U.S. patent application number 15/435553 was filed with the patent office on 2017-06-08 for hexahydrodiazepinoquinolines carrying a cyclic radical.
The applicant listed for this patent is AbbVie Deutschland GmbH & Co. KG, AbbVie Inc.. Invention is credited to Gisela BACKFISCH, Margaretha Henrica Maria BAKKER, Gunter BLAICH, Wilfried BRAJE, Karla DRESCHER, Thomas ERHARD, Andreas HAUPT, Hannes KOOLMAN, Viktor LAKICS, Anna LINSENMEIER, Helmut MACK, Raimund PETER, Ana Lucia RELO, Jincheng WANG, Xiaona ZHAO.
Application Number | 20170158693 15/435553 |
Document ID | / |
Family ID | 52706153 |
Filed Date | 2017-06-08 |
United States Patent
Application |
20170158693 |
Kind Code |
A1 |
BACKFISCH; Gisela ; et
al. |
June 8, 2017 |
HEXAHYDRODIAZEPINOQUINOLINES CARRYING A CYCLIC RADICAL
Abstract
The present invention relates to tricyclic
hexahydrodiazepinoquinolines carrying a cyclic substituent, to a
method for producing them, to a pharmaceutical composition
containing such compounds, to their use as modulators, especially
agonists or partial agonists, of the 5-HT.sub.2C receptor, their
use for preparing a medicament for the prevention or treatment of
conditions and disorders which respond to the modulation of
5-HT.sub.2C receptor, to a method for preventing or treating
conditions and disorders which respond to the modulation of
5-HT.sub.2C receptor, and processes for preparing such compounds
and compositions.
Inventors: |
BACKFISCH; Gisela;
(Ludwigshafen, DE) ; BAKKER; Margaretha Henrica
Maria; (Ludwigshafen, DE) ; BLAICH; Gunter;
(Ludwigshafen, DE) ; BRAJE; Wilfried;
(Ludwigshafen, DE) ; DRESCHER; Karla;
(Ludwigshafen, DE) ; ERHARD; Thomas;
(Ludwigshafen, DE) ; HAUPT; Andreas;
(Ludwigshafen, DE) ; KOOLMAN; Hannes; (North
Chicago, IL) ; LAKICS; Viktor; (Ludwigshafen, DE)
; LINSENMEIER; Anna; (Ludwigshafen, DE) ; MACK;
Helmut; (Ludwigshafen, DE) ; PETER; Raimund;
(Wilmslow, GB) ; RELO; Ana Lucia; (Ludwigshafen,
DE) ; ZHAO; Xiaona; (Tianjin, CN) ; WANG;
Jincheng; (Tianjin, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Deutschland GmbH & Co. KG
AbbVie Inc. |
Wiesbaden
North Chicago |
IL |
DE
US |
|
|
Family ID: |
52706153 |
Appl. No.: |
15/435553 |
Filed: |
February 17, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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14657840 |
Mar 13, 2015 |
9573950 |
|
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15435553 |
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61953424 |
Mar 14, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/06 20130101;
A61P 25/00 20180101; C07D 471/04 20130101 |
International
Class: |
C07D 471/06 20060101
C07D471/06 |
Claims
1. A compound of the formula I ##STR00016## wherein R.sup.1 is
selected from the group consisting of hydrogen, cyano,
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy,
--C(.dbd.O)R.sup.9, phenyl, phenyl-C.sub.1-C.sub.2-alkyl and a 3-,
4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or
maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4
heteroatoms or heteroatom groups independently selected from N, O,
S, NO, SO and SO.sub.2 and optionally also 1 or 2 C.dbd.O and/or
C.dbd.S groups as ring members, where the cyclic moieties in the
three last-mentioned radicals may be substituted with one or more
substituents R.sup.10; each R.sup.2 is independently selected from
the group consisting of cyano, nitro, C.sub.1-C.sub.6-alkyl,
fluorinated C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-hydroxyalkyl,
C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
--CH.sub.2NR.sup.11aR.sup.11b, --C(O)R.sup.9, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, and a 3-, 4-, 5-, 6-, 7- or
8-membered saturated, partially unsaturated or maximally
unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom
groups independently selected from N, O, S, NO, SO, SO.sub.2,
C.dbd.O and C.dbd.S as ring members, where the cyclic moieties in
the six last-mentioned radicals may be substituted with one or more
substituents R.sup.10; or two radicals R.sup.2 bound to the same
carbon atom, together with the carbon atom they are bound to, form
a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated
or maximally unsaturated ring, where the ring may contain 1, 2, 3
or 4 heteroatoms or heteroatom-containing groups selected from O,
S, N, SO, SO.sub.2, C.dbd.O and C.dbd.S as ring members, and where
the ring may be substituted with one or more substituents R.sup.10;
R.sup.3a and R.sup.3b, independently of each other, are selected
from the group consisting of hydrogen, cyano, nitro,
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-hydroxyalkyl, C.sub.2-C.sub.6-alkenyl, fluorinated
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
--CH.sub.2NR.sup.11aR.sup.11b, --C(.dbd.O)R.sup.9, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, and a 3-, 4-, 5-, 6-, 7- or
8-membered saturated, partially unsaturated or maximally
unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom
groups independently selected from N, O, S, NO, SO, SO.sub.2,
C.dbd.O and C.dbd.S as ring members, where the cyclic moieties in
the six last-mentioned radicals may be substituted with one or more
substituents R.sup.10; R.sup.4a and R.sup.4b, independently of each
other, are selected from the group consisting of hydrogen, cyano,
nitro, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-hydroxyalkyl, C.sub.2-C.sub.6-alkenyl, fluorinated
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
--CH.sub.2NR.sup.11aR.sup.11b, --C(.dbd.O)R.sup.9, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, and a 3-, 4-, 5-, 6-, 7- or
8-membered saturated, partially unsaturated or maximally
unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom
groups independently selected from N, O, S, NO, SO, SO.sub.2,
C.dbd.O and C.dbd.S as ring members, where the cyclic moieties in
the six last-mentioned radicals may be substituted with one or more
substituents R.sup.10; or R.sup.4a and R.sup.4b form together a
group .dbd.O or .dbd.S; or R.sup.4a and R.sup.4b, together with the
carbon atom they are bound to, form a 3-, 4-, 5-, 6-, 7- or
8-membered saturated, partially unsaturated or maximally
unsaturated ring, where the ring may contain 1, 2, 3 or 4
heteroatoms or heteroatom-containing groups selected from O, S, N,
SO, SO.sub.2, C.dbd.O and C.dbd.S as ring members, and where the
ring may be substituted with one or more substituents R.sup.10;
R.sup.5a and R.sup.5b, independently of each other, are selected
from the group consisting of hydrogen, halogen, cyano, nitro,
hydroxyl, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-hydroxyalkyl, C.sub.2-C.sub.6-alkenyl, fluorinated
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.6-alkoxy, fluorinated
C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.6-hydroxyalkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.6-alkylthio, fluorinated C.sub.1-C.sub.6-alkylthio,
C.sub.1-C.sub.6-alkylsulfinyl, fluorinated
C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl,
fluorinated C.sub.1-C.sub.6-alkylsulfonyl, --NR.sup.11aR.sup.11b,
--CH.sub.2NR.sup.11aR.sup.11b, --NR.sup.11aC(O)R.sup.9,
--C(.dbd.O)R.sup.9, SO.sub.2NR.sup.11aR.sup.11b,
C.sub.1-C.sub.6-alkylcarbonyloxy, fluorinated
C.sub.1-C.sub.6-alkylcarbonyloxy, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, phenoxy, phenylsulfonyl, benzyloxy
and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially
unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4
heteroatoms or heteroatom groups independently selected from N, O,
S, NO, SO, SO.sub.2, C.dbd.O and C.dbd.S as ring members, where the
cyclic moieties in the six last-mentioned radicals may be
substituted with one or more substituents R.sup.10; where R.sup.5a
and R.sup.5b are not simultaneously hydroxyl; or R.sup.5a and
R.sup.5b, together with the carbon atom they are bound to, form a
3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated
or maximally unsaturated ring, where the ring may contain 1, 2, 3
or 4 heteroatoms or heteroatom-containing groups selected from O,
S, N, SO, SO.sub.2, C.dbd.O and C.dbd.S as ring members, and where
the ring may be substituted with one or more substituents R.sup.10;
R.sup.6 is a cyclic radical selected from the group consisting of
C.sub.3-C.sub.6-cycloalkyl which may carry one or more radicals
R.sup.8; and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated,
partially unsaturated or maximally unsaturated heterocyclic ring
containing 1, 2, 3 or 4 heteroatoms or heteroatom groups
independently selected from N, O, S, NO, SO and SO.sub.2, and
optionally also 1 or 2 groups C.dbd.O and/or C.dbd.S, as ring
members, where the heterocyclic ring may be substituted with one or
more substituents R.sup.10; each R.sup.7 is independently selected
from the group consisting of halogen, cyano, nitro, hydroxyl,
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-hydroxyalkyl, C.sub.2-C.sub.6-alkenyl, fluorinated
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl,
fluorinated C.sub.3-C.sub.8-cycloalkenyl, C.sub.1-C.sub.6-alkoxy,
fluorinated C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.6-hydroxyalkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.6-alkylthio, fluorinated C.sub.1-C.sub.6-alkylthio,
C.sub.1-C.sub.6-alkylsulfinyl, fluorinated
C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl,
fluorinated C.sub.1-C.sub.6-alkylsulfonyl, --NR.sup.11aR.sup.11b,
--CH.sub.2NR.sup.11aR.sup.11b, --NR.sup.11aC(O)R.sup.9,
--C(.dbd.O)R.sup.9, SO.sub.2NR.sup.11aR.sup.11b,
C.sub.1-C.sub.6-alkylcarbonyloxy, fluorinated
C.sub.1-C.sub.6-alkylcarbonyloxy, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, phenoxy, phenylsulfonyl, benzyloxy
and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially
unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4
heteroatoms or heteroatom groups independently selected from N, O,
S, NO, SO, SO.sub.2, C.dbd.O and C.dbd.S as ring members, where the
cyclic moieties in the six last-mentioned radicals may be
substituted with one or more substituents R.sup.10; or two radicals
R.sup.7 bound on neighboring carbon atoms, together with the carbon
atoms they are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered
partially unsaturated or maximally unsaturated ring, where the ring
may contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing
groups selected from O, S, N, SO, SO.sub.2, C.dbd.O and C.dbd.S as
ring members, and where the ring may be substituted with one or
more substituents R.sup.10; each R.sup.8 is independently selected
from the group consisting of halogen, cyano, hydroxyl,
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-hydroxyalkyl, C.sub.2-C.sub.6-alkenyl, fluorinated
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.6-alkoxy, fluorinated
C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
--NR.sup.11aR.sup.11b, --CH.sub.2NR.sup.11aR.sup.11b, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-,
6-, 7- or 8-membered saturated, partially unsaturated or maximally
unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom
groups independently selected from N, O, S, NO, SO, SO.sub.2,
C.dbd.O and C.dbd.S as ring members, where the cyclic moieties in
the five last-mentioned radicals may be substituted with one or
more substituents R.sup.10; or two radicals R.sup.8 bound to the
same carbon atom may form together a group .dbd.O or .dbd.S; each
R.sup.9 is independently selected from the group consisting of
hydrogen, cyano, hydroxyl, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-hydroxyalkyl,
C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy,
--NR.sup.11aR.sup.11b, --CH.sub.2NR.sup.11aR.sup.11b, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-,
6-, 7- or 8-membered saturated, partially unsaturated or maximally
unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom
groups independently selected from N, O, S, NO, SO, SO.sub.2,
C.dbd.O and C.dbd.S as ring members, where the cyclic moieties in
the five last-mentioned radicals may be substituted with one or
more substituents R.sup.10; each R.sup.10 is independently selected
from the group consisting of halogen, cyano, nitro, hydroxyl,
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-hydroxyalkyl, C.sub.2-C.sub.6-alkenyl, fluorinated
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.6-alkoxy, fluorinated
C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.6-hydroxyalkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.6-alkylthio, fluorinated C.sub.1-C.sub.6-alkylthio,
C.sub.1-C.sub.6-alkylsulfinyl, fluorinated C.sub.1-C.sub.6
alkylsulfinyl C.sub.1-C.sub.6-alkylsulfonyl, fluorinated
C.sub.1-C.sub.6-alkylsulfonyl, --COOH, --NR.sup.11aR.sup.11b,
--CH.sub.2NR.sup.11aR.sup.11b, C.sub.1-C.sub.6-alkylcarbonyl,
fluorinated C.sub.1-C.sub.6-alkylcarbonyl,
C.sub.1-C.sub.6-alkoxycarbonyl, fluorinated
C.sub.1-C.sub.6-alkoxycarbonyl, SO.sub.2NR.sup.11aR.sup.11b,
C.sub.1-C.sub.6-alkylcarbonyloxy and fluorinated
C.sub.1-C.sub.6-alkylcarbonyloxy; or two radicals R.sup.10,
together with the atom(s) they are bound to, form a saturated,
partially unsaturated or maximally unsaturated 3-, 4-, 5-, 6- or
7-membered carbocyclic or heterocyclic ring, where the heterocyclic
ring contains 1, 2 or 3 heteroatoms or heteroatom groups
independently selected from N, O, S, NO, SO, SO.sub.2, C.dbd.O and
C.dbd.S as ring members; R.sup.11a and R.sup.11b independently of
each other and independently of each occurrence, are selected from
the group consisting of hydrogen, cyano, C.sub.1-C.sub.6-alkyl,
fluorinated C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
fluorinated C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
fluorinated C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl,
fluorinated C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.6-alkoxy,
fluorinated C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylcarbonyl,
fluorinated C.sub.1-C.sub.6-alkylcarbonyl,
C.sub.1-C.sub.6-alkoxycarbonyl, fluorinated
C.sub.1-C.sub.6-alkoxycarbonyl, phenyl and benzyl, where the phenyl
moieties in the two last-mentioned radicals may carry 1, 2 or 3
substituents selected from halogen, cyano nitro,
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy and fluorinated C.sub.1-C.sub.6-alkoxy; or,
if R.sup.11a and R.sup.11b are bound to the same nitrogen atom,
together with this nitrogen atom may form a 3-, 4-, 5-, 6-, 7- or
8-membered saturated, partially unsaturated or maximally
unsaturated heterocyclic ring, where the ring may further contain
1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected
from O, S, N, SO, SO.sub.2, C.dbd.O and C.dbd.S as ring members,
and where the ring may be substituted with one or more substituents
selected from halogen, cyano nitro, C.sub.1-C.sub.6-alkyl,
fluorinated C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy and
fluorinated C.sub.1-C.sub.6-alkoxy; a is 0, 1 or 2; and b is 0, 1,
2 or 3; or an N-oxide, a tautomeric form, a stereoisomer or a
pharmaceutically acceptable salt thereof.
2. The compound as claimed in claim 1, where R.sup.1 is selected
from hydrogen and C.sub.1-C.sub.6-alkyl.
3. The compound as claimed in claim 2, where R.sup.1 is
hydrogen.
4. The compound as claimed in any of the preceding claims, where
R.sup.2 is selected from C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl
and fluorinated C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl.
5. The compound as claimed in claim 4, where R.sup.2 is selected
from C.sub.1-C.sub.6-alkyl and fluorinated
C.sub.1-C.sub.6-alkyl.
6. The compound as claimed in claim 5, where R.sup.2 is selected
from methyl and CF.sub.3.
7. The compound as claimed in any of the preceding claims, where
R.sup.3a and R.sup.3b, independently of each other, are selected
from hydrogen, cyano, nitro, C.sub.1-C.sub.6-alkyl and fluorinated
C.sub.1-C.sub.6-alkyl.
8. The compound as claimed in claim 7, where R.sup.3a is selected
from hydrogen, cyano, nitro, C.sub.1-C.sub.6-alkyl and fluorinated
C.sub.1-C.sub.6-alkyl; and R.sup.3b is hydrogen.
9. The compound as claimed in claim 8, where R.sup.3a is selected
from hydrogen and methyl; and R.sup.3b is hydrogen.
10. The compound as claimed in claim 9, where R.sup.3a and R.sup.3b
are hydrogen.
11. The compound as claimed in any of the preceding claims, where
R.sup.4a and R.sup.4b, independently of each other, are selected
from hydrogen, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl
and fluorinated C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, or
form together a group .dbd.O, or form together a group
--(CH.sub.2).sub.m--, where m is 2, 3 or 4.
12. The compound as claimed in claim 11, where R.sup.4a and
R.sup.4b are hydrogen.
13. The compound as claimed in any of the preceding claims, where
R.sup.5a is selected from hydrogen, halogen, C.sub.1-C.sub.6-alkyl,
fluorinated C.sub.1-C.sub.6-alkyl and
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl and R.sup.5b is
hydrogen.
14. The compound as claimed in claim 13, where R.sup.5a is hydrogen
or methyl and R.sup.5b is hydrogen.
15. The compound as claimed in any of the preceding claims, where
R.sup.6 is C.sub.3-C.sub.6-cycloalkyl which may carry one or more
radicals R.sup.8; where R.sup.8 is as defined in claim 1.
16. The compound as claimed in claim 15, where each R.sup.8 is
independently selected from the group consisting of halogen, cyano,
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl and fluorinated
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl.
17. The compound as claimed in any of claim 15 or 16, where R.sup.6
is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
2,2-difluorocyclopropyl and 3,3-difluorocyclobutyl.
18. The compound as claimed in claim 17, where R.sup.6 is selected
from cyclopropyl and cyclobutyl.
19. The compound as claimed in claim 18, where R.sup.6 is
cyclopropyl.
20. The compound as claimed in claim 17, where R.sup.6 is
2,2-difluorocyclopropyl.
21. The compound as claimed in any of claims 1 to 14, where R.sup.6
is a 3-, 4-, 5-, 6- or 7-membered saturated heterocyclic ring
containing 1, 2 or 3 heteroatoms or heteroatom groups independently
selected from N, O, S, NO, SO and SO.sub.2, and optionally also 1
or 2 groups C.dbd.O and/or C.dbd.S, as ring members, where the
heterocyclic ring may be substituted with one or more substituents
R.sup.10; where R.sup.10 is as defined in claim 1.
22. The compound as claimed in claim 21, where R.sup.6 is a 3-, 4-,
5- or 6-membered saturated heterocyclic ring containing 1 or 2
heteroatoms or heteroatom groups independently selected from N, O,
S, NO, SO and SO.sub.2 as ring members, where the heterocyclic ring
may be substituted with one or more substituents R.sup.10; where
R.sup.10 is as defined in claim 1.
23. The compound as claimed in claim 22, where R.sup.6 is a
4-membered saturated heterocyclic ring containing 1 heteroatom or
heteroatom group selected from N, O, S, NO, SO and SO.sub.2 as ring
member, where the heterocyclic ring may be substituted with one or
more substituents R.sup.10; where R.sup.10 is as defined in claim
1.
24. The compound as claimed in claim 23, where R.sup.6 is a
4-membered saturated heterocyclic ring containing an oxygen atom as
ring member, where the heterocyclic ring may be substituted with
one or more substituents R.sup.10; where R.sup.10 is as defined in
claim 1.
25. The compound as claimed in claim 24, where R.sup.6 is
oxetan-3-yl which may be substituted with one or more substituents
R.sup.10; where R.sup.10 is as defined in claim 1.
26. The compound as claimed in claim 22, where R.sup.6 is a 5- or
6-membered saturated heterocyclic ring containing 1 heteroatom or
heteroatom group selected from N, O, S, NO, SO and SO.sub.2 as ring
member, where the heterocyclic ring may be substituted with one or
more substituents R.sup.10; where R.sup.10 is as defined in claim
1.
27. The compound as claimed in claim 26, where R.sup.6 is a 5- or
6-membered saturated heterocyclic ring containing an oxygen atom as
ring member, where the heterocyclic ring may be substituted with
one or more substituents R.sup.10; where R.sup.10 is as defined in
claim 1.
28. The compound as claimed in claim 27, where R.sup.6 is
tetrahydrofuran-3-yl or tetrahydropyran-4-yl which may be
substituted with one or more substituents R.sup.10; where R.sup.10
is as defined in claim 1.
29. The compound as claimed in any of claims 21 to 28, where
R.sup.10 is selected from the group consisting of halogen,
C.sub.1-C.sub.6-alkyl and fluorinated C.sub.1-C.sub.6-alkyl.
30. The compound as claimed in claim 29, where R.sup.10 is
methyl.
31. The compound as claimed in any of the preceding claims, where
each R.sup.7 is independently selected from the group consisting of
halogen, cyano, nitro, hydroxyl, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, fluorinated
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.6-alkoxy and fluorinated
C.sub.1-C.sub.6-alkoxy.
32. The compound as claimed in claim 31, where each R.sup.7 is
independently selected from halogen, C.sub.1-C.sub.4-alkyl,
fluorinated C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy and
fluorinated C.sub.1-C.sub.4-alkoxy.
33. The compound as claimed in claim 32, where R.sup.7 is
fluorine.
34. The compound as claimed in any of claims 1 to 31, where each
R.sup.7 is independently selected from the group consisting of
cyano and C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl.
35. The compound as claimed in any of the preceding claims, where a
is 0 or 1.
36. The compound as claimed in claim 35, where in case that a is 1,
R.sup.2 is bound in .beta.-position to the nitrogen ring atom
carrying R.sup.1.
37. The compound as claimed in any of the preceding claims, where b
is 0 or 1.
38. The compound as claimed in any of the preceding claims, of
formula I.1 ##STR00017## wherein R.sup.2, R.sup.6, R.sup.7 and b
are as defined in any of claims 1, 4 to 6, 15 to 34 and 37 and a is
0 or 1.
39. The compound as claimed in claim 38, of formula I.1.1
##STR00018## wherein R.sup.7a is H, Cl, F or methyl; a is 0 or 1;
and R.sup.2, R.sup.6, R.sup.7 and b are as defined in any of claims
1, 4 to 6, 15 to 34 and 37.
40. A compound selected from the group consisting of
8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;
(R)-8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinol-
ine;
(S)-8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]qu-
inoline;
8-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]qui-
noline;
(R)-8-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]-
quinoline;
(S)-8-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1--
ij]quinoline;
8-(3-Methyloxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]-
quinoline;
8-(2,2-Difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diaze-
pino[6,7,1-ij]quinoline;
8-(Oxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-
e;
8-(Tetrahydro-2H-pyran-4-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,-
7,1-ij]quinoline;
8-(Tetrahydrofuran-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij-
]quinoline;
8-Cyclopropyl-10-(2-methoxyethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino-
[6,7,1-ij]quinoline;
8-Cyclopropyl-10-(methoxymethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[-
6,7,1-ij]quinoline; and
8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline--
10-carbonitrile; and stereoisomers and pharmaceutically acceptable
salts thereof.
41. A method for producing a compound of formula I according to
claim 1 wherein R.sup.1, R.sup.4b and R.sup.5b are hydrogen and
R.sup.2, if present, is bound in .beta.-position to the nitrogen
ring atom carrying R.sup.1 (compound I'), comprising following
steps: reacting a quinoline compound 1 in which X is a leaving
group with a boron compound of R.sup.6 to the quinoline compound 2
in the presence of a Pd catalyst; reacting the quinoline compound 2
with benzyl bromide to the N-protected quinolinium compound 3;
reducing the quinolinium compound 3 to the N-protected
1,2,3,4-tetrahydroquinoline compound 4; deprotecting the
N-protected 1,2,3,4-tetrahydroquinoline compound 4 to the
1,2,3,4-tetrahydroquinoline compound 5; reacting the
1,2,3,4-tetrahydroquinoline compound 5 with the 2-halogenoacetamide
6, wherein Y is Cl, Br or I, to the 1-acetamide-substituted
1,2,3,4-tetrahydroquinoline compound 7; reducing the carbonyl group
of the 1-acetamide-substituted 1,2,3,4-tetrahydroquinoline compound
7 to the ethylamine-substituted tetrahydroquinoline compound 8;
reacting 8 with the aldehyde or ketone 9, wherein R.sup.ia and
R.sup.ab are as defined in claim 1, but for nitro or cyano, in the
presence of a strong acid to I'; or reacting 2 with the
2-halogenoacetamide 6 to 10, which is then reduced to 7, which is
further reacted as described above: ##STR00019##
42. A method for producing a compound of formula I according to
claim 1 wherein R.sup.1, R.sup.4a, R.sup.4b and R.sup.5b are
hydrogen, and R.sup.2, if present, is bound in .beta.-position to
the nitrogen ring atom carrying R.sup.1 (compound I''), comprising
following steps: reacting the boronic acid 11 and the
.alpha.,.beta.-unsaturated ester 12 in the presence of a Rhodium
catalyst to the dihydroquinolone 13; reducing the dihydroquinolone
13 to the 1,2,3,4-tetrahydroquinoline 14; reacting the
1,2,3,4-tetrahydroquinoline 14 with the 2-halogenoacetamide 6,
wherein Y is Cl, Br or I, to the 1-acetamide-substituted
1,2,3,4-tetrahydroquinoline compound 15; reducing the carbonyl
group of the 1-acetamide-substituted 1,2,3,4-tetrahydroquinoline
compound 15 to the ethylamine-substituted tetrahydroquinoline
compound 16; and reacting 16 with the aldehyde or ketone 9, wherein
R.sup.3a and R.sup.3b are as defined in claim 1, but for nitro or
cyano, in the presence of a strong acid to I'': ##STR00020##
43. A pharmaceutical composition comprising a therapeutically
effective amount of at least one compound as claimed in any of
claims 1 to 40 or an N-oxide, a tautomeric form, a stereoisomer or
a pharmaceutically acceptable salt thereof, in combination with at
least one pharmaceutically acceptable carrier and/or auxiliary
substance.
44. The compound as claimed in any of claims 1 to 40 or an N-oxide,
a tautomeric form, a stereoisomer or a pharmaceutically acceptable
salt thereof for use as a medicament.
45. The compound as claimed in any of claims 1 to 40 or an N-oxide,
a tautomeric form, a stereoisomer or a pharmaceutically acceptable
salt thereof for the treatment of disorders which respond to the
modulation of the 5-HT.sub.2c receptor.
46. The use of a compound as claimed in any of claims 1 to 40 or of
an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically
acceptable salt thereof for the manufacture of a medicament for the
treatment of disorders which respond to the modulation of the
5-HT.sub.2c receptor.
47. A method for treating disorders which respond to the modulation
of the 5-HT.sub.2c receptor, which method comprises administering
to a subject in need thereof at least one compound as defined in
any of claims 1 to 40 or an N-oxide, a tautomeric form, a
stereoisomer or a pharmaceutically acceptable salt thereof.
48. The compound as claimed in claim 45 or the use as claimed in
claim 46 or the method as claimed in claim 47, where the disorders
are selected from the group consisting of damage of the central
nervous system, disorders of the central nervous system, eating
disorders, ocular hypertension, cardiovascular disorders,
gastrointestinal disorders and diabetes.
49. The compound or the use or the method as claimed in claim 48,
where the disorders are selected from the group consisting of
bipolar disorder, depression, atypical depression, mood episodes,
adjustment disorders, anxiety, panic disorders, post-traumatic
syndrome, psychoses, schizophrenia, cognitive deficits of
schizophrenia, memory loss, dementia of aging, Alzheimer's disease,
neuropsychiatric symptoms in Alzheimer's disease, behavioral
disorders associated with dementia, social phobia, mental disorders
in childhood, attention deficit hyperactivity disorder, organic
mental disorders, autism, mutism, disruptive behavior disorder,
impulse control disorder, borderline personality disorder,
obsessive compulsive disorder, migraine and other conditions
associated with cephalic pain or other pain, raised intracranial
pressure, seizure disorders, epilepsy, substance use disorders,
alcohol abuse, cocaine abuse, tobacco abuse, smoking cessation,
sexual dysfunction/erectile dysfunction in males, sexual
dysfunction in females, premenstrual syndrome, late luteal phase
syndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea,
chronic fatigue syndrome, psoriasis, Parkinson's disease, psychosis
in Parkinson's disease, neuropsychiatric symptoms in Parkinson's
disease, Lewy Body dementia, neuropsychiatric symptoms in Lewy Body
dementia, spinal cord injury, trauma, stroke, pain, bladder
dysfunction/urinary incontinence, encephalitis, meningitis, eating
disorders, obesity, bulimia, weight loss, anorexia nervosa, ocular
hypertension, cardiovascular disorders, gastrointestinal disorders,
diabetes insipidus, diabetes mellitus, type I diabetes, type II
diabetes, type III diabetes, diabetes secondary to pancreatic
diseases, diabetes related to steroid use, diabetes complications,
hyperglycemia and insulin resistance.
50. The compound or the use or the method as claimed in claim 49,
where the disorders are selected from schizophrenia, depression,
bipolar disorders, obesity, substance use disorders,
neuropsychiatric symptoms in Alzheimer's disease and
neuropsychiatric symptoms in Parkinson's disease.
Description
CROSS-REFERENCE TO RELATED APPLICATION(S)
[0001] This claims priority to U.S. Provisional Patent Application
No. 61/953,424, filed on Mar. 14, 2014, the entire contents of
which are fully incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to tricyclic
hexahydrodiazepinoquinolines carrying a cyclic substituent, to a
method for producing them, to a pharmaceutical composition
containing such compounds, to their use as modulators, especially
agonists or partial agonists, of the 5-HT.sub.2C receptor, their
use for preparing a medicament for the prevention or treatment of
conditions and disorders which respond to the modulation of
5-HT.sub.2C receptor, to a method for preventing or treating
conditions and disorders which respond to the modulation of
5-HT.sub.2C receptor, and processes for preparing such compounds
and compositions.
BACKGROUND OF THE INVENTION
[0003] Diseases, disorders and conditions where 5-HT.sub.2C
modulation is desired are for example depression, anxiety,
schizophrenia, bipolar disorder, obsessive compulsive disorder,
migraine, pain, epilepsy, substance abuse, eating disorders,
obesity, diabetes, erectile dysfunction and others.
[0004] Serotonin (5-hydroxytryptamine, 5-HT), a monoamine
neurotransmitter and local hormone, is formed by the hydroxylation
and decarboxylation of tryptophan. The greatest concentration is
found in the enterochromaffin cells of the gastrointestinal tract,
the remainder being predominantly present in platelets and in the
Central Nervous System (CNS). 5-HT is implicated in a vast array of
physiological and pathophysiological pathways. In the periphery, it
contracts a number of smooth muscles and induces
endothelium-dependent vasodilation. In the CNS, it is believed to
be involved in a wide range of functions, including the control of
appetite, mood, anxiety, hallucinations, sleep, vomiting and pain
perception.
[0005] Neurons that secrete 5-HT are termed serotonergic. The
function of 5-HT is exerted upon its interaction with specific
(serotonergic) neurons. Seven types of 5-HT receptors have been
identified: 5-HT.sub.1 (with subtypes 5-HT.sub.1A, 5-HT.sub.1B,
5-HT.sub.1D, 5-HT.sub.1E and 5-HT.sub.1F), 5-HT.sub.2 (with
subtypes 5-HT.sub.2A, 5-HT.sub.2B and 5-HT.sub.2C), 5-HT.sub.3,
5-HT.sub.4, 5-HT.sub.5 (with subtypes 5-HT.sub.5A and 5-HT.sub.5B),
5-HT.sub.6 and 5-HT.sub.7. Most of these receptors are coupled to
G-proteins that affect the activities of adenylate cyclase or
phospholipase C.gamma..
[0006] Alterations in the activity of multiple neurotransmitter
receptor systems (dopamine, serotonin, glutamate, GABA,
acetylcholine) have been implicated in the manifestation of the
symptoms of schizophrenia. The most widely accepted "Dopamine
Hypothesis of Schizophrenia" in its simplest form states that the
positive symptoms of this pathology relate to a functional
hyperactivity of the mesolimbic dopaminergic system, while the
negative and cognitive aspects can be traced to a functional
hypoactivity of the mesocortical dopaminergic projections. Atypical
antipsychotics block the mesolimbic dopaminergic neurotransmission,
thereby controlling positive symptoms, with little or no effect on
the nigrostriatal system, leading to less induction of
extrapyramidal side effects (EPS).
[0007] Primary negative and cognitive symptoms of schizophrenia
reflect a dysfunction of the frontal cortex ("hypofrontality"),
which is thought to be induced by a decreased tone in the
mesocortical dopaminergic projection field [Davis K L, Kahn R S, Ko
G and Davidson M (1991). Dopamine in schizophrenia: a review and
re-conceptualization. Am J Psychiatry 148: 1474-86. Weinberger D R
and Berman K F (1996). Prefrontal function in schizophrenia:
confounds and controversies. Philos Trans R Soc Lond B Biol Sci
351: 1495-503]. Agents that selectively enhance dopamine levels in
the cortex have the potential to address the negative symptoms of
this disorder. Atypical antipsychotics lack robust efficacy against
negative and cognitive components of the schizophrenic
syndrome.
[0008] The schizophrenic symptomatology is further complicated by
the occurrence of drug-induced so-called secondary negative
symptoms and cognitive impairment, which are difficult to
distinguish from primary negative and cognitive symptoms [Remington
G and Kapur S (2000). Atypical antipsychotics: are some more
atypical than others? Psychopharmacol 148: 3-15]. The occurrence of
secondary negative symptoms not only limits therapeutic efficacy
but also, together with these side effects, negatively affects
patient compliance.
[0009] It may thus be hypothesized that a novel mechanistic
approach that blocks dopaminergic neurotransmission in the limbic
system but does not affect the striatal and pituitary projection
fields, and stimulates frontocortical projection fields, would
provide an efficacious treatment for all parts of the schizophrenic
pathology, including its positive, negative and cognitive symptoms.
Moreover, a selective compound that is substantially free of the
ancillary pharmacology that characterizes current agents would be
expected to avoid a variety of off-target side effects that plague
current treatments such as extrapyramidal side effects (EPS) and
weight gain.
