U.S. patent application number 10/414474 was filed with the patent office on 2003-12-04 for derivatives of quinoline as alpha-2 antagonists.
This patent application is currently assigned to Orion Corporation. Invention is credited to Engstrom, Mia, Haapalinna, Antti, Hoffren, Anna-Marja Katariina, Hoglund, Iisa, Sallinen, Jukka, Salo, Harri Elias, Savola, Juha-Matti, Tauber, Andrei Yurievitch, Wurster, Siegfried.
Application Number | 20030225078 10/414474 |
Document ID | / |
Family ID | 26881946 |
Filed Date | 2003-12-04 |
United States Patent
Application |
20030225078 |
Kind Code |
A1 |
Wurster, Siegfried ; et
al. |
December 4, 2003 |
Derivatives of quinoline as alpha-2 antagonists
Abstract
A compound of formula I, 1 wherein A, Ra, Rb, R.sub.1 to
R.sub.5, m and t are as defined as disclosed, or a pharmaceutically
acceptable salt or ester thereof, useful as an alpha-2 antagonist.
The compounds I can be used for the treatment of diseases or
conditions where alpha-2 antagonists are indicated to be
effective.
Inventors: |
Wurster, Siegfried;
(Piikkio, FI) ; Engstrom, Mia; (Turku, FI)
; Savola, Juha-Matti; (Turku, FI) ; Hoglund,
Iisa; (Turku, FI) ; Sallinen, Jukka; (Turku,
FI) ; Haapalinna, Antti; (Turku, FI) ; Tauber,
Andrei Yurievitch; (Helsinki, FI) ; Hoffren,
Anna-Marja Katariina; (Turku, FI) ; Salo, Harri
Elias; (Turku, FI) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
1300 I STREET, NW
WASHINGTON
DC
20005
US
|
Assignee: |
Orion Corporation
Oy Juvantia Pharma Ltd.
|
Family ID: |
26881946 |
Appl. No.: |
10/414474 |
Filed: |
April 16, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10414474 |
Apr 16, 2003 |
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09794277 |
Feb 28, 2001 |
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6593324 |
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60186290 |
Mar 1, 2000 |
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Current U.S.
Class: |
514/233.5 ;
514/253.06; 514/313 |
Current CPC
Class: |
A61K 31/496 20130101;
A61K 31/4706 20130101; A61K 31/5377 20130101; C07D 215/44 20130101;
C07D 219/12 20130101 |
Class at
Publication: |
514/233.5 ;
514/253.06; 514/313 |
International
Class: |
A61K 031/5377; A61K
031/496; A61K 031/4709 |
Claims
We claim:
1. A method for the treatment of a disease or condition where an
antagonist of alpha-2 adrenoceptors is indicated to be useful,
which comprises administering to a mammal in need of the treatment
an effective amount of at least one compound of formula I, 20or a
pharmaceutically acceptable salt or ester thereof, wherein, R.sub.1
is H or (C.sub.1-C.sub.6)alkyl; each R.sub.2 is independently OH,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy- , halo(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-S-- or hydroxy(C.sub.1-C.sub.6)alkyl; A is a
benzene ring or (C.sub.5-C.sub.7)cycloalkyl; when A is a benzene
ring each R.sub.3 is independently OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, halo-(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-CO--, mono- or
di(C.sub.1-C.sub.6)-alkylcarbamoyl, (C.sub.1-C.sub.6)alkyl-S--,
hydroxy(C.sub.1-C.sub.6)alkyl or NH.sub.2--CO--; when A is
(C.sub.5-C.sub.7)cycloalkyl each R.sub.3 is independently OH,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, mono- or
di(C.sub.1-C.sub.6)alkylamino or hydroxy(C.sub.1-C.sub.6)alkyl;
R.sub.4 and R.sub.5 form, together with the N-atom to which they
are attached, 21wherein X is O or .dbd.NR.sub.6; R.sub.6 is H, OH,
NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
CN--(C.sub.1-C.sub.6)al- kyl,
(C.sub.1-C.sub.6)alkoxy-CO--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-CO--, NH.sub.2--CO--, mono- or
di(C.sub.1-C.sub.6)alkylcarbamoyl, hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, phenyl, naphthyl or benzyl, wherein
the said phenyl, naphthyl or benzyl is optionally substituted with
one to three substituent(s) each independently being OH, halogen,
NO.sub.2, NH.sub.2, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, mono- or di(C.sub.1-C.sub.6)alkylamino or
halo-(C.sub.1-C.sub.6)alkyl; or R.sub.4 and R.sub.5 form, together
with the N-atom to which they are attached, 22wherein n=1 or 2;
R.sub.6 is as defined above; and r=0 to 3; or R.sub.4 and R.sub.5
form, together with the N-atom to which they are attached,
1-imidazolyl, 1-imidazolinyl or 1-triazolyl, each of which can
optionally be substituted with one to three substituent(s) R.sub.7
each independently being (C.sub.1-C.sub.6)alkyl or NH.sub.2; or one
of R.sub.4 and R.sub.5 is --SO.sub.2R.sub.8 and the other of
R.sub.4 and R.sub.5 is H or (C.sub.1-C.sub.6)alkyl; R.sub.8 is
(C.sub.1-C.sub.6)alkyl, phenyl, naphthyl or benzyl, wherein the
said phenyl, naphthyl or benzyl is optionally substituted with one
to three substituent(s) R.sub.9 each independently being OH,
halogen, NO.sub.2, NH.sub.2, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy or mono- or di(C.sub.1-C.sub.6)alkylamino;
Ra and Rb are independently H, OH, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-S-- or CN; or Ra and Rb form, together with
the carbon ring atoms to which they are attached, a condensed
benzene ring optionally substituted with one to three
substituent(s) R'.sub.3 each independently being OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy- , halo-(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-CO--, mono- or
di(C.sub.1-C.sub.6)-alkylcarbamoyl or (C.sub.1-C.sub.6)alkyl-S--,
hydroxy(C.sub.1-C.sub.6)alkyl or NH.sub.2--CO--; or Ra and Rb form,
together with the carbon ring atoms to which they are attached, a
condensed five to seven membered carbocyclic ring optionally
substituted with one to four substituent(s) R.sub.10 each
independently being OH, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, mono- or di(C.sub.1-C.sub.6)alkylamino or
hydroxy(C.sub.1-C.sub.6)alkyl; or Ra and Rb form, together with the
carbon ring atoms to which they are attached, a condensed
bicyclo[2.2.1]-heptane ring optionally substituted with one to four
substituent(s) each independently being OH, halogen,
(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy; or Ra and Rb
form, together with the carbon ring atoms to which they are
attached, a condensed five or six membered heterocyclic ring with
one ring heteroatom .dbd.NR.sub.11, which heterocyclic ring is
optionally substituted with one to three substituent(s) R.sub.10 as
defined above; R.sub.11 is H or (C.sub.1-C.sub.6)alkyl, or R.sub.11
is phenyl optionally substituted with one to three substituents
R.sub.12 each independently being OH, halogen, NO.sub.2, NH.sub.2,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy or mono- or
di(C.sub.1-C.sub.6)alkylamino; m is 0 to 3; and t is 0 to 3.
2. The method of claim 1, which comprises administering at least
one compound of formula IA 23or a pharmaceutically acceptable salt
or ester thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.10, m and t are as defined in claim 1; i is 1 to 3;
and j is 0 to 4.
3. The method of claim 1, which comprises administering at least
one compound of formula IB 24or a pharmaceutically acceptable salt
or ester thereof, wherein A, R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, m and t are as defined in claim 1; and Ra and Rb are
independently H, OH, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-S-- or CN; or Ra and Rb form, together with
the carbon ring atoms to which they are attached, a condensed five
to seven membered carbocyclic ring optionally substituted with one
to three substituent(s) R.sub.10; each independently being OH,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, mono- or
di(C.sub.1-C.sub.6)alkylamino or hydroxy(C.sub.1-C.sub.6)alkyl.
4. The method of claim 1, which comprises administering at least
one compound of formula IC 25or a pharmaceutically acceptable salt
or ester thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.10, R.sub.11, m and t are as defined in claim 1; i
is 1 or 2; and j is 0 to 3.
5. The method of claim 1, which comprises administering at least
one compound of formula ID 26or a pharmaceutically acceptable salt
or ester thereof, wherein R.sub.1, R.sub.2, R.sub.3, R'.sub.3,
R.sub.4, R.sub.5, m and t are as defined in claim 1; and p is 0 to
3.
6. The method according to claim 5, wherein m is 1 and R.sub.3 is
(C.sub.1-C.sub.6)alkoxy.
7. The method according to claim 1, wherein R.sub.4 and R.sub.5
form, together with the N-atom to which they are attached,
27wherein X is as defined in claim 1.
8. The method according to claim 7, wherein X is .dbd.NR.sub.6.
9. The method according to claim 8, wherein R.sub.6 is
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkenyl,
(C.sub.3-C.sub.6)cycloa- lkyl or hydroxy(C.sub.1-C.sub.6)alkyl.
10. The method according to claim 9, wherein R.sub.6 is
(C.sub.1-C.sub.6)alkyl.
11. The method according to claim 1, wherein, when one of R.sub.4
and R.sub.5 is --SO.sub.2R.sub.8 and the other of R.sub.4 and
R.sub.5 is H or (C.sub.1-C.sub.6)alkyl; R.sub.8 is not
(C.sub.1-C.sub.6)alkyl.
12. The method according to claim 5, wherein, when one of R.sub.4
and R.sub.5 is --SO.sub.2R.sub.8 and the other of R.sub.4 and
R.sub.5 is H or (C.sub.1-C.sub.6)alkyl; R.sub.8 is not
(C.sub.1-C.sub.6)alkyl.
13. The method according to claim 1, which comprises treating a
disorder of the central nervous system, male sexual impotence,
orthostatic hypotension, non-insulin dependent diabetes, or
obesity.
14. The method according to claim 1, which comprises a treatment to
reverse alpha-2 agonistic effects.
15. The method according to claim 13, which comprises treating a
disorder of the central nervous system.
16. The method according to claim 15, wherein the disorder of the
central nervous system is depression, anxiety, post-traumatic
stress disorder, schizophrenia, Parkinson's disease, or another
movement disorder.
17. A compound of formula II, 28or a pharmaceutically acceptable
salt or ester thereof, wherein, R.sub.1 is H or
(C.sub.1-C.sub.6)alkyl; each R.sub.2 is independently OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-S-- or hydroxy(C.sub.1-C.sub.6)alkyl; A is a
benzene ring or (C.sub.5-C.sub.7)cycloalkyl; when A is a benzene
ring each R.sub.3 is independently OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, halo-(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-CO--, mono- or
di(C.sub.1-C.sub.6)-alkylcarbamoyl, (C.sub.1-C.sub.6)alkyl-S--,
hydroxy(C.sub.1-C.sub.6)alkyl or NH.sub.2--CO--; when A is
(C.sub.5-C.sub.7)cycloalkyl each R.sub.3 is independently OH,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, mono- or
di(C.sub.1-C.sub.6)alkylamino or hydroxy(C.sub.1-C.sub.6)alkyl;
R.sub.4 and R.sub.5 form, together with the N-atom to which they
are attached, 29wherein X is O or .dbd.NR.sub.6; R.sub.6 is H, OH,
NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
CN--(C.sub.1-C.sub.6)al- kyl,
(C.sub.1-C.sub.6)alkoxy-CO--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-CO--, NH.sub.2--C--, mono- or
di(C.sub.1-C.sub.6)alkylcarbamoyl, hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl or benzyl, wherein the said benzyl is
optionally substituted with one to three substituent(s) each
independently being OH, halogen, NO.sub.2, NH.sub.2,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, mono- or
di(C.sub.1-C.sub.6)alkylamino or halo-(C.sub.1-C.sub.6)alkyl; or
R.sub.4 and R.sub.5 form, together with the N-atom to which they
are attached, 30wherein n=1 or 2; R.sub.6 is as defined above; and
r=0 to 3; or R.sub.4 and R.sub.5 form, together with the N-atom to
which they are attached, 1-imidazolyl, 1-imidazolinyl or
1-triazolyl, each of which can optionally be substituted with one
to three substituent(s) R.sub.7 each independently being
(C.sub.1-C.sub.6)alkyl or NH.sub.2; Ra and Rb are independently H,
OH, halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or
di(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)alkyl-S-- or CN; or
Ra and Rb form, together with the carbon ring atoms to which they
are attached, a condensed benzene ring optionally substituted with
one to three substituent(s) R'.sub.3 each independently being OH,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy- , halo-(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-CO--, mono- or
di(C.sub.1-C.sub.6)-alkylcarbamoyl or (C.sub.1-C.sub.6)alkyl-S--,
hydroxy(C.sub.1-C.sub.6)alkyl or NH.sub.2--CO--; or Ra and Rb form,
together with the carbon ring atoms to which they are attached, a
condensed five to seven membered carbocyclic ring optionally
substituted with one to four substituent(s) R.sub.10 each
independently being OH, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, mono- or di(C.sub.1-C.sub.6)alkylamino or
hydroxy(C.sub.1-C.sub.6)alkyl; or Ra and Rb form, together with the
carbon ring atoms to which they are attached, a condensed
bicyclo[2.2.1]-heptane ring optionally substituted with one to four
substituent(s) each independently being OH, halogen,
(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy; or Ra and Rb
form, together with the carbon ring atoms to which they are
attached, a condensed five or six membered heterocyclic ring with
one ring heteroatom .dbd.NR.sub.11, which heterocyclic ring is
optionally substituted with one to three substituent(s) R.sub.10 as
defined above; R.sub.11 is H or (C.sub.1-C.sub.6)alkyl, or R.sub.11
is phenyl optionally substituted with one to three substituents
R.sub.12 each independently being OH, halogen, NO.sub.2, NH.sub.2,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy or mono- or
di(C.sub.1-C.sub.6)alkylamino; m is 0 to 3; and t is 0 to 3, with
the provisos, that a) when A is a benzene ring, m is 0 or 1, t is
0, R.sub.1 is H, R.sub.3 is Cl or NO.sub.2, and Ra and Rb form,
together with the carbon ring atoms to which they are attached, a
condensed benzene ring, and X is NR.sub.6, then R.sub.6 is not H,
--CH.sub.3, --CH.sub.2CH.sub.3, --COCH.sub.3, or --CO--NH.sub.2; b)
when A is a benzene ring, then Ra and Rb are not at the same time
H; c) when A is a benzene ring, m is 1, t is 0, R.sub.1 is H, and
Ra and Rb form, together with the carbon ring atoms to which they
are attached, a condensed benzene ring, which is optionally
substituted with Br, and X is O, then R.sub.3 is not NO.sub.2 or
--OCH.sub.3; d) when A is a benzene ring, m is 0, t is 0, R.sub.1
is H, and Ra and Rb form, together with the carbon ring atoms to
which they are attached, a condensed nonsubstituted benzene ring,
then X is not O; e) the compound is not
4-[4-[(7-Chloro-2-methyl-4--
quinolinyl)amino]phenyl]-1-diethylcarbamoylpiperazine,
4-[4-[(6-Chloro-2-methoxy-9-acridinyl)amino]phenyl]-1-diethylcarbamoylpip-
erazine,
6-amino-4-[[3-chloro-4-(1H-imidazol-1-yl)phenyl]amino]-7-metoxy-3-
-quinolinecarbonitrile or
4-[[3-chloro-4-(1H-imidazol-1-yl)phenyl]amino]-7-
-methoxy-6-nitro-3-quinolinecarbonitrile.
