. Testa, D. M. Lambert,
J. Med. Chem. 45 (9) (2002) 1748-1756) are known to antagonize the
CB.sub.1 receptor respectively to act as an inverse agonist on the
hCB.sub.1 receptor. WO0015609 (FR2783246-A1), WO0164634
(FR2805817-A1), WO0228346, WO0164632 (FR2805818-A1), WO0164633
(FR2805810-A1) discloses substituted 1-bis(aryl)methyl-azetidine
derivatives as antagonists of CB.sub.1. In WO0170700
4,5-dihydro-1H-pyrazole derivatives are described as CB.sub.1
antagonists. In several patents bridged and
non-bridged1,5-diphenyl-3-pyrazolecarboxamide derivatives are
disclosed as CB.sub.1 antagonists/inverse agonists (WO0132663,
WO0046209, WO9719063, EP658546, EP656354, US5624941, EP576357, U.S.
Pat. NO. 3,940,418).
SUMMARY OF THE INVENTION
[0007] It is an object of this invention to provide selective,
directly acting CB1 receptor antagonists respectively inverse
agonists. Such antagonists/inverse antagonists are useful in
medical therapy, particularly in the treatment and/or prevention of
diseases which are associated with the modulation of CB1 receptors.
The present invention is useful in the treatment of obesity.
[0008] The present invention provides a compound of formula (I)
##STR2## wherein [0009] R.sup.1 is phenyl, or phenyl mono-, di- or
tri-substituted, independently, by a group selected from the group
consisting of halogen, lower alkoxy, lower alkyl, halogenated-lower
alkoxy and di-lower alkylamino; [0010] R.sup.2 is phenyl, or phenyl
mono-, di- or tri-substituted, independently, by a group selected
from the group consisting of halogen, halogenated-lower alkyl,
nitro and cyano; [0011] R.sup.3 is hydrogen, lower alkyl, benzyl,
lower alkoxy, halogen, cyano, nitro, amino, --NHSO.sub.2--R.sup.3a
or --NHCO--R.sup.3b; [0012] R.sup.3a is lower alkyl, di-lower
alkylamino, benzyl, phenyl or phenyl mono-, di- or tri-substituted,
independently, by lower alkyl; [0013] R.sup.3b is benzyl, phenyl or
phenyl mono-, di- or tri-substituted, independently, by lower
alkyl; [0014] or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Unless otherwise indicated, the following definitions are
set forth to illustrate and define the meaning and scope of the
various terms used to describe the invention herein. In this
specification the term "lower" is used to mean a group consisting
of one to eight, preferably of one to six, and more preferably of
one to four carbon atom(s).
[0016] The term "halogen" refers to fluorine, chlorine, bromine and
iodine, preferably to chlorine and fluorine.
[0017] The term "alkyl", alone or in combination with other groups,
refers to a branched or straight-chain monovalent saturated
aliphatic hydrocarbon radical of one to twenty carbon atoms,
preferably one to sixteen carbon atoms, more preferably one to ten
carbon atoms.
[0018] The term "lower alkyl", alone or in combination with other
groups, refers to a branched or straight-chain monovalent alkyl
radical of one to eight carbon atoms, preferably one to four carbon
atoms. This term is further exemplified by radicals such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl,
n-pentyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl and the like.
[0019] The term "alkoxy" refers to the group R'--O--, wherein R' is
alkyl. The term "lower alkoxy" refers to the group R'--O--, wherein
R' is lower alkyl. Examples of lower alkoxy groups are e.g.
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and
hexyloxy, with methoxy being especially preferred.
[0020] The term "di-lower alkylamino" refers to the group
--N(R')R'', wherein R' and R'' are each independently a lower alkyl
residue.
[0021] The term "halogenated lower alkyl" refers to a lower alkyl
group wherein at least one of the hydrogens of the lower alkyl
group is replaced by halogen, such as fluorine and chlorine,
preferably fluorine. Among the preferred halogenated lower alkyl
groups are trifluoromethyl, difluoromethyl, fluoromethyl and
chloromethyl, with trifluoromethyl being especially preferred.
[0022] The term "halogenated lower alkoxy" refers to a lower alkoxy
group wherein at least one of the hydrogens of the lower alkoxy
group is replaced by halogen, such as fluorine or chlorine,
preferably by fluorine. Among the preferred halogenated lower
alkoxy groups are fluorinated lower alkoxy groups such as
trifluoromethoxy, difluoromethoxy and fluoromethoxy, with
trifluoromethoxy being especially preferred.
[0023] The term "pharmaceutically acceptable salts" embraces salts
of the compounds of formula (I) with inorganic or organic acids
such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric
acid, phosphoric acid, citric acid, formic acid, maleic acid,
acetic acid, fumaric acid, succinic acid, tartaric acid,
methanesulphonic acid, salicylic acid, p-toluenesulphonic acid and
the like, which are non toxic to living organisms. Preferred salts
with acids are formates, maleates, citrates, hydrochlorides,
hydrobromides and methanesulfonic acid salts, with hydrochlorides
being especially preferred.
[0024] In one embodiment, the present invention relates to a
compound of formula (I), wherein R.sup.1 is phenyl, or phenyl
mono-, di- or tri-substituted, independently, by halogen such as
chloro, by lower alkoxy such as methoxy, ethoxy, and isopropoxy, by
lower alkyl such as methyl, halogenated-lower alkoxy such as
trifluoromethoxy, or by di-lower alkylamino such as dimethylamino
and diethylamino. In a preferable embodiment, R.sup.1 is phenyl
mono- or di-substituted, independently, by halogen such as chloro,
or lower alkoxy such as methoxy. Most preferable R.sup.1 are
4-chloro-phenyl, 4-chloro-3-methoxy-phenyl and
3,4-dimethoxy-phenyl.
[0025] In another embodiment, the present invention relates to a
compound of formula (I), wherein R.sup.2 is phenyl, or phenyl
mono-, di- or tri-substituted, independently, by halogen such as
chloro and fluoro, by halogenated-lower alkyl such as
trifluoromethyl, by nitro or by cyano. In a preferable embodiment,
R.sup.2 is phenyl mono-substituted with halogen. Most preferable
R.sup.2 is ortho-chloro-phenyl or 2,4-dichlorophenyl.
[0026] In another embodiment, the present invention relates to a
compound of formula (I), wherein R.sup.3 is hydrogen, lower alkyl,
benzyl, lower alkoxy, halogen, cyano, nitro, amino,
--NHSO.sub.2--R.sup.3a or --NHCO--R.sup.3b. In a preferable
embodiment, R.sup.3 is hydrogen, nitro, amino,
--NHSO.sub.2--R.sup.3a or --NHCO--R.sup.3b. Most preferable R.sup.3
is hydrogen.
[0027] Substituent R.sup.3 can be present at positions 4, 5, 6 or 7
of the benzthiazole ring. Preferably, substituent R.sup.3 is at the
6-position of the benzthiazole ring.
[0028] In another embodiment, the present invention relates to a
compound of formula (I) for use as therapeutically active substance
as defined above, wherein R.sup.3a is lower alkyl such as methyl or
n-butyl, di-lower alkylamino such as dimethylamino, benzyl, phenyl
or phenyl mono-, di- or tri-substituted, independently, by lower
alkyl such as methyl.
[0029] In another embodiment, the present invention relates to a
compound of formula (I) for use as therapeutically active substance
as defined above, wherein R.sup.3b is lower alkyl, di-lower
alkylamino, benzyl, phenyl or phenyl mono-, di- or tri-substituted,
independently, by lower alkyl such as methyl. In a preferable
embodiment, R.sup.3b is benzyl or phenyl mono-substituted by lower
alkyl, such as methyl.
[0030] In another embodiment, the present invention relates to
compounds of formula (Ia) ##STR3## or pharmaceutically acceptable
salts thereof, wherein [0031] R.sup.1 is phenyl, or phenyl mono-,
di- or tri-substituted, independently, by halogen, lower alkoxy,
lower alkyl, halogenated-lower alkoxy or di-lower alkylamino;
[0032] R.sup.2 is phenyl, or phenyl mono-, di- or tri-substituted,
independently, by halogen, halogenated-lower alkyl, nitro or cyano;
[0033] R.sup.3 is hydrogen, lower alkyl, benzyl, lower alkoxy,
cyano, nitro, amino, --NHSO.sub.2--R.sup.3a or --NHCO--R.sup.3b;
[0034] R.sup.3a is lower alkyl, di-lower alkylamino, benzyl, phenyl
or phenyl mono-, di- or tri-substituted, independently, by lower
alkyl; [0035] R.sup.3b is benzyl, phenyl or phenyl mono-, di- or
tri-substituted, independently, by lower alkyl; [0036] provided
that when R.sup.3 is hydrogen, R.sup.1 is selected from the group
consisting of 2-halogen-phenyl, 4-lower alkoxy-phenyl, 3-lower
alkyl-phenyl, 4-halogen-2-lower alkyl-phenyl, 3-halogen-2-lower
alkyl-phenyl, 4-halogen-3-lower alkyl-phenyl, 2-halogen-4-lower
alkyl-phenyl, 3-halogen-4-lower alkyl-phenyl, 2-lower
alkoxy-4-lower alkyl-phenyl, 3-lower alkoxy-4-lower alkyl-phenyl,
4-lower alkoxy-2-lower alkyl-phenyl, 4-lower alkoxy-3-lower
alkyl-phenyl, 3-lower alkoxy-2-lower alkyl-phenyl, phenyl
substituted by halogenated-lower alkoxy or di-lower alkylamino,
phenyl substituted by two or three groups independently selected
from halogen, lower alkoxy, halogenated alkoxy and di-lower
alkylamino, phenyl substituted by a lower alkyl group and one or
two groups selected from halogenated alkoxy and di-lower
alkylamino, and phenyl substituted by two lower alkyl groups and a
group selected from halogen, lower alkoxy, halogenated alkoxy and
di-lower alkylamino.
[0037] In a preferred embodiment, the invention relates to
compounds of formula (Ia) or pharmaceutically acceptable salts
thereof, wherein [0038] R.sup.1 is phenyl, or phenyl mono-, di- or
tri-substituted, independently, by halogen, lower alkoxy, lower
alkyl, halogenated-lower alkoxy or di-lower alkylamino; [0039]
R.sup.2 is phenyl, or phenyl mono-, di- or tri-substituted,
independently, by halogen, halogenated-lower alkyl, nitro or cyano;
[0040] R.sup.3 is lower alkyl, benzyl, lower alkoxy, cyano, nitro,
amino, --NHSO.sub.2--R.sup.3a or --NHCO--R.sup.3b; [0041] R.sup.3a
is lower alkyl, di-lower alkylamino, benzyl, phenyl or phenyl
mono-, di- or tri-substituted, independently, by lower alkyl; and
[0042] R.sup.3b is benzyl, phenyl or phenyl mono-, di- or
tri-substituted, independently, by lower alkyl.
