U.S. patent application number 16/179050 was filed with the patent office on 2019-03-07 for tricyclic quinoline and quinoxaline derivatives.
The applicant listed for this patent is AbbVie Deutschland GmbH & Co. KG, AbbVie Inc.. Invention is credited to Margaretha Henrica Maria Bakker, Wilfried Braje, Karla Drescher, Andreas Haupt, Carolin Hoft, Hannes Koolman, Viktor Lakics, Helmut Mack, Ana Lucia Relo, Ruxu Xu, Xiaona Zhao.
Application Number | 20190071443 16/179050 |
Document ID | / |
Family ID | 50275085 |
Filed Date | 2019-03-07 |
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United States Patent
Application |
20190071443 |
Kind Code |
A1 |
Koolman; Hannes ; et
al. |
March 7, 2019 |
TRICYCLIC QUINOLINE AND QUINOXALINE DERIVATIVES
Abstract
The present invention relates to tricyclic quinoline and
quinoxaline derivatives, 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, and to a method for preventing or treating
conditions and disorders which respond to the modulation of
5-HT.sub.2C receptor.
Inventors: |
Koolman; Hannes; (North
Chicago, IL) ; Braje; Wilfried; (Ludwigshafen,
DE) ; Mack; Helmut; (Ludwigshafen, DE) ;
Haupt; Andreas; (Ludwigshafen, DE) ; Relo; Ana
Lucia; (Ludwigshafen, DE) ; Drescher; Karla;
(Ludwigshafen, DE) ; Bakker; Margaretha Henrica
Maria; (Ludwigshafen, DE) ; Lakics; Viktor;
(Ludwigshafen, DE) ; Hoft; Carolin; (Ludwigshafen,
DE) ; Xu; Ruxu; (Tianjin, CN) ; Zhao;
Xiaona; (Tianjin, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Deutschland GmbH & Co. KG
AbbVie Inc. |
Wiesbaden
North Chicago |
IL |
DE
US |
|
|
Family ID: |
50275085 |
Appl. No.: |
16/179050 |
Filed: |
November 2, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14026354 |
Sep 13, 2013 |
10118926 |
|
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16179050 |
|
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61793033 |
Mar 15, 2013 |
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61701514 |
Sep 14, 2012 |
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61701531 |
Sep 14, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/24 20180101;
A61P 15/00 20180101; A61P 27/02 20180101; A61P 15/10 20180101; A61P
25/00 20180101; A61P 17/02 20180101; A61P 25/28 20180101; A61P
25/20 20180101; A61P 25/22 20180101; C07D 487/06 20130101; A61P
17/06 20180101; A61P 25/16 20180101; A61P 13/10 20180101; A61P
25/18 20180101; A61P 3/04 20180101; A61P 15/12 20180101; A61P 25/06
20180101; C07D 471/06 20130101; A61P 7/12 20180101; C07D 487/16
20130101; A61P 17/00 20180101; A61P 9/00 20180101; A61P 25/08
20180101; A61P 25/30 20180101; A61P 25/36 20180101; A61P 29/00
20180101; A61P 43/00 20180101; A61P 3/10 20180101; A61P 1/00
20180101; A61P 25/32 20180101; A61P 25/34 20180101 |
International
Class: |
C07D 471/06 20060101
C07D471/06; C07D 487/16 20060101 C07D487/16; C07D 487/06 20060101
C07D487/06 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 11, 2013 |
CN |
201310410951.1 |
Claims
1. A compound of the formula I ##STR00025## wherein G is
(CR.sup.3aR.sup.3b).sup.n; X is NR.sup.6 or CR.sup.7R.sup.8;
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.10, 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.11; 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, fluorinated C.sub.1-C.sub.6-alkoxy,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; 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, fluorinated C.sub.1-C.sub.6-alkoxy,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; 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, fluorinated C.sub.1-C.sub.6-alkoxy,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; or R.sup.4a and
R.sup.4b form together a group .dbd.O or .dbd.S; R.sup.5a and
R.sup.5b, independently of each other, are selected from the group
consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxy,
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,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; where R.sup.5a
and R.sup.5b are not simultaneously hydroxy; 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.11;
or R.sup.5a and R.sup.6, together with the atoms they are bound to,
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 R.sup.11; or R.sup.5a and
R.sup.7, together with the carbon atoms 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.11;
R.sup.6 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.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy,
--C(.dbd.O)R.sup.10, --SO.sub.2R.sup.10, 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.11;
R.sup.7 and R.sup.8, independently of each other, are selected from
the group consisting of deuterium, 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,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; where R.sup.7
and R.sup.8 are not simultaneously hydroxyl; and where R.sup.7 is
not hydroxyl if R.sup.8 is C.sub.1-C.sub.6-alkoxy, fluorinated
C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-hydroxyalkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, phenoxy or
benzyloxy; or R.sup.7 and R.sup.8, 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.11; each R.sup.9 is
independently selected from the group consisting of halogen, cyano,
nitro, hydroxy, 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,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; or two radicals
R.sup.9 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.11; each R.sup.10 is independently selected
from the group consisting of hydrogen, cyano, hydroxy,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, 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.11; each R.sup.11 is independently selected
from the group consisting of halogen, cyano, nitro, hydroxy,
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,
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.12aR.sup.12b, --CH.sub.2NR.sup.12aR.sup.12b, 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.12aR.sup.12b, C.sub.1-C.sub.6-alkylcarbonyloxy and
fluorinated C.sub.1-C.sub.6-alkylcarbonyloxy; or two radicals
R.sup.11, 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.12a and R.sup.12b,
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.12a and R.sup.12b 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; b is 0, 1, 2 or
3; and n is 1 or 2; and the N-oxides, tautomeric forms,
stereoisomers and pharmaceutically acceptable salts thereof, and
the compound of the general formula I, wherein at least one of the
atoms has been replaced by its stable, non-radioactive isotope.
2. The compound as claimed in claim 1, wherein at least one
hydrogen atom has been replaced by a deuterium atom.
3. The compound as claimed in any of the preceding claims, where
R.sup.1 is selected from hydrogen and C.sub.1-C.sub.6-alkyl and is
preferably hydrogen.
4. The compound as claimed in any of the preceding claims, where
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 and
fluorinated C.sub.1-C.sub.6-alkoxy, in particular from
C.sub.1-C.sub.6-alkyl and especially from methyl.
5. 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, fluorinated
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy and fluorinated
C.sub.1-C.sub.6-alkoxy.
6. The compound as claimed in claim 5, where R.sup.3a is selected
from hydrogen, 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, and R.sup.3b is hydrogen.
7. The compound as claimed in claim 6, where R.sup.3a is selected
from hydrogen and methyl, and R.sup.3b is hydrogen.
8. The compound as claimed in claim 7, where R.sup.3a and R.sup.3b
are hydrogen.
9. 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 and fluorinated
C.sub.1-C.sub.6-alkyl or form together a group .dbd.O, and are in
particular hydrogen or methyl or form together a group .dbd.O, and
are especially hydrogen.
10. The compound as claimed in any of the preceding claims, where
R.sup.5a is selected from hydrogen, cyano, nitro, hydroxy,
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; and
in case that X is CR.sup.7R.sup.8 is further selected from halogen;
or R.sup.5a and R.sup.6, together with the atoms they are bound to,
form a 3-, 4-, 5-, 6- or 7-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 R.sup.11; or R.sup.5a and
R.sup.7, together with the carbon atoms they are bound to, form a
3-, 4-, 5-, 6- or 7-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.11; and
R.sup.5b is selected from hydrogen and deuterium.
11. The compound as claimed in claim 10, where R.sup.5a is selected
from hydrogen, C.sub.1-C.sub.6-alkyl and fluorinated
C.sub.1-C.sub.6-alkyl; and in case that X is CR.sup.7R.sup.8 is
further selected from halogen; and is in particular hydrogen; or
R.sup.5a and R.sup.6 form together a group (CH.sub.2).sub.r, where
r is 2, 3, 4 or 5; or R.sup.5a and R.sup.7 form together a group
(CH.sub.2).sub.s, where s is 2, 3, 4 or 5; and R.sup.5b is selected
from hydrogen and deuterium.
12. The compound as claimed in claim 10, where R.sup.5a is selected
from hydrogen, C.sub.1-C.sub.6-alkyl and fluorinated
C.sub.1-C.sub.6-alkyl; and in case that X is CR.sup.7R.sup.8 is
further selected from halogen; and is in particular hydrogen; or
R.sup.5a and R.sup.6 form together a group (CH.sub.2).sub.r, where
r is 2, 3, 4 or 5, where two hydrogen atoms bound to adjacent
CH.sub.2 groups may be replaced by two radicals R.sup.11, where the
two radicals R.sup.11 form together a group (CH.sub.2).sub.t, where
t is 1, 2, 3, 4 or 5; or R.sup.5a and R.sup.7 form together a group
(CH.sub.2).sub.s, where s is 2, 3, 4 or 5; and R.sup.5b is selected
from hydrogen and deuterium.
13. The compound as claimed in any of claims 1 to 9, where 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.11;
and form preferably a 5- or 6-membered saturated or partially
unsaturated carbocyclic ring, and where the ring may be substituted
with one or more substituents R.sup.11.
14. The compound as claimed in any of the preceding claims, where X
is NR.sup.6, where R.sup.6 is as defined in claim 1.
15. The compound as claimed in claim 14, where X is NR.sup.6, where
R.sup.6 is --SO.sub.2R.sup.10, where R.sup.10 is as defined in
claim 1.
16. The compound as claimed in claim 15, where R.sup.10 is selected
from C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl and
phenyl, where phenyl may be substituted with 1, 2, 3, 4 or 5
radicals R.sup.11.
17. The compound as claimed in claim 14, where X is NR.sup.6, where
R.sup.6 is selected from hydrogen, C.sub.1-C.sub.6-alkyl,
fluorinated C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl,
fluorinated C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy,
--C(.dbd.O)R.sup.10, where R.sup.10 is selected from
C.sub.1-C.sub.6-alkyl and C.sub.3-C.sub.6-cycloalkyl; phenyl,
phenyl-C.sub.1-C.sub.2-alkyl and a 3-, 4-, 5- or 6-membered
saturated 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.11.
18. The compound as claimed in claim 17, where R.sup.6 is selected
from hydrogen, C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl,
C.sub.3-C.sub.6-cycloalkylcarbonyl, C.sub.1-C.sub.4-alkoxy,
fluorinated C.sub.1-C.sub.4-alkoxy, phenyl-C.sub.1-C.sub.2-alkyl
and 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; and is
in particular selected from C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl, and 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.
19. The compound as claimed in claim 18, where R.sup.6 is selected
from C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl and
oxetanyl.
20. The compound as claimed in claim 14, where X is NR.sup.6, where
R.sup.5a and R.sup.6, together with the atoms they are bound to,
form a 3-, 4-, 5-, 6- or 7-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 R.sup.11.
21. The compound as claimed in claim 20, where R.sup.5a and R.sup.6
form together a group (CH.sub.2).sub.r, where r is 2, 3, 4 or 5 and
in particular 3, 4 or 5.
22. The compound as claimed in claim 20, where R.sup.5a and R.sup.6
form together a group (CH.sub.2).sub.r, where r is 2, 3, 4 or 5 and
in particular 3, 4 or 5, where two hydrogen atoms bound to adjacent
CH.sub.2 groups may be replaced by two radicals R.sup.11, where the
two radicals R.sup.11 form together a group (CH.sub.2).sub.t, where
t is 1, 2, 3, 4 or 5 and in particular 1, 2 or 3.
23. The compound as claimed in any of claims 1 to 13, where X is
CR.sup.7R.sup.8, where R.sup.7 and R.sup.8 are as defined in claim
1.
24. The compound as claimed in claim 23, where R.sup.7 and R.sup.8,
independently of each other, are selected from the group consisting
of halogen, 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, fluorinated C.sub.1-C.sub.6-alkoxy,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12R.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; or R.sup.7 and
R.sup.8, 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.11;
or R.sup.5a and R.sup.7, together with the carbon atoms 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.11; in which case R.sup.8 has one of the
above meanings or is deuterium.
25. The compound as claimed in claim 22, where R.sup.7 and R.sup.8,
independently of each other, are selected from halogen, cyano,
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, benzyloxy and a 3-, 4-, 5- or
6-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 four last-mentioned radicals may be substituted with one or
more substituents R.sup.11; or R.sup.7 and R.sup.8, together with
the carbon atom they are bound to, form a 3-, 4-, 5-, 6- or 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.11; or
R.sup.5a and R.sup.7, together with the carbon atoms they are bound
to, form a 3-, 4-, 5-, 6- or 7-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.11; in which case R.sup.8 has one of the above
meanings or is deuterium; and R.sup.5b is selected from hydrogen
and deuterium.
26. The compound as claimed in claim 23, where R.sup.7 and R.sup.8,
independently of each other, are selected from halogen, cyano,
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl and
phenyl, or R.sup.7 and R.sup.8, together with the carbon atom they
are bound to, form a 3-, 4-, 5-, 6- or 7- or 8-membered saturated,
partially unsaturated or maximally unsaturated ring, where the ring
may be substituted with one or more substituents R.sup.11; or
R.sup.5a and R.sup.7 form together a group (CH.sub.2).sub.s, where
s is 2, 3, 4 or 5; in which case R.sup.8 has one of the above
meanings or is deuterium; and R.sup.5b is selected from hydrogen
and deuterium.
27. The compound as claimed in claim 24, where R.sup.8 is selected
from halogen, cyano, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl and phenyl; and R.sup.7 is selected from
C.sub.1-C.sub.6-alkyl and fluorinated C.sub.1-C.sub.6-alkyl,
preferably from methyl and CF.sub.3 and is in particular methyl; or
R.sup.7 and R.sup.8, together with the carbon atom they are bound
to, form a 3-, 4-, 5-, 6- or 7- or 8-membered saturated, partially
unsaturated or maximally unsaturated ring, where the ring may be
substituted with one or more substituents R.sup.11; or R.sup.5a and
R.sup.7 form together a group (CH.sub.2).sub.s, where s is 2, 3 or
4; in which case R.sup.8 has one of the above meanings or is
deuterium; and R.sup.5b is selected from hydrogen and
deuterium.
28. The compound as claimed in claim 22, where R.sup.7 is
C.sub.1-C.sub.6-alkyl and is in particular methyl; R.sup.8 is
selected from hydroxyl, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, 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 phenyl and in particular from
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy and
phenyl; or R.sup.7 and R.sup.8, together with the carbon atom they
are bound to, form a 3-, 4-, 5-, 6- or 7-membered saturated or
partially unsaturated ring, where the ring may be substituted with
one or more substituents R.sup.11; or R.sup.5a and R.sup.7 form
together a group (CH.sub.2).sub.s, where s is 2, 3 or 4 and where
R.sup.8 is methyl; and R.sup.5b is hydrogen.
29. The compound as claimed in any of claims 20 to 26, wherein the
ring formed by R.sup.7 and R.sup.8 together with the carbon atom
they are bound is a carbocyclic ring, in particular a saturated
carbocyclic ring.
30. The compound as claimed in claim 27, where R.sup.7 and R.sup.8,
together with the carbon atom they are bound to, form a 3, 4-, 5-
or 6-membered saturated or partially unsaturated carbocyclic ring,
preferably a 3, 4- or 5-membered saturated carbocyclic ring, in
particular a 4-membered saturated carbocyclic ring, where the ring
may be substituted with one or more substituents R.sup.11.
31. The compound as claimed in any of claims 20 to 26, wherein the
ring formed by R.sup.7 and R.sup.8 together with the carbon atom
they are bound is a heterocyclic ring containing 1, 2, 3 or 4
heteroatoms or heteroatom-containing groups selected from O, S, N,
SO and SO.sub.2 as ring members preferably containing 1 or 2
heteroatoms selected from O, S and N as ring members.
32. The compound as claimed in claim 29, wherein the heterocyclic
ring is a saturated 3-, 4- or 5-membered heterocyclic ring
containing one heteroatom selected from O, S and N as ring member,
where the ring may be substituted with one or more substituents
R.sup.11, and is in particular oxetanyl which may be substituted
with one or more substituents R.sup.11.
33. The compound as claimed in any of the preceding claims, where
each R.sup.9 is independently selected from halogen, cyano, nitro,
hydroxy, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
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 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.11, in particular from halogen, C.sub.1-C.sub.6-alkyl,
fluorinated C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and
C.sub.1-C.sub.6-alkoxy, and is especially halogen.
34. The compound as claimed in any of the preceding claims, where
each R.sup.11 is independently selected from halogen, cyano, nitro,
hydroxy, 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, and
is in particular halogen or C.sub.1-C.sub.4-alkyl.
35. The compound as claimed in any of the preceding claims, where a
is 0 or 1, in particular 0.
36. The compound as claimed in claim 33, where a is 1 and R.sup.2
is bound in 3-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, where n
is 1.
39. The compound as claimed in any of the preceding claims, of
formula I.1 ##STR00026## wherein X, R.sup.5a, R.sup.5b, R.sup.9 and
b are as defined in any of claims 1 and 10 to 34.
40. The compound as claimed in claim 37, of formula I.1.1
##STR00027## wherein R.sup.9a is selected from H, halogen,
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.6-cycloalkyl and fluorinated
C.sub.3-C.sub.6-cycloalkyl; and R.sup.5a, R.sup.5b, R.sup.6,
R.sup.9 and b are as defined in any of claims 1 and 10 to 35.
41. The compound as claimed in claim 37, of formula I.1.2
##STR00028## wherein R.sup.7 is selected from C.sub.1-C.sub.4-alkyl
and fluorinated C.sub.1-C.sub.4-alkyl, in particular from methyl
and CF.sub.3, and is especially methyl; R.sup.8 is selected from
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy and
phenyl; and in particular from methyl and CF.sub.3; or R.sup.7 and
R.sup.8, together with the carbon atom they are bound to, form a
3-, 4-, 5-, 6- or 7-membered, in particular a 3- or 4-membered
saturated or partially unsaturated ring, where the ring may be
substituted with one or more substituents R.sup.11; R.sup.9a is H,
Cl, F or methyl; and R.sup.9 and b are as defined in any of claims
1, 31, 32, 34 and 35.
42. The compound as claimed in claim 37, of formula I.1.3
##STR00029## wherein R.sup.8 is selected from deuterium, F, Cl, CN
and CH.sub.3.
43. The compound as claimed in any of claims 1 to 36, of formula
I.2 ##STR00030## wherein X, R.sup.5a, R.sup.5b, R.sup.9 and b are
as defined in any of claims 1 and 10 to 35.
44. The compound as claimed in claim 41 of formula I.2.1
##STR00031## wherein R.sup.2a, R.sup.2b and R.sup.3a, independently
of each other, are selected from hydrogen and methyl; and where in
particular at most one of R.sup.2a, R.sup.2b and R.sup.3a is
methyl; R.sup.9a is selected from H, halogen,
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.6-cycloalkyl and fluorinated
C.sub.3-C.sub.6-cycloalkyl; and R.sup.5a, R.sup.5b, R.sup.6,
R.sup.9 and b are as defined in any of claims 1 and 10 to 19, 30,
31 and 32.
45. The compound as claimed in claim 42, where R.sup.2b is methyl
and R.sup.2a and R.sup.3a are hydrogen.
46. The compound as claimed in claim 41, of formula I.2.2
##STR00032## wherein R.sup.2a, R.sup.2b, R.sup.3a and R.sup.5a,
independently of each other, are selected from hydrogen, methyl and
ethyl, in particular from hydrogen and methyl; R.sup.7 is selected
from C.sub.1-C.sub.4-alkyl and fluorinated C.sub.1-C.sub.4-alkyl,
in particular from methyl and CF.sub.3, and is especially methyl;
R.sup.8 is selected from C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, fluorinated
C.sub.1-C.sub.4-alkoxy and phenyl; and in particular from methyl
and CF.sub.3; or R.sup.7 and R.sup.8, together with the carbon atom
they are bound to, form a 3-, 4-, 5-, 6- or 7-membered, in
particular a 3- or 4-membered saturated or partially unsaturated
ring, where the ring may be substituted with one or more
substituents R.sup.11; R.sup.9a is H, Cl, F or methyl; and R.sup.9
and b are as defined in any of claims 1, 31, 32 and 34.
47. The compound as claimed in claim 44, wherein R.sup.2a,
R.sup.2b, R.sup.3a and R.sup.5a are selected from hydrogen and
methyl, with the proviso that at most 2, preferably at most 1, of
R.sup.2a, R.sup.2b, R.sup.3a and R.sup.5a are methyl.
48. The compound as claimed in claim 45, where R.sup.2b is methyl
and R.sup.2a, R.sup.3a and R.sup.5a are hydrogen.
49. The compound as claimed in any of claims 44 to 46, where
R.sup.7 and R.sup.8, together with the carbon atom they are bound
to, form a 3, 4-, 5- or 6-membered saturated or partially
unsaturated carbocyclic ring, preferably a 3, 4- or 5-membered
saturated carbocyclic ring, in particular a 4-membered saturated
carbocyclic ring, where the ring may be substituted with one or
more substituents R.sup.11.
50. A compound of formula I as claimed in any of the preceding
claims, selected from
8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolone;
1,2,3,4-tetrahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-cyclopent[-
2]en]-6(7H)-one;
8-methyl-8-phenyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin--
6(2H)-one;
8,8-dimethyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quin-
olin-6(2H)-one;
1,2,3,4-tetrahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-cyclopenta-
n]-6(7H)-one;
1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-cyclope-
ntane];
12a-methyl-4,5,6,7,10,11,12,12a-octahydrocyclopenta[c][1,4]diazepi-
no[6,7,1-ij]quinolin-9(9aH)-one;
8-methyl-8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,-
1-ij]quinolone;
12a-methyl-4,5,6,7,10,11,12,12a-octahydrocyclopenta[c][1,4]diazepino[6,7,-
1-ij]quinolin-9(9aH)-one; 12a-methyl-4,5,6,7,9,9a,
10,11,12,12a-decahydrocyclopenta[c][1,4]diazepino-[6,7,1-ij]quinoline;
8-methyl-8-(trifluoromethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-i-
j]quinolin-6(2H)-one; 12a-methyl-4,5,6,7,9,9a,
10,11,12,12a-decahydrocyclopenta[c][1,4]diazepino-[6,7,1-ij]quinoline;
8-methyl-8-phenyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinol-
ine;
(R)-5,6,7,9,9a,10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[-
1,2-a]quinoxaline; (S)-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline;
9-chloro-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]qu-
inoline;
10-chloro-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,-
7,1-ij]quinoline;
9-chloro-8,8-dimethyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quino-
lin-6(2H)-one;
10-chloro-8,8-dimethyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quin-
olin-6(2H)-one;
9-fluoro-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]qu-
inoline;
10-fluoro-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,-
7,1-ij]quinoline;
1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-cyclohe-
xane];
1',2',3',4',6',7'-hexahydrospiro[cyclobutane-1,8'-]1,4]diazepino[6,-
7,1-ij]quinoline;
9'-fluoro-1',2',3',4',6',7'-hexahydrospiro[cyclobutane-1,8'-[1,4]diazepin-
o[6,7,1-ij]quinoline];
7,8,8-trimethyl-1,2,3,4,7,8-hexahydro-6H-[1,4]diazepino[6,7,1-ij]quinolin-
e];
9-fluoro-1-methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]q-
uinoline-8,1'-cyclobutane];
3-methyl-1',2',3',4',6',7'-hexahydrospiro[cyclobutane-1,8'-[1,4]diazepino-
[6,7,1-ij]quinoline];
3-benzyl-2',3',7',8',9',10'-hexahydro-1H-3',8',10a'-triaza-cyclohepta[de]-
naphthalene;
2,3,5,6,7,8-Hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline;
1-Cyclobutyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline-
;
1-Methyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline;
1-(Oxetan-3-yl)-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxal-
ine;
1-(Cyclopropylmethyl)-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-d-
e]quinoxaline;
1-(Cyclopentylmethyl)-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]qu-
inoxaline;
Cyclopropyl(2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]qu-
inoxalin-1-yl)methanone;
Cyclopentyl(2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxalin-1-
-yl)methanone;
1-Cyclopropyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxalin-
e;
1-Cyclopentyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxal-
ine;
1-Cyclopropyl-5-methyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6--
de]quinoxaline;
6,6-Dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;
5,6,7,9,9a,
10,11,12,13,14-decahydro-4H-azepino[1,2-a][1,4]diazepino[1,7,6-de]quinoxa-
line; 7-Methyl-5,6,7,9,9.sup.a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline;
1-Fluoro-7-methyl-5,6,7,9,9.sup.a,10,11,12-octahydro-4H-[1,4]diazepino[1,-
7,6-de]pyrrolo[1,2-a]quinoxaline;
1,2,3,4,6,7-Hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-cyclopr-
opane];
4-Methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinol-
ine-8,1'-cyclopropane];
11-Fluoro-8,8-Dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]q-
uinoline;
10-Methoxy-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[-
6,7,1-ij]quinoline;
4,8,8-Trimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-
e;
4-Ethyl-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]q-
uinoline;
6,8,8-Trimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij-
]quinoline;
8-ethyl-8-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoli-
ne;
(R)-8-ethyl-8-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]-
quinoline;
(S)-8-ethyl-8-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,-
7,1-ij]quinoline;
4-Methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1-
'-cyclobutane]; 1-Fluoro-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline;
1-Bromo-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline;
1-Methyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline;
1-Cyclopropyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline;
1-Cyclobutyl-5,6,7,9,9a,10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyr-
rolo[1,2-a]quinoxaline; 1-Cyclopentyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline;
8-Methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-8-ol;
8-Methoxy-8-methyl-2,3,4,67,8-hexahydro-6H-[1,4]diazepino[6,7,1-ij]quinol-
ine;
2,8-Dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoli-
n-8-ol;
11-Methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quino-
line-8,1'-cyclobutane];
9-Methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1-
'-cyclobutane]; 4,5,6,7,9,9a,9b,10,10a,
11-Decahydrocyclopropa[3,4]pyrrolo[1,2-a][1,4]diazepino[1,7,6-de]quinoxal-
ine;
1-Ethyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline;
1-Propyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline;
1-Cyclobutyl-5-methyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]qu-
inoxaline;
5-Methyl-1-(oxetan-3-yl)-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepin-
o[1,7,6-de]quinoxaline;
1-Ethyl-5-methyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxa-
line;
5-Methyl-1-propyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]q-
uinoxaline;
9-Chloro-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1-
'-cyclobutane];
10-Methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,-
1'-cyclobutane];
10-Chloro-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,-
1'-cyclobutane]; and the stereoisomers and pharmaceutically
acceptable salts thereof.
51. A pharmaceutical composition comprising a therapeutically
effective amount of at least one compound as claimed in any of the
preceding claims or an N-oxide, a tautomeric form, a stereoisomer
or a pharmaceutically acceptable salt thereof, or comprising at
least one compound as defined in any of the preceding claims
wherein at least one of the atoms has been replaced by its stable,
non-radioactive isotope, preferably wherein at least one hydrogen
atom has been replaced by a deuterium atom, in combination with at
least one pharmaceutically acceptable carrier and/or auxiliary
substance.
52. The compound as claimed in any of claims 1 to 50 or an N-oxide,
a tautomeric form, a stereoisomer or a pharmaceutically acceptable
salt thereof for use as a medicament.
53. The compound as claimed in any of claims 1 to 50 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.
54. The use of a compound as claimed in any of claims 1 to 50 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.
55. 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 50 or an N-oxide, a tautomeric form, a
stereoisomer or a pharmaceutically acceptable salt thereof.
56. The compound as claimed in claim 53 or the use as claimed in
claim 54 or the method as claimed in claim 55, 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.
57. The compound or the use or the method as claimed in claim 56,
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,
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, 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.
58. The compound or the use or the method as claimed in claim 57,
where the disorders are selected from schizophrenia, depression,
bipolar disorders, obesity and substance use disorders.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a non-provisional of U.S. Patent Application No.
61/701,514, filed on Sep. 14, 2012, U.S. Patent Application No.
61/701,531, filed on Sep. 14, 2012, U.S. Patent Application No.
61/793,033, filed on Mar. 15, 2013, and claims priority to Chinese
Patent Application No. CN 201310410951.1, filed on Sep. 11, 2013,
the contents of all of which are fully incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to tricyclic quinoline and
quinoxaline derivatives, 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, 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] There is an ongoing need for providing compounds having high
affinity and 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
al-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.
[0013] 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
[0014] The invention is directed to tricyclic quinoline and
quinoxaline derivatives, 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.
[0015] In one aspect, the present invention relates to compounds of
the formula (I):
##STR00001## [0016] wherein [0017] G is (CR.sup.3aR.sup.3b).sub.n;
[0018] X is NR.sup.6 or CR.sup.7R.sup.8; [0019] 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.10, 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.11; [0020] 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, fluorinated
C.sub.1-C.sub.6-alkoxy,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, [0021] NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; [0022] 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, fluorinated C.sub.1-C.sub.6-alkoxy,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, [0023] --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; [0024] 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, fluorinated C.sub.1-C.sub.6-alkoxy,
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, [0025]
NR.sup.12aR.sup.12b, --CH.sub.2NR.sup.12aR.sup.12b,
--NR.sup.12aC(O)R.sup.10, --C(.dbd.O)R.sup.10,
SO.sub.2NR.sup.12aR.sup.12b, 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.11; or [0026]
R.sup.4a and R.sup.4b form together a group .dbd.O or .dbd.S;
[0027] R.sup.5a and R.sup.5b, independently of each other, are
selected from the group consisting of hydrogen, deuterium, halogen,
cyano, nitro, hydroxy, 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,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; where R.sup.5a
and R.sup.5b are not simultaneously hydroxy; or [0028] 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 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.11; or [0029] R.sup.5a and R.sup.6,
together with the atoms they are bound to, 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
R.sup.11; or [0030] R.sup.5a and R.sup.7, together with the carbon
atoms 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.11; [0031] R.sup.6
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.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy,
--C(.dbd.O)R.sup.10, --SO.sub.2R.sup.10, 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.11;
[0032] R.sup.7 and R.sup.8, independently of each other, are
selected from the group consisting of deuterium, 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,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; where R.sup.7
and R.sup.8 are not simultaneously hydroxyl; and where R.sup.7 is
not hydroxyl if R.sup.8 is C.sub.1-C.sub.6-alkoxy, fluorinated
C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-hydroxyalkoxy,
C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, phenoxy or
benzyloxy; or [0033] R.sup.7 and R.sup.8, 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 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.11;
[0034] each R.sup.9 is independently selected from the group
consisting of halogen, cyano, nitro, hydroxy,
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,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b. --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; or [0035] two
radicals R.sup.9 bound on neighbouring 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.11; [0036] each
R.sup.10 is independently selected from the group consisting of
hydrogen, cyano, hydroxy, 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.12aR.sup.12b, --CH.sub.2NR.sup.12aR.sup.12b, 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.11; [0037] each R.sup.11 is independently
selected from the group consisting of halogen, cyano, nitro,
hydroxy, 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,
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.12aR.sup.12b, --CH.sub.2NR.sup.12aR.sup.12b,
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.12aR.sup.12b, C.sub.1-C.sub.6-alkylcarbonyloxy and
fluorinated C.sub.1-C.sub.6-alkylcarbonyloxy; [0038] or two
radicals R.sup.11, 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; [0039] R.sup.12a and
R.sup.12b, 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,
[0040] if R.sup.12a and R.sup.12b 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; [0041] a is 0, 1 or 2; [0042] b
is 0, 1, 2 or 3; and [0043] n is 1 or 2; and the N-oxides,
tautomeric forms, stereoisomers and pharmaceutically acceptable
salts thereof, and the compound of the general formula I, wherein
at least one of the atoms has been replaced by its stable,
non-radioactive isotope.
[0044] In another aspect, the invention relates to compounds of
formula I as defined above, [0045] wherein [0046] G is
(CR.sup.3aR.sup.3b).sub.n; [0047] X is NR.sup.6 or CR.sup.7R.sup.8;
[0048] 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.10, 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.11; [0049] 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, fluorinated
C.sub.1-C.sub.6-alkoxy,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, [0050] NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; [0051] 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, fluorinated C.sub.1-C.sub.6-alkoxy,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, [0052] NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; [0053] 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, fluorinated C.sub.1-C.sub.6-alkoxy,
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, [0054]
--NR.sup.12aR.sup.12b, --CH.sub.2NR.sup.12aR.sup.12b,
--NR.sup.12aC(O)R.sup.10, --C(.dbd.O)R.sup.10,
SO.sub.2NR.sup.12aR.sup.12b, 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.11; or R.sup.4a and
R.sup.4b form together a group .dbd.O or .dbd.S; [0055] R.sup.5a
and R.sup.5b, independently of each other, are selected from the
group consisting of hydrogen, deuterium, halogen, cyano, nitro,
hydroxy, 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,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; or [0056]
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.11; or [0057] R.sup.5a and R.sup.6, together
with the atoms they are bound to, 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
R.sup.11; or [0058] R.sup.5a and R.sup.7, together with the carbon
atoms 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.11; [0059] R.sup.6
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.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy,
--C(.dbd.O)R.sup.10, --SO.sub.2R.sup.10, 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.11;
[0060] R.sup.7 and R.sup.8, independently of each other, are
selected from the group consisting of deuterium, halogen, 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, fluorinated
C.sub.1-C.sub.6-alkoxy,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; or [0061]
R.sup.7 and R.sup.8, 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.11; [0062] each R.sup.9 is independently
selected from the group consisting of halogen, cyano, nitro,
hydroxy, 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,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; or [0063] two
radicals R.sup.9 bound on neighbouring 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.11; [0064] each
R.sup.10 is independently selected from the group consisting of
hydrogen, cyano, hydroxy, 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.12aR.sup.12b, --CH.sub.2NR.sup.12aR.sup.12b, 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.11; [0065] each R.sup.11 is independently
selected from the group consisting of halogen, cyano, nitro,
hydroxy, 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,
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.12aR.sup.12b, --CH.sub.2NR.sup.12aR.sup.12b,
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.12aR.sup.12b,
C.sub.1-C.sub.6-alkylcarbonyloxy and fluorinated
C.sub.1-C.sub.6-alkylcarbonyloxy; [0066] R.sup.12a and R.sup.12b,
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,
[0067] if R.sup.12a and R.sup.12b 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; [0068] a is 0, 1 or 2; [0069] b
is 0, 1, 2 or 3; and [0070] n is 1 or 2; [0071] and the N-oxides,
tautomeric forms, stereoisomers and pharmaceutically acceptable
salts thereof, and the compound of the general formula I, wherein
at least one of the atoms has been replaced by its stable,
non-radioactive isotope.