18. A compound according to claim 17, which is a compound of
formula IIA, 31or a pharmaceutically acceptable salt or ester
thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.10, m and t are as defined in claim 17; i is 1 to 3; and j is
0 to 4.
19. A compound according to claim 18, wherein i is 2, j is 0 or 1
and R.sub.10 is (C.sub.1-C.sub.3)alkyl, wherein the
(C.sub.1-C.sub.3)alkyl includes both straight and branched chain
radicals of up to 3 carbon atoms.
20. A compound according to claim 18, wherein m is 0 or 1 and
R.sub.3 is (C.sub.1-C.sub.3)alkyl or halogen, wherein the
(C.sub.1-C.sub.3)alkyl includes both straight and branched chain
radicals of up to 3 carbon atoms.
21. A compound according to claim 18, wherein the compound is
[4-(4-Methylpiperazin-1-yl)phenyl]-(1,2,3,4-tetrahydroacridin-9-yl)amine,
2-{4-[4-(1,2,3,4-Tetrahydroacridin-9-yl)aminophenyl]piperazin-1-yl}ethano-
l,
[4-(4-Methylpiperazin-1-yl)phenyl]-(2-methyl-1,2,3,4-tetrahydro-acridin-
-9-yl)amine,
(8-Fluoro-1,2,3,4-tetrahydroacridin-9-yl)-[4-(4-methylpiperaz-
in-1-yl)phenyl]amine,
[4-(4-Methylpiperazin-1-yl)phenyl]-(2,7-dimethyl-1,2-
,3,4-tetrahydroacridin-9-yl)amine,
[4-(4-Methylpiperazin-1-yl)phenyl]-(7,8-
,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amine or
[4-(4-Methylpiperazin-1-yl)phenyl]-(1,1,3,3-tetramethyl-1,2,3,4-tetrahydr-
oacridin-9-yl)amine.
22. A compound according to claim 17, which is a compound of
formula IIB, 32or a pharmaceutically acceptable salt or ester
thereof, wherein A, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, m
and t are as defined in claim 17; and Ra and Rb are independently
H, OH, halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkyny- l, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or
di(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)alkyl-- S-- or CN;
or Ra and Rb form, together with the carbon ring atoms to which
they are attached, a condensed five to seven membered carbocyclic
ring optionally substituted with one to three substituent(s)
R.sub.10; each independently being OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, mono- or
di(C.sub.1-C.sub.6)alkylamino or hydroxy(C.sub.1-C.sub.6)alkyl.
23. A compound according to claim 22, wherein A is a benzene
ring.
24. A compound according to claim 22, wherein m is 0 or 1.
25. A compound according to claim 22, wherein R.sub.3 is
(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy.
26. A compound according to claim 22, wherein Ra and Rb are
independently H or (C.sub.1-C.sub.3)alkyl, wherein the
(C.sub.1-C.sub.3)alkyl includes both straight and branched chain
radicals of up to 3 carbon atoms.
27. A compound according to claim 22, wherein A is a six membered
carbocyclic ring and Ra and Rb form, together with the carbon ring
atoms to which they are attached, a condensed five to seven
membered carbocyclic ring, wherein the carbocyclic ring can
optionally be substituted with one to three substituent(s) each
independently being OH, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy or hydroxy(C.sub.1-C.sub.6)alkyl.
28. A compound according to claim 22, wherein the compound is
(3-Ethyl-2,8-dimethylquinolin-4-yl)-[4-(4-methylpiperizin-1-yl)phenyl]ami-
ne,
(2-Methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine,
(3-Ethyl-2,6-dimethylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]ami-
ne,
(3-Ethyl-6-methoxy-2-methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)p-
henyl]amine,
(3-Ethyl-2-methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)ph-
enyl]amine,
4-[4-(4-Methylpiperazin-1-yl)phenylamino]quinoline-3-carbonitr-
ile,
3-Isopropyl-2-methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]-
amine,
(2,3-Dimethylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine-
,
[4-(4-Methylpiperazin-1-yl)phenyl]-(1,2,3,4,5,6,7,8-octahydroacridin-9-y-
l)amine or
(3-Ethyl-2-methylquinolin-4-yl)-methyl-[4-(4-methylpiperazin-1--
yl)phenyl]amine.
29. A compound according to claim 17, which is a compound of
formula IIC, 33or a pharmaceutically acceptable salt or ester
thereof, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.10, R.sub.11, m and t are as defined in claim 17; i is 1 or
2; and j is 0 to 3.
30. A compound according to claim 17, which is a compound of
formula IID, 34or a pharmaceutically acceptable salt or ester
thereof, wherein R.sub.1, R.sub.2, R.sub.3, R'.sub.3, R.sub.4,
R.sub.5, m and t are as defined in claim 17; and p is 0 to 3.
31. A compound according to claim 30, wherein m is 1 and R.sub.3 is
(C.sub.1-C.sub.6)alkoxy.
32. A compound of according to claim 30, wherein the compound is
2-{4-[4-(Acridin-9-yl)aminophenyl]piperazin-1-yl}-ethanol,
(4-Methoxyacridin-9-yl)-[4-(4-methylpiperazin-1-yl)-phenyl]amine,
Acridin-9-yl-[4-(piperidin-1-yl)phenyl]amine,
Acridin-9-yl-[4-(4-benzylpi- perazin-1-yl)phenyl]amine,
Acridin-9-yl-[4-(4-methylpiperidin-1-yl)phenyl]- amine,
Acridin-9-yl-[4-(3-hydroxymethylpiperidin-1-yl)-phenyl]amine,
Acridin-9-yl-[4-pyrrolidin-1-yl)phenyl]amine,
Acridin-9-yl-[4-(4-cyclopro- pylpiperazin-1-yl)phenyl]amine,
Acridin-9-yl-[4-(4-isopropylpiperazine-1-y- l)phenyl]amine,
(Acridin-9-yl)-methyl-[4-(4-methylpiperazin-1-yl)phenyl]am- ine or
Acridin-9-yl-[2,5-diethoxy-4-(morpholin-4-yl)phenyl]amine.
33. A compound according to claim 17, wherein R.sub.4 and R.sub.5
form, together with the N-atom to which they are attached,
35wherein R.sub.6 is (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkenyl, (C.sub.3-C.sub.6)cycloalkyl or
hydroxy(C.sub.1-C.sub.6)alkyl.
34. A compound according to claim 33, wherein R.sub.6 is
(C.sub.1-C.sub.6)alkyl.
35. A pharmaceutical composition comprising at least one compound
according to claim 17 and a pharmaceutically acceptable diluent,
carrier and/or excipient.
36. A method for the treatment of a disease or condition where an
antagonist of alpha-2 adrenoceptors is indicated to be useful,
which comprises administering to a mammal in need of the treatment
an effective amount of at least one compound according to claim
17.
37. The method according to claim 36, which comprises treating a
disorder of the central nervous system, male sexual impotence,
orthostatic hypotension, non-insulin dependent diabetes, or
obesity.
38. The method according to claim 36, which comprises a treatment
to reverse alpha-2 agonistic effects.
39. The method according to claim 37, which comprises treating a
disorder of the central nervous system.
40. The method according to claim 39, wherein the disorder of the
central nervous system is depression, anxiety, post-traumatic
stress disorder, schizophrenia, Parkinson's disease, or another
movement disorder.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35
U.S.C. .sctn. 119(e) to U.S. provisional application No.
60/186,290, filed on Mar. 1, 2000, the contents of which are
incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The present invention relates to therapeutically active
derivatives of quinoline, including the pharmaceutically acceptable
salts and esters thereof, and their use as alpha-2 antagonists.
BACKGROUND
[0003] Some compounds exhibiting alpha adrenergic activity are well
known in the art. Those compounds may be used for the treatment of
a wide variety of diseases and conditions of the peripheric system
and the central nervous system (CNS).
[0004] The alpha adrenergic receptors are divided into alpha-1 and
alpha-2 adrenoceptors, each of which are further divided into
subtypes. Accordingly, alpha-2 adrenoceptors in humans have been
subdivided into three pharmacological subtypes known as alpha-2A,
alpha-2B and alpha-2C adrenoceptors. A fourth subtype, alpha-2D, is
known in rat, bovine and porcine and it corresponds to alpha-2A in
man. These subtypes have a distinct distribution in human and
animal tissues. For instance, alpha-2C adrenoceptors are
concentrated in the CNS, and they appear to play a role in the
modulation of various CNS-mediated behavioural and physiological
responses.
[0005] Compounds that are non-specific to any of the
above-mentioned alpha-2 subtypes, and compounds that are specific
to certain alpha-2 subtypes, are already known. For example,
atipamezole is a non-specific alpha-2 antagonists. Atipamezole has
been described in, for example, EP-A-183 492 (cf. p.13, compound
XV) and A. Haapalinna et al., Naunyn-Schimiedeberg's Arch.
Pharmacol. Vol. 356, 1997, p.570-582. U.S. Pat. No. 5,902,807
describes compounds that are selective antagonists for the alpha-2C
subtype and may be used in the treatment of mental illnesses, e.g.
mental disturbances induced by stress. Such compounds include, for
example, MK-912 and BAM-1303. Furthermore, WO-A-99 28300 discloses
substituted imidazole derivatives having agonist-like activity for
alpha-2B or 2B/2C adrenoceptors. The disclosures of all documents
cited above in this paragraph are incorporated by reference
herein.
[0006] As to the derivatives of quinoline, Medicinskaja
parazitologija I parazitarnye bolezni, vol.5, 1991, 55-7
(Mikhailitsyn F. S. et al.) and J. Med. Chem., vol.20(8), 1977,
987-996 (Cain F. C. et al.) describe, for example, acridine
derivatives as anticancer and/or antiparasitic agents. In addition,
a publication by Adams et al in 1985 (Mol. Pharm. 27, 480-491)
reports on the binding of diquinolines, diacridines and a number of
monoacridines on rat brain alpha-1-, alpha-2- and
beta-adrenoceptors.
SUMMARY OF THE INVENTION
[0007] An object of the present invention is to provide further
antagonists of alpha-2 adrenoceptors that can be used for the
treatment of diseases or conditions of the pheripheric or central
nervous system where alpha-2 antagonists are indicated to be
useful. Accordingly, an object of the present invention is to
provide further compounds to be used as alpha-2 antagonist agents
in the treatment of mammals, including humans and animals.