[0043] The following compounds of formula (Ia) are examples
thereof: [0044]
2-chloro-N-(4-ethoxy-phenyl)-4-fluoro-N-(6-nitro-benzothiazol-2-y-
l)-benzamide, [0045]
2-chloro-N-(4-ethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzamide,
[0046]
2,4-dichloro-N-(4-ethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-be-
nzamide, [0047]
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benza-
mide, [0048]
N-(6-amino-benzothiazol-2-yl)-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benza-
mide, [0049]
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-methanesulfonylamino-benzothia-
zol-2-yl)-benzamide, [0050]
N-[6-(butane-1-sulfonylamino)-benzothiazol-2-yl]-2,4-dichloro-N-(3,4-dime-
thoxy-phenyl)-benzamide, [0051]
N-[6-(dimethylamino-1-sulfonylamino)-benzothiazol-2-yl]-2,4-dichloro-N-(3-
,4-dimethoxy-phenyl)-benzamide, [0052]
N-(6-benzenesulfonylamino-benzothiazol-2-yl)-2,4-dichloro-N-(3,4-dimethox-
y-phenyl)-benzamide, [0053]
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-phenylmethanesulfonylamino-ben-
zothiazol-2-yl)-benzamide, [0054]
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-[6-(toluene-2-sulfonylamino)-benz-
othiazol-2-yl]-benzamide, [0055]
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-phenylacetylamino-benzothiazol-
-2-yl)-benzamide, [0056]
2-chloro-N-(3,4-dimethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzamide-
, [0057]
N-(6-amino-benzothiazol-2-yl)-2-chloro-N-(3,4-dimethoxy-phenyl)-
-benzamide, [0058]
2-chloro-N-(3,4-dimethoxy-phenyl)-N-(6-methanesulfonylamino-benzothiazol--
2-yl)-benzamide [0059]
N-[6-(butane-1-sulfonylamino)-benzothiazol-2-yl]-2-chloro-N-
(3,4-dimethoxy-phenyl)-benzamide [0060]
N-[6-(dimethylamino-1-sulfonylamino)-benzothiazol-2-yl]-2-chloro-N-(3,4-d-
imethoxy-phenyl)-benzamide [0061]
N-(6-benzenesulfonylamino-benzothiazol-2-yl)-2-chloro-N-(3,4-dimethoxy-ph-
enyl)-benzamide [0062]
2-chloro-N-(3,4-dimethoxy-phenyl)-N-(6-phenylmethanesulfonylamino-benzoth-
iazol-2-yl)-benzamide [0063]
2-chloro-N-(3,4-dimethoxy-phenyl)-N-[6-(toluene-2-sulfonylamino)-benzothi-
azol-2-yl]-benzamide, [0064]
N-(6-(2-methylbenzoylamino)-benzothiazol-2-yl)-2-chloro-N-(3,4-dimethoxy--
phenyl)-benzamide, [0065] or pharmaceutically acceptable salts
thereof.
[0066] In a further preferred embodiment, the invention relates to
compounds of formula (Ia) as defined above, wherein R.sup.3 is
hydrogen and R.sup.1 is selected from 3,5-dichlorophenyl,
3,4-dichlorophenyl, 4-chloro-2-methyl-phenyl and
4-chloro-3-methoxyphenyl.
[0067] In another preferred embodiment, the invention relates to
compounds of formula (Ia) as defined above, wherein R.sup.3 is
hydrogen and R.sup.1 is selected from 4-lower alkoxy-phenyl,
3,4-di-lower alkoxy-phenyl, 3,4,5-tri-lower alkoxy-phenyl and
3-lower alkoxy-4-lower alkyl-phenyl.
[0068] In another preferred embodiment, the invention relates to
compounds of formula (Ia) as defined above, wherein R.sup.3 is
hydrogen and R.sup.1 is phenyl substituted by halogenated-lower
alkoxy or di-lower alkylamino.
[0069] Preferred compounds of formula (Ia) wherein R.sup.3 is
hydrogen are the following: [0070]
N-benzothiazol-2-yl-2-chloro-N-(3,5-dichloro-phenyl)-benzamide,
[0071]
N-benzothiazol-2-yl-2-chloro-N-(3,4-dichloro-phenyl)-benzamide,
[0072]
N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dichloro-phenyl)-benzamide,
[0073] N-benzothiazol-2-yl-2-chloro-N-(4-methoxy-phenyl)-benzamide,
[0074]
N-benzothiazol-2-yl-2,4-dichloro-N-(4-methoxy-phenyl)-benzamide,
[0075]
N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-2-methyl-phenyl)-ben-
zamide, [0076]
N-benzothiazol-2-yl-2-fluoro-N-(4-methoxy-phenyl)-4-trifluoromethyl-benza-
mide, [0077]
N-benzothiazol-2-yl-N-(4-methoxy-phenyl)-2,4-bis-trifluoromethyl-benzamid-
e, [0078]
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-methoxy-phenyl)-benzamide,
[0079]
N-benzothiazol-2-yl-2-chloro-N-(4-methoxy-phenyl)-4-nitro-benzami-
de, [0080]
N-benzothiazol-2-yl-4-cyano-N-(4-methoxy-phenyl)-benzamide, [0081]
N-benzothiazol-2-yl-N-(4-ethoxy-phenyl)-2-fluoro-4-trifluoromethy-
l-benzamide, [0082]
N-benzothiazol-2-yl-2-chloro-N-(4-ethoxy-phenyl)-4-fluoro-benzamide,
[0083]
N-benzothiazol-2-yl-2-chloro-N-(4-ethoxy-phenyl)-4-nitro-benzamid-
e, [0084]
N-benzothiazol-2-yl-4-cyano-N-(4-ethoxy-phenyl)-benzamide, [0085]
N-benzothiazol-2-yl-2-chloro-N-(4-ethoxy-phenyl)-benzamide,
[0086]
N-benzothiazol-2-yl-2,4-dichloro-N-(4-ethoxy-phenyl)-benzamide,
[0087]
N-benzothiazol-2-yl-N-(3,4-dimethoxy-phenyl)-2-fluoro-4-trifluoro-
methyl-benzamide, [0088]
N-benzothiazol-2-yl-N-(3,4-dimethoxy-phenyl)-2,4-bis-trifluoromethyl-benz-
amide, [0089]
N-benzothiazol-2-yl-2-chloro-N-(3,4-dimethoxy-phenyl)-4-fluoro-benzamide,
[0090]
N-benzothiazol-2-yl-2-chloro-N-(3,4-dimethoxy-phenyl)-4-nitro-be-
nzamide, [0091]
N-benzothiazol-2-yl-2-chloro-N-(3,4-dimethoxy-phenyl)-benzamide,
[0092]
N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benzamide,
[0093]
N-benzothiazol-2-yl-2-chloro-N-(4-dimethylamino-phenyl)-4-fluoro--
benzamide, [0094]
N-benzothiazol-2-yl-2-chloro-N-(4-dimethylamino-phenyl)-benzamide,
[0095]
N-benzothiazol-2-yl-2-chloro-N-(4-diethylamino-phenyl)-4-nitro-be-
nzamide, [0096]
N-benzothiazol-2-yl-2,4-dichloro-N-(4-diethylamino-phenyl)-benzamide,
[0097]
N-benzothiazol-2-yl-2-chloro-N-(3-methoxy-4-methyl-phenyl)-benzam-
ide, [0098]
N-benzothiazol-2-yl-2-chloro-N-(3,4-diethoxy-phenyl)-benzamide,
[0099]
N-benzothiazol-2-yl-2-chloro-N-(3,4,5-trimethoxy-phenyl)-benzamide,
[0100]
N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-diethoxy-phenyl)-benzamid-
e, [0101]
N-benzothiazol-2-yl-2,4-dichloro-N-(3,4,5-trimethoxy-phenyl)-benzamide,
[0102]
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(3-methoxy-4-methyl-pheny-
l)-benzamide, [0103]
N-benzothiazol-2-yl-2-chloro-N-(3,4-diethoxy-phenyl)-4-fluoro-benzamide,
[0104]
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-isopropoxy-phenyl)-ben-
zamide, [0105]
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(3,4,5-trimethoxy-phenyl)-benzami-
de, [0106]
N-benzothiazol-2-yl-2-chloro-N-(4-trifluoromethoxy-phenyl)-benzamide,
[0107]
N-benzothiazol-2-yl-2,4-dichloro-N-(4-trifluoromethoxy-phenyl)-be-
nzamide, [0108]
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-trifluoromethoxy-phenyl)-benza-
mide, [0109]
N-benzothiazol-2-yl-2-chloro-N-(4-chloro-3-methoxy-phenyl)-benzamide,
[0110] N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-3-methoxy
-phenyl)-benzamide, [0111]
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-chloro-3-methoxy-phenyl)-benza-
mide, [0112] and pharmaceutically acceptable salts thereof.