[0010] The 5-HT.sub.2C receptor, previously named 5-HT1C, is a
G-protein-coupled receptor, which couples to multiple cellular
effector systems including the phospholipase C, A and D pathways.
It is found primarily in the brain and its distribution is
particularly high in the plexus choroideus, where it is assumed to
control cerebrospinal fluid production [Kaufman M J, Hirata F
(1996) Cyclic GMP inhibits phosphoinositide turnover in choroid
plexus: evidence for interactions between second messengers
concurrently triggered by 5-HT.sub.2C receptors. Neurosci Lett
206:153-156]. Very high levels were also found in the
retrosplenial, piriform and entorhinal cortex, anterior olfactory
nucleus, lateral septal nucleus, subthalamic nucleus, amygdala,
subiculum and ventral part of CA3, lateral habenula, substantia
nigra pars compacta, several brainstem nuclei and the whole grey
matter of the spinal cord [Pompeiano M, Palacios J M, Mengod G
(1994). Distribution of the serotonin 5-HT2 receptor family mRNAs:
comparison between 5-HT.sub.2A and 5-HT.sub.2C receptors. Brain Res
Mol Brain Res 23:163-178]. A comparison of the distribution of
5-HT.sub.2C mRNA with that of 5-HT.sub.2C protein in monkey and
human brains has revealed both pre- and postsynaptic localization
[Lopez-Gimenez J F, Mengod G, Palacios J M, Vilaro M T (2001)
Regional distribution and cellular localization of 5-HT.sub.2C
receptor mRNA in monkey brain: comparison with [.sup.3H]mesulergine
binding sites and choline acetyltransferase mRNA. Synapse
42:12-26].
[0011] It is anticipated that modulation of the 5-HT.sub.2C
receptor will improve disorders such as depression, anxiety,
schizophrenia, cognitive deficits of schizophrenia, obsessive
compulsive disorder, bipolar disorder, neuropsychiatric symptoms in
Parkinson' disease, in Alzheimer's disease or Lewy Body dementia,
migraine, epilepsy, substance abuse, eating disorders, obesity,
diabetes, sexual dysfunction/erectile dysfunction, sleep disorders,
psoriasis, Parkinson's disease, pain conditions and disorders, and
spinal cord injury, smoking cessation, ocular hypertension and
Alzheimer's disease. Modulators of the 5-HT.sub.2C receptor are
also shown to be useful in the modulation of bladder function,
including the prevention or treatment of urinary incontinence.
[0012] Compounds with a structure similar to the compounds of the
present invention have been described in WO 2014/041131 and WO
03/091250.
[0013] There is an ongoing need for providing compounds having high
affinity and in particular also high selectivity for the
5-HT.sub.2C receptor. In particular the compounds should have low
affinity to adrenergic receptors, such as the
.alpha..sub.1-adrenergic receptor, histamine receptors, such as the
H.sub.1-receptor, and dopaminergic receptors, such as the
D.sub.2-receptor, in order to avoid or reduce side effects
associated with modulation of these receptors, such as postural
hypotension, reflex tachycardia, potentiation of the
antihypertensive effect of prazosin, terazosin, doxazosin and
labetalol or dizziness associated with the blockade of the
.alpha..sub.1-adrenergic receptor, weight gain, sedation,
drowsiness or potentiation of central depressant drugs associated
with the blockade of the H.sub.1-receptor, or extrapyramidal
movement disorder, such as dystonia, parkinsonism, akathisia,
tardive dyskinesia or rabbit syndrome, or endocrine effects, such
as prolactin elevation (galactorrhea, gynecomastia, mentstrual
changes, sexual dysfunction in males), associated with the blockade
of the D.sub.2-receptor, and even more important no induction of
weight gain in combination with severe metabolic dysfunction found
for marketed antipsychotic drugs.
[0014] It is moreover desirable that the compounds have low
affinity or alternatively an antagonistic effect to/on other
serotonergic receptors, especially the 5-HT.sub.2A and/or
5-HT.sub.2B receptors, in order to avoid or reduce side effects
associated with modulation of these receptors, such as changes
(thickening) of the heart tissue associated with agonism at the
5-HT.sub.2B receptor, and psychotomimetic effect induced by agonism
at the 5-HT.sub.2A receptor. Ideally they should show an agonistic
action on the 5-HT.sub.2C receptor, an antagonistic action on the
5-HT.sub.2A receptor or alternatively no affinity to the
5-HT.sub.2A receptor and no affinity to the 5-HT.sub.2B receptor or
alternatively an antagonistic action on the 5-HT.sub.2B receptor.
Even more ideally the compounds should display an agonistic action
on the 5-HT.sub.2C receptor in combination with an antagonistic
action on the 5-HT.sub.2A receptor and no affinity to the
5-HT.sub.2B receptor.
[0015] Besides the affinity and selectivity for the 5-HT.sub.2C
receptor, further properties may be advantageous for the treatment
and/or prophylaxis of 5-HT.sub.2C-related disorders, such as, for
example:
[0016] 1.) the metabolic stability, for example determined from the
half-lives, measured in vitro, in liver microsomes from various
species (e.g. rat or human);
[0017] 2.) no or only low inhibition of cytochrome P450 (CYP)
enzymes: cytochrome P450 (CYP) is the name for a superfamily of
heme proteins having enzymatic activity (oxidase). They are also
particularly important for the degradation (metabolism) of foreign
substances such as drugs or xenobiotics in mammalian organisms. The
principal representatives of the types and subtypes of CYP in the
human body are: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4
inhibitors (e.g. grapefruit juice, cimetidine, erythromycin) are
used at the same time as medicinal substances which are degraded by
this enzyme system and thus compete for the same binding site on
the enzyme, the degradation thereof may be slowed down and thus
effects and side effects of the administered medicinal substance
may be undesirably enhanced;
[0018] 3.) a suitable solubility in water (in mg/mL);
[0019] 4.) suitable pharmacokinetics (time course of the
concentration of the compound of the invention in plasma or in
tissue, for example brain). The pharmacokinetics can be described
by the following parameters: half-life (in h), volume of
distribution (in lkg-1), plasma clearance (in lh-1kg-1), AUC (area
under the curve, area under the concentration-time curve, in
nghl-1), oral bioavailability (the dose-normalized ratio of AUC
after oral administration and AUC after intravenous
administration), the so-called brain-plasma ratio (the ratio of AUC
in brain tissue and AUC in plasma);
[0020] 5.) no or only low blockade of the hERG channel: compounds
which block the hERG channel may cause a prolongation of the QT
interval and thus lead to serious disturbances of cardiac rhythm
(for example so-called "torsade de pointes"). The potential of
compounds to block the hERG channel can be determined by means of
the displacement assay with radiolabelled dofetilide which is
described in the literature (G. J. Diaz et al., Journal of
Pharmacological and Toxicological Methods, 50 (2004), 187 199). A
smaller IC50 in this dofetilide assay means a greater probability
of potent hERG blockade. In addition, the blockade of the hERG
channel can be measured by electrophysiological experiments on
cells which have been transfected with the hERG channel, by
so-called whole-cell patch clamping (G. J. Diaz et al., Journal of
Pharmacological and Toxicological Methods, 50 (2004), 187-199).
[0021] It was an object of the present invention to provide
compounds for the treatment or prophylaxis of various
5-HT.sub.2C-related diseases. The compounds were intended to have a
high affinity to the 5-HT.sub.2C receptor and be potent and
efficacious 5-HT.sub.2C agonists. In addition, the compounds of the
invention were intended to have one or more of the aforementioned
advantages, namely low affinity on other serotonergic receptors,
and especially the lack of potent agonistic effect (antagonism
preferred) on the 5-HT.sub.2A and/or 5-HT.sub.2B receptors, and
additionally one or more of those advantages mentioned under 1.) to
5.).
[0022] The present invention provides compounds which have an
affinity for the 5-HT.sub.2C, thus allowing the treatment of
disorders related to or affected by the 5-HT.sub.2C receptor.
SUMMARY OF THE INVENTION
[0023] The present invention relates to tricyclic
hexahydrodiazepinoquinolines carrying a cyclic substituent, to a
method for producing them, to compositions comprising such
compounds, their use as modulators, especially agonists or partial
agonists, of the 5-HT.sub.2C receptor, their use for preparing a
medicament for the prevention or treatment of conditions and
disorders which respond to the modulation of 5-HT.sub.2C receptor,
to a method for preventing or treating conditions and disorders
which respond to the modulation of 5-HT.sub.2C receptor, and
processes for preparing such compounds and compositions.
[0024] In one aspect, the present invention relates to compounds of
the formula (I):
##STR00001##
wherein [0025] R.sup.1 is selected from the group consisting of
hydrogen, cyano, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, fluorinated
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.6-alkoxy, fluorinated
C.sub.1-C.sub.6-alkoxy, --C(.dbd.O)R.sup.9, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl and a 3-, 4-, 5-, 6-, 7- or 8-membered
saturated, partially unsaturated or maximally unsaturated
heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom
groups independently selected from N, O, S, NO, SO and SO.sub.2 and
optionally also 1 or 2 C.dbd.O and/or C.dbd.S groups as ring
members, where the cyclic moieties in the three last-mentioned
radicals may be substituted with one or more substituents R.sup.10;
[0026] each R.sup.2 is independently selected from the group
consisting of cyano, nitro, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-hydroxyalkyl,
C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
--CH.sub.2NR.sup.11aR.sup.11b, --C(.dbd.O)R.sup.9, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, and a 3-, 4-, 5-, 6-, 7- or
8-membered saturated, partially unsaturated or maximally
unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom
groups independently selected from N, O, S, NO, SO, SO.sub.2,
C.dbd.O and C.dbd.S as ring members, where the cyclic moieties in
the six last-mentioned radicals may be substituted with one or more
substituents R.sup.10; or [0027] two radicals R.sup.2 bound to the
same carbon atom, together with the carbon atom they are bound to,
form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially
unsaturated or maximally unsaturated ring (i.e. a spiro-bound
ring), where the ring may contain 1, 2, 3 or 4 heteroatoms or
heteroatom-containing groups selected from O, S, N, SO, SO.sub.2,
C.dbd.O and C.dbd.S as ring members, and where the ring may be
substituted with one or more substituents R.sup.10; [0028] R.sup.3a
and R.sup.3b, independently of each other, are selected from the
group consisting of hydrogen, cyano, nitro, C.sub.1-C.sub.6-alkyl,
fluorinated C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-hydroxyalkyl,
C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
--CH.sub.2NR.sup.11aR.sup.11b, --C(.dbd.O)R.sup.9, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, and a 3-, 4-, 5-, 6-, 7- or
8-membered saturated, partially unsaturated or maximally
unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom
groups independently selected from N, O, S, NO, SO, SO.sub.2,
C.dbd.O and C.dbd.S as ring members, where the cyclic moieties in
the six last-mentioned radicals may be substituted with one or more
substituents R.sup.10; [0029] R.sup.4a and R.sup.4b, independently
of each other, are selected from the group consisting of hydrogen,
cyano, nitro, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-hydroxyalkyl,
C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
--CH.sub.2NR.sup.11aR.sup.11b, --C(.dbd.O)R.sup.9, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, and a 3-, 4-, 5-, 6-, 7- or
8-membered saturated, partially unsaturated or maximally
unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom
groups independently selected from N, O, S, NO, SO, SO.sub.2,
C.dbd.O and C.dbd.S as ring members, where the cyclic moieties in
the six last-mentioned radicals may be substituted with one or more
substituents R.sup.10; or [0030] R.sup.4a and R.sup.4b form
together a group .dbd.O or .dbd.S; or [0031] R.sup.4a and R.sup.4b,
together with the carbon atom they are bound to, form a 3-, 4-, 5-,
6-, 7- or 8-membered saturated, partially unsaturated or maximally
unsaturated ring (i.e. a spiro-bound ring), where the ring may
contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups
selected from O, S, N, SO, SO.sub.2, C.dbd.O and C.dbd.S as ring
members, and where the ring may be substituted with one or more
substituents R.sup.10; [0032] R.sup.5a and R.sup.5b, independently
of each other, are selected from the group consisting of hydrogen,
halogen, cyano, nitro, hydroxyl, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-hydroxyalkyl,
C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.6-hydroxyalkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.6-alkylthio, fluorinated C.sub.1-C.sub.6-alkylthio,
C.sub.1-C.sub.6-alkylsulfinyl, fluorinated
C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl,
fluorinated C.sub.1-C.sub.6-alkylsulfonyl, --NR.sup.11aR.sup.11b,
--CH.sub.2NR.sup.11aR.sup.11b, --NR.sup.11aC(O)R.sup.9,
--C(.dbd.O)R.sup.9, SO.sub.2NR.sup.11aR.sup.11b,
C.sub.1-C.sub.6-alkylcarbonyloxy, fluorinated
C.sub.1-C.sub.6-alkylcarbonyloxy, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, phenoxy, phenylsulfonyl, benzyloxy
and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially
unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4
heteroatoms or heteroatom groups independently selected from N, O,
S, NO, SO, SO.sub.2, C.dbd.O and C.dbd.S as ring members, where the
cyclic moieties in the six last-mentioned radicals may be
substituted with one or more substituents R.sup.10; where [0033]
R.sup.5a and R.sup.5b are not simultaneously hydroxyl; or [0034]
R.sup.5a and R.sup.5b, together with the carbon atom they are bound
to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially
unsaturated or maximally unsaturated ring (i.e. a spiro-bound
ring), where the ring may contain 1, 2, 3 or 4 heteroatoms or
heteroatom-containing groups selected from O, S, N, SO, SO.sub.2,
C.dbd.O and C.dbd.S as ring members, and where the ring may be
substituted with one or more substituents R.sup.10; [0035] R.sup.6
is a cyclic radical selected from the group consisting of
C.sub.3-C.sub.6-cycloalkyl which may carry one or more radicals
R.sup.8; and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated,
partially unsaturated or maximally unsaturated heterocyclic ring
containing 1, 2, 3 or 4 heteroatoms or heteroatom groups
independently selected from N, O, S, NO, SO and SO.sub.2, and
optionally also 1 or 2 groups C.dbd.O and/or C.dbd.S, as ring
members, where the heterocyclic ring may be substituted with one or
more substituents R.sup.10; [0036] each R.sup.7 is independently
selected from the group consisting of halogen, cyano, nitro,
hydroxyl, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-hydroxyalkyl, C.sub.2-C.sub.6-alkenyl, fluorinated
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl,
fluorinated C.sub.3-C.sub.8-cycloalkenyl, C.sub.1-C.sub.6-alkoxy,
fluorinated C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.6-hydroxyalkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.6-alkylthio, fluorinated C.sub.1-C.sub.6-alkylthio,
C.sub.1-C.sub.6-alkylsulfinyl, fluorinated
C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl,
fluorinated C.sub.1-C.sub.6-alkylsulfonyl, --NR.sup.11aR.sup.11b,
--CH.sub.2NR.sup.11aR.sup.11b, --NR.sup.11aC(O)R.sup.9,
--C(.dbd.O)R.sup.9, SO.sub.2NR.sup.11aR.sup.11b,
C.sub.1-C.sub.6-alkylcarbonyloxy, fluorinated
C.sub.1-C.sub.6-alkylcarbonyloxy, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, phenoxy, phenylsulfonyl, benzyloxy
and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially
unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4
heteroatoms or heteroatom groups independently selected from N, O,
S, NO, SO, SO.sub.2, C.dbd.O and C.dbd.S as ring members, where the
cyclic moieties in the six last-mentioned radicals may be
substituted with one or more substituents R.sup.10; or [0037] two
radicals R.sup.7 bound on neighboring carbon atoms, together with
the carbon atoms they are bound to, form a 3-, 4-, 5-, 6-, 7- or
8-membered partially unsaturated or maximally unsaturated ring,
where the ring may contain 1, 2, 3 or 4 heteroatoms or
heteroatom-containing groups selected from O, S, N, SO, SO.sub.2,
C.dbd.O and C.dbd.S as ring members, and where the ring may be
substituted with one or more substituents R.sup.10; [0038] each
R.sup.8 is independently selected from the group consisting of
halogen, cyano, hydroxyl, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-hydroxyalkyl,
C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
--NR.sup.11aR.sup.11b, --CH.sub.2NR.sup.11aR.sup.11b, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-,
6-, 7- or 8-membered saturated, partially unsaturated or maximally
unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom
groups independently selected from N, O, S, NO, SO, SO.sub.2,
C.dbd.O and C.dbd.S as ring members, where the cyclic moieties in
the five last-mentioned radicals may be substituted with one or
more substituents R.sup.10; [0039] or two radicals R.sup.8 bound to
the same carbon atom may form together a group .dbd.O or .dbd.S;
[0040] each R.sup.9 is independently selected from the group
consisting of hydrogen, cyano, hydroxyl, C.sub.1-C.sub.6-alkyl,
fluorinated C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-hydroxyalkyl,
C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy,
--NR.sup.11aR.sup.11b, --CH.sub.2NR.sup.11aR.sup.11b, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-,
6-, 7- or 8-membered saturated, partially unsaturated or maximally
unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom
groups independently selected from N, O, S, NO, SO, SO.sub.2,
C.dbd.O and C.dbd.S as ring members, where the cyclic moieties in
the five last-mentioned radicals may be substituted with one or
more substituents R.sup.10; [0041] each R.sup.10 is independently
selected from the group consisting of halogen, cyano, nitro,
hydroxyl, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-hydroxyalkyl, C.sub.2-C.sub.6-alkenyl, fluorinated
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, fluorinated
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.6-alkoxy, fluorinated
C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.6-hydroxyalkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.6-alkylthio, fluorinated C.sub.1-C.sub.6-alkylthio,
C.sub.1-C.sub.6-alkylsulfinyl, fluorinated
C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl,
fluorinated C.sub.1-C.sub.6-alkylsulfonyl, --COOH,
--NR.sup.11aR.sup.11b, --CH.sub.2NR.sup.11aR.sup.11b,
C.sub.1-C.sub.6-alkylcarbonyl, fluorinated
C.sub.1-C.sub.6-alkylcarbonyl, C.sub.1-C.sub.6-alkoxycarbonyl,
fluorinated C.sub.1-C.sub.6-alkoxycarbonyl,
SO.sub.2NR.sup.11aR.sup.11b, C.sub.1-C.sub.6-alkylcarbonyloxy and
fluorinated C.sub.1-C.sub.6-alkylcarbonyloxy; [0042] or two
radicals R.sup.10, together with the atom(s) they are bound to,
form a saturated, partially unsaturated or maximally unsaturated
3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring,
where the heterocyclic ring contains 1, 2 or 3 heteroatoms or
heteroatom groups independently selected from N, O, S, NO, SO,
SO.sub.2, C.dbd.O and C.dbd.S as ring members; [0043] R.sup.11a and
R.sup.11b, independently of each other and independently of each
occurrence, are selected from the group consisting of hydrogen,
cyano, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-alkylcarbonyl, fluorinated
C.sub.1-C.sub.6-alkylcarbonyl, C.sub.1-C.sub.6-alkoxycarbonyl,
fluorinated C.sub.1-C.sub.6-alkoxycarbonyl, phenyl and benzyl,
where the phenyl moieties in the two last-mentioned radicals may
carry 1, 2 or 3 substituents selected from halogen, cyano nitro,
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy and fluorinated C.sub.1-C.sub.6-alkoxy; or,
[0044] if R.sup.11a and R.sup.11b are bound to the same nitrogen
atom, together with this nitrogen atom may form a 3-, 4-, 5-, 6-,
7- or 8-membered saturated, partially unsaturated or maximally
unsaturated heterocyclic ring, where the ring may further contain
1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected
from O, S, N, SO, SO.sub.2, C.dbd.O and C.dbd.S as ring members,
and where the ring may be substituted with one or more substituents
selected from halogen, cyano nitro, C.sub.1-C.sub.6-alkyl,
fluorinated C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy and
fluorinated C.sub.1-C.sub.6-alkoxy; [0045] a is 0, 1 or 2; and
[0046] b is 0, 1, 2 or 3; or an N-oxide, a tautomeric form, a
stereoisomer or a pharmaceutically acceptable salt thereof.
[0047] In another aspect, the invention relates to a pharmaceutical
composition comprising a therapeutically effective amount of at
least one compound of formula I or an N-oxide, a tautomeric form, a
stereoisomer or a pharmaceutically acceptable salt thereof, in
combination with at least one pharmaceutically acceptable carrier
and/or auxiliary substance.
[0048] In yet another aspect, the invention relates to a compound
of formula I or an N-oxide, a tautomeric form, a stereoisomer or a
pharmaceutically acceptable salt thereof for use as a
medicament.
[0049] In yet another aspect, the invention relates to a compound
of formula I or an N-oxide, a tautomeric form, a stereoisomer or a
pharmaceutically acceptable salt thereof for the treatment of
disorders which responds to the modulation of the 5-HT.sub.2C
receptor.
[0050] In yet another aspect, the invention relates to the use of a
compound of formula I or of an N-oxide, a tautomeric form, a
stereoisomer or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament for the treatment of disorders which
respond to the modulation of the 5-HT.sub.2C receptor.
[0051] In yet another aspect, the invention relates to the use of a
compound of formula I or of an N-oxide, a tautomeric form, a
stereoisomer or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament for the treatment of disorders selected
from the group consisting of damage of the central nervous system,
disorders of the central nervous system, eating disorders, ocular
hypertension, cardiovascular disorders, gastrointestinal disorders
and diabetes, and especially from the group consisting of bipolar
disorder, depression, atypical depression, mood episodes,
adjustment disorders, anxiety, panic disorders, post-traumatic
syndrome, psychoses, schizophrenia, cognitive deficits of
schizophrenia, memory loss, dementia of aging, Alzheimer's disease,
neuropsychiatric symptoms in Alzheimer's disease (e.g. aggression),
behavioral disorders associated with dementia, social phobia,
mental disorders in childhood, attention deficit hyperactivity
disorder, organic mental disorders, autism, mutism, disruptive
behavior disorder, impulse control disorder, borderline personality
disorder, obsessive compulsive disorder, migraine and other
conditions associated with cephalic pain or other pain, raised
intracranial pressure, seizure disorders, epilepsy, substance use
disorders, alcohol abuse, cocaine abuse, tobacco abuse, smoking
cessation, sexual dysfunction/erectile dysfunction in males, sexual
dysfunction in females, premenstrual syndrome, late luteal phase
syndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea,
chronic fatigue syndrome, psoriasis, Parkinson's disease,
neuropsychiatric symptoms in Parkinson's disease (e.g. aggression),
Lewy Body dementia, neuropsychiatric symptoms in Lewy Body dementia
(e.g. aggression), spinal cord injury, trauma, stroke, pain,
bladder dysfunction/urinary incontinence, encephalitis, meningitis,
eating disorders, obesity, bulimia, weight loss, anorexia nervosa,
ocular hypertension, cardiovascular disorders, gastrointestinal
disorders, diabetes insipidus, diabetes mellitus, type I diabetes,
type II diabetes, type III diabetes, diabetes secondary to
pancreatic diseases, diabetes related to steroid use, diabetes
complications, hyperglycemia and insulin resistance.
[0052] In yet another aspect, the invention relates to a method for
treating disorders which respond to the modulation of the
5-HT.sub.2C receptor, which method comprises administering to a
subject in need thereof at least one compound of formula I or an
N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically
acceptable salt thereof.
[0053] In yet another aspect, the invention relates to a method for
treating disorders selected from the group consisting of damage of
the central nervous system, disorders of the central nervous
system, eating disorders, ocular hypertension, cardiovascular
disorders, gastrointestinal disorders and diabetes, and especially
from the group consisting of bipolar disorder, depression, atypical
depression, mood episodes, adjustment disorders, anxiety, panic
disorders, post-traumatic syndrome, psychoses, schizophrenia,
cognitive deficits of schizophrenia, memory loss, dementia of
aging, Alzheimer's disease, neuropsychiatric symptoms in
Alzheimer's disease (e.g. aggression), behavioral disorders
associated with dementia, social phobia, mental disorders in
childhood, attention deficit hyperactivity disorder, organic mental
disorders, autism, mutism, disruptive behavior disorder, impulse
control disorder, borderline personality disorder, obsessive
compulsive disorder, migraine and other conditions associated with
cephalic pain or other pain, raised intracranial pressure, seizure
disorders, epilepsy, substance use disorders, alcohol abuse,
cocaine abuse, tobacco abuse, smoking cessation, sexual
dysfunction/erectile dysfunction in males, sexual dysfunction in
females, premenstrual syndrome, late luteal phase syndrome, chronic
fatigue syndrome, sleep disorders, sleep apnoea, chronic fatigue
syndrome, psoriasis, Parkinson's disease, neuropsychiatric symptoms
in Parkinson's disease (e.g. aggression), Lewy Body dementia,
neuropsychiatric symptoms in Lewy Body dementia (e.g. aggression),
spinal cord injury, trauma, stroke, pain, bladder
dysfunction/urinary incontinence, encephalitis, meningitis, eating
disorders, obesity, bulimia, weight loss, anorexia nervosa, ocular
hypertension, cardiovascular disorders, gastrointestinal disorders,
diabetes insipidus, diabetes mellitus, type I diabetes, type II
diabetes, type III diabetes, diabetes secondary to pancreatic
diseases, diabetes related to steroid use, diabetes complications,
hyperglycemia and insulin resistance, which method comprises
administering to a subject in need thereof at least one compound of
formula I or an N-oxide, a tautomeric form, a stereoisomer or a
pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION
[0054] The compounds of the formula I may exist in different
spatial arrangements. For example, if the compounds possess one or
more centers of asymmetry, polysubstituted rings or double bonds,
or as different tautomers, the present invention contemplates the
possible use of enantiomeric mixtures, in particular racemates,
diastereomeric mixtures and tautomeric mixtures, such as the
respective essentially pure enantiomers, diastereomers and
tautomers of the compounds of formula I and/or their salts.
[0055] It is likewise possible to use physiologically tolerated
salts of the compounds of the formula I, especially acid addition
salts with physiologically tolerated acids. Examples of suitable
physiologically tolerated organic and inorganic acids are
hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric
acid, acetic acid, trifluoroacetic acid,
C.sub.1-C.sub.4-alkylsulfonic acids, such as methanesulfonic acid,
aromatic sulfonic acids, such as benzenesulfonic acid and
toluenesulfonic acid, oxalic acid, maleic acid, fumaric acid,
lactic acid, tartaric acid, adipic acid and benzoic acid. Other
utilizable acids are described in Fortschritte der
Arzneimittelforschung [Advances in drug research], Volume 10, pages
224 et seq., Birkhaauser Verlag, Basel and Stuttgart, 1966.
[0056] The compounds of formula I may also be present in the form
of tautomers. In one aspect, tautomery may be present in compounds
I wherein R.sup.4a and R.sup.4b form together a group .dbd.O and
R.sup.5a or R.sup.5b is H. For example, the compounds of formula I
may have the following tautomeric formulae:
##STR00002##
[0057] In another aspect, tautomery may be present in compounds I
containing rings which have one or more C.dbd.O groups as ring
members which are neighboured to a CH.sub.2 group.
[0058] The organic moieties mentioned in the above definitions of
the variables are, like the term halogen, collective terms for
individual listings of the individual group members. The prefix
C.sub.n-C.sub.m indicates in each case the possible number of
carbon atoms in the group.
[0059] The term "halogen" denotes in each case fluorine, bromine,
chlorine or iodine. In one aspect, the halogen may be fluorine,
chlorine or bromine.
[0060] The term "alkyl" as used herein and in the alkyl moieties of
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl,
alkoxycarbonyl and the like refers to saturated straight-chain or
branched hydrocarbon radicals having 1 to 2
("C.sub.1-C.sub.2-alkyl"), 1 to 3 ("C.sub.1-C.sub.3-alkyl"), 1 to 4
("C.sub.1-C.sub.4-alkyl") or 1 to 6 ("C.sub.1-C.sub.6-alkyl")
carbon atoms. C.sub.1-C.sub.2-Alkyl is methyl or ethyl.
C.sub.1-C.sub.3-Alkyl is additionally propyl and isopropyl.
C.sub.1-C.sub.4-Alkyl is additionally butyl, 1-methylpropyl
(sec-butyl), 2-methylpropyl (isobutyl) or 1,1-dimethylethyl
(tert-butyl). C.sub.1-C.sub.6-Alkyl is additionally also, for
example, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,
2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl,
1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl,
3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl,
1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,
2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,
1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,
1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl.
[0061] The term "fluorinated alkyl" as used herein refers to
straight-chain or branched alkyl groups having 1 to 2 ("fluorinated
C.sub.1-C.sub.2-alkyl"), 1 to 3 ("fluorinated
C.sub.1-C.sub.3-alkyl"), 1 to 4 ("fluorinated
C.sub.1-C.sub.4-alkyl") or 1 to 6 ("fluorinated
C.sub.1-C.sub.6-alkyl") carbon atoms (as mentioned above), where
some or all of the hydrogen atoms in these groups are replaced by
fluorine atoms. Fluorinated C.sub.1-C.sub.2-alkyl is an alkyl group
having 1 or 2 carbon atoms (as mentioned above), where at least one
of the hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these
groups are replaced by fluorine atoms, such as difluoromethyl,
trifluoromethyl, 1-fluoroethyl, (R)-1-fluoroethyl,
(S)-1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, or pentafluoroethyl. Fluorinated
C.sub.1-C.sub.4-alkyl is a straight-chain or branched alkyl group
having 1 to 4 carbon atoms (as mentioned above), where at least one
of the hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these
groups are replaced by fluorine atoms. Examples are, apart those
listed above for C.sub.1-C.sub.2-fluoroalkyl, 1-fluoropropyl,
(R)-1-fluoropropyl, (S)-1-fluoropropyl, 2-fluoropropyl,
(R)-2-fluoropropyl, (S)-2-fluoropropyl, 3-fluoropropyl,
1,1-difluoropropyl, 2,2-difluoropropyl, 1,2-difluoropropyl,
2,3-difluoropropyl, 1,3-difluoropropyl, 3,3-difluoropropyl,
1,1,2-trifluoropropyl, 1,2,2-trifluoropropyl,
1,2,3-trifluoropropyl, 2,2,3-trifluoropropyl,
3,3,3-trifluoropropyl, 1,1,1-trifluoroprop-2-yl,
2-fluoro-1-methylethyl, (R)-2-fluoro-1-methylethyl,
(S)-2-fluoro-1-methylethyl, 2,2-difluoro-1-methylethyl,
(R)-2,2-difluoro-1-methylethyl, (S)-2,2-difluoro-1-methylethyl,
1,2-difluoro-1-methylethyl, (R)-1,2-difluoro-1-methylethyl,
(S)-1,2-difluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl,
(R)-2,2,2-trifluoro-1-methylethyl,
(S)-2,2,2-trifluoro-1-methylethyl, 2-fluoro-1-(fluoromethyl)ethyl,
1-(difluoromethyl)-2,2-difluoroethyl,
1-(trifluoromethyl)-2,2,2-trifluoroethyl,
1-(trifluoromethyl)-1,2,2,2-tetrafluoroethyl, 1-fluorobutyl,
(R)-1-fluorobutyl, (S)-1-fluorobutyl, 2-fluorobutyl,
(R)-2-fluorobutyl, (S)-2-fluorobutyl, 3-fluorobutyl,
(R)-3-fluorobutyl, (S)-3-fluorobutyl, 4-fluorobutyl,
1,1-difluorobutyl, 2,2-difluorobutyl, 3,3-difluorobutyl,
4,4-difluorobutyl, 4,4,4-trifluorobutyl and the like. Fluorinated
C.sub.1-C.sub.6-alkyl is a straight-chain or branched alkyl group
having 1 to 6 carbon atoms (as mentioned above), where at least one
of the hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these
groups are replaced by fluorine atoms. Additionally examples
include for C.sub.1-C.sub.4-fluoroalkyl, 1-fluoropentyl,
(R)-1-fluoropentyl, (S)-1-fluoropentyl, 2-fluoropentyl,
(R)-2-fluoropentyl, (S)-2-fluoropentyl, 3-fluoropentyl,
(R)-3-fluoropentyl, (S)-3-fluoropentyl, 4-fluoropentyl,
(R)-4-fluoropentyl, (S)-4-fluoropentyl, 5-fluoropentyl,
(R)-5-fluoropentyl, (S)-5-fluoropentyl, 1-fluorohexyl,
(R)-1-fluorohexyl, (S)-1-fluorohexyl, 2-fluorohexyl,
(R)-2-fluorohexyl, (S)-2-fluorohexyl, 3-fluorohexyl,
(R)-3-fluorohexyl, (S)-3-fluorohexyl, 4-fluorohexyl,
(R)-4-fluorohexyl, (S)-4-fluorohexyl, 5-fluorohexyl,
(R)-5-fluorohexyl, (S)-5-fluorohexyl, 6-fluorohexyl,
(R)-6-fluorohexyl, (S)-6-fluorohexyl, and the like.
[0062] The term "alkenyl" as used herein refers to monounsaturated
straight-chain or branched hydrocarbon radicals having 2 to 3
("C.sub.2-C.sub.3-alkenyl"), 2 to 4 ("C.sub.2-C.sub.4-alkenyl") or
2 to 6 ("C.sub.2-C.sub.6-alkenyl") carbon atoms and a double bond
in any position, such as C.sub.2-C.sub.3-alkenyl, such as ethenyl,
1-propenyl, 2-propenyl or 1-methylethenyl; C.sub.2-C.sub.4-alkenyl,
such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl,
1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,
2-methyl-1-propenyl, 1-methyl-2-propenyl or 2-methyl-2-propenyl;
and C.sub.2-C.sub.6-alkenyl, such as ethenyl, 1-propenyl,
2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl,
1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl,
2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,
4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl,
3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl,
3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,
3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl,
1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl,
1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl,
3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl,
2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl,
1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl,
4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl,
3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl,
2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl,
1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,
1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl,
1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl,
1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,
2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl,
2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl,
3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl,
1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl,
2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,
1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl,
1-ethyl-2-methyl-2-propenyl and the like.