[0008] Another object of the present invention is to provide
further compounds useful as selective alpha-2C antagonist agents
for the treatment of various disorders or conditions of the central
nervous system where alpha-2C antagonists are indicated to be
useful.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 shows the effects of atipamezole and compound 1 on
dexmedetomidine-induced hypolocomotion.
[0010] FIG. 2 shows the effects of atipamezole and compound 1 in a
forced swimming test in Balb/c mice.
DETAILED DESCRIPTION OF THE INVENTION
[0011] One embodiment of the present invention covers a method of
treatment using compounds of formula I: 2
[0012] wherein,
[0013] R.sub.1 is H or (C.sub.1-C.sub.6)alkyl;
[0014] each R.sub.2 is independently OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-S-- or hydroxy(C.sub.1-C.sub.6)alkyl;
[0015] A is a benzene ring or (C.sub.5-C.sub.7)cycloalkyl;
[0016] when A is a benzene ring each R.sub.3 is independently OH,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy- , halo-(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-CO--, mono- or
di(C.sub.1-C.sub.6)-alkylcarbamoyl, (C.sub.1-C.sub.6)alkyl-S--,
hydroxy(C.sub.1-C.sub.6)alkyl or NH.sub.2--CO--;
[0017] when A is (C.sub.5-C.sub.7)cycloalkyl each R.sub.3 is
independently OH, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, mono- or di(C.sub.1-C.sub.6)alkylamino or
hydroxy(C.sub.1-C.sub.6)alkyl;
[0018] R.sub.4 and R.sub.5 form, together with the N-atom to which
they are attached, 3
[0019] wherein X is O or .dbd.NR.sub.6; R.sub.6 is H, OH, NH.sub.2,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
CN--(C.sub.1-C.sub.6)al- kyl,
(C.sub.1-C.sub.6)alkoxy-CO--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-CO--, NH.sub.2--CO--, mono- or
di(C.sub.1-C.sub.6)alkylcarbamoyl, hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, phenyl, naphthyl or benzyl, wherein
the said phenyl, naphthyl or benzyl is optionally substituted with
one to three substituent(s) each independently being OH, halogen,
NO.sub.2, NH.sub.2, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, mono- or di(C.sub.1-C.sub.6)alkylamino or
halo-(C.sub.1-C.sub.6)alkyl;
[0020] or R.sub.4 and R.sub.5 form, together with the N-atom to
which they are attached, 4
[0021] wherein n=1 or 2; R.sub.6 is as defined above; and r=0 to
3;
[0022] or R.sub.4 and R.sub.5 form, together with the N-atom to
which they are attached, 1-imidazolyl, 1-imidazolinyl or
1-triazolyl, each of which can optionally be substituted with one
to three substituent(s) R.sub.7 each independently being
(C.sub.1-C.sub.6)alkyl or NH.sub.2;
[0023] or one of R.sub.4 and R.sub.5 is --SO.sub.2R.sub.8 and the
other of R.sub.4 and R.sub.5 is H or (C.sub.1-C.sub.6)alkyl;
R.sub.8 is (C.sub.1-C.sub.6)alkyl, phenyl, naphthyl or benzyl,
wherein the said phenyl, naphthyl or benzyl is optionally
substituted with one to three substituent(s) R.sub.9 each
independently being OH, halogen, NO.sub.2, NH.sub.2,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy or mono- or
di(C.sub.1-C.sub.6)alkylamino;
[0024] Ra and Rb are independently H, OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or
di(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)alkyl-S-- or
CN;
[0025] or Ra and Rb form, together with the carbon ring atoms to
which they are attached, a condensed benzene ring optionally
substituted with one to three substituent(s) R'.sub.3 each
independently being OH, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
halo-(C.sub.1-C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or
di(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)alkyl-CO--, mono-
or di(C.sub.1-C.sub.6)-alkylcarbamoyl or
(C.sub.1-C.sub.6)alkyl-S--- , hydroxy(C.sub.1-C.sub.6)alkyl or
NH.sub.2--CO--;
[0026] or Ra and Rb form, together with the carbon ring atoms to
which they are attached, a condensed five to seven membered
carbocyclic ring optionally substituted with one to four
substituent(s) R.sub.10 each independently being OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, mono- or
di(C.sub.1-C.sub.6)alkylamino or hydroxy(C.sub.1-C.sub.6)alkyl;
[0027] or Ra and Rb form, together with the carbon ring atoms to
which they are attached, a condensed bicyclo[2.2.1]-heptane ring
optionally substituted with one to four substituent(s) each
independently being OH, halogen, (C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)alkoxy;
[0028] or Ra and Rb form, together with the carbon ring atoms to
which they are attached, a condensed five or six membered
heterocyclic ring with one ring heteroatom .dbd.NR.sub.11, which
heterocyclic ring is optionally substituted with one to three
substituent(s) R.sub.10 as defined above; R.sub.11 is H or
(C.sub.1-C.sub.6)alkyl, or R.sub.11 is phenyl optionally
substituted with one to three substituents R.sub.12 each
independently being OH, halogen, NO.sub.2, NH.sub.2,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy or mono- or
di(C.sub.1-C.sub.6)alkylamino;
[0029] m is 0 to 3; and
[0030] t is 0 to 3,
[0031] or pharmaceutically acceptable salts and esters thereof.
[0032] Those compounds can be used for the treatment of diseases or
conditions where alpha-2 antagonists are indicated to be effective,
and for the manufacture of a medicament for such treatment.
[0033] The following subgroups (1) to (18) of compounds of formula
I taken alone or in any combination with each other are
possible:
[0034] (1) A is a benzene ring;
[0035] (2) A is a (C.sub.5-C.sub.7)cycloalkyl;
[0036] (3) Ra and Rb are independently H, OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkyny- l, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or
di(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)alkyl-- S-- or CN;
e.g. H, halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy or
halo(C.sub.1-C.sub.6)alkyl; such as H, halogen,
(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy; e.g. H or
(C.sub.1-C.sub.3)alkyl, wherein the (C.sub.1-C.sub.3)alkyl includes
both straight and branched chain radicals of up to 3 carbon
atoms;
[0037] (4) Ra and Rb form, together with the carbon ring atoms to
which they are attached, a condensed benzene ring unsubstituted or
substituted with one to three, e.g. one or two, such as one,
substituent(s) R'.sub.3 each independently being OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, halo-(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-CO--, NH.sub.2--CO--, mono- or
di(C.sub.1-C.sub.6)alkylcarbamoyl, (C.sub.1-C.sub.6)alkyl-S or
hydroxy(C.sub.1-C.sub.6)alkyl; e.g. OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl or
(C.sub.1-C.sub.6)alkoxy; such as halogen, (C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)alkoxy; e.g. (C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)alkoxy;
[0038] (5) Ra and Rb form, together with the carbon ring atoms to
which they are attached, a condensed five to seven membered
carbocyclic ring optionally substituted with one to four, e.g. one
or two, such as one, substituent(s) R.sub.10 each independently
being OH, halogen, (C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)alkoxy, mono- or di(C.sub.1-C.sub.6)alkylamino or
hydroxy(C.sub.1-C.sub.6)alkyl; such as (C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)alkoxy; e.g. (C.sub.1-C.sub.6)alkyl;
[0039] (6) Ra and Rb form, together with the carbon ring atoms to
which they are attached, a condensed bicyclo[2.2.1]-heptane ring
optionally substituted with one to four, e.g. one or two, such as
one, substituent(s) each independently being OH, halogen,
(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy; e.g.
(C.sub.1-C.sub.6)alkyl
[0040] (7) Ra and Rb form, together with the carbon ring atoms to
which they are attached, a condensed five or six membered
heterocyclic ring with one ring heteroatom .dbd.NR.sub.11, which
heterocyclic ring is optionally substituted with one to three, e.g.
one or two, such as one substituent(s) R.sub.10 as defined above;
and R.sub.11 is H or (C.sub.1-C.sub.6)alkyl, or R.sub.11 is phenyl
optionally substituted with one to three, e.g. one or two, such as
one, substituents R.sub.12 each independently being OH, halogen,
NO.sub.2, NH.sub.2, (C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)alkoxy or mono- or
di(C.sub.1-C.sub.6)alkylamino;
[0041] (8) R.sub.4 and R.sub.5 form, together with the N-atom,
1-piperazinyl which is 4-substituted with R.sub.6, wherein R.sub.6
is as defined above; e.g. (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, CN--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--(C.sub.1-C.sub.6)- alkyl,
(C.sub.1-C.sub.6)alkyl-CO--, NH.sub.2--CO--, mono- or
di(C.sub.1-C.sub.6)alkylcarbamoyl, hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl or optionally substituted benzyl; such
as (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
hydroxy(C.sub.1-C.sub.6- )alkyl, (C.sub.3-C.sub.6)cycloalkyl; e.g.
(C.sub.1-C.sub.6)alkyl;
[0042] (9) R.sub.4 and R.sub.5 form, together with the N-atom, a
morpholino ring;
[0043] (10) R.sub.4 and R.sub.5 form, together with the N-atom, a
1-piperidinyl or 1-pyrrolidinyl optionally substituted with
R.sub.6, wherein R.sub.6 is as defined above, possibly
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
CN--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-CO--, NH.sub.2--CO--, mono- or
di(C.sub.1-C.sub.6)alkylcarbamoyl, hydroxy(C.sub.1-C.sub.6)alkyl or
(C.sub.3-C.sub.6)cycloalkyl; such as (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl; e.g. (C.sub.1-C.sub.6)alkyl;
[0044] (11) R.sub.4 and R.sub.5 form, together with the N-atom,
1-imidazolyl, 1-imidazolinyl or 1-triazolyl, each of which can
optionally be substituted with one to three, e.g. one or two, such
as one, substituent(s) R.sub.7 each independently being
(C.sub.1-C.sub.6)alkyl or NH.sub.2; e.g. R.sub.4 and R.sub.5 form,
together with the N-atom, 2-amino-imidazol-1-yl or
2-amino-imidazolin-1-yl;
[0045] (12) one of R.sub.4 and R.sub.5 is --SO.sub.2R.sub.8 and the
other of R.sub.4 and R.sub.5 is H or (C.sub.1-C.sub.6)alkyl;
R.sub.8 is independently (C.sub.1-C.sub.6)alkyl, phenyl, naphthyl
and benzyl, wherein the said phenyl, naphthyl or benzyl is
optionally substituted with one to three, e.g. one or two, such as
one, substituent(s) R.sub.9 each independently being OH, halogen,
NO.sub.2, NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy
or mono- or di(C.sub.1-C.sub.6)alkylamino;
[0046] (13) m is 0 to 3; e.g. 0, 1 or 2; e.g. 0 or 1; such as
0;
[0047] (14) t is 0 to 3; e.g. 0, 1 or 2; e.g. 0 or 1; such as
0;
[0048] (15) R.sub.1 is H;
[0049] (16) R.sub.1 is (C.sub.1-C.sub.6)alkyl;
[0050] (17) R.sub.2 is independently OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-S-- or hydroxy(C.sub.1-C.sub.6)alkyl; such
as OH, halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy or
hydroxy(C.sub.1-C.sub.6)alkyl; e.g. (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy; and/or
[0051] (18) R.sub.3 is independently OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, halo-(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-CO--, mono- or
di(C.sub.1-C.sub.6)-alkylcarbamoyl, (C.sub.1-C.sub.6)alkyl-S--,
hydroxy(C.sub.1-C.sub.6)alkyl or NH.sub.2--CO--; such as OH,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy- , halo-(C.sub.1-C.sub.6)alkyl; e.g.
halogen, (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy
[0052] A possible subgroup of the compound of formula I is a
compound of formula IA: 5
[0053] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.10; m and t are as defined above; i is 1 to 3; and j is 0 to
4.
[0054] Another possible subgroup of the compound of formula I is a
compound of formula IB: 6
[0055] wherein A, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, Ra,
Rb, m and t are as defined above; and Ra and Rb are independently
H, OH, halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or
di(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)alkyl-S-- or CN; or
Ra and Rb form, together with the carbon ring atoms to which they
are attached, a condensed five to seven membered carbocyclic ring
optionally substituted with one to three substituent(s) R.sub.10;
each independently being OH, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, mono- or di(C.sub.1-C.sub.6)alkylamino or
hydroxy(C.sub.1-C.sub.6)alkyl.
[0056] Another possible subgroup of the compound of formula I is a
compound of formula IC: 7
[0057] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.10, R.sub.11, m and t are as defined above; i is 1 or 2; and
j is 0 to 3.
[0058] Another possible subgroup of the compound of formula I is a
compound of formula ID: 8
[0059] wherein R.sub.1, R.sub.2, R.sub.3, R'.sub.3, R.sub.4,
R.sub.5, m and t are as defined above and p is 0 to 3; for example
wherein m is 1 and R.sub.3 is (C.sub.1-C.sub.6)alkoxy.