[0113] Preferred compounds of general formula (I) are the compounds
selected from the group consisting of: [0114]
N-benzothiazol-2-yl-2-chloro-N-(4-chloro-phenyl)-benzamide, [0115]
N-benzothiazol-2-yl-2-chloro-N-(3,5-dichloro-phenyl)-benzamide,
[0116]
N-benzothiazol-2-yl-2-chloro-N-(3,4-dichloro-phenyl)-benzamide,
[0117]
N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dichloro-phenyl)-benzamide,
[0118] N-benzothiazol-2-yl-2-chloro-N-(4-methoxy-phenyl)-benzamide,
[0119]
N-benzothiazol-2-yl-2,4-dichloro-N-(4-methoxy-phenyl)-benzamide,
[0120]
N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-2-methyl-phenyl)-ben-
zamide, [0121]
N-benzothiazol-2-yl-2-fluoro-N-(4-methoxy-phenyl)-4-trifluoromethyl-benza-
mide, [0122]
N-benzothiazol-2-yl-N-(4-methoxy-phenyl)-2,4-bis-trifluoromethyl-benzamid-
e, [0123]
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-methoxy-phenyl)-benzamide,
[0124]
N-benzothiazol-2-yl-2-chloro-N-(4-methoxy-phenyl)-4-nitro-benzami-
de, [0125]
N-benzothiazol-2-yl-4-cyano-N-(4-methoxy-phenyl)-benzamide, [0126]
N-benzothiazol-2-yl-N-(4-ethoxy-phenyl)-2-fluoro-4-trifluoromethy-
l-benzamide, [0127]
N-benzothiazol-2-yl-2-chloro-N-(4-ethoxy-phenyl)-4-fluoro-benzamide,
[0128]
N-benzothiazol-2-yl-2-chloro-N-(4-ethoxy-phenyl)-4-nitro-benzamid-
e, [0129]
N-benzothiazol-2-yl-4-cyano-N-(4-ethoxy-phenyl)-benzamide, [0130]
N-benzothiazol-2-yl-2-chloro-N-(4-ethoxy-phenyl)-benzamide, [0131]
N-benzothiazol-2-yl-2,4-dichloro-N-(4-ethoxy-phenyl)-benzamide,
[0132]
N-benzothiazol-2-yl-N-(3,4-dimethoxy-phenyl)-2-fluoro-4-trifluoro-
methyl-benzamide, [0133]
N-benzothiazol-2-yl-N-(3,4-dimethoxy-phenyl)-2,4-bis-trifluoromethyl-benz-
amide, [0134]
N-benzothiazol-2-yl-2-chloro-N-(3,4-dimethoxy-phenyl)-4-fluoro-benzamide,
[0135]
N-benzothiazol-2-yl-2-chloro-N-(3,4-dimethoxy-phenyl)-4-nitro-be-
nzamide, [0136]
N-benzothiazol-2-yl-2-chloro-N-(3,4-dimethoxy-phenyl)-benzamide,
[0137]
N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benzamide,
[0138]
N-benzothiazol-2-yl-2-chloro-N-(4-dimethylamino-phenyl)-4-fluoro--
benzamide, [0139]
N-benzothiazol-2-yl-2-chloro-N-(4-dimethylamino-phenyl)-benzamide,
[0140]
N-benzothiazol-2-yl-2-chloro-N-(4-diethylamino-phenyl)-4-nitro-be-
nzamide, [0141]
N-benzothiazol-2-yl-2,4-dichloro-N-(4-diethylamino-phenyl)-benzamide,
[0142]
2-chloro-N-(4-ethoxy-phenyl)-4-fluoro-N-(6-nitro-benzothiazol-2-y-
l)-benzamide, [0143]
2-chloro-N-(4-ethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzamide,
[0144]
2,4-dichloro-N-(4-ethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-be-
nzamide, [0145]
N-benzothiazol-2-yl-2-chloro-N-(3-methoxy-phenyl)-benzamide, [0146]
N-benzothiazol-2-yl-2,4-dichloro-N-(3-methoxy-phenyl)-benzamide,
[0147]
N-benzothiazol-2-yl-2-chloro-N-(3-methoxy-4-methyl-phenyl)-benzamide,
[0148]
N-benzothiazol-2-yl-2-chloro-N-(3,4-diethoxy-phenyl)-benzamide,
[0149]
N-benzothiazol-2-yl-2-chloro-N-(3,4,5-trimethoxy-phenyl)-benzamid-
e, [0150]
N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-diethoxy-phenyl)-benzamide,
[0151] N-benzothiazol-2-yl-2,4-dichloro-N-(
3,4,5-trimethoxy-phenyl)-benzamide, [0152]
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(
3-methoxy-4-methyl-phenyl)-benzamide, [0153]
N-benzothiazol-2-yl-2-chloro-N-(3,4-diethoxy-phenyl)-4-fluoro-benzamide,
[0154]
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-isopropoxy-phenyl)-ben-
zamide, [0155]
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(3,4,5-trimethoxy-phenyl)-benzami-
de, [0156]
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benza-
mide, [0157]
N-(6-amino-benzothiazol-2-yl)-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benza-
mide, [0158]
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-methanesulfonylamino-benzothia-
zol-2-yl)-benzamide, [0159]
N-[6-(butane-1-sulfonylamino)-benzothiazol-2-yl]-2,4-dichloro-N-(3,4-dime-
thoxy-phenyl)-benzamide, [0160]
N-[6-(dimethylamino-1-sulfonylamino)-benzothiazol-2-yl]-2,4-dichloro-N-(3-
,4-dimethoxy-phenyl)-benzamide, [0161]
N-(6-benzenesulfonylamino-benzothiazol-2-yl)-2,4-dichloro-N-(3,4-dimethox-
y-phenyl)-benzamide, [0162]
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-phenylmethanesulfonylamino-ben-
zothiazol-2-yl)-benzamide, [0163]
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-[6-(toluene-2-sulfonylamino)-benz-
othiazol-2-yl]-benzamide, [0164]
2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-phenylacetylamino-benzothiazol-
-2-yl)-benzamide, [0165]
2-chloro-N-(3,4-dimethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzamide-
, [0166]
N-(6-amino-benzothiazol-2-yl)-2-chloro-N-(3,4-dimethoxy-phenyl)-
-benzamide, [0167]
2-chloro-N-(3,4-dimethoxy-phenyl)-N-(6-methanesulfonylamino-benzothiazol--
2-yl)-benzamide, [0168]
N-[6-(butane-1-sulfonylamino)-benzothiazol-2-yl]-2-chloro-N-(3,4-dimethox-
y-phenyl)-benzamide, [0169]
N-[6-(dimethylamino-1-sulfonylamino)-benzothiazol-2-yl]-2-chloro-N-(3,4-d-
imethoxy-phenyl)-benzamide, [0170]
N-(6-benzenesulfonylamino-benzothiazol-2-yl)-2-chloro-N-(3,4-dimethoxy-ph-
enyl)-benzamide, [0171]
2-chloro-N-(3,4-dimethoxy-phenyl)-N-(6-phenylmethanesulfonylamino-benzoth-
iazol-2-yl)-benzamide, [0172]
2-chloro-N-(3,4-dimethoxy-phenyl)-N-[6-(toluene-2-sulfonylamino)-benzothi-
azol-2-yl]-benzamide, [0173]
N-(6-(2-methylbenzoylamino)-benzothiazol-2-yl)-2-chloro-N-(3,4-dimethoxy--
phenyl)-benzamide, [0174]
N-benzothiazol-2-yl-2-chloro-N-(4-trifluoromethoxy-phenyl)-benzamide,
[0175]
N-benzothiazol-2-yl-2,4-dichloro-N-(4-trifluoromethoxy-phenyl)-be-
nzamide, [0176]
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-trifluoromethoxy-phenyl)-benza-
mide, [0177]
N-benzothiazol-2-yl-2-chloro-N-(4-chloro-3-methoxy-phenyl)-benzamide,
[0178] N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-3-methoxy
-phenyl)-benzamide, [0179]
N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-chloro-3-methoxy-phenyl)-benza-
mide, [0180] and pharmaceutically acceptable salts thereof.
[0181] Most preferred compounds of general formula (I) are those
selected from the group consisting of: [0182]
N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dichloro-phenyl)-benzamide,
[0183]
N-benzothiazol-2-yl-2-chloro-N-(3,4-dimethoxy-phenyl)-4-fluoro-be-
nzamide, [0184]
N-benzothiazol-2-yl-2-chloro-N-(3,4-dimethoxy-phenyl)-4-nitro-benzamide,
[0185]
N-benzothiazol-2-yl-2-chloro-N-(3,4-dimethoxy-phenyl)-benzamide,
[0186]
N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benzami-
de, [0187]
2,4-dichloro-N-(4-ethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzamide,
[0188] N-benzothiazol-2-yl-2-chloro-N-(
3-methoxy-phenyl)-benzamide, [0189]
N-benzothiazol-2-yl-2,4-dichloro-N-(3-methoxy-phenyl)-benzamide,
[0190]
N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-diethoxy-phenyl)-benzamid-
e, [0191]
N-[6-(butane-1-sulfonylamino)-benzothiazol-2-yl]-2,4-dichloro-N-(3,4-dime-
thoxy-phenyl)-benzamide, [0192]
N-benzothiazol-2-yl-2-chloro-N-(4-chloro-3-methoxy-phenyl)-benzamide,
[0193] N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-3-methoxy
-phenyl)-benzamide, [0194] and pharmaceutically acceptable salts
thereof.
[0195] The compounds of formula (I) may be prepared using the
general methods described below:
[0196] The preparation of compounds of formula (I) or formula (Ia)
of the present invention (compounds of formulae IB, IC and ID,
respectively, in Scheme 1 below) may be carried out in sequential
or convergent synthetic routes. Syntheses of the compounds of the
present invention are illustrated in the following Scheme 1. The
skills required for carrying out the reaction and purification of
the resulting products are known to those in the art. The
substituents and indices used in the following description of the
processes have the significance given above unless indicated to the
contrary. ##STR4##
[0197] Compounds of formula IB (compounds of formula I wherein
R.sup.3 is hydrogen, lower alkyl, benzyl, alkoxy, halogen, nitro or
cyano) can be prepared according to Scheme 1 as follows:
[0198] (a) N-aryl-1,3-benzothiazole-2-amine derivatives IV are
either commercially available or can be prepared from commercially
available precursors by methods known in the art, preferably from a
suitable 1,3-benzothiazole II, which are either commercially
available or synthetically accessible via general procedures
described for example in EP 0 043 013 (X=suitable leaving group
which does not cause adverse side reaction during the preparation
procedure; commonly Cl or halogen, and the like), and an aniline
III (commercially available) by mixing the starting materials with
or without a solvent in the presence or absence of an acid. There
is no particular restriction on the nature of the solvent to be
employed, provided that it has no adverse effect on the reaction or
the reagents involved and that it can dissolve the reagents, at
least to some extent. Examples for suitable solvents include:
ethanol, methanol, dioxane, and the like. There is no particular
restriction on the nature of the acid used in this stage, and any
acid commonly used in this type of reaction may equally be employed
here. Examples of such acids include: HCl, HOAc, and the like in a
solvent or without a solvent present. The reaction can take place
over a wide range of temperatures, and the precise reaction
temperature is not critical to the invention. We find it convenient
to carry out the reaction with heating from ambient temperature to
reflux. The time required for the reaction may also vary widely,
depending on many factors, notably the reaction temperature and the
nature of the reagents. However, a period of from 0.5 h to several
days will usually suffice to yield the respective
N-aryl-1,3-benzothiazole-2-amine derivatives IV. This described
conversion can be effected by methods described in literature (see
for example WO97/49704 or Sawhney, S. N.; Akora, S. K.; Singh, J.
V.; Bansal, O. P.; Singh, S. P., Indian J. Chem. 1978, 16,
605-609).
[0199] (b) The conversion of the respective
N-aryl-1,3-benzothiazole-2-amine derivatives IV to access the
corresponding 1,3-benzothiazol-2-yl-N-aryl-benzamide derivatives IB
can be carried out from suitable starting materials according to
methods known in the art. For example, the conversion of the
aniline-moiety of compounds of formula IV can be effected by
reaction of IV with suitable acid chlorides V in the presence or
absence of a solvent and in the presence or the absence of a base
to obtain the respective amides IB. There is no particular
restriction on the nature of the solvent to be employed, provided
that it has no adverse effect on the reaction or the reagents
involved and that it can dissolve the reagents, at least to some
extent. Examples for suitable solvents include: dichloromethane,
THF, dioxane, and the like. There is no particular restriction on
the nature of the base used in this stage, and any base commonly
used in this type of reaction may equally be employed here.
Examples of such bases include triethylamine,
diisopropylethylamine, potassium tert-butoxide (KOtBu), and the
like. The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. We find it convenient to carry out the reaction
with heating from ambient temperature to reflux. The time required
for the reaction may also vary widely, depending on many factors,
notably the reaction temperature and the nature of the reagents.
However, a period of from 0.5 h to several days will usually
suffice to yield the desired 1,3-benzothiazol-2-yl-N-aryl-benzamide
derivatives IA. This type of conversion can be effected by methods
described in literature (see, for example, Comprehensive Organic
Transformations: A Guide to Functional Group Preparations, 2nd
Edition, Richard C. Larock. John Wiley & Sons, New York, N.Y.
1999). The resulting compounds of formula IB (compounds of formula
I wherein R.sup.3 is hydrogen, lower alkyl, benzyl, alkoxy,
halogen, nitro or cyano) are compounds of the present invention and
may be the desired product; alternatively they may be subjected to
consecutive reactions.