[0063] The term "fluorinated alkenyl" as used herein refers to
unsaturated straight-chain or branched hydrocarbon radicals having
2 to 3 ("fluorinated C.sub.2-C.sub.3-alkenyl"), 2 to 4
("fluorinated C.sub.2-C.sub.4-alkenyl") or 2 to 6 ("fluorinated
C.sub.2-C.sub.6-alkenyl") carbon atoms and a double bond in any
position (as mentioned above), where some or all of the hydrogen
atoms in these groups are replaced by fluorine atoms, such as,
fluorovinyl, fluoroallyl and the like.
[0064] The term "alkynyl" as used herein refers to straight-chain
or branched hydrocarbon groups having 2 to 3
("C.sub.2-C.sub.3-alkynyl"), 2 to 4 ("C.sub.2-C.sub.4-alkynyl") or
2 to 6 ("C.sub.2-C.sub.6-alkynyl") carbon atoms and one or two
triple bonds in any position, such as C.sub.2-C.sub.3-alkynyl, such
as ethynyl, 1-propynyl or 2-propynyl; C.sub.2-C.sub.4-alkynyl, such
as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,
3-butynyl, 1-methyl-2-propynyl and the like, and
C.sub.2-C.sub.6-alkynyl, such as ethynyl, 1-propynyl, 2-propynyl,
1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl,
2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl,
1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl,
1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl,
3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl,
1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl,
2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl,
4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl,
1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,
2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl,
1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl
and the like.
[0065] The term "fluorinated alkynyl" as used herein refers to
unsaturated straight-chain or branched hydrocarbon radicals having
2 to 3 ("fluorinated C.sub.2-C.sub.3-alkynyl"), 3 to 4
("fluorinated C.sub.3-C.sub.4-alkynyl") or 2 to 6 ("fluorinated
C.sub.2-C.sub.6-alkynyl") carbon atoms and one or two triple bonds
in any position (as mentioned above), where some or all of the
hydrogen atoms in these groups are replaced by fluorine atoms.
[0066] The term "cycloalkyl" as used herein refers to monocyclic
saturated hydrocarbon radicals having 3 to 8
("C.sub.3-C.sub.8-cycloalkyl"), in particular 3 to 6 carbon atoms
("C.sub.3-C.sub.6-cycloalkyl") or 3 to 5 carbon atoms
("C.sub.3-C.sub.5-cycloalkyl") or 3 or 4 carbon atoms
("C.sub.3-C.sub.4-cycloalkyl"). Examples for
C.sub.3-C.sub.4-cycloalkyl are cyclopropyl and cyclobutyl. Examples
of C.sub.3-C.sub.5-cycloalkyl are cyclopropyl, cyclobutyl and
cyclopentyl. Examples of C.sub.3-C.sub.6-cycloalkyl are
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of
C.sub.3-C.sub.8-cycloalkyl are cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0067] The term "fluorinated cycloalkyl" as used herein refers to
monocyclic saturated hydrocarbon groups having 3 to 8
("C.sub.3-C.sub.8-halocycloalkyl") or preferably 3 to 6
("C.sub.3-C.sub.6-halocycloalkyl") or 3 to 5
("C.sub.3-C.sub.5-halocycloalkyl") carbon ring members (as
mentioned above) in which some or all of the hydrogen atoms are
replaced by fluorine atoms. Examples include 1-fluorocyclopropyl,
2-fluorocyclopropyl, (S)- and (R)-2,2-difluorocyclopropyl,
1,2-difluorocyclopropyl, 2,3-difluorocyclopropyl,
pentafluorocyclopropyl, 1-fluorocyclobutyl, 2-fluorocyclobutyl,
3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl,
1,2-difluorocyclobutyl, 1,3-difluorocyclobutyl,
2,3-difluorocyclobutyl, 2,4-difluorocyclobutyl,
1,2,2-trifluorocyclobutyl, 1-fluorocycloheptyl,
2-fluorocycloheptyl, 3-fluorocycloheptyl, 4-fluorocycloheptyl,
1,2-difluorocycloheptyl, 1,3-difluorocycloheptyl,
1,4-difluorocycloheptyl, 2,2-difluorocycloheptyl,
2,3-difluorocycloheptyl, 2,4-difluorocycloheptyl,
2,5-difluorocycloheptyl, 2,6-difluorocycloheptyl,
2,7-difluorocycloheptyl, 3,3-difluorocycloheptyl,
3,4-difluorocycloheptyl, 3,5-difluorocycloheptyl,
3,6-difluorocycloheptyl, 4,4-difluorocycloheptyl,
4,5-difluorocycloheptyl, and the like.
[0068] The term "cycloalkenyl" as used herein refers to monocyclic
partially unsaturated, non-aromatic hydrocarbon radicals having 3
to 8 ("C.sub.3-C.sub.8-cycloalkenyl"), in particular 5 to 7 carbon
atoms ("C.sub.5-C.sub.7-cycloalkenyl") or 5 or 6 carbon atoms
("C.sub.5-C.sub.6-cycloalkenyl") and one or more non-cumulative,
preferably one, C--C double bonds in the ring. Examples for
C.sub.5-C.sub.6-cycloalkenyl are cyclopent-1-en-1-yl,
cyclopent-1-en-3-yl, cyclopent-1-en-4-yl, cyclopenta-1,3-dien-1-yl,
cyclopenta-1,3-dien-2-yl, cyclopenta-1,3-dien-5-yl,
cyclohex-1-en-1-yl, cyclohex-1-en-3-yl, cyclohex-1-en-4-yl,
cyclohexa-1,3-dien-1-yl, cyclohexa-1,3-dien-2-yl,
cyclohexa-1,3-dien-5-yl, cyclohexa-1,4-dien-1-yl and
cyclohexa-1,4-dien-3-yl. Examples of C.sub.5-C.sub.7-cycloalkenyl
are, apart those mentioned above, include for
C.sub.5-C.sub.6-cycloalkenyl, cyclohept-1-en-1-yl,
cyclohept-1-en-3-yl, cyclohept-1-en-4-yl, cyclohept-1-en-5-yl,
cyclohepta-1,3-dien-1-yl, cyclohepta-1,3-dien-2-yl,
cyclohepta-1,3-dien-5-yl, cyclohepta-1,3-dien-6-yl,
cyclohepta-1,4-dien-1-yl, cyclohepta-1,4-dien-2-yl,
cyclohepta-1,4-dien-3-yl and cyclohepta-1,4-dien-6-yl. Examples of
C.sub.3-C.sub.8-cycloalkenyl are, apart those mentioned above for
C.sub.5-C.sub.6-cycloalkenyl, cycloprop-1-en-1-yl,
cycloprop-1-en-3-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,
cyclooct-1-en-1-yl, cyclooct-1-en-3-yl, cyclooct-1-en-4-yl,
cyclooct-1-en-5-yl, cycloocta-1,3-dien-1-yl,
cycloocta-1,3-dien-2-yl, cycloocta-1,3-dien-5-yl,
cycloocta-1,3-dien-6-yl, cycloocta-1,4-dien-1-yl,
cycloocta-1,4-dien-2-yl, cycloocta-1,4-dien-3-yl,
cycloocta-1,4-dien-6-yl, cycloocta-1,4-dien-7-yl,
cycloocta-1,5-dien-1-yl, and cycloocta-1,5-dien-3-yl.
[0069] The term "fluorinated cycloalkenyl" as used herein refers to
monocyclic partially unsaturated, non-aromatic hydrocarbon radicals
having 3 to 8 ("fluorinated C.sub.3-C.sub.8-cycloalkenyl"), in
particular 5 to 7 carbon atoms ("fluorinated
C.sub.5-C.sub.7-cycloalkenyl") or 5 or 6 carbon atoms ("fluorinated
C.sub.5-C.sub.6-cycloalkenyl") and one or more non-cumulative,
preferably one, C--C double bonds in the ring and in which some or
all of the hydrogen atoms are replaced by fluorine atoms.
[0070] The term "cycloalkyl-C.sub.1-C.sub.4-alkyl" refers to a
C.sub.3-C.sub.8-cycloalkyl group
("C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl"), preferably a
C.sub.3-C.sub.6-cycloalkyl group
("C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl") as defined
above which is bound to the remainder of the molecule via a
C.sub.1-C.sub.4-alkyl group, as defined above. The term
"cycloalkyl-C.sub.1-C.sub.2-alkyl" refers to a
C.sub.3-C.sub.8-cycloalkyl group
("C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.2-alkyl"), preferably a
C.sub.3-C.sub.6-cycloalkyl group
("C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl") as defined
above which is bound to the remainder of the molecule via a
C.sub.1-C.sub.2-alkyl group, as defined above. Examples for
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl are
cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl,
cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl,
cyclohexylmethyl and cyclohexylethyl. Examples for
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, apart those
mentioned for C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl, are
cyclopropylpropyl, cyclopropylbutyl, cyclobutylpropyl,
cyclobutylbutyl, cyclopentylpropyl, cyclopentylbutyl,
cyclohexylpropyl and cyclohexylbutyl. Examples for
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.2-alkyl, apart those
mentioned for C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl, are
cycloheptylmethyl, cycloheptylethyl, cyclooctylmethyl and
cyclooctylethyl. Examples for
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, apart those
mentioned for C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.2-alkyl, are
cycloheptylpropyl, cycloheptylbutyl, cyclooctylpropyland
cyclooctylbutyl.
[0071] The term "fluorinated cycloalkyl-C.sub.1-C.sub.4-alkyl"
refers to a fluorinated C.sub.3-C.sub.8-cycloalkyl group
("fluorinated C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl"),
preferably a fluorinated C.sub.3-C.sub.6-cycloalkyl group
("fluorinated C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl") as
defined above which is bound to the remainder of the molecule via a
C.sub.1-C.sub.4-alkyl group, as defined above. The term
"fluorinated cycloalkyl-C.sub.1-C.sub.2-alkyl" refers to a
fluorinated C.sub.3-C.sub.8-cycloalkyl group ("fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.2-alkyl"), preferably a
fluorinated C.sub.3-C.sub.6-cycloalkyl group ("fluorinated
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl") as defined above
which is bound to the remainder of the molecule via a
C.sub.1-C.sub.2-alkyl group, as defined above.
[0072] The term "C.sub.1-C.sub.2-alkoxy" is a C.sub.1-C.sub.2-alkyl
group, as defined above, attached via an oxygen atom. The term
"C.sub.1-C.sub.3-alkoxy" is a C.sub.1-C.sub.3-alkyl group, as
defined above, attached via an oxygen atom. The term
"C.sub.1-C.sub.4-alkoxy" is a C.sub.1-C.sub.4-alkyl group, as
defined above, attached via an oxygen atom. The term
"C.sub.1-C.sub.6-alkoxy" is a C.sub.1-C.sub.6-alkyl group, as
defined above, attached via an oxygen atom. C.sub.1-C.sub.2-Alkoxy
is methoxy or ethoxy. C.sub.1-C.sub.3-Alkoxy is additionally, for
example, n-propoxy and 1-methylethoxy (isopropoxy).
C.sub.1-C.sub.4-Alkoxy is additionally, for example, butoxy,
1-methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) or
1,1-dimethylethoxy (tert-butoxy). C.sub.1-C.sub.6-Alkoxy is
additionally, for example, pentoxy, 1-methylbutoxy, 2-methylbutoxy,
3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy,
2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy,
2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy,
1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,
2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy,
1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy,
1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy or
1-ethyl-2-methylpropoxy. C.sub.1-C.sub.8-Alkoxy is additionally,
for example, heptyloxy, octyloxy, 2-ethylhexyloxy and positional
isomers thereof.
[0073] The term "fluorinated C.sub.1-C.sub.2-alkoxy" is a
fluorinated C.sub.1-C.sub.2-alkyl group, as defined above, attached
via an oxygen atom. The term "fluorinated C.sub.1-C.sub.3-alkoxy"
is a fluorinated C.sub.1-C.sub.3-alkyl group, as defined above,
attached via an oxygen atom. The term "fluorinated
C.sub.1-C.sub.6-haloalkoxy" is a fluorinated C.sub.1-C.sub.6-alkyl
group, as defined above, attached via an oxygen atom. Fluorinated
C.sub.1-C.sub.2-alkoxy is, for example, OCH.sub.2F, OCHF.sub.2,
OCF.sub.3, 1-fluoroethoxy, (R)-1-fluoroethoxy, (S)-1-fluoroethoxy,
2-fluoroethoxy, 1,1-difluoroethoxy, 1,2-difluoroethoxy,
2,2-difluoroethoxy, 1,1,2-trifluoroethoxy, 1,2,2-trifluoroethoxy,
2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy or
OC.sub.2F.sub.5. Fluorinated C.sub.1-C.sub.3-alkoxy is
additionally, for example, 1-fluoropropoxy, (R)-1-fluoropropoxy,
(S)-1-fluoropropoxy, 2-fluoropropoxy, (R)-2-fluoropropoxy,
(S)-2-fluoropropoxy, 3-fluoropropoxy, 1,1-difluoropropoxy,
2,2-difluoropropoxy, 2,3-difluoropropoxy, 3,3-difluoropropoxy,
3,3,3-trifluoropropoxy, (R)-2-fluoro-1-methylethoxy,
(S)-2-fluoro-1-methylethoxy, (R)-2,2-difluoro-1-methylethoxy,
(S)-2,2-difluoro-1-methylethoxy, (R)-1,2-difluoro-1-methylethoxy,
(S)-1,2-difluoro-1-methylethoxy,
(R)-2,2,2-trifluoro-1-methylethoxy,
(S)-2,2,2-trifluoro-1-methylethoxy,
2-fluoro-1-(fluoromethyl)ethoxy,
1-(difluoromethyl)-2,2-difluoroethoxy, OCH.sub.2--C.sub.2F.sub.5,
OCF.sub.2--C.sub.2F.sub.5 or 1-(CH.sub.2F)-2-fluoroethoxy.
Fluorinated C.sub.1-C.sub.4-alkoxy is additionally, for example,
1-fluorobutoxy, (R)-1-fluorobutoxy, (S)-1-fluorobutoxy,
2-fluorobutoxy, 3-fluorobutoxy, 4-fluorobutoxy, 1,1-difluorobutoxy,
2,2-difluorobutoxy, 3,3-difluorobutoxy, 4,4-difluorobutoxy,
4,4,4-trifluorobutoxy or nonafluorobutoxy. Fluorinated
C.sub.1-C.sub.6-alkoxy is additionally, for example,
5-fluoropentoxy, undecafluoropentoxy, 6-fluorohexoxy or
tridecafluorohexoxy.
[0074] The term "C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl" as
used herein, refers to a straight-chain or branched alkyl group
having 1 to 4 carbon atoms, as defined above, where one hydrogen
atom is replaced by a C.sub.1-C.sub.4-alkoxy group, as defined
above. The term "C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl" as
used herein, refers to a straight-chain or branched alkyl group
having 1 to 4 carbon atoms, as defined above, where one hydrogen
atom is replaced by a C.sub.1-C.sub.6-alkoxy group, as defined
above. Examples are methoxymethyl, ethoxymethyl, propoxymethyl,
isopropoxymethyl, n-butoxymethyl, sec-butoxymethyl,
isobutoxymethyl, tert-butoxymethyl, 1-methoxyethyl, 1-ethoxyethyl,
1-propoxyethyl, 1-isopropoxyethyl, 1-n-butoxyethyl,
1-sec-butoxyethyl, 1-isobutoxyethyl, 1-tert-butoxyethyl,
2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl,
2-n-butoxyethyl, 2-sec-butoxyethyl, 2-isobutoxyethyl,
2-tert-butoxyethyl, 1-methoxypropyl, 1-ethoxypropyl,
1-propoxypropyl, 1-isopropoxypropyl, 1-n-butoxypropyl,
1-sec-butoxypropyl, 1-isobutoxypropyl, 1-tert-butoxypropyl,
2-methoxypropyl, 2-ethoxypropyl, 2-propoxypropyl,
2-isopropoxypropyl, 2-n-butoxypropyl, 2-sec-butoxypropyl,
2-isobutoxypropyl, 2-tert-butoxypropyl, 3-methoxypropyl,
3-ethoxypropyl, 3-propoxypropyl, 3-isopropoxypropyl,
3-n-butoxypropyl, 3-sec-butoxypropyl, 3-isobutoxypropyl,
3-tert-butoxypropyl and the like.
[0075] The term "fluorinated
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl" as used herein,
refers to a straight-chain or branched alkyl group having 1 to 4
carbon atoms, as defined above, where one hydrogen atom is replaced
by a C.sub.1-C.sub.4-alkoxy group, as defined above, and wherein at
least one, e.g. 1, 2, 3, 4 or all of the remaining hydrogen atoms
(either in the alkoxy moiety or in the alkyl moiety or in both) are
replaced by fluorine atoms. The term "fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl" as used herein,
refers to a straight-chain or branched alkyl group having 1 to 4
carbon atoms, as defined above, where one hydrogen atom is replaced
by a C.sub.1-C.sub.6-alkoxy group, as defined above, and wherein at
least one, e.g. 1, 2, 3, 4 or all of the remaining hydrogen atoms
(either in the alkoxy moiety or in the alkyl moiety or in both) are
replaced by fluorine atoms. Examples are difluoromethoxymethyl
(CHF.sub.2OCH.sub.2), trifluoromethoxymethyl,
1-difluoromethoxyethyl (CHF.sub.2OCH(CH.sub.3)),
1-trifluoromethoxyethyl (CF.sub.3OCH(CH.sub.3)),
2-difluoromethoxyethyl (CHF.sub.2OCH.sub.2CH.sub.2),
2-trifluoromethoxyethyl (CF.sub.3OCH.sub.2CH.sub.2),
methoxy-difluoromethyl (CH.sub.3OCF.sub.2),
2-methoxy-1,1-difluoroethyl (CH.sub.3OCH.sub.2CF.sub.2),
2-methoxy-2,2-difluoroethyl (CH.sub.3OCF.sub.2CH.sub.2), and the
like.
[0076] The term "hydroxy-C.sub.1-C.sub.4-alkyl" as used herein,
refers to a straight-chain or branched alkyl group having 1 to 4
carbon atoms, as defined above, where one hydrogen atom is replaced
by a hydroxyl group. The term "hydroxy-C.sub.1-C.sub.6-alkyl" as
used herein, refers to a straight-chain or branched alkyl group
having 1 to 6 carbon atoms, as defined above, where one hydrogen
atom is replaced by a hydroxyl group. Examples for
hydroxy-C.sub.1-C.sub.4-alkyl include hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl,
3-hydroxypropyl, 1-hydroxyprop-2-yl, 2-hydroxyprop-2-yl,
1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl,
1-hydroxybut-2-yl, 2-hydroxybut-2-yl, 3-hydroxybut-2-yl,
4-hydroxybut-2-yl, hydroxy-tert-butyl and the like. Examples for
hydroxy-C.sub.1-C.sub.6-alkyl are, apart those mentioned for
hydroxy-C.sub.1-C.sub.4-alkyl, 1-hydroxypentyl, 2-hydroxypentyl,
3-hydroxypentyl, 4-hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl,
2-hydroxyhexyl, 3-hydroxyhexyl, 4-hydroxyhexyl, 5-hydroxyhexyl,
6-hydroxyhexyl and the like.
[0077] The term "hydroxy-C.sub.1-C.sub.4-alkoxy" as used herein,
refers to a C.sub.1-C.sub.4-alkoxy group, as defined above, where
one hydrogen atom is replaced by a hydroxy group. The term
"hydroxy-C.sub.1-C.sub.6-alkoxy" as used herein, refers to a
C.sub.1-C.sub.6-alkoxy group, as defined above, where one hydrogen
atom is replaced by a hydroxy group. Examples for
hydroxy-C.sub.1-C.sub.4-alkoxy include hydroxymethoxy,
1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxypropoxy,
2-hydroxypropoxy, 3-hydroxypropoxy, 1-hydroxy-2-propoxy,
2-hydroxy-2-propoxy, 1-hydroxybutoxy, 2-hydroxybutoxy,
3-hydroxybutoxy, 4-hydroxybutoxy, 1-hydroxy-2-butoxy,
2-hydroxy-2-butoxy, 3-hydroxy-2-butoxy, 4-hydroxy-2-butoxy,
hydroxy-tert-butoxy and the like. Examples for
hydroxy-C.sub.1-C.sub.6-alkoxy include, apart those mentioned for
hydroxy-C.sub.1-C.sub.4-alkoxy, 1-hydroxypentoxy, 2-hydroxypentoxy,
3-hydroxypentoxy, 4-hydroxypentoxy, 5-hydroxypentoxy,
1-hydroxyhexoxy, 2-hydroxyhexoxy, 3-hydroxyhexoxy, 4-hydroxyhexoxy,
5-hydroxyhexoxy, 6-hydroxyhexoxy and the like.
[0078] The term "C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkoxy" as
used herein, refers to a C.sub.1-C.sub.4-alkoxy group, as defined
above, where one hydrogen atom is replaced by a
C.sub.1-C.sub.4-alkoxy group, as defined above. The term
"C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy" as used herein,
refers to a C.sub.1-C.sub.4-alkoxy group, as defined above, where
one hydrogen atom is replaced by a C.sub.1-C.sub.6-alkoxy group, as
defined above. Examples are methoxymethoxy, ethoxymethoxy,
propoxymethoxy, isopropoxymethoxy, butoxymethoxy,
sec-butoxymethoxy, isobutoxymethoxy, tert-butoxymethoxy,
1-methoxyethoxy, 1-ethoxyethoxy, 1-propoxyethoxy,
1-isopropoxyethoxy, 1-butoxyethoxy, 1-sec-butoxyethoxy,
1-isobutoxyethoxy, 1-tert-butoxyethoxy, 2-methoxyethoxy,
2-ethoxyethoxy, 2-propoxyethoxy, 2-isopropoxyethoxy,
2-butoxyethoxy, 2-sec-butoxyethoxy, 2-isobutoxyethoxy,
2-tert-butoxyethoxy, 1-methoxypropoxy, 1-ethoxypropoxy,
1-propoxypropoxy, 1-isopropoxypropoxy, 1-butoxypropoxy,
1-sec-butoxypropoxy, 1-isobutoxypropoxy, 1-tert-butoxypropoxy,
2-methoxypropoxy, 2-ethoxypropoxy, 2-propoxypropoxy,
2-isopropoxypropoxy, 2-butoxypropoxy, 2-sec-butoxypropoxy,
2-isobutoxypropoxy, 2-tert-butoxypropoxy, 3-methoxypropoxy,
3-ethoxypropoxy, 3-propoxypropoxy, 3-isopropoxypropoxy,
3-butoxypropoxy, 3-sec-butoxypropoxy, 3-isobutoxypropoxy,
3-tert-butoxypropoxy and the like.
[0079] The term "C.sub.1-C.sub.2-alkylthio" is a
C.sub.1-C.sub.2-alkyl group, as defined above, attached via a
sulfur atom. The term "C.sub.1-C.sub.3-alkylthio" refers to a
C.sub.1-C.sub.3-alkyl group, as defined above, attached via a
sulfur atom. The term "C.sub.1-C.sub.4-alkylthio" is a
C.sub.1-C.sub.4-alkyl group, as defined above, attached via a
sulfur atom. The term "C.sub.1-C.sub.6-alkylthio" refers to a
C.sub.1-C.sub.6-alkyl group, as defined above, attached via a
sulfur atom. The term "C.sub.1-C.sub.10-alkylthio" refers to a
C.sub.1-C.sub.10-alkyl group, as defined above, attached via a
sulfur atom. C.sub.1-C.sub.2-Alkylthio is methylthio or ethylthio.
C.sub.1-C.sub.3-Alkylthio is additionally, for example,
n-propylthio or 1-methylethylthio (isopropylthio).
C.sub.1-C.sub.4-Alkylthio is additionally, for example, butylthio,
1-methylpropylthio (sec-butylthio), 2-methylpropylthio
(isobutylthio) or 1,1-dimethylethylthio (tert-butylthio).
C.sub.1-C.sub.6-Alkylthio is additionally, for example, pentylthio,
1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio,
1,1-dimethylpropylthio, 1,2-dimethylpropylthio,
2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio,
1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio,
4-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio,
1,3-dimethylbutylthio, 2,2-dimethylbutylthio,
2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio,
2-ethylbutylthio, 1,1,2-trimethylpropylthio,
1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropylthio or
1-ethyl-2-methylpropylthio.
[0080] The term "fluorinated C.sub.1-C.sub.2-alkylthio" refers to a
fluorinated C.sub.1-C.sub.2-alkyl group, as defined above, attached
via a sulfur atom. The term "fluorinated C.sub.1-C.sub.3-alkylthio"
refers to a fluorinated C.sub.1-C.sub.3-alkyl group, as defined
above, attached via a sulfur atom. The term "fluorinated
C.sub.1-C.sub.4-alkylthio" refers to a fluorinated
C.sub.1-C.sub.4-alkyl group, as defined above, attached via a
sulfur atom. The term "fluorinated C.sub.1-C.sub.6-alkylthio"
refers to a fluorinated C.sub.1-C.sub.6-alkyl group, as defined
above, attached via a sulfur atom. Fluorinated
C.sub.1-C.sub.2-alkylthio refers to, for example, SCH.sub.2F,
SCHF.sub.2, SCF.sub.3, 2-fluoroethylthio, 2,2-difluoroethylthio,
2,2,2-trifluoroethylthio, or SC.sub.2F.sub.5. Fluorinated
C.sub.1-C.sub.3-alkylthio may additionally, for example, include
2-fluoropropylthio, 3-fluoropropylthio, 2,2-difluoropropylthio,
2,3-difluoropropylthio, 3,3,3-trifluoropropylthio,
SCH.sub.2--C.sub.2F.sub.5, SCF.sub.2--C.sub.2F.sub.5 or
1-(CH.sub.2F)-2-fluoroethylthio. Fluorinated
C.sub.1-C.sub.4-alkylthio may additionally, for example, include
4-fluorobutylthio or nonafluorobutylthio. Fluorinated
C.sub.1-C.sub.6-alkylthio is additionally, for example,
5-fluoropentylthio, undecafluoropentylthio, 6-fluorohexylthio or
dodecafluorohexylthio.
[0081] The term "C.sub.1-C.sub.2-alkylsulfinyl" refers to a
C.sub.1-C.sub.2-alkyl group, as defined above, attached via a
sulfinyl [S(O)] group. The term "C.sub.1-C.sub.4-alkylsulfinyl" is
a C.sub.1-C.sub.4-alkyl group, as defined above, attached via a
sulfinyl [S(O)] group. The term "C.sub.1-C.sub.6-alkylsulfinyl" is
a C.sub.1-C.sub.6-alkyl group, as defined above, attached via a
sulfinyl [S(O)] group. C.sub.1-C.sub.2-Alkylsulfinyl is
methylsulfinyl or ethylsulfinyl. C.sub.1-C.sub.4-Alkylsulfinyl is
additionally, for example, n-propylsulfinyl, 1-methylethylsulfinyl
(isopropylsulfinyl), butylsulfinyl, 1-methylpropylsulfinyl
(sec-butylsulfinyl), 2-methylpropylsulfinyl (isobutylsulfinyl) or
1,1-dimethylethylsulfinyl (tert-butylsulfinyl).
C.sub.1-C.sub.6-Alkylsulfinyl is additionally, for example,
pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl,
3-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl,
1,2-dimethylpropylsulfinyl, 2,2-dimethylpropylsulfinyl,
1-ethylpropylsulfinyl, hexylsulfinyl, 1-methylpentylsulfinyl,
2-methylpentylsulfinyl, 3-methylpentylsulfinyl,
4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl,
1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl,
2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl,
3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl,
2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl,
1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl or
1-ethyl-2-methylpropylsulfinyl.
[0082] The term "fluorinated C.sub.1-C.sub.2-alkylsulfinyl" refers
to a fluorinated C.sub.1-C.sub.2-alkyl group, as defined above,
attached via a sulfinyl [S(O)] group. The term "fluorinated
C.sub.1-C.sub.3-alkylsulfinyl" refers to a fluorinated
C.sub.1-C.sub.3-alkyl group, as defined above, attached via a
sulfinyl [S(O)] group. The term "fluorinated
C.sub.1-C.sub.4-alkylsulfinyl" refers to a fluorinated
C.sub.1-C.sub.4-alkyl group, as defined above, attached via a
sulfinyl [S(O)] group. The term "fluorinated
C.sub.1-C.sub.6-alkylsulfinyl" refers to a fluorinated
C.sub.1-C.sub.6-alkyl group, as defined above, attached via a
sulfinyl [S(O)] group. Fluorinated C.sub.1-C.sub.2-alkylsulfinyl
is, for example, S(O)CH.sub.2F, S(O)CHF.sub.2, S(O)CF.sub.3,
2-fluoroethylsulfinyl, 2,2-difluoroethylsulfinyl,
2,2,2-trifluoroethylsulfinyl, or S(O)C.sub.2F.sub.5. Fluorinated
C.sub.1-C.sub.3-alkylsulfinyl may additionally, for example,
include 2-fluoropropylsulfinyl, 3-fluoropropylsulfinyl,
2,2-difluoropropylsulfinyl, 2,3-difluoropropylsulfinyl,
3,3,3-trifluoropropylsulfinyl, S(O)CH.sub.2--C.sub.2F.sub.5,
S(O)CF.sub.2--C.sub.2F.sub.5 or
1-(CH.sub.2F)-2-fluoroethylsulfinyl. Fluorinated
C.sub.1-C.sub.4-alkylsulfinyl may additionally, for example,
include 4-fluorobutylsulfinyl or nonafluorobutylsulfinyl.
Fluorinated C.sub.1-C.sub.6-alkylsulfinyl may additionally, for
example, include 5-fluoropentylsulfinyl,
undecafluoropentylsulfinyl, 6-fluorohexylsulfinyl or
dodecafluorohexylsulfinyl.
[0083] The term "C.sub.1-C.sub.2-alkylsulfonyl" refers to a
C.sub.1-C.sub.2-alkyl group, as defined above, attached via a
sulfonyl [S(O).sub.2] group. The term
"C.sub.1-C.sub.4-alkylsulfonyl" refers to a C.sub.1-C.sub.4-alkyl
group, as defined above, attached via a sulfonyl [S(O).sub.2]
group. The term "C.sub.1-C.sub.6-alkylsulfonyl" is a
C.sub.1-C.sub.6-alkyl group, as defined above, attached via a
sulfonyl [S(O).sub.2] group. C.sub.1-C.sub.2-Alkylsulfonyl refers
to a methylsulfonyl or ethylsulfonyl. C.sub.1-C.sub.4-Alkylsulfonyl
is additionally, for example, n-propylsulfonyl,
1-methylethylsulfonyl (isopropylsulfonyl), butylsulfonyl,
1-methylpropylsulfonyl (sec-butylsulfonyl), 2-methylpropylsulfonyl
(isobutylsulfonyl) or 1,1-dimethylethylsulfonyl
(tert-butylsulfonyl). C.sub.1-C.sub.6-Alkylsulfonyl is
additionally, for example, pentylsulfonyl, 1-methylbutylsulfonyl,
2-methylbutylsulfonyl, 3-methylbutylsulfonyl,
1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl,
2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl,
1-methylpentylsulfonyl, 2-methylpentylsulfonyl,
3-methylpentylsulfonyl, 4-methylpentylsulfonyl,
1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl,
1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl,
2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl,
1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl,
1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl,
1-ethyl-1-methylpropylsulfonyl or
1-ethyl-2-methylpropylsulfonyl.
[0084] The term "fluorinated C.sub.1-C.sub.2-alkylsulfonyl" refers
to a fluorinated C.sub.1-C.sub.2-alkyl group, as defined above,
attached via a sulfonyl [S(O).sub.2] group. The term "fluorinated
C.sub.1-C.sub.3-alkylsulfonyl" refers to a fluorinated
C.sub.1-C.sub.3-alkyl group, as defined above, attached via a
sulfonyl [S(O).sub.2] group. The term "fluorinated
C.sub.1-C.sub.4-alkylsulfonyl" refers to a fluorinated
C.sub.1-C.sub.4-alkyl group, as defined above, attached via a
sulfonyl [S(O).sub.2] group. The term "fluorinated
C.sub.1-C.sub.6-alkylsulfonyl" refers to a fluorinated
C.sub.1-C.sub.6-alkyl group, as defined above, attached via a
sulfonyl [S(O).sub.2] group. Fluorinated
C.sub.1-C.sub.2-alkylsulfonyl is, for example, S(O).sub.2CH.sub.2F,
S(O).sub.2CHF.sub.2, S(O).sub.2CF.sub.3, 2-fluoroethylsulfonyl,
2,2-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, or
S(O).sub.2C.sub.2F.sub.5. Fluorinated C.sub.1-C.sub.3-alkylsulfonyl
is additionally, for example, 2-fluoropropylsulfonyl,
3-fluoropropylsulfonyl, 2,2-difluoropropylsulfonyl,
2,3-difluoropropylsulfonyl, 3,3,3-trifluoropropylsulfonyl,
S(O).sub.2CH.sub.2--C.sub.2F.sub.5,
S(O).sub.2CF.sub.2--C.sub.2F.sub.5 or
1-(CH.sub.2F)-2-fluoroethylsulfonyl. Fluorinated
C.sub.1-C.sub.4-alkylsulfonyl is additionally, for example,
4-fluorobutylsulfonyl or nonafluorobutylsulfonyl. Fluorinated
C.sub.1-C.sub.6-alkylsulfonyl is additionally, for example,
5-fluoropentylsulfonyl, undecafluoropentylsulfonyl,
6-fluorohexylsulfonyl or dodecafluorohexylsulfonyl.
[0085] C.sub.1-C.sub.4-Alkylcarbonyl refers to a straight-chain or
branched alkyl group having from 1 to 4 carbon atoms), which is
bound to the remainder of the molecule via a carbonyl group (CO),
such as in acetyl, propionyl, isopropylcarbonyl, butylcarbonyl,
sec-butylcarbonyl, isobutylcarbonyl, and tert-butylcarbonyl.