[0060] In a possible subgroup of the compound of formula I, IA, IB,
IC or ID, R.sub.4 and R.sub.5 form, together with the N-atom to
which they are attached, 9
[0061] wherein X is .dbd.NR.sub.6; R.sub.6 is as defined above
under formula I; such as (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, hydroxy(C.sub.1-C.sub.6)alkyl or
(C.sub.3-C.sub.6)cycloalkyl; e.g. (C.sub.1-C.sub.6)alkyl.
[0062] Another possible subgroup of the compound of formula I is,
wherein, when one of R.sub.4 and R.sub.5 is --SO.sub.2R.sub.8 and
the other of R.sub.4 and R.sub.5 is H or (C.sub.1-C.sub.6)alkyl;
then R.sub.8 is not (C.sub.1-C.sub.6)alkyl.
[0063] Another possible subgroup of the compound of formula ID is,
wherein, when one of R.sub.4 and R.sub.5 is --SO.sub.2R.sub.8 and
the other of R.sub.4 and R.sub.5 is H or (C.sub.1-C.sub.6)alkyl;
then R.sub.8 is not (C.sub.1-C.sub.6)alkyl.
[0064] Another embodiment of the invention provides new compounds
of formula II and a method of treatment using the compounds of
formula II: 10
[0065] wherein,
[0066] R.sub.1 is H or (C.sub.1-C.sub.6)alkyl;
[0067] each R.sub.2 is independently OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-S-- or hydroxy(C.sub.1-C.sub.6)alkyl;
[0068] A is a benzene ring or (C.sub.5-C.sub.7)cycloalkyl;
[0069] when A is a benzene ring each R.sub.3 is independently OH,
halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)alkoxy- , halo-(C.sub.1-C.sub.6)alkyl, NO.sub.2,
NH.sub.2, mono- or di(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkyl-CO--, mono- or
di(C.sub.1-C.sub.6)-alkylcarbamoyl, (C.sub.1-C.sub.6)alkyl-S--,
hydroxy(C.sub.1-C.sub.6)alkyl or NH.sub.2--CO--;
[0070] when A is (C.sub.5-C.sub.7)cycloalkyl each R.sub.3 is
independently OH, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, mono- or di(C.sub.1-C.sub.6)alkylamino or
hydroxy(C.sub.1-C.sub.6)alkyl;
[0071] R.sub.4 and R.sub.5 form, together with the N-atom to which
they are attached, 11
[0072] wherein X is O or .dbd.NR.sub.6; R.sub.6 is H, OH, NH.sub.2,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
CN--(C.sub.1-C.sub.6)al- kyl,
(C.sub.1-C.sub.6)alkoxy-CO--(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-CO--, NH.sub.2--CO--, mono- or
di(C.sub.1-C.sub.6)alkylcarbamoyl, hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl or benzyl, wherein the said benzyl is
optionally substituted with one to three substituent(s) each
independently being OH, halogen, NO.sub.2, NH.sub.2,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, mono- or
di(C.sub.1-C.sub.6)alkylamino or halo-(C.sub.1-C.sub.6)alkyl;
[0073] or R.sub.4 and R.sub.5 form, together with the N-atom to
which they are attached, 12
[0074] wherein n=1 or 2; R.sub.6 is as defined above; and r=0 to
3;
[0075] or R.sub.4 and R.sub.5 form, together with the N-atom to
which they are attached, 1-imidazolyl, 1-imidazolinyl or
1-triazolyl, each of which can optionally be substituted with one
to three substituent(s) R.sub.7 each independently being
(C.sub.1-C.sub.6)alkyl or NH.sub.2;
[0076] Ra and Rb are independently H, OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or
di(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)alkyl-S-- or
CN;
[0077] or Ra and Rb form, together with the carbon ring atoms to
which they are attached, a condensed benzene ring optionally
substituted with one to three substituent(s) R'.sub.3 each
independently being OH, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkoxy,
halo-(C.sub.1-C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or
di(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)alkyl-CO--, mono-
or di(C.sub.1-C.sub.6)-alkylcarbamoyl or
(C.sub.1-C.sub.6)alkyl-S--- , hydroxy(C.sub.1-C.sub.6)alkyl or
NH.sub.2--CO--;
[0078] or Ra and Rb form, together with the carbon ring atoms to
which they are attached, a condensed five to seven membered
carbocyclic ring optionally substituted with one to four
substituent(s) R.sub.10 each independently being OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, mono- or
di(C.sub.1-C.sub.6)alkylamino or hydroxy(C.sub.1-C.sub.6)alkyl;
[0079] or Ra and Rb form, together with the carbon ring atoms to
which they are attached, a condensed bicyclo[2.2.1]-heptane ring
optionally substituted with one to four substituent(s) each
independently being OH, halogen, (C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)alkoxy;
[0080] or Ra and Rb form, together with the carbon ring atoms to
which they are attached, a condensed five or six membered
heterocyclic ring with one ring heteroatom .dbd.NR.sub.11, which
heterocyclic ring is optionally substituted with one to three
substituent(s) R.sub.10 as defined above; R.sub.11 is H or
(C.sub.1-C.sub.6)alkyl, or R.sub.11 is phenyl optionally
substituted with one to three substituents R.sub.12 each
independently being OH, halogen, NO.sub.2, NH.sub.2,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy or mono- or
di(C.sub.1-C.sub.6)alkylamino;
[0081] m is 0 to 3; and
[0082] t is 0 to 3,
[0083] or of a pharmaceutically acceptable salt or ester thereof,
with the provisos, that
[0084] a) when A is a benzene ring, m is 0 or 1, t is 0, R.sub.1 is
H, R.sub.3 is Cl.sub.1 or NO.sub.2, and Ra and Rb form, together
with the carbon ring atoms to which they are attached, a condensed
benzene ring, and X is NR.sub.6, then R.sub.6 is not H, --CH.sub.3,
--CH.sub.2CH.sub.3, --COCH.sub.3, or --CO--NH.sub.2;
[0085] b) when A is a benzene ring, then Ra and Rb are not at the
same time H;
[0086] c) when A is a benzene ring, m is 1, t is 0, R.sub.1 is H,
and Ra and Rb form, together with the carbon ring atoms to which
they are attached, a condensed benzene ring, which is optionally
substituted with Br, and X is O, then R.sub.3 is not NO.sub.2 or
--OCH.sub.3;
[0087] d) when A is a benzene ring, m is 0, t is 0, R.sub.1 is H,
and Ra and Rb form, together with the carbon ring atoms to which
they are attached, a condensed nonsubstituted benzene ring, then X
is not O;
[0088] e) the compound is not
4-[4-[(7-Chloro-2-methyl-4-quinolinyl)amino]-
phenyl]-1-diethylcarbamoylpiperazine,
4-[4-[(6-Chloro-2-methoxy-9-acridiny-
l)amino]phenyl]-1-diethylcarbamoylpiperazine,
6-amino-4-[[3-chloro-4-(1H-i-
midazol-1-yl)phenyl]amino]-7-metoxy-3-quinolinecarbonitrile or
4-[[3-chloro-4-(1H-imidazol-1-yl)phenyl]amino]-7-methoxy-6-nitro-3-quinol-
inecarbonitrile.
[0089] A possible subgroup of the compound of formula II is a
compound of formula IIA, 13
[0090] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.10, m and t are as defined in formula II; i is 1 to 3; and j
is 0 to 4; for example
[0091] wherein i is 2, j is 0 or 1 and R.sub.10 is
(C.sub.1-C.sub.3)alkyl, wherein the (C.sub.1-C.sub.3)alkyl includes
both straight and branched chain radicals of up to 3 carbon atoms;
or
[0092] wherein m is 0 or 1 and R.sub.3 is (C.sub.1-C.sub.3)alkyl or
halogen, wherein the (C.sub.1-C.sub.3)alkyl includes both straight
and branched chain radicals of up to 3 carbon atoms; or
[0093] wherein the compound is
[4-(4-Methylpiperazin-1-yl)phenyl]-(1,2,3,4-
-tetrahydroacridin-9-yl)amine,
2-{4-[4-(1,2,3,4-Tetrahydroacridin-9-yl)ami-
nophenyl]piperazin-1-yl}ethanol,
[4-(4-Methylpiperazin-1-yl)phenyl]-(2-met-
hyl-1,2,3,4-tetrahydro-acridin-9-yl)amine,
(8-Fluoro-1,2,3,4-tetrahydroacr- idin-9-yl)-[4-(4-methyl
piperazin-1-yl)phenyl]amine,
[4-(4-Methylpiperazin-1-yl)phenyl]-(2,7-dimethyl-1,2,3,4-tetrahydroacridi-
n-9-yl)amine,
[4-(4-Methylpiperazin-1-yl)phenyl]-(7,8,9,10-tetrahydro-6H-c-
yclohepta[b]quinolin-11-yl)amine or
[4-(4-Methylpiperazin-1-yl)phenyl]-(1,-
1,3,3-tetramethyl-1,2,3,4-tetrahydroacridin-9-yl)amine.
[0094] Another possible subgroup of the compound of formula II is a
compound of formula IIB, 14
[0095] wherein A, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, m
and t are as defined in formula II; and
[0096] Ra and Rb are independently H, OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or
di(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)alkyl-S-- or CN; or
Ra and Rb form, together with the carbon ring atoms to which they
are attached, a condensed five to seven membered carbocyclic ring
optionally substituted with one to three substituent(s) R.sub.10;
each independently being OH, halogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, mono- or di (C.sub.1-C.sub.6)alkylamino or
hydroxy(C.sub.1-C.sub.6)alkyl; for example
[0097] wherein A is a benzene ring; or
[0098] wherein m is 0 or 1; or
[0099] wherein R.sub.3 is (C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)alkoxy; or
[0100] wherein Ra and Rb are independently H or
(C.sub.1-C.sub.3)alkyl, wherein the (C.sub.1-C.sub.3)alkyl includes
both straight and branched chain radicals of up to 3 carbon atoms;
or
[0101] wherein A is a six membered carbocyclic ring and Ra and Rb
form, together with the carbon ring atoms to which they are
attached, a condensed five to seven membered carbocyclic ring,
wherein the carbocyclic ring can optionally be substituted with one
to three substituent(s) each independently being OH, halogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy or
hydroxy(C.sub.1-C.sub.6)alkyl; or
[0102] wherein the compound is
(3-Ethyl-2,8-dimethylquinolin-4-yl)-[4-(4-m-
ethylpiperizin-1-yl)phenyl]amine,
(2-Methylquinolin-4-yl)-[4-(4-methylpipe- razin-1-yl)phenyl]amine,
(3-Ethyl-2,6-dimethylquinolin-4-yl)-[4-(4-methylp-
iperazin-1-yl)phenyl]amine,
(3-Ethyl-6-methoxy-2-methylquinolin-4-yl)-[4-(-
4-methylpiperazin-1-yl)phenyl]amine,
(3-Ethyl-2-methylquinolin-4-yl)-[4-(4-
-methylpiperazin-1-yl)phenyl]amine,
4-[4-(4-Methylpiperazin-1-yl)phenylami-
no]quinoline-3-carbonitrile,
3-Isopropyl-2-methylquinolin-4-yl)-[4-(4-meth-
ylpiperazin-1-yl)phenyl]amine,
(2,3-Dimethylquinolin-4-yl)-[4-(4-methylpip-
erazin-1-yl)phenyl]amine,
[4-(4-Methylpiperazin-1-yl)phenyl]-(1,2,3,4,5,6,-
7,8-octahydroacridin-9-yl)amine or
(3-Ethyl-2-methylquinolin-4-yl)-methyl--
[4-(4-methylpiperazin-1-yl)phenyl]amine.
[0103] Another possible subgroup of the compound of formula II is a
compound of formula IIC, 15
[0104] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.10, R.sub.11, m and t are as defined in formula II; i is 1 or
2; and j is 0 to 3.
[0105] Another possible subgroup of the compound of formula II is a
compound of formula IID, 16
[0106] wherein R.sub.1, R.sub.2, R.sub.3, R'.sub.3, R.sub.4,
R.sub.5, m and t are as defined in formula II; and p is 0 to 3; for
example
[0107] wherein m is 1 and R.sub.3 is (C.sub.1-C.sub.6)alkoxy;
or
[0108] wherein the compound is
2-{4-[4-(Acridin-9-yl)aminophenyl]piperazin- -1-yl}-ethanol,
(4-Methoxyacridin-9-yl)-[4-(4-methylpiperazin-1-yl)-phenyl- ]amine,
Acridin-9-yl-[4-(piperidin-1-yl)phenyl]amine,
Acridin-9-yl-[4-(4-benzylpiperazin-1-yl)phenyl]amine,
Acridin-9-yl-[4-(4-methylpiperidin-1-yl)phenyl]amine,
Acridin-9-yl-[4-(3-hydroxymethylpiperidin-1-yl)-phenyl]amine,
Acridin-9-yl-[4-pyrrolidin-1-yl)phenyl]amine,
Acridin-9-yl-[4-(4-cyclopro- pylpiperazin-1-yl)phenyl]amine,
Acridin-9-yl-[4-(4-isopropylpiperazine-1-y- l)phenyl]amine,
(Acridin-9-yl)-methyl-[4-(4-methylpiperazin-1-yl)phenyl]am- ine or
Acridin-9-yl-[2,5-diethoxy-4-(morpholin-4-yl)phenyl]amine.