[0200] Compounds of formula IC (compounds of formula I wherein
R.sup.3 is amino) can be prepared according to Scheme 1 as
follows:
[0201] (a) Compounds of formula IB wherein R.sup.3 is nitro can be
converted to their respective amine-derivatives IC by reduction
methods which are widely described in literature and known to those
skilled in the art. For example, the reduction of the
nitro-functionality of compounds of formula IB (R.sup.3=nitro;
preferably in position 6) can be effected by reaction of IB
(R.sup.3=nitro; preferably in position 6) with a reducing agent in
the presence or absence of a solvent and in the presence or absence
of an acid. There is no particular restriction on the nature of the
reducing agent used in this stage, and any reducing agent commonly
used in this type of reaction may equally be employed here.
Examples of such reducing agents include tinchloride, hydrogen, and
the like. There is no particular restriction on the nature of the
acid used in this stage, and any acid commonly used in this type of
reaction may equally be employed here. Examples of such acids
include HCl, HOAc, and the like in a solvent or without a solvent
present. There is no particular restriction on the nature of the
solvent to be employed, provided that it has no adverse effect on
the reaction or the reagents involved and that it can dissolve the
reagents, at least to some extent. Examples for suitable solvents
include dimethylformamide (DMF), tetrahydrofuran (THF), dioxane,
and the like. The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. We find it convenient to carry out the reaction
with heating from ambient temperature to reflux. The time required
for the reaction may also vary widely, depending on many factors,
notably the reaction temperature and the nature of the reagents.
However, a period of from 0.5 h to several days will usually
suffice to yield the desired products ID. The resulting compounds
of formula ID are compounds of the present invention and may be the
desired product; alternatively they may be subjected to consecutive
reactions.
[0202] Compounds of formula ID (compounds of formula I wherein
R.sup.3 is --NHSO.sub.2--R.sup.3a or --NHCO--R.sup.3b) can be
prepared according to Scheme 1 as follows:
[0203] Compounds of formula ID can be prepared from suitable
starting materials according to methods known in the art. The
conversion of the amino-moiety in IC to access sulfonamides or
amides ID (R.sup.3.dbd.--NHSO.sub.2--R.sup.3a or --NHCO--R.sup.3b;
preferably in position 6) can be effected by methods described in
literature. For example the conversion of the amine derivatives IC
or their respective salts to access compounds of formula ID is
effected by reaction of IC with suitable acid chlorides VI or
sulfonyl chlorides VII (compounds known or compounds prepared by
known methods) respectively in the presence or absence of a solvent
and in the presence or the absence of a base. There is no
particular restriction on the nature of the solvent to be employed,
provided that it has no adverse effect on the reaction or the
reagents involved and that it can dissolve the reagents, at least
to some extent. Examples for suitable solvents include
dichloromethane (DCM), dioxane, tetrahydrofuran (THF), and the
like. There is no particular restriction on the nature of the base
used in this stage, and any base commonly used in this type of
reaction may equally be employed here. Examples of such bases
include triethylamine, diisopropylethylamine, and the like. The
reaction can take place over a wide range of temperatures, and the
precise reaction temperature is not critical to the invention. We
find it convenient to carry out the reaction with heating from
ambient temperature to reflux. The time required for the reaction
may also vary widely, depending on many factors, notably the
reaction temperature and the nature of the reagents. However, a
period of from 0.5 h to several days will usually suffice to yield
amide or sulfonamide derivatives ID
(R.sup.3.dbd.--NHSO.sub.2--R.sup.3a or --NHCO--R.sup.3b; preferably
in position 6). For reaction conditions described in literature
effecting such reactions see for example Comprehensive Organic
Transformations: A Guide to Functional Group Preparations, 2nd
Edition, Richard C. Larock. John Wiley & Sons, New York, N.Y.
1999.
[0204] It will be appreciated, that the compounds of general
formula (I) in this invention may be derivatised at functional
groups to provide derivatives which are capable of conversion back
to the parent compound in vivo.
[0205] As described above, the compounds of formula (I) or
pharmaceutically acceptable salts thereof can be used as
therapeutically active substances, especially as therapeutically
active substances for the treatment and/or prophylaxis of diseases
which are associated with the modulation of the CB1 receptors. In
one embodiment, the invention therefore relates to compounds as
defined above for use as therapeutic active substances,
particularly as therapeutic active substances for the treatment
and/or prophylaxis of diseases which are associated with the
modulation of CB1 receptors.
[0206] The invention also relates to pharmaceutical compositions
comprising a compound of formula (I): ##STR5## wherein [0207]
R.sup.1 is phenyl, or phenyl mono-, di- or tri-substituted,
independently, by halogen, lower alkoxy, lower alkyl,
halogenated-lower alkoxy or di-lower alkylamino; [0208] R.sup.2 is
phenyl, or phenyl mono-, di- or tri-substituted, independently, by
halogen, halogenated-lower alkyl, nitro or cyano; [0209] R.sup.3 is
hydrogen, lower alkyl, benzyl, lower alkoxy, halogen, cyano, nitro,
amino, --NHSO.sub.2--R.sup.3a or --NHCO--R.sup.3b; [0210] R.sup.3a
is lower alkyl, di-lower alkylamino, benzyl, phenyl or phenyl
mono-, di- or tri-substituted, independently, by lower alkyl;
[0211] R.sup.3b is benzyl, phenyl or phenyl mono-, di- or
tri-substituted, independently, by lower alkyl; [0212] or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier and/or adjuvant.
[0213] In another embodiment, the invention relates to a method for
the treatment and/or prophylaxis of diseases which are associated
with the modulation of CB1 receptors, which method comprises
administering a compound of formula (I): ##STR6## wherein [0214]
R.sup.1 is phenyl, or phenyl mono-, di- or tri-substituted,
independently, by halogen, lower alkoxy, lower alkyl,
halogenated-lower alkoxy or di-lower alkylamino; [0215] R.sup.2 is
phenyl, or phenyl mono-, di- or tri-substituted, independently, by
halogen, halogenated-lower alkyl, nitro or cyano; [0216] R.sup.3 is
hydrogen, lower alkyl, benzyl, lower alkoxy, halogen, cyano, nitro,
amino, --NHSO.sub.2--R.sup.3a or --NHCO--R.sup.3b; [0217] R.sup.3a
is lower alkyl, di-lower alkylamino, benzyl, phenyl or phenyl
mono-, di- or tri-substituted, independently, by lower alkyl;
[0218] R.sup.3b is benzyl, phenyl or phenyl mono-, di- or
tri-substituted, independently, by lower alkyl; [0219] or a
pharmaceutically acceptable salt thereof, to a human being or
animal.
[0220] The invention further relates to the use of compounds as
defined above for the treatment and/or prophylaxis of diseases
which are associated with the modulation of CB1 receptors.
[0221] In addition, the invention relates to the use of compounds
of formula (I), ##STR7## wherein [0222] R.sup.1 is phenyl, or
phenyl mono-, di- or tri-substituted, independently, by halogen,
lower alkoxy, lower alkyl, halogenated-lower alkoxy or di-lower
alkylamino; [0223] R.sup.2 is phenyl, or phenyl mono-, di- or
tri-substituted, independently, by halogen, halogenated-lower
alkyl, nitro or cyano; [0224] R.sup.3 is hydrogen, lower alkyl,
benzyl, lower alkoxy, halogen, cyano, nitro, amino,
--NHSO.sub.2--R.sup.3a or --NHCO--R.sup.3b; [0225] R.sup.3a is
lower alkyl, di-lower alkylamino, benzyl, phenyl or phenyl mono-,
di- or tri-substituted, independently, by lower alkyl; [0226]
R.sup.3b is benzyl, phenyl or phenyl mono-, di- or tri-substituted,
independently, by lower alkyl; [0227] or of a pharmaceutically
acceptable salt thereof, for the preparation of medicaments for the
treatment and/or prophylaxis of diseases which are associated with
the modulation of CB1 receptors. Such medicaments comprise a
compound as defined above.
[0228] In this context, the expression `diseases associated with
modulation of CB1 receptors` means diseases which can be treated
and/or prevented by modulation of CB1 receptors. Such diseases
encompass, but are not limited to, psychic disorders, especially
anxiety and anxiety disorders, psychosis, schizophrenia,
depression, substance abuse disorders including abuse of
psychotropes, for example for the abuse and/or dependence of
substances, including alcohol dependency and nicotine dependency,
neuropathies, migraine, stress, epilepsy, dyskinesias, Parkinson's
disease, amnesia, memory and cognitive disorders, senile dementia,
Alzheimer's disease, eating disorders, obesity, diabetes type II or
non insulin dependent diabetes (NIDD), gastrointestinal diseases,
vomiting, diarrhea, urinary disorders, cardiovascular disorders,
infertility disorders, inflammations, infections, cancer,
demyelinisation related disorders, neuroinflammation, in particular
in atherosclerosis, or the Guillain-Barre syndrome, viral
encephalitis, cerebral vascular incidents and cranial trauma.
[0229] In a preferable aspect, the expression `diseases associated
with modulation of CB1 receptors` relates to eating disorders,
obesity, diabetes type II or non insulin dependent diabetes (NIDD),
neuroinflammation, diarrhea, abuse and/or dependence of a
substances, including alcohol dependency and nicotine dependency.
In a more preferable aspect, the said term related to eating
disorders, obesity, diabetes type II or non insulin dependent
diabetes (NIDD), abuse and/or dependence of a substances, including
alcohol dependency and nicotine dependency, with obesity being
especially preferred.
[0230] It is a further preferred object to provide a method of
treatment or prevention of Type II diabetes (non-insulin dependent
diabetes mellitus (NIDDM)) in a human which comprises
administration of a therapeutically effective amount of a compound
according to formula (I) in combination or association with a
therapeutically effective amount of a lipase inhibitor,
particularly, wherein the lipase inhibitor is orlistat. Also an
object of the invention is the method as described above for the
simultaneous, separate or sequential administration of a compound
according to formula (I) and a lipase inhibitor, particularly
tetrahydrolipstatin.
[0231] It is a further preferred object to provide a method for the
treatment or prevention of obesity and obesity related disorders
which comprises administration of a therapeutically effective
amount of a compound according to formula (I) in combination or
association with a therapeutically effective amount of other drugs
for the treatment of obesity or eating disorders so that together
they give effective relief. Suitable other drugs include but are
not limited to anorectic agents, lipase inhibitors and selective
serotonin reuptake inhibitors (SSRI). Combinations or associations
of the above agents may be encompassing separate, sequential or
simultaneous administration.
[0232] Preferable lipase inhibitor is tetrahydrolipstatin.
[0233] Suitable anorectic agents of use in combination with a
compound of the present invention include, but are not limited to,
aminorex, amphechloral, amphetamine, benzphetamine,
chlorphentermine, clobenzorex, cloforex, clominorex, clortermine,
cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion,
diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine,
fenisorex, fenproporex, fludorex, fluminorex,
furfurylmethylamphetamine, levamfetamine, levophacetoperane,
mazindol, mefenorex, metamfepramone, methamphetamine,
norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,
phentermine, phenylpropanolamine, picilorex and sibutramine, and
pharmaceutically acceptable salts thereof.
[0234] Most preferable anorectic agents are sibutramine and
phentermine.
[0235] Suitable selective serotonin reuptake inhibitors of use in
combination with a compound of the present invention include:
fluoxetine, fluvoxamine, paroxetine and sertraline, and
pharmaceutically acceptable salts thereof.