C.sub.1-C.sub.6-Alkylcarbonyl is a straight-chain or branched alkyl
group having from 1 to 6 carbon atoms, which is bound to the
remainder of the molecule via a carbonyl group (CO). Examples
include, apart those listed above for
C.sub.1-C.sub.4-alkylcarbonylpentylcarbonyl, hexylcarbonyl and the
constitutional isomers thereof.
[0086] Fluorinated C.sub.1-C.sub.4-alkylcarbonyl refers to a
straight-chain or branched fluorinated alkyl group having from 1 to
4 carbon atoms as defined above, which is bound to the remainder of
the molecule via a carbonyl group (CO). Fluorinated
C.sub.1-C.sub.6-alkylcarbonyl is a straight-chain or branched
fluorinated alkyl group having from 1 to 6 carbon atoms as defined
above, which is bound to the remainder of the molecule via a
carbonyl group (CO). Examples include trifluoromethylcarbonyl,
2,2,2-trifluoroethylcarbonyl and the like.
[0087] C.sub.3-C.sub.6-cycloalkylcarbonyl relates to a
C.sub.3-C.sub.6-cycloalkyl group as defined above which is bound to
the remainder of the molecule via a carbonyl group (CO), such as in
cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and
cyclohexylcarbonyl.
[0088] C.sub.1-C.sub.6-Alkoxycarbonyl refers to a straight-chain or
branched alkoxy group having from 1 to 6, especially 1 to 4 carbon
atoms (.dbd.C.sub.1-C.sub.4-alkoxycarbonyl), in particular 1 to 3
carbon atoms (.dbd.C.sub.1-C.sub.3-alkoxycarbonyl), which is bound
to the remainder of the molecule via a carbonyl group (CO), such as
in methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, and
isopropyloxycarbonyl.
[0089] Fluorinated C.sub.1-C.sub.6-alkoxycarbonyl refers to a
straight-chain or branched fluorinated alkoxy group having from 1
to 6, especially 1 to 4 carbon atoms (=fluorinated
C.sub.1-C.sub.4-alkoxycarbonyl), in particular 1 to 3 carbon atoms
(=fluorinated C.sub.1-C.sub.3-alkoxycarbonyl) as defined above,
which is bound to the remainder of the molecule via a carbonyl
group (CO). Examples include trifluoromethoxycarbonyl,
2,2,2-trifluoroethoxycarbonyl and the like.
[0090] C.sub.1-C.sub.4-Alkylcarbonyloxy refers to a straight-chain
or branched alkyl group having from 1 to 4 carbon atoms, which is
bound to the remainder of the molecule via a carbonyloxy group
[C(O)--O--], such as in acet(yl)oxy, propionyloxy,
isopropylcarbonyloxy, butylcarbonyloxy, sec-butylcarbonyloxy,
isobutylcarbonyloxy, and tert-butylcarbonyloxy.
C.sub.1-C.sub.6-Alkylcarbonyloxy is a straight-chain or branched
alkyl group having from 1 to 6 carbon atoms, which is bound to the
remainder of the molecule via a carbonyloxy group [C(O--O--].
Examples include, apart those listed above for
C.sub.1-C.sub.4-alkylcarbonyloxy, pentylcarbonyloxy,
hexylcarbonyloxy and the constitutional isomers thereof.
[0091] Fluorinated C.sub.1-C.sub.4-alkylcarbonyloxy refers to a
straight-chain or branched fluorinated alkyl group having from 1 to
4 carbon atoms as defined above, which is bound to the remainder of
the molecule via a carbonyloxy group [C(O)--O--]. Fluorinated
C.sub.1-C.sub.6-alkylcarbonyloxy is a straight-chain or branched
fluorinated alkyl group having from 1 to 6 carbon atoms as defined
above, which is bound to the remainder of the molecule via a
carbonyloxy group [C(O)--O--]. Examples include
trifluoromethylcarbonyloxy, 2,2,2-trifluoroethylcarbonyloxy and the
like.
[0092] Phenyl-C.sub.1-C.sub.2-alkyl is a phenyl group bound to the
remainder of the molecule via a C.sub.1-C.sub.2-alkyl group.
Examples are benzyl, 1-phenylethyl and 2-phenylethyl
(phenethyl).
[0093] The term "3-, 4-, 5-, 6-, 7- or 8-membered saturated,
partially unsaturated or maximally unsaturated heterocyclic ring
containing 1, 2, 3 or 4 heteroatoms or heteroatom groups
independently selected from N, O, S, NO, SO and SO.sub.2 and
optionally also 1 or 2 C.dbd.O and/or C.dbd.S groups as ring
members" denotes a 3-, 4-, 5-, 6-, 7- or 8-membered, preferably a
3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or
maximum unsaturated heteromonocyclic ring containing 1, 2, 3 or 4
(preferably 1, 2 or 3) heteroatoms or heteroatom groups selected
from N, O, S, SO and SO.sub.2 and optionally also 1 or 2 C.dbd.O
and/or C.dbd.S groups as ring members.
[0094] Unsaturated rings contain at least one C--C and/or C--N
and/or N--N double bond(s). Maximally unsaturated rings contain as
many conjugated C--C and/or C--N and/or N--N double bonds as
allowed by the ring size. Maximally unsaturated 5- or 6-membered
heterocyclic rings are aromatic. 7- and 8-membered rings cannot be
aromatic. They are homoaromatic (7-membered ring, 3 double bonds)
or have 4 double bonds (8-membered ring). Partially unsaturated
rings contain less than the maximum number of C--C and/or C--N
and/or N--N double bond(s) allowed by the ring size. The
heterocyclic ring may be attached to the remainder of the molecule
via a carbon ring member or via a nitrogen ring member. As a matter
of course, the heterocyclic ring contains at least one carbon ring
atom. If the ring contains more than one 0 ring atom, these are not
adjacent.
[0095] In heterocyclic rings containing N as a ring member this
nitrogen atom may either be present as tertiary N formally bound by
a double and a single bond (like in pyridyl) or may be present as
secondary NH (if N is not part of a ring double bond). In case that
N is actually present as NH, and the ring is substituted, the
substituent may either be bound to a carbon ring atom or to such a
secondary nitrogen ring atom. In case that N is actually present as
NH, the ring may either be bound to the remainder of the molecule
via a carbon ring atom or such a secondary nitrogen ring atom.
[0096] Examples of a 3-, 4-, 5-, 6- or 7-membered saturated
heterocyclic ring include: Oxiranyl, thiiranyl, aziridinyl,
oxetanyl, thietanyl, azetidinyl, tetrahydrofuran-2-yl,
tetrahydrofuran-3-yl, tetrahydrofuran-2-on-3-yl,
tetrahydrofuran-2-on-4-yl, tetrahydrofuran-2-on-5-yl,
tetrahydrofuran-2-thion-3-yl, tetrahydrofuran-2-thion-4-yl,
tetrahydrofuran-2-thion-5-yl, tetrahydrothien-2-yl,
tetrahydrothien-3-yl, tetrahydrothien-2-on-3-yl,
tetrahydrothien-2-on-4-yl, tetrahydrothien-2-on-5-yl,
tetrahydrothien-2-thion-3-yl, tetrahydrothien-2-thion-4-yl,
tetrahydrothien-2-thion-5-yl, pyrrolidin-1-yl,
pyrrolidine-2-on-1-yl, pyrrolidine-2,5-dion-1-yl,
pyrrolidine-2-thion-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,
pyrrolidine-2-on-3-yl, pyrrolidine-2-on-4-yl,
pyrrolidine-2-on-5-yl, pyrrolidine-2,5-dion-3-yl,
pyrrolidine-2-thion-3-yl, pyrrolidine-2-thion-4-yl,
pyrrolidine-2-thion-5-yl, pyrazolidin-1-yl, pyrazolidin-3-yl,
pyrazolidin-4-yl, pyrazolidin-5-yl, imidazolidin-1-yl,
imidazolidin-2-on-1-yl, imidazolidin-2-thion-1-yl,
imidazolidin-2-yl, imidazolidin-4-yl, imidazolidin-2-on-4-yl,
imidazolidin-2-thion-4-yl, oxazolidin-2-yl, oxazolidin-3-yl,
oxazolidin-4-yl, oxazolidin-5-yl, isoxazolidin-2-yl,
isoxazolidin-3-yl, isoxazolidin-4-yl, isoxazolidin-5-yl,
thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl,
thiazolidin-5-yl, isothiazolidin-2-yl, isothiazolidin-3-yl,
isothiazolidin-4-yl, isothiazolidin-5-yl, 1,2,4-oxadiazolidin-3-yl,
1,2,4-oxadiazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl,
1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-3-yl,
1,3,4-oxadiazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl,
1,3,4-triazolidin-1-yl, 1,3,4-triazolidin-2-yl,
2-tetrahydropyranyl, 4-tetrahydropyranyl, 1,3-dioxan-5-yl,
1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-on-1-yl,
piperidin-2,5-dion-1-yl, piperidine-2-thion-1-yl, piperidin-2-yl,
piperidin-3-yl, piperidin-2-on-3-yl, piperidin-2,5-dion-3-yl,
piperidin-2-thion-3-yl, piperidin-4-yl, hexahydropyridazin-3-yl,
hexahydropyridazin-4-yl, hexahydropyrimidin-2-yl,
hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, piperazin-1-yl,
piperazin-2-yl, 1,3,5-hexahydrotriazin-1-yl,
1,3,5-hexahydrotriazin-2-yl and 1,2,4-hexahydrotriazin-3-yl,
morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiomorpholin-2-yl,
thiomorpholin-3-yl, thiomorpholin-4-yl, 1-oxothiomorpholin-2-yl,
1-oxothiomorpholin-3-yl, 1-oxothiomorpholin-4-yl,
1,1-dioxothiomorpholin-2-yl, 1,1-dioxothiomorpholin-3-yl,
1,1-dioxothiomorpholin-4-yl, azepan-1-, -2-, -3- or -4-yl,
oxepan-2-, -3-, -4- or -5-yl, hexahydro-1,3-diazepinyl,
hexahydro-1,4-diazepinyl, hexahydro-1,3-oxazepinyl,
hexahydro-1,4-oxazepinyl, hexahydro-1,3-dioxepinyl,
hexahydro-1,4-dioxepinyl and the like.
[0097] Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered saturated
heterocyclic ring further include oxocane, thiocane, azocane,
[1,3]diazocane, [1,4]diazocane, [1,5]diazocane, [1,5]oxazocane and
the like.
[0098] Examples of a 3-, 4-, 5-, 6- or 7-membered partially
unsaturated heterocyclic ring include: 2,3-dihydrofur-2-yl,
2,3-dihydrofur-3-yl, 2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl,
2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl,
2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl,
2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl,
2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl,
2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl,
2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl,
2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl,
2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl,
2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl,
2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl,
2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl,
2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl,
3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl,
3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl,
4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl,
4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl,
2,3-dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl,
2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl,
3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl,
3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl,
3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 2-, 3-, 4-, 5- or
6-di- or tetrahydropyridinyl, 3-di- or tetrahydropyridazinyl, 4-di-
or tetrahydropyridazinyl, 2-di- or tetrahydropyrimidinyl, 4-di- or
tetrahydropyrimidinyl, 5-di- or tetrahydropyrimidinyl, di- or
tetrahydropyrazinyl, 1,3,5-di- or tetrahydrotriazin-2-yl, 1,2,4-di-
or tetrahydrotriazin-3-yl, 2,3,4,5-tetrahydro[1H]azepin-1-, -2-,
-3-, -4-, -5-, -6- or -7-yl, 3,4,5,6-tetrahydro[2H]azepin-2-, -3-,
-4-, -5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]azepin-1-, -2-, -3-,
-4-, -5-, -6- or -7-yl, 2,3,6,7-tetrahydro[1H]azepin-1-, -2-, -3-,
-4-, -5-, -6- or -7-yl, tetrahydrooxepinyl, such as
2,3,4,5-tetrahydro[1H]oxepin 2-, -3-, -4-, -5-, -6- or -7-yl,
2,3,4,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl,
2,3,6,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl,
tetrahydro-1,3-diazepinyl, tetrahydro-1,4-diazepinyl,
tetrahydro-1,3-oxazepinyl, tetrahydro-1,4-oxazepinyl,
tetrahydro-1,3-dioxepinyl and tetrahydro-1,4-dioxepinyl.
[0099] Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered partially
unsaturated heterocyclic ring further include
1,2,3,4,5,6-hexahydroazocine, 2,3,4,5,6,7-hexahydroazocine,
1,2,3,4,5,8-hexahydroazocine, 1,2,3,4,7,8-hexahydroazocine,
1,2,3,4,5,6-hexahydro-[1,5]diazocine,1,2,3,4,7,8-hexahydro-[1,5]diazocine
and the like.
[0100] Examples of a 3-, 4-, 5-, 6- or 7-membered maximally
unsaturated (including aromatic) heterocyclic ring include 5- or
6-membered heteroaromatic rings, such as 2-furyl, 3-furyl,
2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,
1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl,
4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,
1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1,3,4-triazol-1-yl,
1,3,4-triazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,
1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl,
3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl and 2-pyrazinyl, and also homoaromatic radicals, such
as 1H-azepine, 1H-[1,3]-diazepine and 1H-[1,4]-diazepine.
[0101] Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered maximally
unsaturated heterocyclic ring further include [1,3]diazocine,
[1,5]diazocine and [1,5]diazocine.
[0102] A 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially
unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4
heteroatoms or heteroatom groups independently selected from N, O,
S, NO, SO, SO.sub.2, C.dbd.O and C.dbd.S as ring members is either
saturated, partially unsaturated and carbocyclic (if it contains
only C.dbd.O and/or C.dbd.S as heteroatom group and no further
heteroatoms or heteroatom groups) or saturated, partially
unsaturated or maximally unsaturated heterocyclic. Examples are, in
addition to the heterocyclic rings mentioned above, carbocyclic
rings, such as cyclopropanonyl, cyclobutanonyl, cyclopentanonyl,
cyclohexanonyl, cyclohexandionyl, cycloheptanonyl, cyclooctanonyl,
cyclopropanthionyl, cyclobutanthionyl, cyclopentanthionyl,
cyclohexanthionyl, cyclohexandithionyl, cycloheptanthionyl,
cyclooctanthionyl, cyclopropenonyl, cyclopentenonyl, cyclohexenonyl
and the like.
[0103] Examples of a 4-membered saturated heterocyclic ring
containing 1 heteroatom or heteroatom group selected from N, O, S,
NO, SO and SO.sub.2 as ring member are oxetan-3-yl, oxetan-4-yl,
azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thietan-2-yl,
thietan-3-yl, 1-oxothietan-2-yl, 1-oxothietan-3-yl,
1,1-dioxothietan-2-yl and 1,1-dioxothietan-3-yl.
[0104] Examples of a 3-, 4-, 5- or 6-membered saturated
heterocyclic ring containing 1 or 2 heteroatoms or heteroatom
groups independently selected from N, O, S, NO, SO and SO.sub.2 as
ring members are, apart those listed above for the 4-membered
saturated heterocyclic ring containing 1 heteroatom or heteroatom
group selected from N, O, S, NO, SO and SO.sub.2 as ring member,
oxiral-2-yl, aziridin-1-yl, aziridin-2-yl, thiiran-2-yl,
1-oxothiiran-2-yl, 1,1-dioxothiiran-2-yl, tetrahydrofuran-2-yl,
tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,
pyrrolidin-1-yl, pyrroldin-2-yl, pyrrolidin-3-yl, pyrazolidin-1-yl,
pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl,
imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl,
oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, oxazolidin-5-yl,
isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl,
isoxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-3-yl,
thiazolidin-4-yl, thiazolidin-5-yl, isothiazolidin-2-yl,
isothiazolidin-3-yl, isothiazolidin-4-yl, isothiazolidin-5-yl,
tetrahydropyranyl, 4-tetrahydropyranyl, 1,3-dioxan-5-yl,
1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl,
piperidin-4-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl,
hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl,
hexahydropyrimidin-5-yl, piperazin-1-yl, piperazin-2-yl,
morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiomorpholin-2-yl,
thiomorpholin-3-yl, thiomorpholin-4-yl, 1-oxothiomorpholin-2-yl,
1-oxothiomorpholin-3-yl, 1-oxothiomorpholin-4-yl,
1,1-dioxothiomorpholin-2-yl, 1,1-dioxothiomorpholin-3-yl and
1,1-dioxothiomorpholin-4-yl.
[0105] The remarks made above and in the following with respect to
preferred aspects of the invention, e.g. to preferred meanings of
the variables R.sup.1, R.sup.2, R.sup.3a, R.sup.3b, R.sup.4a,
R.sup.4b, R.sup.5a, R.sup.5b, R.sup.6, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11a, R.sup.11b, a and b of compounds I, to
preferred compounds I and to preferred embodiments of the method or
the use according to the invention, apply in each case on their own
or in particular to combinations thereof.
[0106] In a preferred embodiment, R.sup.1 is selected from hydrogen
and C.sub.1-C.sub.6-alkyl, in particular from hydrogen and methyl,
and is specifically hydrogen.
[0107] In a preferred embodiment, R.sup.2 is selected from cyano,
nitro, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl and fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, more preferably from
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl and fluorinated
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, even more preferably
from C.sub.1-C.sub.6-alkyl and fluorinated C.sub.1-C.sub.6-alkyl,
in particular from methyl, ethyl, propyl, isopropyl and CF.sub.3,
more particularly from methyl, ethyl and CF.sub.3, and is
specifically methyl or CF.sub.3. Among
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl and fluorinated
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl radicals R.sup.2,
preference is given to CH.sub.2OCH.sub.3,
CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3,
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3, CH.sub.2OCF.sub.3,
CH.sub.2CH.sub.2OCF.sub.3, CH.sub.2OCHF.sub.2 and
CH.sub.2CH.sub.2OCHF.sub.2.
[0108] In a preferred embodiment, R.sup.3a and R.sup.3b,
independently of each other, are selected from hydrogen, cyano,
nitro, C.sub.1-C.sub.6-alkyl and fluorinated C.sub.1-C.sub.6-alkyl.
More preferably, R.sup.3a is selected from hydrogen, cyano, nitro,
C.sub.1-C.sub.6-alkyl and fluorinated C.sub.1-C.sub.6-alkyl, and
R.sup.3b is hydrogen. Even more preferably, R.sup.3a is selected
from hydrogen and methyl and R.sup.3b is hydrogen. In particular,
both R.sup.3a and R.sup.3b are hydrogen.
[0109] In a preferred embodiment, R.sup.4a and R.sup.4b,
independently of each other, are selected from hydrogen,
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl and fluorinated
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, or form together a
group .dbd.O, or form together a group --(CH.sub.2).sub.m--, where
m is 2, 3 or 4, in particular 2 or 3, especially 2, thus forming
together a spiro-bound ring. More preferably, R.sup.4a is selected
from hydrogen, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl
and fluorinated C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl and
R.sup.ob is hydrogen, or R.sup.4a and R.sup.4b are methyl, or
R.sup.4a and R.sup.4b form together a group --(CH.sub.2).sub.m--,
where m is 2, 3 or 4, in particular 2 or 3, especially 2, thus
forming together a spiro-bound ring. In a particular embodiment,
they are hydrogen.
[0110] In a preferred embodiment, R.sup.5a is selected from
hydrogen, halogen, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl and
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl and R.sup.5b is
hydrogen. In particular, R.sup.5a is hydrogen or methyl,
specifically hydrogen, and R.sup.5b is hydrogen.
[0111] Among C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl and fluorinated
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl radicals R.sup.4a,
R.sup.4b and R.sup.5b preference is given to CH.sub.2OCH.sub.3,
CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3,
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3, CH.sub.2OCF.sub.3,
CH.sub.2CH.sub.2OCF.sub.3, CH.sub.2OCHF.sub.2 and
CH.sub.2CH.sub.2OCHF.sub.2.
[0112] In one embodiment, R.sup.6 is C.sub.3-C.sub.6-cycloalkyl
which may carry one or more, in particular one, radicals
R.sup.8.
[0113] In another embodiment, R.sup.6 is a 3-, 4-, 5-, 6-, 7- or
8-membered saturated, partially unsaturated or maximally
unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms
or heteroatom groups independently selected from N, O, S, NO, SO
and SO.sub.2, and optionally also 1 or 2 groups C.dbd.O and/or
C.dbd.S, as ring members, where the heterocyclic ring may be
substituted with one or more substituents R.sup.10.
[0114] As a substituent on a cycloalkyl radical R.sup.6, preferably
each R.sup.8 is independently selected from the group consisting of
halogen, cyano, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl
and fluorinated C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl. Among
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl and fluorinated
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl radicals R.sup.8,
preference is given to CH.sub.2OCH.sub.3,
CH.sub.2CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3,
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3, CH.sub.2OCF.sub.3,
CH.sub.2CH.sub.2OCF.sub.3, CH.sub.2OCHF.sub.2 and
CH.sub.2CH.sub.2OCHF.sub.2. In particular, R.sup.8 is halogen,
specifically F.
[0115] In a preferred embodiment, R.sup.6 is unsubstituted
C.sub.3-C.sub.6-cycloalkyl; i.e. is selected from cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl. In another preferred
embodiment, R.sup.6 is fluorinated C.sub.3-C.sub.6-cycloalkyl, such
as 1-fluorocyclopropyl, 2-fluorocyclopropyl,
2,2-difluorocyclopropyl, 1-fluorocyclobutyl, 2-fluorocyclobutyl,
3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl
and the like. More preferably, R.sup.6 is selected from
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
2,2-difluorocyclopropyl or 3,3-difluorocyclobutyl. In particular,
R.sup.6 is selected from cyclopropyl and cyclobutyl, and is
particularly preferably cyclopropyl. In another particular
embodiment R.sup.6 is 2,2-difluorocyclopropyl.
[0116] In an alternatively preferred embodiment, R.sup.6 is a 3-,
4-, 5- or 6-membered saturated heterocyclic ring containing 1 or 2
heteroatoms or heteroatom groups independently selected from N, O,
S, NO, SO and SO.sub.2 as ring members, where the heterocyclic ring
may be substituted with one or more substituents R.sup.10, where
R.sup.10 has one of the above general or, in particular, one of the
below preferred meanings.
[0117] In an alternative particular embodiment, R.sup.6 is a
4-membered saturated heterocyclic ring containing 1 heteroatom or
heteroatom group selected from N, O, S, NO, SO and SO.sub.2, in
particular from O, as ring member, where the heterocyclic ring may
be substituted with one or more substituents R.sup.10, where
R.sup.10 has one of the above general or, in particular, one of the
below preferred meanings. Specifically, R.sup.6 is oxetan-3-yl
which may be substituted with one or more, especially one,
substituents R.sup.10, where R.sup.10 has one of the above general
or, in particular, one of the below preferred meanings.
[0118] In an alternative particular embodiment, R.sup.6 is a 5- or
6-membered saturated heterocyclic ring containing 1 heteroatom or
heteroatom group selected from N, O, S, NO, SO and SO.sub.2, in
particular from O, as ring member, where the heterocyclic ring may
be substituted with one or more substituents R.sup.10, where
R.sup.10 has one of the above general or, in particular, one of the
below preferred meanings. Specifically, R.sup.6 is
tetrahydrofuran-3-yl or tetrahydropyran-4-yl which may be
substituted with one or more, especially one, substituents
R.sup.10, where R.sup.10 has one of the above general or, in
particular, one of the below preferred meanings.
[0119] As a substituent on a heterocyclic ring R.sup.6, each
R.sup.10 is independently preferably selected from the group
consisting of halogen, cyano, C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy and fluorinated
C.sub.1-C.sub.4-alkoxy, more preferably from F, Cl, cyano,
CH.sub.3, CF.sub.3, OCH.sub.3 and OCF.sub.3, and in particular from
F, CH.sub.3, CF.sub.3, OCH.sub.3 and OCF.sub.3. Specifically
R.sup.10 is CH.sub.3.
[0120] In a preferred embodiment, each R.sup.2 is independently
selected from the group consisting of halogen, cyano, nitro,
hydroxyl, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, fluorinated C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, fluorinated C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.6-alkoxy and fluorinated C.sub.1-C.sub.6-alkoxy. More
preferably, each R.sup.7 is independently selected from halogen,
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy and fluorinated C.sub.1-C.sub.4-alkoxy, and
is in particular fluorine. In an alternative embodiment, each
R.sup.2 is independently selected from the group consisting of
cyano and C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl.
[0121] In a preferred embodiment, a is 0 or 1. If a is 1, R.sup.2
is preferably bound in .beta.-position to the nitrogen ring atom
carrying R.sup.1.
[0122] In particular, a is 0 if R.sup.6 is carbocyclic, i.e.
C.sub.3-C.sub.6-cycloalkyl which may carry one or more radicals
R.sup.8; and a is 0 or 1 if R.sup.6 is heterocyclic, i.e. a 3-, 4-,
5-, 6-, 7- or 8-membered saturated, partially unsaturated or
maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4
heteroatoms or heteroatom groups independently selected from N, O,
S, NO, SO and SO.sub.2, and optionally also 1 or 2 groups C.dbd.O
and/or C.dbd.S, as ring members, where the heterocyclic ring may be
substituted with one or more substituents R.sup.10.
[0123] In a preferred embodiment, b is 0 or 1 and specifically
0.
[0124] If not specified otherwise in a specific context, R.sup.9,
R.sup.10, R.sup.11a and R.sup.11b have following preferred
meanings:
[0125] Preferably each R.sup.9 is independently selected from the
group consisting of hydrogen, hydroxyl, C.sub.1-C.sub.6-alkyl,
fluorinated C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-hydroxyalkyl,
C.sub.3-C.sub.6-cycloalkyl, fluorinated C.sub.3-C.sub.6-cycloalkyl,
C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy, and
--NR.sup.11aR.sup.11b, where R.sup.11a and R.sup.11b have one of
the above general or, in particular, one of the below preferred
meanings. In particular, each R.sup.9 is independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.4-alkyl,
fluorinated C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.4-hydroxyalkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.2-alkoxy, and
--NR.sup.11aR.sup.11b, where R.sup.11a and R.sup.11b have one of
the above general or, in particular, one of the below preferred
meanings.
[0126] Preferably, each R.sup.10 is independently selected from the
group consisting of halogen, cyano, C.sub.1-C.sub.4-alkyl,
fluorinated C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy and
fluorinated C.sub.1-C.sub.4-alkoxy, more preferably from F, Cl,
cyano, CH.sub.3, CF.sub.3, OCH.sub.3 and OCF.sub.3, and in
particular from F, CH.sub.3, CF.sub.3, OCH.sub.3 and OCF.sub.3.
[0127] Preferably, R.sup.11a and R.sup.11b, independently of each
other and independently of each occurrence, are selected from the
group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylcarbonyl and
fluorinated C.sub.1-C.sub.6-alkylcarbonyl.
[0128] In a particular embodiment, the compounds of the invention
are compounds of formula I.1
##STR00003## [0129] wherein R.sup.2, R.sup.6, R.sup.7 and b have
one of the above general or, in particular, one of the above
preferred meanings, and a is 0 or 1.
[0130] In a more particular embodiment, the compounds of the
invention are compounds of formula I.1.1
##STR00004## [0131] wherein [0132] R.sup.7a is H, Cl, F or methyl,
in particular H or F, specifically H; [0133] a is 0 or 1; and
[0134] R.sup.2, R.sup.6, R.sup.7 and b have one of the above
general or, in particular, one of the above preferred meanings.
[0135] In compounds I.1.1 (b-1) is preferably 0.
[0136] In compounds I.1 and I.1.1 R.sup.2 is preferably methyl.
[0137] In compounds I.1 and I.1.1 a is preferably 0 if R.sup.6 is a
carbocyclic (i.e. cycloalkyl) radical, and is 0 or 1 if R.sup.6 is
heterocyclic.
[0138] Examples of preferred compounds are compounds of the
following formulae Ia.1 to Ia.36, where the variables have one of
the general or preferred meanings given above. Examples of
preferred compounds are the individual compounds compiled in the
tables 1 to 28080 below. Moreover, the meanings mentioned below for
the individual variables in the tables are per se, independently of
the combination in which they are mentioned, a particularly
preferred embodiment of the substituents in question.
##STR00005## ##STR00006## ##STR00007## ##STR00008## ##STR00009##
##STR00010##
Table 1
[0139] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is cyclopropyl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 2
[0140] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1-fluorocyclopropyl and the combination
of R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in
each case to one row of Table A.
Table 3
[0141] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 2-fluorocyclopropyl and the combination
of R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in
each case to one row of Table A.
Table 4
[0142] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 2,2-difluorocyclopropyl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 5
[0143] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is cyclobutyl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 6
[0144] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1-fluorocyclobutyl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 7
[0145] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 2-fluorocyclobutyl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 8
[0146] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 3-fluorocyclobutyl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 9
[0147] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 2,2-difluorocyclobutyl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 10
[0148] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 3,3-difluorocyclobutyl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 11
[0149] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is cyclopentyl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 12
[0150] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1-fluorocyclopentyl and the combination
of R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in
each case to one row of Table A.
Table 13
[0151] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 2-fluorocyclopentyl and the combination
of R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in
each case to one row of Table A.
Table 14
[0152] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 3-fluorocyclopentyl and the combination
of R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in
each case to one row of Table A.
Table 15
[0153] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 2,2-difluorocyclopentyl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 16
[0154] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 3,3-difluorocyclopentyl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 17
[0155] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is cyclohexyl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 18
[0156] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1-fluorocyclohexyl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 19
[0157] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 2-fluorocyclohexyl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 20
[0158] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 3-fluorocyclohexyl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 21
[0159] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 4-fluorocyclohexyl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 22
[0160] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is aziridin-1-yl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 23
[0161] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1-(oxetan-3-yl)-aziridin-2-yl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 24
[0162] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1-(tetrahydrofuran-3-yl)-aziridin-2-yl
and the combination of R.sup.5a, R.sup.5b and R.sup.7a for a
compound corresponds in each case to one row of Table A.
Table 25
[0163] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is oxiran-2-yl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 26
[0164] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is azetidin-1-yl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 27
[0165] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1-(oxetan-3-yl)-azetidin-2-yl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 28
[0166] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1-(tetrahydrofuran-3-yl)-azetidin-2-yl
and the combination of R.sup.5a, R.sup.5b and R.sup.7a for a
compound corresponds in each case to one row of Table A.
Table 29
[0167] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1-(oxetan-3-yl)-azetidin-3-yl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 30
[0168] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1-(tetrahydrofuran-3-yl)-azetidin-2-yl
and the combination of R.sup.5a, R.sup.5b and R.sup.7a for a
compound corresponds in each case to one row of Table A.
Table 31
[0169] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is oxetan-2-yl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 32
[0170] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is oxetan-3-yl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 33
[0171] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 3-methyloxetan-2-yl and the combination
of R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in
each case to one row of Table A.
Table 34
[0172] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 3-methyloxetan-3-yl and the combination
of R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in
each case to one row of Table A.
Table 35
[0173] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 2-methyloxetan-3-yl and the combination
of R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in
each case to one row of Table A.
Table 36
[0174] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is pyrrolidin-1-yl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 37
[0175] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1-(oxetan-3-yl)-pyrrolidin-2-yl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 38
[0176] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1-(tetrahydrofuran-3-yl)-azetidin-2-yl
and the combination of R.sup.5a, R.sup.5b and R.sup.7a for a
compound corresponds in each case to one row of Table A.
Table 39
[0177] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1-(oxetan-3-yl)-pyrrolidin-3-yl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 40
[0178] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1-(tetrahydrofuran-3-yl)-pyrrolidin-3-yl
and the combination of R.sup.5a, R.sup.5b and R.sup.7a for a
compound corresponds in each case to one row of Table A.
Table 41
[0179] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is tetrahydrofuran-2-yl and the combination
of R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in
each case to one row of Table A.
Table 42
[0180] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is tetrahydrofuran-3-yl and the combination
of R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in
each case to one row of Table A.
Table 43
[0181] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 3-(oxetan-3-yl)-oxazolidin-2-yl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 44
[0182] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is oxazolidin-3-yl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 45
[0183] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 3-(oxetan-3-yl)-oxazolidin-4-yl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 46
[0184] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 3-(oxetan-3-yl)-oxazolidin-5-yl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 47
[0185] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is isoxazolidin-2-yl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 48
[0186] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 2-(oxetan-3-yl)-isoxazolidin-3-yl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 49
[0187] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 2-(oxetan-3-yl)-isoxazolidin-4-yl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 50
[0188] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 2-(oxetan-3-yl)-isoxazolidin-5-yl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 51
[0189] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is piperidin-1-yl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 52
[0190] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 4-(oxetan-3-yl)-piperazine-1-yl and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Table 53
[0191] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 4-(tetrahydrofuran-3-yl)-piperazine-1-yl
and the combination of R.sup.5a, R.sup.5b and R.sup.7a for a
compound corresponds in each case to one row of Table A.
Table 54
[0192] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is morpholin-4-yl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 55
[0193] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is tetrahydropyran-2-yl and the combination
of R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in
each case to one row of Table A.
Table 56
[0194] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is tetrahydropyran-3-yl and the combination
of R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in
each case to one row of Table A.
Table 57
[0195] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is tetrahydropyran-4-yl and the combination
of R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in
each case to one row of Table A.
Table 58
[0196] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1,3-dioxan-2-yl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 59
[0197] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1,3-dioxan-4-yl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Table 60
[0198] Compounds of the formula Ia.1 in which R.sup.4a is H,
R.sup.4b is H, R.sup.6 is 1,4-dioxan-2-yl and the combination of
R.sup.5a, R.sup.5b and R.sup.7a for a compound corresponds in each
case to one row of Table A.