[0109] In a possible subgroup of the compound of Formula II, IIA,
IIB, IIC, or IID, R.sub.4 and R.sub.5 form, together with the
N-atom to which they are attached, 17
[0110] wherein R.sub.6 is (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkenyl- , (C.sub.3-C.sub.6)cycloalkyl or
hydroxy(C.sub.1-C.sub.6)alkyl, for example, R.sub.6 is
(C.sub.1-C.sub.6)alkyl.
[0111] The compounds of formulae I and II and the subgroups IA, IB,
IC, ID, IIA, IIB, IIC, and IID thereof, as well as the
pharmaceutically acceptable esters and salts thereof, are referred
to below as the compounds of the invention, unless otherwise
indicated.
[0112] The compounds of the invention may have chiral carbon
atom(s) in their structure. The invention includes within its scope
all the possible stereoisomers of the compounds, including
geometric isomers, e.g. Z and E isomers (cis and trans isomers),
and optical isomers, e.g. diastereomers and enantiomers.
Furthermore, the invention includes in its scope both the
individual isomers and any mixtures thereof, e.g. racemic mixtures.
The individual isomers may be obtained using the corresponding
isomeric forms of the starting material or they may be separated
after the preparation of the end compound according to conventional
separation methods. For the separation of, for example, optical
isomers, e.g. enantiomers, from the mixture thereof the
conventional resolution methods, e.g. fractional crystallisation,
may be used.
[0113] Physiologically acceptable salts, e.g. acid addition salts
with both organic and inorganic acids are well known in the field
of pharmaceuticals. Non-limiting examples of these salts include
chlorides, bromides, sulfates, nitrates, phosphates, sulfonates,
formates, tartrates, maleates, citrates, benzoates, salicylates and
ascorbates. Pharmaceutically acceptable esters, when applicable,
may be prepared by known methods using pharmaceutically acceptable
acids that are conventional in the field of pharmaceuticals and
that retain the pharmacological properties of the free form.
Non-limiting examples of those esters include esters of aliphatic
or aromatic alcohols, e.g. lower alkyl esters, e.g. methyl, ethyl
and propyl esters.
[0114] Terms employed herein have the following meanings: A halogen
or halo refers to fluorine, chlorine, bromine or iodine, e.g.
fluorine or chlorine. The term (C.sub.1-C.sub.6)alkyl as employed
herein as such or as part of another group includes both straight,
and branched chain radicals of up to 6 carbon atoms, for example of
1 to 4 carbon atoms, e.g. methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl or s-butyl. The term (C.sub.1-C.sub.6)alkoxy as
such or as part of another group refers to
--O--(C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is as
defined above. The term (C.sub.2-C.sub.6)alkenyl includes both
straight and branched chain radicals of up to 6 carbon atoms, for
example of 2 to 4 carbon atoms, containing (a) double bond(s). The
term (C.sub.2-C.sub.6)alkynyl includes both straight and branched
chain radicals of up to 6 carbon atoms, for example of 2 to 4
carbon atoms, containing (a) triple bond(s). The term
halo-(C.sub.1-C.sub.6)alkyl refers to (C.sub.1-C.sub.6)alkyl
radical, as defined above, that is substituted by one or more halo
radicals as defined above, for example trifluoromethyl,
difluoromethyl etc. The term mono- or
di(C.sub.1-C.sub.6)alkylcarbamoyl refers to a carbamoyl radical
which is N-substituted with one or two (C.sub.1-C.sub.6)alkyl
radical(s), as defined above.
[0115] The compounds of the invention can be prepared analogously
or according to a variety of synthetic routes known in the
literature using suitable starting materials, for example,
according to or analogous to methods described by B. F. Cain et al.
in J.Med.Chem., vol.20(8), 1977, pp. 987-996, and by W. A. Denny et
al. in J.Med.Chem., vol.25, 1982, p.276-315, the contents of which
are hereby incorporated by reference.
[0116] In general, the compounds of the invention can be prepared
e.g. analogously or according to the following reaction scheme 1:
18
[0117] wherein Ra, Rb, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
m and t are as defined above.
[0118] The above reaction is a conventional acid-catalyzed coupling
of the chloro-compound of formula II with a substituted aromatic
amine of formula IV. The reaction is carried out at room or
elevated temperature in a suitable solvent, e.g. alcohol, such as
methanol, in acidic conditions, to obtain the compound of formula
I' which is then isolated from the reaction mixture in a usual
manner.
[0119] The starting compounds III and IV are commercially available
or can be prepared according to or analogously to the methods
described in the literature (see e.g. J.Med.Chem., vol.20(8), 1977,
pp. 987-996, and J.Med.Chem., vol.25, 1982, p.276-315, as mentioned
above).
[0120] Accordingly, a substituted aromatic NR.sub.1-amine IV can
e.g. be prepared starting from the corresponding nitro compound
which is reduced with a reducing agent, e.g. in the presence of
SnCl.sub.2.H.sub.2O, in a suitable solvent, e.g. DMF, and
optionally alkylated with R.sub.1 in a manner known in the art,
when R.sub.1=(C.sub.1-6)alkyl is desired.
[0121] The starting material III can be prepared e.g. according to
following scheme 2: 19
[0122] wherein Ra, Rb, R.sub.3, and m are as defined above.
[0123] In scheme 2 a compound V is reacted e.g. with thionyl
chloride in the presence of a small amount of DMF, to obtain the
9-chlorinated reactant III. The reaction is carried out at room or
elevated temperature.
[0124] It is obvious for a skilled person that, in the above
reactions, any starting material or intermediate can be protected,
if necessary, in a manner well known in the chemical field. Any
protected functionality can subsequently be deprotected in a manner
known in the art.
[0125] The above disclosed synthetic routes are meant to illustrate
the preparation of the compounds of the invention, and the
preparation is by no means limited thereto, i.e. other synthetic
methods that are within the general knowledge of a skilled person
are also possible.
[0126] The compounds of the invention may be converted, if desired,
into their pharmaceutically acceptable salt or ester form using
methods well known in the art.
[0127] The following examples are meant only for illustrating
purposes and do not limit the scope of the invention defined in
claims.
EXAMPLE 1
Acridin-9-yl-[4-(4-methylpiperazin-1-yl)-phenyl]amine
[0128] Step 1
[0129] 1.04 g (5.0 mmol) of N-(4-nitrophenyl)piperazine was
dissolved in 5 ml of dimethylformamide. Sodium hydride (0.24 g, 6.0
mmol) was added to the reaction mixture in three portions under
nitrogen atmosphere and cooling over a period of 10 min. After 30
min of stirring, 0.31 ml (6.0 mmol) of methyl iodide was added
dropwise to the reaction mixture at 0.degree. C. Stirring was
continued for 1 h at room temperature, the reaction mixture was
then evaporated to dryness, and purified by silica gel
chromatography (methylene chloride:methanol:triethylamine 94:5:1)
to yield 1.0 g (90%) of 1-methyl-4-(4-nitrophenyl)piperazine.
[0130] Step 2
[0131] 0.999 g (4.5 mmol) of 1-methyl-4-(4-nitrophenyl)piperazine,
10.15 g (45 mmol) of tin(II)chloride dihydrate and 20 ml of
dimethylformamide were mixed and is stirred overnight at 80.degree.
C. Most of dimethylformamide was evaporated under vacuum. The
remaining slurry was poured into ice water, neutralized with a
sodium bicarbonate (sat.) solution, and filtered. The filtrate was
extracted several times with ethylacetate and chloroform to provide
0.636 g (74%) of 4-(4-methylpiperazin-1-yl)aniline.
[0132] Step 3
[0133] 0.488 g (2.5 mmol) of 9-(10H)acridone, 2.5 ml of thionyl
chloride and a catalytic amount (a few drops) of dimethylformamide
were mixed at 80.degree. C. After 30 min of stirring, the reaction
mixture was evaporated, the residue was dissolved in chloroform and
poured into cold aqueous ammonia. The ammonia solution was
extracted several times with chloroform. The combined organic
phases were washed with 2M ammonia solution, dried over sodium
sulfate and evaporated to obtain 0.517 g (97%) of
9-chloroacridine.
[0134] Step 4
[0135] 0.191 g (1.0 mmol) of 4-(4-methylpiperazin-1-yl)aniline, 2.5
ml of methanol and a few drops of concentrated hydrochloric acid
were mixed and heated under reflux. The 9-chloroacridine (1-1,5
equivalents) and 2.5 ml methanol were mixed separately and added to
the reaction mixture in small portions. After 30 min of stirring,
two drops of concentrated hydrochloric acid were added, and heating
was continued for 2 h. The reaction mixture was then evaporated to
dryness and purified by chromatography (silica gel column; gradient
from 100% methylene chloride to 90% methylene chloride and 10%
methanol; when 4-(4-methylpiperazin-1-y- l)aniline eluted from the
column, the eluent was changed to methylene
chloride:methanol:triethylamine 94:5:1). A final amount of 0.126 g
(34%, overall yield 12%) of the title compound in pure form was
obtained.
[0136] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): 8.05 (2H, m), 7.73 (2H,
m), 7.66 (2H, m), 7.13 (2H, m), 6.97 (4H, m), 3.35 (4H, m), 2.98
(4H, m), 2.58 (3H, s); MS (EI.sup.+): 368 (M.sup.+)
EXAMPLE 2
Acridin-9-yl-[2,5-diethoxy-4-(morpholin-4-yl)phenyl]amine
[0137] Following the procedure outlined in Step 4 of Example 1, but
substituting 2,5-diethoxy-4-morpholinoaniline dihydrochloride for
4-(4-methylpiperazin-1-yl)aniline, afforded the title compound with
an overall yield of 23%.
[0138] .sup.1H NMR (CDCl.sub.3, 500 MHz): 8.19 (2H, m), 8.13 (2H,
m), 7.56 (1H, s), 7.42 (2H, m), 7.04 (2H, m), 6.42 (1H, s), 3.91
(4H, m), 3.15 (4H, m), 3,10 (4H, q, J=7.27Hz), 1.41 (6H, t, J=7.27
Hz); MS (ESI.sup.+ TOF): 444 (M.sup.+)
EXAMPLE 3
Acridin-9-yl-[4-(morpholin-4-yl)phenyl]amine
[0139] Following the procedure outlined in Step 4 of Example 1, but
substituting 4-(morpholin-1-yl)aniline for
4-(4-methylpiperazin-1-yl)anil- ine, afforded the title compound
with an overall yield of 64%.
[0140] .sup.1H NMR (CDCl.sub.3, 500 MHz): 7.99 (4H, m), 7.55 (2H,
m), 7.17 (2H, m), 7.04 (2H, m), 6.88 (2H, m), 3.88 (4H, m), 3.15
(4H, m); MS (ESI.sup.+ TOF): 356 (M.sup.+)
EXAMPLE 4
(3-Ethyl-2,8-dimethylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amin-
e
[0141] Following the procedure outlined in Step 4 of Example 1, but
substituting 4-chloro-2,8-dimethyl-3-ethylquinoline for
9-chloroacridine, afforded the title compound with 27% overall
yield.
[0142] .sup.1H NMR (CDCl.sub.3, 500 MHz): 7.60 (1H, m), 7.41 (1H,
m), 7.16 (1H, m), 6.79 (2H, m), 6.62 (2H, m), 5.62 (1H, s), 3.12
(4H, m), 2.79 (3H, s), 2.79 (2H, q, J=7.63 Hz), 2.78 (3H, s), 2.59
(4H, m), 2.36 (3H, s), 1.15 (3H, t, J=7.63 Hz); MS (ESI.sup.+ TOF):
375 (M.sup.+)
EXAMPLE 5
(2-Methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine
[0143] Following the procedure outlined in Step 4 of Example 1, but
substituting 4-chloro-2-methylquinoline for 9-chloroacridine,
afforded the title compound with 24% overall yield.
[0144] .sup.1H NMR (CDCl.sub.3, 500 MHz): 8.02 (1H, m), 7.91 (1H,
m), 7.64 (1H, m), 7.44 (1H, m), 7.23 (2H, m), 7.00 (2H, m), 6.59
(1H, m), 3.26 (4H, m), 2.61 (4H, m), 2.55 (3H, s), 2.38 (3H, s); MS
(ESI.sup.+ TOF): 333 (M.sup.+)
EXAMPLE 6
[4-(4-Methylpiperazin-1-yl)phenyl]-(quinolin-4-yl)amine
[0145] Following the procedure outlined in Step 4 of Example 1, but
substituting 4-chloroquinoline for 9-chloroacridine, afforded the
title compound with 11% overall yield.