[0236] The following tests were carried out in order to determine
the activity of the compounds of formula (I).
[0237] The affinity of the compounds of the invention for
cannabinoid CB1 receptors was determined using membrane
preparations of human embryonic kidney (HEK) cells in which the
human cannabis CB1 receptor is transiently transfected using the
Semliki Forest Virus system in conjunction with [3H]-CP-55,940 as
radioligand. After incubation of a freshly prepared cell membrane
preparation with the [3H]-ligand, with or without addition of
compounds of the invention, separation of bound and free ligand was
performed by filtration over glassfiber filters. Radioactivity on
the filter was measured by liquid scintillation counting.
[0238] The affinity of the compounds of the invention for
cannabinoid CB2 receptors was determined using membrane
preparations of human embryonic kidney (HEK) cells in which the
human cannabis CB2 receptor is transiently transfected using the
Semliki Forest virus system in conjunction with [3H]-CP-55,940 as
radioligand. After incubation of a freshly prepared cell membrane
preparation with the [3H]-ligand, with or without addition of
compounds of the invention, separation of bound of bound and free
ligand was performed by filtration over glassfiber filters.
Radioactivity on the filter was measured by liquid scintillation
counting.
[0239] The cannabinoid CB1 antagonistic activity of compounds of
the invention was determined by functional studies using CHO cells
in which human cannabinoid CB1 receptors are stably expressed (see
M. Rinaldi-Carmona et. al., J. Pharmacol. Exp. Ther. 278 (1996)
871). The stable expression of the human cannabinoid receptor in
cell systems was first described in Nature 1990, 346, 561-564 (CB1)
and Nature 1993, 365, 61-65 (CB2) respectively. Adenylyl cyclase
was stimulated using forskolin and measured by quantifying the
amount of accumulated cyclic AMP. Concomitant activation of CB1
receptors by CB1 receptor agonists (e.g. CP-55,940 or
(R)-WIN-55212-2) can attenuate the forskolin-induced accumulation
of cAMP in a concentration dependent manner. This CB1 receptor
mediated response can be antagonised by CB1 receptor antagonists
such as the compounds of the invention.
[0240] The compound of formula (I) show an excellent affinity for
the CB1 receptor, determined with the experimental conditions
described in Devane et. al., Mol. Pharmacol. 34 (1988) 605-613. The
compounds of the present invention or the pharmaceutically
acceptable salts or solvates are antagonists and selective for the
CB1 receptor with affinities below IC.sub.50=5 .mu.M, preferably
below IC.sub.50=2 .mu.M. They exhibit at least a 10 fold
selectivity against the CB2 receptor. TABLE-US-00001 Compound of
Example IC.sub.50 [.mu.M] 8 0.73 9 1.96 12 2.48 28 1.38 45 0.83 52
1.59 57 1.42
[0241] The compounds of formula (I) and/or their pharmaceutically
acceptable salts can be used as medicaments, e.g. in the form of
pharmaceutical preparations for enteral, parenteral or topcal
administration. They can be administered, for example, perorally,
e.g. in the form of tablets, coated tablets, dragees, hard and soft
gelatine capsules, solutions, emulsions or suspensions, rectally,
e.g. in the form of suppositories, parenterally, e.g. in the form
of injection solutions or infusion solutions, or topically, e.g. in
the form of ointments, creams or oils. Oral administration is
preferred.
[0242] The production of the pharmaceutical preparations can be
effected in a manner which will be familiar to any person skilled
in the art by bringing the described compounds of formula (I)
and/or their pharmaceutically acceptable salts, optionally in
combination with other therapeutically valuable substances, into a
galenical administration form together with suitable, non-toxic,
inert, therapeutically compatible solid or liquid carrier materials
and, if desired, usual pharmaceutical adjuvants.
[0243] Suitable carrier materials are not only inorganic carrier
materials, but also organic carrier materials. Thus, for example,
lactose, corn starch or derivatives thereof, talc, stearic acid or
its salts can be used as carrier materials for tablets, coated
tablets, dragees and hard gelatine capsules. Suitable carrier
materials for soft gelatine capsules are, for example, vegetable
oils, waxes, fats and semi-solid and liquid polyols (depending on
the nature of the active ingredient no carriers might, however, be
required in the case of soft gelatine capsules). Suitable carrier
materials for the production of solutions and syrups are, for
example, water, polyols, sucrose, invert sugar and the like.
Suitable carrier materials for injection solutions are, for
example, water, alcohols, polyols, glycerol and vegetable oils.
Suitable carrier materials for suppositories are, for example,
natural or hardened oils, waxes, fats and semi-liquid or liquid
polyols. Suitable carrier materials for topical preparations are
glycerides, semi-synthetic and synthetic glycerides, hydrogenated
oils, liquid waxes, liquid paraffins, liquid fatty alcohols,
sterols, polyethylene glycols and cellulose derivatives.
[0244] Usual stabilizers, preservatives, wetting and emulsifying
agents, consistency-improving agents, flavour-improving agents,
salts for varying the osmotic pressure, buffer substances,
solubilizers, colorants and masking agents and antioxidants come
into consideration as pharmaceutical adjuvants.
[0245] The dosage of the compounds of formula (I) can vary within
wide limits depending on the disease to be controlled, the age and
the individual condition of the patient and the mode of
administration, and will, of course, be fitted to the individual
requirements in each particular case. For adult patients a daily
dosage of about 1 to 1000 mg, especially about 1 to 100 mg, comes
into consideration. Depending on severity of the disease and the
precise pharmacokinetic profile the compound could be administered
with one or several daily dosage units, e.g. in 1 to 3 dosage
units.
[0246] The pharmaceutical preparations conveniently contain about
1-500 mg, preferably 1-100 mg, of a compound of formula (I).
[0247] The following examples serve to illustrate the present
invention in more detail. They are, however, not intended to limit
its scope in any manner.
EXAMPLES
[0248] MS=mass spectrometry; ISP=ion spray (positive ion),
corresponds to ESI (electrospray, positive ion); mp=melting point,
aq=aqueous, THF=tetrahydrofuran, DMSO=dimethylsulfoxide,
DMF=dimethylformamide, DCM=dichloromethane, KOtBu=potassium
tert-butoxide, NMR=nuclear magnetic resonance spectroscopy.
Example 1
Starting Materials
(a) Benzothiazol-2-yl-(4-chloro-phenyl)-amine
[0249] A mixture of 1.7 g (10 mmol) 2-chloro-1,3-benzothiazole and
2.6 g (10 mmol) 4-chloroaniline in 20 ml acetic acid was heated to
110.degree. C. for 3 h. The reaction mixtures was diluted with 200
ml water and the resulting mixture was extracted with 3.times.150
ml ethyl acetate. The combined organic phases were washed with
2.times.100 ml water, dried with MgSO.sub.4, filtered and
evaporated to dryness. The residue was recrystallysed from a
mixture of hexane/ethyl acetate to yield 1.4 g (54%) of the title
compound.
[0250] 1-H-NMR (300 MHz, CDCl.sub.3) .delta.=10.6 (s, br, 1H, NH),
7.82 (m, 3H, (Ar--H-3/H-5)/H-7), 7.62 (d, J=7.8 Hz, 1H, H-4), 7.42
(d, J=6.8 Hz, 2H, Ar--H-2/H-6), 7.35 (t, J=8.1 Hz, 1H), H-6), 7.18
(t, J=7.5 Hz, 1H, H-5). MS (m/e): 261.2 (MH.sup.+, 100%).
(b) Benzothiazol-2-yl-(3,5-dichloro-phenyl)-amine
[0251] The title compound was synthesised from
2-Chloro-benzothiazole (commercially available) and
3,5-Dichloroaniline (commercially available) according to the
procedure described for Example 1 a) above.
[0252] 1-H-NMR (300 MHz, CDCl.sub.3) .delta.=7.68 (d, J=7.9 Hz, 1H,
H-7), 7.63 (d, J=8.1 Hz, 1H, H-4), 7.37 (m, 3H, H-5,
(Ar--H-2/H-6)/H-6), 7.22 (t, J=7.9 Hz, 1H, H-5), 7.18 (d, J=1.7 Hz,
1H, Ar--H-4). MS (m/e): 295.2 (MH.sup.+, 100%).
(c) Benzothiazol-2-yl-(3,4-dichloro-phenyl)-amine
[0253] The title compound was synthesised from
2-Chloro-benzothiazole (commercially available) and
3,4-Dichloroaniline (commercially available) according to the
procedure described for Example 1 a) above.
[0254] 1-H-NMR (300 MHz, DMSO-d6) .delta.=10.81(s, br, 1H, NH),
8.24 (d, J=2.3 Hz, 1H, Ar--H-2), 7.86 (d, J=7.8 Hz, 1H, H-7), 7.63
(m, 3H, (Ar--H-5/H-6)/H-4), 7.36 (t, J=7.8 Hz, 1H, H-6), 7.21 (t,
J=7.7 Hz, 1H, H-5). MS (m/e): 295.2 (MH.sup.+, 100%).
(d) Benzothiazol-2-yl-(4-methoxy-phenyl)-amine
[0255] The title compound was synthesised from
2-Chloro-benzothiazole (commercially available) and
4-Methoxyaniline (commercially available) according to the
procedure described for Example 1 a) above.
[0256] 1-H-NMR (300 MHz, DMSO-d6) .delta.=11.75(s, br, 1H, NH),
7.76 (d, J=7.7 Hz, 1H, H-7), 7.68 (d, J=8.9 Hz, 2H,
(Ar--H-2/Ar--H-6)), 7.55 (d, J=7.9 Hz, 1H, H-4), 7.29 (t, J=7.7 Hz,
1H, H-6), 7.09 (t, J=7.9 Hz, 1H, H-5), 6.96 (d, J=8.9 Hz, 2H,
(Ar--H-3/Ar--H-5)), 3.75 (s, 3H, OCH.sub.3). MS (m/e): 257.1
(MH.sup.+, 100%).
(e) Benzothiazol-2-yl-(4-chloro-2-methyl-phenyl)-amine
[0257] The title compound was synthesised from
2-Chloro-benzothiazole (commercially available) and
4-Chloro-2-methylaniline (commercially available) according to the
procedure described for Example 1 a) above.
[0258] 1-H-NMR (300 MHz, DMSO-d6) .delta.=9.68(s, br, 1H, NH), 8.01
(d, J=8.5 Hz, 1H, H-7), 7.76 (d, J=7.2 Hz, 1H, Ar--H-5), 7.50 (d,
J=7.8 Hz, 1H, H-4), 7.31 (m, 3H, (Ar--H-2/Ar--H-6)/H-5), 7.15 (t,
J=8.5 Hz, 1H, H-6), 2.29 (s, 3H, CH.sub.3). MS (m/e): 275.2
(MH.sup.+, 100%).
(f) Benzothiazol-2-yl-(4-ethoxy-phenyl)-amine
[0259] The title compound was synthesised from
2-Chloro-benzothiazole (commercially available) and 4-Ethoxyaniline
(commercially available) according to the procedure described for
Example 1 a) above.