Tables 61 to 120
[0199] Compounds of the formula Ia.1 in which R.sup.4a is methyl,
R.sup.4b is H, R.sup.6 is as defined in tables 1 to 60 and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 121 to 180
[0200] Compounds of the formula Ia.1 in which R.sup.4a is ethyl,
R.sup.4b is H, R.sup.6 is as defined in tables 1 to 60 and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 181 to 240
[0201] Compounds of the formula Ia.1 in which R.sup.4a is
CH.sub.2OCH.sub.3, R.sup.4b is H, R.sup.6 is as defined in tables 1
to 60 and the combination of R.sup.5a, R.sup.5b and R.sup.7a for a
compound corresponds in each case to one row of Table A.
Tables 241 to 300
[0202] Compounds of the formula Ia.1 in which R.sup.4a is
CH.sub.2OCH.sub.2CH.sub.3, R.sup.4b is H, R.sup.6 is as defined in
tables 1 to 60 and the combination of R.sup.5a, R.sup.5b and
R.sup.7a for a compound corresponds in each case to one row of
Table A.
Tables 301 to 360
[0203] Compounds of the formula Ia.1 in which R.sup.4a is
CH.sub.2CH.sub.2OCH.sub.3, R.sup.4b is H, R.sup.6 is as defined in
tables 1 to 60 and the combination of R.sup.5a, R.sup.5b and
R.sup.7a for a compound corresponds in each case to one row of
Table A.
Tables 361 to 420
[0204] Compounds of the formula Ia.1 in which R.sup.4a is
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3, R.sup.4b is H, R.sup.6 is as
defined in tables 1 to 60 and the combination of R.sup.5a, R.sup.5b
and R.sup.7a for a compound corresponds in each case to one row of
Table A.
Tables 421 to 480
[0205] Compounds of the formula Ia.1 in which R.sup.4a is
CH.sub.2OCHF.sub.2, R.sup.4b is H, R.sup.6 is as defined in tables
1 to 60 and the combination of R.sup.5a, R.sup.5b and R.sup.7a for
a compound corresponds in each case to one row of Table A.
Tables 481 to 540
[0206] Compounds of the formula Ia.1 in which R.sup.4a is
CH.sub.2OCF.sub.3, R.sup.4b is H, R.sup.6 is as defined in tables 1
to 60 and the combination of R.sup.5a, R.sup.5b and R.sup.7a for a
compound corresponds in each case to one row of Table A.
Tables 541 to 600
[0207] Compounds of the formula Ia.1 in which R.sup.4a is
CH.sub.2CH.sub.2OCHF.sub.2, R.sup.4b is H, R.sup.6 is as defined in
tables 1 to 60 and the combination of R.sup.5a, R.sup.5b and
R.sup.7a for a compound corresponds in each case to one row of
Table A.
Tables 601 to 660
[0208] Compounds of the formula Ia.1 in which R.sup.4a is
CH.sub.2CH.sub.2OCF.sub.3, R.sup.4b is H, R.sup.6 is as defined in
tables 1 to 60 and the combination of R.sup.5a, R.sup.5b and
R.sup.7a for a compound corresponds in each case to one row of
Table A.
Tables 661 to 720
[0209] Compounds of the formula Ia.1 in which R.sup.4a is methyl,
R.sup.4b is methyl, R.sup.6 is as defined in tables 1 to 60 and the
combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 721 to 780
[0210] Compounds of the formula Ia.1 in which R.sup.4a and R.sup.4b
form together --CH.sub.2--CH.sub.2--, R.sup.6 is as defined in
tables 1 to 60 and the combination of R.sup.5a, R.sup.5b and
R.sup.7a for a compound corresponds in each case to one row of
Table A.
Tables 781 to 1560
[0211] Compounds of the formula Ia.2 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 1561 to 2340
[0212] Compounds of the formula Ia.3 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 2341 to 3120
[0213] Compounds of the formula Ia.4 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 3121 to 3900
[0214] Compounds of the formula Ia.5 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 3901 to 4680
[0215] Compounds of the formula Ia.6 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 4681 to 5460
[0216] Compounds of the formula Ia.7 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 5461 to 6240
[0217] Compounds of the formula Ia.8 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 6241 to 7020
[0218] Compounds of the formula Ia.9 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 7021 to 7800
[0219] Compounds of the formula Ia.10 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 7801 to 8580
[0220] Compounds of the formula Ia.11 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 8581 to 9360
[0221] Compounds of the formula Ia.12 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 9361 to 10140
[0222] Compounds of the formula Ia.13 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 10141 to 10920
[0223] Compounds of the formula Ia.14 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 10921 to 11700
[0224] Compounds of the formula Ia.15 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 11701 to 12480
[0225] Compounds of the formula Ia.16 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 12481 to 13260
[0226] Compounds of the formula Ia.17 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 13261 to 14040
[0227] Compounds of the formula Ia.18 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 14041 to 14820
[0228] Compounds of the formula Ia.19 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 14821 to 15600
[0229] Compounds of the formula Ia.20 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 15601 to 16380
[0230] Compounds of the formula Ia.21 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 16381 to 17160
[0231] Compounds of the formula Ia.22 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 17161 to 17940
[0232] Compounds of the formula Ia.23 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 17941 to 18720
[0233] Compounds of the formula Ia.24 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 18721 to 19500
[0234] Compounds of the formula Ia.25 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 19501 to 20280
[0235] Compounds of the formula Ia.26 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 20281 to 21060
[0236] Compounds of the formula Ia.27 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 21061 to 21840
[0237] Compounds of the formula Ia.28 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 21841 to 22620
[0238] Compounds of the formula Ia.29 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 22621 to 23400
[0239] Compounds of the formula Ia.30 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 23401 to 24180
[0240] Compounds of the formula Ia.31 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 24181 to 24960
[0241] Compounds of the formula Ia.32 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 24961 to 25740
[0242] Compounds of the formula Ia.33 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 25741 to 26520
[0243] Compounds of the formula Ia.34 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 26521 to 27300
[0244] Compounds of the formula Ia.35 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
Tables 27301 to 28080
[0245] Compounds of the formula Ia.36 in which the combination of
R.sup.4a, R.sup.4b and R.sup.6 is as defined in tables 1 to 780 and
the combination of R.sup.5a, R.sup.5b and R.sup.7a for a compound
corresponds in each case to one row of Table A.
TABLE-US-00001 TABLE A No. R.sup.7a R.sup.5a R.sup.5b A-1 H H H A-2
F H H A-3 Cl H H A-4 CH.sub.3 H H A-5 CHF.sub.2 H H A-6 CF.sub.3 H
H A-7 OCH.sub.3 H H A-8 OCHF.sub.2 H H A-9 OCF.sub.3 H H A-10
cyclopropyl H H A-11 CN H H A-12 CH.sub.2OCH.sub.3 H H A-13
CH.sub.2CH.sub.2OCH.sub.3 H H A-14 H CH.sub.3 H A-15 F CH.sub.3 H
A-16 Cl CH.sub.3 H A-17 CH.sub.3 CH.sub.3 H A-18 CHF.sub.2 CH.sub.3
H A-19 CF.sub.3 CH.sub.3 H A-20 OCH.sub.3 CH.sub.3 H A-21
OCHF.sub.2 CH.sub.3 H A-22 OCF.sub.3 CH.sub.3 H A-23 cyclopropyl
CH.sub.3 H A-24 CN CH.sub.3 H A-25 CH.sub.2OCH.sub.3 CH.sub.3 H
A-26 CH.sub.2CH.sub.2OCH.sub.3 CH.sub.3 H A-27 H CH.sub.2CH.sub.3 H
A-28 F CH.sub.2CH.sub.3 H A-29 Cl CH.sub.2CH.sub.3 H A-30 CH.sub.3
CH.sub.2CH.sub.3 H A-31 CHF.sub.2 CH.sub.2CH.sub.3 H A-32 CF.sub.3
CH.sub.2CH.sub.3 H A-33 OCH.sub.3 CH.sub.2CH.sub.3 H A-34
OCHF.sub.2 CH.sub.2CH.sub.3 H A-35 OCF.sub.3 CH.sub.2CH.sub.3 H
A-36 cyclopropyl CH.sub.2CH.sub.3 H A-37 CN CH.sub.2CH.sub.3 H A-38
CH.sub.2OCH.sub.3 CH.sub.2CH.sub.3 H A-39 CH.sub.2CH.sub.2OCH.sub.3
CH.sub.2CH.sub.3 H A-40 H CH.sub.2OCH.sub.3 H A-41 F
CH.sub.2OCH.sub.3 H A-42 Cl CH.sub.2OCH.sub.3 H A-43 CH.sub.3
CH.sub.2OCH.sub.3 H A-44 CHF.sub.2 CH.sub.2OCH.sub.3 H A-45
CF.sub.3 CH.sub.2OCH.sub.3 H A-46 OCH.sub.3 CH.sub.2OCH.sub.3 H
A-47 OCHF.sub.2 CH.sub.2OCH.sub.3 H A-48 OCF.sub.3
CH.sub.2OCH.sub.3 H A-49 cyclopropyl CH.sub.2OCH.sub.3 H A-50 CN
CH.sub.2OCH.sub.3 H A-51 CH.sub.2OCH.sub.3 CH.sub.2OCH.sub.3 H A-52
CH.sub.2CH.sub.2OCH.sub.3 CH.sub.2OCH.sub.3 H A-53 H
CH.sub.2OCH.sub.2CH.sub.3 H A-54 F CH.sub.2OCH.sub.2CH.sub.3 H A-55
Cl CH.sub.2OCH.sub.2CH.sub.3 H A-56 CH.sub.3
CH.sub.2OCH.sub.2CH.sub.3 H A-57 CHF.sub.2
CH.sub.2OCH.sub.2CH.sub.3 H A-58 CF.sub.3 CH.sub.2OCH.sub.2CH.sub.3
H A-59 OCH.sub.3 CH.sub.2OCH.sub.2CH.sub.3 H A-60 OCHF.sub.2
CH.sub.2OCH.sub.2CH.sub.3 H A-61 OCF.sub.3
CH.sub.2OCH.sub.2CH.sub.3 H A-62 cyclopropyl
CH.sub.2OCH.sub.2CH.sub.3 H A-63 CN CH.sub.2OCH.sub.2CH.sub.3 H
A-64 CH.sub.2OCH.sub.3 CH.sub.2OCH.sub.2CH.sub.3 H A-65
CH.sub.2CH.sub.2OCH.sub.3 CH.sub.2OCH.sub.2CH.sub.3 H A-66 H
CH.sub.2CH.sub.2OCH.sub.3 H A-67 F CH.sub.2CH.sub.2OCH.sub.3 H A-68
Cl CH.sub.2CH.sub.2OCH.sub.3 H A-69 CH.sub.3
CH.sub.2CH.sub.2OCH.sub.3 H A-70 CHF.sub.2
CH.sub.2CH.sub.2OCH.sub.3 H A-71 CF.sub.3 CH.sub.2CH.sub.2OCH.sub.3
H A-72 OCH.sub.3 CH.sub.2CH.sub.2OCH.sub.3 H A-73 OCHF.sub.2
CH.sub.2CH.sub.2OCH.sub.3 H A-74 OCF.sub.3
CH.sub.2CH.sub.2OCH.sub.3 H A-75 cyclopropyl
CH.sub.2CH.sub.2OCH.sub.3 H A-76 CN CH.sub.2CH.sub.2OCH.sub.3 H
A-77 CH.sub.2OCH.sub.3 CH.sub.2CH.sub.2OCH.sub.3 H A-78
CH.sub.2CH.sub.2OCH.sub.3 CH.sub.2CH.sub.2OCH.sub.3 H A-79 H
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 H A-80 F
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 H A-81 Cl
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 H A-82 CH.sub.3
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 H A-83 CHF.sub.2
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 H A-84 CF.sub.3
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 H A-85 OCH.sub.3
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 H A-86 OCHF.sub.2
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 H A-87 OCF.sub.3
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 H A-88 cyclopropyl
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 H A-89 CN
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 H A-90 CH.sub.2OCH.sub.3
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 H A-91 CH.sub.2CH.sub.2OCH.sub.3
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3 H A-92 H CH.sub.3 CH.sub.3 A-93 F
CH.sub.3 CH.sub.3 A-94 Cl CH.sub.3 CH.sub.3 A-95 CH.sub.3 CH.sub.3
CH.sub.3 A-96 CHF.sub.2 CH.sub.3 CH.sub.3 A-97 CF.sub.3 CH.sub.3
CH.sub.3 A-98 OCH.sub.3 CH.sub.3 CH.sub.3 A-99 OCHF.sub.2 CH.sub.3
CH.sub.3 A-100 OCF.sub.3 CH.sub.3 CH.sub.3 A-101 cyclopropyl
CH.sub.3 CH.sub.3 A-102 CN CH.sub.3 CH.sub.3 A-103
CH.sub.2OCH.sub.3 CH.sub.3 CH.sub.3 A-104 CH.sub.2CH.sub.2OCH.sub.3
CH.sub.3 CH.sub.3 A-105 H CH.sub.2CH.sub.3 CH.sub.3 A-106 F
CH.sub.2CH.sub.3 CH.sub.3 A-107 Cl CH.sub.2CH.sub.3 CH.sub.3 A-108
CH.sub.3 CH.sub.2CH.sub.3 CH.sub.3 A-109 CHF.sub.2 CH.sub.2CH.sub.3
CH.sub.3 A-110 CF.sub.3 CH.sub.2CH.sub.3 CH.sub.3 A-111 OCH.sub.3
CH.sub.2CH.sub.3 CH.sub.3 A-112 OCHF.sub.2 CH.sub.2CH.sub.3
CH.sub.3 A-113 OCF.sub.3 CH.sub.2CH.sub.3 CH.sub.3 A-114
cyclopropyl CH.sub.2CH.sub.3 CH.sub.3 A-115 CN CH.sub.2CH.sub.3
CH.sub.3 A-116 CH.sub.2OCH.sub.3 CH.sub.2CH.sub.3 CH.sub.3 A-117
CH.sub.2CH.sub.2OCH.sub.3 CH.sub.2CH.sub.3 CH.sub.3
[0246] Among the above compounds, preference is given to compounds
Ia.1 and Ia.10; the latter especially if R.sup.6 is a heterocyclic
ring, for examples as defined in table 22 to 60.
[0247] In a specific embodiment, the invention relates to compounds
I selected from the compounds of the examples, either in form of
free bases or of any pharmaceutically acceptable salt thereof or a
stereoisomer, the racemate or any mixture of stereoisomers
thereof.
[0248] The compounds of the present invention can be prepared by
using routine techniques familiar to a skilled person. In
particular, the compounds of the formula I can be prepared
according to the following schemes, wherein the variables, if not
stated otherwise, are as defined above.
[0249] Compounds of formula I wherein R.sup.4b and R.sup.5b are H
(=compounds I') can be synthesized as described in scheme 1 below.
The readily available quinoline 1 in which X is a leaving group,
such as Cl, Br I or triflate, is reacted with a suitable boron
compound of R.sup.6, such as R.sup.6-boronic acid
(R.sup.6--B(OH).sub.2) or the potassium (trifluoro)borate of
R.sup.6 (e.g. potassium cyclobutyl(trifluoro)borate or potassium
cyclopropyl(trifluoro)borate) in a Suzuki coupling reaction to 2.
The reaction is carried out in the presence of a Pd catalyst, such
as Pd(OAc).sub.2, in general in the presence of a phosphine ligand
(e.g. tricyclohexylphosphine; di(adamantan-1-yl)(butyl)-phosphine
etc.), or tetrakis(triphenylphosphine)palladium(0) and the like.
Quinoline 2 is then N-alkylated with a suitable protective group,
such as benzyl, e.g. by reaction with benzyl bromide, to 3.
Reduction of the quinolinium compound 3 with a suitable reduction
agent, such as sodium borohydride and H.sub.2/Raney nickel, yields
the 1,2,3,4-tetrahydroquinoline 4, which is then deprotected to 5.
Reaction with the 2-halogenoacetamide 6, wherein Y is Cl, Br or I,
affords the acetamide 7, the keto group of which is reduced with
common reduction agents, like borane,
borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex or
borohydrides such as sodium borohydride or LAH (lithium aluminium
hydride) or DIBAL-H (diisobutyl aluminium hydride), to 8.
Cyclization with formaldehyde/aldehyde/ketone 9
(C(O)R.sup.3aR.sup.3b=formaldehyde if R.sup.3a and R.sup.3b are
hydrogen; another aldehyde if R.sup.3a is hydrogen and R.sup.3b is
(fluorinated) alkyl, hydroxyalkyl, (fluorinated) alkenyl,
(fluorinated) alkynyl, (fluorinated) cycloalkyl, phenyl,
phenyl-alkyl or a heterocyclic ring; a ketone if R.sup.3a and
R.sup.3b are (fluorinated) alkyl, hydroxyalkyl, (fluorinated)
alkenyl, (fluorinated) alkynyl, (fluorinated) cycloalkyl, phenyl,
phenyl-alkyl or a heterocyclic ring), generally in the presence of
a strong acid, such as trifluoroacetic acid, yields I'.
Alternatively, 2 can be reacted with the 2-halogenoacetamide 6 to
10, which is then reduced to 7.
##STR00011##
[0250] Compounds of formula I wherein R.sup.4a, R.sup.4b and
R.sup.5b are H (=compounds I'') can alternatively be synthesized as
described in scheme 2 below. The boronic acid 11 and the
.alpha.,.beta.-unsaturated ester 12 are reacted in a 1,4-addition
in the presence of a Rhodium catalyst, e.g. [RhOH(COD)].sub.2 or
Rh(acac)(CO).sub.2, if desired in the presence of a phosphine
ligand, such as 1,4-bis(diphenylphosphino)butane (dppb), followed
by lactam formation. The lactam 13 is then reduced with common
reduction agents, like borane, borane-tetrahydrofurane-complex,
borane-dimethylsulfide-complex or borohydrides such as sodium
borohydride, to the tetrahydroquinoline 14. Like in the reaction
sequence of scheme 1, reaction with the 2-halogenoacetamide 6,
wherein Y is Cl, Br or I, affords the acetamide 15, the keto group
of which is reduced with common reduction agents, like borane,
borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex or
borohydrides such as sodium borohydride or LAH (lithium aluminium
hydride) or DIBAL-H (diisobutyl aluminium hydride), to 16.
Cyclization with formaldehyde/aldehyde/ketone 9, generally in the
presence of a strong acid, such as trifluoroacetic acid, yields
I''.
##STR00012##
[0251] For obtaining compounds I wherein R.sup.4a and R.sup.4b form
together .dbd.O, the lactam 13 is not reduced, but is directly
reacted with the 2-halogenoacetamide 6 to 17, followed by reduction
of the CO group in the amide to 18 and finally cyclisation, as
shown in scheme 3 below. Alternatively, compounds I''' can be
obtained as described below scheme 4.
##STR00013##
[0252] Compounds of formula I wherein R.sup.4a, R.sup.4b and
R.sup.5b are H (=compounds I'') can alternatively be synthesized as
described in scheme 4 below. The protected tetrahydrobenzodiazepine
19, wherein Z is a hydrogen or a halogen atom, such as Cl, Br or I
and PG is a common protective group, such as a carbamate,
especially boc, is acylated with the acrylic acid derivative 20,
wherein LG is an appropriate leaving group, such as Cl or an
anhydride or a chloroformate, in the presence of a base, such as
triethylamine or Hunig's base, in an organic solvent, such as ether
or methylene chloride. Reaction of 21 with a Lewis acid or a
Bronstedt acid HA or irradiation with a suitable wavelength
commonly derived from a mercury lamp in an adequate solvent, such
as acetone or toluene, in a common photoreactor yields cyclization
to 22. Reduction of the carbonyl group with common reduction agents
like borohydrides such as sodium borohydride or
borane-tetrahydrofurane-complex yields 23, which is deprotected
using suitable reagents such as strong bases or acids to I'',
wherein R.sup.4a and R.sup.4b and R.sup.5b are H. Compounds I''''
wherein R.sup.4a and R.sup.4b form together .dbd.O can be obtained
by skipping the reduction step to 23 and deprotecting 22.
[0253] Alternatively, compound 22 can be directly synthesized by
reacting the tetrahydrobenzodiazepine 19, wherein Z is
--B(OH).sub.2 with the acrylic acid derivative 20 in a 1,4-addition
in the presence of a Rhodium catalyst, e.g. [RhOH(COD)].sub.2 or
Rh(acac)(CO).sub.2, if desired in the presence of a phosphine
ligand, such as 1,4-bis(diphenylphosphino)butane (dppb), followed
by lactam formation to 22. This is then further reacted as
described above.
##STR00014##
[0254] If compound 22 is deprotected, this yields compound I''' as
well as other compounds I in which (R.sup.2).sub.a is not
necessarily bound to the same position as in compounds I'''.
[0255] If desired, substituents R.sup.1 different from hydrogen can
be introduced for example via alkylation under typical conditions
such as stirring in an appropriate solvent in the presence of an
alkylhalide and a base or via other common substitution reactions,
or via reductive amination using a suitable aldehyde or ketone in
the presence of reduction agent, such as borohydrides, e.g.
triacetoxyborohydride, sodium cyanoborohydride or sodium
borohydride. --C(.dbd.O)R.sup.9 as radical R.sup.1 can be
introduced via amidation under typical amidation conditions, e.g.
via reaction with a compound X--C(.dbd.O)R.sup.9, where X is OH or
a halogen atom, under heating and removal of reaction water or
using a coupling reagent, such as DCC (dicyclohexylcarbodiimide),
DIC (diisopropylcarbodiimide), HATU
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate), HBTU
((0-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate), HCTU
(1H-benzotriazolium-1-[bis(dimethylamino)methylene]-5-chloro
tetrafluoroborate), BOP
((benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium
hexafluorophosphate), Py-BOP
((benzotriazol-1-yloxy)-tripyrrolidinphosphonium
hexafluorophosphate) or Py-BrOP (bromotripyrrolidinphosphonium
hexafluorophosphate).
[0256] Compounds I wherein R.sup.5b is different from H can be
prepared, for example, by reacting compound 22 with a compound
LG-R.sup.5b in the presence of a base, wherein LG is an appropriate
leaving group, such as Cl or Br.
[0257] Alternatively to the method depicted in scheme 4, compounds
I wherein R.sup.4a, R.sup.4b and R.sup.5b are H (=compounds I'')
can be synthesized as described in scheme 5 below. Readily
available anilines 24 are derivatized with carbonyl moieties 25 by
acylation procedures employing appropriate leaving groups LG, such
as chlorides or anhydrides, in the presence of a base such as
triethylamine or Hunig's base, in an organic solvent, such as
diethyl ether or methylene chloride to yield 26. Cyclization
products 13 are received by irradiation with a suitable wavelength
commonly derived from a mercury lamp in an adequate solvent such as
acetone or toluene in a common photoreactor known to those skilled
in the art. These are further reacted as depicted in schemes 2 and
3.
##STR00015##
[0258] Compounds I wherein R.sup.4a and R.sup.4b are not H or do
not form together a group .dbd.O can be prepared by standard
derivatization methods of compounds wherein R.sup.4a and R.sup.4b
form together a group .dbd.O. For instance, compounds wherein
R.sup.4a and R.sup.4b form together a group .dbd.S may be prepared
by reaction with a sulfurization agent, such as Lawesson's reagent
or P.sub.2S.sub.5. Alkyl and related groups as radicals R.sup.4a
and R.sup.4b may be introduced via Grignard reduction. Amino and
related groups may be introduced via reductive amination. Hydroxyl
group R.sup.4a or R.sup.4b may be introduced by reducing the
carbonyl group. This may be alkylated to yield alkoxy and related
groups R.sup.4a and R.sup.4b or substituted by diverse groups.
[0259] If not otherwise indicated, the above-described reactions
are generally carried out in a solvent at temperatures between room
temperature and the boiling temperature of the solvent employed.
Alternatively, the activation energy which is required for the
reaction can be introduced into the reaction mixture using
microwaves, something which has proved to be of value, in
particular, in the case of the reactions catalyzed by transition
metals (with regard to reactions using microwaves, see Tetrahedron
2001, 57, p. 9199 ff. p. 9225 ff. and also, in a general manner,
"Microwaves in Organic Synthesis", Andre Loupy (Ed.), Wiley-VCH
2002.
[0260] The acid addition salts of compounds I are prepared in a
customary manner by mixing the free base with a corresponding acid,
where appropriate in solution in an organic solvent, for example a
lower alcohol, such as methanol, ethanol or propanol, an ether,
such as methyl tert-butyl ether or diisopropyl ether, a ketone,
such as acetone or methyl ethyl ketone, or an ester, such as ethyl
acetate.
[0261] Routine experimentations, including appropriate manipulation
of the reaction conditions, reagents and sequence of the synthetic
route, protection of any chemical functionality that may not be
compatible with the reaction conditions, and deprotection at a
suitable point in the reaction sequence of the preparation methods
are within routine techniques.
[0262] Suitable protecting groups and the methods for protecting
and deprotecting different substituents using such suitable
protecting groups are well known to those skilled in the art;
examples of which may be found in T. Greene and P. Wuts, Protective
Groups in Organic Synthesis (3.sup.rd ed.), John Wiley & Sons,
NY (1999), which is herein incorporated by reference in its
entirety. Synthesis of the compounds of the invention may be
accomplished by methods analogous to those described in the
synthetic schemes described hereinabove and in specific
examples.
[0263] Starting materials, if not commercially available, may be
prepared by procedures selected from standard organic chemical
techniques, techniques that are analogous to the synthesis of
known, structurally similar compounds, or techniques that are
analogous to the above described schemes or the procedures
described in the synthetic examples section.
[0264] When an optically active form of a compound of the invention
is required, it may be obtained by carrying out one of the
procedures described herein using an optically active starting
material (prepared, for example, by asymmetric induction of a
suitable reaction step), or by resolution of a mixture of the
stereoisomers of the compound or intermediates using a standard
procedure (such as chromatographic separation, recrystallization or
enzymatic resolution).
[0265] Similarly, when a pure geometric isomer of a compound of the
invention is required, it may be obtained by carrying out one of
the above procedures using a pure geometric isomer as a starting
material, or by resolution of a mixture of the geometric isomers of
the compound or intermediates using a standard procedure such as
chromatographic separation.
[0266] The present invention further relates to a pharmaceutical
composition comprising a therapeutically effective amount of at
least one compound I as defined above or an N-oxide, a tautomeric
form, a stereoisomer or a pharmaceutically acceptable salt thereof,
in combination with at least one pharmaceutically acceptable
carrier and/or auxiliary substance.
[0267] The present invention further relates to a compound I as
defined above or an N-oxide, a tautomeric form, a stereoisomer or a
pharmaceutically acceptable salt thereof for use as a
medicament.
[0268] The present invention also relates to a compound I as
defined above or an N-oxide, a tautomeric form, a stereoisomer or a
pharmaceutically acceptable salt thereof for the treatment of
disorders which respond to the modulation of the 5-HT.sub.2C
receptor.
[0269] The present invention also relates to the use of a compound
I as defined above or of an N-oxide, a tautomeric form, a
stereoisomer or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament for the treatment of disorders which
respond to the modulation of the 5-HT.sub.2C receptor, and to a
method for treating disorders which respond to the modulation of
the 5-HT.sub.2C receptor, which method comprises administering to a
subject in need thereof at least one compound I as defined above or
an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically
acceptable salt thereof.
[0270] The compounds of the present invention are modulators of the
5-HT.sub.2C receptor. Specifically, the compounds of formula I are
agonists or partial agonists of the 5-HT.sub.2C receptor. Thus, in
a specific embodiment, the invention relates to a compound I as
defined above or an N-oxide, a tautomeric form, a stereoisomer or a
pharmaceutically acceptable salt thereof for the treatment of
disorders which respond to 5-HT.sub.2C receptor agonists, further
to the use of a compound I as defined above or of an N-oxide, a
tautomeric form, a stereoisomer or a pharmaceutically acceptable
salt thereof for the manufacture of a medicament for the treatment
of disorders which respond to 5-HT.sub.2C receptor agonists, and to
a method for treating disorders which respond to 5-HT.sub.2C
receptor agonists, which method comprises administering to a
subject in need thereof at least one compound I as defined above or
an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically
acceptable salt thereof.
[0271] Within the meaning of the invention, the term "disorder"
denotes disturbances and/or anomalies which are as a rule regarded
as being pathological conditions or functions and which can
manifest themselves in the form of particular signs, symptoms
and/or malfunctions. While the treatment according to the invention
can be directed toward individual disorders, i.e. anomalies or
pathological conditions, it is also possible for several anomalies,
which may be causatively linked to each other, to be combined into
patterns, i.e. syndromes, which can be treated in accordance with
the invention.
[0272] In one aspect of the invention, the diseases to be treated
are disorders are damage of the central nervous system, disorders
of the central nervous system, eating disorders, ocular
hypertension, cardiovascular disorders, gastrointestinal disorders
and diabetes.
[0273] Disorders or diseases of the central nervous system are
understood as meaning disorders which affect the spinal cord and,
in particular, the brain. These are, for example, cognitive
dysfunction, attention deficit disorder/hyperactivity syndrome and
cognitive deficits related with schizophrenia, attention
deficit/hyperactivity syndrome, personality disorders, affective
disorders, motion or motor disorders, pain, migraine, sleep
disorders (including disturbances of the Circadian rhythm), feeding
disorders, diseases associated with neurodegeneration, addiction
diseases, obesity or psoriasis.
[0274] Examples of cognitive dysfunction are deficits in memory,
cognition, and learning, Alzheimer's disease, age-related cognitive
decline, and mild cognitive impairment, or any combinations
thereof. Examples of personality disorders are schizophrenia and
cognitive deficits related to schizophrenia. Examples of affective
disorders are depression, anxiety, bipolar disorder and obsessive
compulsive disorders, or any combination thereof. Examples of
motion or motor disorders are Parkinson's disease and epilepsy.
Examples of feeding disorders are obesity, bulimia, weight loss and
anorexia, especially anorexia nervosa. Examples of diseases
associated with neurodegeneration are stroke, spinal or head
trauma, and head injuries, such as hydrocephalus.
[0275] Pain condition includes nociceptive pain, neuropathic pain
or a combination thereof. Such pain conditions or disorders can
include, but are not limited to, post-operative pain,
osteoarthritis pain, pain due to inflammation, rheumatoid arthritis
pain, musculoskeletal pain, burn pain (including sunburn), ocular
pain, the pain associated with dental conditions (such as dental
caries and gingivitis), post-partum pain, bone fracture, herpes,
HIV, traumatic nerve injury, stroke, post-ischemia, fibromyalgia,
reflex sympathetic dystrophy, complex regional pain syndrome,
spinal cord injury, sciatica, phantom limb pain, diabetic
neuropathy, hyperalgesia and cancer.
[0276] In certain other embodiments, the disease condition is
bladder dysfunction, including urinary incontinence.
[0277] Diabetes includes diabetes insipidus, diabetes mellitus,
type I diabetes, type II diabetes, type III diabetes, diabetes
secondary to pancreatic diseases, diabetes related to steroid use,
diabetes complications, hyperglycemia and insulin resistance.
[0278] The addiction diseases include psychiatric disorders and
behavioral disturbances which are caused by the abuse of
psychotropic substances, such as pharmaceuticals or narcotics, and
also other addiction diseases, such as addiction to gaming (impulse
control disorders not elsewhere classified). Examples of addictive
substances are: opioids (e.g. morphine, heroin and codeine),
cocaine; nicotine; alcohol; substances which interact with the GABA
chloride channel complex, sedatives, hypnotics and tranquilizers,
for example benzodiazepines; LSD; cannabinoids; psychomotor
stimulants, such as 3,4-methylenedioxy-N-methylamphetamine
(ecstasy); amphetamine and amphetamine-like substances such as
methylphenidate, other stimulants including caffeine and nicotine.
Addictive substances which come particularly into consideration are
opioids, cocaine, amphetamine or amphetamine-like substances,
nicotine and alcohol. Especially, addiction disorders include
alcohol abuse, cocaine abuse, tobacco abuse and smoking
cessation.
[0279] With regard to the treatment of addiction diseases,
particular preference is given to those compounds according to the
invention of the formula (I) which themselves do not possess any
psychotropic effect. This can also be observed in a test using
rats, which, after having been administered compounds which can be
used in accordance with the invention, reduce their self
administration of psychotropic substances, for example cocaine.
[0280] Examples of gastrointestinal disorders are irritable bowel
syndrome.
[0281] Preferably, the disorders are selected from the group
consisting of bipolar disorder, depression, atypical depression,
mood episodes, adjustment disorders, anxiety, panic disorders,
post-traumatic syndrome, psychoses, schizophrenia, cognitive
deficits of schizophrenia, memory loss, dementia of aging,
Alzheimer's disease, neuropsychiatric symptoms in Alzheimer's
disease (e.g. aggression), behavioral disorders associated with
dementia, social phobia, mental disorders in childhood, attention
deficit hyperactivity disorder, organic mental disorders, autism,
mutism, disruptive behavior disorder, impulse control disorder,
borderline personality disorder, obsessive compulsive disorder,
migraine and other conditions associated with cephalic pain or
other pain, raised intracranial pressure, seizure disorders,
epilepsy, substance use disorders, alcohol abuse, cocaine abuse,
tobacco abuse, smoking cessation, sexual dysfunction/erectile
dysfunction in males, sexual dysfunction in females, premenstrual
syndrome, late luteal phase syndrome, chronic fatigue syndrome,
sleep disorders, sleep apnoea, chronic fatigue syndrome, psoriasis,
Parkinson's disease, psychosis in Parkinson's disease,
neuropsychiatric symptoms in Parkinson's disease (e.g. aggression),
Lewy Body dementia, neuropsychiatric symptoms in Lewy Body dementia
(e.g. aggression), spinal cord injury, trauma, stroke, pain,
bladder dysfunction/urinary incontinence, encephalitis, meningitis,
eating disorders, obesity, bulimia, weight loss, anorexia nervosa,
ocular hypertension, cardiovascular disorders, gastrointestinal
disorders, diabetes insipidus, diabetes mellitus, type I diabetes,
type II diabetes, type III diabetes, diabetes secondary to
pancreatic diseases, diabetes related to steroid use, diabetes
complications, hyperglycemia and insulin resistance, and are
specifically schizophrenia, depression, bipolar disorders, obesity,
substance use disorders, neuropsychiatric symptoms in Alzheimer's
disease (e.g. aggression) or neuropsychiatric symptoms in
Parkinson's disease (e.g. aggression).