[0146] .sup.1H NMR (CDCl.sub.3, 500 MHz): 8.28 (1H, m), 8.25 (1H,
m), 8.06 (1H, m), 7.66 (1H, m), 7.50 (1H, m), 7.25 (2H, m), 6.97
(2H, m), 3.25 (4H, m), 2.64 (4H, m), 2.40 (3H, s); MS (ESI.sup.+
TOF): 319 (M.sup.+)
EXAMPLE 7
(3-Ethyl-2,6-dimethylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amin-
e
[0147] Following the procedure outlined in Step 4 of Example 1, but
substituting 4-chloro-1,6-dimethyl-3-ethylquinoline for
9-chloroacridine, afforded the title compound with 18% overall
yield.
[0148] .sup.1H NMR (CDCl.sub.3, 500 MHz): 7.90 (1H, m), 7.49 (1H,
m), 7.40 (1H, m), 6.81 (2H, m), 6.67 (2H, m), 3.12 (4H, m), 2.77
(2H, q, J=7.56 Hz), 2.78 (3H, s), 2.58 (4H, m), 2.36 (3H, s), 2.35
(3H, s), 1.15 (3H, t, J=7.56 Hz); MS (ESI.sup.+ TOF): 375
(M.sup.+)
EXAMPLE 8
(3-Ethyl-6-methoxy-2-methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)pheny-
l]amine
[0149] Following the procedure outlined in Step 4 of Example 1, but
substituting 4-chloro-3-ethyl-6-methoxy-2-methylquinoline for
9-chloroacridine, afforded the title compound with 5% overall
yield.
[0150] MS (ESI.sup.+ TOF): 391 (M.sup.+)
EXAMPLE 9
(3-Ethyl-2-methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine
[0151] Following the procedure outlined in Step 4 of Example 1, but
substituting 4-chloro-3-ethyl-2-methylquinoline for
9-chloroacridine, afforded the title compound with 17% overall
yield.
[0152] .sup.1H NMR (CDCl.sub.3, 500 MHz): 7.91 (1H, m), 7.72 (1H,
m), 7.55 (1H, m), 7.25 (1H, m), 6.80 (2H, m), 6.67 (2H, m), 5.72
(1H, s), 3.11 (4H, m), 2.79 (2H, q, J=7.59 Hz), 2.77 (3H, s), 2.57
(4H, m), 2.34 (3H, s), 1.17 (3H, t, J=7.59 Hz); MS (ESI.sup.+ TOF):
361 (M.sup.+)
EXAMPLE 10
(4-Methoxyacridin-9-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine
[0153] Following the procedure outlined in Step 3 of Example 1, but
substituting 9-hydroxy-4-methoxyacridine for 9-(10H)acridone,
afforded 9-chloro-4-methoxyacridine, which was reacted with
4-(4-methylpiperazin-1-yl)aniline (according to the Step 4 in the
procedure of Example 1) to obtain the title compound with 24%
overall yield.
[0154] MS (ESI.sup.+ TOF): 399 (M.sup.+)
EXAMPLE 11
[4-(4-Methylpiperazin-1-yl)phenyl]-(1,2,3,4-tetrahydroacridin-9-yl)amine
[0155] Following the procedure outlined in Step 3 of Example 1, but
substituting 1,2,3,4-tetrahydro-9-(10H)acridone for
9-(10H)acridone, afforded 9-chloro-1,2,3,4-tetrahydroacridine,
which was reacted with 4-(4-methylpiperazin-1-yl)aniline (according
to Step 4 in the procedure of Example 1) to obtain the title
compound with 46% overall yield.
[0156] .sup.1H NMR (CDCl.sub.3, 500 MHz): 7.96 (1H, m), 7.72 (1H,
m), 7.56 (1H, m), 7.27 (1H, m), 6.83 (2H, m), 6.73 (2H, m), 5.82
(1H, s), 3.14 (6H, m), 2.67 (2H, m), 2.58 (4H, m), 2.35 (3H, s),
1.94 (2H, m), 1.84 (2H, m); MS (ESI.sup.+ TOF): 373 (M.sup.+)
EXAMPLE 12
Acridin-9-yl-[4-(piperidin-1-yl)phenyl]amine
[0157] 0.202 g (1.0 mmol) of 1-bromo-4-nitrobenzene and 0.20 ml of
piperidine (2.0 mmol) were dissolved in 3 ml of dimethylsulfoxide.
0.207 g (1.5 mmol) of potassium carbonate was added and the
reaction mixture was heated to 100.degree. C. After 2 h 100 ml of
water was added, and the mixture was extracted a few times with
dichloromethane. The combined organic layers were dried over sodium
sulfate and evaporated to obtain crude
4-(piperidin-1-yl)-1-nitrobenzene. Following the procedure outlined
in Step 2 of Example 1, but substituting
4-piperidin-1-yl-1-nitrobenzene for
1-methyl-4-(4-nitrophenyl)piperazine, afforded
4-piperidin-1-ylaniline, which was reacted with 9-chloroacridine
(according to Step 4 in the procedure of Example 1) to obtain the
title compound with 6% overall yield.
[0158] .sup.1H NMR (CDCl.sub.3, 500 MHz): 8.05 (2H, m), 8.00 (2H,
m), 7.48 (2H, m), 7.09 (4H, m), 6.86 (2H, m), 3.13 (4H, m), 1.71
(4H, m), 1.58 (2H, m); MS (ESI.sup.+ TOF): 354 (M.sup.+)
EXAMPLE 13
Acridin-9-yl-[4-(4-methylpiperidin-1-yl)phenyl]amine
[0159] Following the procedure of Example 12, but substituting
4-methylpiperidine for piperidine, afforded the title compound with
6% overall yield.
[0160] MS (ESI.sup.+ TOF): 368 (M.sup.+)
EXAMPLE 14
Acridin-9-yl-[4-(3-hydroxymethylpiperidin-1-yl)phenyl]amine
[0161] Following the procedure of Example 12, but substituting
3-hydroxymethylpiperidine for piperidine, afforded the title
compound with 3% overall yield.
[0162] .sup.1H NMR (CDCl.sub.3, 500 MHz): 7.93 (2H, m), 7.81 (2H,
m), 7.47 (2H, m), 7.04 (4H, m), 6.92 (2H, m), 3.68 (2H, m), 3.59
(2H, m), 2.78 (1H, m), 2.61 (1H, m), 1.95 (1H, br s), 1.83 (2H, m),
1.72 (1H, m), 1.23 (2H, m); MS (ESI.sup.+ TOF): 384 (M.sup.+)
EXAMPLE 15
Acridin-9-yl-[4-(pyrrolidin-1-yl)phenyl]amine
[0163] Following the procedure of Example 12, but substituting
pyrrolidine for piperidine, afforded the title compound with 50%
overall yield.
[0164] .sup.1H NMR (CDCl.sub.3, 500 MHz): 8.00 (4H, m), 7.56 (2H,
m), 7.18 (2H, m), 7.00 (2H, m), 6.50 (2H, m), 3.27 (4H, m), 2.02
(4H, m); MS (ESI.sup.+ TOF): 340 (M.sup.+)
EXAMPLE 16
Acridin-9-yl-[4-(piperazine-1-yl)phenyl]amine
[0165] Following the procedure outlined in Step 2 of Example 1, but
substituting N-(4-nitrophenyl)piperazine for
1-methyl-4-(4-nitrophenyl)pi- perazine, afforded
4-(piperazin-1-yl)aniline, which was reacted with 9-chloroacridine
(according to Step 4 in the procedure of Example 1) to obtain the
title compound with 16% overall yield.
[0166] .sup.1H NMR (CD.sub.3OD, 500 MHz): 8.21 (2H, m), 7.94 (4H,
m), 7.42 (2H, m), 7.38 (2H, m), 7.20 (2H, m), 3.56 (4H, m), 3.43
(4H, m); MS (ESI.sup.+ TOF): 355 (M.sup.+)
EXAMPLE 17
Acridin-9-yl-[4-(4-acetylpiperazine-1-yl)phenyl]amine
[0167] 35 mg (0.10 mmol) of
9-[4-(piperazin-1-yl)phenyl]aminoacridine (Example 16) was
dissolved in 2 ml of chloroform, 7.1 .mu.l (0.10 mmol) of acetyl
chloride and catalytical amounts of pyridine and triethylamine were
added. After 2 h of stirring at room temperature, the solvents were
removed under vacuum, and the residue was purified by silica gel
chromatography (eluent chloroform:methanol 6:1). The fractions with
the title compound were combined, evaporated, taken up to water and
extracted with chloroform. After drying over sodium sulfate, the
organic layer was evaporated to obtain the title compound (6%,
overall yield 1%).
[0168] MS (ESI.sup.+ TOF): 397 (M.sup.+)
EXAMPLE 18
Acridin-9-yl-[4-(4-benzylpiperazine-1-yl)phenyl]amine
[0169] Following the procedure outlined in Step 1 of Example 1, but
substituting 9-[4-(piperazin-1-yl)phenyl]aminoacridine (Example 16)
for N-(4-nitrophenyl)piperazine, and benzyl bromide for methyl
iodide, afforded the title compound (15%, overall yield 2%).
[0170] .sup.1H NMR (CDCl.sub.3, 500 MHz): 8.00 (4H, m), 7.48 (2H,
m), 7.34 (4H, m), 7.28 (1H, m), 7.12 (4H, m), 6.88 (2H, m), 3.59
(2H, s), 3.21 (4H, m), 2.63 (4H, m); MS (ESI.sup.+ TOF): 445
(M.sup.+)
EXAMPLE 19
Acridin-9-yl-[4-(4-isopropylpiperazine-1-yl)phenyl]amine
[0171] Following the procedure outlined in Step 1 of Example 1, but
substituting 9-[4-(piperazin-1-yl)phenyl]aminoacridine (Example 16)
for N-(4-nitrophenyl)piperazine, and isopropyl iodide for methyl
iodide, afforded the title compound (11%, overall yield 2%).
[0172] MS (ESI.sup.+ TOF): 397 (M.sup.+)
EXAMPLE 20
2-{4-[4-(1,2,3,4-Tetrahydroacridin-9-yl)aminophenyl]piperazin-1-yl}ethanol
[0173] 0.14 ml (2.0 mmol) of 2-bromoethanol and 0.17 ml (2.4 mmol)
of acetyl chloride were dissolved in 2 ml of dichloromethane. 0.28
ml (2.0 mmol) of triethylamine was added, and the reaction mixture
was stirred at room temperature. After 1 h 50 ml of dichloromethane
was added to the reaction mixture, which was then washed with a
sodium bicarbonate (sat.) solution, a 10% citric acid solution and
water. The organic phase was dried over sodium sulfate and
evaporated to obtain 0.241 g (72%) of 2-bromoethylacetate.
Following the procedure outlined in Step 1 of Example 1, but
substituting 2-bromoethylacetate for methyl iodide, afforded
2-[4-(4-nitrophenyl)piperazin-1-yl]ethylacetate (64%), which was
reduced according to the procedure of Step 2 in Example 1 to give
the corresponding amine
2-[4-(4-aminophenyl)piperazin-1-yl]ethylacetate in quantitative
yield. 2-[4-(4-aminophenyl)piperazin-1-yl]ethylacetate was reacted
with 9-chloro-1,2,3,4-tetrahydroacridine (according to the
procedure of Step 4 in Example 1) to obtain
2-{4-[4-amino-(1,2,3,4-tetrah-
ydroacridin-9-yl)phenyl]piperazin-1-yl}ethyl acetate with 47%
yield. Treating the ester with 4 equivalents of lithium hydroxide
in a dioxane/water solution overnight, afforded the title compound
with 60% yield (overall yield 20%).
[0174] MS (ESI.sup.+ TOF): 403 (M.sup.+)
EXAMPLE 21
2-{4-[4-(Acridin-9-yl)aminophenyl]piperazin-1-yl}ethanol
[0175] Following the procedure outlined in Step 1 of Example 1, but
substituting 9-[4-(piperazin-1-yl)phenyl]aminoacridine (Example 16)
for N-(4-nitrophenyl)piperazine, and 2-bromoethyl-acetate for
methyl iodide, afforded
2-{4-[4-amino-(1,2,3,4-tetrahydroacridin-9-yl)phenyl]piperazin-1-
-yl}ethyl acetate (31%). Treating the ester with 8 equivalents of
lithium hydroxide in dioxane/water solution overnight, afforded the
title compound with 37% yield (overall yield 2%).
[0176] MS (ESI.sup.+ TOF): 399 (M.sup.+)
EXAMPLE 22
Acridin-9-yl-[4-(4-cyclopropylpiperazine-1-yl)phenyl]amine
[0177] 35 mg (0.10 mmol) of
9-[4-(piperazin-1-yl)phenyl]aminoacridine (Example 16) was
dissolved in 1 ml of methanol. 57 .mu.l (1.0 mmol) of acetic acid,
22 .mu.l (0.11 mmol) of (1-ethoxycyclopropyloxy)-trimethylsi- lane
and a small amount of 3 .ANG. molecular sieves were added. The
reaction mixture was stirred at room temperature under nitrogen
atmosphere. After 30 min 28 mg (0.45 mmol) of sodium
cyanoborohydride was added and the reaction mixture was heated at
50.degree. C. over night. The solvents were removed under vacuum,
and the residue was purified by chromatography (silica gel column,
eluent chloroform/methanol 6:1) to obtain 3.8 mg (10%, overall
yield 2%) of the title compound.