[0072] Preferably, R.sup.5a and R.sup.5b are not simultaneously
hydroxyl.
[0073] In another aspect, the invention relates to compounds of
formula I
##STR00002## [0074] wherein [0075] G is (CR.sup.3aR.sup.3b).sub.n;
[0076] X is NR.sup.6 or CR.sup.7R.sup.8; [0077] 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.10, 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.11; [0078] 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, fluorinated
C.sub.1-C.sub.6-alkoxy,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, [0079] NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; [0080] 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, fluorinated C.sub.1-C.sub.6-alkoxy,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, [0081] NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; [0082] 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, fluorinated C.sub.1-C.sub.6-alkoxy,
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, [0083]
--NR.sup.12aR.sup.12b, --CH.sub.2NR.sup.12aR.sup.12b,
--NR.sup.12aC(O)R.sup.10, --C(.dbd.O)R.sup.10,
SO.sub.2NR.sup.12aR.sup.12b, 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.11; or [0084]
R.sup.4a and R.sup.4b form together a group .dbd.O or .dbd.S;
R.sup.5a and R.sup.5b, independently of each other, are selected
from the group consisting of hydrogen, deuterium, halogen, cyano,
nitro, hydroxy, 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,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; or [0085]
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.11; or [0086] R.sup.5a and R.sup.6, together
with the atoms they are bound to, 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
R.sup.11; or [0087] R.sup.5a and R.sup.7, together with the carbon
atoms 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.11; [0088] R.sup.6
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.10, --SO.sub.2R.sup.10, 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.11;
[0089] R.sup.7 and R.sup.8, independently of each other, are
selected from the group consisting of deuterium, halogen, 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, fluorinated
C.sub.1-C.sub.6-alkoxy,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; or [0090]
R.sup.7 and R.sup.8, 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.11; [0091] each R.sup.9 is independently
selected from the group consisting of halogen, cyano, nitro,
hydroxy, 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,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; or [0092] two
radicals R.sup.9 bound on neighbouring 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.11; [0093] each
R.sup.10 is independently selected from the group consisting of
hydrogen, cyano, hydroxy, 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.12aR.sup.12b, --CH.sub.2NR.sup.12aR.sup.12b, 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.11; [0094] each R.sup.11 is independently
selected from the group consisting of halogen, cyano, nitro,
hydroxy, 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.sup.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,
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.12aR.sup.12b, --CH.sub.2NR.sup.12aR.sup.12b,
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.12aR.sup.12b, C.sub.1-C.sub.6-alkylcarbonyloxy and
fluorinated C.sub.1-C.sub.6-alkylcarbonyloxy; [0095] R.sup.12a and
R.sup.12b, 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,
[0096] if R.sup.12a and R.sup.12b 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; [0097] a is 0, 1 or 2; [0098] b
is 0, 1, 2 or 3; and [0099] n is 1 or 2; [0100] and the N-oxides,
tautomeric forms, stereoisomers and pharmaceutically acceptable
salts thereof, and the compound of the general formula I, wherein
at least one of the atoms has been replaced by its stable,
non-radioactive isotope.
[0101] Preferably, R.sup.5a and R.sup.5b are not simultaneously
hydroxyl.
[0102] 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, or
comprising at least one compound as defined above or below wherein
at least one of the atoms has been replaced by its stable,
non-radioactive isotope, preferably wherein at least one hydrogen
atom has been replaced by a deuterium atom, in combination with at
least one pharmaceutically acceptable carrier and/or auxiliary
substance.
[0103] 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.
[0104] 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.
[0105] 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.
[0106] 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,
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, 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.
[0107] 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.
[0108] 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, 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, 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
[0109] 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.
[0110] 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., Birkhauser Verlag, Basel and Stuttgart, 1966.
[0111] 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:
##STR00003##
[0112] 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.
[0113] 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.
[0114] The term "halogen" denotes in each case fluorine, bromine,
chlorine or iodine. In one aspect, the halogen may be fluorine,
chlorine or bromine.
[0115] 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.
[0116] 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.
[0117] 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.
[0118] 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.
[0119] 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.
[0120] 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.
[0121] The term "cycloalkyl" as used herein refers to mono- or
bicyclic 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"). In one aspect,
C.sub.3-C.sub.4-cycloalkyl, C.sub.3-C.sub.5-cycloalkyl and
C.sub.3-C.sub.6-cycloalkyl are monocyclic. Examples for
C.sub.3-C.sub.4-cycloalkyl are cyclopropyl and cyclobutyl. Examples
of monocyclic radicals having 3 to 5 carbon atoms are cyclopropyl,
cyclobutyl and cyclopentyl. Examples of monocyclic radicals having
3 to 6 carbon atoms are cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl. Examples of monocyclic radicals having 3 to 8 carbon
atoms are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl and cyclooctyl. Examples of bicyclic radicals having 7
or 8 carbon atoms comprise bicyclo[2.2.1]heptyl,
bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and bicyclo[3.2.1]octyl.
In one aspect, the term cycloalkyl denotes a monocyclic saturated
hydrocarbon radical.
[0122] The term "fluorinated cycloalkyl" as used herein refers to
mono- or bicyclic 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.8-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.
[0123] 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.
[0124] 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.
[0125] 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.
[0126] 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.
[0127] 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.
[0128] 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.
[0129] 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.
[0130] 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 hydroxy 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 hydroxy 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, include, 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.
[0131] 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.
[0132] 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.4-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.
[0133] 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.
[0134] 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.
[0135] 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.
[0136] 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.
[0137] 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.
[0138] 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.
[0139] 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.
[0140] 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.
[0141] 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.
[0142] 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.
[0143] 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.
[0144] 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.
[0145] 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.
[0146] 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).
[0147] 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.
[0148] 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 O ring atom, these are not
adjacent.
[0149] 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.
[0150] 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.
[0151] 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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,
a, b and n 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.
[0157] In a preferred embodiment, R.sup.1 is selected from
hydrogen, cyano, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, --C(.dbd.O)R.sup.10, phenyl and benzyl,
where the phenyl moiety in the two last-mentioned radicals may
carry 1, 2 or 3 radicals R.sup.11, where R.sup.10 and R.sup.11 have
one of the general meanings given above, or, in particular, one of
the preferred meanings given below.
[0158] In the above group --C(.dbd.O)R.sup.10 as a meaning for
R.sup.1, R.sup.10 is preferably selected from C.sub.1-C.sub.4-alkyl
and C.sub.1-C.sub.4-alkoxy and more preferably from
C.sub.1-C.sub.2-alkyl and tert-butoxy.
[0159] More preferably, 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.
[0160] 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 and fluorinated C.sub.1-C.sub.6-alkoxy, more
preferably from C.sub.1-C.sub.6-alkyl, in particular from methyl,
ethyl, propyl and isopropyl, more particularly from methyl and
ethyl, and is specifically methyl.
[0161] 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, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy and fluorinated C.sub.1-C.sub.6-alkoxy. More
preferably, R.sup.3a is selected from hydrogen, 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, 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.
[0162] 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 and fluorinated C.sub.1-C.sub.6-alkyl or form
together a group .dbd.O. More preferably, they are hydrogen or form
together a group .dbd.O. In another embodiment, one of R.sup.4a and
R.sup.4b is hydrogen and the other is methyl; especially if X is
CR.sup.7R.sup.8. In particular, both R.sup.4a and R.sup.4b are
hydrogen.
[0163] In a preferred embodiment, [0164] R.sup.5a is selected from
hydrogen, cyano, nitro, hydroxy, 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; and in case that X is CR.sup.7R.sup.8 is
further selected from halogen; or [0165] R.sup.5a and R.sup.6,
together with the atoms they are bound to, form a 3-, 4-, 5-, 6- or
7-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
R.sup.11; or [0166] R.sup.5a and R.sup.7, together with the carbon
atoms they are bound to, form a 3-, 4-, 5-, 6- or 7-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.11; and [0167]
R.sup.5b is selected from hydrogen and deuterium and is preferably
hydrogen; [0168] where R.sup.11 has one of the general meanings
given above, or, in particular, one of the preferred meanings given
below.
[0169] More preferably, [0170] R.sup.5a is selected from hydrogen,
C.sub.1-C.sub.6-alkyl and fluorinated C.sub.1-C.sub.6-alkyl; and in
case that X is CR.sup.7R.sup.8 is further selected from halogen;
and is preferably selected from hydrogen and methyl, or [0171]
R.sup.5a and R.sup.6 form together a group (CH.sub.2).sub.r, where
r is 2, 3, 4 or 5, preferably 2, 3 or 4; or [0172] R.sup.5a and
R.sup.7 form together a group (CH.sub.2).sub.s, where s is 2, 3, 4
or 5, preferably 2, 3 or 4; and [0173] R.sup.5b is selected from
hydrogen and deuterium and is preferably hydrogen.
[0174] In an alternative more preferred embodiment, [0175] R.sup.5a
is selected from hydrogen, C.sub.1-C.sub.6-alkyl and fluorinated
C.sub.1-C.sub.6-alkyl; and in case that [0176] X is CR.sup.7R.sup.8
is further selected from halogen; and is preferably selected from
hydrogen and methyl, or [0177] R.sup.5a and R.sup.6 form together a
group (CH.sub.2).sub.r, where r is 2, 3, 4 or 5, where two hydrogen
atoms bound to adjacent CH.sub.2 groups may be replaced by two
radicals R.sup.11, where the two radicals R.sup.11 form together a
group (CH.sub.2).sub.t, where t is 1, 2, 3, 4 or 5, preferably 1, 2
or 3; or [0178] R.sup.5a and R.sup.7 form together a group
(CH.sub.2).sub.s, where s is 2, 3, 4 or 5, preferably 2, 3 or 4;
and [0179] R.sup.5b is selected from hydrogen and deuterium and is
preferably hydrogen.
[0180] In particular, [0181] R.sup.5a is hydrogen; and in case that
X is CR.sup.7R.sup.8, is selected from hydrogen and methyl and is
in particular hydrogen; or [0182] R.sup.5a and R.sup.6 form
together a group (CH.sub.2).sub.r, where r is 3, 4 or 5, where two
hydrogen atoms bound to adjacent CH.sub.2 groups may be replaced by
two radicals R.sup.11, where the two radicals R.sup.11 form
together a group (CH.sub.2).sub.t, where t is 1, 2, 3, 4 or 5,
preferably 1, 2 or 3 and specifically 1; or [0183] R.sup.5a and
R.sup.7 form together a group (CH.sub.2).sub.s, where s is 2, 3 or
4, in particular 3; and [0184] R.sup.5b is hydrogen.
[0185] In an alternatively preferred embodiment, 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.11;
and form in particular a 5- or 6-membered saturated or partially
unsaturated carbocyclic ring, and where the ring may be substituted
with one or more substituents R.sup.11.
[0186] In one embodiment, X is NR.sup.6, where R.sup.6 has one of
the general meanings given above, or, in particular, one of the
preferred meanings given below.
[0187] Preferably, [0188] R.sup.6 is selected from the group
consisting of hydrogen, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, --C(.dbd.O)R.sup.10, --SO.sub.2R.sup.10,
phenyl and benzyl, where the phenyl moiety in the two
last-mentioned radicals may carry 1, 2 or 3 radicals R.sup.11; or
[0189] R.sup.5a and R.sup.6, together with the atoms they are bound
to, form a 3-, 4-, 5-, 6- or 7-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 R.sup.11; [0190] where
R.sup.10 and R.sup.11 have one of the general meanings given above,
or, in particular, one of the preferred meanings given below.
[0191] In the above group --C(.dbd.O)R.sup.10, R.sup.6, R.sup.10 is
preferably selected from C.sub.1-C.sub.4-alkyl and
C.sub.1-C.sub.4-alkoxy and more preferably from
C.sub.1-C.sub.2-alkyl and tert-butoxy.
[0192] In the above group --SO.sub.2R.sup.10, R.sup.6, R.sup.10 is
preferably selected from C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl and phenyl, where phenyl may be substituted
with 1, 2, 3, 4 or 5, preferably 1, 2 or 3, in particular 1,
radicals R.sup.11, where R.sup.11 has one of the general meanings
given above, or, in particular, one of the preferred meanings given
below.
[0193] In one more preferred embodiment, R.sup.6 is
--SO.sub.2R.sup.10, where R.sup.10 has one of the general meanings
given above or is preferably selected from C.sub.1-C.sub.6-alkyl,
fluorinated C.sub.1-C.sub.6-alkyl and phenyl, where phenyl may be
substituted with 1, 2, 3, 4 or 5, preferably 1, 2 or 3, in
particular 1, radicals R.sup.11, where R.sup.11 has one of the
general meanings given above, or, in particular, one of the
preferred meanings given below.
[0194] In another preferred embodiment, R.sup.6 is selected from
hydrogen, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-cycloalkyl, fluorinated C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy,
--C(.dbd.O)R.sup.10, where R.sup.10 is selected from
C.sub.1-C.sub.6-alkyl and C.sub.3-C.sub.6-cycloalkyl; phenyl,
phenyl-C.sub.1-C.sub.2-alkyl and a 3-, 4-, 5- or 6-membered
saturated 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.11.
[0195] In another preferred embodiment, R.sup.6 is selected from
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-cycloalkyl, fluorinated C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl, fluorinated
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl and a 3-, 4-, 5- or 6-membered
saturated 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.11.
[0196] In a more preferred embodiment, R.sup.6 is
phenyl-C.sub.1-C.sub.2-alkyl, and in particular benzyl.
[0197] In another more preferred embodiment, R.sup.6 is selected
from C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-cycloalkyl, fluorinated C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl and fluorinated
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl, and in particular
from C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.6-cycloalkyl, fluorinated C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-methyl and fluorinated
C.sub.3-C.sub.6-cycloalkyl-methyl.
[0198] In another more preferred embodiment, R.sup.6 is a 3-, 4-,
5- or 6-membered saturated 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.11. Even more preferably, R.sup.6 is a 3-, 4- or
5-membered saturated heterocyclic ring containing 1 or 2
heteroatoms independently selected from N, O and S, where the
heterocyclic ring may be substituted with one or two substituents
selected from halogen and C.sub.1-C.sub.4-alkyl, and is in
particular oxetanyl which may carry one or two substituents
selected from halogen and C.sub.1-C.sub.4-alkyl and especially from
F.
[0199] In another more preferred embodiment, R.sup.6 is selected
from hydrogen, C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl,
C.sub.3-C.sub.6-cycloalkylcarbonyl, C.sub.1-C.sub.4-alkoxy,
fluorinated C.sub.1-C.sub.4-alkoxy, phenyl-C.sub.1-C.sub.2-alkyl
and 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; and is
in particular selected from C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl, and 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 saturated
heterocyclic ring preferably contains 1 heteroatom selected from O
and S as ring member. Specifically, R.sup.6 is selected from
C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl and oxetanyl and
very specifically from ethyl, n-propyl, cyclopropyl, cyclobutyl and
3-oxetanyl.
[0200] In another more preferred embodiment, R.sup.5a and R.sup.6,
together with the atoms they are bound to, form a 3-, 4-, 5-, 6- or
7-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
R.sup.11; [0201] where R.sup.11 has one of the general meanings
given above, or, in particular, one of the preferred meanings given
below.
[0202] In particular, R.sup.5a and R.sup.6 form together a group
(CH.sub.2).sub.r, where r is 2, 3, 4 or 5, preferably 2, 3 or 4 or,
in particular, 3, 4 or 5. Alternatively, R.sup.5a and R.sup.6 form
together a group (CH.sub.2).sub.r, where r is 2, 3, 4 or 5 and in
particular 3, 4 or 5, where two hydrogen atoms bound to adjacent
CH.sub.2 groups may be replaced by two radicals R.sup.11, where the
two radicals R.sup.11 form together a group (CH.sub.2).sub.t, where
t is 1, 2, 3, 4 or 5, in particular 1, 2 or 3 and specifically
1.
[0203] In an alternative embodiment, X is CR.sup.7R.sup.8, where
R.sup.7 and R.sup.8 have one of the general meanings given above,
or, in particular, one of the preferred meanings given below.
[0204] In case that R.sup.7 and R.sup.8, together with the carbon
atom they are bound to, form a ring, this ring is spiro-bound to
the carbon atom carrying R.sup.7 and R.sup.8.
[0205] Preferably, [0206] R.sup.7 and R.sup.8, independently of
each other, are selected from the group consisting of halogen,
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, fluorinated C.sub.1-C.sub.6-alkoxy,
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.12aR.sup.12b,
--CH.sub.2NR.sup.12aR.sup.12b, [0207] --NR.sup.12aC(O)R.sup.10,
--C(.dbd.O)R.sup.10, SO.sub.2NR.sup.12aR.sup.12b,
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.11; or [0208]
R.sup.7 and R.sup.8, 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.11; or [0209] R.sup.5a and R.sup.7, together
with the carbon atoms 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.11;
[0210] in which case R.sup.8 has one of the above meanings or is
deuterium; [0211] where R.sup.11 has one of the general meanings
given above, or, in particular, one of the preferred meanings given
below.
[0212] More preferably, [0213] R.sup.7 and R.sup.8, independently
of each other, are selected from halogen, cyano,
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy, fluorinated C.sub.1-C.sub.6-alkoxy, phenyl,
phenyl-C.sub.1-C.sub.2-alkyl, benzyloxy and a 3-, 4-, 5- or
6-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 four last-mentioned radicals may be substituted with one or
more substituents R.sup.11; or [0214] R.sup.7 and R.sup.8, together
with the carbon atom they are bound to, form a 3-, 4-, 5-, 6- or 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.11; or
[0215] R.sup.5a and R.sup.7, together with the carbon atoms they
are bound to, form a 3-, 4-, 5-, 6- or 7-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.11; [0216] in which case R.sup.8 has one of
the above meanings or is deuterium; and [0217] R.sup.5b is selected
from hydrogen and deuterium and is preferably hydrogen; where
R.sup.11 has one of the general meanings given above, or, in
particular, one of the preferred meanings given below.
[0218] Even more preferably, [0219] R.sup.7 and R.sup.8,
independently of each other, are selected from halogen, cyano,
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl and
phenyl, or [0220] R.sup.7 and R.sup.8, together with the carbon
atom they are bound to, form a 3-, 4-, 5-, 6- or 7- or 8-membered
saturated, partially unsaturated or maximally unsaturated ring,
where the ring may be substituted with one or more substituents
R.sup.11; or [0221] R.sup.5 and R.sup.7 form together a group
(CH.sub.2).sub.s, where s is 2, 3, 4 or 5, preferably 2, 3 or 4; in
which case R.sup.8 has one of the above meanings or is deuterium;
and [0222] R.sup.5b is selected from hydrogen and deuterium and is
preferably hydrogen; where R.sup.11 has one of the general meanings
given above, or, in particular, one of the preferred meanings given
below.
[0223] In particular, [0224] R.sup.8 is selected from halogen,
cyano, C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl and
phenyl; and [0225] R.sup.7 is selected from C.sub.1-C.sub.6-alkyl
and fluorinated C.sub.1-C.sub.6-alkyl, preferably from methyl and
CF.sub.3 and is in particular methyl; or [0226] R.sup.7 and
R.sup.8, together with the carbon atom they are bound to, form a
3-, 4-, 5-, 6- or 7- or 8-membered saturated, partially unsaturated
or maximally unsaturated ring, where the ring may be substituted
with one or more substituents R.sup.11; or [0227] R.sup.5a and
R.sup.7 form together a group (CH.sub.2).sub.s, where s is 2, 3, 4
or 5, preferably 2, 3 or 4; in which case R.sup.8 has one of the
above meanings or is deuterium; and [0228] R.sup.5b is selected
from hydrogen and deuterium and is preferably hydrogen; [0229]
where R.sup.11 has one of the general meanings given above, or, in
particular, one of the preferred meanings given below.
[0230] In an alternative particular embodiment, [0231] R.sup.7 is
C.sub.1-C.sub.6-alkyl and is in particular methyl; [0232] R.sup.8
is selected from hydroxyl, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, 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 phenyl and in particular from
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy and
phenyl; or [0233] R.sup.7 and R.sup.8, together with the carbon
atom they are bound to, form a 3-, 4-, 5-, 6- or 7-membered
saturated or partially unsaturated ring, where the ring may be
substituted with one or more substituents R.sup.11; or [0234]
R.sup.5a and R.sup.7 form together a group (CH.sub.2).sub.s, where
s is 2, 3 or 4 and where R.sup.8 is methyl; and [0235] R.sup.5b is
hydrogen.
[0236] Specifically, [0237] R.sup.8 is selected from
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.2-alkyl and phenyl
and specifically from methyl, CF.sub.3 and phenyl; and [0238]
R.sup.7 is methyl; or [0239] R.sup.7 and R.sup.8, together with the
carbon atom they are bound to, form a 3-, 4-, 5- or 6-membered
saturated or partially unsaturated ring, where the ring may be
substituted with one or more substituents R.sup.11; or [0240]
R.sup.5a and R.sup.7 form together a group (CH.sub.2).sub.s, where
s is 3 or 4, specifically 3; in which case R.sup.8 is selected from
methyl and deuterium; and [0241] R.sup.5b is selected from hydrogen
and deuterium and is specifically hydrogen; where R.sup.11 has one
of the general meanings given above, or, in particular, one of the
preferred meanings given below.
[0242] In an alternative specific embodiment, [0243] R.sup.7 is
methyl; [0244] R.sup.8 is selected from hydroxyl, methyl, ethyl,
CF.sub.3, methoxy and phenyl; or [0245] R.sup.7 and R.sup.8,
together with the carbon atom they are bound to, form a 3-, 4-, 5-
or 6-membered saturated or partially unsaturated ring, where the
ring may be substituted with one or more substituents R.sup.11; or
[0246] R.sup.5a and R.sup.7 form together a group (CH.sub.2).sub.s,
where s is 2, 3 or 4 and in particular and where R.sup.8 is methyl;
and [0247] R.sup.5b is hydrogen.
[0248] Very specifically, [0249] R.sup.8 is selected from methyl,
CF.sub.3 and phenyl; and [0250] R.sup.7 is methyl; or [0251]
R.sup.7 and R.sup.8, together with the carbon atom they are bound
to, form a 4, 5- or 6-membered saturated or partially unsaturated
ring, where the ring may be substituted with one or more
substituents R.sup.11; or form a 3-membered saturated or partially
unsaturated ring, where the ring may be substituted with one or
more substituents R.sup.11; or [0252] R.sup.5a and R.sup.7 form
together a group (CH.sub.2).sub.s, where s is 3 or 4, specifically
3; in which case R.sup.8 is selected from methyl and deuterium and
in particular methyl; and [0253] R.sup.5b is selected from hydrogen
and deuterium and is specifically hydrogen; where R.sup.11 has one
of the general meanings given above, or, in particular, one of the
preferred meanings given below.
[0254] In one particular embodiment, the ring formed by R.sup.7 and
R.sup.8 together with the carbon atom they are bound to is a
carbocyclic ring, preferably a saturated or partially unsaturated
carbocyclic ring, in particular a saturated carbocyclic ring.
[0255] If R.sup.7 and R.sup.8, together with the carbon atom they
are bound to, form a carbocyclic ring, this is particularly
preferably a 4- or 5-membered saturated carbocyclic ring (i.e.
R.sup.7 and R.sup.8 form together a group --(CH.sub.2).sub.3-- or
--(CH.sub.2).sub.4--) and in particular a 4-membered saturated
carbocyclic ring (i.e. R.sup.7 and R.sup.8 form together a group
--(CH.sub.2).sub.3-), where the ring may be substituted with one or
more substituents R.sup.11. Specifically, the ring is not
substituted. Alternatively, the carbocyclic ring is 3-membered
(i.e. R.sup.7 and R.sup.8 form together a group
--(CH.sub.2).sub.2--)--), where the ring may be substituted with
one or more substituents R.sup.11. Specifically, the ring is not
substituted.
[0256] In an alternative particular embodiment, the ring formed by
R.sup.7 and R.sup.8 together with the carbon atom they are bound to
is a heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or
heteroatom-containing groups selected from O, S, N, SO and SO.sub.2
as ring members, preferably containing 1 or 2 heteroatoms or
heteroatom-containing groups selected from O, S, N, SO and SO.sub.2
as ring members. Preferably, the heterocyclic ring is 3-, 4-, 5- or
6-membered and saturated and may carry one or more substituents
R.sup.11. In particular, the heterocyclic ring is oxetanyl which
may carry one or more substituents R.sup.11.
[0257] Specifically, R.sup.7 and R.sup.8, together with the carbon
atom they are bound to, form a 3- or 4-membered saturated
carbocyclic ring (i.e. R.sup.7 and R.sup.8 form together a group
--(CH.sub.2).sub.2-- or --(CH.sub.2).sub.3--) and in particular a
4-membered saturated carbocyclic ring (i.e. R.sup.7 and R.sup.8
form together a group --(CH.sub.2).sub.3--); the ring not being
substituted.
[0258] In a preferred embodiment, each R.sup.9 is independently
selected from halogen, cyano, nitro, hydroxy,
C.sub.1-C.sub.6-alkyl, fluorinated C.sub.1-C.sub.6-alkyl,
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 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.11. The heterocyclic ring is specifically oxetanyl.
[0259] More preferably, each R.sup.9 is independently selected from
halogen, cyano, nitro, hydroxy, 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, even more preferably from 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, and
is in particular selected from halogen, C.sub.1-C.sub.6-alkyl,
fluorinated C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and
C.sub.1-C.sub.6-alkoxy, more particularly from halogen,
C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-alkoxy, and is
specifically halogen, especially F or Cl, and more specifically
F.
[0260] In case that X is NR.sup.6, in alternatively more preferred
embodiment, each R.sup.9 is independently selected from halogen,
cyano, nitro, hydroxy, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, fluorinated
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy and fluorinated
C.sub.1-C.sub.6-alkoxy, even more preferably from halogen,
C.sub.1-C.sub.6-alkyl and C.sub.3-C.sub.6-cycloalkyl, and in
particular from halogen and C.sub.1-C.sub.6-alkyl.
[0261] In a preferred embodiment, R.sup.10 is selected from
hydrogen, hydroxy, 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.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.12aR.sup.12b, --CH.sub.2NR.sup.12aR.sup.12b 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.11, where R.sup.11, R.sup.12a and R.sup.12b
have one of the general meanings given above, or, in particular,
one of the preferred meanings given below. More preferably,
R.sup.10 is selected from hydrogen, 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, and even more preferably from
C.sub.1-C.sub.4-alkyl and C.sub.1-C.sub.4-alkoxy. In particular,
R.sup.10 is selected from C.sub.1-C.sub.2-alkyl and
tert-butoxy.
[0262] In a preferred embodiment, each R.sup.11 is independently
selected from halogen, cyano, nitro, hydroxy,
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, and
is in particular halogen or C.sub.1-C.sub.4-alkyl. Alternatively,
two radicals R.sup.11 bound on adjacent ring atoms form together a
group (CH.sub.2).sub.t, where t is 1, 2, 3, 4 or 5 and in
particular 1, 2 or 3.
[0263] In a preferred embodiment, R.sup.12a and R.sup.12b,
independently of each other and independently of each occurrence,
are selected from hydrogen, C.sub.1-C.sub.6-alkyl, fluorinated
C.sub.1-C.sub.6-alkyl, 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.12a and R.sup.12b are bound to the same nitrogen atom,
together with this nitrogen atom may form a 3-, 4-, 5-, 6- or
7-membered saturated, partially unsaturated or maximally
unsaturated heterocyclic ring, where the ring may further contain 1
or 2 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.
[0264] More preferably, R.sup.12a and R.sup.12b, independently of
each other and independently of each occurrence, are selected from
hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylcarbonyl,
C.sub.1-C.sub.6-alkoxycarbonyl and benzyl, where the phenyl moiety
in the last-mentioned radical may carry 1, 2 or 3 substituents
selected from halogen, cyano nitro, 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; or, if R.sup.12a and R.sup.12b
are bound to the same nitrogen atom, together with this nitrogen
atom may form a 5- or 6-membered saturated or aromatic heterocyclic
ring, where the ring may further contain 1 or 2 heteroatoms or
heteroatom-containing groups selected from O, S, N, SO, SO.sub.2
and C.dbd.O as ring members, and where the ring may be substituted
with 1 or 2 substituents selected from halogen, cyano nitro,
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.
[0265] In particular, R.sup.12a and R.sup.12b, independently of
each other and independently of each occurrence, are selected from
hydrogen and C.sub.1-C.sub.6-alkyl.
[0266] In a preferred embodiment, a is 0 or 1 and in particular
0.
[0267] In a particular embodiment, a is 1 and R.sup.2 is bound in
3-position to the nitrogen ring atom carrying R.sup.1 (this is for
the example the position of R.sup.2b in below formula I.2).
[0268] In a preferred embodiment, b is 0, 1 or 2 and in particular
0 or 1.
[0269] In a preferred embodiment, n is 1.
[0270] In a particular embodiment, the compound of formula I is a
compound of formula I.1
##STR00004##
wherein X, R.sup.5a, R.sup.5b, R.sup.9 and b have one of the above
general, or, in particular, one of the above preferred
meanings.
[0271] In a specific embodiment, the compound of formula I is a
compound of formula I.1.1
##STR00005## [0272] wherein [0273] R.sup.9a is selected from H,
halogen, C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.6-cycloalkyl and fluorinated
C.sub.3-C.sub.6-cycloalkyl, especially from H or F; and [0274]
R.sup.5a, R.sup.5b, R.sup.6, R.sup.9 and b have one of the above
general, or, in particular, one of the above preferred
meanings.
[0275] In another specific embodiment, the compound of formula I is
a compound of formula I.1.2
##STR00006## [0276] wherein [0277] R.sup.7 is selected from
C.sub.1-C.sub.4-alkyl and fluorinated C.sub.1-C.sub.4-alkyl; [0278]
R.sup.8 is selected from C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, fluorinated
C.sub.1-C.sub.4-alkoxy and phenyl; or [0279] R.sup.7 and R.sup.8,
together with the carbon atom they are bound to, form a 3-, 4-, 5-,
6- or 7-membered, in particular a 3- or 4-membered saturated or
partially unsaturated ring, especially a saturated carbocyclic
ring, where the ring may be substituted with one or more
substituents R.sup.11, and form especially a 3- or 4-membered
saturated carbocyclic ring; [0280] R.sup.9a is H, Cl, F or methyl,
especially H, Cl or F; and [0281] R.sup.9 and b have one of the
above general, or, in particular, one of the above preferred
meanings.
[0282] In an alternative embodiment, in compounds I.1.2, [0283]
R.sup.7 is selected from C.sub.1-C.sub.4-alkyl and fluorinated
C.sub.1-C.sub.4-alkyl, preferably from methyl and CF.sub.3, and is
in particular methyl; [0284] R.sup.8 is selected from
C.sub.1-C.sub.4-alkyl and fluorinated C.sub.1-C.sub.4-alkyl, and
preferably from methyl and CF.sub.3; or [0285] R.sup.7 and R.sup.8,
together with the carbon atom they are bound to, form a 3-, 4-, 5-,
6- or 7-membered saturated or partially unsaturated ring, where the
ring may be substituted with one or more substituents R.sup.11, and
form preferably a 5- or 6-membered saturated or partially
unsaturated ring; [0286] R.sup.9a is H or F; and [0287] R.sup.9 and
b have one of the above general, or, in particular, one of the
above preferred meanings.
[0288] In another specific embodiment, the compound of formula I is
a compound of formula I.1.3
##STR00007##
wherein R.sup.8 is selected from deuterium, F, Cl, CN and CH.sub.3,
in particular from deuterium, F, Cl and CN.
[0289] Among these, preference is given to the trans compounds,
i.e. of formula I.1.3-trans:
##STR00008## [0290] wherein R.sup.8 is selected from deuterium, F,
Cl, CN and CH.sub.3, in particular from deuterium, F, Cl and
CN.
[0291] In another particular embodiment, the compound of formula I
is a compound of formula I.2
##STR00009##
wherein X, R.sup.5a, R.sup.5b, R.sup.9 and b have one of the above
general, or, in particular, one of the above preferred
meanings.
[0292] In another particular embodiment, the compound of formula I
is a compound of formula I.2.1
##STR00010## [0293] wherein [0294] R.sup.2a, R.sup.2b and R.sup.3a,
independently of each other, are selected from hydrogen and methyl;
and where in particular at most one of R.sup.2a, R.sup.2b and
R.sup.3a is methyl; [0295] R.sup.9a is selected from H, halogen,
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.6-cycloalkyl and fluorinated
C.sub.3-C.sub.6-cycloalkyl; and [0296] R.sup.5a, R.sup.5b, R.sup.6,
R.sup.9 and b have one of the above general, or, in particular, one
of the above preferred meanings.
[0297] In particular, in compounds I.2.1, [0298] R.sup.9a is H or
F; and [0299] R.sup.5a, R.sup.5b, R.sup.6, R.sup.9 and b have one
of the above general, or, in particular, one of the above preferred
meanings.
[0300] In particular, in compounds I.2.1, R.sup.2b is methyl and
R.sup.2a and R.sup.3a are hydrogen.
[0301] In another particular embodiment, the compound of formula I
is a compound of formula I.2.2
##STR00011## [0302] wherein [0303] R.sup.2a, R.sup.2b, R.sup.3a and
R.sup.5a, independently of each other, are selected from hydrogen,
methyl and ethyl, in particular from hydrogen and methyl; [0304]
R.sup.7 is selected from C.sub.1-C.sub.4-alkyl and fluorinated
C.sub.1-C.sub.4-alkyl, in particular from methyl and CF.sub.3, and
is especially methyl; [0305] R.sup.8 is selected from
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy and
phenyl; and in particular from methyl and CF.sub.3; or [0306]
R.sup.7 and R.sup.8, together with the carbon atom they are bound
to, form a 3-, 4-, 5-, 6- or 7-membered, in particular a 3- or
4-membered saturated or partially unsaturated, especially a
saturated carbocyclic ring, ring, where the ring may be substituted
with one or more substituents R.sup.11, and form especially a 3- or
4-membered saturated carbocyclic ring; [0307] R.sup.9a is H, Cl, F
or methyl, especially H, Cl or F; and [0308] R.sup.9 and b have one
of the above general, or, in particular, one of the above preferred
meanings.
[0309] In particular, in compound I.2.2, [0310] R.sup.2a, R.sup.2b,
R.sup.3a and R.sup.5a, independently of each other, are selected
from hydrogen and methyl; [0311] R.sup.7 is selected from
C.sub.1-C.sub.4-alkyl and fluorinated C.sub.1-C.sub.4-alkyl,
preferably from methyl and CF.sub.3, and is in particular methyl;
[0312] R.sup.8 is selected from C.sub.1-C.sub.4-alkyl and
fluorinated C.sub.1-C.sub.4-alkyl, and preferably from methyl and
CF.sub.3; or [0313] R.sup.7 and R.sup.8, together with the carbon
atom they are bound to, form a 3-, 4-, 5-, 6- or 7-membered
saturated or partially unsaturated ring, where the ring may be
substituted with one or more substituents R.sup.11; [0314] R.sup.9a
is H or F; and [0315] R.sup.9 and b have one of the above general,
or, in particular, one of the above preferred meanings.