[0282] The compounds of the invention may be used for a preventive
treatment (prophylaxis), in particular as relapse prophylaxis or
phase prophylaxis, but are preferably used for a treatment in its
proper sense (i.e. non-prophylactic), i.e. for the treatment of
acute or chronic signs, symptoms and/or malfunctions. The treatment
can be orientated symptomatically, for example as the suppression
of symptoms. It can be effected over a short period, be orientated
over the medium term or can be a long-term treatment, for example
within the context of a maintenance therapy.
[0283] In another embodiment, the present invention relates to the
use of a compound I as defined above or an N-oxide, a tautomeric
form, a stereoisomer or a pharmaceutically acceptable salt thereof
for preparing a medicament for preventing (the development of) a
disease condition as described above and to a method for preventing
(the development of) a disease condition as described above
comprises administering to the subject in need of treatment thereof
(e.g., a mammal, such as a human) a therapeutically effective
amount of a compound I as defined above or an N-oxide, a tautomeric
form, a stereoisomer or a pharmaceutically acceptable salt thereof.
As used herein, the term "prevent" a disease condition by
administration of any of the compounds described herein means that
the detectable physical characteristics or symptoms of the disease
or condition do not develop following the administration of the
compound described herein. Alternatively, the method comprises
administering to the subject a therapeutically effective amount of
a compound I as defined above or an N-oxide, a tautomeric form, a
stereoisomer or a pharmaceutically acceptable salt thereof, in
combination with a therapeutically effective amount of at least one
cognitive enhancing drug.
[0284] In yet another embodiment, the present invention relates to
the use a compound I as defined above or an N-oxide, a tautomeric
form, a stereoisomer or a pharmaceutically acceptable salt thereof
for preparing a medicament for preventing the progression (e.g.,
worsening) of a disease condition and to a method for preventing
the progression (e.g., worsening) of a disease condition, which
method comprises administering to the subject in need of treatment
thereof (e.g., a mammal, such as a human) a therapeutically
effective amount of a compound I as defined above or an N-oxide, a
tautomeric form, a stereoisomer or a pharmaceutically acceptable
salt thereof.
[0285] There are several lines of evidence suggesting that
5-HT.sub.2C agonists or partial agonists would have therapeutic use
in a variety of diseases, disorders and conditions.
[0286] Knockout mice models lacking the 5-HT.sub.2C receptor
exhibit hyperphagia, obesity and are more prone to seizures and
sudden death [Tecott L H, Sun L M, Akana S F, Strack A M,
Lowenstein D H, Dallman M F, Julius D (1995) Eating disorder and
epilepsy in mice lacking 5-HT.sub.2C serotonin receptors. Nature
374:542-546]. They also exhibit compulsive-like behavior
[Chou-Green J M, Holscher T D, Dallman M F, Akana S F (2003).
Compulsive behavior in the 5-HT.sub.2C receptor knockout mouse.
Phys. Behav. 78:641-649], hyperresponsiveness to repeated stress
[Chou-Green J M, Holscher T D, Dallman M F, Akana S F (2003).
Repeated stress in young and old 5-HT.sub.2C receptor knockout
mouse. Phys. Behav. 79:217-226], wakefulness [Frank M G, Stryker M
P, Tecott L H (2002). Sleep and sleep homeostasis in mice lacking
the 5-HT.sub.2C receptor. Neuropsychopharmacology 27:869-873],
hyperactivity and drug dependence [Rocha. B A, Goulding E H, O'Dell
L E, Mead A N, Coufal N G, Parsons L H, Tecott L H (2002). Enhanced
locomotor, reinforcing and neurochemical effects of cocaine in
serotonin 5-hydroxytryptamine 2C receptor mutant mice. J. Neurosci.
22:10039-10045].
[0287] 5-HT.sub.2C is unique among other G-protein-coupled
receptors (GPCRs) in that its pre-mRNA is a substrate for base
modification via hydrolytic deamination of adenosines to yield
inosines. Five adenosines, located within a sequence encoding the
putative second intracellular domain can be converted to inosines.
This editing can alter the coding potential of the triplet codons
and allows for the generation of multiple different receptor
isoforms. The edited receptor isoforms were shown to have reduced
ability to interact with G-proteins in the absence of agonist
stimulation [Werry, T D, Loiacono R, Sexton P A, Christopoulos A
(2008). RNA editing of the serotonin 5-HT.sub.2C receptor and its
effects on cell signaling, pharmacology and brain function.
Pharmac. Therap. 119:7-23].
[0288] Edited 5-HT.sub.2C isoforms with reduced function are
significantly expressed in the brains of depressed suicide victims
[Schmauss C (2003) Serotonin 2C receptors: suicide, serotonin, and
runaway RNA editing. Neuroscientist 9:237-242. Iwamoto K, Kato T
(2003). RNA editing of serotonin 2C receptor in human postmortem
brains of major mental disorders. Neurosci. Lett. 346:169-172] and
in the learned helplessness rats (a well established animal model
of depression) [Iwamotoa K, Nakatanib N, Bundoa M, Yoshikawab T,
Katoa T (2005). Altered RNA editing of serotonin 2C receptor in a
rat model of depression. Neurosci. Res. 53: 69-76] suggesting a
link between 5-HT.sub.2C function and depression. There are also
implications of edited 5-HT.sub.2C isoforms and spatial memory [Du
Y, Stasko M, Costa A C, Davissone M T, Gardiner K J (2007). Editing
of the serotonin 2C receptor pre-mRNA Effects of the Morris Water
Maze. Gene 391:186-197]. In addition, fully edited isoforms of the
human 5-HT.sub.2C receptor display a striking reduction in
sensitivity to lysergic acid diethylamide (LSD) and to atypical
antipsychotic drugs clozapine and loxapine, suggesting a possible
role of the receptor in the etiology and pharmacology of
schizophrenia [Niswender C M, Herrick-Davis K., Dilley G E, Meltzer
H Y, Overholser J C, Stockmeier C A, Emeson R B, Sanders-Bush E
(2001). RNA Editing of the Human Serotonin 5-HT.sub.2C Receptor:
Alterations in Suicide and Implications for Serotonergic
Pharmacotherapy. Neuropsychopharm. 24:478-491].
[0289] Recently, the availability of potent and selective
5-HT.sub.2C receptor agonists made it possible to directly
investigate the effects of 5-HT.sub.2C agonists and their
therapeutic potential. Thus recent studies demonstrated that
selective 5-HT.sub.2C agonists resulted in decreased food intake
and body weight gain in normal and obese rats [Smith B M, et al.
(2008). Discovery and structure-activity relationship of
(1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine
(Lorcaserin), a selective serotonin 5-HT.sub.2C receptor agonist
for the treatment of obesity. J Med Chem 51:305-313. Thomsen W J,
Grottick A J, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D,
Whelan K, Martin M, Morgan M, Chen W, Al-Shama H, Smith B, Chalmers
D, Behan D (2008) Lorcaserin, A Novel Selective Human 5-HT.sub.2C
Agonist: In Vitro and In Vivo Pharmacological Characterization. J
Pharmacol Exp Ther. 325:577-587. Rosenzweig-Lipson S, Zhang J,
Mazandarani H, Harrison B L, Sabb A, Sabalski J, Stack G, Welmaker
G, Barrett J E, Dunlop J (2006) Antiobesity-like effects of the
5-HT.sub.2C receptor agonist WAY-161503. Brain Res.
1073-1074:240-251. Dunlop J, Sabb A L, Mazandarani H, Zhang J,
Kalgaonker S, Shukhina E, Sukoff S, Vogel R L, Stack G, Schechter
L, Harrison B L, Rosenzweig-Lipson S (2005). WAY-163909
[97bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino-
[6,7,1hi]indole], a novel 5-hydroxytryptamine 2C receptor-selective
agonist with anorectic activity. J Pharmacol Exp Ther.
313:862-869.].
[0290] Furthermore, selective 5-HT.sub.2C receptor agonists produce
antidepressant effects in animal models of depression comparable to
those of SSRIs but with a much faster onset of action and a
therapeutic window that avoids antidepressant-induced sexual
dysfunction. These agonists were also effective in animal models of
compulsive behavior such as scheduled induced polydipsia and they
also exhibited decreased hyperactivity and aggression in rodents
[Rosenzweig-Lipson S, Sabb A, Stack G, Mitchell P, Lucki I, Malberg
J E, Grauer S, Brennan J, Cryan J F, Sukoff Rizzo S J, Dunlop J,
Barrett J E, Marquis K L (2007) Antidepressant-like effects of the
novel, selective, 5-HT.sub.2C receptor agonist WAY-163909 in
rodents. Psychopharmacology (Berlin) 192:159-170. Rosenzweig-Lipson
S, Dunlop J, Marquis K L (2007) 5-HT.sub.2C receptor agonists as an
innovative approach for psychiatric disorders. Drug news Perspect,
20: 565-571. Cryan, J F, Lucki I (2000). Antidepressant-like
behavioral effects mediated by 5-Hydroxytryptamine 2C receptors. J.
Pharm. Exp. Ther. 295:1120-1126.].
[0291] Acute or chronic administration of 5-HT.sub.2C agonists
decreases the firing rate of ventral tegmental area dopamine
neurons but not that of substantia nigra. In addition 5-HT.sub.2C
agonists reduce dopamine levels in the nucleus accumbens but not in
the striatum (the region of the brain mostly associated with
extrapyramidal side effects) [Di Matteo, V., Di Giovanni, G., Di
Mascio, M., & Esposito, E. (1999). SB 242084, a selective
serotonin 2C receptor antagonist, increases dopaminergic
transmission in the mesolimbic system. Neuropharmacology 38,
1195-1205. Di Giovanni, G., Di Matteo, V., Di Mascio, M., &
Esposito, E. (2000). Preferential modulation of mesolimbic vs.
nigrostriatal dopaminergic function by serotonin2C/2B receptor
agonists: a combined in vivo electrophysiological and microdialysis
study. Synapse 35, 53-61. Marquis K L, Sabb A L, Logue S F, Brennan
J A, Piesla M J, Comery T A, Grauer S M, Ashby C R, Jr., Nguyen H
Q, Dawson L A, Barrett J E, Stack G, Meltzer H Y, Harrison B L,
Rosenzweig-Lipson S (2007) WAY-163909
[(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino-
[6,7,1hi]indole]: A novel 5-hydroxytryptamine 2C receptor-selective
agonist with preclinical antipsychotic-like activity. J Pharmacol
Exp Ther 320:486-496.]. Therefore it is expected that 5-HT.sub.2C
receptor agonists will selectively decrease mesolimibic dopamine
levels without affecting the nigrostriatal pathway thus avoiding
the EPS side effects of typical antipsychotics. Several 5-HT.sub.2C
receptor agonists have shown antipsychotic activity in animal
models of schizophrenia without EPS based on the lack of effect in
catalepsy [Marquis K L, Sabb A L, Logue S F, Brennan J A, Piesla M
J, Comery T A, Grauer S M, Ashby C R, Jr., Nguyen H Q, Dawson L A,
Barrett J E, Stack G, Meltzer H Y, Harrison B L, Rosenzweig-Lipson
S (2007) WAY-163909
[(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino-
[6,7,1hi]indole]: A novel 5-hydroxytryptamine 2C receptor-selective
agonist with preclinical antipsychotic-like activity. J Pharmacol
Exp Ther 320:486-496. Siuciak J A, Chapin D S, McCarthy S A,
Guanowsky V, Brown J, Chiang P, Marala R, Patterson T, Seymour P A,
Swick A, Iredale P A (2007) CP-809,101, a selective 5-HT.sub.2C
agonist, shows activity in animal models of antipsychotic activity.
Neuropharmacology 52:279-290]. The antipsychotic activity of
5-HT.sub.2C receptor agonists without EPS coupled with their
beneficial effects in mood disorders and cognition and their
antiobesity like effects render 5-HT.sub.2C receptor agonists as
unique agents to treat schizophrenia [Rosenzweig-Lipson S, Dunlop
J, Marquis K L (2007) 5-HT.sub.2C receptor agonists as an
innovative approach for psychiatric disorders. Drug news Perspect,
20: 565-571. Dunlop J, Marquis K L, Lim H K, Leung L, Kao J,
Cheesman C, Rosenzweig-Lipson S (2006). Pharmacological profile of
the 5-HT.sub.2C receptor agonist WAY-163909; therapeutic potential
in multiple indications. CNS Dug Rev. 12:167-177.].
[0292] In addition 5-HT.sub.2C modulation has been implicated in
epilepsy [Isaac M (2005). Serotonergic 5-HT.sub.2C receptors as a
potential therapeutic target for the antiepileptic drugs. Curr.
Topics Med. Chem. 5:59:67], psoriasis [Thorslund K, Nordlind K
(2007). Serotonergic drugs--a possible role in the treatment of
psoriasis? Drug News Perspect 20:521-525], Parkinson's disease and
related motor disorders [Esposito E, Di Matteo V, Pierucci M,
Benigno A, Di Giavanni, G (2007). Role of central 5-HT.sub.2C
receptor in the control of basal ganglia functions. The Basal
Ganglia Pathophysiology: Recent Advances 97-127], behavioral
deficits [Barr A M, Lahmann-Masten V, Paulus M, Gainetdinov R P,
Caron M G, Geyer M A (2004). The selective serotonin-2A receptor
antagonist M100907 reverses behavioral deficits in dopamine
transporter knockout mice. Neuropsychopharmacology 29:221-228],
anxiety [Dekeyne A, Mannoury la Cour C, Gobert A, Brocco M, Lejuene
F, Serres F, Sharp T, Daszuta A, Soumier A, Papp M, Rivet J M, Flik
G, Cremers T I, Muller O, Lavielle G, Millan M J (2208). 532006, a
novel 5-HT.sub.2C receptor antagonists displaying broad-based
antidepressant and anxiolytic properties in rodent models.
Psychopharmacology 199:549-568. Nunes-de-Souza V, Nunes-de-Souza R
L, Rodgers R J, Canto-de-Souza A (2008). 5-HT2 receptor activation
in the midbrain periaqueductal grey (PAG) reduces anxiety-like
behavior in mice. Behav. Brain Res. 187:72-79.], migraine [Leone M,
Rigamonti A, D'Amico D, Grazzi L, Usai S, Bussone G (2001). The
serotonergic system in migraine. Journal of Headache and Pain 2
(Suppl. 1):S43-S46], Alzheimer's disease [Atjona A A, Pooler A M,
Lee R K, Wurtman R J (2002). Effect of a 5-HT.sub.2C serotonin
agonist, dexnorfenfluramine, on amyloid precursor protein
metabolism in guinea pigs. Brain Res. 951:135-140], pain and spinal
cord injury [Nakae A, Nakai K, Tanaka T, Hagihira S, Shibata M,
Ueda K, Masimo T (2008). The role of RNA editing of the serotonin
2C receptor in a rat model of oro-facial neuropathic pain. The
European Journal of Neuroscience 27:2373-2379. Nakae A, Nakai. K,
Tanaka T, Takashina M, Hagihira S, Shibata M, Ueda K, Mashimo T
(2008). Serotonin 2C receptor mRNA editing in neuropathic pain
model. Neurosci. Res. 60:228-231. Kao T, Shumsky J S, Jacob-Vadakot
S, Timothy H B, Murray M, Moxon, K A (2006). Role of the
5-HT.sub.2C receptor in improving weight-supported stepping in
adult rats spinalized as neonates. Brain Res. 1112:159-168.],
sexual dysfunction [Motofei I G (2008). A dual physiological
character for sexual function: the role of serotonergic receptors.
BJU International 101:531-534. Shimada I, Maeno K, Kondoh Y, Kaku
H, Sugasawa K Kimura Y, Hatanaka K.; Naitou Y, Wanibuchi F,
Sakamoto S.; Tsukamoto S (2008). Synthesis and structure-activity
relationships of a series of benzazepine derivatives as 5-HT.sub.2C
receptor agonists. Bioorg. Med. Chem. 16:3309-3320.], smoking
cessation [Fletcher P J, Le A D, Higgins G A (2008). Serotonin
receptors as potential targets for modulation of nicotine use and
dependence. Progress Brain Res. 172:361-83], substance dependence
[Bubar M J, Cunningham K A (2008). Prospects for serotonin 5-HT2R
pharmacotherapy in psychostimulant abuse. Progress Brain Res.
172:319-46], and ocular hypertension [Sharif N A, McLaughlin M A,
Kelly C R (2006). AL-34662: a potent, selective, and efficacious
ocular hypotensive serotonin-2 receptor agonist. J Ocul Pharmacol
Ther. 23:1-13].
[0293] Further, 5HT modulation can be useful in the treatment of
pain, both neuropathic and nociceptive pain, see for example U.S.
Patent application publication US2007/0225277. Obata, Hideaki; Ito,
Naomi; Sasaki, Masayuki; Saito, Shigeru; Goto, Fumio. Possible
involvement of spinal noradrenergic mechanisms in the antiallodynic
effect of intrathecally administered 5-HT2C receptor agonists in
the rats with peripheral nerve injury. European Journal of
Pharmacology (2007), 567(1-2), 89-94. Serotonin2C receptor mRNA
editing in neuropathic pain model. Nakae, Aya;
[0294] Nakai, Kunihiro; Tanaka, Tatsuya; Takashina, Masaki;
Hagihira, Satoshi; Shibata, Masahiko; Ueda, Koichi; Mashimo,
Takashi. Department of Anesthesiology & Intensive Care
Medicine, Graduate School of Medicine, Osaka University,
Neuroscience Research (Amsterdam, Netherlands) (2008), 60(2),
228-231. Antiallodynic effects of intrathecally administered 5-HT2C
receptor agonists in rats with nerve injury. Obata, Hideaki; Saito,
Shigeru; Sakurazawa, Shinobu; Sasaki, Masayuki; Usui, Tadashi;
Goto, Fumio. Department of Anesthesiology, Gunma University
Graduate School of Medicine, Maebashi, Gunma, Japan. Pain (2004),
108(1-2), 163-169. Influence of 5,7-dihydroxytryptamine (5,7-DHT)
on the antinociceptive effect of serotonin (5-HT) 5-HT2C receptor
agonist in male and female rats. Brus, Ryszard; Kasperska, Alicja;
Oswiecimska, Joanna; Szkilnik, Ryszard. Department of Pharmacology,
Silesian Medical University, Zabrze, Pol. Medical Science Monitor
(1997), 3(5), 654-656.
[0295] Modulation of 5HT2 receptors may be beneficial in the
treatment of conditions related to bladder function, in particular,
urinary incontinence. [Discovery of a novel azepine series of
potent and selective 5-HT2C agonists as potential treatments for
urinary incontinence. Brennan, Paul E.; Whitlock, Gavin A.; Ho,
Danny K. H.; Conlon, Kelly; McMurray, Gordon. Bioorganic &
Medicinal Chemistry Letters (2009), 19(17), 4999-5003.
Investigation of the role of 5-HT2 receptor subtypes in the control
of the bladder and the urethra in the anesthetized female rat.
Mbaki, Y.; Ramage, A. G. Department of Pharmacology, University
College London, London, UK. British Journal of Pharmacology (2008),
155(3), 343-356.] In particular, compounds with agonist activity at
5-H.sub.2C have been shown to be useful in treating urinary
incontinence, see for example U.S. Patent application publications
US2008/0146583 and US 2007/0225274.
[0296] Further pre-clinical data suggest that 5-HT.sub.2C agonists
could be useful for the treatment of a number of psychiatric
diseases, including schizophrenia, bipolar disorders,
depression/anxiety, substance use disorders and especially
disorders like neuropsychiatric symptoms in Alzheimer's disease:
Aggression, psychosis/agitation represent key unmet medical needs.
Clinical (Shen J H Q et al., A 6-week randomized, double-blind,
placebo-controlled, comparator referenced trial of vabicaserin in
acute schizophrenia. Journal of Psychiatric Research 53 (2014)
14-22; Liu J et al., Prediction of Efficacy of Vabicaserin, a
5-HT.sub.2C Agonist, for the Treatment of Schizophrenia Using a
Quantitative Systems Pharmacology Model. CPT Pharmacometrics Syst.
Pharmacol. (2014) 3, e111) and preclinical data (Dunlop J et al.,
Characterization of Vabicaserin (SCA-136), a Selective
5-Hydroxytryptamine 2C Receptor Agonist. J Pharmacol Exp Ther
(2011) 337, 673-80; Siuciak J et al., CP-809,101, a selective
5-HT.sub.2C agonist, shows activity in animal models of
antipsychotic activity. Neuropharmacology 52 (2007) 279-290;
Mosienko V et al., Exaggerated aggression and decreased anxiety in
mice deficient in brain serotonin. Transl Psychiatry (2012) 2,
e122; Del Guidice T et al., Stimulation of 5-HT.sub.2C Receptors
Improves Cognitive Deficits Induced by Human Tryptophan
Hydroxylase2 Loss of Function Mutation. Neuropsychopharmacology
(2014) 39, 1125-1134; Rosenzweig-Lipson et al., Antidepressant-like
effects of the novel, selective, 5-HT.sub.2C receptor agonist
WAY-163909 in rodents. Psychopharmacology (2007) 192:159-170)
suggest 5-HT.sub.2C receptor stimulation to result in therapeutic
efficacy in aggression, psychosis agitation and moderate
pro-cognitive effects (Del Guidice T et al., Stimulation of
5-HT.sub.2C Receptors Improves Cognitive Deficits Induced by Human
Tryptophan Hydroxylase2 Loss of Function Mutation.
Neuropsychopharmacology (2014) 39, 1125-1134; Siuciak J et al.,
CP-809,101, a selective 5-HT.sub.2C agonist, shows activity in
animal models of antipsychotic activity. Neuropharmacology 52
(2007) 279-290).
[0297] In the use and the method of the invention, an effective
quantity of one or more compounds, as a rule formulated in
accordance with pharmaceutical and veterinary practice, is
administered to the individual to be treated, preferably a mammal,
in particular a human being, productive animal or domestic animal.
Whether such a treatment is indicated, and in which form it is to
take place, depends on the individual case and is subject to
medical assessment (diagnosis) which takes into consideration
signs, symptoms and/or malfunctions which are present, the risks of
developing particular signs, symptoms and/or malfunctions, and
other factors.
[0298] Actual dosage levels of active ingredients in the
pharmaceutical compositions of the present invention can be varied
so as to obtain an amount of the active compound(s) that is
effective to achieve the desired therapeutic response for a
particular subject (e.g., a mammal, preferably, a human (patient)),
compositions and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated and
the condition and prior medical history of the patient being
treated. However, it is within the skill of the art to start doses
of the compound at levels lower than required to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved.
[0299] Compounds of the present invention can also be administered
to a subject as a pharmaceutical composition comprising the
compounds of interest in combination with at least one
pharmaceutically acceptable carriers. The phrase "therapeutically
effective amount" of the compound of the present invention means a
sufficient amount of the compound to treat disorders, at a
reasonable benefit/risk ratio applicable to any medical treatment.
It will be understood, however, that the total daily usage of the
compounds and compositions of the present invention will be decided
by the attending physician within the scope of sound medical
judgment. The specific therapeutically effective dose level for any
particular patient will depend upon a variety of factors including
the disorder being treated and the severity of the disorder;
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed; and like
factors well-known in the medical arts. For example, it is well
within the skill of the art to start doses of the compound at
levels lower than required to achieve the desired therapeutic
effect and to gradually increase the dosage until the desired
effect is achieved.
[0300] The total daily dose of the compounds of this invention
administered to a subject (namely, a mammal, such as a human)
ranges from about 0.01 mg/kg body weight to about 100 mg/kg body
weight. More preferable doses can be in the range of from about
0.01 mg/kg body weight to about 30 mg/kg body weight. If desired,
the effective daily dose can be divided into multiple doses for
purposes of administration. Consequently, single dose compositions
may contain such amounts or submultiples thereof to make up the
daily dose.
[0301] In one aspect, the present invention provides pharmaceutical
compositions. The pharmaceutical compositions of the present
invention comprise the compounds of the present invention or an
N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically
acceptable salt or solvate thereof. The pharmaceutical compositions
of the present invention comprise compounds of the present
invention that can be formulated together with at least one
non-toxic pharmaceutically acceptable carrier.
[0302] In yet another embodiment, the present invention provides a
pharmaceutical composition comprising compounds of the present
invention or an N-oxide, a tautomeric form, a stereoisomer or a
pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable carriers, alone or in combination with
one or more compounds that are not the compounds of the present
invention. Examples of one or more compounds that can be combined
with the compounds of the present invention in pharmaceutical
compositions, include, but are not limited to, one or more
cognitive enhancing drugs.
[0303] The pharmaceutical compositions of this present invention
can be administered to a subject (e.g., a mammal, such as a human)
orally, rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments or drops),
bucally or as an oral or nasal spray. The term "parenterally" as
used herein, refers to modes of administration which include
intravenous, intramuscular, intraperitoneal, intrasternal,
subcutaneous and intraarticular injection and infusion.
[0304] The term "pharmaceutically acceptable carrier" as used
herein, means a non-toxic, inert solid, semi-solid or liquid
filler, diluent, encapsulating material or formulation auxiliary of
any type. Some examples of materials which can serve as
pharmaceutically acceptable carriers are sugars such as, but not
limited to, lactose, glucose and sucrose; starches such as, but not
limited to, corn starch and potato starch; cellulose and its
derivatives such as, but not limited to, sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; excipients such as, but not
limited to, cocoa butter and suppository waxes; oils such as, but
not limited to, peanut oil, cottonseed oil, safflower oil, sesame
oil, olive oil, corn oil and soybean oil; glycols; such a propylene
glycol; esters such as, but not limited to, ethyl oleate and ethyl
laurate; agar; buffering agents such as, but not limited to,
magnesium hydroxide and aluminum hydroxide; alginic acid;
pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as, but not limited to, sodium lauryl
sulfate and magnesium stearate, as well as coloring agents,
releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of the
formulator.
[0305] Pharmaceutical compositions of the present invention for
parenteral injection comprise pharmaceutically acceptable sterile
aqueous or nonaqueous solutions, dispersions, suspensions or
emulsions as well as sterile powders for reconstitution into
sterile injectable solutions or dispersions just prior to use.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents or vehicles include water, ethanol, polyols (such as
glycerol, propylene glycol, polyethylene glycol and the like),
vegetable oils (such as olive oil), injectable organic esters (such
as ethyl oleate) and suitable mixtures thereof. Proper fluidity can
be maintained, for example, by the use of coating materials such as
lecithin, by the maintenance of the required particle size in the
case of dispersions and by the use of surfactants.
[0306] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms can be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid and the
like. It may also be desirable to include isotonic agents such as
sugars, sodium chloride and the like. Prolonged absorption of the
injectable pharmaceutical form can be brought about by the
inclusion of agents which delay absorption such as aluminum
monostearate and gelatin.
[0307] In some cases, in order to prolong the effect of the drug,
it is desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This can be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally administered drug form is
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0308] Injectable depot forms are made by forming microencapsule
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0309] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0310] Solid dosage forms for oral administration include capsules,
tablets, pills, powders and granules. In such solid dosage forms,
the active compound may be mixed with at least one inert,
pharmaceutically acceptable excipient or carrier, such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol and silicic acid;
b) binders such as carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidone, sucrose and acacia; c) humectants such as
glycerol; d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates and sodium carbonate; e) solution retarding agents such
as paraffin; f) absorption accelerators such as quaternary ammonium
compounds; g) wetting agents such as cetyl alcohol and glycerol
monostearate; h) absorbents such as kaolin and bentonite clay and
i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents.
[0311] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
carriers as lactose or milk sugar as well as high molecular weight
polyethylene glycols and the like.
[0312] The solid dosage forms of tablets, dragees, capsules, pills
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well-known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and may also be of a composition such that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes.
[0313] The active compounds can also be in micro-encapsulated form,
if appropriate, with one or more of the above-mentioned
carriers.
[0314] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents
and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan and mixtures thereof.
[0315] Besides inert diluents, the oral compositions may also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring and perfuming agents.
[0316] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, tragacanth and mixtures thereof.
[0317] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating carriers
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at room temperature but liquid at
body temperature and therefore melt in the rectum or vaginal cavity
and release the active compound.
[0318] Compounds of the present invention can also be administered
in the form of liposomes. As is known in the art, liposomes are
generally derived from phospholipids or other lipid substances.
Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals which are dispersed in an aqueous medium. Any non-toxic,
physiologically acceptable and metabolizable lipid capable of
forming liposomes can be used. The present compositions in liposome
form can contain, in addition to a compound of the present
invention, stabilizers, preservatives, excipients and the like. The
preferred lipids are natural and synthetic phospholipids and
phosphatidyl cholines (lecithins) used separately or together.
[0319] Methods to form liposomes are known in the art. See, for
example, Prescott, Ed., Methods in Cell Biology, Volume XIV,
Academic Press, New York, N.Y. (1976), p. 33 et seq.
[0320] Dosage forms for topical administration of a compound of the
present invention include powders, sprays, ointments and inhalants.
The active compound may be mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants which may be required. Ophthalmic
formulations, eye ointments, powders and solutions are also
contemplated as being within the scope of this invention.
[0321] The compounds of the present invention can be used in the
form of pharmaceutically acceptable salts derived from inorganic or
organic acids. The phrase "pharmaceutically acceptable salt" means
those salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like and are commensurate with a reasonable benefit/risk
ratio.
[0322] Pharmaceutically acceptable salts are well known in the art.
For example, S. M. Berge et al. describe pharmaceutically
acceptable salts in detail in (J. Pharmaceutical Sciences, 1977,
66: 1 et seq.). The salts can be prepared in situ during the final
isolation and purification of the compounds of the invention or
separately by reacting a free base function with a suitable organic
acid. Representative acid addition salts include, but are not
limited to acetate, adipate, alginate, citrate, aspartate,
benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate,
malate, maleate, methanesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate,
p-toluenesulfonate and undecanoate. Also, the basic
nitrogen-containing groups can be quaternized with such agents as
lower alkyl halides such as, but not limited to, methyl, ethyl,
propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates
like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain
halides such as, but not limited to, decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides; arylalkyl halides like
benzyl and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained. Examples of acids which
can be employed to form pharmaceutically acceptable acid addition
salts include such inorganic acids as hydrochloric acid,
hydrobromic acid, sulfuric acid, and phosphoric acid and such
organic acids as acetic acid, fumaric acid, maleic acid,
4-methylbenzenesulfonic acid, succinic acid and citric acid.
[0323] Basic addition salts can be prepared in situ during the
final isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as, but not limited to, the hydroxide, carbonate or
bicarbonate of a pharmaceutically acceptable metal cation or with
ammonia or an organic primary, secondary or tertiary amine.
Pharmaceutically acceptable salts include, but are not limited to,
cations based on alkali metals or alkaline earth metals such as,
but not limited to, lithium, sodium, potassium, calcium, magnesium
and aluminum salts and the like and nontoxic quaternary ammonia and
amine cations including ammonium, tetramethylammonium,
tetraethylammonium, methylammonium, dimethylammonium,
trimethylammonium, triethylammonium, diethylammonium, ethylammonium
and the like. Other representative organic amines useful for the
formation of base addition salts include ethylenediamine,
ethanolamine, diethanolamine, piperidine, piperazine and the
like.
[0324] The compounds of the present invention can exist in
unsolvated as well as solvated forms, including hydrated forms,
such as hemi-hydrates. In general, the solvated forms, with
pharmaceutically acceptable solvents such as water and ethanol
among others are equivalent to the unsolvated forms for the
purposes of the invention.
[0325] The following examples serve to explain the invention
without limiting it.
EXAMPLES
[0326] The compounds were either characterized via proton-NMR in
d.sub.6-dimethylsulfoxide, d-chloroform or d.sub.4-methanol on a
400 MHz, 500 MHz or 600 MHz NMR instrument (Bruker AVANCE), or by
.sup.13C-NMR at 125 MHz, or by mass spectrometry, generally
recorded via HPLC-MS in a fast gradient on C18-material
(electrospray-ionisation (ESI) mode).
[0327] The magnetic nuclear resonance spectral properties (NMR)
refer to the chemical shifts (.delta.) expressed in parts per
million (ppm). The relative area of the shifts in the .sup.1H-NMR
spectrum corresponds to the number of hydrogen atoms for a
particular functional type in the molecule. The nature of the
shift, as regards multiplicity, is indicated as singlet (s), broad
singlet (s. br.), doublet (d), broad doublet (d br.), triplet (t),
broad triplet (t br.), quartet (q), quintet (quint.), multiplet
(m), doublet of doublets (dd), doublet of doublets of doublets
(ddd) etc.
[0328] Enantiomers were separated/purified by chiral supercritical
fluid chromatography (SFC) (method A).
Method A:
Analytical Separation Method:
[0329] Instrument: Thar analytical SFC Column: Chiralpak AD-3 3
.mu.m, 0.46 cm id.times.10 cm L Mobile phase: A for SFC CO.sub.2
and B for EtOH (0.05% IPAm) Gradient: B in A from 10% to 40% in 5
minutes Flow rate: 4.0 mL/min
Wavelength: 220 nm
System Back Pressure: 100 bar
Preparative Separation Method:
Instrument: Thar SFC Pre-80
[0330] Column: Chiralpak AD-H 5 .mu.m, 3.0 cm id.times.25 cm L
Mobile phase: A for SFC CO.sub.2 and B EtOH (0.05% NH.sub.4OH)
Gradient: A:B=78:22
[0331] Flow rate: 60 mL/min
Wavelength: 220 nm
System Back Pressure: 100 bar
[0332] Sample preparation: dissolved in Methanol, 14 mg/mL
Injection: 1.0 ml per injection.