[0260] 1-H-NMR (300 MHz, DMSO-d6) .delta.=10.26 (s, br, 1H, NH),
7.76 (d, J=7.5 Hz, 1H, H-7), 7.68 (d, J=6.9 Hz, 2H,
(Ar--H-2/Ar--H-6)), 7.55 (d, J=7.9 Hz, 1H, H-4), 7.29 (t, J=7.5 Hz,
1H, H-6), 7.09 (t, J=7.9 Hz, 1H, H-5), 6.96 (d, J=6.9 Hz, 2H,
(Ar--H-3/Ar--H-5)), 4.01 (q, J=7.0 Hz, 2H, OCH.sub.2), 1.32 (t,
J=7.0 Hz, 3H, CH.sub.3). MS (m/e): 271.1 (MH.sup.+, 100%).
(g) Benzothiazol-2-yl-(3,4-dimethoxy-phenyl)-amine
[0261] The title compound was synthesised from
2-Chloro-benzothiazole (commercially available) and
3,4-Dimethoxyaniline (commercially available) according to the
procedure described for Example 1 a) above.
[0262] 1-H-NMR (300 MHz, DMSO-d6) .delta.=10.26(s, br, 1H, NH),
7.77 (d, J=7.1 Hz, 1H, H-7), 7.53 (d, J=7.6 Hz, 1H, H-4), 7.40 (s,
1H, Ar--H-2), 7.30 (m, 2H, (Ar--H-6)/H-5), 7.15 (t, J=7.1 Hz, 1H,
H-6), 6.97 (d, J=8.7 Hz, 1H, Ar--H-5), 3.78 (s, 3H, OCH.sub.3),
3.74 (s, 3H, OCH.sub.3). MS (m/e): 287.0 (MH.sup.+, 100%).
(h) N-Benzothiazol-2-yl-N',N'-dimethyl-benzene-1,4-diamine
[0263] The title compound was synthesised from
2-Chloro-benzothiazole (commercially available) and
N,N-Dimethyl-p-phenylenediamine (commercially available) according
to the procedure described for Example 1 a) above.
[0264] 1-H-NMR (300 MHz, DMSO-d6) .delta.=10.08 (s, br, 1H, NH),
7.71 (d, J=7.1 Hz, 1H, H-7), 7.50 (m, 3H, (Ar--H-2/Ar--H-6)/H4),
7.27 (t, J=7.1 Hz, 1H, H-6), 7.10 (t, J=7.8 Hz, 1H, H-5), 6.78 (d,
J=9.0 Hz, 2H, (Ar--H-3/Ar--H-5)), 2.86 (s, 6H, N(CH.sub.3).sub.2).
MS (m/e): 270.2 (MH.sup.+, 100%).
(i) N-Benzothiazol-2-yl-N',N'-diethyl-benzene-1,4-diamine
[0265] The title compound was synthesised from
2-Chloro-benzothiazole (commercially available) and
N,N-Diethyl-p-phenylenediamine (commercially available) according
to the procedure described for Example 1 a) above. MS (m/e): 298.2
(MH.sup.+, 100%).
(j) Benzothiazol-2-yl-(3-methoxy-phenyl)-amine
[0266] The title compound is either commercially available or can
be synthesised from 2-Chloro-benzothiazole (commercially available)
and 3-methoxyaniline (commercially available) according to the
procedure described for Example 1 a) above. MS (m/e): 257.0
(MH.sup.+, 100%).
(k) Benzothiazol-2-yl-(4-chloro-3-methoxy-phenyl)-amine
[0267] The title compound was synthesised from
2-chloro-benzothiazole (commercially available) and
4-chloro-3-methoxyaniline (commercially available) according to the
procedure described for Example 1 a) above. MS (m/z): 291.3
(MH.sup.+, 100%).
(l) Benzothiazol-2-yl-(4-trifluoromethoxy-phenyl)-amine
[0268] The title compound was synthesised from
2-chloro-benzothiazole (commercially available) and
4-trifluoromethoxyaniline (commercially available) according to the
procedure described for Example A. MS (m/z): 310.0 (MH.sup.+,
100%).
(m) (4-Ethoxy-phenyl)-(6-nitro-benzothiazol-2-yl)-amine
[0269] The title compound was synthesised from
2-Chloro-6-nitro-benzothiazole (commercially available) and
4-ethoxyaniline (commercially available) according to the procedure
described for Example 1 a) above.
[0270] 1-H-NMR (300 MHz, DMSO-d6) .delta.=10.8 (s, br, 1H, NH),
8.80 (d, J=2.4 Hz, 1H, H-7), 8.16 (dd, J1=8.9 Hz, J2=2.4 Hz, 1H,
H-5), 7.65 (m, 3H, (Ar--H-2/Ar--H-6)/H4) 6.97 (d, J=6.8 Hz, 2H,
(Ar--H-3/Ar--H-5)), 4.02 (q, J=6.9 Hz, 2H, OCH.sub.2), 1.28 (t,
J=6.9 Hz, 3H, CH.sub.3). MS (m/e): 316.2 (MH.sup.+, 100%).
(n) (3,4-Dimethoxy-phenyl)-(6-nitro-benzothiazol-2-yl)-amine
[0271] The title compound was synthesised from
2-Chloro-6-nitro-benzothiazole (commercially available) and
3,4-dimethoxyaniline (commercially available) according to the
procedure described for Example 1 a) above. MS (m/e): 332.2
(MH.sup.+, 100%).
Example 2
N-Benzothiazol-2-yl-2-chloro-N-(4-chloro-phenyl)-benzamide
[0272] ##STR8##
[0273] A mixture of 39.1 mg (0.15 mmol)
Benzothiazol-2-yl-(4-chloro-phenyl)-amine in 0.5 ml THF, 45.2 mg
(0.18 mmol) 2-chlorobenzoyl chloride in 0.18 ml THF and 0.17 ml of
a 1 M solution of KOtBu in THF was heated to 50.degree. C. for 16
h. After addition of 0.5 ml formic acid the mixtures are subjected
to preparative HPLC separation on reversed phase eluting with an
acetonitrile/water gradient. Evaporation of the product fractions
yielded 40.1 mg (67%) of the title compound. MS (m/e): 399.3
(MH.sup.+, 100%).
[0274] According to the procedure described for Example 2
N-Benzothiazol-2-yl-N-aryl-benzamide derivatives have been
synthesised from Benzothiazol-2-yl-aryl-amine derivatives and acid
chlorides. The results are shown in table 1 below and comprise
Example 3 to Example 34. TABLE-US-00002 TABLE 1 Ex- MW ample
(MH.sup.+, No. Structure Compound Name Starting Materials 100%) 3
##STR9## N-Benzothiazol-2-yl-2-chloro-N-(3,5-di-
chloro-phenyl)-benz- amide Benzothiazol-2-yl-(3,5-di-
chloro-phenyl)-amine and 2-Chloro-benzoyl chloride (commercially
available) 433.2 4 ##STR10##
N-Benzothiazol-2-yl-2-chloro-N-(3,4-di- chloro-phenyl)-benz- amide
Benzothiazol-2-yl-(3,4-di- chloro-phenyl)-amine and
2-Chloro-benzoyl chloride (commercially available) 433.0 5
##STR11## N-Benzothiazol-2-yl-2,4-di- chloro-N-(3,4-dichloro-
phenyl)-benzamide Benzothiazol-2-yl-(3,4-di- chloro-phenyl)-amine
and 2,4-Dichloro-benzoyl chloride (commercially available) 469.0 6
##STR12## N-benzothiazol-2-yl-2-chloro-N-(4-meth- oxy-phenyl)-benz-
amide Benzothiazol-2-yl-(4-meth- oxy-phenyl)-amine and
2-Chloro-benzoyl chloride (commercially available) 395.3 7
##STR13## N-Benzothiazol-2-yl-2,4-di- chloro-N-(4-methoxy-
phenyl)-benzamide Benzothiazol-2-yl-(4-meth- oxy-phenyl)-amine and
2,4-Dichloro-benzoyl chloride (commercially available) 429.4 8
##STR14## N-Benzothiazol-2-yl-2,4-di- chloro-N-(4-chloro-2-meth-
yl-phenyl)-benzamide Benzothia- zol-2-yl-(4-chloro-2-meth-
yl-phenyl)-amine and 2,4-Dichloro-benzoyl chloride (commercially
available) 447.1 9 ##STR15##
N-Benzothiazol-2-yl-2-fluoro-N-(4-meth- oxy-phenyl)-4-tri-
fluoromethyl-benzamide Benzothiazol-2-yl-(4-meth- oxy-phenyl)-amine
and 2-Fluoro-4-triflouoromethyl- benzoyl chloride (commercially
available) 447.2 10 ##STR16## N-Benzothiazol-2-yl-N-(4-meth-
oxy-phenyl)-2,4-bis- trifluoromethyl-benzamide
Benzothiazol-2-yl-(4-meth- oxy-phenyl)-amine and
2,4-Bis-trifluoromethyl- benzoyl chloride (commercially available)
497.1 11 ##STR17## N-Benzothiazol-2-yl-2-chloro-4-fluor-
o-N-(4-methoxy- phenyl)-benzamide Benzothiazol-2-yl-(4-meth-
oxy-phenyl)-amine and 2-Chloro-4-fluoro-benzoyl chloride
(commercially available) 413.1 12 ##STR18##
N-Benzothiazol-2-yl-2-chloro-N-(4-meth- oxy-phenyl)-4-nitro-
benzamide Benzothiazol-2-yl-(4-meth- oxy-phenyl)-amine and
2-Chloro-4-nitro-benzoyl chloride (commercially available) 440.2 13
##STR19## N-Benzothiazol-2-yl-4-cyano-N-(4-meth-
oxy-phenyl)-benzamide Benzothiazol-2-yl-(4-meth- oxy-phenyl)-amine
and 4-cyano-benzoyl chloride (commercially available) 386.2 14
##STR20## N-Benzothiazol-2-yl-N-(4-eth- oxy-phenyl)-2-fluoro-4-tri-
fluoromethyl-benzamide Benzothiazol-2-yl-(4-ethoxy- phenyl)-amine
and 2-Fluoro-4-tri- fluoromethyl-benzoyl chloride (commercially
available) 461.2 15 ##STR21##
N-Benzothiazol-2-yl-2-chloro-N-(4-eth- oxy-phenyl)-4-fluoro-
benzamide Benzothiazol-2-yl-(4-ethoxy- phenyl)-amine and 2-Chlor-
o-4-fluoro-benzoyl chloride (commercially available) 427.3 16
##STR22## N-Benzothiazol-2-yl-2-chloro-N-(4-eth-
oxy-phenyl)-4-nitro- benzamide Benzothiazol-2-yl-(4-ethoxy-
phenyl)-amine and 2-Chloro-4-ni- tro-benzoyl chloride (commercially
available) 454.3 17 ##STR23## N-Benzothiazol-2-yl-4-cyano-N-(4-eth-
oxy-phenyl)-benzamide Benzothiazol-2-yl-(4-ethoxy- phenyl)-amine
and 4-cyano- benzoyl chloride (commercially available) 400.3 18
##STR24## N-Benzothiazol-2-yl-2-chloro-N-(4-eth-
oxy-phenyl)-benzamide Benzothiazol-2-yl-(4-ethoxy- phenyl)-amine
and 2-Chloro- benzoyl chloride (commercially available) 409.2 19
##STR25## N-Benzothiazol-2-yl-2,4-di- chloro-N-(4-ethoxy-
phenyl)-benzamide Benzothiazol-2-yl-(4-ethoxy- phenyl)-amine and