[0316] In particular, in compound I.2.2, R.sup.2b is methyl and
R.sup.2a, R.sup.3a and R.sup.5a are hydrogen.
[0317] In the above formulae I.1.1, I.1.2, I.2.1 and I.2.2, (b-1)
is preferably 0.
[0318] Preferably, in the above formulae I.2, I.2.1 and I.2.2,
R.sup.2a, R.sup.2b, R.sup.3a and R.sup.5a are selected from
hydrogen and methyl, with the proviso that at most two, preferably
at most one, of the substituents R.sup.2a, R.sup.2b, R.sup.3a and
R.sup.5a are methyl. In particular, R.sup.2b is hydrogen and
R.sup.2a, R.sup.3a and R.sup.5a are selected from hydrogen and
methyl, with the proviso that at most two, preferably at most one,
of the substituents R.sup.2a, R.sup.3a and R.sup.5a are methyl.
However, more particularly, R.sup.2b is hydrogen or methyl,
especially methyl, and R.sup.2a, R.sup.3a and R.sup.5a are hydrogen
(if the latter does not form a ring together with R.sup.6 or
R.sup.7 and the atoms they are bond to).
[0319] Preferably, in the above formulae I.2, I.2.1 and I1.2.2,
R.sup.7 and R.sup.8, together with the carbon atom they are bound
to, form a 3, 4-, 5- or 6-membered saturated or partially
unsaturated carbocyclic ring, preferably a 3, 4- or 5-membered
saturated carbocyclic ring, in particular a 4-membered saturated
carbocyclic ring, where the ring may be substituted with one or
more substituents R.sup.11.
[0320] Examples of preferred compounds are compounds of the
following formulae I.a to I.ii, where the variables have one of the
general or preferred meanings given above.
[0321] Examples of preferred compounds are the individual compounds
compiled in the tables 1 to 36 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.
##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016##
##STR00017##
[0322] Table 1
[0323] Compounds of the formula I.a in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
[0324] Table 2
[0325] Compounds of the formula I.b in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
[0326] Table 3
[0327] Compounds of the formula I.c in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
[0328] Table 4
[0329] Compounds of the formula I.d in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
[0330] Table 5
[0331] Compounds of the formula I.e in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
[0332] Table 6
[0333] Compounds of the formula I.f in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
[0334] Table 7
[0335] Compounds of the formula I.g in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0336] Table 8
[0337] Compounds of the formula I.h in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0338] Table 9
[0339] Compounds of the formula I.i in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0340] Table 10
[0341] Compounds of the formula I.j in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0342] Table 11
[0343] Compounds of the formula I.k in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0344] Table 12
[0345] Compounds of the formula I.1 in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0346] Table 13
[0347] Compounds of the formula I.m in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0348] Table 14
[0349] Compounds of the formula I.n in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0350] Table 15
[0351] Compounds of the formula I.o in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0352] Table 16
[0353] Compounds of the formula I.p in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0354] Table 17
[0355] Compounds of the formula I.q in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0356] Table 18
[0357] Compounds of the formula I.r in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0358] Table 19
[0359] Compounds of the formula I.s in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0360] Table 20
[0361] Compounds of the formula I.t in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0362] Table 21
[0363] Compounds of the formula I.u in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0364] Table 22
[0365] Compounds of the formula I.v in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0366] Table 23
[0367] Compounds of the formula I.w in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0368] Table 24
[0369] Compounds of the formula I.x in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0370] Table 25
[0371] Compounds of the formula I.y in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0372] Table 26
[0373] Compounds of the formula I.z in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0374] Table 27
[0375] Compounds of the formula I.zz in which the combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a for a compound
corresponds in each case to one row of Table B.
[0376] Table 28
[0377] Compounds of the formula I.aa in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
[0378] Table 29
[0379] Compounds of the formula I.bb in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
[0380] Table 30
[0381] Compounds of the formula I.cc in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
[0382] Table 31
[0383] Compounds of the formula I.dd in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
[0384] Table 32
[0385] Compounds of the formula I.ee in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
[0386] Table 33
[0387] Compounds of the formula I.ff in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
[0388] Table 34
[0389] Compounds of the formula I.gg in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
[0390] Table 35
[0391] Compounds of the formula I.hh in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
[0392] Table 36
[0393] Compounds of the formula I.ii in which the combination of
R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a for a compound corresponds
in each case to one row of Table A.
TABLE-US-00001 TABLE A No. R.sup.9a R.sup.5b R.sup.5a R.sup.6 A-1 H
H H --SO.sub.2--CH.sub.3 A-2 F H H --SO.sub.2--CH.sub.3 A-3 Cl H H
--SO.sub.2--CH.sub.3 A-4 Br H H --SO.sub.2--CH.sub.3 A-5 CH.sub.3 H
H --SO.sub.2--CH.sub.3 A-6 CF.sub.3 H H --SO.sub.2--CH.sub.3 A-7
OCH.sub.3 H H --SO.sub.2--CH.sub.3 A-8 OCF.sub.3 H H
--SO.sub.2--CH.sub.3 A-9 cyclopropyl H H --SO.sub.2--CH.sub.3 A-10
cyclobutyl H H --SO.sub.2--CH.sub.3 A-11 cyclopentyl H H
--SO.sub.2--CH.sub.3 A-12 cyclohexyl H H --SO.sub.2--CH.sub.3 A-13
H CH.sub.3 H --SO.sub.2--CH.sub.3 A-14 F CH.sub.3 H
--SO.sub.2--CH.sub.3 A-15 Cl CH.sub.3 H --SO.sub.2--CH.sub.3 A-16
Br CH.sub.3 H --SO.sub.2--CH.sub.3 A-17 CH.sub.3 CH.sub.3 H
--SO.sub.2--CH.sub.3 A-18 CF.sub.3 CH.sub.3 H --SO.sub.2--CH.sub.3
A-19 OCH.sub.3 CH.sub.3 H --SO.sub.2--CH.sub.3 A-20 OCF.sub.3
CH.sub.3 H --SO.sub.2--CH.sub.3 A-21 cyclopropyl CH.sub.3 H
--SO.sub.2--CH.sub.3 A-22 cyclobutyl CH.sub.3 H
--SO.sub.2--CH.sub.3 A-23 cyclopentyl CH.sub.3 H
--SO.sub.2--CH.sub.3 A-24 cyclohexyl CH.sub.3 H
--SO.sub.2--CH.sub.3 A-25 H CH.sub.3 CH.sub.3 --SO.sub.2--CH.sub.3
A-26 F CH.sub.3 CH.sub.3 --SO.sub.2--CH.sub.3 A-27 Cl CH.sub.3
CH.sub.3 --SO.sub.2--CH.sub.3 A-28 Br CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.3 A-29 CH.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.3 A-30 CF.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.3 A-31 OCH.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.3 A-32 OCF.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.3 A-33 cyclopropyl CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.3 A-34 cyclobutyl CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.3 A-35 cyclopentyl CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.3 A-36 cyclohexyl CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.3 A-37 H H H --SO.sub.2--CH.sub.2CH.sub.3 A-38 F
H H --SO.sub.2--CH.sub.2CH.sub.3 A-39 Cl H H
--SO.sub.2--CH.sub.2CH.sub.3 A-40 Br H H
--SO.sub.2--CH.sub.2CH.sub.3 A-41 CH.sub.3 H H
--SO.sub.2--CH.sub.2CH.sub.3 A-42 CF.sub.3 H H
--SO.sub.2--CH.sub.2CH.sub.3 A-43 OCH.sub.3 H H
--SO.sub.2--CH.sub.2CH.sub.3 A-44 OCF.sub.3 H H
--SO.sub.2--CH.sub.2CH.sub.3 A-45 cyclopropyl H H
--SO.sub.2--CH.sub.2CH.sub.3 A-46 cyclobutyl H H
--SO.sub.2--CH.sub.2CH.sub.3 A-47 cyclopentyl H H
--SO.sub.2--CH.sub.2CH.sub.3 A-48 cyclohexyl H H
--SO.sub.2--CH.sub.2CH.sub.3 A-49 H CH.sub.3 H
--SO.sub.2--CH.sub.2CH.sub.3 A-50 F CH.sub.3 H
--SO.sub.2--CH.sub.2CH.sub.3 A-51 Cl CH.sub.3 H
--SO.sub.2--CH.sub.2CH.sub.3 A-52 Br CH.sub.3 H
--SO.sub.2--CH.sub.2CH.sub.3 A-53 CH.sub.3 CH.sub.3 H
--SO.sub.2--CH.sub.2CH.sub.3 A-54 CF.sub.3 CH.sub.3 H
--SO.sub.2--CH.sub.2CH.sub.3 A-55 OCH.sub.3 CH.sub.3 H
--SO.sub.2--CH.sub.2CH.sub.3 A-56 OCF.sub.3 CH.sub.3 H
--SO.sub.2--CH.sub.2CH.sub.3 A-57 cyclopropyl CH.sub.3 H
--SO.sub.2--CH.sub.2CH.sub.3 A-58 cyclobutyl CH.sub.3 H
--SO.sub.2--CH.sub.2CH.sub.3 A-59 cyclopentyl CH.sub.3 H
--SO.sub.2--CH.sub.2CH.sub.3 A-60 cyclohexyl CH.sub.3 H
--SO.sub.2--CH.sub.2CH.sub.3 A-61 H CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.2CH.sub.3 A-62 F CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.2CH.sub.3 A-63 Cl CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.2CH.sub.3 A-64 Br CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.2CH.sub.3 A-65 CH.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.2CH.sub.3 A-66 CF.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.2CH.sub.3 A-67 OCH.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.2CH.sub.3 A-68 OCF.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.2CH.sub.3 A-69 cyclopropyl CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.2CH.sub.3 A-70 cyclobutyl CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.2CH.sub.3 A-71 cyclopentyl CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.2CH.sub.3 A-72 cyclohexyl CH.sub.3 CH.sub.3
--SO.sub.2--CH.sub.2CH.sub.3 A-73 H H H --SO.sub.2--CF.sub.3 A-74 F
H H --SO.sub.2--CF.sub.3 A-75 Cl H H --SO.sub.2--CF.sub.3 A-76 Br H
H --SO.sub.2--CF.sub.3 A-77 CH.sub.3 H H --SO.sub.2--CF.sub.3 A-78
CF.sub.3 H H --SO.sub.2--CF.sub.3 A-79 OCH.sub.3 H H
--SO.sub.2--CF.sub.3 A-80 OCF.sub.3 H H --SO.sub.2--CF.sub.3 A-81
cyclopropyl H H --SO.sub.2--CF.sub.3 A-82 cyclobutyl H H
--SO.sub.2--CF.sub.3 A-83 cyclopentyl H H --SO.sub.2--CF.sub.3 A-84
cyclohexyl H H --SO.sub.2--CF.sub.3 A-85 H CH.sub.3 H
--SO.sub.2--CF.sub.3 A-86 F CH.sub.3 H --SO.sub.2--CF.sub.3 A-87 Cl
CH.sub.3 H --SO.sub.2--CF.sub.3 A-88 Br CH.sub.3 H
--SO.sub.2--CF.sub.3 A-89 CH.sub.3 CH.sub.3 H --SO.sub.2--CF.sub.3
A-90 CF.sub.3 CH.sub.3 H --SO.sub.2--CF.sub.3 A-91 OCH.sub.3
CH.sub.3 H --SO.sub.2--CF.sub.3 A-92 OCF.sub.3 CH.sub.3 H
--SO.sub.2--CF.sub.3 A-93 cyclopropyl CH.sub.3 H
--SO.sub.2--CF.sub.3 A-94 cyclobutyl CH.sub.3 H
--SO.sub.2--CF.sub.3 A-95 cyclopentyl CH.sub.3 H
--SO.sub.2--CF.sub.3 A-96 cyclohexyl CH.sub.3 H
--SO.sub.2--CF.sub.3 A-97 H CH.sub.3 CH.sub.3 --SO.sub.2--CF.sub.3
A-98 F CH.sub.3 CH.sub.3 --SO.sub.2--CF.sub.3 A-99 Cl CH.sub.3
CH.sub.3 --SO.sub.2--CF.sub.3 A-100 Br CH.sub.3 CH.sub.3
--SO.sub.2--CF.sub.3 A-101 CH.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--CF.sub.3 A-102 CF.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--CF.sub.3 A-103 OCH.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--CF.sub.3 A-104 OCF.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--CF.sub.3 A-105 cyclopropyl CH.sub.3 CH.sub.3
--SO.sub.2--CF.sub.3 A-106 cyclobutyl CH.sub.3 CH.sub.3
--SO.sub.2--CF.sub.3 A-107 cyclopentyl CH.sub.3 CH.sub.3
--SO.sub.2--CF.sub.3 A-108 cyclohexyl CH.sub.3 CH.sub.3
--SO.sub.2--CF.sub.3 A-109 H H H --SO.sub.2--C.sub.6H.sub.5* A-110
F H H --SO.sub.2--C.sub.6H.sub.5 A-111 Cl H H
--SO.sub.2--C.sub.6H.sub.5 A-112 Br H H --SO.sub.2--C.sub.6H.sub.5
A-113 CH.sub.3 H H --SO.sub.2--C.sub.6H.sub.5 A-114 CF.sub.3 H H
--SO.sub.2--C.sub.6H.sub.5 A-115 OCH.sub.3 H H
--SO.sub.2--C.sub.6H.sub.5 A-116 OCF.sub.3 H H
--SO.sub.2--C.sub.6H.sub.5 A-117 cyclopropyl H H
--SO.sub.2--C.sub.6H.sub.5 A-118 cyclobutyl H H
--SO.sub.2--C.sub.6H.sub.5 A-119 cyclopentyl H H
--SO.sub.2--C.sub.6H.sub.5 A-120 cyclohexyl H H
--SO.sub.2--C.sub.6H.sub.5 A-121 H CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.5 A-122 F CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.5 A-123 Cl CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.5 A-124 Br CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.5 A-125 CH.sub.3 CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.5 A-126 CF.sub.3 CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.5 A-127 OCH.sub.3 CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.5 A-128 OCF.sub.3 CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.5 A-129 cyclopropyl CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.5 A-130 cyclobutyl CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.5 A-131 cyclopentyl CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.5 A-132 cyclohexyl CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.5 A-133 H CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.5 A-134 F CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.5 A-135 Cl CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.5 A-136 Br CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.5 A-137 CH.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.5 A-138 CF.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.5 A-139 OCH.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.5 A-140 OCF.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.5 A-141 cyclopropyl CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.5 A-142 cyclobutyl CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.5 A-143 cyclopentyl CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.5 A-144 cyclohexyl CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.5 A-145 H H H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3** A-146 F H H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-147 Cl H H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-148 Br H H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-149 CH.sub.3 H H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-150 CF.sub.3 H H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-151 OCH.sub.3 H H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-152 OCF.sub.3 H H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-153 cyclopropyl H H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-154 cyclobutyl H H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-155 cyclopentyl H H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-156 cyclohexyl H H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-157 H CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-158 F CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-159 Cl CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-160 Br CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-161 CH.sub.3 CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-162 CF.sub.3 CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-163 OCH.sub.3 CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-164 OCF.sub.3 CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-165 cyclopropyl CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-166 cyclobutyl CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-167 cyclopentyl CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-168 cyclohexyl CH.sub.3 H
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-169 H CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-170 F CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-171 Cl CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-172 Br CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-173 CH.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-174 CF.sub.3 CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-175 OCH.sub.3 CH.sub.3
CH.sub.3 --SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-176 OCF.sub.3
CH.sub.3 CH.sub.3 --SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-177
cyclopropyl CH.sub.3 CH.sub.3 --SO.sub.2--C.sub.6H.sub.4CH.sub.3
A-178 cyclobutyl CH.sub.3 CH.sub.3
--SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-179 cyclopentyl CH.sub.3
CH.sub.3 --SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-180 cyclohexyl
CH.sub.3 CH.sub.3 --SO.sub.2--C.sub.6H.sub.4CH.sub.3 A-181 H H H
benzyl A-182 F H H benzyl A-183 Cl H H benzyl A-184 Br H H benzyl
A-185 CH.sub.3 H H benzyl A-186 CF.sub.3 H H benzyl A-187 OCH.sub.3
H H benzyl A-188 OCF.sub.3 H H benzyl A-189 cyclopropyl H H benzyl
A-190 cyclobutyl H H benzyl A-191 cyclopentyl H H benzyl A-192
cyclohexyl H H benzyl A-193 H CH.sub.3 H benzyl A-194 F CH.sub.3 H
benzyl A-195 Cl CH.sub.3 H benzyl A-196 Br CH.sub.3 H benzyl A-197
CH.sub.3 CH.sub.3 H benzyl A-198 CF.sub.3 CH.sub.3 H benzyl A-199
OCH.sub.3 CH.sub.3 H benzyl A-200 OCF.sub.3 CH.sub.3 H benzyl A-201
cyclopropyl CH.sub.3 H benzyl A-202 cyclobutyl CH.sub.3 H benzyl
A-203 cyclopentyl CH.sub.3 H benzyl A-204 cyclohexyl CH.sub.3 H
benzyl A-205 H CH.sub.3 CH.sub.3 benzyl A-206 F CH.sub.3 CH.sub.3
benzyl A-207 Cl CH.sub.3 CH.sub.3 benzyl A-208 Br CH.sub.3 CH.sub.3
benzyl A-209 CH.sub.3 CH.sub.3 CH.sub.3 benzyl A-210 CF.sub.3
CH.sub.3 CH.sub.3 benzyl A-211 OCH.sub.3 CH.sub.3 CH.sub.3 benzyl
A-212 OCF.sub.3 CH.sub.3 CH.sub.3 benzyl A-213 cyclopropyl CH.sub.3
CH.sub.3 benzyl A-214 cyclobutyl CH.sub.3 CH.sub.3 benzyl A-215
cyclopentyl CH.sub.3 CH.sub.3 benzyl A-216 cyclohexyl CH.sub.3
CH.sub.3 benzyl A-217 H H H H A-218 F H H H A-219 Cl H H H A-220 Br
H H H A-221 CH.sub.3 H H H A-222 CF.sub.3 H H H A-223 OCH.sub.3 H H
H A-224 OCF.sub.3 H H H A-225 cyclopropyl H H H A-226 cyclobutyl H
H H A-227 cyclopentyl H H H A-228 cyclohexyl H H H A-229 H CH.sub.3
H H A-230 F CH.sub.3 H H A-231 Cl CH.sub.3 H H A-232 Br CH.sub.3 H
H A-233 CH.sub.3 CH.sub.3 H H A-234 CF.sub.3 CH.sub.3 H H A-235
OCH.sub.3 CH.sub.3 H H A-236 OCF.sub.3 CH.sub.3 H H A-237
cyclopropyl CH.sub.3 H H A-238 cyclobutyl CH.sub.3 H H A-239
cyclopentyl CH.sub.3 H H A-240 cyclohexyl CH.sub.3 H H A-241 H
CH.sub.3 CH.sub.3 H A-242 F CH.sub.3 CH.sub.3 H A-243 Cl CH.sub.3
CH.sub.3 H A-244 Br CH.sub.3 CH.sub.3 H A-245 CH.sub.3 CH.sub.3
CH.sub.3 H A-246 CF.sub.3 CH.sub.3 CH.sub.3 H
A-247 OCH.sub.3 CH.sub.3 CH.sub.3 H A-248 OCF.sub.3 CH.sub.3
CH.sub.3 H A-249 cyclopropyl CH.sub.3 CH.sub.3 H A-250 cyclobutyl
CH.sub.3 CH.sub.3 H A-251 cyclopentyl CH.sub.3 CH.sub.3 H A-252
cyclohexyl CH.sub.3 CH.sub.3 H A-253 H H H CH.sub.3 A-254 F H H
CH.sub.3 A-255 Cl H H CH.sub.3 A-256 Br H H CH.sub.3 A-257 CH.sub.3
H H CH.sub.3 A-258 CF.sub.3 H H CH.sub.3 A-259 OCH.sub.3 H H
CH.sub.3 A-260 OCF.sub.3 H H CH.sub.3 A-261 cyclopropyl H H
CH.sub.3 A-262 cyclobutyl H H CH.sub.3 A-263 cyclopentyl H H
CH.sub.3 A-264 cyclohexyl H H CH.sub.3 A-265 H CH.sub.3 H CH.sub.3
A-266 F CH.sub.3 H CH.sub.3 A-267 Cl CH.sub.3 H CH.sub.3 A-268 Br
CH.sub.3 H CH.sub.3 A-269 CH.sub.3 CH.sub.3 H CH.sub.3 A-270
CF.sub.3 CH.sub.3 H CH.sub.3 A-271 OCH.sub.3 CH.sub.3 H CH.sub.3
A-272 OCF.sub.3 CH.sub.3 H CH.sub.3 A-273 cyclopropyl CH.sub.3 H
CH.sub.3 A-274 cyclobutyl CH.sub.3 H CH.sub.3 A-275 cyclopentyl
CH.sub.3 CH.sub.3 H A-276 cyclohexyl CH.sub.3 H CH.sub.3 A-277 H
CH.sub.3 CH.sub.3 CH.sub.3 A-278 F CH.sub.3 CH.sub.3 CH.sub.3 A-279
Cl CH.sub.3 CH.sub.3 CH.sub.3 A-280 Br CH.sub.3 CH.sub.3 CH.sub.3
A-281 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 A-282 CF.sub.3 CH.sub.3
CH.sub.3 CH.sub.3 A-283 OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 A-284
OCF.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 A-285 cyclopropyl CH.sub.3
CH.sub.3 CH.sub.3 A-286 cyclobutyl CH.sub.3 CH.sub.3 CH.sub.3 A-287
cyclopentyl CH.sub.3 CH.sub.3 CH.sub.3 A-288 cyclohexyl CH.sub.3
CH.sub.3 CH.sub.3 A-289 H H H C.sub.2H.sub.5 A-290 F H H
C.sub.2H.sub.5 A-291 Cl H H C.sub.2H.sub.5 A-292 Br H H
C.sub.2H.sub.5 A-293 CH.sub.3 H H C.sub.2H.sub.5 A-294 CF.sub.3 H H
C.sub.2H.sub.5 A-295 OCH.sub.3 H H C.sub.2H.sub.5 A-296 OCF.sub.3 H
H C.sub.2H.sub.5 A-297 cyclopropyl H H C.sub.2H.sub.5 A-298
cyclobutyl H H C.sub.2H.sub.5 A-299 cyclopentyl H H C.sub.2H.sub.5
A-300 cyclohexyl H H C.sub.2H.sub.5 A-301 H CH.sub.3 H
C.sub.2H.sub.5 A-302 F CH.sub.3 H C.sub.2H.sub.5 A-303 Cl CH.sub.3
H C.sub.2H.sub.5 A-304 Br CH.sub.3 H C.sub.2H.sub.5 A-305 CH.sub.3
CH.sub.3 H C.sub.2H.sub.5 A-306 CF.sub.3 CH.sub.3 H C.sub.2H.sub.5
A-307 OCH.sub.3 CH.sub.3 H C.sub.2H.sub.5 A-308 OCF.sub.3 CH.sub.3
H C.sub.2H.sub.5 A-309 cyclopropyl CH.sub.3 H C.sub.2H.sub.5 A-310
cyclobutyl CH.sub.3 H C.sub.2H.sub.5 A-311 cyclopentyl CH.sub.3 H
C.sub.2H.sub.5 A-312 cyclohexyl CH.sub.3 H C.sub.2H.sub.5 A-313 H
CH.sub.3 CH.sub.3 C.sub.2H.sub.5 A-314 F CH.sub.3 CH.sub.3
C.sub.2H.sub.5 A-315 Cl CH.sub.3 CH.sub.3 C.sub.2H.sub.5 A-316 Br
CH.sub.3 CH.sub.3 C.sub.2H.sub.5 A-317 CH.sub.3 CH.sub.3 CH.sub.3
C.sub.2H.sub.5 A-318 CF.sub.3 CH.sub.3 CH.sub.3 C.sub.2H.sub.5
A-319 OCH.sub.3 CH.sub.3 CH.sub.3 C.sub.2H.sub.5 A-320 OCF.sub.3
CH.sub.3 CH.sub.3 C.sub.2H.sub.5 A-321 cyclopropyl CH.sub.3
CH.sub.3 C.sub.2H.sub.5 A-322 cyclobutyl CH.sub.3 CH.sub.3
C.sub.2H.sub.5 A-323 cyclopentyl CH.sub.3 CH.sub.3 C.sub.2H.sub.5
A-324 cyclohexyl CH.sub.3 CH.sub.3 C.sub.2H.sub.5 A-325 H H H
n-propyl A-326 F H H n-propyl A-327 Cl H H n-propyl A-328 Br H H
n-propyl A-329 CH.sub.3 H H n-propyl A-330 CF.sub.3 H H n-propyl
A-331 OCH.sub.3 H H n-propyl A-332 OCF.sub.3 H H n-propyl A-333
cyclopropyl H H n-propyl A-334 cyclobutyl H H n-propyl A-335
cyclopentyl H H n-propyl A-336 cyclohexyl H H n-propyl A-337 H
CH.sub.3 H n-propyl A-338 F CH.sub.3 H n-propyl A-339 Cl CH.sub.3 H
n-propyl A-340 Br CH.sub.3 H n-propyl A-341 CH.sub.3 CH.sub.3 H
n-propyl A-342 CF.sub.3 CH.sub.3 H n-propyl A-343 OCH.sub.3
CH.sub.3 H n-propyl A-344 OCF.sub.3 CH.sub.3 H n-propyl A-345
cyclopropyl CH.sub.3 H n-propyl A-346 cyclobutyl CH.sub.3 H
n-propyl A-347 cyclopentyl CH.sub.3 H n-propyl A-348 cyclohexyl
CH.sub.3 H n-propyl A-349 H CH.sub.3 CH.sub.3 n-propyl A-350 F
CH.sub.3 CH.sub.3 n-propyl A-351 Cl CH.sub.3 CH.sub.3 n-propyl
A-352 Br CH.sub.3 CH.sub.3 n-propyl A-353 CH.sub.3 CH.sub.3
CH.sub.3 n-propyl A-354 CF.sub.3 CH.sub.3 CH.sub.3 n-propyl A-355
OCH.sub.3 CH.sub.3 CH.sub.3 n-propyl A-356 OCF.sub.3 CH.sub.3
CH.sub.3 n-propyl A-357 cyclopropyl CH.sub.3 CH.sub.3 n-propyl
A-358 cyclobutyl CH.sub.3 CH.sub.3 n-propyl A-359 cyclopentyl
CH.sub.3 CH.sub.3 n-propyl A-360 cyclohexyl CH.sub.3 CH.sub.3
n-propyl A-361 H H H isopropyl A-362 F H H isopropyl A-363 Cl H H
isopropyl A-364 Br H H isopropyl A-365 CH.sub.3 H H isopropyl A-366
CF.sub.3 H H isopropyl A-367 OCH.sub.3 H H isopropyl A-368
OCF.sub.3 H H isopropyl A-369 cyclopropyl H H isopropyl A-370
cyclobutyl H H isopropyl A-371 cyclopentyl H H isopropyl A-372
cyclohexyl H H isopropyl A-373 H CH.sub.3 H isopropyl A-374 F
CH.sub.3 H isopropyl A-375 Cl CH.sub.3 H isopropyl A-376 Br
CH.sub.3 H isopropyl A-377 CH.sub.3 CH.sub.3 H isopropyl A-378
CF.sub.3 CH.sub.3 H isopropyl A-379 OCH.sub.3 CH.sub.3 H isopropyl
A-380 OCF.sub.3 CH.sub.3 H isopropyl A-381 cyclopropyl CH.sub.3 H
isopropyl A-382 cyclobutyl CH.sub.3 H isopropyl A-383 cyclopentyl
CH.sub.3 H isopropyl A-384 cyclohexyl CH.sub.3 H isopropyl A-385 H
CH.sub.3 CH.sub.3 isopropyl A-386 F CH.sub.3 CH.sub.3 isopropyl
A-387 Cl CH.sub.3 CH.sub.3 isopropyl A-388 Br CH.sub.3 CH.sub.3
isopropyl A-389 CH.sub.3 CH.sub.3 CH.sub.3 isopropyl A-390 CF.sub.3
CH.sub.3 CH.sub.3 isopropyl A-391 OCH.sub.3 CH.sub.3 CH.sub.3
isopropyl A-392 OCF.sub.3 CH.sub.3 CH.sub.3 isopropyl A-393
cyclopropyl CH.sub.3 CH.sub.3 isopropyl A-394 cyclobutyl CH.sub.3
CH.sub.3 isopropyl A-395 cyclopentyl CH.sub.3 CH.sub.3 isopropyl
A-396 cyclohexyl CH.sub.3 CH.sub.3 isopropyl A-397 H H H n-butyl
A-398 F H H n-butyl A-399 Cl H H n-butyl A-400 Br H H n-butyl A-401
CH.sub.3 H H n-butyl A-402 CF.sub.3 H H n-butyl A-403 OCH.sub.3 H H
n-butyl A-404 OCF.sub.3 H H n-butyl A-405 cyclopropyl H H n-butyl
A-406 cyclobutyl H H n-butyl A-407 cyclopentyl H H n-butyl A-408
cyclohexyl H H n-butyl A-409 H CH.sub.3 H n-butyl A-410 F CH.sub.3
H n-butyl A-411 Cl CH.sub.3 H n-butyl A-412 Br CH.sub.3 H n-butyl
A-413 CH.sub.3 CH.sub.3 H n-butyl A-414 CF.sub.3 CH.sub.3 H n-butyl
A-415 OCH.sub.3 CH.sub.3 H n-butyl A-416 OCF.sub.3 CH.sub.3 H
n-butyl A-417 cyclopropyl CH.sub.3 H n-butyl A-418 cyclobutyl
CH.sub.3 H n-butyl A-419 cyclopentyl CH.sub.3 H n-butyl A-420
cyclohexyl CH.sub.3 H n-butyl A-421 H CH.sub.3 CH.sub.3 n-butyl
A-422 F CH.sub.3 CH.sub.3 n-butyl A-423 Cl CH.sub.3 CH.sub.3
n-butyl A-424 Br CH.sub.3 CH.sub.3 n-butyl A-425 CH.sub.3 CH.sub.3
CH.sub.3 n-butyl A-426 CF.sub.3 CH.sub.3 CH.sub.3 n-butyl A-427
OCH.sub.3 CH.sub.3 CH.sub.3 n-butyl A-428 OCF.sub.3 CH.sub.3
CH.sub.3 n-butyl A-429 cyclopropyl CH.sub.3 CH.sub.3 n-butyl A-430
cyclobutyl CH.sub.3 CH.sub.3 n-butyl A-431 cyclopentyl CH.sub.3
CH.sub.3 n-butyl A-432 cyclohexyl CH.sub.3 CH.sub.3 n-butyl A-433 H
H H cyclopropyl A-434 F H H cyclopropyl A-435 Cl H H cyclopropyl
A-436 Br H H cyclopropyl A-437 CH.sub.3 H H cyclopropyl A-438
CF.sub.3 H H cyclopropyl A-439 OCH.sub.3 H H cyclopropyl A-440
OCF.sub.3 H H cyclopropyl A-441 cyclopropyl H H cyclopropyl A-442
cyclobutyl H H cyclopropyl A-443 cyclopentyl H H cyclopropyl A-444
cyclohexyl H H cyclopropyl A-445 H CH.sub.3 H cyclopropyl A-446 F
CH.sub.3 H cyclopropyl A-447 Cl CH.sub.3 H cyclopropyl A-448 Br
CH.sub.3 H cyclopropyl A-449 CH.sub.3 CH.sub.3 H cyclopropyl A-450
CF.sub.3 CH.sub.3 H cyclopropyl A-451 OCH.sub.3 CH.sub.3 H
cyclopropyl A-452 OCF.sub.3 CH.sub.3 H cyclopropyl A-453
cyclopropyl CH.sub.3 H cyclopropyl A-454 cyclobutyl CH.sub.3 H
cyclopropyl A-455 cyclopentyl CH.sub.3 H cyclopropyl A-456
cyclohexyl CH.sub.3 H cyclopropyl A-457 H CH.sub.3 CH.sub.3
cyclopropyl A-458 F CH.sub.3 CH.sub.3 cyclopropyl A-459 Cl CH.sub.3
CH.sub.3 cyclopropyl A-460 Br CH.sub.3 CH.sub.3 cyclopropyl A-461
CH.sub.3 CH.sub.3 CH.sub.3 cyclopropyl A-462 CF.sub.3 CH.sub.3
CH.sub.3 cyclopropyl A-463 OCH.sub.3 CH.sub.3 CH.sub.3 cyclopropyl
A-464 OCF.sub.3 CH.sub.3 CH.sub.3 cyclopropyl A-465 cyclopropyl
CH.sub.3 CH.sub.3 cyclopropyl A-466 cyclobutyl CH.sub.3 CH.sub.3
cyclopropyl A-467 cyclopentyl CH.sub.3 CH.sub.3 cyclopropyl A-468
cyclohexyl CH.sub.3 CH.sub.3 cyclopropyl A-469 H H H cyclobutyl
A-470 F H H cyclobutyl A-471 Cl H H cyclobutyl A-472 Br H H