[0178] MS (ESI.sup.+ TOF): 395 (M.sup.+)
EXAMPLE 23
4-[4-(4-Methylpiperazin-1-yl)phenylamino]quinoline-3-carbonitrile
[0179] 0.91 ml (10 mmol) of aniline and 1.69 g (10 mmol of
ethyl(ethoxymethylene)cyanoacetate were dissolved in 10 ml of
pyridine and heated under reflux. After 3 h pyridine was removed
under vacuum, and the residue was purified by chromatography
(silica gel column, eluent 1% methanol in dichloromethane). 1.08 g
(50%) of ethyl(anilinomethylene)cyan- oacetate were obtained. The
compound was cyclized by heating in a biphenyl/phenyl ether
mixture. After cooling a precipitate was filtered and washed with
diethyl ether to give 4-hydroxyquinoline-3-carbonitrile (49%).
Following the procedure outlined in Step 3 of Example 1, but
substituting 4-hydroxyquinoline-3-carbonitrile for 9-(10H)acridone,
4-chloro-3-cyanoquinoline (90%) was obtained, which was reacted
with 4-(4-methylpiperazin-1-yl)aniline (according to the procedure
of Step 4 in Example 1), to afford the title compound with 12%
yield (overall yield 3%).
[0180] .sup.1H NMR (CDCl.sub.3, 500 MHz): 8.66 (1H, s), 8.01 (1H,
m), 7.78 (1H, m), 7.73 (1H, m), 7.42 (1H, m), 7.15 (2H, m), 6.94
(2H, m), 3.29 (4H, m), 2.63 (4H, m), 2.39 (3H, s); MS (ESI.sup.+
TOF): 344 (M.sup.+)
EXAMPLE 24
(3-Isopropyl-2-methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amin-
e
[0181] 4.56 ml (50 mmol) of aniline and 10.7 ml (60 mmol) of ethyl
2-isopropylacetoacetate were mixed with 50 ml of chloroform. 0.48 g
(2.5 mmol) of para-toluenesulfonic acid was added, and the reaction
mixture was refluxed with continuous removal of the water produced
in the reaction. After 2 d chloroform was removed in vacuum, and
the residue was refluxed in 10 ml of phenyl ether. After cooling,
the precipitate was filtered and washed with diethyl ether to give
4-hydroxy-3-isopropyl-2-me- thylquinoline (21%). Following the
procedure of Step 3 in Example 1, but substituting
4-hydroxy-3-isopropyl-2-methylquinoline for 9-(10H)acridone,
4-chloro-3-isopropyl-2-methylquinoline (100%) was obtained, which
was reacted with 4-(4-methylpiperazin-1-yl)aniline (following the
procedure of Step 4 in Example 1), to afford the title compound
with 61% yield (overall yield 13%).
[0182] .sup.1H NMR (CDCl.sub.3, 500 MHz): 7.95 (1H, m), 7.73 (1H,
m), 7.54 (1H, m), 7.24 (1H, m), 6.79 (2H, m), 6.60 (2H, m), 5.72
(1H, s), 3.61 (1H, q, J=7.28), 3.11 (4H, m), 2.81 (3H, s), 2.57
(4H, m), 2.34 (3H, s), 1.38 (6H, d, J=7.28); MS (ESI.sup.+ TOF):
375 (M.sup.+)
EXAMPLE 25
(2,3-Dimethylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine
[0183] Following the procedure of Example 24, but substituting
ethyl 2-methylacetoacetate for ethyl 2-isopropylacetoacetate,
afforded the title compound with 11% yield.
[0184] .sup.1H NMR (CDCl.sub.3, 500 MHz): 8.02 (1H, m), 7.78 (1H,
m), 7.59 (1H, m), 7.33 (1H, m), 6.83 (2H, m), 6.69 (2H, m), 5.90
(1H, s), 3.13 (4H, m), 2.73 (3H, s), 2.58 (4H, m), 2.35 (3H, s),
2.24 (3H, s); MS (ESI.sup.+ TOF): 347 (M.sup.+)
EXAMPLE 26
[4-(4-Methylpiperazin-1-yl)phenyl]-(2-methyl-1,2,3,4-tetrahydro-acridin-9--
yl)amine
[0185] 1.37 g (10 mmol) of 2-aminobenzoic acid and 1.23 ml (10
mmol) of 4-methylcyclohexanone were dissolved in 10 ml of
phosphorus oxychloride and the reaction mixture was heated under
reflux in a nitrogen atmosphere. After 3 h most of the phosphorus
oxychloride was removed under vacuum. The remaining brown syrup was
poured into a cold sodium bicarbonate (sat.) solution and washed
once with chloroform. The yellow precipitate forming in the basic
water solution was filtered
(2-methyl-1,2,3,4-tetrahydro-9-(10H)-acridone, 46%). Following the
procedure of Step 3 in Example 1, but substituting
2-methyl-1,2,3,4-tetrahydro-9-(10H)acridone for 9-(10H)acridone,
gave 9-chloro-2-methyl-1,2,3,4-tetrahydroacridine (40%), which was
reacted with 4-(4-methylpiperazin-1-yl)aniline (according to the
procedure of Step 4 in Example 1), to afford the title compound
with 39% yield (overall yield 7%).
[0186] .sup.1H NMR (CDCl.sub.3, 500 MHz): 7.97 (1H, m), 7.70 (1H,
m), 7.55 (1H, m), 7.24 (1H, m), 6.83 (2H, m), 6.72 (2H, m), 5.81
(1H, br s), 3.23 (1H, m), 3.14 (5H, m), 2.86 (1H, m), 2.57 (4H, m),
2.35 (3H, s), 2.24 (1H, m), 2.03 (1H, m), 1.93 (1H, m), 1.57 (1H,
m), 1.10 (3H, d); MS (ESI.sup.+ TOF): 387 (M.sup.+)
EXAMPLE 27
[4-(4-methylpiperazin-1-yl)phenyl]-(7,8,9,10-tetrahydro-6H-cyclohepta[b]qu-
inolin-11-yl)amine
[0187] Following the procedure of Example 26, but substituting
cycloheptanone for 4-methylcyclo-hexanone, afforded the title
compound (0,2%).
[0188] (ESI.sup.+ TOF): 387 (M.sup.+)
EXAMPLE 28
[4-(4-Methylpiperazin-1-yl)phenyl]-(2,7-dimethyl-1
,2,3,4-tetrahydroacridi- n-9-yl)amine
[0189] Following the procedure of Example 26, but substituting
2-amino-5-methylbenzoic acid for 2-aminobenzoic acid, afforded the
title compound (4%).
[0190] .sup.1H NMR (CDCl.sub.3, 500 MHz):. 8.10 (1H, m), 7.43 (2H,
m), 6.85 (2H, m), 6.83 (2H, m), 6.27 (1H, br s), 3.37 (1H, m), 3.18
(4H, m), 2.78 (1H, m), 2.61 (4H, m), 2.37 (3H, s), 2.33 (3H, s),
2.18 (1H, m), 2.02 (1H, m), 1.91 (1H, m), 1.52 (1H, m), 1.09 (1H,
m), 1.10 (3H, d); MS (ESI.sup.+ TOF): 401 (M.sup.+)
EXAMPLE 29
(8-Fluoro-1,2,3,4-tetrahydroacridin-9-yl)-[4-(4-methylpiperazin-1-yl)pheny-
l]amine
[0191] Following the procedure of Example 26, but substituting
2-amino-6-fluorobenzoic acid for 2-aminobenzoic acid, and
cyclohexanone for 4-methylcyclohexanone, afforded the title
compound (3%).
[0192] .sup.1H NMR (CDCl.sub.3, 500 MHz): 7.89 (1H, m), 7.51 (1H,
m), 7.05 (1H, m), 6.87 (2H, m), 6.82 (2H, m), 3.22 (4H, m), 3.14
(2H, m), 2.66 (4H, m), 2.41 (3H, s), 2.34 (2H, m), 1.88 (2H, m),
1.67 (2H, m); MS (ESI.sup.+ TOF): 391 (M.sup.+)
EXAMPLE 30
[4-(4-Methylpiperazin-1-yl)phenyl]-(1,1,3,3-tetramethyl-1,2,3,4-tetrahydro-
acridin-9-yl)amine
[0193] 1.49 ml (10 mmol) of ethyl 2-aminobenzoate and 1.73 ml (10
mmol) of 3,3,5,5-tetramethyl-cyclohexanone were mixed with 20 ml of
toluene. 20 mg (0.1 mmol) of para-toluenesulfonic acid was added,
and the reaction mixture was refluxed with continuous removal of
the water produced in the reaction. After 9 h, toluene was removed
under vacuum, and the residue was refluxed in 10 ml of phenyl
ether. After cooling, the precipitate was filtered and washed with
diethyl ether to obtain 1,1,3,3-tetramethyl-1,2,-
3,4-tetrahydro-9(10H)-acridone (18%). Following the procedure of
Step 3 in Example 1, but substituting
1,1,3,3-tetramethyl-1,2,3,4-tetrahydro-9(10H)- acridone for
9-(10H)acridone, gave 9-chloro-1,1,3,3-tetramethyl-1,2,3,4-te-
trahydroacridine (21%), which was reacted with
4-(4-methylpiperazin-1-yl)a- niline (according to the procedure of
Step 4 in Example 1), to afford the title compound (3%, overall
yield 0,1%).
[0194] MS (ESI.sup.+ TOF): 429 (M.sup.+)
EXAMPLE 31
(1,4-Methano-1,2,3,4-tetrahydroacridin-9-yl)-[4-(4-methylpiperazin-1-yl)ph-
enyl]amine
[0195] Following the procedure of Example 30, but substituting
norcamphore for 3,3,5,5-tetramethyl-cyclohexanone, afforded the
title compound (overall yield 1%).
[0196] .sup.1H NMR (CDCl.sub.3, 500 MHz): 7.99 (1H, m), 7.84 (1H,
m), 7.58 (1H, m), 7.38 (1H, m), 7.02 (2H, m), 6.91 (2H, m), 6.13
(1H, s), 3.44 (1H, m), 3.21 (4H, m), 3.00 (1H, m), 2.61 (4H, m),
2.37 (3H, s), 1.97 (1H, m), 1.77 (2H, m), 1.48 (2H, m), 1.26 (1H,
m); MS (ESI.sup.+ TOF): 385 (M.sup.+)
EXAMPLE 32
[4-(4-Methylpiperazin-1-yl)phenyl]-(1,2,3,4,5,6,7,8-octahydroacridin-9-yl)-
amine
[0197] Following the procedure of Example 30, but substituting
ethyl 2-amino-1-cyclohexene-1-carboxylate for ethyl
2-aminobenzoate, and cyclohexanone for
3,3,5,5-tetramethylcyclo-hexanone, afforded the title compound
(overall yield 0,2%).
[0198] MS (ESI.sup.+ TOF): 377 (M.sup.+)
EXAMPLE 33
(3-Ethyl-2-methylquinolin4-yl)-methyl-[4-(4-methylpiperazin-1-yl)phenyl]am-
ine
[0199] Following the procedure of Step 1 in Example 1, but
substituting
(3-ethyl-2-methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine
(Example 9) for N-(4-nitrophenyl)piperazine, afforded the title
compound (overall yield 12%).
[0200] .sup.1H NMR (CDCl.sub.3, 500 MHz): 8.03 (1H, m), 7.58 (2H,
m), 7.34 (1H, m), 6.81 (2H, m), 6.42 (2H, m), 3.33 (3H, s), 3.07
(4H, m), 2.80 (3H, s), 2.71 (2H, q, J=7.50 Hz), 2.57 (4H, m), 2.34
(3H, s), 1.12 (3H, t, J=7.50 Hz); MS (ESI.sup.+ TOF): 375
(M.sup.+)
EXAMPLE 34
Acridin-9-yl-methyl-[4-(4-(methylpiperazin-1-yl)phenyl]amine
[0201] Following the procedure of Step 1 in Example 1, but
substituting
acridin-9-yl-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (Example 1)
for N-(4-nitrophenyl)piperazine, afforded the title compound
(overall yield 9%).
[0202] .sup.1H NMR (CD.sub.3OD, 500 MHz): 7.8 (2H, br s), 7.54 (2H,
m), 7.48 (2H, m), 6.98 (4H, m), 6.79 (2H, m), 3.77 (3H, s), 3.18
(4H, m), 2.65 (4H, m), 2.36 (3H, s); MS (EI.sup.+): 383
(M.sup.+)
[0203] The compounds of the invention show interesting
pharmacological properties, namely, they exhibit antagonistic
affinity for alpha-2 adrenoceptors. This activity is demonstrated
in the pharmacological tests presented below.