2,4-Di- chloro-benzoyl chloride (commercially available) 443.1 20
##STR26## N-Benzothiazol-2-yl-N-(3,4-di-
methoxy-phenyl)-2-fluoro-4-tri- fluoromethyl-benzamide
Benzothiazol-2-yl-(3,4-di- methoxy-phenyl)-amine and
2-Fluoro-4-trifluoromethyl- benzoyl chloride (commercially
available) 477.2 21 ##STR27## N-Benzothiazol-2-yl-N-(3,4-di-
methoxy-phenyl)-2,4-bis- trifluoromethyl-benzamide
Benzothiazol-2-yl-(3,4-di- methoxy-phenyl)-amine and
2,4-Bis-trifluoromethyl- benzoyl chloride (commercially available)
527.2 22 ##STR28## N-Benzothiazol-2-yl-2-chloro-N-(3,4-di-
methoxy-phenyl)-4-fluoro- benzamide Benzothiazol-2-yl-(3,4-di-
methoxy-phenyl)-amine and 2-Chloro-4-fluoro-benzoyl chloride
(commercially available) 443.2 23 ##STR29##
N-Benzothiazol-2-yl-2-chloro-N-(3,4-di- methoxy-phenyl)-4-nitro-
benzamide Benzothiazol-2-yl-(3,4-di- methoxy-phenyl)-amine and
2-Chloro-4-nitro-benzoyl chloride (commercially available) 469.9 24
##STR30## N-Benzothiazol-2-yl-2-chloro-N-(3,4-di-
methoxy-phenyl)-benzamide Benzothiazol-2-yl-(3,4-di-
methoxy-phenyl)-amine and 2-Chloro-benzoyl chloride (commerically
available) 425.3 25 ##STR31## N-Benzothiazol-2-yl-2,4-di-
chloro-N-(3,4-dimethoxy- phenyl)-benzamide
Benzothiazol-2-yl-(3,4-di- methoxy-phenyl)-amine and
2,4-Dichloro-benzoyl chloride (commercially available) 461.2 26
##STR32## N-Benzothiazol-2-yl-2-chloro-N-(4-di-
methylamino-phenyl)-4-fluoro- benzamide
N-Benzothiazol-2-yl-N',N'-di- methyl-benzene-1,4-diamine and
2-Chloro-4-fluoro- benzoyl chloride (commercially available) 426.3
27 ##STR33## N-Benzothiazol-2-yl-2-chloro-N-(4-di-
methylamino-phenyl)-benzamide N-Benzothiazol-2-yl-N',N'-di-
methyl-benzene-1,4-diamine and 2-Chloro-benzoyl chloride
(commercially available) 408.2 28 ##STR34##
N-Benzothiazol-2-yl-2-chloro-N-(4-di- ethylamino-phenyl)-4-nitro-
benzamide N-Benzothiazol-2-yl-N',N'-di- ethyl-benzene-1,4-diamine
and 2-Chloro-4-nitro-benzoyl chloride (commercially available)
481.3 29 ##STR35## N-Benzothiazol-2-yl-2,4-di-
chloro-N-(4-diethylamino- phenyl)-benzamide
N-Benzothiazol-2-yl-N',N'-di- ethyl-benzene-1,4-diamine and
2,4-Dichloro-benzoyl chloride (commercially available) 470.1 30
##STR36## 2-Chloro-N-(4-ethoxy- phenyl)-4-fluoro-N-(6-nitro-
benzothiazol-2-yl)-benzamide (4-Ethoxy-phenyl)-(6-nitro-
benzothiazol-2-yl)-amine and 2-Chloro-4-fluoro-benzoyl chloride
(commercially available) 472.1 31 ##STR37## 2-Chloro-N-(4-ethoxy-
phenyl)-N-(6-nitro- benzothiazol-2-yl)-benzamide
(4-Ethoxy-phenyl)-(6-nitro- benzothiazol-2-yl)-amine and
2-Chloro-benzoyl chloride (commercially available) 454.3 32
##STR38## 2,4-Dichloro-N-(4-ethoxy- phenyl)-N-(6-nitro-
benzothiazol-2-yl)-benzamide (4-Ethoxy-phenyl)-(6-nitro-
benzothiazol-2-yl)-amine and 2,4-Dichloro-benzoyl chloride
(commercially available) 488.2 33 ##STR39##
N-Benzothiazol-2-yl-2-chloro-N-(3-meth- oxy-phenyl)-benzamide
Benzothiazol-2-yl-(3-meth- oxy-phenyl)-amine and 2-Chloro-benzoyl
chloride (commercially available) 395.2 34 ##STR40##
N-Benzothiazol-2-yl-2,4-di- chloro-N-(3-methoxy- phenyl)-benzamide
Benzothiazol-2-yl-(3-meth- oxy-phenyl)-amine and
2,4-Dichloro-benzoyl chloride (commercially available) 429.3
Example 35
N-Benzothiazol-2-yl-2-chloro-N-(3-methoxy-4-methyl-phenyl)-benzamide
[0275] ##STR41##
[0276] A mixture of 0.339 g (2 mmol) 2-Chlorobenzthiazole
(commercially available) and 0.275 g (2 mmol)
3-methoxy-4-methylaniline (commercially available) in 4 ml acetic
acid was heated to 115.degree. C. for 4 h. After cooling to room
temperature the mixture was subjected to preparative HPLC
separation on reversed phase eluting with an acetonitrile/water
gradient. The product fractions of
Benzothiazol-2-yl-(3-methoxy-4-methyl-phenyl)-amine were evaporated
to dryness and reacted according to the procedure described for
Example 2 with 2-chlorobenzoyl chloride to yield the title
compound. MS (m/e): 409.3 (MH.sup.+, 100%). According to the
procedure described for Example 35 further
N-Benzothiazol-2-yl-N-(aryl)-benzamide derivatives have been
synthesised by reaction of 2-chlorobenzthiazole with the respective
aniline (commercially available) and subsequently with the
respective acid chloride. The results are shown in table 2 below
and comprise Example 36 to Example 43. TABLE-US-00003 TABLE 2 MW
Example (MH.sup.+, No. Structure Compound Name Starting Materials
100%) 36 ##STR42## N-Benzothiazol-2-yl-2-chloro-N-(3,4-di-
ethoxy-phenyl)-benz- amide Benzothiazol-2-yl-(3,4-di-
ethoxy-phenyl)-amine and 2-Chloro-benzoyl chloride (commercially
available) 453.4 37 ##STR43##
N-Benzothiazol-2-yl-2-chloro-N-(3,4,5-tri- methoxy-phenyl)-benz-
amide Benzothiazol-2-yl-(3,4,5-tri- methoxy-phenyl)-amine and
2-Chloro-benzoyl chloride (commercially available) 455.4 38
##STR44## N-Benzothiazol-2-yl-2,4-di- chloro-N-(3,4-diethoxy-
phenyl)-benzamide Benzothiazol-2-yl-(3,4-di- ethoxy-phenyl)-amine
and 2,4-Dichloro-benzoyl chloride (commercially available) 487.2 39
##STR45## N-Benzothiazol-2-yl-2,4-di- chloro-N-(3,4,5-trimethoxy-
phenyl)-benzamide Benzothiazol-2-yl-(3,4,5-tri-
methoxy-phenyl)-amine and 2,4-Dichloro-benzoyl chloride
(commercially available) 489.2 40 ##STR46##
N-Benzothiazol-2-yl-2-chloro-4-fluor- o-N-(3-methoxy-4-meth-
yl-phenyl)-benzamide Benzothiazol-2-yl-(3-meth-
oxy-4-methyl-phenyl)-a- mine and 2-Chloro-4-fluoro- benzoyl
chloride (commercially available) 427.3 41 ##STR47##
N-Benzothiazol-2-yl-2-chloro-N-(3,4-di- ethoxy-phenyl)-4-fluoro-
benzamide Benzothiazol-2-yl-(3,4-di- ethoxy-phenyl)-amine and
2-Chloro-4-fluoro-benzoyl chloride (commercially available) 471.2
42 ##STR48## N-Benzothiazol-2-yl-2-chloro-4-fluor-
o-N-(4-isopropoxy- phenyl)-benzamide Benzothiazol-2-yl-(4-iso-
propoxy-phenyl)-amine and 2-Chloro-4-fluoro- benzoyl chloride
(commercially available) 441.3 43 ##STR49##
N-Benzothiazol-2-yl-2-chloro-4-fluor- o-N-(3,4,5-trimethoxy-
phenyl)-benzamide Benzothiazol-2-yl-(3,4,5-tri-
methoxy-phenyl)-amine and 2-Chloro-4-fluoro- benzoyl chloride
(commercially available) 473.1
Example 44
2,4-Dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzam-
ide
[0277] ##STR50##
[0278] The title compound was synthesised from
(3,4-Dimethoxy-phenyl)-(6-nitro-benzothiazol-2-yl)-amine and
2,4-dichlorobenzoyl chloride (commercially available) according to
the procedure described for Example 2. MS (m/e): 504.1 (MH.sup.+,
100%).
Example 45
N-(6-Amino-benzothiazol-2-yl)-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benzam-
ide
[0279] ##STR51##
[0280] A mixture of 2 g (3.97 mmol)
2,4-Dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benza-
mide in 25 ml DMF and 4 ml 1N HCl was treated with 2.24 g tin(II)
chloride dihydrate and heated to 80.degree. C. for 4 h. After
cooling to room temperature 50 ml saturated NaHCO.sub.3 was added
and the mixture was extracted with ethyl acetate. The organic phase
is treated with decalit and filtered. The organic phase of the
filtrate was washed with saturated NaCl, dried with MgSO.sub.4,
filtered and evaporated to dryness. The residue was purified on
reversed phase preparative HPLC eluting with an acetonitrile/water
gradient to obtain 536 mg (29%) of the title compound as yellowish
amorphous solid. MS (m/e): 474.0 (MH.sup.+, 100%).
Example 46
2,4-Dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-methanesulfonylamino-benzothiaz-
ol-2-yl)-benzamide
[0281] ##STR52##
[0282] A mixture of 33.2 mg (0.07 mmol)
N-(6-Amino-benzothiazol-2-yl)-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benza-
mide in 0.7 ml DCM, 18.2 mg (0.18 mmol) NEt.sub.3 and 10.3 mg
(0.091 mmol) methanesulfonyl chloride in 0.2 ml DCM was reacted for
16 h at room temperature. After evaporation of all volatiles the
residue was taken up in DMF/acetonitrile and subjected to
preparative HPLC separation on reversed phase eluting with an
acetonitrile/water gradient to yield 9.6 mg (25%) of the title
compound. MS (m/e): 552.1 (MH.sup.+, 100%).