cyclobutyl A-473 CH.sub.3 H H cyclobutyl A-474 CF.sub.3 H H
cyclobutyl A-475 OCH.sub.3 H H cyclobutyl A-476 OCF.sub.3 H H
cyclobutyl A-477 cyclopropyl H H cyclobutyl A-478 cyclobutyl H H
cyclobutyl A-479 cyclopentyl H H cyclobutyl A-480 cyclohexyl H H
cyclobutyl A-481 H CH.sub.3 H cyclobutyl A-482 F CH.sub.3 H
cyclobutyl A-483 Cl CH.sub.3 H cyclobutyl A-484 Br CH.sub.3 H
cyclobutyl A-485 CH.sub.3 CH.sub.3 H cyclobutyl A-486 CF.sub.3
CH.sub.3 H cyclobutyl A-487 OCH.sub.3 CH.sub.3 H cyclobutyl A-488
OCF.sub.3 CH.sub.3 H cyclobutyl A-489 cyclopropyl CH.sub.3 H
cyclobutyl A-490 cyclobutyl CH.sub.3 H cyclobutyl A-491 cyclopentyl
CH.sub.3 H cyclobutyl A-492 cyclohexyl CH.sub.3 H cyclobutyl A-493
H CH.sub.3 CH.sub.3 cyclobutyl A-494 F CH.sub.3 CH.sub.3 cyclobutyl
A-495 Cl CH.sub.3 CH.sub.3 cyclobutyl A-496 Br CH.sub.3 CH.sub.3
cyclobutyl A-497 CH.sub.3 CH.sub.3 CH.sub.3 cyclobutyl
A-498 CF.sub.3 CH.sub.3 CH.sub.3 cyclobutyl A-499 OCH.sub.3
CH.sub.3 CH.sub.3 cyclobutyl A-500 OCF.sub.3 CH.sub.3 CH.sub.3
cyclobutyl A-501 cyclopropyl CH.sub.3 CH.sub.3 cyclobutyl A-502
cyclobutyl CH.sub.3 CH.sub.3 cyclobutyl A-503 cyclopentyl CH.sub.3
CH.sub.3 cyclobutyl A-504 cyclohexyl CH.sub.3 CH.sub.3 cyclobutyl
A-505 H H H cyclopentyl A-506 F H H cyclopentyl A-507 Cl H H
cyclopentyl A-508 Br H H cyclopentyl A-509 CH.sub.3 H H cyclopentyl
A-510 CF.sub.3 H H cyclopentyl A-511 OCH.sub.3 H H cyclopentyl
A-512 OCF.sub.3 H H cyclopentyl A-513 cyclopropyl H H cyclopentyl
A-514 cyclobutyl H H cyclopentyl A-515 cyclopentyl H H cyclopentyl
A-516 cyclohexyl H H cyclopentyl A-517 H CH.sub.3 H cyclopentyl
A-518 F CH.sub.3 H cyclopentyl A-519 Cl CH.sub.3 H cyclopentyl
A-520 Br CH.sub.3 H cyclopentyl A-521 CH.sub.3 CH.sub.3 H
cyclopentyl A-522 CF.sub.3 CH.sub.3 H cyclopentyl A-523 OCH.sub.3
CH.sub.3 H cyclopentyl A-524 OCF.sub.3 CH.sub.3 H cyclopentyl A-525
cyclopropyl CH.sub.3 H cyclopentyl A-526 cyclobutyl CH.sub.3 H
cyclopentyl A-527 cyclopentyl CH.sub.3 H cyclopentyl A-528
cyclohexyl CH.sub.3 H cyclopentyl A-529 H CH.sub.3 CH.sub.3
cyclopentyl A-530 F CH.sub.3 CH.sub.3 cyclopentyl A-531 Cl CH.sub.3
CH.sub.3 cyclopentyl A-532 Br CH.sub.3 CH.sub.3 cyclopentyl A-533
CH.sub.3 CH.sub.3 CH.sub.3 cyclopentyl A-534 CF.sub.3 CH.sub.3
CH.sub.3 cyclopentyl A-535 OCH.sub.3 CH.sub.3 CH.sub.3 cyclopentyl
A-536 OCF.sub.3 CH.sub.3 CH.sub.3 cyclopentyl A-537 cyclopropyl
CH.sub.3 CH.sub.3 cyclopentyl A-538 cyclobutyl CH.sub.3 CH.sub.3
cyclopentyl A-539 cyclopentyl CH.sub.3 CH.sub.3 cyclopentyl A-540
cyclohexyl CH.sub.3 CH.sub.3 cyclopentyl A-541 H H H cyclohexyl
A-542 F H H cyclohexyl A-543 Cl H H cyclohexyl A-544 Br H H
cyclohexyl A-545 CH.sub.3 H H cyclohexyl A-546 CF.sub.3 H H
cyclohexyl A-547 OCH.sub.3 H H cyclohexyl A-548 OCF.sub.3 H H
cyclohexyl A-549 cyclopropyl H H cyclohexyl A-550 cyclobutyl H H
cyclohexyl A-551 cyclopentyl H H cyclohexyl A-552 cyclohexyl H H
cyclohexyl A-553 H CH.sub.3 H cyclohexyl A-554 F CH.sub.3 H
cyclohexyl A-555 Cl CH.sub.3 H cyclohexyl A-556 Br CH.sub.3 H
cyclohexyl A-557 CH.sub.3 CH.sub.3 H cyclohexyl A-558 CF.sub.3
CH.sub.3 H cyclohexyl A-559 OCH.sub.3 CH.sub.3 H cyclohexyl A-560
OCF.sub.3 CH.sub.3 H cyclohexyl A-561 cyclopropyl CH.sub.3 H
cyclohexyl A-562 cyclobutyl CH.sub.3 H cyclohexyl A-563 cyclopentyl
CH.sub.3 H cyclohexyl A-564 cyclohexyl CH.sub.3 H cyclohexyl A-565
H CH.sub.3 CH.sub.3 cyclohexyl A-566 F CH.sub.3 CH.sub.3 cyclohexyl
A-567 Cl CH.sub.3 CH.sub.3 cyclohexyl A-568 Br CH.sub.3 CH.sub.3
cyclohexyl A-569 CH.sub.3 CH.sub.3 CH.sub.3 cyclohexyl A-570
CF.sub.3 CH.sub.3 CH.sub.3 cyclohexyl A-571 OCH.sub.3 CH.sub.3
CH.sub.3 cyclohexyl A-572 OCF.sub.3 CH.sub.3 CH.sub.3 cyclohexyl
A-573 cyclopropyl CH.sub.3 CH.sub.3 cyclohexyl A-574 cyclobutyl
CH.sub.3 CH.sub.3 cyclohexyl A-575 cyclopentyl CH.sub.3 CH.sub.3
cyclohexyl A-576 cyclohexyl CH.sub.3 CH.sub.3 cyclohexyl A-577 H H
H oxetan-.sub.3-yl A-578 F H H oxetan-.sub.3-yl A-579 Cl H H
oxetan-.sub.3-yl A-580 Br H H oxetan-.sub.3-yl A-581 CH.sub.3 H H
oxetan-.sub.3-yl A-582 CF.sub.3 H H oxetan-.sub.3-yl A-583
OCH.sub.3 H H oxetan-.sub.3-yl A-584 OCF.sub.3 H H oxetan-.sub.3-yl
A-585 cyclopropyl H H oxetan-.sub.3-yl A-586 cyclobutyl H H
oxetan-.sub.3-yl A-587 cyclopentyl H H oxetan-.sub.3-yl A-588
cyclohexyl H H oxetan-.sub.3-yl A-589 H CH.sub.3 H oxetan-.sub.3-yl
A-590 F CH.sub.3 H oxetan-.sub.3-yl A-591 Cl CH.sub.3 H
oxetan-.sub.3-yl A-592 Br CH.sub.3 H oxetan-.sub.3-yl A-593
CH.sub.3 CH.sub.3 H oxetan-.sub.3-yl A-594 CF.sub.3 CH.sub.3 H
oxetan-.sub.3-yl A-595 OCH.sub.3 CH.sub.3 H oxetan-.sub.3-yl A-596
OCF.sub.3 CH.sub.3 H oxetan-.sub.3-yl A-597 cyclopropyl CH.sub.3 H
oxetan-.sub.3-yl A-598 cyclobutyl CH.sub.3 H oxetan-.sub.3-yl A-599
cyclopentyl CH.sub.3 H oxetan-.sub.3-yl A-600 cyclohexyl CH.sub.3 H
oxetan-.sub.3-yl A-601 H CH.sub.3 CH.sub.3 oxetan-.sub.3-yl A-602 F
CH.sub.3 CH.sub.3 oxetan-.sub.3-yl A-603 Cl CH.sub.3 CH.sub.3
oxetan-.sub.3-yl A-604 Br CH.sub.3 CH.sub.3 oxetan-.sub.3-yl A-605
CH.sub.3 CH.sub.3 CH.sub.3 oxetan-.sub.3-yl A-606 CF.sub.3 CH.sub.3
CH.sub.3 oxetan-.sub.3-yl A-607 OCH.sub.3 CH.sub.3 CH.sub.3
oxetan-.sub.3-yl A-608 OCF.sub.3 CH.sub.3 CH.sub.3 oxetan-.sub.3-yl
A-609 cyclopropyl CH.sub.3 CH.sub.3 oxetan-.sub.3-yl A-610
cyclobutyl CH.sub.3 CH.sub.3 oxetan-.sub.3-yl A-611 cyclopentyl
CH.sub.3 CH.sub.3 oxetan-.sub.3-yl A-612 cyclohexyl CH.sub.3
CH.sub.3 oxetan-.sub.3-yl A-613 H H H --CH.sub.2-cyclopropyl A-614
F H H --CH.sub.2-cyclopropyl A-615 Cl H H --CH.sub.2-cyclopropyl
A-616 Br H H --CH.sub.2-cyclopropyl A-617 CH.sub.3 H H
--CH.sub.2-cyclopropyl A-618 CF.sub.3 H H --CH.sub.2-cyclopropyl
A-619 OCH.sub.3 H H --CH.sub.2-cyclopropyl A-620 OCF.sub.3 H H
--CH.sub.2-cyclopropyl A-621 cyclopropyl H H --CH.sub.2-cyclopropyl
A-622 cyclobutyl H H --CH.sub.2-cyclopropyl A-623 cyclopentyl H H
--CH.sub.2-cyclopropyl A-624 cyclohexyl H H --CH.sub.2-cyclopropyl
A-625 H CH.sub.3 H --CH.sub.2-cyclopropyl A-626 F CH.sub.3 H
--CH.sub.2-cyclopropyl A-627 Cl CH.sub.3 H --CH.sub.2-cyclopropyl
A-628 Br CH.sub.3 H --CH.sub.2-cyclopropyl A-629 CH.sub.3 CH.sub.3
H --CH.sub.2-cyclopropyl A-630 CF.sub.3 CH.sub.3 H
--CH.sub.2-cyclopropyl A-631 OCH.sub.3 CH.sub.3 H
--CH.sub.2-cyclopropyl A-632 OCF.sub.3 CH.sub.3 H
--CH.sub.2-cyclopropyl A-633 cyclopropyl CH.sub.3 H
--CH.sub.2-cyclopropyl A-634 cyclobutyl CH.sub.3 H
--CH.sub.2-cyclopropyl A-635 cyclopentyl CH.sub.3 H
--CH.sub.2-cyclopropyl A-636 cyclohexyl CH.sub.3 H
--CH.sub.2-cyclopropyl A-637 H CH.sub.3 CH.sub.3
--CH.sub.2-cyclopropyl A-638 F CH.sub.3 CH.sub.3
--CH.sub.2-cyclopropyl A-639 Cl CH.sub.3 CH.sub.3
--CH.sub.2-cyclopropyl A-640 Br CH.sub.3 CH.sub.3
--CH.sub.2-cyclopropyl A-641 CH.sub.3 CH.sub.3 CH.sub.3
--CH.sub.2-cyclopropyl A-642 CF.sub.3 CH.sub.3 CH.sub.3
--CH.sub.2-cyclopropyl A-643 OCH.sub.3 CH.sub.3 CH.sub.3
--CH.sub.2-cyclopropyl A-644 OCF.sub.3 CH.sub.3 CH.sub.3
--CH.sub.2-cyclopropyl A-645 cyclopropyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclopropyl A-646 cyclobutyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclopropyl A-647 cyclopentyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclopropyl A-648 cyclohexyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclopropyl A-649 H H H --CH.sub.2-cyclobutyl A-650 F H
H --CH.sub.2-cyclobutyl A-651 Cl H H --CH.sub.2-cyclobutyl A-652 Br
H H --CH.sub.2-cyclobutyl A-653 CH.sub.3 H H --CH.sub.2-cyclobutyl
A-654 CF.sub.3 H H --CH.sub.2-cyclobutyl A-655 OCH.sub.3 H H
--CH.sub.2-cyclobutyl A-656 OCF.sub.3 H H --CH.sub.2-cyclobutyl
A-657 cyclopropyl H H --CH.sub.2-cyclobutyl A-658 cyclobutyl H H
--CH.sub.2-cyclobutyl A-659 cyclopentyl H H --CH.sub.2-cyclobutyl
A-660 cyclohexyl H H --CH.sub.2-cyclobutyl A-661 H CH.sub.3 H
--CH.sub.2-cyclobutyl A-662 F CH.sub.3 H --CH.sub.2-cyclobutyl
A-663 Cl CH.sub.3 H --CH.sub.2-cyclobutyl A-664 Br CH.sub.3 H
--CH.sub.2-cyclobutyl A-665 CH.sub.3 CH.sub.3 H
--CH.sub.2-cyclobutyl A-666 CF.sub.3 CH.sub.3 H
--CH.sub.2-cyclobutyl A-667 OCH.sub.3 CH.sub.3 H
--CH.sub.2-cyclobutyl A-668 OCF.sub.3 CH.sub.3 H
--CH.sub.2-cyclobutyl A-669 cyclopropyl CH.sub.3 H
--CH.sub.2-cyclobutyl A-670 cyclobutyl CH.sub.3 H
--CH.sub.2-cyclobutyl A-671 cyclopentyl CH.sub.3 H
--CH.sub.2-cyclobutyl A-672 cyclohexyl CH.sub.3 H
--CH.sub.2-cyclobutyl A-673 H CH.sub.3 CH.sub.3
--CH.sub.2-cyclobutyl A-674 F CH.sub.3 CH.sub.3
--CH.sub.2-cyclobutyl A-675 Cl CH.sub.3 CH.sub.3
--CH.sub.2-cyclobutyl A-676 Br CH.sub.3 CH.sub.3
--CH.sub.2-cyclobutyl A-677 CH.sub.3 CH.sub.3 CH.sub.3
--CH.sub.2-cyclobutyl A-678 CF.sub.3 CH.sub.3 CH.sub.3
--CH.sub.2-cyclobutyl A-679 OCH.sub.3 CH.sub.3 CH.sub.3
--CH.sub.2-cyclobutyl A-680 OCF.sub.3 CH.sub.3 CH.sub.3
--CH.sub.2-cyclobutyl A-681 cyclopropyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclobutyl A-682 cyclobutyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclobutyl A-683 cyclopentyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclobutyl A-684 cyclohexyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclobutyl A-685 H H H --CH.sub.2-cyclopentyl A-686 F H
H --CH.sub.2-cyclopentyl A-687 Cl H H --CH.sub.2-cyclopentyl A-688
Br H H --CH.sub.2-cyclopentyl A-689 CH.sub.3 H H
--CH.sub.2-cyclopentyl A-690 CF.sub.3 H H --CH.sub.2-cyclopentyl
A-691 OCH.sub.3 H H --CH.sub.2-cyclopentyl A-692 OCF.sub.3 H H
--CH.sub.2-cyclopentyl A-693 cyclopropyl H H --CH.sub.2-cyclopentyl
A-694 cyclobutyl H H --CH.sub.2-cyclopentyl A-695 cyclopentyl H H
--CH.sub.2-cyclopentyl A-696 cyclohexyl H H --CH.sub.2-cyclopentyl
A-697 H CH.sub.3 H --CH.sub.2-cyclopentyl A-698 F CH.sub.3 H
--CH.sub.2-cyclopentyl A-699 Cl CH.sub.3 H --CH.sub.2-cyclopentyl
A-700 Br CH.sub.3 H --CH.sub.2-cyclopentyl A-701 CH.sub.3 CH.sub.3
H --CH.sub.2-cyclopentyl A-702 CF.sub.3 CH.sub.3 H
--CH.sub.2-cyclopentyl A-703 OCH.sub.3 CH.sub.3 H
--CH.sub.2-cyclopentyl A-704 OCF.sub.3 CH.sub.3 H
--CH.sub.2-cyclopentyl A-705 cyclopropyl CH.sub.3 H
--CH.sub.2-cyclopentyl A-706 cyclobutyl CH.sub.3 H
--CH.sub.2-cyclopentyl A-707 cyclopentyl CH.sub.3 H
--CH.sub.2-cyclopentyl A-708 cyclohexyl CH.sub.3 H
--CH.sub.2-cyclopentyl A-709 H CH.sub.3 CH.sub.3
--CH.sub.2-cyclopentyl A-710 F CH.sub.3 CH.sub.3
--CH.sub.2-cyclopentyl A-711 Cl CH.sub.3 CH.sub.3
--CH.sub.2-cyclopentyl A-712 Br CH.sub.3 CH.sub.3
--CH.sub.2-cyclopentyl A-713 CH.sub.3 CH.sub.3 CH.sub.3
--CH.sub.2-cyclopentyl A-714 CF.sub.3 CH.sub.3 CH.sub.3
--CH.sub.2-cyclopentyl A-715 OCH.sub.3 CH.sub.3 CH.sub.3
--CH.sub.2-cyclopentyl A-716 OCF.sub.3 CH.sub.3 CH.sub.3
--CH.sub.2-cyclopentyl A-717 cyclopropyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclopentyl A-718 cyclobutyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclopentyl A-719 cyclopentyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclopentyl A-720 cyclohexyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclopentyl A-721 H H H --CH.sub.2-cyclohexyl A-722 F H
H --CH.sub.2-cyclohexyl A-723 Cl H H --CH.sub.2-cyclohexyl A-724 Br
H H --CH.sub.2-cyclohexyl A-725 CH.sub.3 H H --CH.sub.2-cyclohexyl
A-726 CF.sub.3 H H --CH.sub.2-cyclohexyl A-727 OCH.sub.3 H H
--CH.sub.2-cyclohexyl A-728 OCF.sub.3 H H --CH.sub.2-cyclohexyl
A-729 cyclopropyl H H --CH.sub.2-cyclohexyl A-730 cyclobutyl H H
--CH.sub.2-cyclohexyl A-731 cyclopentyl H H --CH.sub.2-cyclohexyl
A-732 cyclohexyl H H --CH.sub.2-cyclohexyl A-733 H CH.sub.3 H
--CH.sub.2-cyclohexyl A-734 F CH.sub.3 H --CH.sub.2-cyclohexyl
A-735 Cl CH.sub.3 H --CH.sub.2-cyclohexyl A-736 Br CH.sub.3 H
--CH.sub.2-cyclohexyl A-737 CH.sub.3 CH.sub.3 H
--CH.sub.2-cyclohexyl A-738 CF.sub.3 CH.sub.3 H
--CH.sub.2-cyclohexyl A-739 OCH.sub.3 CH.sub.3 H
--CH.sub.2-cyclohexyl A-740 OCF.sub.3 CH.sub.3 H
--CH.sub.2-cyclohexyl A-741 cyclopropyl CH.sub.3 H
--CH.sub.2-cyclohexyl A-742 cyclobutyl CH.sub.3 H
--CH.sub.2-cyclohexyl A-743 cyclopentyl CH.sub.3 H
--CH.sub.2-cyclohexyl A-744 cyclohexyl CH.sub.3 H
--CH.sub.2-cyclohexyl A-745 H CH.sub.3 CH.sub.3
--CH.sub.2-cyclohexyl A-746 F CH.sub.3 CH.sub.3
--CH.sub.2-cyclohexyl A-747 Cl CH.sub.3 CH.sub.3
--CH.sub.2-cyclohexyl A-748 Br CH.sub.3 CH.sub.3
--CH.sub.2-cyclohexyl
A-749 CH.sub.3 CH.sub.3 CH.sub.3 --CH.sub.2-cyclohexyl A-750
CF.sub.3 CH.sub.3 CH.sub.3 --CH.sub.2-cyclohexyl A-751 OCH.sub.3
CH.sub.3 CH.sub.3 --CH.sub.2-cyclohexyl A-752 OCF.sub.3 CH.sub.3
CH.sub.3 --CH.sub.2-cyclohexyl A-753 cyclopropyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclohexyl A-754 cyclobutyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclohexyl A-755 cyclopentyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclohexyl A-756 cyclohexyl CH.sub.3 CH.sub.3
--CH.sub.2-cyclohexyl A-757 H H H --C(O)-cyclopropyl A-758 F H H
--C(O)-cyclopropyl A-759 Cl H H --C(O)-cyclopropyl A-760 Br H H
--C(O)-cyclopropyl A-761 CH.sub.3 H H --C(O)-cyclopropyl A-762
CF.sub.3 H H --C(O)-cyclopropyl A-763 OCH.sub.3 H H
--C(O)-cyclopropyl A-764 OCF.sub.3 H H --C(O)-cyclopropyl A-765
cyclopropyl H H --C(O)-cyclopropyl A-766 cyclobutyl H H
--C(O)-cyclopropyl A-767 cyclopentyl H H --C(O)-cyclopropyl A-768
cyclohexyl H H --C(O)-cyclopropyl A-769 H CH.sub.3 H
--C(O)-cyclopropyl A-770 F CH.sub.3 H --C(O)-cyclopropyl A-771 Cl
CH.sub.3 H --C(O)-cyclopropyl A-772 Br CH.sub.3 H
--C(O)-cyclopropyl A-773 CH.sub.3 CH.sub.3 H --C(O)-cyclopropyl
A-774 CF.sub.3 CH.sub.3 H --C(O)-cyclopropyl A-775 OCH.sub.3
CH.sub.3 H --C(O)-cyclopropyl A-776 OCF.sub.3 CH.sub.3 H
--C(O)-cyclopropyl A-777 cyclopropyl CH.sub.3 H --C(O)-cyclopropyl
A-778 cyclobutyl CH.sub.3 H --C(O)-cyclopropyl A-779 cyclopentyl
CH.sub.3 H --C(O)-cyclopropyl A-780 cyclohexyl CH.sub.3 H
--C(O)-cyclopropyl A-781 H CH.sub.3 CH.sub.3 --C(O)-cyclopropyl
A-782 F CH.sub.3 CH.sub.3 --C(O)-cyclopropyl A-783 Cl CH.sub.3
CH.sub.3 --C(O)-cyclopropyl A-784 Br CH.sub.3 CH.sub.3
--C(O)-cyclopropyl A-785 CH.sub.3 CH.sub.3 CH.sub.3
--C(O)-cyclopropyl A-786 CF.sub.3 CH.sub.3 CH.sub.3
--C(O)-cyclopropyl A-787 OCH.sub.3 CH.sub.3 CH.sub.3
--C(O)-cyclopropyl A-788 OCF.sub.3 CH.sub.3 CH.sub.3
--C(O)-cyclopropyl A-789 cyclopropyl CH.sub.3 CH.sub.3
--C(O)-cyclopropyl A-790 cyclobutyl CH.sub.3 CH.sub.3
--C(O)-cyclopropyl A-791 cyclopentyl CH.sub.3 CH.sub.3
--C(O)-cyclopropyl A-792 cyclohexyl CH.sub.3 CH.sub.3
--C(O)-cyclopropyl A-793 H H H --C(O)-cyclobutyl A-794 F H H
--C(O)-cyclobutyl A-795 Cl H H --C(O)-cyclobutyl A-796 Br H H
--C(O)-cyclobutyl A-797 CH.sub.3 H H --C(O)-cyclobutyl A-798
CF.sub.3 H H --C(O)-cyclobutyl A-799 OCH.sub.3 H H
--C(O)-cyclobutyl A-800 OCF.sub.3 H H --C(O)-cyclobutyl A-801
cyclopropyl H H --C(O)-cyclobutyl A-802 cyclobutyl H H
--C(O)-cyclobutyl A-803 cyclopentyl H H --C(O)-cyclobutyl A-804
cyclohexyl H H --C(O)-cyclobutyl A-805 H CH.sub.3 H
--C(O)-cyclobutyl A-806 F CH.sub.3 H --C(O)-cyclobutyl A-807 Cl
CH.sub.3 H --C(O)-cyclobutyl A-808 Br CH.sub.3 H --C(O)-cyclobutyl
A-809 CH.sub.3 CH.sub.3 H --C(O)-cyclobutyl A-810 CF.sub.3 CH.sub.3
H --C(O)-cyclobutyl A-811 OCH.sub.3 CH.sub.3 H --C(O)-cyclobutyl
A-812 OCF.sub.3 CH.sub.3 H --C(O)-cyclobutyl A-813 cyclopropyl
CH.sub.3 H --C(O)-cyclobutyl A-814 cyclobutyl CH.sub.3 H
--C(O)-cyclobutyl A-815 cyclopentyl CH.sub.3 H --C(O)-cyclobutyl
A-816 cyclohexyl CH.sub.3 H --C(O)-cyclobutyl A-817 H CH.sub.3
CH.sub.3 --C(O)-cyclobutyl A-818 F CH.sub.3 CH.sub.3
--C(O)-cyclobutyl A-819 Cl CH.sub.3 CH.sub.3 --C(O)-cyclobutyl
A-820 Br CH.sub.3 CH.sub.3 --C(O)-cyclobutyl A-821 CH.sub.3
CH.sub.3 CH.sub.3 --C(O)-cyclobutyl A-822 CF.sub.3 CH.sub.3
CH.sub.3 --C(O)-cyclobutyl A-823 OCH.sub.3 CH.sub.3 CH.sub.3
--C(O)-cyclobutyl A-824 OCF.sub.3 CH.sub.3 CH.sub.3
--C(O)-cyclobutyl A-825 cyclopropyl CH.sub.3 CH.sub.3
--C(O)-cyclobutyl A-826 cyclobutyl CH.sub.3 CH.sub.3
--C(O)-cyclobutyl A-827 cyclopentyl CH.sub.3 CH.sub.3
--C(O)-cyclobutyl A-828 cyclohexyl CH.sub.3 CH.sub.3
--C(O)-cyclobutyl A-829 H H H --C(O)-cyclopentyl A-830 F H H
--C(O)-cyclopentyl A-831 Cl H H --C(O)-cyclopentyl A-832 Br H H
--C(O)-cyclopentyl A-833 CH.sub.3 H H --C(O)-cyclopentyl A-834
CF.sub.3 H H --C(O)-cyclopentyl A-835 OCH.sub.3 H H
--C(O)-cyclopentyl A-836 OCF.sub.3 H H --C(O)-cyclopentyl A-837
cyclopropyl H H --C(O)-cyclopentyl A-838 cyclobutyl H H
--C(O)-cyclopentyl A-839 cyclopentyl H H --C(O)-cyclopentyl A-840
cyclohexyl H H --C(O)-cyclopentyl A-841 H CH.sub.3 H
--C(O)-cyclopentyl A-842 F CH.sub.3 H --C(O)-cyclopentyl A-843 Cl
CH.sub.3 H --C(O)-cyclopentyl A-844 Br CH.sub.3 H
--C(O)-cyclopentyl A-845 CH.sub.3 CH.sub.3 H --C(O)-cyclopentyl
A-846 CF.sub.3 CH.sub.3 H --C(O)-cyclopentyl A-847 OCH.sub.3
CH.sub.3 H --C(O)-cyclopentyl A-848 OCF.sub.3 CH.sub.3 H
--C(O)-cyclopentyl A-849 cyclopropyl CH.sub.3 H --C(O)-cyclopentyl
A-850 cyclobutyl CH.sub.3 H --C(O)-cyclopentyl A-851 cyclopentyl
CH.sub.3 H --C(O)-cyclopentyl A-852 cyclohexyl CH.sub.3 H
--C(O)-cyclopentyl A-853 H CH.sub.3 CH.sub.3 --C(O)-cyclopentyl
A-854 F CH.sub.3 CH.sub.3 --C(O)-cyclopentyl A-855 Cl CH.sub.3
CH.sub.3 --C(O)-cyclopentyl A-856 Br CH.sub.3 CH.sub.3
--C(O)-cyclopentyl A-857 CH.sub.3 CH.sub.3 CH.sub.3
--C(O)-cyclopentyl A-858 CF.sub.3 CH.sub.3 CH.sub.3
--C(O)-cyclopentyl A-859 OCH.sub.3 CH.sub.3 CH.sub.3
--C(O)-cyclopentyl A-860 OCF.sub.3 CH.sub.3 CH.sub.3
--C(O)-cyclopentyl A-861 cyclopropyl CH.sub.3 CH.sub.3
--C(O)-cyclopentyl A-862 cyclobutyl CH.sub.3 CH.sub.3
--C(O)-cyclopentyl A-863 cyclopentyl CH.sub.3 CH.sub.3
--C(O)-cyclopentyl A-864 cyclohexyl CH.sub.3 CH.sub.3
--C(O)-cyclopentyl A-865 H H H --C(O)-cyclohexyl A-866 F H H
--C(O)-cyclohexyl A-867 Cl H H --C(O)-cyclohexyl A-868 Br H H
--C(O)-cyclohexyl A-869 CH.sub.3 H H --C(O)-cyclohexyl A-870
CF.sub.3 H H --C(O)-cyclohexyl A-871 OCH.sub.3 H H
--C(O)-cyclohexyl A-872 OCF.sub.3 H H --C(O)-cyclohexyl A-873
cyclopropyl H H --C(O)-cyclohexyl A-874 cyclobutyl H H
--C(O)-cyclohexyl A-875 cyclopentyl H H --C(O)-cyclohexyl A-876
cyclohexyl H H --C(O)-cyclohexyl A-877 H CH.sub.3 H
--C(O)-cyclohexyl A-878 F CH.sub.3 H --C(O)-cyclohexyl A-879 Cl
CH.sub.3 H --C(O)-cyclohexyl A-880 Br CH.sub.3 H --C(O)-cyclohexyl
A-881 CH.sub.3 CH.sub.3 H --C(O)-cyclohexyl A-882 CF.sub.3 CH.sub.3
H --C(O)-cyclohexyl A-883 OCH.sub.3 CH.sub.3 H --C(O)-cyclohexyl
A-884 OCF.sub.3 CH.sub.3 H --C(O)-cyclohexyl A-885 cyclopropyl
CH.sub.3 H --C(O)-cyclohexyl A-886 cyclobutyl CH.sub.3 H
--C(O)-cyclohexyl A-887 cyclopentyl CH.sub.3 H --C(O)-cyclohexyl
A-888 cyclohexyl CH.sub.3 H --C(O)-cyclohexyl A-889 H CH.sub.3
CH.sub.3 --C(O)-cyclohexyl A-890 F CH.sub.3 CH.sub.3
--C(O)-cyclohexyl A-891 Cl CH.sub.3 CH.sub.3 --C(O)-cyclohexyl
A-892 Br CH.sub.3 CH.sub.3 --C(O)-cyclohexyl A-893 CH.sub.3
CH.sub.3 CH.sub.3 --C(O)-cyclohexyl A-894 CF.sub.3 CH.sub.3
CH.sub.3 --C(O)-cyclohexyl A-895 OCH.sub.3 CH.sub.3 CH.sub.3
--C(O)-cyclohexyl A-896 OCF.sub.3 CH.sub.3 CH.sub.3
--C(O)-cyclohexyl A-897 cyclopropyl CH.sub.3 CH.sub.3
--C(O)-cyclohexyl A-898 cyclobutyl CH.sub.3 CH.sub.3
--C(O)-cyclohexyl A-899 cyclopentyl CH.sub.3 CH.sub.3
--C(O)-cyclohexyl A-900 cyclohexyl CH.sub.3 CH.sub.3
--C(O)-cyclohexyl A-901 H H --(CH.sub.2).sub.3-- A-902 F H
--(CH.sub.2).sub.3-- A-903 Cl H --(CH.sub.2).sub.3-- A-904 Br H
--(CH.sub.2).sub.3-- A-905 CH.sub.3 H --(CH.sub.2).sub.3-- A-906
CF.sub.3 H --(CH.sub.2).sub.3-- A-907 OCH.sub.3 H
--(CH.sub.2).sub.3-- A-908 OCF.sub.3 H --(CH.sub.2).sub.3-- A-909
cyclopropyl H --(CH.sub.2).sub.3-- A-910 cyclobutyl H
--(CH.sub.2).sub.3-- A-911 cyclopentyl H --(CH.sub.2).sub.3-- A-912
cyclohexyl H --(CH.sub.2).sub.3-- A-913 H CH.sub.3
--(CH.sub.2).sub.3-- A-914 F CH.sub.3 --(CH.sub.2).sub.3-- A-915 Cl
CH.sub.3 --(CH.sub.2).sub.3-- A-916 Br CH.sub.3
--(CH.sub.2).sub.3-- A-917 CH.sub.3 CH.sub.3 --(CH.sub.2).sub.3--
A-918 CF.sub.3 CH.sub.3 --(CH.sub.2).sub.3-- A-919 OCH.sub.3
CH.sub.3 --(CH.sub.2).sub.3-- A-920 OCF.sub.3 CH.sub.3
--(CH.sub.2).sub.3-- A-921 cyclopropyl CH.sub.3
--(CH.sub.2).sub.3-- A-922 cyclobutyl CH.sub.3 --(CH.sub.2).sub.3--
A-923 cyclopentyl CH.sub.3 --(CH.sub.2).sub.3-- A-924 cyclohexyl
CH.sub.3 --(CH.sub.2).sub.3-- A-925 H D --(CH.sub.2).sub.3-- A-926
F D --(CH.sub.2).sub.3-- A-927 Cl D --(CH.sub.2).sub.3-- A-928 Br D
--(CH.sub.2).sub.3-- A-929 CH.sub.3 D --(CH.sub.2).sub.3-- A-930
CF.sub.3 D --(CH.sub.2).sub.3-- A-931 OCH.sub.3 D
--(CH.sub.2).sub.3-- A-932 OCF.sub.3 D --(CH.sub.2).sub.3-- A-933
cyclopropyl D --(CH.sub.2).sub.3-- A-934 cyclobutyl D
--(CH.sub.2).sub.3-- A-935 cyclopentyl D --(CH.sub.2).sub.3-- A-936
cyclohexyl D --(CH.sub.2).sub.3-- A-937 H H --(CH.sub.2).sub.4--
A-938 F H --(CH.sub.2).sub.4-- A-939 Cl H --(CH.sub.2).sub.4--
A-940 Br H --(CH.sub.2).sub.4-- A-941 CH.sub.3 H
--(CH.sub.2).sub.4-- A-942 CF.sub.3 H --(CH.sub.2).sub.4-- A-943
OCH.sub.3 H --(CH.sub.2).sub.4-- A-944 OCF.sub.3 H
--(CH.sub.2).sub.4-- A-945 cyclopropyl H --(CH.sub.2).sub.4-- A-946
cyclobutyl H --(CH.sub.2).sub.4-- A-947 cyclopentyl H
--(CH.sub.2).sub.4-- A-948 cyclohexyl H --(CH.sub.2).sub.4-- A-949
H CH.sub.3 --(CH.sub.2).sub.4-- A-950 F CH.sub.3
--(CH.sub.2).sub.4-- A-951 Cl CH.sub.3 --(CH.sub.2).sub.4-- A-952
Br CH.sub.3 --(CH.sub.2).sub.4-- A-953 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.4-- A-954 CF.sub.3 CH.sub.3 --(CH.sub.2).sub.4--
A-955 OCH.sub.3 CH.sub.3 --(CH.sub.2).sub.4-- A-956 OCF.sub.3
CH.sub.3 --(CH.sub.2).sub.4-- A-957 cyclopropyl CH.sub.3
--(CH.sub.2).sub.4-- A-958 cyclobutyl CH.sub.3 --(CH.sub.2).sub.4--
A-959 cyclopentyl CH.sub.3 --(CH.sub.2).sub.4-- A-960 cyclohexyl
CH.sub.3 --(CH.sub.2).sub.4-- A-961 H D --(CH.sub.2).sub.4-- A-962
F D --(CH.sub.2).sub.4-- A-963 Cl D --(CH.sub.2).sub.4-- A-964 Br D
--(CH.sub.2).sub.4-- A-965 CH.sub.3 D --(CH.sub.2).sub.4-- A-966
CF.sub.3 D --(CH.sub.2).sub.4-- A-967 OCH.sub.3 D
--(CH.sub.2).sub.4-- A-968 OCF.sub.3 D --(CH.sub.2).sub.4-- A-969
cyclopropyl D --(CH.sub.2).sub.4-- A-970 cyclobutyl D
--(CH.sub.2).sub.4-- A-971 cyclopentyl D --(CH.sub.2).sub.4-- A-972
cyclohexyl D --(CH.sub.2).sub.4-- A-973 H H --(CH.sub.2).sub.5--
A-974 F H --(CH.sub.2).sub.5-- A-975 Cl H --(CH.sub.2).sub.5--
A-976 Br H --(CH.sub.2).sub.5-- A-977 CH.sub.3 H
--(CH.sub.2).sub.5-- A-978 CF.sub.3 H --(CH.sub.2).sub.5-- A-979
OCH.sub.3 H --(CH.sub.2).sub.5-- A-980 OCF.sub.3 H
--(CH.sub.2).sub.5-- A-981 cyclopropyl H --(CH.sub.2).sub.5-- A-982
cyclobutyl H --(CH.sub.2).sub.5-- A-983 cyclopentyl H
--(CH.sub.2).sub.5-- A-984 cyclohexyl H --(CH.sub.2).sub.5-- A-985
H CH.sub.3 --(CH.sub.2).sub.5-- A-986 F CH.sub.3
--(CH.sub.2).sub.5-- A-987 Cl CH.sub.3 --(CH.sub.2).sub.5-- A-988
Br CH.sub.3 --(CH.sub.2).sub.5-- A-989 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.5-- A-990 CF.sub.3 CH.sub.3 --(CH.sub.2).sub.5--
A-991 OCH.sub.3 CH.sub.3 --(CH.sub.2).sub.5-- A-992 OCF.sub.3
CH.sub.3 --(CH.sub.2).sub.5-- A-993 cyclopropyl CH.sub.3
--(CH.sub.2).sub.5-- A-994 cyclobutyl CH.sub.3 --(CH.sub.2).sub.5--
A-995 cyclopentyl CH.sub.3 --(CH.sub.2).sub.5-- A-996 cyclohexyl
CH.sub.3 --(CH.sub.2).sub.5-- A-997 H D --(CH.sub.2).sub.5-- A-998
F D --(CH.sub.2).sub.5-- A-999 Cl D --(CH.sub.2).sub.5--
A-1000 Br D --(CH.sub.2).sub.5-- A-1001 CH.sub.3 D
--(CH.sub.2).sub.5-- A-1002 CF.sub.3 D --(CH.sub.2).sub.5-- A-1003
OCH.sub.3 D --(CH.sub.2).sub.5-- A-1004 OCF.sub.3 D
--(CH.sub.2).sub.5-- A-1005 cyclopropyl D --(CH.sub.2).sub.5--
A-1006 cyclobutyl D --(CH.sub.2).sub.5-- A-1007 cyclopentyl D
--(CH.sub.2).sub.5-- A-1008 cyclohexyl D --(CH.sub.2).sub.5--
A-1009 F H --(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)--*** A-1010 Cl H
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1011 Br H
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1012 CH.sub.3 H
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1013 CF.sub.3 H
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1014 OCH.sub.3 H
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1015 OCF.sub.3 H
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1016 cyclopropyl H
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1017 cyclobutyl H
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1018 cyclopentyl H
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1019 cyclohexyl H
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1020 H CH.sub.3
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1021 F CH.sub.3
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1022 Cl CH.sub.3
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1023 Br CH.sub.3
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1024 CH.sub.3 CH.sub.3
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1025 CF.sub.3 CH.sub.3
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1026 OCH.sub.3 CH.sub.3
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1027 OCF.sub.3 CH.sub.3
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1028 cyclopropyl CH.sub.3
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1029 cyclobutyl CH.sub.3
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1030 cyclopentyl CH.sub.3
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1031 cyclohexyl CH.sub.3
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1032 H D
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1033 F D
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1034 Cl D
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1035 Br D
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1036 CH.sub.3 D
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1037 CF.sub.3 D
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1038 OCH.sub.3 D
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1039 OCF.sub.3 D
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1040 cyclopropyl D
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1041 cyclobutyl D
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1042 cyclopentyl D
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- A-1043 cyclohexyl D
--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- *C.sub.6H.sub.5 = phenyl
**C.sub.6H.sub.4CH.sub.3 = 4-methylphenyl (p-tolyl)
***--(CH.sub.2--CH--(.mu.-CH.sub.2)--CH)-- = ##STR00018##
TABLE-US-00002 TABLE B No. R.sup.9a R.sup.5b R.sup.5a R.sup.7
R.sup.8 B-1 H H H CH.sub.3 CH.sub.3 B-2 F H H CH.sub.3 CH.sub.3 B-3
Cl H H CH.sub.3 CH.sub.3 B-4 Br H H CH.sub.3 CH.sub.3 B-5 CH.sub.3
H H CH.sub.3 CH.sub.3 B-6 CF.sub.3 H H CH.sub.3 CH.sub.3 B-7
OCH.sub.3 H H CH.sub.3 CH.sub.3 B-8 OCF.sub.3 H H CH.sub.3 CH.sub.3
B-9 H F H CH.sub.3 CH.sub.3 B-10 F F H CH.sub.3 CH.sub.3 B-11 Cl F