IPAm: Isopropylamine
[0333] Preparative HPLC was carried out under following
conditions:
Method A:
[0334] Instrument: Shimadzu LC-20AP preparative HPLC
Column: Luna(2) C18 250*50 mm i.d. 10 u
[0335] Mobile phase: A for H.sub.2O (0.075% TFA) and B for MeCN
Gradient: B from 12% to 42% in 20 min Flow rate: 80 ml/min
Wavelength: 220 &254 nm
[0336] Injection amount: 0.65 g per injection
Method B:
[0337] Instrument: Gilson 281 semi-preparative HPLC system Mobile
phase: A for H.sub.2O (0.075% TFA) and B for MeCN
Column: Luna C18 100*30, 5 um, 100 A
[0338] Flow rate: 25 ml/min Monitor wavelength: 220&254 nm
Gradient:
TABLE-US-00002 [0339] Time B % 0.00 80 12.0 100 12.2 100 14.2 100
14.4 80 16.0 80
Method C
C.1 Analytical SFC
[0340] Analytical samples were run on an Agilent 1260 Infinity
Hybrid SFC System, controlled by Agilent OpenLab CDS ChemStation
Edition. The system consists of an injector, a heated column
compartment including a switch for 6 columns, a CO.sub.2-booster
pump, a binary pump module for CO.sub.2 and modifier flow and an
UV-detector. The backpressure regulator was set to 160 bars and
heated to 60.degree. C. If not stated otherwise, the columns were
100 mm in length, 4.6 mm in diameter and packed with 5 .mu.m
material. They were kept at room temperature during analysis. As
mobile phase, a mixture of liquefied CO.sub.2 and organic modifier
with additive was used as indicated for each sample. The flow rate
was kept at 3.5 mL/min.
C.2 Preparative SFC
[0341] Preparative separations were carried out on a Waters Prep
100q SFC System, controlled by Waters MassLynx Software. The system
consists of an open bed injector/collector, a heated column
compartment including a switch for 6 columns, a CO.sub.2-booster
pump, a pump module for modifier flow and an UV-detector. To enable
quantitative collection, the gas liquid separator was driven with a
make-up flow of 30 mL/min Methanol. The backpressure regulator was
set to 120 bar and heated to 60.degree. C. If not stated otherwise,
the columns were 250 mm in length, 20 mm in diameter and packed
with 5 .mu.m material. They were kept at 30.degree. C. during the
separation. As mobile phase, a mixture of liquefied CO.sub.2 and
organic modifier with additive was used as indicated for each
sample. The flow rate was kept at 100 g/min.
LCMS Method:
[0342] LC/MS (The gradient was 1-90% B in 3.4 min, 90-100% B in
0.45 min, 100-1% B in 0.01 min, and then held at 1% B for 0.65 min
(0.8 mL/min flow rate). Mobile phase A was 0.0375% TFA in water,
mobile phase B was 0.018% TFA in MeCN. The column used for the
chromatography was a 2.1.times.50 mm Venusil XBP-C18 column (5
.mu.m particles). Detection methods are diode array (DAD) and
evaporative light scattering (ELSD) detection as well as
positive/negative electrospray ionization).
Abbreviations:
[0343] h hour(s) [0344] min minute(s) [0345] r.t. room temperature
(20-25.degree. C.) [0346] PE petroleum ether [0347] EtOH ethanol
[0348] MeOH methanol [0349] DCM dichloromethane [0350] DCE
dichloroethane [0351] THF tetrahydrofuran [0352] DMF
N,N-dimethylformamide [0353] MeCN acetonitrile [0354] EtOAc ethyl
acetate [0355] TFA trifluoroacetic acid [0356] DIPEA
diisopropylethyl amine [0357] X-Phos
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
I. Preparation Examples
Example 1
8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline
(Compound Ia.1 wherein R.sup.6 is cyclopropyl and R.sup.4a,
R.sup.4b, R.sup.5a, R.sup.5b and R.sup.7a are hydrogen)
1.1 4-Cyclopropylquinoline
[0358] A mixture of 4-bromoquinoline (18 g, 87 mmol),
cyclopropylboronic acid (29.7 g, 346 mmol), tricyclohexylphosphine
(4.85 g, 17.3 mmol), K.sub.3PO.sub.4 (73.5 g, 346 mmol) and
PdOAc.sub.2 (1.942 g, 8.65 mmol) in toluene (200 mL) and water (20
mL) was stirred for 16 h at 100.degree. C. under N.sub.2. The
resulting mixture was concentrated under reduced pressure and the
residue was purified by column chromatography on silica gel
(PE:EtOAc=10:1) to give the title compound (10 g, yield 61.2%).
[0359] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. 9.00 (d, J=4.4
Hz, 1H), 8.55 (d, J=8.4 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 7.93 (t,
J=8.0 Hz, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.24 (d, J=4.4 Hz, 1H),
2.68-2.61 (m, 1H), 1.42-1.36 (m, 2H), 1.09-1.05 (m, 2H).
1.2 1-(2-Amino-2-oxoethyl)-4-cyclopropylquinolin-1-ium bromide
[0360] A mixture of 4-cyclopropylquinoline from step 1.1 (9 g, 53.2
mmol) and 2-bromoacetamide (14.67 g, 106 mmol) in EtOH (100 mL) was
stirred at 90.degree. C. for 16 h. After cooling to 20.degree. C.,
the mixture was filtered, and the residue was dried in high vacuum
to give the title compound (9 g, yield 55.1%).
[0361] .sup.1H NMR (400 MHz; d.sub.6-DMSO): .delta. 9.24 (d, J=6.0
Hz, 1H), 8.88 (d, J=8.0 Hz, 1H), 8.24-8.13 (m, 3H), 8.03 (t, J=8.0
Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=6.4 Hz, 1H), 5.71 (s, 2H),
3.11-3.05 (m, 1H), 1.55-1.52 (m, 2H), 1.34-1.31 (m, 2H).
1.3 2-(4-Cyclopropyl-2H-quinolin-1-yl)acetamide
[0362] To a solution of
1-(2-amino-2-oxoethyl)-4-cyclopropylquinolin-1-ium bromide from
step 1.2 (9 g, 29.3 mmol) in MeOH (200 mL), NaBH.sub.4 (11.08 g,
293 mmol) was added in portions at 0.degree. C., and then the
mixture was stirred at 60.degree. C. for 2 hours. After cooled to
20.degree. C., water (50 mL) was added, and the reaction mixture
was extracted with DCM (50 mL.times.2), and the organic phase was
dried with Na.sub.2SO.sub.4, concentrated under reduced pressure to
give crude title compound (5 g, 74.8% yield), which was used
directly in the next step.
[0363] LCMS (ESI.sup.+): m/z 228.9 (M+H).sup.+, RT: 1.03 min.
1.4 2-(4-Cyclopropyl-3,4-dihydroquinolin-1(2H)-yl)acetamide
[0364] To a solution of 2-(4-cyclopropyl-2H-quinolin-1-yl)acetamide
from step 1.3 (5 g, 21.9 mmol) in MeOH (100 mL), Raney Ni (1.286 g,
21.9 mmol) was added under Ar, and the reaction mixture was stirred
for 12 h at 20.degree. C. under H.sub.2 (15 psi of pressure). Then
the mixture was filtered, the filtrate was concentrated under
reduced pressure and the residue was purified by preparative HPLC
(method A) to give the title compound (1.8 g, yield 35.7%)
[0365] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. 7.18 (d, J=7.2
Hz, 1H), 6.93 (t, J=7.2 Hz, 1H), 6.57 (t, J=7.6 Hz, 1H), 6.45 (s,
1H), 6.25 (d, J=8.4 Hz, 1H), 6.25 (s, 1H), 3.65 (s, 2H), 3.30-3.27
(m, 1H), 3.16-3.14 (m, 1H), 1.96-1.81 (m, 3H), 0.73-0.70 (m, 1H),
0.53-0.52 (m, 1H), 0.33-0.32 (m, 1H), 0.27-0.23 (m, 1H), 0.05-0.02
(m, 1H)
1.5 2-(4-Cyclopropyl-3,4-dihydroquinolin-1(2H)-yl)ethanamine
[0366] To a solution of
2-(4-cyclopropyl-3,4-dihydroquinolin-1(2H)-yl)acetamide from step
1.4 (1.8 g, 7.82 mmol) in THF (50 mL), a solution of BH.sub.3-THF
(15.6 mL, 15.63 mmol) was added at 0.degree. C., and the reaction
solution was stirred for 12 h at 70.degree. C. After cooling to
20.degree. C., MeOH (20 mL) was added dropwise at 0.degree. C. The
reaction solution was stirred for 30 minutes at 20.degree. C. and
then concentrated under reduced pressure to give a residue, which
was purified by preparative HPLC (method A) to give the title
compound (900 mg, yield 53.2%)
[0367] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. 7.81 (s, 1H),
7.19 (d, J=7.6 Hz, 1H), 6.93 (t, J=7.6 Hz, 1H), 6.57-6.49 (m, 2H),
3.41-3.38 (m, 3H), 3.33-3.19 (m, 1H), 3.08-3.07 (m, 1H), 2.99-2.96
(m, 2H), 1.89-1.86 (m, 1H), 1.80-1.73 (m, 2H), 0.71-0.68 (m, 1H),
0.53-0.52 (m, 1H), 0.35-0.32 (m, 1H), 0.25-0.22 (m, 1H), 0.05-0.02
(m, 1H)
1.6
8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoli-
ne
[0368] To a solution of
2-(4-cyclopropyl-3,4-dihydroquinolin-1(2H)-yl)ethanamine from step
1.5 (900 mg, 4.16 mmol) and 37% formaldehyde solution (0.93 mL,
12.48 mmol) in EtOH (15 mL), TFA (0.962 mL, 12.48 mmol) was added
at 0.degree. C., and the reaction mixture was stirred for 2 h at
80.degree. C. Then the reaction solution was concentrated under
reduced pressure and the residue was purified by preparative HPLC
(method A) to give the title compound (500 mg, yield 52.6%).
[0369] LCMS (ESI.sup.+): m/z 229.1 (M+H).sup.+, RT: 0.979 min.
1.7 Racemic Resolution of
8-cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline
to
(S)-8-cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]qui-
noline and
(R)-8-cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-
-ij]quinoline
[0370]
8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quin-
oline (500 mg, 2.19 mmol) was separated by chiral SFC (method A) to
give enantiomer 1.A (107.7 mg, yield 21.5%), and enantiomer 1.B
(125.6 mg, yield 25.1%).
[0371] Enantiomer 1.A was collected from 7.0 min to 9.6 min; and
enantiomer 1.B was collected from 10.2 min to 12.8 min.
[0372] .sup.1H NMR of enantiomer 1.A (400 MHz; CD.sub.3OD): .delta.
7.33 (d, J=7.6 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 6.78 (t, J=7.6 Hz,
1H), 3.85 (s, 2H), 3.43-3.41 (m, 1H), 3.29-3.26 (m, 1H), 3.14-3.12
(m, 2H), 3.06-3.04 (m, 2H), 2.06-1.96 (m, 2H), 1.86-1.84 (m, 1H),
0.87-0.85 (m, 1H), 0.71-0.69 (m, 1H), 0.51-0.46 (m, 2H), 0.25-0.24
(m, 1H)
[0373] LCMS (ESI.sup.+) of enantiomer A: m/z 229.1 (M+H).sup.+, RT:
2.455 min.
[0374] .sup.1H NMR of enantiomer 1.B (400 MHz; CD.sub.3OD): .delta.
7.45 (d, J=7.6 Hz, 1H), 7.12 (d, J=7.2 Hz, 1H), 6.87 (t, J=7.6 Hz,
1H), 4.16 (s, 2H), 3.48-3.43 (m, 1H), 3.32-3.30 (m, 5H), 2.07-1.98
(m, 2H), 1.87-1.86 (m, 1H), 0.87-0.85 (m, 1H), 0.71-0.69 (m, 1H),
0.51-0.46 (m, 2H), 0.26-0.25 (m, 1H)
[0375] LCMS (ESI.sup.+) of enantiomer B: m/z 229.1 (M+H).sup.+, RT:
2.460 min.
Example 2
8-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline
(Compound Ia.1 wherein R.sup.6 is cyclobutyl and R.sup.4a,
R.sup.4b, R.sup.5a, R.sup.5b and R.sup.7a are hydrogen)
2.1 4-Cyclobutylquinoline
[0376] A mixture of 4-bromoquinoline (600 mg, 2.88 mmol),
di(adamantan-1-yl)(butyl)-phosphine (70 mg, 0.195 mmol),
Pd(OAc).sub.2 (26 mg, 0.116 mmol), potassium
cyclobutyltrifluoroborate (600 mg, 3.70 mmol) and Cs.sub.2CO.sub.3
(2819 mg, 8.65 mmol) in toluene (11 mL) and water (1.1 mL) was
heated at 100.degree. C. for 72 h under N.sub.2. After cooling to
25.degree. C., water (20 mL) was added, and the mixture was
extracted with EtOAc (30 mL.times.2). The organic phase was dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to give a residue, which was purified by preparative HPLC
(method A) to give the title compound (300 mg, 56.8% yield) as
yellow oil.
[0377] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. 8.85 (s, 1H),
8.10 (d, J=8.4 Hz, 1H), 7.93-7.91 (m, 1H), 7.68 (t, J=8.0 Hz, 1H),
7.54-7.50 (m, 1H), 7.26 (d, J=4.9 Hz, 1H), 4.19-4.10 (m, 1H),
2.59-2.51 (m, 2H), 2.36-2.26 (m, 2H), 2.24-2.13 (m, 1H), 1.97-1.90
(m, 1H)
2.2 1-Benzyl-4-cyclobutyl-quinolin-1-ium bromide
[0378] A mixture of 4-cyclobutylquinoline from step 2.1 (100 mg,
0.546 mmol) and (bromomethyl)benzene (747 mg, 4.37 mmol) in toluene
(15 mL) was stirred for 12 h at 80.degree. C. After cooling, the
resulting mixture was filtered and the residue was dried by high
vacuum to give the title compound (50 mg, yield 13%), which was
used in the next step without further purification.
2.3 1-Benzyl-4-cyclobutyl-1,2,3,4-tetrahydroquinoline
[0379] To a solution of 1-benzyl-4-cyclobutyl-quinolin-1-ium
bromide from step 2.2 (200 mg, 0.565 mmol) in MeOH (20 mL) was
added NaBH.sub.4 (320 mg, 8.47 mmol) in portions at 25.degree. C.
and the reaction mixture was stirred for 3 h at 25.degree. C. Then
Raney nickel (128 mg, 2.179 mmol) was added at 25.degree. C. under
Ar, and the reaction solution was stirred for 2 h at 15 psi
pressure of H.sub.2. The reaction mixture was filtered, the
filtrate was concentrated under reduced pressure and the residue
was purified by preparative HPLC (method B) to give the title
compound (100 mg, yield 49.6%).
[0380] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. 7.26-7.14 (m,
5H), 6.93-6.89 (m, 2H), 6.5-6.43 (m, 2H), 4.42 (t, J=4.9 Hz, 2H),
3.34-3.27 (m, 1H), 3.20-3.14 (m, 1H), 2.63-2.58 (m, 1H), 2.47-2.37
(m, 1H), 2.01-1.83 (m, 4H), 1.78-1.65 (m, 4H).
2.4 4-Cyclobutyl-1,2,3,4-tetrahydroquinoline
[0381] To a solution of
1-benzyl-4-cyclobutyl-1,2,3,4-tetrahydroquinoline from step 2.3
(195 mg, 0.703 mmol) in DCE (20 mL), 1-chloroethyl
carbonochloridate (502 mg, 3.51 mmol) was added and the solution
was heated to 80.degree. C. for 12 h under N.sub.2. After cooling
to 20.degree. C., MeOH (5 mL) was added and the resulting solution
was heated to 80.degree. C. for 3 h. The mixture was concentrated
under reduced pressure and the residue was purified by preparative
HPLC (method A, however gradient: B from 5% to 35% in 20 min and
0.25 g per injection) to give the title compound (126 mg, yield
96%).
[0382] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. 6.92-6.88 (m,
2H), 6.52-6.48 (m, 1H), 6.30 (d, J=8.0 Hz, 1H), 3.23-3.15 (m, 2H),
2.57-2.55 (m, 1H), 2.45-2.35 (m, 1H), 2.0-1.9 (m, 3H), 1.73-1.66
(m, 6H).
2.5 2-(4-Cyclobutyl-3,4-dihydroquinolin-1(2H)-yl)acetamide
[0383] To a solution of 4-cyclobutyl-1,2,3,4-tetrahydroquinoline
from step 2.4 (100 mg, 0.534 mmol) in DMF (20 mL), 2-iodoacetamide
(593 mg, 3.2 mmol) was added and the solution was heated to
120.degree. C. for 12 h under N.sub.2. Water (20 mL) was added; the
mixture was extracted with EtOAc (50 mL.times.2), and the organic
phase was washed with HCl (20 mL, 1N) and brine, dried and
concentrated under reduced pressure to give the title compound (100
mg, yield 77%).
[0384] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. 7.04-6.96 (m,
2H), 6.64-6.60 (m, 1H), 6.438 (d, J=8.0 Hz, 1H), 6.35 (s, 1H), 5.35
(s, 1H), 3.82-3.69 (m, 2H), 3.29-3.25 (m, 1H), 3.17-3.14 (m, 1H),
2.62-2.59 (m, 1H), 2.39-2.35 (m, 1H), 1.98-1.85 (m, 4H), 1.75-1.69
(m, 4H).
2.6 2-(4-Cyclobutyl-3,4-dihydroquinolin-1(2H)-yl)ethanamine
[0385] To a solution of
2-(4-cyclobutyl-3,4-dihydroquinolin-1(2H)-yl)acetamide from step
2.5 (150 mg, 0.614 mmol) in THF (20 mL), BH.sub.3.THF (5 mL, 5
mmol) was added, and the solution was heated to 80.degree. C. for
12 h under N.sub.2. After cooling to 25'C, MeOH (15 mL) was added
dropwise, and the reaction solution mixture was stirred 30 minutes
at 25.degree. C. Then the resulting solution was concentrated under
reduced pressure and the residue was purified by preparative HPLC
to give the title compound (100 mg, yield 77%) (method B, however
with following gradient:
TABLE-US-00003 Time B % 0.00 15 12.0 55 12.1 55 12.2 100 13.5 100
13.6 15 15.0 15)
.sup.1H NMR (400 MHz; CD.sub.3OD): .delta. 7.04-6.96 (m, 2H), 6.54
(d, J=8.0, 1H), 6.58-6.54 (m, 1H), 3.59-3.51 (m, 2H), 3.21-3.11 (m,
3H), 3.82-3.69 (m, 2H), 3.29-3.25 (m, 1H), 3.17-3.14 (m, 1H),
2.62-2.59 (m, 1H), 2.65-2.55 (m, 1H), 2.5-2.4 (m, 1H), 2.06-1.76
(m, 9H).
2.7
8-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-
e
[0386] To a solution of
2-(4-cyclobutyl-3,4-dihydroquinolin-1(2H)-yl)ethanamine from step
2.6 (150 mg, 0.651 mmol) in EtOH (20 mL), formaldehyde (0.448 mL,
6.51 mmol) and TFA (0.502 mL, 6.51 mmol) were added and the
reaction mixture was heated at 80.degree. C. for 2 h under N.sub.2.
The resulting solution was concentrated under reduced pressure and
the residue was purified by preparative HPLC to give the title
compound (50 mg, yield 31.3%) (method B, however with following
gradient:
TABLE-US-00004 Time B % 0.00 10 12.0 50 12.1 50 12.2 100 13.5 100
13.6 10 15.0 10).
Example 3
8-(3-Methyloxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]q-
uinoline (Compound Ia.1 wherein R.sup.6 is 3-methyloxetan-3-yl and
R.sup.4a, R.sup.4b, R.sup.5a, R.sup.5b and R.sup.7a are
hydrogen)
3.1 4-(3-Methyloxetan-3-yl)-3,4-dihydroquinolin-2(1H)-one
[0387] In a 5 mL microwave vial containing
3-(3-methyloxetan-3-yl)-acrylic acid ethyl ester (500 mg, 0.588
mmol, 1.00 eq), 2-aminophenyl boronic ester (805 mg, 1.18 mmol,
2.00 eq), potassium carbonate (812 mg, 1.18 mmol, 2.00 eq) and
[RhOH(COD)].sub.2 (67 mg, 0.029 mmol, 0.05 eq) was added 2% wt.
TPGS-750-M solution in water (3 mL) (TPGS-750-M: a surfactant
composed of a lipophilic .alpha.-tocopherol moiety and a
hydrophilic PEG-750-M chain, joined by a succinic acid linker;
forms spontaneously micelles upon dissolution in water. From
Sigma-Aldrich.). The mixture was stirred vigorously at ambient
temperature for 24 h. Then the reaction mixture was extracted with
ethyl acetate. The organic phase was dried over MgSO.sub.4,
filtrated and reduced under vacuum. The crude product was purified
by column chromatography on silica (eluent: 0-10% methanol in
dichloromethane) to yield the title compound (680 mg, 96%
yield).
[0388] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.15 (s, 1H), 7.22
(ddd, J=8.0, 6.5, 2.3 Hz, 1H), 7.06-6.97 (m, 2H), 6.89-6.83 (m,
1H), 4.83 (d, J=5.9 Hz, 1H), 4.63 (d, J=5.8 Hz, 1H), 4.41 (d, J=5.7
Hz, 1H), 4.29 (d, J=6.0 Hz, 1H), 3.57 (dd, J=7.3, 4.7 Hz, 1H), 2.70
(dd, J=16.6, 7.3 Hz, 1H), 2.40 (dd, J=16.7, 4.7 Hz, 1H), 1.32 (s,
3H) ppm.
[0389] .sup.13C NMR (125 MHz, CDCl.sub.3) .delta. 171.45, 137.42,
128.34, 128.06, 123.40, 122.79, 116.16, 82.07, 81.95, 43.56, 42.78,
31.98, 19.10 ppm.
[0390] ESI-MS: m/z (%): 218.20 (100, [M+H].sup.+).
3.2 4-(3-Methyloxetan-3-yl)-1,2,3,4-tetrahydroquinoline
[0391] 640 mg of
4-(3-methyloxetan-3-yl)-3,4-dihydroquinolin-2(1H)-one from step 3.1
(2.95 mmol, 1.00 eq) was dissolved in 2 mL of THF (anhydrous) and
5.89 mL of borane tetrahydrofurane complex (5.89 mmol, 1 M in THF,
2.00 eq) was slowly added. The mixture was heated in a microwave at
60.degree. C. for 20 min. Then the reaction mixture was quenched
with HCl (1 M) and the aqueous phase was extracted with ethyl
acetate. Subsequently the organic phase was extracted three times
with HCl (1M) and NaOH (1M) was added to the aqueous phase until pH
10. This was then extracted with dichloromethane three times. The
organic phase was dried over MgSO.sub.4 and reduced under vacuum.
The crude product was purified by column chromatography on silica
(eluent: 0-10% methanol in dichloromethane) to yield the title
compound (345 mg, 52% yield).
[0392] ESI-MS: m/z (%): 204.10 (100, [M+H].sup.+).
3.3
2-(4-(3-Methyloxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide
[0393] A mixture of 170 mg of
4-(3-methyloxetan-3-yl)-1,2,3,4-tetrahydroquinoline from step 3.2
(0.836 mmol, 1.00 eq), 2-iodoacetamide (309 mg, 1.67 mmol, 2.00 eq)
and DIPEA (0.57 ml, 3.35 mmol, 4.00 eq) in DMF (3 mL) was heated in
a microwave at 130.degree. C. for 2 h. Then NaOH (1M) was added and
the mixture was extracted with dichloromethane. The organic phase
was dried over MgSO.sub.4 and reduced under vacuum. The crude
product was purified by column chromatography on silica (eluent:
0-10% methanol in dichloromethane) to yield the title compound (136
mg, 56% yield).
[0394] ESI-MS: m/z (%): 261.20 (100, [M+H].sup.+).
3.4
2-(4-(3-Methyloxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine
[0395] To a solution of 50 mg of
2-(4-(3-methyloxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide
from step 3.3 (0,192 mmol, 1.00 eq) in THF (2 ml) 0.768 mL of
lithium aluminium hydride (1 M in THF, 0.768 mmol, 4.00 eq) was
slowly added at 0.degree. C. The mixture was stirred at 0.degree.
C. for 10 min and was then warmed up to r.t. and stirred for
further 6 h at r.t. Then water (0.02 mL) was added followed by 10%
aqueous NaOH (0.02 mL) and water (0.069 mL) again. Subsequently
MgSO.sub.4 was added, the mixture was filtrated and the solvent was
evaporated. The crude product was purified by column chromatography
on silica (eluent: 0-10% methanol in dichloromethane) to yield the
title compound (30 mg, 63% yield).
[0396] ESI-MS: m/z (%): 247.20 (100, [M+H].sup.+).
3.5
8-(3-Methyloxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1--
ij]quinoline
[0397] A mixture of 30 mg of
2-(4-(3-methyloxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine
from step 3.4 (0.122 mmol, 1.00 eq), formaldehyde (9.5 .mu.L, 0.128
mmol, 1.10 eq) and TFA (10.3 .mu.L, 0.128 mmol, 1.10 eq) in ethanol
(1 mL) was stirred at ambient temperature for 2 h. Then NaOH (1M)
was added and the mixture was extracted with dichloromethane. The
organic phase was dried over MgSO.sub.4 and reduced under vacuum.
The crude product was purified by column chromatography on silica
(eluent: 0-10% methanol in dichloromethane) to yield the title
compound (16 mg, 51% yield).
[0398] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 6.98 (d, 1H), 6.74
(t, J=7.5 Hz, 1H), 6.44 (d, J=7.8, 1.3 Hz, 1H), 4.97 (d, J=5.4 Hz,
1H), 4.77 (d, J=5.5 Hz, 1H), 4.50 (dd, J=5.4, 0.8 Hz, 1H), 4.31
(dd, J=5.5, 0.8 Hz, 1H), 3.96 (d, J=14.3 Hz, 1H), 3.84 (d, J=14.3
Hz, 1H), 3.38 (dd, J=10.6, 5.5 Hz, 1H), 3.26-3.22 (m, 2H),
3.13-3.03 (m, 3H), 1.70-1.62 (m, 1H), 1.62-1.52 (m, 1H), 1.28 (s,
3H).
[0399] ESI-MS: m/z (%): 259.20 (100, [M+H].sup.+).
Example 4
8-(2,2-Difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino
[6,7,1-ij]quinoline (Compound Ia.1 wherein R.sup.6 is
2,2-difluorocyclopropyl and R.sup.4a, R.sup.4b, R.sup.5a, R.sup.5b
and R.sup.7a are hydrogen)
4.1 4-(2,2-Difluorocyclopropyl)-3,4-dihydroquinolin-2(1H)-one
[0400] A mixture of 1.26 g of (2,2-difluorocyclopropyl)-acrylic
acid ethyl ester (7.16 mmol, 1.00 eq), 1.86 g of 2-aminophenyl
boronic ester (13.6 mmol, 1.90 eq), 1.60 g of potassium
tert-butoxide (14.3 mmol, 2.00 eq) and 163 mg of [RhOH(COD)].sub.2
(0.358 mmol, 0.05 eq) in dioxane (10 mL) was heated in the
microwave at 145.degree. C. for 1 h. Then water and 1M HCl were
added and the reaction mixture was extracted with ethyl acetate.
The organic phase was dried over MgSO.sub.4, filtrated and reduced
under vacuum. The crude product was purified by column
chromatography on silica (eluent: 0-10% methanol in
dichloromethane) to yield the title product (44%, 3.17 mmol).
ESI-MS: m/z (%): 224.10 (100, [M+H].sup.+).
4.2 4-(2,2-Difluorocyclopropyl)-1,2,3,4-tetrahydroquinoline
[0401] 885 mg of
4-(2,2-difluorocyclopropyl)-3,4-dihydroquinolin-2(1H)-one (3.96
mmol, 1.00 eq) from step 4.1 was dissolved in 10 mL of THF (dry)
and 5.95 mL of borane tetrahydrofurane complex (1 M in THF, 3.00
eq) were slowly added. The mixture was heated in a microwave at
90.degree. C. for 2 h. Then the reaction mixture was quenched with
HCl (1 M) and the aqueous phase was extracted with ethyl acetate.
The organic phase was extracted three times with HCl (1M) and to
the aqueous phase was added NaOH (1M) until pH 10 and was then
extracted with dichloromethane three times. The organic phase was
dried over MgSO.sub.4 and reduced under vacuum. The crude product
was purified by column chromatography on silica (eluent: 0-10%
methanol in dichloromethane) to yield the desired product (19%,
0.765 mmol).
[0402] ESI-MS: m/z (%): 210.15 (100, [M+H].sup.+).
4.3
2-(4-(2,2-Difluorocyclopropyl)-3,4-dihydroquinolin-1(2H)-yl)acetamide
[0403] A mixture of 180 mg of
4-(2,2-difluorocyclopropyl)-1,2,3,4-tetrahydroquinoline (0.860
mmol, 1.00 eq) from step 4.2, 318 mg 2-iodoacetamide (1.72 mmol,
2.00 eq) and 0.585 mL of DIPEA (3.35 mmol, 4.00 eq) in DMF (2 mL)
was heated in a microwave at 100.degree. C. for 8 h. Then NaOH (1M)
was added and the mixture was extracted with dichloromethane. The
organic phase was dried over MgSO.sub.4 and reduced under vacuum.
The crude product was purified by column chromatography on silica
(eluent: 0-10% methanol in dichloromethane) to yield the title
product (93%, 0.803 mmol). ESI-MS: m/z (%): 267.15 (100,
[M+H].sup.+).
4.4
2-(4-(2,2-Difluorocyclopropyl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine
[0404] To a solution of 225 mg of
2-(4-(2,2-difluorocyclopropyl)-3,4-dihydroquinolin-1(2H)-yl)acetamide
(0.845 mmol, 1.00 eq) from step 4.3 in THF (10 ml) was added 1.27
mL of borane tetrahydrofurane complex (2 M in THF, 2.53 mmol, 3.00
eq). The mixture was heated in a microwave at 90.degree. C. for 2
h. Then the reaction mixture was quenched with HCl (1 M) and the
aqueous phase was extracted with ethyl acetate. The organic phase
was extracted three times with HCl (1M) and to the aqueous phase
was added NaOH (1M) until pH 10 and was then extracted with
dichloromethane three times. The organic phase was dried over
MgSO.sub.4 and reduced under vacuum. The crude product was purified
by column chromatography on silica (eluent: 0-30% methanol in
dichloromethane) to yield the title product (64%, 0.543 mmol).
[0405] ESI-MS: m/z (%): 253.15 (100, [M+H].sup.+).
4.5
8-(2,2-Difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,-
7,1-ij]quinoline
[0406] A mixture of 137 mg of
2-(4-(2,2-difluorocyclopropyl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine
(0.543 mmol, 1.00 eq) from step 4.4, formaldehyde (0.570 mmol, 1.05
eq) and TFA (0.597 mmol, 1.10 eq) in ethanol (5 mL) was stirred at
ambient temperature for 24 h. Then NaOH (1M) was added and the
mixture was extracted with dichloromethane. The organic phase was
dried over MgSO.sub.4 and reduced under vacuum. The crude product
was purified by column chromatography on silica (eluent: 0-10%
methanol in dichloromethane) to yield the title product (64%, 0.346
mmol).
[0407] ESI-MS: m/z (%): 265.20 (100, [M+H].sup.+).
[0408] .sup.1H NMR (500 MHz, CDCl.sub.3) of mixture of
diastereomers: .delta. 7.21-7.13 (m, 2H), 7.04-6.98 (m, 2H), 6.85
(t, J=7.5 Hz, 1H), 6.77 (t, J=7.5 Hz, 1H), 3.96-3.88 (m, 4H),
3.39-3.17 (m, 4H), 3.15-3.08 (m, 8H), 2.63-2.53 (m, 2H), 2.11-2.01
(m, 1H), 2.01-1.91 (m, 1H), 1.89-1.75 (m, 2H), 1.73-1.59 (m, 3H),
1.53-1.43 (m, 1H), 1.42-1.34 (m, 1H), 1.14-1.05 (m, 1H). (NH not
detected)
4.6 Analytical Separation of the 4 Isomers of
8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-
-ij]quinoline Obtained in Step 4.5
[0409] The separation was carried out in two steps via method
C:
[0410] Two peaks were separated on a Phenomenex LUX Amylose-2
Column (250.times.4.6 mm, 5 .mu.m) (t.sub.R [min]=3.4, 4.1). The
mobile phase consisted of 90% CO.sub.2 and 10% modifier. As
modifier, MeOH with 0.2 Vol % of aqueous ammonia solution (25%) was
used.
[0411] The first peak was then subjected to a second separation on
a Daicel Chiralcel.RTM. OD-H column (100.times.4.6 mm, 5 .mu.m)
(t.sub.R [min]=4.1, 4.6). The mobile phase consisted of 95%
CO.sub.2 and 5% modifier. As modifier, MeOH with 0.2 Vol % of
aqueous ammonia solution (25%) was used.
[0412] The second peak was separated on a Daicel Chiralpak.RTM.
AD-H (100.times.4.6 mm, 5 .mu.m) (t.sub.R [min]=3.7, 4.5). The
mobile phase consisted of 95% CO.sub.2 and 5% modifier. As
modifier, MeOH with 0.2 Vol % of aqueous ammonia solution (25%) was
used.