[0283] According to the procedure described for the synthesis of
Example 46
2,4-Dichloro-N-(3,4-dimethoxy-phenyl)-6-amido-benzothiazol-2-yl)-benza-
mide or
2,4-Dichloro-N-(3,4-dimethoxy-phenyl)-6-sulfonamido-benzothiazol-2-
-yl)-benzamide derivatives have been synthesised from
N-(6-Amino-benzothiazol-2-yl)-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benza-
mide and sulfonylchlorides or acid chlorides (commercially
available). The results are shown in table 3 below and comprise
Example 47 to Example 52. TABLE-US-00004 TABLE 3 Ex- MW ample
(MH.sup.+, No. Structure Compound Name Starting Materials 100%) 47
##STR53## N-[6-(Butane-1-sul- fonylamino)-benzo-
thiazol-2-yl]-2,4-di- chloro-N-(3,4-di- methoxy-phenyl)-benz- amide
N-(6-Amino-benzo- thiazol-2-yl)-2,4-di- chloro-N-(3,4-di-
methoxy-phenyl)-benzamide and butyl sulfonyl chloride 594.2 48
##STR54## N-[6-(Dimethylamino-1-sul- fonylamino)-benzo-
thiazol-2-yl]-2,4-di- chloro-N-(3,4-di- methoxy-phenyl)-benzamide
N-(6-Amino-benzo- thiazol-2-yl)-2,4-di- chloro-N-(3,4-di-
methoxy-phenyl)-benz- amide and dimethylamino sulfonyl chloride
581.2 49 ##STR55## N-(6-Benzenesulfonylamino-
benzothiazol-2-yl)-2,4-di- chloro-N-(3,4-dimethoxy-
phenyl)-benzamide N-(6-Amino-benzo- thiazol-2-yl)-2,4-di-
chloro-N-(3,4-di- methoxy-phenyl)-benzamide and Benzenesulfonyl
chloride 614.1 50 ##STR56## 2,4-Dichloro-N-(3,4-di-
methoxy-phenyl)-N-(6-phenyl- methanesulfonylamino-
benzothiazol-2-yl)-benzamide N-(6-Amino-benzo-
thiazol-2-yl)-2,4-di- chloro-N-(3,4-di- methoxy-phenyl)-benz- amide
and Phenyl- methanesulfonyl chloride 628.1 51 ##STR57##
2,4-Dichloro-N-(3,4-di- methoxy-phenyl)-N-[6-(tol-
uene-2-sulfonylamino)-benzo- thiazol-2-yl]-benzamide
N-(6-Amino-benzo- thiazol-2-yl)-2,4-di- chloro-N-(3,4-di-
methoxy-phenyl)-benz- amide and 2-Methyl- benzenesulfonyl chloride
628.1 52 ##STR58## 2,4-Dichloro-N-(3,4-di-
methoxy-phenyl)-N-(6-phenyl- acetylamino-
benzothiazol-2-yl)-benzamide N-(6-Amino-benzo-
thiazol-2-yl)-2,4-di- chloro-N-(3,4-di- methoxy-phenyl)-benzamide
and Phenyl-acetyl chloride 592.2
Example 53
2-Chloro-N-(3,4-dimethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzamide
[0284] ##STR59##
[0285] The title compound was synthesised from
(3,4-Dimethoxy-phenyl)-(6-nitro-benzothiazol-2-yl)-amine and
2-chlorobenzoyl chloride (commercially available) according to the
procedure described for Example 2. MS (m/e): 469.7 (MH.sup.+,
100%).
Example 54
N-(6-Amino-benzothiazol-2-yl)-2-chloro-N-(3,4-dimethoxy-phenyl)-benzamide
[0286] ##STR60##
[0287] The title compound was synthesised from
2-Chloro-N-(3,4-dimethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzamide
according to the procedure described for Example 45. MS (m/e):
440.1 (MH.sup.+, 100%).
[0288] According to the procedure described for the synthesis of
Example 46
2-Chloro-N-(3,4-dimethoxy-phenyl)-6-amido-benzothiazol-2-yl)-benzamide
or
2-Chloro-N-(3,4-dimethoxy-phenyl)-6-sulfonamido-benzothiazol-2-yl)-ben-
zamide derivatives have been synthesised from
N-(6-Amino-benzothiazol-2-yl)-2-chloro-N-(3,4-dimethoxy-phenyl)-benzamide
and sulfonylchlorides or acid chlorides (commercially available).
The results are shown in table 4 below and comprise Example 55 to
Example 61. TABLE-US-00005 TABLE 4 Ex- MW ample (MH.sup.+, No.
Structure Compound Name Starting Materials 100%) 55 ##STR61##
2-Chlor- o-N-(3,4-dimethoxy- phenyl)-N-(6-meth- anesulfonylamino-
benzothia- zol-2-yl)-benzamide
N-(6-Amino-benzothiazol-2-yl)-2-chloro-N-(3,4-di-
methoxy-phenyl)-benz- amide and methane sulfonyl chloride 518.2 56
##STR62## N-[6-(Butane-1-sulfonyl- amino)-benzo-
thiazol-2-yl]-2-chlor- o-N-(3,4-di- methoxy- phenyl)-benzamide
N-(6-Amino-benzothiazol-2-yl)-2-chlor- o-N-(3,4-di-
methoxy-phenyl)-benz- amide and butane sulfonyl chloride 560.2 57
##STR63## N-[6-(Dimeth- ylamino-1-sul- fonylamino)-benzo-
thiazol-2-yl]-2-chlor- o-N-(3,4-di- methoxy- phenyl)-benzamide
N-(6-Amino-benzothiazol-2-yl)-2-chlor- o-N-(3,4-di-
methoxy-phenyl)-benz- amide and dimethylamino sulfonyl chloride
547.2 58 ##STR64## N-(6-Benzene- sulfonylamino- benzothia-
zol-2-yl)-2-chlor- o-N-(3,4-di- methoxy- phenyl)-benzamide
N-(6-Amino-benzothiazol-2-yl)-2-chlor- o-N-(3,4-di-
methoxy-phenyl)-benz- amide and Benzenesulfonyl chloride 580.2 59
##STR65## 2-Chloro-N-(3,4-di- methoxy- phenyl)-N-(6-phenyl-
methanesulfonylamino- benzothia- zol-2-yl)-benzamide
N-(6-Amino-benzothiazol-2-yl)-2-chlor- o-N-(3,4-di-
methoxy-phenyl)-benz- amide and Phenyl- methanesulfonyl chloride
594.2 60 ##STR66## 2-Chloro-N-(3,4-di- methoxy- phenyl)-N-[6-(tol-
uene-2-sul- fonylamino)-benzo- thiazol-2-yl]-benz- amide
N-(6-Amino-benzothiazol-2-yl)-2-chlor- o-N-(3,4-di-
methoxy-phenyl)-benz- amide and 2-Methyl- benzenesulfonyl chloride
594.2 61 ##STR67## N-(6-(2-meth- ylbenzoylamino)-benzo-
thiazol-2-yl)-2-chlor- o-N-(3,4-di- methoxy- phenyl)-benzamide
N-(6-Amino-benzothiazol-2-yl)-2-chlor- o-N-(3,4-di-
methoxy-phenyl)-benz- amide and 2-Methyl- benzoyl chloride
558.2
Example 62
N-Benzothiazol-2-yl-2-chloro-N-(4-trifluoromethoxy-phenyl)-benzamide
[0289] ##STR68##
[0290] To 0.2 g (0.6 mmol)
benzothiazol-2-yl-(4-trifluoromethoxy-phenyl)-amine dissolved in
tetrahydrofuran (5 mL), potassium-t-butylate (0.11 g, 1.0 mmol) and
2-chlorobenzoylchloride (0.13 g, 0.7 mmol) were added. The mixture
was stirred for 3h at room temperature. Water (10 mL) was added and
the mixture was extracted with ethylacetate (2.times.20 mL).
Organic phases were pooled, dried with MgSO.sub.4 and yielded after
evaporation and chromatography (silica gel; n-hexane/ethylacetate)
the title compound (0.26 g; 89%). MS (m/z): 449.4 (MH.sup.+,
100%).
[0291] According to the procedure described for the synthesis of
Example 61 benzothiazol-2-yl-benzamide derivatives have been
synthesised from benzothiazol-2-yl-phenylamine derivatives and acid
chlorides. The results are shown in table 5 below and comprise
Example 63 to Example 67. TABLE-US-00006 TABLE 5 MW Example
(MH.sup.+, No. Structure Compound Name Starting Materials 100%) 63
##STR69## N-Benzothiazol-2-yl-2,4-di- chloro-N-(4-tri-
fluoromethoxy-phenyl)-benz- amide benzothiazol-2-yl-(4-tri-
fluoromethoxy-phenyl)-amine and 2,4-di- chlorobenzoylchloride
(commercially available) 483.5 64 ##STR70##
N-Benzothiazol-2-yl-2-chloro-4-fluor- o-N-(4-tri-
fluoromethoxy-phenyl)-benzamide benzothiazol-2-yl-(4-tri-
fluoromethoxy-phenyl)-amine and 2-chloro-4-fluoro- benzoylchloride
(commercially available) 467.5 65 ##STR71##
N-Benzothiazol-2-yl-2-chloro-N-(4-chlor- o-3-methoxy-
phenyl)-benzamide benzothia- zol-2-yl-(4-chloro-3-meth-
oxy-phenyl)-amine and 2-chlorobenzoylchloride (commerically
available) 429.4 66 ##STR72## N-Benzothiazol-2-yl-2,4-di-
chloro-N-(4-chloro-3-meth- oxy-phenyl)-benzamide benzothia-
zol-2-yl-(4-chloro-3-meth- oxy-phenyl)-amine and
2,4-dichlorobenzoylchloride (commercially available) 463.7 67
##STR73## N-Benzothiazol-2-yl-2-chloro-4-fluor-
o-N-(4-chloro-3-meth- oxy-phenyl)-benzamide
benzothiazol-2-yl-(4-tri- fluoromethoxy-phenyl)-amine and
2-chloro-4-fluoro- benzoylchloride (commercially available)
447.4
Galenical Examples
Example A
[0292] Film coated tablets containing the following ingredients can
be manufactured in a conventional manner: TABLE-US-00007
Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg
200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous
60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch
glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Kernel
Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl cellulose
3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg
2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1.6
mg
[0293] The active ingredient is sieved and mixed with
microcrystalline cellulose and the mixture is granulated with a
solution of polyvinylpyrrolidone in water. The granulate is mixed
with sodium starch glycolate and magnesium stearate and compressed
to yield kernels of 120 or 350 mg respectively. The kernels are
lacquered with an aq. solution/suspension of the above mentioned
film coat.
Example B
[0294] Capsules containing the following ingredients can be
manufactured in a conventional manner: TABLE-US-00008 Ingredients
Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg Maize
starch 20.0 mg Talc 5.0 mg
[0295] The components are sieved and mixed and filled into capsules
of size 2.
Example C
[0296] Injection solutions can have the following composition:
TABLE-US-00009 Compound of formula (I) 3.0 mg Polyethylene glycol
400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for injection
solutions ad 1.0 ml
[0297] The active ingredient is dissolved in a mixture of
Polyethylene glycol 400 and water for injection (part). The pH is
adjusted to 5.0 by addition of acetic acid. The volume is adjusted
to 1.0 ml by addition of the residual amount of water. The solution
is filtered, filled into vials using an appropriate overage and
sterilized.
* * * * *