H CH.sub.3 CH.sub.3 B-12 Br F H CH.sub.3 CH.sub.3 B-13 CH.sub.3 F H
CH.sub.3 CH.sub.3 B-14 CF.sub.3 F H CH.sub.3 CH.sub.3 B-15
OCH.sub.3 F H CH.sub.3 CH.sub.3 B-16 OCF.sub.3 F H CH.sub.3
CH.sub.3 B-17 H Cl H CH.sub.3 CH.sub.3 B-18 F Cl H CH.sub.3
CH.sub.3 B-19 Cl Cl H CH.sub.3 CH.sub.3 B-20 Br Cl H CH.sub.3
CH.sub.3 B-21 CH.sub.3 Cl H CH.sub.3 CH.sub.3 B-22 CF.sub.3 Cl H
CH.sub.3 CH.sub.3 B-23 OCH.sub.3 Cl H CH.sub.3 CH.sub.3 B-24
OCF.sub.3 Cl H CH.sub.3 CH.sub.3 B-25 H CH.sub.3 H CH.sub.3
CH.sub.3 B-26 F CH.sub.3 H CH.sub.3 CH.sub.3 B-27 Cl CH.sub.3 H
CH.sub.3 CH.sub.3 B-28 Br CH.sub.3 H CH.sub.3 CH.sub.3 B-29
CH.sub.3 CH.sub.3 H CH.sub.3 CH.sub.3 B-30 CF.sub.3 CH.sub.3 H
CH.sub.3 CH.sub.3 B-31 OCH.sub.3 CH.sub.3 H CH.sub.3 CH.sub.3 B-32
OCF.sub.3 CH.sub.3 H CH.sub.3 CH.sub.3 B-33 H CH.sub.3 CH.sub.3
CH.sub.3 CH.sub.3 B-34 F CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 B-35
Cl CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 B-36 Br CH.sub.3 CH.sub.3
CH.sub.3 CH.sub.3 B-37 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3
B-38 CF.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 B-39 OCH.sub.3
CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 B-40 OCF.sub.3 CH.sub.3
CH.sub.3 CH.sub.3 CH.sub.3 B-41 H H H CH.sub.3 CH.sub.2CH.sub.3
B-42 F H H CH.sub.3 CH.sub.2CH.sub.3 B-43 Cl H H CH.sub.3
CH.sub.2CH.sub.3 B-44 Br H H CH.sub.3 CH.sub.2CH.sub.3 B-45
CH.sub.3 H H CH.sub.3 CH.sub.2CH.sub.3 B-46 CF.sub.3 H H CH.sub.3
CH.sub.2CH.sub.3 B-47 OCH.sub.3 H H CH.sub.3 CH.sub.2CH.sub.3 B-48
OCF.sub.3 H H CH.sub.3 CH.sub.2CH.sub.3 B-49 H F H CH.sub.3
CH.sub.2CH.sub.3 B-50 F F H CH.sub.3 CH.sub.2CH.sub.3 B-51 Cl F H
CH.sub.3 CH.sub.2CH.sub.3 B-52 Br F H CH.sub.3 CH.sub.2CH.sub.3
B-53 CH.sub.3 F H CH.sub.3 CH.sub.2CH.sub.3 B-54 CF.sub.3 F H
CH.sub.3 CH.sub.2CH.sub.3 B-55 OCH.sub.3 F H CH.sub.3
CH.sub.2CH.sub.3 B-56 OCF.sub.3 F H CH.sub.3 CH.sub.2CH.sub.3 B-57
H Cl H CH.sub.3 CH.sub.2CH.sub.3 B-58 F Cl H CH.sub.3
CH.sub.2CH.sub.3 B-59 Cl Cl H CH.sub.3 CH.sub.2CH.sub.3 B-60 Br Cl
H CH.sub.3 CH.sub.2CH.sub.3 B-61 CH.sub.3 Cl H CH.sub.3
CH.sub.2CH.sub.3 B-62 CF.sub.3 Cl H CH.sub.3 CH.sub.2CH.sub.3 B-63
OCH.sub.3 Cl H CH.sub.3 CH.sub.2CH.sub.3 B-64 OCF.sub.3 Cl H
CH.sub.3 CH.sub.2CH.sub.3 B-65 H CH.sub.3 H CH.sub.3
CH.sub.2CH.sub.3 B-66 F CH.sub.3 H CH.sub.3 CH.sub.2CH.sub.3 B-67
Cl CH.sub.3 H CH.sub.3 CH.sub.2CH.sub.3 B-68 Br CH.sub.3 H CH.sub.3
CH.sub.2CH.sub.3 B-69 CH.sub.3 CH.sub.3 H CH.sub.3 CH.sub.2CH.sub.3
B-70 CF.sub.3 CH.sub.3 H CH.sub.3 CH.sub.2CH.sub.3 B-71 OCH.sub.3
CH.sub.3 H CH.sub.3 CH.sub.2CH.sub.3 B-72 OCF.sub.3 CH.sub.3 H
CH.sub.3 CH.sub.2CH.sub.3 B-73 H CH.sub.3 CH.sub.3 CH.sub.3
CH.sub.2CH.sub.3 B-74 F CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2CH.sub.3
B-75 Cl CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2CH.sub.3 B-76 Br
CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2CH.sub.3 B-77 CH.sub.3 CH.sub.3
CH.sub.3 CH.sub.3 CH.sub.2CH.sub.3 B-78 CF.sub.3 CH.sub.3 CH.sub.3
CH.sub.3 CH.sub.2CH.sub.3 B-79 OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3
CH.sub.2CH.sub.3 B-80 OCF.sub.3 CH.sub.3 CH.sub.3 CH.sub.3
CH.sub.2CH.sub.3 B-81 H H H CH.sub.3 CF.sub.3 B-82 F H H CH.sub.3
CF.sub.3 B-83 Cl H H CH.sub.3 CF.sub.3 B-84 Br H H CH.sub.3
CF.sub.3 B-85 CH.sub.3 H H CH.sub.3 CF.sub.3 B-86 CF.sub.3 H H
CH.sub.3 CF.sub.3 B-87 OCH.sub.3 H H CH.sub.3 CF.sub.3 B-88
OCF.sub.3 H H CH.sub.3 CF.sub.3 B-89 H F H CH.sub.3 CF.sub.3 B-90 F
F H CH.sub.3 CF.sub.3 B-91 Cl F H CH.sub.3 CF.sub.3 B-92 Br F H
CH.sub.3 CF.sub.3 B-93 CH.sub.3 F H CH.sub.3 CF.sub.3 B-94 CF.sub.3
F H CH.sub.3 CF.sub.3 B-95 OCH.sub.3 F H CH.sub.3 CF.sub.3 B-96
OCF.sub.3 F H CH.sub.3 CF.sub.3 B-97 H Cl H CH.sub.3 CF.sub.3 B-98
F Cl H CH.sub.3 CF.sub.3 B-99 Cl Cl H CH.sub.3 CF.sub.3 B-100 Br Cl
H CH.sub.3 CF.sub.3 B-101 CH.sub.3 Cl H CH.sub.3 CF.sub.3 B-102
CF.sub.3 Cl H CH.sub.3 CF.sub.3 B-103 OCH.sub.3 Cl H CH.sub.3
CF.sub.3 B-104 OCF.sub.3 Cl H CH.sub.3 CF.sub.3 B-105 H CH.sub.3 H
CH.sub.3 CF.sub.3 B-106 F CH.sub.3 H CH.sub.3 CF.sub.3 B-107 Cl
CH.sub.3 H CH.sub.3 CF.sub.3 B-108 Br CH.sub.3 H CH.sub.3 CF.sub.3
B-109 CH.sub.3 CH.sub.3 H CH.sub.3 CF.sub.3 B-110 CF.sub.3 CH.sub.3
H CH.sub.3 CF.sub.3 B-111 OCH.sub.3 CH.sub.3 H CH.sub.3 CF.sub.3
B-112 OCF.sub.3 CH.sub.3 H CH.sub.3 CF.sub.3 B-113 H CH.sub.3
CH.sub.3 CH.sub.3 CF.sub.3 B-114 F CH.sub.3 CH.sub.3 CH.sub.3
CF.sub.3 B-115 Cl CH.sub.3 CH.sub.3 CH.sub.3 CF.sub.3 B-116 Br
CH.sub.3 CH.sub.3 CH.sub.3 CF.sub.3 B-117 CH.sub.3 CH.sub.3
CH.sub.3 CH.sub.3 CF.sub.3 B-118 CF.sub.3 CH.sub.3 CH.sub.3
CH.sub.3 CF.sub.3 B-119 OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3
CF.sub.3 B-120 OCF.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 CF.sub.3 B-121
H H H CF.sub.3 CF.sub.3 B-122 F H H CF.sub.3 CF.sub.3 B-123 Cl H H
CF.sub.3 CF.sub.3 B-124 Br H H CF.sub.3 CF.sub.3 B-125 CH.sub.3 H H
CF.sub.3 CF.sub.3 B-126 CF.sub.3 H H CF.sub.3 CF.sub.3 B-127
OCH.sub.3 H H CF.sub.3 CF.sub.3 B-128 OCF.sub.3 H H CF.sub.3
CF.sub.3 B-129 H F H CF.sub.3 CF.sub.3 B-130 F F H CF.sub.3
CF.sub.3 B-131 Cl F H CF.sub.3 CF.sub.3 B-132 Br F H CF.sub.3
CF.sub.3 B-133 CH.sub.3 F H CF.sub.3 CF.sub.3 B-134 CF.sub.3 F H
CF.sub.3 CF.sub.3 B-135 OCH.sub.3 F H CF.sub.3 CF.sub.3 B-136
OCF.sub.3 F H CF.sub.3 CF.sub.3 B-137 H Cl H CF.sub.3 CF.sub.3
B-138 F Cl H CF.sub.3 CF.sub.3 B-139 Cl Cl H CF.sub.3 CF.sub.3
B-140 Br Cl H CF.sub.3 CF.sub.3 B-141 CH.sub.3 Cl H CF.sub.3
CF.sub.3 B-142 CF.sub.3 Cl H CF.sub.3 CF.sub.3 B-143 OCH.sub.3 Cl H
CF.sub.3 CF.sub.3 B-144 OCF.sub.3 Cl H CF.sub.3 CF.sub.3 B-145 H
CH.sub.3 H CF.sub.3 CF.sub.3 B-146 F CH.sub.3 H CF.sub.3 CF.sub.3
B-147 Cl CH.sub.3 H CF.sub.3 CF.sub.3 B-148 Br CH.sub.3 H CF.sub.3
CF.sub.3 B-149 CH.sub.3 CH.sub.3 H CF.sub.3 CF.sub.3 B-150 CF.sub.3
CH.sub.3 H CF.sub.3 CF.sub.3 B-151 OCH.sub.3 CH.sub.3 H CF.sub.3
CF.sub.3 B-152 OCF.sub.3 CH.sub.3 H CF.sub.3 CF.sub.3 B-153 H
CH.sub.3 CH.sub.3 CF.sub.3 CF.sub.3 B-154 F CH.sub.3 CH.sub.3
CF.sub.3 CF.sub.3 B-155 Cl CH.sub.3 CH.sub.3 CF.sub.3 CF.sub.3
B-156 Br CH.sub.3 CH.sub.3 CF.sub.3 CF.sub.3 B-157 CH.sub.3
CH.sub.3 CH.sub.3 CF.sub.3 CF.sub.3 B-158 CF.sub.3 CH.sub.3
CH.sub.3 CF.sub.3 CF.sub.3 B-159 OCH.sub.3 CH.sub.3 CH.sub.3
CF.sub.3 CF.sub.3 B-160 OCF.sub.3 CH.sub.3 CH.sub.3 CF.sub.3
CF.sub.3 B-161 H H H CH.sub.3 C.sub.6H.sub.5* B-162 F H H CH.sub.3
C.sub.6H.sub.5 B-163 Cl H H CH.sub.3 C.sub.6H.sub.5 B-164 Br H H
CH.sub.3 C.sub.6H.sub.5 B-165 CH.sub.3 H H CH.sub.3 C.sub.6H.sub.5
B-166 CF.sub.3 H H CH.sub.3 C.sub.6H.sub.5 B-167 OCH.sub.3 H H
CH.sub.3 C.sub.6H.sub.5 B-168 OCF.sub.3 H H CH.sub.3 C.sub.6H.sub.5
B-169 H F H CH.sub.3 C.sub.6H.sub.5 B-170 F F H CH.sub.3
C.sub.6H.sub.5 B-171 Cl F H CH.sub.3 C.sub.6H.sub.5 B-172 Br F H
CH.sub.3 C.sub.6H.sub.5 B-173 CH.sub.3 F H CH.sub.3 C.sub.6H.sub.5
B-174 CF.sub.3 F H CH.sub.3 C.sub.6H.sub.5 B-175 OCH.sub.3 F H
CH.sub.3 C.sub.6H.sub.5 B-176 OCF.sub.3 F H CH.sub.3 C.sub.6H.sub.5
B-177 H Cl H CH.sub.3 C.sub.6H.sub.5 B-178 F Cl H CH.sub.3
C.sub.6H.sub.5 B-179 Cl Cl H CH.sub.3 C.sub.6H.sub.5 B-180 Br Cl H
CH.sub.3 C.sub.6H.sub.5 B-181 CH.sub.3 Cl H CH.sub.3 C.sub.6H.sub.5
B-182 CF.sub.3 Cl H CH.sub.3 C.sub.6H.sub.5 B-183 OCH.sub.3 Cl H
CH.sub.3 C.sub.6H.sub.5 B-184 OCF.sub.3 Cl H CH.sub.3
C.sub.6H.sub.5 B-185 H CH.sub.3 H CH.sub.3 C.sub.6H.sub.5 B-186 F
CH.sub.3 H CH.sub.3 C.sub.6H.sub.5 B-187 Cl CH.sub.3 H CH.sub.3
C.sub.6H.sub.5 B-188 Br CH.sub.3 H CH.sub.3 C.sub.6H.sub.5 B-189
CH.sub.3 CH.sub.3 H CH.sub.3 C.sub.6H.sub.5 B-190 CF.sub.3 CH.sub.3
H CH.sub.3 C.sub.6H.sub.5 B-191 OCH.sub.3 CH.sub.3 H CH.sub.3
C.sub.6H.sub.5 B-192 OCF.sub.3 CH.sub.3 H CH.sub.3 C.sub.6H.sub.5
B-193 H CH.sub.3 CH.sub.3 CH.sub.3 C.sub.6H.sub.5 B-194 F CH.sub.3
CH.sub.3 CH.sub.3 C.sub.6H.sub.5 B-195 Cl CH.sub.3 CH.sub.3
CH.sub.3 C.sub.6H.sub.5 B-196 Br CH.sub.3 CH.sub.3 CH.sub.3
C.sub.6H.sub.5 B-197 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3
C.sub.6H.sub.5 B-198 CF.sub.3 CH.sub.3 CH.sub.3 CH.sub.3
C.sub.6H.sub.5 B-199 OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3
C.sub.6H.sub.5 B-200 OCF.sub.3 CH.sub.3 CH.sub.3 CH.sub.3
C.sub.6H.sub.5 B-201 H H H CH.sub.3 OCH.sub.3 B-202 F H H CH.sub.3
OCH.sub.3 B-203 Cl H H CH.sub.3 OCH.sub.3 B-204 Br H H CH.sub.3
OCH.sub.3 B-205 CH.sub.3 H H CH.sub.3 OCH.sub.3 B-206 CF.sub.3 H H
CH.sub.3 OCH.sub.3 B-207 OCH.sub.3 H H CH.sub.3 OCH.sub.3 B-208
OCF.sub.3 H H CH.sub.3 OCH.sub.3 B-209 H F H CH.sub.3 OCH.sub.3
B-210 F F H CH.sub.3 OCH.sub.3 B-211 Cl F H CH.sub.3 OCH.sub.3
B-212 Br F H CH.sub.3 OCH.sub.3 B-213 CH.sub.3 F H CH.sub.3
OCH.sub.3 B-214 CF.sub.3 F H CH.sub.3 OCH.sub.3 B-215 OCH.sub.3 F H
CH.sub.3 OCH.sub.3 B-216 OCF.sub.3 F H CH.sub.3 OCH.sub.3 B-217 H
Cl H CH.sub.3 OCH.sub.3 B-218 F Cl H CH.sub.3 OCH.sub.3 B-219 Cl Cl
H CH.sub.3 OCH.sub.3 B-220 Br Cl H CH.sub.3 OCH.sub.3 B-221
CH.sub.3 Cl H CH.sub.3 OCH.sub.3 B-222 CF.sub.3 Cl H CH.sub.3
OCH.sub.3 B-223 OCH.sub.3 Cl H CH.sub.3 OCH.sub.3 B-224 OCF.sub.3
Cl H CH.sub.3 OCH.sub.3 B-225 H CH.sub.3 H CH.sub.3 OCH.sub.3 B-226
F CH.sub.3 H CH.sub.3 OCH.sub.3 B-227 Cl CH.sub.3 H CH.sub.3
OCH.sub.3 B-228 Br CH.sub.3 H CH.sub.3 OCH.sub.3 B-229 CH.sub.3
CH.sub.3 H CH.sub.3 OCH.sub.3 B-230 CF.sub.3 CH.sub.3 H CH.sub.3
OCH.sub.3 B-231 OCH.sub.3 CH.sub.3 H CH.sub.3 OCH.sub.3 B-232
OCF.sub.3 CH.sub.3 H CH.sub.3 OCH.sub.3 B-233 H CH.sub.3 CH.sub.3
CH.sub.3 OCH.sub.3 B-234 F CH.sub.3 CH.sub.3 CH.sub.3 OCH.sub.3
B-235 Cl CH.sub.3 CH.sub.3 CH.sub.3 OCH.sub.3 B-236 Br CH.sub.3
CH.sub.3 CH.sub.3 OCH.sub.3 B-237 CH.sub.3 CH.sub.3 CH.sub.3
CH.sub.3 OCH.sub.3 B-238 CF.sub.3 CH.sub.3 CH.sub.3 CH.sub.3
OCH.sub.3 B-239 OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 OCH.sub.3
B-240 OCF.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 OCH.sub.3 B-241 H H H
CH.sub.3 OH B-242 F H H CH.sub.3 OH B-243 Cl H H CH.sub.3 OH B-244
Br H H CH.sub.3 OH B-245 CH.sub.3 H H CH.sub.3 OH B-246 CF.sub.3 H
H CH.sub.3 OH
B-247 OCH.sub.3 H H CH.sub.3 OH B-248 OCF.sub.3 H H CH.sub.3 OH
B-249 H F H CH.sub.3 OH B-250 F F H CH.sub.3 OH B-251 Cl F H
CH.sub.3 OH B-252 Br F H CH.sub.3 OH B-253 CH.sub.3 F H CH.sub.3 OH
B-254 CF.sub.3 F H CH.sub.3 OH B-255 OCH.sub.3 F H CH.sub.3 OH
B-256 OCF.sub.3 F H CH.sub.3 OH B-257 H Cl H CH.sub.3 OH B-258 F Cl
H CH.sub.3 OH B-259 Cl Cl H CH.sub.3 OH B-260 Br Cl H CH.sub.3 OH
B-261 CH.sub.3 Cl H CH.sub.3 OH B-262 CF.sub.3 Cl H CH.sub.3 OH
B-263 OCH.sub.3 Cl H CH.sub.3 OH B-264 OCF.sub.3 Cl H CH.sub.3 OH
B-265 H CH.sub.3 H CH.sub.3 OH B-266 F CH.sub.3 H CH.sub.3 OH B-267
Cl CH.sub.3 H CH.sub.3 OH B-268 Br CH.sub.3 H CH.sub.3 OH B-269
CH.sub.3 CH.sub.3 H CH.sub.3 OH B-270 CF.sub.3 CH.sub.3 H CH.sub.3
OH B-271 OCH.sub.3 CH.sub.3 H CH.sub.3 OH B-272 OCF.sub.3 CH.sub.3
H CH.sub.3 OH B-273 H CH.sub.3 CH.sub.3 CH.sub.3 OH B-274 F
CH.sub.3 CH.sub.3 CH.sub.3 OH B-275 Cl CH.sub.3 CH.sub.3 CH.sub.3
OH B-276 Br CH.sub.3 CH.sub.3 CH.sub.3 OH B-277 CH.sub.3 CH.sub.3
CH.sub.3 CH.sub.3 OH B-278 CF.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 OH
B-279 OCH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 OH B-280 OCF.sub.3
CH.sub.3 CH.sub.3 CH.sub.3 OH B-281 H H H --(CH.sub.2).sub.2--
B-282 F H H --(CH.sub.2).sub.2-- B-283 Cl H H --(CH.sub.2).sub.2--
B-284 Br H H --(CH.sub.2).sub.2-- B-285 CH.sub.3 H H
--(CH.sub.2).sub.2-- B-286 CF.sub.3 H H --(CH.sub.2).sub.2-- B-287
OCH.sub.3 H H --(CH.sub.2).sub.2-- B-288 OCF.sub.3 H H
--(CH.sub.2).sub.2-- B-289 H F H --(CH.sub.2).sub.2-- B-290 F F H
--(CH.sub.2).sub.2-- B-291 Cl F H --(CH.sub.2).sub.2-- B-292 Br F H
--(CH.sub.2).sub.2-- B-293 CH.sub.3 F H --(CH.sub.2).sub.2-- B-294
CF.sub.3 F H --(CH.sub.2).sub.2-- B-295 OCH.sub.3 F H
--(CH.sub.2).sub.2-- B-296 OCF.sub.3 F H --(CH.sub.2).sub.2-- B-297
H Cl H --(CH.sub.2).sub.2-- B-298 F Cl H --(CH.sub.2).sub.2-- B-299
Cl Cl H --(CH.sub.2).sub.2-- B-300 Br Cl H --(CH.sub.2).sub.2--
B-301 CH.sub.3 Cl H --(CH.sub.2).sub.2-- B-302 CF.sub.3 Cl H
--(CH.sub.2).sub.2-- B-303 OCH.sub.3 Cl H --(CH.sub.2).sub.2--
B-304 OCF.sub.3 Cl H --(CH.sub.2).sub.2-- B-305 H CH.sub.3 H
--(CH.sub.2).sub.2-- B-306 F CH.sub.3 H --(CH.sub.2).sub.2-- B-307
Cl CH.sub.3 H --(CH.sub.2).sub.2-- B-308 Br CH.sub.3 H
--(CH.sub.2).sub.2-- B-309 CH.sub.3 CH.sub.3 H --(CH.sub.2).sub.2--
B-310 CF.sub.3 CH.sub.3 H --(CH.sub.2).sub.2-- B-311 OCH.sub.3
CH.sub.3 H --(CH.sub.2).sub.2-- B-312 OCF.sub.3 CH.sub.3 H
--(CH.sub.2).sub.2-- B-313 H CH.sub.3 CH.sub.3 --(CH.sub.2).sub.2--
B-314 F CH.sub.3 CH.sub.3 --(CH.sub.2).sub.2-- B-315 Cl CH.sub.3
CH.sub.3 --(CH.sub.2).sub.2-- B-316 Br CH.sub.3 CH.sub.3
--(CH.sub.2).sub.2-- B-317 CH.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.2-- B-318 CF.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.2-- B-319 OCH.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.2-- B-320 OCF.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.2-- B-321 H H H --(CH.sub.2).sub.3-- B-322 F H H
--(CH.sub.2).sub.3-- B-323 Cl H H --(CH.sub.2).sub.3-- B-324 Br H H
--(CH.sub.2).sub.3-- B-325 CH.sub.3 H H --(CH.sub.2).sub.3-- B-326
CF.sub.3 H H --(CH.sub.2).sub.3-- B-327 OCH.sub.3 H H
--(CH.sub.2).sub.3-- B-328 OCF.sub.3 H H --(CH.sub.2).sub.3-- B-329
H F H --(CH.sub.2).sub.3-- B-330 F F H --(CH.sub.2).sub.3-- B-331
Cl F H --(CH.sub.2).sub.3-- B-332 Br F H --(CH.sub.2).sub.3-- B-333
CH.sub.3 F H --(CH.sub.2).sub.3-- B-334 CF.sub.3 F H
--(CH.sub.2).sub.3-- B-335 OCH.sub.3 F H --(CH.sub.2).sub.3-- B-336
OCF.sub.3 F H --(CH.sub.2).sub.3-- B-337 H Cl H
--(CH.sub.2).sub.3-- B-338 F Cl H --(CH.sub.2).sub.3-- B-339 Cl Cl
H --(CH.sub.2).sub.3-- B-340 Br Cl H --(CH.sub.2).sub.3-- B-341
CH.sub.3 Cl H --(CH.sub.2).sub.3-- B-342 CF.sub.3 Cl H
--(CH.sub.2).sub.3-- B-343 OCH.sub.3 Cl H --(CH.sub.2).sub.3--
B-344 OCF.sub.3 Cl H --(CH.sub.2).sub.3-- B-345 H CH.sub.3 H
--(CH.sub.2).sub.3-- B-346 F CH.sub.3 H --(CH.sub.2).sub.3-- B-347
Cl CH.sub.3 H --(CH.sub.2).sub.3-- B-348 Br CH.sub.3 H
--(CH.sub.2).sub.3-- B-349 CH.sub.3 CH.sub.3 H --(CH.sub.2).sub.3--
B-350 CF.sub.3 CH.sub.3 H --(CH.sub.2).sub.3-- B-351 OCH.sub.3
CH.sub.3 H --(CH.sub.2).sub.3-- B-352 OCF.sub.3 CH.sub.3 H
--(CH.sub.2).sub.3-- B-353 H CH.sub.3 CH.sub.3 --(CH.sub.2).sub.3--
B-354 F CH.sub.3 CH.sub.3 --(CH.sub.2).sub.3-- B-355 Cl CH.sub.3
CH.sub.3 --(CH.sub.2).sub.3-- B-356 Br CH.sub.3 CH.sub.3
--(CH.sub.2).sub.3-- B-357 CH.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.3-- B-358 CF.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.3-- B-359 OCH.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.3-- B-360 OCF.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.3-- B-361 H H H --(CH.sub.2).sub.4-- B-362 F H H
--(CH.sub.2).sub.4-- B-363 Cl H H --(CH.sub.2).sub.4-- B-364 Br H H
--(CH.sub.2).sub.4-- B-365 CH.sub.3 H H --(CH.sub.2).sub.4-- B-366
CF.sub.3 H H --(CH.sub.2).sub.4-- B-367 OCH.sub.3 H H
--(CH.sub.2).sub.4-- B-368 OCF.sub.3 H H --(CH.sub.2).sub.4-- B-369
H F H --(CH.sub.2).sub.4-- B-370 F F H --(CH.sub.2).sub.4-- B-371
Cl F H --(CH.sub.2).sub.4-- B-372 Br F H --(CH.sub.2).sub.4-- B-373
CH.sub.3 F H --(CH.sub.2).sub.4-- B-374 CF.sub.3 F H
--(CH.sub.2).sub.4-- B-375 OCH.sub.3 F H --(CH.sub.2).sub.4-- B-376
OCF.sub.3 F H --(CH.sub.2).sub.4-- B-377 H Cl H
--(CH.sub.2).sub.4-- B-378 F Cl H --(CH.sub.2).sub.4-- B-379 Cl Cl
H --(CH.sub.2).sub.4-- B-380 Br Cl H --(CH.sub.2).sub.4-- B-381
CH.sub.3 Cl H --(CH.sub.2).sub.4-- B-382 CF.sub.3 Cl H
--(CH.sub.2).sub.4-- B-383 OCH.sub.3 Cl H --(CH.sub.2).sub.4--
B-384 OCF.sub.3 Cl H --(CH.sub.2).sub.4-- B-385 H CH.sub.3 H
--(CH.sub.2).sub.4-- B-386 F CH.sub.3 H --(CH.sub.2).sub.4-- B-387
Cl CH.sub.3 H --(CH.sub.2).sub.4-- B-388 Br CH.sub.3 H
--(CH.sub.2).sub.4-- B-389 CH.sub.3 CH.sub.3 H --(CH.sub.2).sub.4--
B-390 CF.sub.3 CH.sub.3 H --(CH.sub.2).sub.4-- B-391 OCH.sub.3
CH.sub.3 H --(CH.sub.2).sub.4-- B-392 OCF.sub.3 CH.sub.3 H
--(CH.sub.2).sub.4-- B-393 H CH.sub.3 CH.sub.3 --(CH.sub.2).sub.4--
B-394 F CH.sub.3 CH.sub.3 --(CH.sub.2).sub.4-- B-395 Cl CH.sub.3
CH.sub.3 --(CH.sub.2).sub.4-- B-396 Br CH.sub.3 CH.sub.3
--(CH.sub.2).sub.4-- B-397 CH.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.4-- B-398 CF.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.4-- B-399 OCH.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.4-- B-400 OCF.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.4-- B-401 H H H --(CH.sub.2).sub.5-- B-402 F H H
--(CH.sub.2).sub.5-- B-403 Cl H H --(CH.sub.2).sub.5-- B-404 Br H H
--(CH.sub.2).sub.5-- B-405 CH.sub.3 H H --(CH.sub.2).sub.5-- B-406
CF.sub.3 H H --(CH.sub.2).sub.5-- B-407 OCH.sub.3 H H
--(CH.sub.2).sub.5-- B-408 OCF.sub.3 H H --(CH.sub.2).sub.5-- B-409
H F H --(CH.sub.2).sub.5-- B-410 F F H --(CH.sub.2).sub.5-- B-411
Cl F H --(CH.sub.2).sub.5-- B-412 Br F H --(CH.sub.2).sub.5-- B-413
CH.sub.3 F H --(CH.sub.2).sub.5-- B-414 CF.sub.3 F H
--(CH.sub.2).sub.5-- B-415 OCH.sub.3 F H --(CH.sub.2).sub.5-- B-416
OCF.sub.3 F H --(CH.sub.2).sub.5-- B-417 H Cl H
--(CH.sub.2).sub.5-- B-418 F Cl H --(CH.sub.2).sub.5-- B-419 Cl Cl
H --(CH.sub.2).sub.5-- B-420 Br Cl H --(CH.sub.2).sub.5-- B-421
CH.sub.3 Cl H --(CH.sub.2).sub.5-- B-422 CF.sub.3 Cl H
--(CH.sub.2).sub.5-- B-423 OCH.sub.3 Cl H --(CH.sub.2).sub.5--
B-424 OCF.sub.3 Cl H --(CH.sub.2).sub.5-- B-425 H CH.sub.3 H
--(CH.sub.2).sub.5-- B-426 F CH.sub.3 H --(CH.sub.2).sub.5-- B-427
Cl CH.sub.3 H --(CH.sub.2).sub.5-- B-428 Br CH.sub.3 H
--(CH.sub.2).sub.5-- B-429 CH.sub.3 CH.sub.3 H --(CH.sub.2).sub.5--
B-430 CF.sub.3 CH.sub.3 H --(CH.sub.2).sub.5-- B-431 OCH.sub.3
CH.sub.3 H --(CH.sub.2).sub.5-- B-432 OCF.sub.3 CH.sub.3 H
--(CH.sub.2).sub.5-- B-433 H CH.sub.3 CH.sub.3 --(CH.sub.2).sub.5--
B-434 F CH.sub.3 CH.sub.3 --(CH.sub.2).sub.5-- B-435 Cl CH.sub.3
CH.sub.3 --(CH.sub.2).sub.5-- B-436 Br CH.sub.3 CH.sub.3
--(CH.sub.2).sub.5-- B-437 CH.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.5-- B-438 CF.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.5-- B-439 OCH.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.5-- B-440 OCF.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.5-- B-441 H H H --(CH.sub.2).sub.6-- B-442 F H H
--(CH.sub.2).sub.6-- B-443 Cl H H --(CH.sub.2).sub.6-- B-444 Br H H
--(CH.sub.2).sub.6-- B-445 CH.sub.3 H H --(CH.sub.2).sub.6-- B-446
CF.sub.3 H H --(CH.sub.2).sub.6-- B-447 OCH.sub.3 H H
--(CH.sub.2).sub.6-- B-448 OCF.sub.3 H H --(CH.sub.2).sub.6-- B-449
H F H --(CH.sub.2).sub.6-- B-450 F F H --(CH.sub.2).sub.6-- B-451
Cl F H --(CH.sub.2).sub.6-- B-452 Br F H --(CH.sub.2).sub.6-- B-453
CH.sub.3 F H --(CH.sub.2).sub.6-- B-454 CF.sub.3 F H
--(CH.sub.2).sub.6-- B-455 OCH.sub.3 F H --(CH.sub.2).sub.6-- B-456
OCF.sub.3 F H --(CH.sub.2).sub.6-- B-457 H Cl H
--(CH.sub.2).sub.6-- B-458 F Cl H --(CH.sub.2).sub.6-- B-459 Cl Cl
H --(CH.sub.2).sub.6-- B-460 Br Cl H --(CH.sub.2).sub.6-- B-461
CH.sub.3 Cl H --(CH.sub.2).sub.6-- B-462 CF.sub.3 Cl H
--(CH.sub.2).sub.6-- B-463 OCH.sub.3 Cl H --(CH.sub.2).sub.6--
B-464 OCF.sub.3 Cl H --(CH.sub.2).sub.6-- B-465 H CH.sub.3 H
--(CH.sub.2).sub.6-- B-466 F CH.sub.3 H --(CH.sub.2).sub.6-- B-467
Cl CH.sub.3 H --(CH.sub.2).sub.6-- B-468 Br CH.sub.3 H
--(CH.sub.2).sub.6-- B-469 CH.sub.3 CH.sub.3 H --(CH.sub.2).sub.6--
B-470 CF.sub.3 CH.sub.3 H --(CH.sub.2).sub.6-- B-471 OCH.sub.3
CH.sub.3 H --(CH.sub.2).sub.6-- B-472 OCF.sub.3 CH.sub.3 H
--(CH.sub.2).sub.6-- B-473 H CH.sub.3 CH.sub.3 --(CH.sub.2).sub.6--
B-474 F CH.sub.3 CH.sub.3 --(CH.sub.2).sub.6-- B-475 Cl CH.sub.3
CH.sub.3 --(CH.sub.2).sub.6-- B-476 Br CH.sub.3 CH.sub.3
--(CH.sub.2).sub.6-- B-477 CH.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.6-- B-478 CF.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.6-- B-479 OCH.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.6-- B-480 OCF.sub.3 CH.sub.3 CH.sub.3
--(CH.sub.2).sub.6-- B-481 H H H --CH.dbd.CH--CH.sub.2--CH.sub.2--
B-482 F H H --CH.dbd.CH--CH.sub.2--CH.sub.2-- B-483 Cl H H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-484 Br H H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-485 CH.sub.3 H H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-486 CF.sub.3 H H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-487 OCH.sub.3 H H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-488 OCF.sub.3 H H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-489 H F H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-490 F F H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-491 Cl F H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-492 Br F H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-493 CH.sub.3 F H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-494 CF.sub.3 F H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-495 OCH.sub.3 F H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-496 OCF.sub.3 F H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-497 H Cl H
--CH.dbd.CH--CH.sub.2--CH.sub.2--
B-498 F Cl H --CH.dbd.CH--CH.sub.2--CH.sub.2-- B-499 Cl Cl H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-500 Br Cl H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-501 CH.sub.3 Cl H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-502 CF.sub.3 Cl H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-503 OCH.sub.3 Cl H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-504 OCF.sub.3 Cl H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-505 H CH.sub.3 H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-506 F CH.sub.3 H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-507 Cl CH.sub.3 H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-508 Br CH.sub.3 H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-509 CH.sub.3 CH.sub.3 H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-510 CF.sub.3 CH.sub.3 H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-511 OCH.sub.3 CH.sub.3 H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-512 OCF.sub.3 CH.sub.3 H
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-513 H CH.sub.3 CH.sub.3
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-514 F CH.sub.3 CH.sub.3
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-515 Cl CH.sub.3 CH.sub.3
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-516 Br CH.sub.3 CH.sub.3
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-517 CH.sub.3 CH.sub.3 CH.sub.3
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-518 CF.sub.3 CH.sub.3 CH.sub.3
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-519 OCH.sub.3 CH.sub.3 CH.sub.3
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-520 OCF.sub.3 CH.sub.3 CH.sub.3
--CH.dbd.CH--CH.sub.2--CH.sub.2-- B-521 H H --(CH.sub.2).sub.3--
CH.sub.3 B-522 F H --(CH.sub.2).sub.3-- CH.sub.3 B-523 Cl H
--(CH.sub.2).sub.3-- CH.sub.3 B-524 Br H --(CH.sub.2).sub.3--
CH.sub.3 B-525 CH.sub.3 H --(CH.sub.2).sub.3-- CH.sub.3 B-526
CF.sub.3 H --(CH.sub.2).sub.3-- CH.sub.3 B-527 OCH.sub.3 H
--(CH.sub.2).sub.3-- CH.sub.3 B-528 OCF.sub.3 H
--(CH.sub.2).sub.3-- CH.sub.3 B-529 H D --(CH.sub.2).sub.3--
CH.sub.3 B-530 F D --(CH.sub.2).sub.3-- CH.sub.3 B-531 Cl D
--(CH.sub.2).sub.3-- CH.sub.3 B-532 Br D --(CH.sub.2).sub.3--
CH.sub.3 B-533 CH.sub.3 D --(CH.sub.2).sub.3-- CH.sub.3 B-534
CF.sub.3 D --(CH.sub.2).sub.3-- CH.sub.3 B-535 OCH.sub.3 D
--(CH.sub.2).sub.3-- CH.sub.3 B-536 OCF.sub.3 D
--(CH.sub.2).sub.3-- CH.sub.3 B-537 H H --(CH.sub.2).sub.3-- D
B-538 F H --(CH.sub.2).sub.3-- D B-539 Cl H --(CH.sub.2).sub.3-- D
B-540 Br H --(CH.sub.2).sub.3-- D B-541 CH.sub.3 H
--(CH.sub.2).sub.3-- D B-542 CF.sub.3 H --(CH.sub.2).sub.3-- D
B-543 OCH.sub.3 H --(CH.sub.2).sub.3-- D B-544 OCF.sub.3 H
--(CH.sub.2).sub.3-- D B-545 H D --(CH.sub.2).sub.3-- D B-546 F D
--(CH.sub.2).sub.3-- D B-547 Cl D --(CH.sub.2).sub.3-- D B-548 Br D
--(CH.sub.2).sub.3-- D B-549 CH.sub.3 D --(CH.sub.2).sub.3-- D
B-550 CF.sub.3 D --(CH.sub.2).sub.3-- D B-551 OCH.sub.3 D
--(CH.sub.2).sub.3-- D B-552 OCF.sub.3 D --(CH.sub.2).sub.3-- D
B-553 H H --(CH.sub.2).sub.4-- CH.sub.3 B-554 F H
--(CH.sub.2).sub.4-- CH.sub.3 B-555 Cl H --(CH.sub.2).sub.4--
CH.sub.3 B-556 Br H --(CH.sub.2).sub.4-- CH.sub.3 B-557 CH.sub.3 H
--(CH.sub.2).sub.4-- CH.sub.3 B-558 CF.sub.3 H --(CH.sub.2).sub.4--
CH.sub.3 B-559 OCH.sub.3 H --(CH.sub.2).sub.4-- CH.sub.3 B-560
OCF.sub.3 H --(CH.sub.2).sub.4-- CH.sub.3 B-561 H D
--(CH.sub.2).sub.4-- CH.sub.3 B-562 F D --(CH.sub.2).sub.4--
CH.sub.3 B-563 Cl D --(CH.sub.2).sub.4-- CH.sub.3 B-564 Br D
--(CH.sub.2).sub.4-- CH.sub.3 B-565 CH.sub.3 D --(CH.sub.2).sub.4--
CH.sub.3 B-566 CF.sub.3 D --(CH.sub.2).sub.4-- CH.sub.3 B-567
OCH.sub.3 D --(CH.sub.2).sub.4-- CH.sub.3 B-568 OCF.sub.3 D
--(CH.sub.2).sub.4-- CH.sub.3 B-569 H H --(CH.sub.2).sub.4-- D
B-570 F H --(CH.sub.2).sub.4-- D B-571 Cl H --(CH.sub.2).sub.4-- D
B-572 Br H --(CH.sub.2).sub.4-- D B-573 CH.sub.3 H
--(CH.sub.2).sub.4-- D B-574 CF.sub.3 H --(CH.sub.2).sub.4-- D
B-575 OCH.sub.3 H --(CH.sub.2).sub.4-- D B-576 OCF.sub.3 H
--(CH.sub.2).sub.4-- D B-577 H D --(CH.sub.2).sub.4-- D B-578 F D
--(CH.sub.2).sub.4-- D B-579 Cl D --(CH.sub.2).sub.4-- D B-580 Br D
--(CH.sub.2).sub.4-- D B-581 CH.sub.3 D --(CH.sub.2).sub.4-- D
B-582 CF.sub.3 D --(CH.sub.2).sub.4-- D B-583 OCH.sub.3 D
--(CH.sub.2).sub.4-- D B-584 OCF.sub.3 D --(CH.sub.2).sub.4-- D
*C.sub.6H.sub.5 = phenyl
[0394] 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
steroisomer thereof.
[0395] 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.
[0396] Compounds of formula I wherein X is CR.sup.7R.sup.8 and
R.sup.5b is H (=compounds I') can be synthesized as described in
scheme 1 below. The protected tetrahydrobenzodiazepine or
tetrahydroquinoxaline 1, 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 2, 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 3 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 4. Reduction of the carbonyl group with common reduction agents
like borohydrides such as sodium borohydride or
borane-tetrahydrofurane-complex yields 5, 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 5 and deprotecting 4.
##STR00019##
[0397] 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.
[0398] Compounds I wherein R.sup.5b is different from H can be
prepared, for example, by reacting compound 4 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.
[0399] Compounds I wherein R.sup.5b is different from H and R.sup.8