4.7 Preparative Separation of the 4 isomers of
8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-
-ij]quinoline Obtained in Step 4.5
[0413] The separation of the 4 isomers was carried out in two steps
by UV-detection at 214 nm:
[0414] Two peaks were separated on a Phenomenex LUX Amylose-2
Column (250.times.21.2 mm, 5 .mu.m) (t.sub.R [min]=3.1, 3.8). The
mobile phase consisted of 90% CO.sub.2 and 10% modifier. As
modifier, MeOH with 0.2 Vol % of aqueous ammonia solution (25%) was
used.
[0415] The first peak was then subjected to a second separation on
a Daicel Chiralcel.RTM. OD-H column (250.times.20 mm, 5 .mu.m)
(t.sub.R [min]=9.2, 10.1). The mobile phase consisted of 95%
CO.sub.2 and 5% modifier. As modifier, MeOH with 0.2 Vol % of
aqueous ammonia solution (25%) was used.
[0416] The second peak was separated on a YMC CHIRAL Amylose-C
column (250.times.20 mm, 5 .mu.m) (t.sub.R [min]=7.1, 8.2). The
mobile phase consisted of 95% CO.sub.2 and 5% modifier. As
modifier, MeOH with 0.1 Vol % diethylamine was used.
Isomer 4.A of
8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-
-ij]quinolone (Single Enantiomer of the Compound of Example
4.5)
[0417] ESI-MS: m/z (%): 265.20 (100, [M+H].sup.+).
[0418] The retention time according to the analytical method
described above is 4.1 min and according to the preparative method
described above 9.2 min.
Isomer 4.B of
8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-
-ij]quinolone (Single Enantiomer of the Compound of Example
4.5)
[0419] ESI-MS: m/z (%): 265.20 (100, [M+H].sup.+).
[0420] The retention time according to the analytical method
described above is 4.6 min and according to the preparative method
described above 10.1 min.
Isomer 4.0 of
8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-
-ij]quinolone (Single Enantiomer of the Compound of Example
4.5)
[0421] ESI-MS: m/z (%): 265.20 (100, [M+H].sup.+).
[0422] The retention time according to the analytical method
described above is 3.7 min and according to the preparative method
described above method 7.1 min.
Isomer 4.D of
8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-
-ij]quinolone (Single Enantiomer of the Compound of Example
4.5)
[0423] ESI-MS: m/z (%): 265.20 (100, [M+H].sup.+).
[0424] The retention time according to the analytical method
described above is 4.5 min and according to the preparative method
described above 8.2 min.
Example 5
8-(Oxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline
(Compound Ia.1 Wherein R.sup.6 is oxetan-3-yl and R.sup.4a,
R.sup.4b, R.sup.5a, R.sup.5b and R.sup.7a are hydrogen)
5.1 4-(Oxetan-3-yl)-3,4-dihydroquinolin-2(1H)-one
[0425] A mixture of 750 mg of oxetan-3-yl-acrylic acid ethyl ester
(2.40 mmol, 1.00 eq), 658 mg of 2-aminophenyl boronic ester (4.80
mmol, 2.00 eq), 664 mg of potassium carbonate (4.80 mmol, 2.00 eq)
and 54.8 mg of [RhOH(COD)].sub.2 (0.120 mmol, 0.05 eq) in 2% wt.
TPGS-750-M solution in water (15 mL) was stirred vigorously at
ambient temperature for the 48 h. Then the reaction mixture was
extracted with ethyl acetate. The organic phase was dried over
MgSO.sub.4, filtrated and reduced under vacuum. The crude product
was purified by column chromatography on silica (eluent: 0-10%
methanol in dichloromethane) to yield the title product (90%, 2.17
mmol).
[0426] ESI-MS: m/z (%): 204.10 (100, [M+H].sup.+).
5.2 4-(Oxetan-3-yl)-1,2,3,4-tetrahydroquinoline
[0427] To a solution of 882 mg of
4-(oxetan-3-yl)-3,4-dihydroquinolin-2(1H)-one (2.17 mmol, 1.00 eq)
from step 5.1 in THF (20 ml) 6.51 mL of lithium aluminium hydride
(1 M in THF, 6.51 mmol, 3.00 eq) was slowly added at 0.degree. C.
The mixture was stirred at 0.degree. C. for 10 min and was then
warmed up to room temperature and stirred for further 6 h at room
temperature. Then the mixture was cooled to 0.degree. C. and water
(0.03 mL) was added followed by 10% aqueous NaOH (0.03 mL) and
water (0.1 mL) again. The mixture was stirred at 0.degree. C. for 1
h. Then MgSO.sub.4 was added and the mixture was filtrated and the
solvent was evaporated. The crude product was purified by column
chromatography on silica (eluent: 0-10% methanol in
dichloromethane) to yield the title product (13%, 0.301 mmol).
[0428] ESI-MS: m/z (%): 190.20 (100, [M+H].sup.+).
5.3 2-(4-(Oxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide
[0429] A mixture of 57 mg of
4-(oxetan-3-yl)-1,2,3,4-tetrahydroquinoline (0.301 mmol, 1.00 eq)
from step 5.2, 111 mg of 2-iodoacetamide (0.602 mmol, 2.00 eq) and
0.205 mL of DIPEA (1.20 mmol, 4.00 eq) in DMF (1 mL) was heated in
a microwave at 100.degree. C. for 16 h. Then NaOH (1M) was added
and the mixture was extracted with dichloromethane. The organic
phase was dried over MgSO.sub.4 and reduced under vacuum. The crude
product was purified by column chromatography on silica (eluent:
0-10% methanol in dichloromethane) to yield the title product (55%,
0.166 mmol).
[0430] ESI-MS: m/z (%): 247.20 (100, [M+H].sup.+).
5.4 2-(4-(Oxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine
[0431] To a solution of 41 mg of
2-(4-(oxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide (0.166
mmol, 1.00 eq) from step 5.3 in THF (4 ml) 0.499 mL of lithium
aluminium hydride (1 M in THF, 0.499 mmol, 3.00 eq) was slowly
added at 0.degree. C. The mixture was stirred at 0.degree. C. for
10 min and was then warmed up to room temperature and stirred for
further 6 h at room temperature. Then the mixture was cooled to
0.degree. C. and water (0.03 mL) was added followed by 10% aqueous
NaOH (0.03 mL) and water (0.1 mL) again. The mixture was stirred at
0.degree. C. for 1 h. Then MgSO.sub.4 was added and the mixture was
filtrated and the solvent was evaporated. The crude product was
purified by column chromatography on silica (eluent: 0-10% methanol
in dichloromethane) to yield the title product (38%, 0.064
mmol).
[0432] ESI-MS: m/z (%): 233.20 (100, [M+H].sup.+).
5.5
8-(Oxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quino-
line
[0433] A mixture of 86 mg of
2-(4-(oxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine (0.370
mmol, 1.00 eq) from step 5.4, formaldehyde (0.389 mmol, 1.05 eq)
and TFA (0.407 mmol, 1.10 eq) in ethanol (3 mL) was stirred at
ambient temperature for 2 h. Then NaOH (1M) was added and the
mixture was extracted with dichloromethane. The organic phase was
dried over MgSO.sub.4 and reduced under vacuum. The crude product
was purified by SFC to yield the title product (3.5%, 0.013
mmol).
[0434] ESI-MS: m/z (%): 245.30 (100, [M+H].sup.+).
[0435] .sup.1H NMR (500 MHz, Methanol-d.sub.4): .delta. 6.97 (d,
J=7.3, 1.4 Hz, 1H), 6.79 (d, J=7.4 Hz, 1H), 6.70 (t, J=7.5 Hz, 1H),
4.90-4.80 (m, 1H), 4.79-4.70 (m, 2H), 4.68-4.60 (m, 1H), 3.79 (q,
J=14.0 Hz, 2H), 3.36-3.27 (m, 2H), 3.27-3.17 (m, 2H), 3.20-3.06 (m,
3H), 3.05-2.92 (m, 2H), 1.94-1.84 (m, 1H), 1.67-1.57 (m, 1H).
Example 6
8-(Tetrahydro-2H-pyran-4-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-
-ij]quinoline (Compound Ia.1 wherein R.sup.6 is
tetrahydro-2H-pyran-4-yl and R.sup.4a, R.sup.4b, R.sup.5a, R.sup.5b
and R.sup.7a are hydrogen)
6.1 4-(Tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-2(1H)-one
[0436] A mixture of 100 mg of tetrahydropyran-4-yl-acrylic acid
ethyl ester (0.588 mmol, 1.00 eq), 161 mg of 2-aminophenyl boronic
ester (1.18 mmol, 2.00 eq), 162 mg of potassium carbonate (1.18
mmol, 2.00 eq) and 13.4 mg of [RhOH(COD)].sub.2 (0.029 mmol, 0.05
eq) in 2% wt. TPGS-750-M solution in water (3 mL) was stirred
vigorously at ambient temperature for 48 h and then at 70.degree.
C. for further 20 h. The reaction mixture was extracted with ethyl
acetate. The organic phase was dried over MgSO.sub.4, filtrated and
reduced under vacuum. The crude product was purified by column
chromatography on silica (eluent: 0-20% methanol in
dichloromethane) to yield the title product (67%, 0.395 mmol).
[0437] ESI-MS: m/z (%): 232.20 (100, [M+H].sup.+).
6.2 4-(Tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoline
[0438] To a solution of 91.4 mg of
4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.395
mmol, 1.00 eq) from step 6.1 in THF (2 ml) was added 0.790 mL of
borane tetrahydrofurane complex (2 M in THF, 1.58 mmol, 4.00 eq).
The mixture was stirred at room temperature for 16 h and then
heated in a microwave at 90.degree. C. for 2 h. Then the reaction
mixture was quenched with HCl (1 M) and the aqueous phase was
extracted with ethyl acetate. The organic phase was extracted three
times with HCl (1M) and to the aqueous phase was added NaOH (1M)
until pH 10 and was then extracted with dichloromethane three
times. The organic phase was dried over MgSO.sub.4 and reduced
under vacuum to yield the title product (44%, 0.173 mmol).
[0439] ESI-MS: m/z (%): 218.20 (100, [M+H].sup.+).
6.3
2-(4-(Tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide
[0440] A mixture of 37.6 mg of
4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoline (0.173
mmol, 1.00 eq) from step 6.2, 128 mg of 2-iodoacetamide (0.692
mmol, 4.00 eq) and 0.177 mL of DIPEA (1.04 mmol, 6.00 eq) in DMF (3
mL) was heated in a microwave at 120.degree. C. for 8 h. Then NaOH
(1M) was added and the mixture was extracted with dichloromethane.
The organic phase was dried over MgSO.sub.4 and reduced under
vacuum. The crude product was purified by column chromatography on
silica (eluent: 0-30% methanol in dichloromethane) to yield the
title product.
[0441] ESI-MS: m/z (%): 275.20 (100, [M+H].sup.+).
6.4
2-(4-(Tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamin-
e
[0442] To a solution of 191 mg of
2-(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide
(0.696 mmol, 1.00 eq) from step 6.3 in THF (5 ml) was added 1.74 mL
of borane tetrahydrofurane complex (2 M in THF, 3.48 mmol, 5.00
eq). The mixture was stirred at room temperature for 16 h and then
heated in a microwave at 90.degree. C. for 1 h. Then the reaction
mixture was quenched with HCl (1 M) and the aqueous phase was
extracted with ethyl acetate. The organic phase was extracted three
times with HCl (1M) and to the aqueous phase was added NaOH (1M)
until pH 10 and was then extracted with dichloromethane three
times. The organic phase was dried over MgSO.sub.4 and reduced
under vacuum to yield the title product (76%, 0.529 mmol).
[0443] ESI-MS: m/z (%): 261.20 (100, [M+H].sup.+).
6.5
8-(Tetrahydro-2H-pyran-4-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6-
,7,1-ij]quinoline
[0444] A mixture of 33.8 mg of
2-(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine
(0.130 mmol, 1.00 eq) from step 6.4, formaldehyde (0.130 mmol, 1.00
eq) and TFA (0.143 mmol, 1.10 eq) in ethanol (2 mL) was stirred at
ambient temperature for 48 h and then at 70.degree. C. for further
4 h. The solvent was removed under vacuum. The residue was
dissolved in DCM and washed with saturated aqueous sodium
bicarbonate solution. The organic layer was dried over
Na.sub.2SO.sub.4, filtrated and reduced under vacuum. The crude
product was purified by column chromatography on silica (eluent:
0-30% methanol in dichloromethane) to yield the title compound
(15%, 0.019 mmol).
[0445] ESI-MS: m/z (%): 273.20 (100, [M+H].sup.+).
[0446] .sup.1H NMR (600 MHz, Methanol-d.sub.4): .delta. 7.14 (td,
J=7.4, 1.6 Hz, 2H), 6.85 (t, J=7.5 Hz, 1H), 4.29 (d, J=13.7 Hz,
1H), 4.17 (d, J=13.8 Hz, 1H), 4.01-3.91 (m, 2H), 3.63 (s, 1H),
3.50-3.45 (m, 1H), 3.43-3.30 (m, 4H), 3.26 (ddd, J=12.1, 10.4, 4.0
Hz, 1H), 2.66 (s, 1H), 2.63 (dt, J=7.9, 5.2 Hz, 1H), 2.09-2.01 (m,
1H), 1.89-1.82 (m, 1H), 1.82-1.74 (m, 1H), 1.61-1.55 (m, 1H),
1.55-1.49 (m, 2H), 1.39-1.27 (m, 1H). (NH not detected)
Example 7
8-(Tetrahydrofuran-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]-
quinoline (Compound Ia.1 wherein R.sup.6 is tetrahydrofuran-3-yl
and R.sup.4a, R.sup.4b, R.sup.5a, R.sup.5b and R.sup.7a are
hydrogen)
7.1 4-(Tetrahydrofuran-3-yl)-3,4-dihydroquinolin-2(1H)-one
[0447] A mixture of 100 mg of tetrahydrofuran-3-yl-acrylic acid
methyl ester (0.640 mmol, 1.00 eq), 175 mg of 2-aminophenyl boronic
ester (1.28 mmol, 2.00 eq), 177 mg of potassium carbonate (1.28
mmol, 2.00 eq) and 14.6 mg of [RhOH(COD)].sub.2 (0.032 mmol, 0.05
eq) in 2% wt. TPGS-750-M solution in water (3 mL) was stirred
vigorously at ambient temperature for the 48 h and then at
70.degree. C. for further 6 h. The reaction mixture was extracted
with ethyl acetate. The organic phase was dried over MgSO.sub.4,
filtrated and reduced under vacuum. The crude product was purified
by column chromatography on silica (eluent: 0-30% methanol in
dichloromethane) to yield the title product (81%, 0.516 mmol).
[0448] ESI-MS: m/z (%): 218.20 (100, [M+H].sup.+).
7.2 4-(Tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroquinoline
[0449] To a solution of 112 mg of
4-(tetrahydrofuran-3-yl)-3,4-dihydroquinolin-2(1H)-one (0.516 mmol,
1.00 eq) from step 7.1 in THF (2 ml) was added 1.03 mL of borane
tetrahydrofurane complex (2 M in THF, 2.06 mmol, 4.00 eq). The
mixture was stirred at room temperature for 16 h and then heated in
a microwave at 90.degree. C. for 2 h. Then the reaction mixture was
quenched with HCl (1 M) and the aqueous phase was extracted with
ethyl acetate. The organic phase was extracted three times with HCl
(1M) and to the aqueous phase was added NaOH (1M) until pH 10 and
was then extracted with dichloromethane three times. The organic
phase was dried over MgSO.sub.4 and reduced under vacuum to yield
the title product (69%, 0.358 mmol).
[0450] ESI-MS: m/z (%): 204.20 (100, [M+H].sup.+).
7.3
2-(4-(Tetrahydrofuran-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide
[0451] A mixture of 72.7 mg of
4-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroquinoline (0.358 mmol,
1.00 eq) from step 7.2, 265 mg of 2-iodoacetamide (1.43 mmol, 4.00
eq) and 0.367 mL of DIPEA (1.43 mmol, 6.00 eq) in DMF (3 mL) was
heated in a microwave at 120.degree. C. for 8 h. Then NaOH (1M) was
added and the mixture was extracted with dichloromethane. The
organic phase was dried over MgSO.sub.4 and reduced under vacuum.
The crude product was purified by column chromatography on silica
(eluent: 0-70% methanol in dichloromethane) to yield the title
product.
[0452] ESI-MS: m/z (%): 261.20 (100, [M+H].sup.+).
7.4
2-(4-(Tetrahydrofuran-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine
[0453] To a solution of 480 mg of
2-(4-(tetrahydrofuran-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide
(1.84 mmol, 1.00 eq) from step 7.3 in THF (5 ml) was added 4.61 mL
of borane tetrahydrofurane complex (2 M in THF, 9.22 mmol, 5.00
eq). The mixture was stirred at room temperature for 16 h and then
heated in a microwave at 90.degree. C. for 2 h. Then the reaction
mixture was quenched with HCl (1 M) and the aqueous phase was
extracted with ethyl acetate. The organic phase was extracted three
times with HCl (1M) and to the aqueous phase was added NaOH (1M)
until pH 10 and was then extracted with dichloromethane three
times. The organic phase was dried over MgSO.sub.4 and reduced
under vacuum. The crude product was purified by column
chromatography on silica (eluent: 0-70% methanol in
dichloromethane) to yield the title product (12%, 0.215 mmol).
[0454] ESI-MS: m/z (%): 247.20 (100, [M+H].sup.+).
[0455] 7.5
8-(Tetrahydrofuran-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepin-
o[6,7,1-ij]quinoline
[0456] A mixture of 53.0 mg of
2-(4-(tetrahydrofuran-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine
(0.215 mmol, 1.00 eq) from step 7.4, formaldehyde (0.215 mmol, 1.00
eq) and TFA (0.237 mmol, 1.10 eq) in ethanol (2 mL) was stirred at
ambient temperature for 84 h. Then the solvent was removed under
vacuum. The residue was dissolved with DCM and washed with
saturated aqueous sodium bicarbonate solution. The organic layer
was dried over Na.sub.2SO.sub.4, filtrated and reduced under
vacuum. The crude product was purified by preparative HPLC to yield
the title compound (38%, 0.082 mmol).
[0457] ESI-MS: m/z (%): 259.20 (100, [M+H].sup.+).
[0458] .sup.1H NMR of mixture of diastereomers (600 MHz,
Methanol-d.sub.4): .delta. 7.22-7.05 (m, 4H), 6.87-6.79 (m, 2H),
4.30 (d, J=13.9 Hz, 2H), 4.16 (dd, J=13.8, 4.4 Hz, 2H), 3.98-3.90
(m, 3H), 3.80-3.62 (m, 4H), 3.53-3.30 (m, 13H), 2.82-2.71 (m, 2H),
2.60-2.43 (m, 2H), 2.17-2.09 (m, 1H), 2.04-1.97 (m, 1H), 1.95-1.86
(m, 4H), 1.85-1.79 (m, 1H), 1.72-1.62 (m, 1H). (NH not
detected)
Example 8
8-Cyclopropyl-10-(2-methoxyethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino
[6,7,1-ij]quinoline (Compound Ia.1 wherein R.sup.6 is cyclopropyl,
R.sup.4a, R.sup.4b, R.sup.5a and R.sup.5b are hydrogen, and
R.sup.7a is 2-methoxyethyl)
8.1 tert-Butyl
8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6-
H)-carboxylate
[0459] A solution of 980 mg of
8-cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline
(4.29 mmol, 1.00 eq) from example 1.6, 1.20 mL of triethylamine
(8.58 mmol, 2.00 eq) and 937 mg of di-tert-butyl dicarbonate (4.29
mmol, 1.00 eq) in DCM (20 mL) was stirred 30 min at room
temperature. Then the organic phase was extracted with water, dried
over MgSO.sub.4 and the solvent was evaporated to yield the title
compound (100%, 4.29 mmol).
[0460] ESI-MS: m/z (%): 329.20 (100, [M+H].sup.+).
8.2 tert-Butyl
10-bromo-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quin-
oline-2(6H)-carboxylate
[0461] A solution of 600 mg of tert-butyl
8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6-
H)-carboxylate (1.83 mmol, 1.00 eq) from step 8.1 in THF (20 mL)
was cooled to 0.degree. C. Then 325 mg N-bromosuccinimide (1.83
mmol, 1.00 eq) was added and the mixture was stirred for 30 min at
0.degree. C. The solvent was evaporated to yield the title
compound.
[0462] ESI-MS: m/z (%): 408.20 (100, [M+H].sup.+).
8.3 tert-Butyl
8-cyclopropyl-10-(2-methoxyethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,-
7,1-ij]quinoline-2(6H)-carboxylate
[0463] Under an argon atmosphere a mixture of 100 mg of tert-butyl
10-bromo-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quin-
oline-2(6H)-carboxylate (0.245 mmol, 1.00 eq) from step 8.2, 40.7
mg of potassium trifluoro (2-methoxyehtyl)borate (0.245 mmol, 1.00
eq), 240 mg of cesium carbonate (0.736 mmol, 3.00 eq), 2.04 mg of
Pd(OAc).sub.2 (0.009 mmol, 0.04 eq) and 8.19 mg of X-Phos (0.017
mmol, 0.07 eq) in degassed THF (4 mL) and water (0.5 mL) was heated
in a microwave at 120.degree. C. for 20 h. Then the solvent was
evaporated to yield the title compound.
[0464] ESI-MS: m/z (%): 387.30 (100, [M+H].sup.+).
8.4
8-Cyclopropyl-10-(2-methoxyethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazep-
ino[6,7,1-ij]quinoline
[0465] To a solution of 100 mg of tert-Butyl
8-cyclopropyl-10-(2-methoxyethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,-
7,1-ij]quinoline-2(6H)-carboxylate (0.259 mmol, 1.00 eq) in DCM (3
mL) was added 0.199 mL TFA (2.59 mmol, 10.0 eq) and the mixture was
stirred for 18 h at room temperature and then at 70.degree. C. for
further 8 h. The solvent was evaporated and the crude product was
purified via preparative HPLC to yield the title compound (3.8%,
0.010 mmol).
[0466] ESI-MS: m/z (%): 287.30 (100, [M+H].sup.+).
[0467] .sup.1H NMR (500 MHz, Methanol-d.sub.4): .delta. 7.36 (d,
J=2.1 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 4.20 (d, J=1.8 Hz, 2H), 3.57
(t, J=6.7 Hz, 2H), 3.48-3.40 (m, 1H), 3.35-3.25 (m, 5H), 3.32 (s,
3H), 2.78 (t, J=6.7 Hz, 2H), 2.09-2.01 (m, 1H), 2.01-1.93 (m, 1H),
1.88-1.78 (m, 1H), 1.29 (s, 1H), 0.92-0.79 (m, 1H), 0.74-0.66 (m,
1H), 0.55-0.43 (m, 2H), 0.29-0.20 (m, 1H).
Example 9
8-Cyclopropyl-10-(methoxymethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6-
,7,1-ij]quinoline (Compound Ia.1 wherein R.sup.6 is cyclopropyl,
R.sup.4a, R.sup.4b, R.sup.5a and R.sup.5b are hydrogen, and
R.sup.7a is methoxymethyl)
9.1 tert-butyl
8-cyclopropyl-10-(methoxymethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7-
,1-ij]quinoline-2(6H)-carboxylate
[0468] Under an argon atmosphere a mixture of 70 mg of tert-butyl
10-bromo-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino
[6,7,1-ij]quinoline-2(6H)-carboxylate (0.172 mmol, 1.00 eq) from
step 8.2, 52.2 mg of potassium trifluoro (2-methoxymehtyl)borate
(0.344 mmol, 2.00 eq), 168 mg of cesium carbonate (0.516 mmol, 3.00
eq), 1.43 mg of Pd(OAc).sub.2 (0.006 mmol, 0.04 eq) and 5.73 mg of
X-Phos (0.012 mmol, 0.07 eq) in degassed dioxane (4 mL) and water
(0.5 mL) was heated in a microwave at 130.degree. C. for 40 h. Then
the mixture was extracted with DCM and the organic phase was washed
with water and dried over MgSO.sub.4, filtrated and solvent was
evaporated to yield the title compound.
[0469] ESI-MS: m/z (%): 373.30 (100, [M+H].sup.+).
9.2
8-cyclopropyl-10-(methoxymethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepi-
no[6,7,1-ij]quinoline
[0470] To a solution of 51.6 mg of tert-butyl
8-cyclopropyl-10-(methoxymethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7-
,1-ij]quinoline-2(6H)-carboxylate (0.139 mmol, 1.00 eq) from step
9.2 in DCM (3 mL) was added 0.107 mL of TFA (1.39 mmol, 10.0 eq)
and the mixture was stirred for 48 h at room temperature. Then the
solvent was evaporated and the crude product was purified via
preparative HPLC to yield the title compound (2.2%, 0.003
mmol).
[0471] ESI-MS: m/z (%): 273.20 (100, [M+H].sup.+).
Example 10
8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-1-
0-carbonitrile (compound Ia.1 wherein R.sup.6 is cyclopropyl,
R.sup.4a, R.sup.4b, R.sup.5a and R.sup.5b are hydrogen, and
R.sup.7a is cyano)
10.1 tert-Butyl
10-cyano-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quin-
oline-2(6H)-carboxylate
[0472] Under an argon atmosphere a mixture of 30 mg of tert-butyl
10-bromo-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quin-
oline-2(6H)-carboxylate (0.074 mmol, 1.00 eq) from step 8.2, 38.9
mg of potassium hexacyanoferrate(II) trihydrate (0.092 mmol, 1.25
eq), 25.4 mg of potassium carbonate (0.184 mmol, 2.50 eq), 3.31 mg
of Pd(OAc).sub.2 (0.015 mmol, 0.20 eq) and 14.04 mg of X-Phos
(0.029 mmol, 0.40 eq) in degassed dioxane (2 mL) and water (2 mL)
was heated in a microwave at 100.degree. C. for 10 h. Then the
mixture was extracted with DCM and the organic phase was washed
with water and dried over MgSO.sub.4, filtrated and the solvent was
evaporated to yield the title compound.
[0473] ESI-MS: m/z (%): 354.30 (100, [M+H].sup.+).
10.2
8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinol-
ine-10-carbonitrile
[0474] To a solution of 33.6 mg of tert-butyl
10-cyano-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quin-
oline-2(6H)-carboxylate (0.095 mmol, 1.00 eq) from step 10.1 in DCM
(10 mL) was added 0.073 mL of TFA (0.951 mmol, 10.0 eq) and the
mixture was stirred for 18 h at room temperature and heated in a
microwave for further 4 h at 50.degree. C. and then at 70.degree.
C. for further 3 h. The solvent was evaporated and the crude
product was purified via preparative HPLC to yield the title
compound (10%, 0.009 mmol).
[0475] ESI-MS: m/z (%): 254.20 (100, [M+H].sup.+).
[0476] .sup.1H NMR (600 MHz, Methanol-d.sub.4): .delta. 7.66 (dd,
J=2.1, 0.9 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 4.34 (s, 2H), 3.70-3.61
(m, 2H), 3.56-3.51 (m, 1H), 3.48 (t, J=5.1 Hz, 2H), 3.41-3.36 (m,
1H), 2.08-2.03 (m, 1H), 2.02-1.98 (m, 1H), 1.91-1.83 (m, 1H),
0.91-0.82 (m, 1H), 0.76-0.69 (m, 1H), 0.61-0.54 (m, 1H), 0.48-0.40
(m, 1H), 0.31-0.24 (m, 1H). (NH not detected)
II. Biological Tests
Functional Activity
1. Human 5-HT.sub.2C Functional Assay
[0477] The functional activity of compounds of formula I was
assayed by incubation with U2OS_HTR.sub.2C.sub._.beta.-Arrestin
cells (DiscoverX, 93-0289C3) to induce beta-arrestin2 recruitment
to the 5-HT.sub.2C receptor. The agonist-induced recruitment and
proximity of the receptor and beta-arrestin2 leads to
complementation and formation of active .beta.-galactosidase. The
enzyme complementation results in enzyme activity, which is
measured following the termination of the agonist incubation using
DiscoveRx's detection reagent, which contains a chemiluminescent
substrate which produces a high intensity signal. Cells were plated
and a medium-change to a 1% serum containing medium was performed
24 h later. The next day, test compounds were added and incubated
for 1.5 h before addition of detection reagent.
[0478] The response produced was measured and compared with the
response produced by 10 [mu]M 5-HT or the maximal effect induced by
5-HT (defined as 100%) to which it was expressed as a percentage
response (relative efficacy). Dose response curves were constructed
using Graphpad Prism (Graph Software Inc.) or using in house
adapted software using a 4 parameter dose response model with
variable slope (fit=(Bottom+(Top-Bottom)/(1+10 ((Log
EC50-x)*HillSlope))res=(y-fit)). Results are compiled in the table
below.
2. Human 5-HT.sub.2A Functional Assay
[0479] Functional activity on the 5-HT.sub.2A receptor was
determined by testing the effect of the compounds I on calcium
mobilisation in CHO-K1 cells, stably transfected with human
5-HT.sub.2A receptor. Cells were seeded into sterile black 384-well
plates with clear bottom at 25,000 cells/well in a volume of 25
.mu.l and grown for 5-6 hours at 37.degree. C., in 5% CO.sub.2 in
tissue culture medium ("Ultra CHO" by LONZA), containing 1%
dialysed FCS and 50 .mu.g/ml gentamicin (Invitrogen). After this
incubation, medium was replaced by a serum free version of the same
tissue culture medium followed by incubation overnight at
37.degree. C. and in 5% CO.sub.2. Cells were then loaded with a
fluorescent calcium-sensitive dye in the presence of 0.07%
probenecid for an hour at 37.degree. C., according to the
manufacturer's protocol (Ca5-Assay Kit, Molecular Devices),
followed by an additional 60 min incubation at room temperature.
Serial compound dilutions (final concentrations of 10.sup.-10 to
10.sup.-5M, prepared in HBSS+50 mM HEPES) were first added to the
cells alone ("first addition" to assess agonism on the 5-HT.sub.2A
receptor), then after 8 min, serotonin was added to the same wells
at a final concentration of 3.times.10.sup.-8 M ("second addition"
to see potential antagonistic effect) and the maximal calcium
response was determined using a FLIPR.RTM. Tetra instrument
(Molecular Devices) in each of the two steps. The relative efficacy
of the compounds was calculated as a percentage of the maximal
effect induced by serotonin alone (defined as 100%). To determine
EC.sub.50/IC.sub.50 values, concentration-response curves were
fitted using a four-parameter logistic equation (IDBS Biobook.TM.).
K.sub.b values were calculated from IC.sub.50 values, according to
Cheng & Prusoff.
3. Human 5-HT.sub.2B Functional Assay
[0480] Functional activity on the 5-HT.sub.2B receptor was
determined by testing the effect of the compounds I on calcium
mobilisation in CHO-FlpIn cells, stably transfected with human
5-HT.sub.2B receptor. Cells were seeded into sterile black 384-well
plates with clear bottom at 30,000 cells/well in a volume of 25
.mu.l and grown overnight at 37.degree. C., in 5% CO.sub.2 in
tissue culture medium ("CHO--S-SFM II" by Invitrogen), containing
1% dialysed FCS and 50 .mu.g/ml gentamicin (Invitrogen). On the
next morning, medium was replaced by a serum free version of the
same tissue culture medium for a further incubation for 4 hours at
37.degree. C. and in 5% CO.sub.2. Cells were then loaded with a
fluorescent calcium-sensitive dye in the presence of 0.07%
probenecid for an hour at 37.degree. C., according to the
manufacturer's protocol (Ca5-Assay Kit, Molecular Devices),
followed by an additional 60 min incubation at room temperature.
Serial compound dilutions (final concentrations of 10.sup.-10 to
10.sup.-5M, prepared in HBSS+50 mM HEPES) were first added to the
cells alone ("first addition" to assess agonism on the 5-HT.sub.2B
receptor), then after 8 min, serotonin was added to the same wells
at a final concentration of 10.sup.-8 M ("second addition" to see
potential antagonistic effect) and the maximal calcium response was
determined using a FLIPR.RTM. Tetra instrument (Molecular Devices)
in each of the two steps. The relative efficacy of the compounds
was calculated as a percentage of the maximal effect induced by
serotonin alone (defined as 100%). To determine EC.sub.50/IC.sub.50
values, concentration-response curves were fitted using a
four-parameter logistic equation (IDBS Biobook.TM.). K.sub.b values
were calculated from IC.sub.50 values, according to Cheng &
Prusoff.
TABLE-US-00005 TABLE Selectivity.sup.4 Selectivity.sup.5 EC50 %
EC50 % (based on EC50 (based on # 5-HT.sub.2C.sup.1 efficacy
5-HT.sub.2A.sup.2 efficacy agonism) 5-HT.sub.2B.sup.3 agonism) 1
+++ 105 + 25 122 * antagonist 1.A +++ 89 * .sup. antagonist.sup.6 *
antagonist 1.B +++ 121 ++ 50 23 * antagonist 2 ++ 54 * antagonist *
antagonist 3 ++ 88 * antagonist * full.sup.7 4 ++ 88 ++ 19 6 *
antagonist 4.A ++ 85 * antagonist * full 4.B ++ 99 + 33 18 *
antagonist 4.C ++ 80 * antagonist * antagonist 4.D ++ 111 ** 24 45
* antagonist 5 + 82 * antagonist * full .sup.1Potency (EC50
5-HT.sub.2C) in functional assay .sup.2Potency (EC50 5-HT.sub.2A)
in functional assay .sup.3Potency (EC50 5-HT.sub.2B) in functional
assay .sup.4EC50 5-HT.sub.2A/EC50 5-HT.sub.2C .sup.5EC50
5-HT.sub.2B/EC50 5-HT.sub.2C .sup.6"antagonist" indicates
functional antagonism with no measurable agonistic effect
.sup.7"full" indicates no measurable agonistic effect at 10 .mu.M
(highest concentration in assay) Potency (EC50): * >10 .mu.M **
1 .mu.M to 10 .mu.M + from 200 nM to <1 .mu.M ++ from 20 nM to
<200 nM +++ <20 nM
* * * * *