[0204] EXPERIMENT I: Binding Affinity
[0205] The affinity of test compounds for the three human
alpha-2-adrenoceptor subtypes (alpha-2A, alpha-2B and alpha-2C) was
determined in binding competition assays with .sup.3H-rauwolscine.
The biological material consisted of membranes from Shionogi S115
cells stably transfected with one of the three human alpha-2
subtypes (A. Marjamki et al., Biochem. Biophys. Acta, vol.1134,
1992, p.169). The membrane suspension (about 10 .mu.g total protein
per sample) and 1 nM of .sup.3H-rauwolscine (specific activity
75-85 Ci/mmol) were incubated with a minimum of six concentrations
of the test compound in a total volume of 90 .mu.l (50 mM
KH.sub.2PO.sub.4, pH 7.5, at room temperature). Non-specific
binding was defined by 100 .mu.M oxymetazoline and corresponded to
4-10% of the total binding. After 30 min at room temperature, the
incubation was terminated by rapid filtration (TomTec 96 harvester)
through presoaked GF/B glass-fiber mats (Wallac Oy) and three
washes with ice-cold 50 mM KH.sub.2PO.sub.4 (pH 7.5, at room
temperature). After drying, a solid scintillate (Meltilex; Wallac
Oy) was melted on filter mats, and the radioactivity was measured
(BetaPlate; Wallac Oy). The analysis of the experiments was carried
out by non-linear least square curve fitting. IC.sub.50's were
converted to Ki's by using the equation of Cheng-Prussoff
(K.sub.i=IC.sub.50/(1+[.sup.3H-ligand]/K.s- ub.d, 3H-ligand)). The
K.sub.i values for Compound 1 obtained in a minimum of three
independent experiments were:
[0206] alpha-2A Adrenoceptor: 3150.+-.50 nM
[0207] alpha-2B Adrenoceptor: 1470.+-.130 nM
[0208] alpha-2C Adrenoceptor: 28.+-.2 nM
[0209] EXPERIMENT II: Antagonist Activity
[0210] Antagonist activity was determined as the ability of
compounds to competetively inhibit epinephrine-stimulated
.sup.35S-GTP.gamma.S binding to G proteins (J. R. Jasper et al.,
Biochem. Pharmacol., vol.55, 1998, p.1035) in membranes of CHO
cells stably transfected with one of the three human alpha-2
subtypes (K. Pohjanoksa et al., Eur. J. Pharmacol., vol.335, 1997,
p.53). Membranes (5-10 .mu.g of protein per sample) and 12
concentrations of test compound were preincubated for 30 min at
room temperature in 50 mM Tris, 5 mM MgCl2, 150 mM NaCl, 1 mM DTT,
1 mM EDTA, 10 .mu.M GDP, 30 .mu.M ascorbic acid, pH 7.4, with a
fixed concentration of epinephrine (5 .mu.M for alpha-2A, 15 .mu.M
for alpha-2B, 5 .mu.M for alpha-2C). Then trace amounts of
.sup.35S-GTP.gamma.S (0.08 nM-0.15 nM, specific activity 1250
Ci/mmol) were added to the incubation mixture. After an additional
30 min at room temperature, the incubation was terminated by rapid
vacuum filtration through glass fiber filter. Filters were washed
three times with 5 ml ice cold wash buffer (20 mM Tris, 5 mM
MgCl.sub.2, 1 mM EDTA, pH 7.4, at room temperature), dried and
counted for radioactivity in a scintillation counter. Analysis of
experiments was carried out by nonlinear least square fitting.
Experiments were repeated at least three times. The K.sub.B values
of Compound 1 were found to correspond to:
[0211] alpha-2A Adrenoceptor: 1495.+-.270 nM
[0212] alpha-2B Adrenoceptor: 2175.+-.345 nM
[0213] alpha-2C Adrenoceptor: 16.+-.6 nM
[0214] EXPERIMENT III: Antagonism of Dexmedetomidine-Induced
Locomotor Inhibition by Atipamezole but not by Compound 1;
Demonstration of in vivo alpha2C Selectivity of Compound 1
[0215] Dexmedetomidine and atipamezole are very potent and specific
alpha-2 adrenoceptor agonists and antagonists, respectively, which
lack alpha-2 subtype selectivity (H. Scheinin et al., European
Journal of Pharmacology, Molecular Section, vol.151(1), 1988,
p.35-42). The alpha-2 agonist -induced sedation is known to be an
alpha-2A-mediated phenomenon that can be antagonised by alpha-2
antagonists (J. Sallinen et al., Mol. Pharmacol. Vol.51, 1997,
p.36-46, and A. Haapalinna et al., Naunyn-Schimiedeberg's Arch.
Pharmacol. Vol.356, 1997, p.570-582). The sedative effect of
alpha-2 agonists in mice is measured by the inhibition on locomotor
activity. Therefore, we compared the ability of Compound 1 and
atipamezole to antagonise the dexmedetomidine-induced locomotor
inhibition to evaluate the in vivo alpha-2A adrenoceptor antagonism
(and alpha-2C selectivity) of these compounds.
[0216] Spontaneous locomotor activity of a total of 76 male NMRI
mice (B&K, Sweden) was measured by placing individual animals
into a polypropylene animal cage (38.times.22.times.15 cm). The
cages were surrounded with an infrared photobeam frame system
designed for activity measurements (Photobeam Activity System PAS,
Cage Rack, San Diego Instruments, San Diego, Calif., USA). The
animals were injected with various doses of either Compound 1 or
atipamezole 20 min before injection of dexmedetomidine (50 nmol/kg
s.c.). Spontaneous locomotor activity was measured 20 min after
dexmedetomidine injection.
[0217] The results presented in FIG. 1 show that atipamezole
inhibited dexmedetomidine-induced sedation with doses 0.3 and 1.0
.mu.mol/kg s.c. (p <0.01) as was expected. In contrast, Compound
1 did not antagonise the alpha-2-agonist-induced sedation at all,
demonstrating the lack of alpha-2A antagonism and the alpha-2C
selectivity of Compound 1 in vivo.
[0218] EXPERIMENT IV: Stress-Protective Effect of Compound 1 in the
Mouse Forced Swimming Test
[0219] Exposure of a test animal to an intense stressful stimulus
has been observed to propagate a state of behavioural despair. This
can be observed for example employing the forced swimming test, in
which a rat or mouse is put into a water-filled cylinder. After a
vigorous period of attempts to escape animals adopt an immobile
floating posture; the extent of the immobile period is monitored
and can be reduced by antidepressants and stress-protective agents.
Transgenic mice that lack functional alpha-2C adrenoceptor
tolerated swim-stress better than their similarly treated wild-type
controls (J. Sallinen et al., Mol. Psychiatry, vol.4, 1999,
p.443-452). Therefore, an increase in the forced swimming activity
can be used as a measure of in vivo alpha-2C selective antagonism
of a compound. The non-selective antagonist atipamezole did not
have a clear stress-protective effect and even increased
vocalizations of test animals (T. Kauppila et al., Eur. J.
Pharmacol., vol.205, 1991, p. 177-182). This may have resulted from
the simultaneous alpha-2A antagonistic activity of atipamezole,
since conventionally non-selective alpha-2 adrenoceptor
antagonists, such as yohimbine, have been found to be anxiogenic
(S. Southwick et al., Arch. Gen. Psychiatry, vol.54, 1997,
p.749-758).
[0220] The forced swim test was conducted as originally described
employing the stress sensitive (J. Crawley and L. Davis, Brain
Research Bulletin, vol.8, 1982, p.609-612, and U.S. Pat. No.
5,902,807) Balb/c mouse strain (B&K, Sweden). The mice were
administered either with vehicle (0.1% DMSO, 5 ml/kg
subcutaneously), Compound 1 0.3 .mu.mol/kg, or atipamezole 0.3
.mu.mol/kg 40 min before putting the mice into a vessel (10 cm
diameter, 18.5 cm height, filled with 25.degree. C. water up to 8
cm height). The cumulative activity of each mouse was measured
between 2 and 6 min after introduction to the vessel. Only vigorous
attempts to escape (climbing) were registered. The mice (a total of
96) were tested only once. The results are shown in FIG. 2.
[0221] Mice administered with Compound 1 tolerated clearly better
stress-induced propagation of behavioural despair when compared to
vehicle injected group of mice (1-way ANOVA, followed by LSD post
hoc test; p=0.013) as was expected for an alpha-2C selective
compound. Atipamezole did not have any clear effect on the activity
compared to control mice (p=0.52). A possible marginal effect of
atipamezole was expected, since this subtype-non-selective alpha-2
antagonist blocks also the alpha-2C adrenoceptors. On the other
hand the employed 0.3 .mu.mol/kg dose of atipamezole was shown to
have also alpha2A antagonism in vivo (FIG. 1). The employed doses
of atipamezole have also been shown to have clear neurochemical
effects, i.e. to stimulate noradrenaline release in brain (A.
Haapalinna et al., Naunyn-Schimiedeberg's Arch. Pharmacol. Vol.356,
1997, p.570-582). Therefore, the results support that alpha-2A
adrenoceptor antagonism of atipamezole can counteract the
stress-protective and antidepressant effects of alpha-2C antagonism
in vivo (J. Sallinen et al., Mol. Psychiatry, vol.4, 1999,
p.443-452, and U.S. Pat. No. 5,902,807).
[0222] In general, the compounds of the invention exhibiting
alpha-2 adrenoceptor antagonistic activity may be useful for the
treatment of diseases or conditions wherein alpha-2 antagonists are
effective. For example, the compounds can be used to treat
disorders of the central nervous system, male sexual impotence,
orthostatic hypotension, non-insulin dependent diabetes, and
obesity, for example, disorders of the central nervous system. The
compounds can also be used to reverse effects induced by alpha-2
agonists. Disorders of the central nervous system treatable with
the compounds of the invention include depression, anxiety,
post-traumatic stress disorder, schizophrenia, Parkinson's disease,
and other movement disorders.
[0223] The selective alpha-2C antagonists of the present invention
may be used for the treatment of various diseases or conditions of
CNS-system where alpha2C-antagonists are indicated to be beneficial
(see e.g. U.S. Pat. No. 5,902,807, J. Sallinen et al.,
Neuroscience, vol. 86, 1998, p.959-965, J. Sallinen et al., J.
Neurosci., vol. 18, 1998, p.3035-3042, and M. Bjorklund et al.,
Molecular Pharmacology, vol.54, 1998, p.569-76, the contents of
which are hereby incorporated by reference), for example, in the
treatment of schizophrenia and depression. Furthermore, the present
alpha-2C antagonists can be used as stress-protective agents, or as
agents for the treatment of CNS-disorders induced by stress, e.g.
of post-traumatic stress disorder, as indicated, for example, in
U.S. Pat. No. 5,902,807 cited above. Because alpha-2C antagonists
appear to stimulate central dopaminergic activity, they can be used
as antiparkinsonian agents in Parkinson's disease and other
movement disorders. Moreover, the present alpha-2C antagonists may
also exhibit cognition enhancing properties and thus may be used in
the treatment of Alzheimer's disease and other dementias.
[0224] Due to the selectivity of tissue distribution, the alpha-2C
antagonists of the invention have less or no undesirable
side-effects, such as cardiovascular effects.
[0225] The compounds of the invention may be administered
enterally, topically or parenterally.
[0226] The compounds of the invention may be formulated alone or
together with another active ingredient and/or together with a
pharmaceutically acceptable diluent, carrier and/or excipient in
different pharmaceutical unit dosage forms, e.g. tablets, capsules,
solutions, emulsions and powders etc., depending on the route of
administration, using conventional techniques. The pharmaceutically
acceptable diluent, carrier and/or excipient can be selected from
those conventionally used in the field of pharmaceuticals noticing
the chosen route of administration.
[0227] The amount of the active ingredient in a dosage form may
vary from, for example, 0.01 to 75 weight-% depending on, for
example, the type of the dosage form.
[0228] The specific dose level of the compounds of the invention
depends on several factors such as the compound to be administered,
the species, age and the sex of the subject to be treated, the
condition to be treated and on the route and method of
administration. Accordingly, the dosage for parenteral
administration is typically from 0.5 .mu.g/kg to 10 mg/kg per day
and that for oral administration is from 5 .mu.g/kg to 100 mg/kg
for an adult male.
[0229] The present invention further provides a compound of the
invention for use as alpha-2 antagonist. Furthermore, a method for
the treatment of diseases or conditions where alpha-2 antagonists,
e.g. alpha-2C antagonists, are indicated to be useful, e.g. a
method for the treatment of diseases or conditions of the central
nervous system, is provided. In such a method a therapeutically
effective amount of a compound of the invention is administered to
a subject in need of such treatment. The use of the compounds of
the invention for the manufacture of a medicament to be used for
the above indications is also provided.
[0230] Those skilled in the art will appreciate that the
embodiments described in this application could be modified without
departing from the broad inventive concept. Those skilled in the
art also understand that the invention is not limited to the
particular disclosed embodiments, but is intended to also cover
modifications to the embodiments that are within the spirit and
scope of the invention.
* * * * *