is CH.sub.3 (=compounds I'') can be prepared, for example, as out
lined in scheme 2 below. Acylation of 1 with the allylic acid
derivative 6, 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, yields 7, which is reacted in a
Heck-type reaction, e.g. employing palladium acetate in the
presence of a base, such as potassium carbonate, to yield the
cyclization product 8. Reduction of the carbonyl group with common
reduction agents like borohydrides such as sodium borohydride or
borane-tetrahydrofurane-complex yields 9, which is deprotected
using suitable reagents such as strong bases or acids to I'',
wherein R.sup.4a and R.sup.4b 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 9 and deprotecting 8. 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.
##STR00020##
[0400] Compounds I wherein X is NR.sup.6 (=compounds I''') can be
prepared as outlined in scheme 3 below. Acylation of 1 with the
.beta.-amino acid derivative 10, wherein PG' is a protection group
different from PG and 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, yields 11. This is first
selectively deprotected at the amino group NR.sup.6PG'. The
partially deprotected compound is then reacted in a cyclization
reaction to 12 under Buchwald-Hartwig reaction conditions such as
the use of a Pd catalyst, e.g. tetrakis(triphenylphosphine)
palladium in the presence of as base, such as sodium tert-butylate
and potassium carbonate. Reduction of the carbonyl group of 12 with
common reduction agents like borohydrides such as sodium
borohydride or borane-tetrahydrofurane-complex yields 13, which is
deprotected using suitable reagents such as strong bases or acids
to I''', wherein R.sup.4a and R.sup.4b 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 13 and deprotecting 12. 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.
##STR00021##
[0401] Alternatively to the method depicted in scheme 1, compounds
I wherein X is CR.sup.7R.sup.8 and R.sup.5b is H (=compounds I')
can be synthesized as described in scheme 4 below. Readily
available anilines 14 are derivatized with carbonyl moieties 15 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 16. Cyclization
products 17 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. Reduction with common reduction agents like
borohydrides such as sodium borohydride or
borane-tetrahydrofurane-complex yield suitable intermediates 18
that are alkylated with alkylamides 19 employing suitable leaving
groups LG such as chlorides or bromides. After reduction to the
corresponding amines 20 cyclization is performed in a suitable
solvent like acetonitrile or methanol at room temperature or higher
temperature by addition of an acid and substituted ketones or
aldehydes to obtain compounds I'.
##STR00022##
[0402] Alternatively to the method depicted in scheme 3, compounds
I wherein X is NR.sup.6 (=compounds I''') can be prepared as
outlined in scheme 5 below.
[0403] Readily available starting materials 22 are alkylated with
alkylamides 19 employing suitable leaving groups LG such as
chlorides or bromides to give 23. After reduction to the
corresponding amines 24 cyclization is performed in a suitable
solvent like acetonitrile or methanol at room temperature or higher
temperature by addition of an acid and substituted ketones or
aldehydes 21 to obtain compounds I'''.
##STR00023##
[0404] 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.
[0405] 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.
[0406] 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.
[0407] 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.
[0408] 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.
[0409] 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.
[0410] 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).
[0411] 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.
[0412] Moreover, the present invention relates to compounds of
formula I as defined above, wherein at least one of the atoms has
been replaced by its stable, non-radioactive isotope (e.g.,
hydrogen by deuterium, .sup.12C by .sup.13C, .sup.14N by .sup.15N,
.sup.16O by .sup.18O) and preferably wherein at least one hydrogen
atom has been replaced by a deuterium atom.
[0413] Additionally, the compounds according to the invention
include more of the respective isotope than occurs naturally occurs
and which is present in compounds I.
[0414] Stable isotopes (e.g., deuterium, .sup.13C, .sup.15N,
.sup.18O) are nonradioactive isotopes which contain one additional
neutron than the normally abundant isotope of the respective atom.
Deuterated compounds have been used in pharmaceutical research to
investigate the in vivo metabolic fate of the compounds by
evaluation of the mechanism of action and metabolic pathway of the
non deuterated parent compound (Blake et al. J. Pharm. Sci. 64, 3,
367-391 (1975)). Such metabolic studies are important in the design
of safe, effective therapeutic drugs, either because the in vivo
active compound administered to the patient or because the
metabolites produced from the parent compound prove to be toxic or
carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp.
2-36, Academic press, London, 1985; Kato et al., J. Labelled Comp.
Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J.
Physiol. Pharmacol., 77, 79-88 (1999)).
[0415] Incorporation of a heavy atom, particularly substitution of
deuterium for hydrogen, can give rise to an isotope effect that
could alter the pharmacokinetics of the drug.
[0416] Stable isotope labeling of a drug can alter its
physico-chemical properties such as pK.sub.a and lipid solubility.
These changes may influence the fate of the drug at different steps
along its passage through the body. Absorption, distribution,
metabolism or excretion can be changed. Absorption and distribution
are processes that depend primarily on the molecular size and the
lipophilicity of the substance. These effects and alterations can
affect the pharmacodynamic response of the drug molecule if the
isotopic substitution affects a region involved in a
ligand-receptor interaction.
[0417] Drug metabolism can give rise to large isotopic effect if
the breaking of a chemical bond to a deuterium atom is the rate
limiting step in the process. While some of the physical properties
of a stable isotope-labeled molecule are different from those of
the unlabeled one, the chemical and biological properties are the
same, with one important exception: because of the increased mass
of the heavy isotope, any bond involving the heavy isotope and
another atom will be stronger than the same bond between the light
isotope and that atom. In any reaction in which the breaking of
this bond is the rate limiting step, the reaction will proceed
slower for the molecule with the heavy isotope due to "kinetic
isotope effect". A reaction involving breaking a C--D bond can be
up to 700 percent slower than a similar reaction involving breaking
a C--H bond. If the C--D bond is not involved in any of the steps
leading to the metabolite, there may not be any effect to alter the
behavior of the drug. If a deuterium is placed at a site involved
in the metabolism of a drug, an isotope effect will be observed
only if breaking of the C--D bond is the rate limiting step. There
is evidence to suggest that whenever cleavage of an aliphatic C--H
bond occurs, usually by oxidation catalyzed by a mixed-function
oxidase, replacement of the hydrogen by deuterium will lead to
observable isotope effect. It is also important to understand that
the incorporation of deuterium at the site of metabolism slows its
rate to the point where another metabolite produced by attack at a
carbon atom not substituted by deuterium becomes the major pathway
a process called "metabolic switching".
[0418] Deuterium tracers, such as deuterium-labeled drugs and
doses, in some cases repeatedly, of thousands of milligrams of
deuterated water, are also used in healthy humans of all ages,
including neonates and pregnant women, without reported incident
(e.g. Pons G and Rey E, Pediatrics 1999 104: 633; Coward W A et
al., Lancet 1979 7: 13; Schwarcz H P, Control. Clin. Trials 1984
5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989 114: 885;
Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al. Am.
J. Obstet Gynecol. 1981 139: 948). Thus, it is clear that any
deuterium released, for instance, during the metabolism of
compounds of this invention poses no health risk.
[0419] The weight percentage of hydrogen in a mammal (approximately
9%) and natural abundance of deuterium (approximately 0.015%)
indicates that a 70 kg human normally contains nearly a gram of
deuterium. Furthermore, replacement of up to about 15% of normal
hydrogen with deuterium has been effected and maintained for a
period of days to weeks in mammals, including rodents and dogs,
with minimal observed adverse effects (Czajka D M and Finkel A J,
Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad.
Sci 1960 84: 736; Czakja D M et al., Am. J. Physiol. 1961 201:
357). Higher deuterium concentrations, usually in excess of 20%,
can be toxic in animals. However, acute replacement of as high as
15%-23% of the hydrogen in humans' fluids with deuterium was found
not to cause toxicity (Blagojevic N et al. in "Dosimetry &
Treatment Planning for Neutron Capture Therapy", Zamenhof R,
Solares G and Harling O Eds. 1994. Advanced Medical Publishing,
Madison Wis. pp. 125-134; Diabetes Metab. 23: 251 (1997)).
[0420] Increasing the amount of deuterium present in a compound
above its natural abundance is called enrichment or
deuterium-enrichment. Examples of the amount of enrichment include
from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29,
33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to
about 100 mol %.
[0421] The hydrogens present on a particular organic compound have
different capacities for exchange with deuterium. Certain hydrogen
atoms are easily exchangeable under physiological conditions and,
if replaced by deuterium atoms, it is expected that they will
readily exchange for protons after administration to a patient.
Certain hydrogen atoms may be exchanged for deuterium atoms by the
action of a deuteric acid such as D.sub.2SO.sub.4/D.sub.2O.
Alternatively, deuterium atoms may be incorporated in various
combinations during the synthesis of compounds of the invention.
Certain hydrogen atoms are not easily exchangeable for deuterium
atoms. However, deuterium atoms at the remaining positions may be
incorporated by the use of deuterated starting materials or
intermediates during the construction of compounds of the
invention.
[0422] Deuterated and deuterium-enriched compounds of the invention
can be prepared by using known methods described in the literature.
Such methods can be carried out utilizing corresponding deuterated
and optionally, other isotope-containing reagents and/or
intermediates to synthesize the compounds delineated herein, or
invoking standard synthetic protocols known in the art for
introducing isotopic atoms to a chemical structure. Relevant
procedures and intermediates are disclosed, for instance in
Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996); Brickner, S J et
al., J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org Lett,
5(7), 963 (2003); PCT publications WO1997010223, WO2005099353,
WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189; 7,534,814;
7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and US
Patent Application Publication Nos. 20090137457; 20090131485;
20090131363; 20090118238; 20090111840; 20090105338; 20090105307;
20090105147; 20090093422; 20090088416; 20090082471, the methods are
hereby incorporated by reference.
[0423] 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,
or comprising at least one compound as defined in any of the
preceding claims wherein at least one of the atoms has been
replaced by its stable, non-radioactive isotope, preferably wherein
at least one hydrogen atom has been replaced by a deuterium atom,
in combination with at least one pharmaceutically acceptable
carrier and/or auxiliary substance.
[0424] 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.
[0425] 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.
[0426] 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.
[0427] 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.
[0428] 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.
[0429] 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.
[0430] 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.
[0431] 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.
[0432] 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.
[0433] In certain other embodiments, the disease condition is
bladder dysfunction, including urinary incontinence.
[0434] 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.
[0435] 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.
[0436] 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.
[0437] Examples of gastrointestinal disorders are irritable bowel
syndrome.
[0438] 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, 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, 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
or substance use disorders.
[0439] 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. 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.
[0440] 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.
[0441] 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.
[0442] 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.
[0443] 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 BA, 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].
[0444] 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, TD, 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].
[0445] 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].
[0446] 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,l-
hi]indole], a novel 5-hydroxytryptamine 2C receptor-selective
agonist with anorectic activity. J Pharmacol Exp Ther.
313:862-869.].
[0447] 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.].
[0448] 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,lhi]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,lhi]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.].
[0449] 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 fed. 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, Crerners T I, Muller O, Lavielle G, Millan M J (2208). S32006, 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 [Arjona 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].
[0450] 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; 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.
[0451] 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-HT.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.
[0452] 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.
[0453] 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.
[0454] 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.
[0455] 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.
[0456] 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.
[0457] 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.
[0458] 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.
[0459] 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.
[0460] 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.
[0461] 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.
[0462] 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.
[0463] 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.
[0464] 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.
[0465] 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.
[0466] 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.
[0467] 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.
[0468] The active compounds can also be in micro-encapsulated form,
if appropriate, with one or more of the above-mentioned
carriers.
[0469] 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.
[0470] Besides inert diluents, the oral compositions may also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring and perfuming agents.
[0471] 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.
[0472] 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.
[0473] 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.
[0474] 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.
[0475] 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.
[0476] 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.
[0477] 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.
[0478] 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.
[0479] 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.
[0480] The following examples serve to explain the invention
without limiting it.
EXAMPLES
[0481] The compounds were either characterized via proton-NMR in
d.sub.6-dimethylsulfoxide or d-chloroform or d.sub.4-methanol on a
400 MHz or 500 MHz NMR instrument (Bruker AVANCE), or by mass
spectrometry, generally recorded via HPLC-MS in a fast gradient on
C18-material (electrospray-ionisation (ESI) mode).
[0482] 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.) and multiplet
(m).
[0483] Enantiomers were separated/purified either by chiral
supercritical fluid chromatography (SFC) (method A) or by chiral
HPLC (method B).
Method a--Chiral Analytical SFC
[0484] Analytical SFC was performed on an Aurora A5 SFC Fusion and
Agilent 1100 system running under Agilent Chemstation software
control. The SFC system included a 10-way column switcher, CO2
pump, modifier pump, oven, and backpressure regulator. The mobile
phase comprised of supercritical CO2 supplied by a beverage-grade
CO2 cylinder with a modifier mixture of methanol at a flow rate of
3 mL/min. Oven temperature was at 35.degree. C. and the outlet
pressure at 150 bar. The UV detector was set to collect at
wavelengths of 220 nm and 254 nm. The mobile phase gradient started
with 5% modifier and held it for 0.1 minutes at a flow rate of 1
mL/min, then the flow rate was ramped up to 3 mL/min and held for
0.4 min. The modifier was ramped from 5% to 15% over the next 8
minutes at 3 mL/min then held for 1 minute at 15% modifier (3
mL/min). The gradient was ramped down from 15% to 5% modifier over
0.5 min (3 mL/min). The instrument was fitted with a Chiralpak AS-H
column with dimensions of 4.6 mm i.d..times.150 mm length with 5
.mu.m particles.
Method B--Chiral HPLC
[0485] System: KNAUER preparative HPLC Pump: Preparative pump 1800
Detector: Smartline UV detector 2600 257 nm Sample pump: Knauer
HPLC-Pump K-120 Fractional collector: Smartline Valves Drive S6
Software: ChromGate.RTM. V3.1.7, KNAUER Instrument Control
Column: Whelk O 4.6 mm ID.times.250 mm
[0486] Column temperature: 25.degree. C. Mobile phase:
hexane/isopropylamine 95/5 Flow rate: 1 ml/min
I. PREPARATION EXAMPLES
Example 1
8,8-Dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline
(Compound of the Formula I.g, I.h or I.i in which the Combination
of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is as in Row
B-1 of Table B)
1.1 Preparation of tert-butyl
1-(3-methylbut-2-enoyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carbo-
xylate
[0487] 1 g (4.04 mmol) of tert-butyl
2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate was
dissolved in 20 mL of dichloromethane and treated with 1.54 mL
(8.86 mL) of triethylamine followed by 0.53 mL (4.83 mmol) of
3-methylbut-2-enoyl chloride. The reaction mixture was stirred over
night at room temperature, poured onto water (50 mL) and extracted
three times with 50 mL of dichloromethane each. The organic phases
were combined, washed with a saturated solution of sodium chloride,
dried over magnesium sulfate and concentrated in vacuo. The residue
was purified by column chromatography on silica (eluent: 5-10%
methanol in dichloromethane) to yield 1.27 g of the title compound
as a white solid.
[0488] ESI-MS: m/z (%): 275.10 (100,
[M-C.sub.4H.sub.9+H].sup.+).
1.2 Preparation of tert-butyl
8,8-dimethyl-6-oxo-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-
e-2(6H)-carboxylate
[0489] A solution of 0.33 g (1.0 mmol) of tert-butyl
1-(3-methylbut-2-enoyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carbo-
xylate of step 1.1 was irradiated with a 150 W mercury lamp in an
immersion well reactor with a pyrex filter in 20 mL of acetone
until completion of the reaction monitored by liquid
chromatography. The solution was concentrated in vacuo and the
residue was purified by column chromatography on silica (eluent:
10-30% ethyl acetate in heptane) to yield 202 mg of the title
compound as a beige solid.
[0490] ESI-MS: m/z (%): 275.10 (100,
[M-C.sub.4H.sub.9+H].sup.+).
1.3 Preparation of tert-butyl
8,8-dimethyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H-
)-carboxylate
[0491] A solution of 38 mg (0.115 mmol) tert-butyl
8,8-dimethyl-6-oxo-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-
e-2(6H)-carboxylate of step 1.2 in 1 mL of tetrahydrofuran was
treated with 0.46 mL of 1 molar solution of
borohydride-tetrahydrofuran complex in tetrahydrofuran. The mixture
was stirred over night, and then quenched with water and diluted
hydrochloric acid. The pH was adjusted to pH 9 by addition of
aqueous sodium hydroxide solution and the mixture extracted three
times with 10 mL of dichloromethane each. The solution was dried
over magnesium sulfate and concentrated in vacuo. The residue was
purified by column chromatography on silica (eluent: 20-30% ethyl
acetate in heptane) to yield 21 mg of the title compound as a clear
oil.
[0492] ESI-MS: m/z (%): 317.20 (100, [M+H].sup.+).
1.4 Preparation of
8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline
[0493] 287 mg (0.9 mmol) of tert-butyl
8,8-dimethyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H-
)-carboxylate of step 1.3 were dissolved in 5 mL of dichloromethane
and treated with 2.5 mL of trifluoroacetic acid. The mixture was
stirred over night at room temperature and then extracted once with
water (10 mL). The organic phase was then extracted twice with a
diluted solution of sodium hydroxide (10 mL each), dried over
magnesium sulfate and concentrated in vacuo. The residue was
purified by column chromatography on silica (eluent: 10-30%
methanol in dichloromethane) to yield 141 mg of the title compound
as a yellow oil.
[0494] ESI-MS: m/z (%): 217.15 (100, [M+H].sup.+).
[0495] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=7.15 (d, 1H),
6.85 (d, 1H), 6.75 (m, 1H), 3.80 (s, 2H), 3.15 (m, 2H), 3.00 (s,
4H), 1.65 (m, 2H), 1.20 (s, 6H).
Example 2
1,2,3,4-Tetrahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-cyclopent[2-
]en]-6(7H)-one 2,2,2-trifluoroacetate (Compound of the Formula I.j,
I.k or 1.1 in which the Combination of R.sup.5a, R.sup.5b, R.sup.7,
R.sup.8 and R.sup.9a is as in Row B-481 of Table B)
2.1 Preparation of tert-butyl
6-oxo-3,4,6,7-tetrahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-cycl-
opent[2]ene]-2(1H)-carboxylate (Compound of the Formula I.g, I.h or
I.i in which the Combination of R.sup.5a, R.sup.5b, R.sup.7,
R.sup.8 and R.sup.9a is as in Row B-401 of Table B, Wherein However
R.sup.1 is not H, but Boc)
[0496] A solution of 50 mg (0.128 mmol) tert-butyl
9-chloro-1-(2-cyclopentenylacetyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine--
4(5H)-carboxylate was dissolved in 1 mL of degassed dry
acetonitrile under argon, treated with 1.4 mg (0.006 mmol) of
palladium acetate, 6.10 mg (0.013 mmol)
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine and 53 mg
(0.384 mmol) potassium carbonate. The mixture was stirred for 10
hours at 120.degree. C. in a synthesis microwave system. After
cooling to room temperature the mixture was filtered over celite,
diluted with dichloromethane and then extracted twice with a
diluted solution of sodium chloride (10 mL each), dried over
magnesium sulfate and concentrated in vacuo. The residue was
purified by column chromatography on silica (eluent: 10-30% ethyl
acetate in heptane) to yield 40 mg of the title compound as a
yellow oil.
[0497] ESI-MS: m/z (%): 299.10 (100,
[M-C.sub.4H.sub.9+H].sup.+).
2.2 Preparation of
1,2,3,4-tetrahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-cyclopent[-
2]en]-6(7H)-one 2,2,2-trifluoroacetate
[0498] Boc-deprotection of the compound obtained in step 2.1
analogously to example 1.4 yielded the title compound.
[0499] ESI-MS: m/z (%): 255 (100, [M+H].sup.+).
Example 3
8-Methyl-8-phenyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-6-
(2H)-one, hydrochloride (Compound of the Formula I.j, I.k or 1.1 in
which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and
R.sup.9a is as in Row B-161 of Table B)
[0500] 392 mg (1 mmol) of tert-butyl
1-(3-phenylbut-2-enoyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carbo-
xylate were treated with 1 g of polyphosphoric acid. The mixture
was heated to 90.degree. C. for 2 hours and then quenched with a
saturated solution of potassium carbonate at 0.degree. C. The
mixture was extracted three times with ethyl acetate (20 mL each),
the combined organic fractions dried over magnesium sulfate and
concentrated in vacuo. The residue was purified by column
chromatography on silica (eluent: 10-30% methanol in
dichloromethane) to yield 86 mg of the title compound as a yellow
foam.
[0501] ESI-MS: m/z (%): 293.1 (100, [M+H].sup.+).
[0502] 1H-NMR (500 MHz, DMSO-d6): .delta.=10.05 (bs, 1H), 9.85 (bs,
1H), 7.40 (d, 1H), 7.35 (d, 1H), 7.25 (m, 2H), 7.20 (m, 2H), 7.10
(m, 2H), 4.55 (m, 1H), 4.35 (m, 1H), 4.15 (m, 1H), 3.55 (m, 1H),
3.25 (m, 2H), 3.10 (m, 1H), 2.70 (m, 1H), 1.60 (s, 3H).
[0503] The following example was prepared analogously to example
1.
Example 4
8,8-Dimethyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-6(2H)--
one (Compound of the Formula I.j, I.k or 1.1 in which the
Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is
as in Row B-1 of Table B)
[0504] ESI-MS: m/z (%): 231 (100, [M+H].sup.+).
[0505] 1H-NMR (500 MHz, CDCl.sub.3): .delta.=7.20 (d, 1H), 7.00 (m,
2H), 4.10 (s, 4H), 3.20 (m, 2H), 2.50 (s, 2H), 1.30 (s, 6H).
[0506] The following examples 5 and 6 were prepared analogously to
example 2.
Example 5
1,2,3,4-Tetrahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-cyclopentan-
]-6(7H)-one (Compound of the Formula I.j, I.k or 1.1 in which the
Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is
as in Row B-361 of Table B)
[0507] ESI-MS: m/z (%): 257 (100, [M+H].sup.+).
Example 6
1,2,3,4,6,7-Hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-cyclopen-
tane](Compound of the Formula I.g, I.h or I.i in which the
Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is
as in Row B-361 of Table B)
[0508] ESI-MS: m/z (%): 243 (100, [M+H].sup.+).
[0509] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=7.15 (d, 1H),
6.95 (d, 1H), 6.80 (m, 1H), 3.90 (s, 2H), 3.20 (m, 2H), 3.05 (m,
4H), 1.95-1.65 (m, 10H).
[0510] The following examples 7 to 13 were prepared analogously to
example 1.
Example 7
12a-Methyl-4,5,6,7,10,11,12,12a-octahydrocyclopenta[c][1,4]diazepino[6,7,1-
-ij]quinolin-9(9aH)-one (Racemic Cis Diastereomer of the Compound
of the Formula I.j, I.k or 1.1 in which the Combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is as in Row
B-521 of Table B)
[0511] ESI-MS: m/z (%): 257 (100, [M+H].sup.+).
Example 8
8-Methyl-8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-
-ij]quinoline (Single Enantiomer of the Compound of the Formula
I.g, I.h or I.i in which the Combination of R.sup.5a, R.sup.5b,
R.sup.7, R.sup.8 and R.sup.9a is as in Row B-81 of Table B)
[0512] ESI-MS: m/z (%): 271 (100, [M+H].sup.+).
[0513] The retention time according to method A is 1.396 min.
Example 9
8-Methyl-8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-
-ij]quinoline (Single Enantiomer of the Compound of the Formula
I.g, I.h or I.i in which the Combination of R.sup.5a, R.sup.5b,
R.sup.7, R.sup.8 and R.sup.9a is as in Row B-81 of Table B)
[0514] ESI-MS: m/z (%): 271 (100, [M+H].sup.+).
[0515] The retention time according to method A is 1.543 min.
Example 10
[0516]
12a-Methyl-4,5,6,7,10,11,12,12a-octahydrocyclopenta[c][1,4]diazepin-
o[6,7,1-ij]quinolin-9(9aH)-one (Racemic Trans Diastereomer of the
Compound of the Formula I.j, I.k or 1.1 in which the Combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is as in Row
B-521 of Table B)
[0517] ESI-MS: m/z (%): 257 (100, [M+H].sup.+).
Example 11
12a-Methyl-4,5,6,7,9,9a,
10,11,12,12a-decahydrocyclopenta[c][1,4]diazepino[6,7,1-ij]quinoline
(Racemic Cis Diastereomer of the Compound of the Formula I.g, I.h
or I.i in which the Combination of R.sup.5a, R.sup.5b, R.sup.7,
R.sup.8 and R.sup.9a is as in Row B-521 of Table B)
[0518] ESI-MS: m/z (%): 243 (100, [M+H].sup.+).
[0519] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=7.15 (d, 1H),
6.90 (d, 1H), 6.80 (m, 1H), 3.90 (m, 2H), 3.15 (m, 1H), 3.05 (m,
3H), 2.95 (m, 1H), 2.80 (m, 1H), 1.95 (m, 1H), 1.90 (m, 1H), 1.80
(m, 2H), 1.60 (m, 1H), 1.55 (m, 1H), 1.30 (m, 1H), 1.20 (s,
3H).
Example 12
8-Methyl-8-(trifluoromethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij-
]quinolin-6(2H)-one (Racemic Mixture of Compound of the Formula
I.j, I.k or 1.1 in which the Combination of R.sup.5a, R.sup.5b,
R.sup.7, R.sup.8 and R.sup.9a is as in Row B-81 of Table B)
[0520] ESI-MS: m/z (%): 285 (100, [M+H]f).
Example 13
12a-Methyl-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c][1,4]diazepino--
[6,7,1-ij]quinoline Hydrochloride (Racemic Trans Diastereomer of
the Compound of the Formula I.g, I.h or I.i in which the
Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is
as in Row B-521 of Table B)
[0521] ESI-MS: m/z (%): 243 (100, [M+H].sup.+).
[0522] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=9.45 (bs, 1H),
9.05 (bs, 1H), 7.05 (d, 1H), 7.00 (d, 1H), 6.70 (m, 1H), 4.30 (m,
1H), 3.95 (m, 1H), 3.55 (m, 2H), 3.35 (m, 1H), 3.25 (m, 2H), 2.95
(m, 1H), 1.95 (m, 1H), 1.85 (m, 1H), 1.80 (m, 1H), 1.70 (m, 1H),
1.55 (m, 1H), 1.40 (m, 1H), 1.25 (m, 1H), 0.90 (s, 3H).
[0523] The following examples 14 and 15 were prepared analogously
to example 3.
Example 14
8-Methyl-8-phenyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoli-
ne Hydrochloride (Racemic Mixture in Form of the Salt of the
Compound of the Formula I.g, I.h or I.i in which the Combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is as in Row
B-161 of Table B)
[0524] ESI-MS: m/z (%): 279 (100, [M+H].sup.+)
[0525] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.=7.22-7.27 (m,
2H), 7.11-7.19 (m, 3H), 6.95-7.04 (m, 2H), 6.78 (dd, J=8.0, 7.5 Hz,
1H), 3.99 (d, J=14.4 Hz, 1H), 3.87 99 (d, J=14.5 Hz, 1H), 3.20-3.26
(m, 1H), 3.01-3.08 (m, 4H), 2.87-2.94 (m, 1H), 2.09-2.15 (m, 1H),
1.92-1.99 (m, 1H), 1.73 (s, 3H) ppm.
Example 15
8-Methyl-8-phenyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoli-
ne (Racemic Mixture of Compound of the Formula I.g, I.h or I.i in
which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R and
R.sup.9a is as in Row B-161 of Table B)
[0526] ESI-MS: m/z (%): 279 (100, [M+H].sup.+).
[0527] .sup.1H NMR (CDCl.sub.3, 500 MHz): [ppm]: 7.25 (m, 2H), 7.15
(m, 3H), 7.05 (d, 1H), 6.95 (d, 1H), 6.80 (m, 1H), 4.00 (m, 1H),
3.90 (m, 1H), 3.25 (m, 1H), 3.05 (m, 4H), 2.90 (m, 1H), 2.10 (m,
1H), 1.95 (m, 1H), 1.75 (s, 3H).
Example 16
(R)-5,6,7,9,9a,
10,11,12-Octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
(2,2,2-trifluoroacetate) (R-Enantiomer of the Compound of the
Formula I.a, I.b or I.c in which the Combination of R.sup.5a,
R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is as in Row A-865 of Table
A)
16.1 Preparation of (R)-tert-butyl 9-oxo-6,7,9a,
10,11,12-hexahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline-5-
(9H)-carboxylate
[0528] 65 mg of (R)-tert-butyl
9-chloro-1-(pyrrolidine-2-carbonyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-
-4(5H)-carboxylate was stirred together with 1.8 mg of
2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2.5 mg
Pd.sub.2(dba).sub.3 and 19 mg sodium 2-methylpropan-2-olate at
100.degree. C. over 10 hours in toluene. The reaction mixture was
then cooled to room temperature and evaporated. The residue was
purified by column chromatography on silica (eluent: 10-25% ethyl
acetate in heptane) to yield 20 mg of the title compound as a beige
solid.
[0529] ESI-MS: m/z (%): 344.20 (100, [M+H].sup.+).
16.2 Preparation of (R)-tert-butyl 6,7,9a,
10,11,12-hexahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline-5-
(9H)-carboxylate (R-Enantiomer of the Compound of the Formula I.a,
I.b or I.c in which the Combination of R.sup.5a, R.sup.5b, R.sup.7,
R.sup.8 and R.sup.9a is as in Row A-121 of Table a, Wherein However
R.sup.1 is not H, but Boc)
[0530] Reduction of the compound obtained in step 16.1 analogously
to example 1.3 yielded the title compound.
[0531] ESI-MS: m/z (%): 330.20 (100, [M+H].sup.+).
16.3 Preparation of
(R)-5,6,7,9,9a,10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2--
a]quinoxaline bis(2,2,2-trifluoroacetate) (R-Enantiomer of the
Compound of the Formula I.a, I.b or I.c in which the Combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is as in Row
A-121 of Table A)
[0532] Boc-deprotection of the compound obtained in step 16.2
analogously to example 1.4 yielded the title compound.
[0533] ESI-MS: m/z (%): 230.15 (100, [M+H].sup.+).
[0534] Example 17 was prepared analogously to example 16 employing
(S)-tert-butyl
9-chloro-1-(pyrrolidine-2-carbonyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-
-4(5H)-carboxylate as starting material which was derived from
(R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic
acid.
Example 17
(S)-5,6,7,9,9a,
10,11,12-Octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
(2,2,2-trifluoroacetate) (S-Enantiomer of the Compound of the
Formula I.a, I.b or I.c in which the Combination of R.sup.5a,
R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is as in Row A-865 of Table
A)
[0535] ESI-MS: m/z (%): 230 (100, [M+H].sup.+).
[0536] The following examples 18 to 23 were prepared analogously to
example 1.
Example 18
9-Chloro-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]qui-
noline, (2,2,2-trifluoroacetate) (Compound of the Formula I.g in
which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R and
R.sup.9a is as in Row B-3 of Table B)
[0537] ESI-MS: m/z (%): 251 (100, [M+H].sup.+).
[0538] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 8.95
(bs, 2H), 7.35 (d, 1H), 7.25 (d, 1H), 4.15 (s, 2H), 3.30-3.20 (m,
6H), 1.65 (m, 2H), 1.25 (s, 6H).
Example 19
10-Chloro-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]qu-
inoline (2,2,2-trifluoroacetate) (Compound of the Formula I.h in
which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and
R.sup.9a is as in Row B-3 of Table B)
[0539] ESI-MS: m/z (%): 251 (100, [M+H].sup.+).
[0540] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 9.10
(bs, 2H), 7.35 (m, 1H), 7.20 (m, 1H), 4.15 (s, 2H), 3.30-3.20 (m,
6H), 1.65 (m, 2H), 1.25 (s, 6H).
Example 20
9-Chloro-8,8-dimethyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinol-
in-6(2H)-one 2,2,2-trifluoroacetate (Compound of the Formula I.j in
which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and
R.sup.9a is as in Row B-3 of Table B)
[0541] ESI-MS: m/z (%): 265 (100, [M+H].sup.+).
Example 21
10-Chloro-8,8-dimethyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quino-
lin-6(2H)-one 2,2,2-trifluoroacetate (Compound of the Formula I.k
in which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8
and R.sup.9a is as in Row B-3 of Table B)
[0542] ESI-MS: m/z (%): 265 (100, [M+H].sup.+).
Example 22
9-Fluoro-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]qui-
noline (Compound of the Formula I.g in which the Combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is as in Row B-2
of Table B)
[0543] ESI-MS: m/z (%): 235 (100, [M+H].sup.+).
[0544] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.95 (m,
1H), 6.55 (m, 1H), 3.95 (s, 2H), 3.20-3.10 (m, 6H), 1.70 (m, 2H),
1.40 (s, 6H).
Example 23
10-Fluoro-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]qu-
inoline (2,2,2-trifluoroacetate) (Compound of the Formula I.h in
which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and
R.sup.9a is as in Row B-2 of Table B)
[0545] ESI-MS: m/z (%): 235 (100, [M+H].sup.+).
[0546] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 9.05
(bs, 2H), 7.05 (d, 1H), 6.80 (m, 1H), 4.20 (s, 2H), 3.35 (m, 2H),
3.30 (m, 3.25), 3.25 (m, 2H), 1.70 (m, 2H), 1.30 (s, 6H).
[0547] The following examples 24 to 26 were prepared analogously to
example 2.
Example 24
1,2,3,4,6,7-Hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-cyclohex-
ane] (2,2,2-trifluoroacetate) (Compound of the Formula I.g, I.h or
I.i in which the Combination of R.sup.5a, R.sup.5b, R.sup.7,
R.sup.8 and R.sup.9a is as in Row B-401 of Table B)
[0548] ESI-MS: m/z (%): 257.2 (100, [M+H].sup.+).
[0549] .sup.1H NMR (CDCl.sub.3, 500 MHz): [ppm]: 8.85 (bs, 2H),
7.45 (d, 1H), 7.15 (d, 1H), 6.90 (m, 1H), 4.15 (s, 2H), 3.25 (m,
4H), 3.15 (m, 2H), 1.80 (m, 2H), 1.70 (m, 4H), 1.55 (m, 4H), 1.30
(m, 2H).
Example 25
1',2',3',4',6',7'-Hexahydrospiro[cyclobutane-1,8'-[1,4]diazepino[6,7,1-ij]-
quinoline], Hydrochloride (Compound of the Formula I.g, I.h or I.i
in which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8
and R.sup.9a is as in Row B-321 of Table B)
[0550] ESI-MS [M+H+]=229.20
[0551] .sup.1H NMR (CDCl.sub.3, 500 MHz): [ppm]: 8.80 (bs, 2H),
7.50 (d, 1H), 6.95 (d, 1H), 6.90 (m, 1H), 4.10 (s, 2H), 3.25 (m,
2H), 3.20 (m, 2H), 3.10 (m, 2H), 2.35 (m, 2H), 2.00 (m, 2H), 1.90
(m, 4H).
Example 26
9'-Fluoro-1',2',3',4',6',7'-hexahydrospiro[cyclobutane-1,8'-[1,4]diazepino-
[6,7,1-ij]quinoline], Hydrochloride (Compound of the Formula I.g in
which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and
R.sup.9a is as in Row B-322 of Table B)
[0552] ESI-MS [M+H+]=247.15
[0553] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): [ppm]: 9.00 (bs, 2H),
7.25 (m, 1H), 6.80 (m, 1H), 4.10 (s, 2H), 3.25 (m, 2H), 3.20 (m,
2H), 3.10 (m, 2H), 2.65 (m, 2H), 2.00 (m, 4H), 1.85 (m, 2H).
[0554] The following examples 27 and 28 were prepared analogously
to example 1.
Example 27
Enantiomer of
7,8,8-trimethyl-1,2,3,4,7,8-hexahydro-6H-[1,4]diazepino[6,7,1-ij]quinolin-
e](Enantiomer of the Compound of the Formula I.g, I.h or I.i in
which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and
R.sup.9a is as in Row B-25 of Table B)
[0555] ESI-MS [M+H+]=231.20
[0556] .sup.1H NMR (CDCl.sub.3, 500 MHz): [ppm]: 7.25 (d, 1H), 7.00
(d, 1H), 6.85 (dd, 1H), 4.00 (m, 1H), 3.90 (m, 1H), 3.15 (m, 4H),
3.05 (m, 2H), 1.85 (m, 1H), 1.30 (s, 3H), 1.10 (s, 3H), 0.95 (d,
3H).
[0557] The retention time of the Boc-protected precursor according
to method B is 10.363.
Example 28
Enantiomer of
7,8,8-trimethyl-1,2,3,4,7,8-hexahydro-6H-[1,4]diazepino[6,7,1-ij]quinolin-
e](Enantiomer of the Compound of the Formula I.g, I.h or I.i in
which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and
R.sup.9a is as in Row B-25 of Table B)
[0558] ESI-MS [M+H+]=231.20
[0559] .sup.1H NMR (CDCl.sub.3, 500 MHz): [ppm]: 7.25 (d, 1H), 7.00
(d, 1H), 6.85 (dd, 1H), 4.00 (m, 1H), 3.90 (m, 1H), 3.15 (m, 4H),
3.05 (m, 2H), 1.85 (m, 1H), 1.30 (s, 3H), 1.10 (s, 3H), 0.95 (d,
3H).
[0560] The retention time of the Boc-protected precursor according
to method B is 11.410 min.
[0561] The following example 29 was prepared analogously to example
1.
Example 29
3-Methyl-1',2',3',4',6',7'-hexahydrospiro[cyclobutane-1,8'-[1,4]diazepino[-
6,7,1-ij]quinoline], Hydrochloride (Compound of the Formula I.p,
I.q or I.r in which the Combination of R.sup.5a, R.sup.5b, R.sup.7,
R.sup.8 and R.sup.9a is as in Row B-321 of Table B)
[0562] ESI-MS [M+H+]=243.20
[0563] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): [ppm]: 9.30 (bs, 1H),
8.55 (bs, 1H), 7.60 (d, 1H), 7.20 (d, 1H), 6.95 (dd, 1H), 4.20 (m,
1H), 4.05 (m, 1H), 3.35 (m, 1H), 3.20 (m, 2H), 2.90 (m, 1H), 2.40
(m, 1H), 2.25 (m, 1H), 2.05 (m, 1H), 1.95 (m, 6H), 1.2 (d, 3H).
Example 30
3-Benzyl-2',3',7',8',9',10'-hexahydro-1H-3',8',10a'-triaza-cyclohepta[de]n-
aphthalene (Compound of the Formula I.a, I.b or I.c in which the
Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is
as in Row A-181 of Table A)
30.1 Preparation of
2-(4-benzyl-3,4-dihydro-2H-quinoxalin-1-yl)-acetamide
[0564] A solution of 1 g (4.46 mmol)
1-benzyl-1,2,3,4-tetrahydroquinoxaline in 10 ml of
dimethylformamide was treated with 3.14 ml (18.15 mmol) of
N-Ethyl-N-isopropylpropan-2-amine, and subsequently 863 mg (9.23
mmol) 2-chloroacetamide was added. The reaction mixture was heated
in a microwave system at 100.degree. C. for four hours. The
resulting mixture was quenched with water and extracted once with
ethylacetate. The aqueous phase was set to pH 10 with sodium
hydroxide solution and extracted 3.times. with ethylacetate. The
combined organic extracts were dried with magnesium sulfate,
evaporated till dryness and directly purified by column
chromatography on silica (eluent: starting with heptane and then up
to 100% ethylacetate) to yield 1.224 g of the title compound.
[0565] ESI-MS: m/z (%): 282.10 (100, [M+H].sup.+).
30.2 Preparation of
2-(4-Benzyl-3,4-dihydro-2H-quinoxalin-1-yl)-ethylamine
[0566] To 1.224 g (4.35 mmol) of
2-(4-benzyl-3,4-dihydro-2H-quinoxalin-1-yl)-acetamide were added
10.88 ml (21.75 mmol) borane dimethylsulfide THF solution and
subsequently heated to 60.degree. C. for six hours in a microwave
system. The mixture was quenched with 1 molar hydrochloric acid and
methanol and heated for 15 minutes at 60.degree. C. in a microwave
system. The reaction mixture was diluted with ethylacetate and
extracted 3.times. with 1 molar hydrochlorid acid. The combined
aqueous phases were set to pH 10 with sodium hydroxide solution and
extracted 3.times. with dichloromethane. The combined organic
phases were dried and evaporated to yield 1.089 g of the title
compound as an oil.
[0567] ESI-MS: m/z (%): 268.15 (100, [M+H].sup.+).
30.3 Preparation of
3-benzyl-2,3,7,8,9,10-hexahydro-1H-3,8,10a-triaza-cyclohepta[de]-naphthal-
ene
[0568] A solution of 1.089 g (4.07 mmol) of
2-(4-benzyl-3,4-dihydro-2H-quinoxalin-1-yl)-ethylamine and 20 ml
ethanol was treated with 122 mg (4.07 mmol) of formaldehyde and 511
mg (4.48 mmol) of trifluoroacetic acid and stirred over night at
room temperature. The solvent was evaporated and dichloromethane
was added to the crude mixture. The organic phase was washed with 1
molar sodium hydroxide solution. The organic phase was dried and
purified by column chromatography on silica (eluent: starting with
dichloromethane and then up to 100% methanol) to yield 448 mg of
the title compound.
[0569] ESI-MS [M+H+]=280.10 (100, [M+H].sup.+).
[0570] .sup.1H NMR (CDCl.sub.3, 500 MHz): [ppm]: 7.35 (m, 3H), 7.30
(m, 2H), 6.80 (dd, 1H), 6.65 (d, 1H), 6.60 (d, 1H), 4.55 (s, 2H),
4.10 (s, 2H), 3.30 (m, 4H), 3.25 (m, 2H), 3.10 (m, 2H).
Example 31
9-Fluoro-1-methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quino-
line-8,1'-cyclobutane], Trifluoroacetic Acid Salt (Compound of the
Formula I.m in which the Combination of R.sup.5a, R.sup.5b,
R.sup.7, R.sup.8 and R.sup.9a is as in Row B-322 of Table B)
31.1 Preparation of
2-cyclobutylidene-N-(3-fluorophenyl)-acetamide
[0571] 1.5 g (13.50 mmol) of 3-fluoroaniline were dissolved in 20
ml of dichloromethane and treated with 5.19 g (29.7 mmol) of
N-ethyl-N-isopropylpropan-2-amine. Within 10 min 12.82 g (16.20
mmol) of 2-cyclobutylideneacetyl chloride were added at 0.degree.
C. and the solution was stirred overnight at room temperature. The
mixture was poured on ice water and extracted 2.times. with
dichloromethane. The combined organic phases were washed once with
saturated sodium chloride solution, dried with MgSO.sub.4 and
evaporated in vacuo. The crude oil was treated with heptane and
decanted twice, redissolved in ether-dichloromethane and treated
with heptane till crystallization, yielding 2.2 g (77%) of a beige
solid.
[0572] ESI-MS: m/z (%): 206 (100, [M+H].sup.+).
31.2 Preparation of
5'-fluoro-1'H-spiro[cyclobutane-1,4'-quinolin]-2'(3'H)-one
[0573] A solution of 400 mg (1.94 mmol) of
2-cyclobutylidene-N-(3-fluorophenyl)-acetamide obtained in step
31.1 was dissolved in 19.5 ml of toluene and irradiated with a Hg
middle pressure lamp in a suitable device till completion of the
reaction indicated by liquid chromatography. The crude solution was
concentrated in vacuo and the residue was purified by column
chromatography on silica (eluent: 10-30% ethyl acetate in heptane)
to yield 55 mg (14%) of the title compound as a beige solid.
[0574] ESI-MS: m/z (%): 206 (100, [M+H].sup.+).
31.3 Preparation of
5'-fluoro-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-quinoline]
[0575] A solution of 50 mg (0.244 mmol) of
5'-fluoro-1'H-spiro[cyclobutane-1,4'-quinolin]-2'(3'H)-one obtained
in step 31.2 in 1 mL of tetrahydrofuran was treated with 0.73 mL of
1 M solution of borohydride-tetrahydrofuran complex in
tetrahydrofuran. The mixture was stirred at reflux for 2 h,
quenched with water and evaporated till dryness. The crude compound
was used in the subsequent step without purification.
[0576] ESI-MS: m/z (%): 192 (100, [M+H].sup.+).
31.4 Preparation of
2-(5'-fluoro-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-quinolin]-1'-yl)-ac-
etamide
[0577] A solution of 50 mg (0.26 mmol) of
5'-fluoro-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-quinoline]
obtained in step 31.3 in 1 ml of dimethylformamide was treated with
6.2 mg (0.26 mmol) of sodium hydride followed by 72 mg (0.52 mmol)
2-bromoacetamide and heated in a microwave system at 100.degree. C.
for one hour. The resulting mixture was quenched with water,
evaporated till dryness and directly purified by column
chromatography on silica (eluent: 10% methanol in dichloromethane)
to yield 70 mg of the title compound with about 80% purity
determined by LCMS.
[0578] ESI-MS: m/z (%): 249 (100, [M+H].sup.+).
31.5 Preparation of
2-(5'-fluoro-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-quinolin]-1'-yl)eth-
anamine
[0579] A solution of 40 mg (0.16 mmol) of
2-(5'-fluoro-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-quinolin]-1'-yl)-ac-
etamide obtained in step 31.4 in 1 ml of tetrahydrofurane was
treated with 38 .mu.l (0.38 mmol) of borane dimethylsulfide and
heated to 70.degree. C. for two hours. The mixture was quenched
with water and hydrochloric acid, diluted with dichloromethane and
extracted twice with water. The combined aqueous phases were set to
pH 10 with sodium hydroxide solution and extracted 3.times. with
dichloromethane. The combined organic phases were dried and
evaporated to yield 10 mg of the title compound as an oil.
[0580] ESI-MS: m/z (%): 235 (100, [M+H].sup.+).
31.6 Preparation of
9-fluoro-1-methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quin-
oline-8,1'-cyclobutane], Trifluoroacetic Acid Salt
[0581] A solution of 10 mg (0.043 mmol) of
2-(5'-fluoro-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-quinolin]-1'-yl)eth-
an-amine obtained in step 31.5 in 0.4 ml of acetonitrile/methanol
was treated with 3.8 mg (0.085 mmol) of acetaldehyde and 6.5 l
(0.085 mmol) of trifluoroacetic acid and stirred over night at room
temperature. The solvent was evaporated and the crude mixture
purified with reversed phase liquid chromatography to yield 1.5 mg
of the title compound as beige solid.
[0582] ESI-MS: m/z (%): 261 (100, [M+H].sup.+).
[0583] .sup.1H-NMR (500 MHz, pyridine-d5): .delta.=7.05 (dd, 1H),
6.80 (dd, 1H), 4.20 (q, 1H), 3.05 (m, 2H), 3.00 (m, 2H), 2.85 (m,
2H), 2.75 (m, 2H), 2.05 (m, 2H), 1.90-1.70 (m, 4H), 1.50 (d, 3H)
ppm.
Example 32
2,3,5,6,7,8-Hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline
(Compound of the Formula I.a, I.b or I.c in which the Combination
of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in Row A-217 of
Table A)
32.1 Preparation of tert-butyl
1-benzyl-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline-7(8H)--
carboxylate
[0584] To a solution of 388 mg (1.39 mmol) of
1-benzyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline
(compound of example 30) in 15 ml of dichloromethane was treated
with 0.49 ml (2.78 mmol) of N,N-diisopropylethylamine. 333 mg (1.53
mmol) of di-tert-butyl dicarbonate were dissolved in 5 ml of
dichloromethane, slowly added to the reaction mixture and the
solution was then stirred overnight at room temperature. The
solution was diluted with dichloromethane and treated twice with
10% aqueous solution of citric acid. The organic phase was washed
once with saturated sodium chloride solution, dried with MgSO.sub.4
and concentrated in vacuo, yielding 559 mg of the crude product.
The crude compound was used in the subsequent step without
purification.
[0585] ESI-MS [M+H.sup.+]=380.20
32.2 Preparation of tert-butyl
2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]-quinoxaline-7(8H)-carboxyl-
ate
[0586] 559 mg (1.47 mmol) of tert-butyl
1-benzyl-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline-7(8H)--
carboxylate (559 mg, 1,473 mmol) (from step 32.1) were dissolved in
10 ml of methanol. The solution was hydrogenated with a 10% Pd/C
cartridge using the H-Cube apparatus (from Thales Nano) at 80 bar
and 70.degree. C. with a flow rate of 0.5 ml/min for 6 hours. The
solution was concentrated in vacuo yielding 320 mg of the crude
product. The crude compound was used in the subsequent step without
purification.
[0587] ESI-MS [M+H.sup.+]=290.20
32.3 Preparation of
2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline
[0588] 30 mg (0.104 mmol) of tert-butyl
2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline-7(8H)-carboxyla-
te (from step 32.2) were dissolved in 2 ml of dichloromethane and
treated with 0.20 ml (2.59 mmol) of trifluoroacetic acid at
0.degree. C. The solution was allowed to warm up to room
temperature and stirred for 2 h. The reaction mixture was diluted
with dichloromethane and extracted once with a 1 molar aqueous
solution of sodium hydroxide. The aqueous phase was extracted
3.times. with ethyl acetate. The combined organic phases were dried
with magnesium sulfate, and concentrated in vacuo yielding 14 mg
(0.076 mmol) of the title compound.
[0589] ESI-MS [M+H.sup.+]=190.10
[0590] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.75 (m,
1H), 6.55 (d, 1H), 6.50 (d, 1H), 3.90 (s, 2H), 3.25 (m, 4H), 3.10
(m, 2H), 2.95 (m, 2H).
Example 33
1-Cyclobutyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline
2,2,2-trifluoroacetate (Compound of the Formula I.a, I.b or I.c in
which the Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a
is as in Row A-433 of Table A)
33.1 Preparation of tert-butyl
1-cyclobutyl-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline-7(-
8H)-carboxylate
[0591] A solution of 79 mg (0.237 mmol) of tert-butyl
2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline-7(8H)-carboxyla-
te (from step 32.2) in 2 ml THF was treated with 38.3 mg (0.546
mmol) of cyclobutanone and molecular sieves (4 .ANG.). The reaction
mixture was stirred at room temperature overnight. 231 mg (1.09
mmol) of sodium triacetoxyborohydride was added and the reaction
mixture was stirred overnight at room temperature. The reaction
mixture was diluted with ethyl acetate and extracted once with a 1
molar aqueous solution of sodium hydroxide. The organic phase was
dried with magnesium sulfate, concentrated in vacuo and the residue
was purified by column chromatography on silica (eluent: 0-10%
methanol in dichloromethane) yielding 78 mg (0.205 mmol) of the
title compound.
[0592] ESI-MS [M+H.sup.+]=344.20
33.2 Preparation of
1-cyclobutyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline
2,2,2-trifluoroacetate
[0593] 78.4 mg (0.228 mmol) of tert-butyl
1-cyclobutyl-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline-7(-
8H)-carboxylate (from step 33.1) were dissolved in 1 ml of
dichloromethane and treated with 0.53 ml (6.85 mmol) of
trifluoroacetic acid at 0.degree. C. The solution was stirred for 2
h and then concentrated in vacuo. The residue was purified by
column chromatography on silica (eluent: 0-30% methanol in
dichloromethane) to yield 69 mg of crude product, which was
purified again via preparative HPLC to yield 46 mg of the title
compound.
[0594] ESI-MS [M+H.sup.+]=244.20
[0595] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 8.70
(bs, 2H), 6.80 (m, 1H), 6.75 (d, 1H), 6.70 (d, 1H), 4.10 (m, 2H),
4.05 (m, 1H), 3.25 (m, 2H), 3.20 (m, 2H), 3.10 (m, 4H), 2.20 (m,
2H), 2.10 (m, 2H), 1.65 (m, 2H).
Example 34
1-Methyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline
(Compound of the Formula I.a, I.b or I.c in which the Combination
of R.sup.5, R.sup.5b, R.sup.6 and R.sup.9a is as in Row A-253 of
Table A)
[0596] The title compound was prepared in analogy to example 33,
using however formaldehyde instead of cyclobutanone.
[0597] ESI-MS [M+H.sup.+]=204.10
[0598] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.85 (m,
1H), 6.65 (d, 1H), 6.55 (d, 1H), 3.90 (s, 2H), 3.35 (m, 2H), 3.15
(m, 2H), 3.10 (m, 2H), 2.95 (m, 5H).
Example 35
1-(Oxetan-3-yl)-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxali-
ne 2,2,2-trifluoroacetate (Compound of the Formula I.a, I.b or I.c
in which the Combination of R.sup.5a, R.sup.5b, R.sup.6 and
R.sup.9a is as in Row A-541 of Table A)
[0599] The title compound was prepared in analogy to example 33,
using however oxetan-3-one instead of cyclobutanone.
[0600] ESI-MS [M+H.sup.+]=246.15
[0601] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 8.80 (m,
2H), 6.75 (m, 2H), 6.30 (d, 1H), 4.80 (m, 2H), 4.65 (m, 3H), 4.10
(s, 2H), 3.35 (m, 2H), 3.20 (m, 4H), 3.10 (m, 2H).
Example 36
1-(Cyclopropylmethyl)-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]qui-
noxaline (Compound of the Formula I.a, I.b or I.c in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-577 of Table A)
[0602] The title compound was prepared in analogy to example 33,
using however cyclopropanecarboxaldehyde instead of
cyclobutanone.
[0603] ESI-MS [M+H.sup.+]=244.20
[0604] 1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.85 (m, 1H),
6.75 (m, 1H), 6.55 (m, 1H), 4.00 (m, 2H), 3.35-3.15 (m, 8H), 3.00
(m, 2H), 1.05 (m, 1H), 0.50 (m, 2H), 0.20 (m, 2H).
Example 37
1-(Cyclopentylmethyl)-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]qui-
noxaline (Compound of the Formula I.a, I.b or I.c in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-649 of Table A)
[0605] The title compound was prepared in analogy to example 33,
using however cyclopentanecarboxaldehyde instead of
cyclobutanone.
[0606] ESI-MS [M+H.sup.+]=272.20
[0607] .sup.1H NMR (DMSO-d.sup.6, 500 MHz): .delta. [ppm]: 6.80 (m,
1H), 6.65 (d, 1H), 6.50 (d, 1H), 3.95 (m, 2H), 3.30-3.20 (m, 6H),
3.15 (m, 2H), 2.95 (m, 2H), 2.30 (m, 1H), 1.90-1.55 (m, 6H), 1.25
(m, 2H).
Example 38
Cyclopropyl(2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxalin-1--
yl)methanone (Compound of the Formula I.a, I.b or I.c in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-721 of Table A)
38.1 Preparation of tert-butyl
1-(cyclopropanecarbonyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]qu-
inoxaline-7(8H)-carboxylate
[0608] To 50 mg (0.173 mmol) of tert-butyl
2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline-7(8H)-carboxyla-
te dissolved in 1 ml of dichloromethane were added 0.77 ml (4.43
mmol) of N,N-diisopropylethylamine in an inert atmosphere at
0.degree. C. 19 .mu.l (0.21 mmol) of cyclopropanecarbonyl chloride
was dissolved in 1 ml of dichloromethane and slowly added to the
reaction mixture. The reaction mixture was stirred at room
temperature for 5 h. The solution was diluted with dichloromethane
and treated twice with 10% aqueous solution of citric acid. The
organic phase was washed once with saturated sodium chloride
solution, dried with MgSO.sub.4 and concentrated in vacuo. The
residue was purified by column chromatography on silica (eluent:
0-10% methanol in dichloromethane) yielding 35 mg (0.098 mmol) of
the title compound.
[0609] ESI-MS [M-tert-butyl+H.sup.+]=302.10
38.2 Preparation of
cyclopropyl(2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]-quinoxalin--
1-yl)methanone
[0610] 35 mg (0.098 mmol) of tert-butyl
1-(cyclopropanecarbonyl)-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]qu-
inoxaline-7(8H)-carboxylate were dissolved in 2 ml of
dichloromethane and treated with 150 .mu.l (1.96 mmol) of
trifluoroacetic acid at 0.degree. C. The solution was stirred
overnight at room temperature. 100 .mu.l (1.31 mmol) of
trifluoroacetic acid were added and the reaction mixture was
stirred for 1 h. The reaction mixture was treated 3.times. with
acidified water. The combined aqueous phase was basified with 1 N
sodium hydroxide solution and extracted 5.times. with
dichloromethane. The combined organic phase was dried with
MgSO.sub.4 and concentrated in vacuo to yield 23 mg of the title
compound.
[0611] ESI-MS [M+H.sup.+]=258.20
[0612] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 7.30 (m,
1H), 7.05 (m, 1H), 6.80 (m, 1H), 4.10 (s, 2H), 3.90 (m, 2H), 3.45
(m, 4H), 3.30 (m, 2H), 2.10 (m, 1H), 1.15 (m, 2H), 0.85 (m,
2H).
Example 39
Cyclopentyl(2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxalin-1--
yl)methanone (Compound of the Formula I.a, I.b or I.c in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-793 of Table A)
[0613] The title compound was prepared in analogy to example 38
using cyclopentanecarbonyl chloride.
[0614] ESI-MS [M+H.sup.+]=286.20
[0615] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 7.00 (m,
2H), 6.80 (m, 1H), 4.10 (s, 2H), 3.90 (m, 2H), 3.45-3.20 (m, 7H),
1.80 (m, 6H), 1.55 (m, 2H).
Example 40
1-Cyclopropyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline
(Compound of the Formula I.a, I.b or I.c in which the Combination
of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in Row A-397 of
Table A)
40.1 Preparation of
2-(4-cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)acetamide
[0616] A solution of 500 mg (2.87 mmol) of
1-cyclopropyl-1,2,3,4-tetrahydroquinoxaline in 5 ml
dimethylformamide was treated with 2.0 ml (11.68 mmol) of
N-ethyl-N-isopropylpropan-2-amine, and subsequently 555 mg (5.94
mmol) 2-chloroacetamide were added. The reaction mixture was heated
in a microwave system at 100.degree. C. for 12 hours. The reaction
mixture was quenched with water and basified with 1 N sodium
hydroxide solution. The aqueous phase was extracted 3.times. with
dichloromethane. The combined organic extracts were dried with
magnesium sulfate and concentrated in vacuo. The residue was
purified by column chromatography on silica (eluent: 0-20% methanol
in dichloromethane) to yield 620 mg of the title compound.
[0617] ESI-MS [M+H+]=232.20
40.2 Preparation of
2-(4-cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)ethanamine
[0618] To 620 mg (2.68 mmol) of
2-(4-cyclopropyl-3,4-dihydroquinoxalin-1 (2H)-yl)acetamide in 2 ml
of THF was added 5.4 ml (10.80 mmol) of 2 molar borane
dimethylsulfide THF solution and subsequently heated for 7 hours at
60.degree. C. in a microwave system. An additional 2.7 ml (5.40
mmol) of 2 molar borane dimethylsulfide THF solution was added to
the reaction mixture and heated for 10 hours at 60.degree. C. in a
microwave system. To the reaction mixture were added 2 ml of
methanol, acidified with 2 molar hydrochloric acid and heated for
15 minutes at 60.degree. C. in a microwave system. The reaction
mixture was diluted with ethyl acetate and extracted twice with 1
molar hydrochloric acid. The combined aqueous phases were set to pH
10 with sodium hydroxide solution and extracted 3.times. with
dichloromethane. The combined organic phases were dried and
concentrated in vacuo. The residue was purified by column
chromatography on silica (eluent: 0-15% methanol in
dichloromethane) to yield 347 mg of the title compound.
[0619] ESI-MS [M+H.sup.+]=218.20
40.3 Preparation of
1-Cyclopropyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]-quinoxali-
ne
[0620] A solution of 347 mg (1.6 mmol) of
2-(4-cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)ethanamine in 5 ml
of ethanol were treated with 119 l (1.6 mmol) of 37% aqueous
formaldehyde solution and 135 l (1.76 mmol) of trifluoroacetic
acid. The reaction mixture was stirred for 36 h at room
temperature. Water was added and the reaction mixture was basified
using 2 N aqueous sodium hydroxide solution. The aqueous phase was
extracted three times with dichloromethane. The combined organic
phases were dried and concentrated in vacuo. The residue was
purified by column chromatography on silica (eluent: 0-20% methanol
in dichloromethane) to yield 177 mg of the title compound.
[0621] ESI-MS [M+H.sup.+]=230.20
[0622] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 7.10 (d,
1H), 6.80 (m, 1H), 6.60 (d, 1H), 3.85 (s, 2H), 3.20 (m, 2H), 3.10
(m, 2H), 3.00 (m, 4H), 2.25 (m, 1H), 0.80 (m, 2H), 0.55 (m,
2H).
Example 41
1-Cyclopentyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline
(Compound of the Formula I.a, I.b or I.c in which the Combination
of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in Row A-469 of
Table A)
[0623] The title compound was prepared in analogy to example 40
using 1-cyclopentyl-1,2,3,4-tetrahydroquinoxaline as starting
material.
[0624] ESI-MS [M+H.sup.+]=258.20
[0625] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.80 (d,
1H), 6.70 (m, 1H), 6.45 (d, 1H), 4.25 (m, 1H), 3.75 (s, 2H), 3.15
(m, 2H), 3.05 (m, 2H), 2.90 (m, 2H), 2.85 (m, 2H), 1.80 (m, 2H),
1.65 (m, 2H), 1.55 (m, 4H).
Example 42
1-Cyclopropyl-5-methyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]qu-
inoxaline (Compound of the Formula I.Gg, I.Hh or I.ii in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-397 of Table A)
42.1 Preparation of 2-(4-cyclopropyl-3,4-dihydroquinoxalin-1
(2H)-yl)propanamide
[0626] A solution of 300 mg (1.72 mmol) of
1-cyclopropyl-1,2,3,4-tetrahydroquinoxaline in 3 ml
dimethylformamide was treated with 1.2 ml (7.0 mmol) of
N-ethyl-N-isopropylpropan-2-amine, 387 mg (2.58 mmol) of sodium
iodide and subsequently 523 mg (3.44 mmol) of 2-bromopropanamide
were added. The reaction mixture was heated in a microwave system
at 100.degree. C. for 8 hours. The reaction mixture was quenched
with water and basified with 1 N sodium hydroxide solution. The
aqueous phase was extracted 3.times. with dichloromethane. The
combined organic extracts were dried with magnesium sulfate and
concentrated in vacuo. The residue was purified by column
chromatography on silica (eluent: 0-20% methanol in
dichloromethane) to yield 453 mg of the title compound.
[0627] ESI-MS [M+H.sup.+]=246.20
42.2 Preparation of
2-(4-cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)propan-1-amine
[0628] To 453 mg (1.85 mmol) of
2-(4-cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)propanamide in 2 ml
THF were added 4.3 ml (8.60 mmol) of 2 molar borane dimethylsulfide
THF solution and subsequently heated for 9 hours at 60.degree. C.
and 2 hours at 70.degree. C. in a microwave system. To the reaction
mixture was added 2 ml of methanol, acidified with 2 molar
hydrochloric acid and heated for 15 minutes at 60.degree. C. in a
microwave system. The reaction mixture was diluted with ethyl
acetate and extracted twice with 1 molar hydrochloric acid. The
combined aqueous phases were set to pH 10 with sodium hydroxide
solution and extracted 3.times. with dichloromethane. The combined
organic phases were dried and concentrated in vacuo. The residue
was purified by column chromatography on silica (eluent: 0-15%
methanol in dichloromethane) to yield 209 mg of the title
compound.
[0629] ESI-MS [M+H.sup.+]=232.20
42.3 Preparation of
1-cyclopropyl-5-methyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino-[1,7,6-de]-
quinoxaline
[0630] A solution of 209 mg (0.9 mmol) of
2-(4-cyclopropyl-3,4-dihydroquinoxalin-1(2H)-yl)propan-1-amine in 3
ml of ethanol were treated with 67 l (0.9 mmol) of 37% aqueous
formaldehyde solution and 76 l (0.99 mmol) of trifluoroacetic acid.
The reaction mixture was stirred for 36 h at room temperature.
Water was added and the reaction mixture was basified using 2 N
aqueous sodium hydroxide solution. The aqueous phase was extracted
three times with dichloromethane. The combined organic phases were
dried and concentrated in vacuo. The residue was purified by column
chromatography on silica (eluent: 0-20% methanol in
dichloromethane) to yield 136 mg of the title compound.
[0631] ESI-MS [M+H.sup.+]=244.20
[0632] 1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 7.00 (d, 1H),
6.65 (m, 1H), 6.50 (d, 1H), 3.75 (d, 1H), 3.45 (d, 1H), 3.30-3.15
(m, 4H), 3.05 (m, 1H), 2.80 (d, 1H), 2.65 (d, 1H), 2.20 (m, 1H),
0.90 (d, 3H), 0.80 (m, 2H), 0.50 (m, 2H).
Example 43
1-Cyclopentyl-5-methyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]qu-
inoxaline (Compound of the Formula I.Gg, I.Hh or I.ii in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-469 of Table A)
[0633] The title compound was prepared in analogy to example using
however 1-cyclopentyl-1,2,3,4-tetrahydroquinoxaline instead of
1-cyclopropyl-1,2,3,4-tetrahydroquinoxaline.
[0634] ESI-MS [M+H.sup.+]=272.20
[0635] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.70 (d,
1H), 6.65 (m, 1H), 6.40 (d, 1H), 4.20 (m, 1H), 3.75 (d, 1H), 3.50
(d, 1H), 3.25-3.10 (m, 3H), 3.00 (m, 2H), 2.85 (d, 1H), 2.70 (d,
1H), 1.80 (m, 2H), 1.70-1.55 (m, 5H), 1.50 (m, 1H), 0.90 (d,
3H).
Example 44
5,6,7,9,9a,
10,11,12,13,14-decahydro-4H-azepino[1,2-a][1,4]diazepino[1,7,6-de]quinoxa-
line (Compound of the Formula I.a, I.b or I.c in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-937 of Table A)
44.1 Preparation of ethyl
1-(2-nitrophenyl)azepane-2-carboxylate
[0636] A solution of 450 mg (3.19 mmol) of 1-fluoro-2-nitrobenzene,
546 mg (3.19 mmol) of ethyl azepane-2-carboxylate and 0.89 ml (6.38
mmol) of triethylamine in 10 ml acetonitrile was stirred overnight
at reflux. The reaction mixture was concentrated in vacuo. To the
residue was added aqueous sodium bicarbonate solution and extracted
twice with ethyl acetate. The combined organic extracts were dried
with sodium sulfate and concentrated in vacuo to yield 780 mg of
the crude title compound. The crude product was used without
further purification in the next step.
[0637] ESI-MS [M+H.sup.+]=293.10
44.2 Preparation of
6a,7,8,9,10,11-hexahydroazepino[1,2-a]quinoxalin-6(5H)-one
[0638] 780 mg (2.67 mmol) of ethyl
1-(2-nitrophenyl)azepane-2-carboxylate were dissolved in 30 ml
methanol and treated with 284 mg of 10% Pd/C in a hydrogen
atmosphere. The solution was stirred at room temperature for 1 h.
The catalyst was filtered off and the solution was concentrated in
vacuo. The residue was purified by column chromatography on silica
(eluent: 0-50% ethyl acetate in heptane) to yield 159 mg of the
title compound.
[0639] ESI-MS [M+H.sup.+]=217.10
44.3 Preparation of
5,6,6a,7,8,9,10,11-octahydroazepino[1,2-a]quinoxaline
[0640] To 105 mg (0.485 mmol)
6a,7,8,9,10,11-hexahydroazepino[1,2-a]quinoxalin-6(5H)-one in 4 ml
of THF (tetrahydrofuran) were added 0.97 ml (0.97 mmol) of 1 molar
borane dimethylsulfide THF solution and subsequently heated for 1 h
at 80.degree. C. in a microwave system. The reaction mixture was
poured on ice water, acidified with hydrochloric acid solution to
pH=5 and extracted twice with ethyl acetate. The combined organic
phases were dried and concentrated in vacuo. The residue was
acidified with hydrochloric acid solution and extracted once with
ether. The aqueous phase was basified with aqueous sodium
bicarbonate solution and extracted 3.times. with dichloromethane.
The combined organic phases were dried and concentrated in vacuo to
yield 85 mg of the crude title compound.
[0641] ESI-MS [M+H.sup.+]=203.20
44.4 Preparation of
2-(6a,7,8,9,10,11-hexahydroazepino[1,2-a]quinoxalin-5(6H)-yl)-acetamide
[0642] A solution of 85 mg (0.40 mmol) of
5,6,6a,7,8,9,10,11-octahydroazepino[1,2-a]quinoxaline in 2 ml of
dimethylformamide was treated with 16 mg (0.40 mmol) of sodium
hydride (60% in mineral oil) and stirred for 15 min at room
temperature. 112 mg (1.2 mmol) of 2-chloroacetamide were added and
the reaction mixture was heated in a microwave system at
100.degree. C. for 4 hours. 209 .mu.l (1.2 mmol) of
N-ethyl-N-isopropylpropan-2-amine were added to the reaction
mixture and heated at 100.degree. C. for 2 hours. 110 mg (0.8 mmol)
of 2-bromoacetamide were added and the reaction mixture was heated
in a microwave system at 100.degree. C. for 2 hours. The reaction
mixture was basified with sodium bicarbonate solution and extracted
2.times. with ethyl acetate. The combined organic extracts were
dried with magnesium sulfate and concentrated in vacuo. The residue
was purified by column chromatography on silica (eluent: 0-50%
ethyl acetate in heptane) to yield 42 mg of the title compound.
[0643] ESI-MS [M+H.sup.+]=260.20
44.5 Preparation of
2-(6a,7,8,9,10,11-hexahydroazepino[1,2-a]quinoxalin-5(6H)-yl)-ethanamine
[0644] To 42 mg (0.146 mmol) of
2-(6a,7,8,9,10,11-hexahydroazepino[1,2-a]quinoxalin-5(6H)-yl)acetamide
in 1 ml of THF were added 292 .mu.l (8.60 mmol) of 2 molar borane
dimethylsulfide THF solution and subsequently heated for 6 hours at
60.degree. C. in a microwave system. Additional 292 .mu.l (8.60
mmol) of 2 molar borane dimethylsulfide THF solution were added to
the reaction mixture and heated for 4 hours at 60.degree. C. in a
microwave system. To the reaction mixture was added 2 ml of
methanol, acidified with 2 molar aqueous hydrochloric acid solution
and heated for 15 minutes at 60.degree. C. in a microwave system.
The reaction mixture was diluted with ethyl acetate and extracted
twice with 1 molar hydrochloric acid. The combined aqueous phases
were set to pH 10 with sodium hydroxide solution and extracted
3.times. with dichloromethane. The combined organic phases were
dried and concentrated in vacuo to yield 36 mg of the title
compound.
[0645] ESI-MS [M+H.sup.+]=246.20
44.6 Preparation of
5,6,7,9,9a,10,11,12,13,14-decahydro-4H-azepino[1,2-a][1,4]-diazepino[1,7,-
6-de]quinoxaline
[0646] A solution of 36 mg (0.147 mmol) of
2-(6a,7,8,9,10,11-hexahydroazepino[1,2-a]quinoxalin-5(6H)-yl)ethanamine
in 2 ml of ethanol were treated with 11 .mu.l (0.147 mmol) of 37%
aqueous formaldehyde solution and 12 .mu.l (0.161 mmol) of
trifluoroacetic acid. The reaction mixture was stirred overnight at
room temperature. The reaction mixture was concentrated in vacuo,
treated with aqueous sodium bicarbonate solution and extracted
twice with dichloromethane. The combined organic phases were dried
and concentrated in vacuo. The residue was purified by column
chromatography on silica (eluent: 0-20% methanol in
dichloromethane) to yield 12.7 mg of the title compound.
[0647] ESI-MS [M+H.sup.+]=258.20
[0648] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.65 (m,
1H), 6.50 (d, 1H), 6.35 (d, 1H), 3.70 (m, 1H), 3.60 (m, 1H), 3.20
(m, 2H), 3.10 (m, 1H), 3.00 (m, 3H), 2.95 (m, 1H), 2.85 (m, 1H),
2.80 (m, 1H), 1.80 (m, 2H), 1.65-1.50 (m, 4H), 1.40 (m, 2H).
Example 45
7-Methyl-5,6,7,9,9.sup.a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
(Compound of the Formula I.Gg, I.Hh or I.ii in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-865 of Table A)
[0649] The title compound was prepared in analogy to example 42,
using however 1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxaline and
2-bromopropanamide.
[0650] ESI-MS [M+H.sup.+]=244.20
[0651] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.80 (m,
1H), 6.50 (d, 1H), 6.45 (d, 1H), 3.95 (d, 1H), 3.70 (d, 1H), 3.50
(m, 2H), 3.15 (m, 2H), 2.85 (m, 2H), 2.75 (m, 1H), 2.20 (m, 1H),
2.10 (m, 1H), 2.00 (m, 1H), 1.90 (m, 1H), 1.35 (m, 1H), 1.20 (d,
3H).
Example 46
1-Fluoro-7-methyl-5,6,7,9,9.sup.a,10,11,12-octahydro-4H-[1,4]diazepino[1,7-
,6-de]pyrrolo[1,2-a]quinoxaline (Compound of the Formula I.Gg in
which the Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a
is as in Row A-866 of Table A)
[0652] The title compound was prepared in analogy to example 42,
using however
9-fluoro-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxaline and
2-bromopropanamide.
[0653] ESI-MS [M+H.sup.+]=262.20
[0654] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.60 (m,
1H), 6.55 (m, 1H), 3.90 (d, 1H), 3.80 (m, 1H), 3.55 (d, 1H), 3.20
(d, 1H), 3.00 (m, 2H), 2.80 (m, 2H), 2.55 (m, 1H), 2.15 (m, 2H),
1.80 (m, 2H), 1.50 (m, 1H), 1.25 (d, 3H).
Example 47
1,2,3,4,6,7-Hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-cyclopro-
pane](Compound of the Formula I.g, I.h or I.i in which the
Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is
as in Row B-281 of Table B)
47.1 Preparation of 2-(2',3'-dihydro-1
.sup.1H-spiro[cyclopropane-1,4'-quinolin]-1'-yl)-acetamide
[0655] A solution of 500 mg (3.14 mmol) of
2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-quinoline] in 5 ml of
dimethylformamide was treated with 2.2 ml (12.8 mmol) of
N-ethyl-N-isopropylpropan-2-amine and 706 mg (4.71 mmol) of sodium
iodide; and subsequently 670 mg (7.16 mmol) of 2-chloroacetamide
were added. The reaction mixture was heated in a microwave system
at 100.degree. C. for 10 hours. The reaction mixture was quenched
with water and basified with 1 N sodium hydroxide solution. The
aqueous phase was extracted 3.times. with dichloromethane. The
combined organic extracts were dried with magnesium sulfate and
concentrated in vacuo. The residue was purified by column
chromatography on silica (eluent: 0-20% methanol in
dichloromethane) to yield 624 mg of the title compound.
[0656] ESI-MS [M+H.sup.+]=217.20
47.2 Preparation of 2-(2',3'-dihydro-1
.sup.1H-spiro[cyclopropane-1,4'-quinolin]-1'-yl)ethan-amine
[0657] To 624 mg (2.89 mmol) of 2-(2',3'-dihydro-1
.sup.1H-spiro[cyclopropane-1,4'-quinolin]-1'-yl)acetamide in 2 ml
of THF were added 5.77 ml (11.54 mmol) of 2 molar borane
dimethylsulfide THF solution and subsequently heated for 9 hours at
60.degree. C. in a microwave system. To the reaction mixture were
added 2 ml of methanol, acidified with 2 molar hydrochloric acid
and heated for 15 minutes at 60.degree. C. in a microwave system.
The reaction mixture was diluted with ethyl acetate and extracted
twice with 1 molar hydrochloric acid. The combined aqueous phases
were set to pH 10 with sodium hydroxide solution and extracted
3.times. with dichloromethane. The combined organic phases were
dried and concentrated in vacuo. The residue was purified by column
chromatography on silica (eluent: 0-20% methanol in
dichloromethane) to yield 299 mg of the title compound.
[0658] ESI-MS [M+H.sup.+]=203.20
47.3 Preparation of
1,2,3,4,6,7-Hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-cyclopr-
opane]
[0659] A solution of 299.6 mg (1.48 mmol) of 2-(2',3'-dihydro-1
.sup.1H-spiro[cyclopropane-1,4'-quinolin]-1'-yl)ethanamine in 3 ml
of ethanol was treated with 110 .mu.l (1.48 mmol) of 37% aqueous
formaldehyde solution and 126 .mu.l (1.63 mmol) of trifluoroacetic
acid. The reaction mixture was stirred overnight at room
temperature. Water was added and the reaction mixture was basified
using 2 N aqueous sodium hydroxide solution. The aqueous phase was
extracted three times with dichloromethane. The combined organic
phases were dried and concentrated in vacuo. The residue was
purified by column chromatography on silica (eluent: 0-20% methanol
in dichloromethane) to yield 131 mg of the title compound.
[0660] ESI-MS [M+H.sup.+]=215.20
[0661] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.90 (d,
1H), 6.70 (m, 1H), 6.55 (d, 1H), 3.75 (s, 2H), 3.25 (m, 2H), 3.00
(m, 2H), 2.90 (m, 2H), 1.60 (m, 2H), 0.95 (s, 2H), 0.80 (s,
2H).
Example 48
4-Methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-
-cyclopropane](Compound of the Formula I.s, I.t or I.u in which the
Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is
as in Row B-281 of Table B)
[0662] The title compound was prepared in analogy to example 47,
using however 2',3'-dihydro-1
.sup.1H-spiro[cyclopropane-1,4'-quinoline] and
2-bromopropanamide.
[0663] ESI-MS [M+H+]=229.20
[0664] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.85 (d,
1H), 6.65 (m, 1H), 6.55 (d, 1H), 3.80 (d, 1H), 3.50 (d, 1H), 3.25
(m, 3H), 2.85 (d, 1H), 2.70 (d, 1H), 1.70 (m, 1H), 1.60 (m, 1H),
1.05 (m, 1H), 0.90 (m, 3H), 0.85 (m, 1H), 0.75 (m, 2H).
Example 49
11-Fluoro-8,8-Dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]qu-
inoline (Compound of the Formula I.i in which the Combination of
R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is as in Row B-2
of Table B)
[0665] The title compound was prepared in analogy to example 47,
using however 7-fluoro-4,4-dimethyl-1,2,3,4-tetrahydroquinoline and
2-bromoacetamide.
[0666] ESI-MS [M+H.sup.+]=235.20
[0667] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 7.15
(dd, 1H), 6.55 (dd, 1H), 3.80 (s, 2H), 3.20 (m, 2H), 3.10 (m, 2H),
2.90 (m, 2H), 1.60 (m, 2H), 1.20 (s, 6H).
Example 50
10-Methoxy-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]q-
uinoline, Trifluoroacetic Acid (Compound of the Formula I.h in
which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and
R.sup.9a is as in Row B-7 of Table B)
[0668] The title compound was prepared in analogy to example 1,
using however
7-methoxy-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate
and 3-methylbut-2-enoyl chloride.
[0669] ESI-MS [M+H.sup.+]=247.20
[0670] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 8.75
(bs, 2H), 6.95 (s, 1H), 6.85 (s, 1H), 4.15 (m, 2H), 3.70 (s, 3H),
3.20 (m, 2H), 3.15 (m, 4H), 1.65 (m, 2H), 1.25 (s, 6H).
Example 51
4,8,8-Trimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline
2,2,2-trifluoroacetate (Compound of the Formula I.s, I.t or I.u in
which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and
R.sup.9a is as in Row B-1 of Table B)
[0671] The title compound was prepared in analogy to example 47,
using however 4,4-dimethyl-1,2,3,4-tetrahydroquinoline and
2-bromopropanamide.
[0672] ESI-MS [M+H.sup.+]=231.20
[0673] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 9.90
(bs, 1H), 9.20 (bs, 1H); 7.35 (d, 1H), 7.10 (d, 1H), 6.90 (m, 1H),
4.30 (d, 1H), 4.05 (d, 1H), 3.45 (m, 1H), 3.25 (m, 3H), 3.15 (m,
1H), 1.70 (m, 2H), 1.30 (m, 9H).
Example 52
4-Ethyl-8,8-dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quin-
oline (Compound of the Formula I.v, I.w or I.x in which the
Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is
as in Row B-1 of Table B)
[0674] The title compound was prepared in analogy to example 47,
using however 4,4-dimethyl-1,2,3,4-tetrahydroquinoline and
2-bromobutanamide.
[0675] ESI-MS [M+H.sup.+]=245.20
[0676] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 7.15 (d,
1H), 6.85 (d, 1H), 6.70 (m, 1H), 3.85 (d, 1H), 3.50 (d, 1H), 3.20
(m, 2H), 3.00 (d, 1H), 2.95 (m, 1H), 2.75 (d, 1H), 1.60 (m, 2H),
1.40 (m, 2H), 1.25 (s, 3H), 1.30 (s, 3H), 0.80 (m, 3H).
Example 53
6,8,8-Trimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline
(Compound of the Formula I.y, I.z or I.Zz in which the Combination
of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is as in Row
B-1 of Table B)
[0677] The title compound was prepared in analogy to example 47,
using however 2,4,4-trimethyl-1,2,3,4-tetrahydroquinoline and
2-chloroacetamide.
[0678] ESI-MS [M+H.sup.+]=231.20
[0679] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 7.05 (d,
1H), 6.90 (d, 1H), 6.65 (m, 1H), 3.85 (d, 1H), 3.45 (d, 1H), 3.30
(m, 3H), 3.00 (m, 1H), 2.70 (m, 1H), 1.65 (m, 1H), 1.40 (m, 1H),
1.25 (s, 3H), 1.15 (s, 6H).
Example 54
One Enantiomer of
8-ethyl-8-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]-quinol-
ine, Trifluoroacetic Acid (Enantiomer of the Compound of the
Formula I.g, I.h or I.i in which the Combination of R.sup.5a,
R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is as in Row B-41 of Table
B)
[0680] The title compound was prepared in analogy to example 1,
using however tert-butyl
2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate and
(Z)-3-methylpent-2-enoyl chloride.
[0681] ESI-MS [M+H.sup.+]=231.20
[0682] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 8.90
(bs, 1H), 8.65 (bs, 1H), 7.30 (d, 1H), 7.15 (d, 1H), 6.90 (m, 1H),
4.20 (m, 1H), 4.10 (m, 1H), 3.25 (m, 6H), 1.85 (m, 1H), 1.70 (m,
1H), 1.60 (m, 1H), 1.45 (m, 1H), 1.20 (s, 3H), 0.70 (m, 3H).
Example 55
Other Enantiomer of
8-ethyl-8-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoli-
ne, Trifluoroacetic Acid (Enantiomer of the Compound of the Formula
I.g, I.h or I.i in which the Combination of R.sup.5a, R.sup.5b,
R.sup.7, R.sup.8 and R.sup.9a is as in Row B-41 of Table B)
[0683] The title compound was prepared in analogy to example 1,
using however tert-butyl
2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate and
(Z)-3-methylpent-2-enoyl chloride.
[0684] ESI-MS [M+H.sup.+]=231.10
[0685] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 8.90
(bs, 1H), 8.65 (bs, 1H), 7.30 (d, 1H), 7.15 (d, 1H), 6.90 (m, 1H),
4.20 (m, 1H), 4.10 (m, 1H), 3.20 (m, 6H), 1.85 (m, 1H), 1.70 (m,
1H), 1.60 (m, 1H), 1.45 (m, 1H), 1.20 (s, 3H), 0.70 (m, 3H).
Example 56
4-Methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-
-cyclobutane](Compound of the Formula I.s, I.t or I.u in which the
Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is
as in Row B-321 of Table B)
56.1 Preparation of 2-cyclobutylidene-N-phenylacetamide
[0686] 3.35 g (36 mmol) of aniline were dissolved in 60 ml of
dichloromethane and treated with 13.83 ml (79 mmol) of
N-ethyl-N-isopropylpropan-2-amine. Within 10 min 19.80 ml of a 1
molar solution of 2-cyclobutylideneacetyl chloride in
dichloromethane was added at 0.degree. C. and the solution was
stirred overnight at room temperature. The reaction mixture was
poured on ice water and extracted 2.times. with dichloromethane.
The combined organic phases were washed once with saturated sodium
chloride solution, dried with magnesium sulfate and concentrated in
vacuo. The crude oil was dissolved in dichloromethane and treated
with ether till crystallization, yielding 5.5 g of the title
compound.
[0687] ESI-MS [M+H.sup.+]=188.10
56.2 Preparation of
1'H-spiro[cyclobutane-1,4'-quinolin]-2'(3'H)-one
[0688] A solution of 2.0 g (10.68 mmol) of
2-cyclobutylidene-N-phenylacetamide in 214 ml of toluene was
irradiated with a 700 W mercury lamp in a flow reactor (FEP-tubing,
pyrex filter) with a flow rate of 1 ml per min at a temperature
range of 0.degree. C. to 20.degree. C. with a residence time of 5
to 7 min. The reaction mixture was concentrated in vacuo and the
residue was purified by column chromatography on silica (eluent:
0-55% ethyl acetate in cyclohexane) to yield 940 mg of the title
compound.
[0689] ESI-MS [M+H.sup.+]=188.10
56.3 Preparation of
2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-quinoline]
[0690] To 850 mg (4.54 mmol) of
1'H-spiro[cyclobutane-1,4'-quinolin]-2'(3'H)-one in 5 ml of THF
were added 9.08 ml (9.08 mmol) of 1 molar borane dimethylsulfide
THF solution and subsequently heated for 30 min at 80.degree. C. in
a microwave system. The reaction mixture was acidified with 6 molar
hydrochloric acid solution and treated with ethyl acetate. The
organic phase was extracted twice with 1 molar hydrochloric acid
solution. The combined aqueous phases were set to pH 10 with sodium
bicarbonate and extracted 3.times. with ethyl acetate. The combined
organic phases were dried and concentrated in vacuo to yield 565 mg
of the crude title compound.
[0691] ESI-MS [M+H.sup.+]=174.10
56.4 Preparation of
2-(2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-quinolin]-1'-yl)propanamide
[0692] ESI-MS [M+H.sup.+]=245.20
[0693] A solution of 300 mg (1.73 mmol) of
2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-quinoline] in 10 ml
dimethylformamide was treated with 69 mg (1.73 mmol) of sodium
hydride (60% in mineral oil) and stirred for 15 min at 50.degree.
C., then transferred to a microwave vial and stirred for 5 min at
70.degree. C. in a microwave system. Subsequently 790 mg (5.19
mmol) of 2-bromoacetamide were added and the reaction mixture was
heated in a microwave system at 100.degree. C. for 7 hours.
Additional 263 mg (1.73 mmol) of 2-bromoacetamide were added and
the reaction mixture was heated in a microwave system at
100.degree. C. for 2 hours. The reaction mixture was quenched with
ice water, acidified to pH=5 and extracted with ether. The aqueous
phase was basified with sodium bicarbonate solution and extracted
3.times. with dichloromethane. The combined organic extracts were
dried with magnesium sulfate and concentrated in vacuo. The residue
was purified by column chromatography on silica (eluent: 0-55%
ethyl acetate in heptane) to yield 258 mg of the title
compound.
56.5 Preparation of
2-(2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-quinolin]-1'-yl)propan-1-amin-
e
[0694] To 258 mg (0.348 mmol) of
2-(2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-quinolin]-1'-yl)propanamide
in 2 ml THF were added 1.05 ml (2.10 mmol) of 2 molar borane
dimethylsulfide THF solution and subsequently heated for 6 hours at
60.degree. C. in a microwave system. Subsequently 348 .mu.l (0.70
mmol) of 2 molar borane dimethylsulfide THF solution was added to
the reaction mixture and heated for 2 hours at 60.degree. C. in a
microwave system. Subsequently 697 .mu.l (1.39 mmol) of 2 molar
borane dimethylsulfide THF solution was added to the reaction
mixture and heated for 3 hours at 60.degree. C. in a microwave
system. To the reaction mixture was added 2 ml of methanol,
acidified with 2 molar hydrochloric acid and heated for 5 minutes
at 60.degree. C. in a microwave system. The reaction mixture was
diluted with ethyl acetate and extracted twice with 1 molar
hydrochloric acid. The combined aqueous phases were set to pH 10
with sodium bicarbonate solution and extracted 3.times. with
dichloromethane. The combined organic phases were dried and
concentrated in vacuo. The residue was purified by column
chromatography on silica (eluent: 0-20% methanol in
dichloromethane) to yield 90 mg of the title compound.
[0695] ESI-MS [M+H.sup.+]=231.20
[0696] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 7.35 (d,
1H), 6.95 (dd, 1H), 6.70 (d, 1H), 6.55 (dd, 1H), 3.80 (m, 1H), 3.05
(m, 1H), 3.00 (m, 1H), 2.70 (m, 1H), 2.55 (m, 1H), 2.35 (m, 1H),
2.25 (m, 1H), 2.00 (m, 1H), 1.90 (m, 5H), 1.05 (d, 3H).
56.6 Preparation of
4-methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]-quinoline-8,-
1'-cyclobutane]
[0697] A solution of 90 mg (0.313 mmol) of
2-(2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-quinolin]-1'-yl)propan-1-amin-
e in 2 ml of ethanol was treated with 23 .mu.l (0.313 mmol) of 37%
aqueous formaldehyde solution and 26 .mu.l (0.344 mmol) of
trifluoroacetic acid. The reaction mixture was stirred overnight at
room temperature. Further 12 .mu.l (0.156 mmol) of 37% aqueous
formaldehyde solution and 12 .mu.l (0.156 mmol) of trifluoroacetic
acid were added to the reaction mixture and stirring was continued
overnight at room temperature. The reaction mixture was
concentrated in vacuo and to the residue was added aqueous sodium
bicarbonate solution. The aqueous phase was extracted twice with
dichloromethane. The combined organic phases were dried and
concentrated in vacuo. The residue was purified by column
chromatography on silica (eluent: 0-10% methanol in
dichloromethane) to yield 38 mg of the title compound.
[0698] ESI-MS [M+H.sup.+]=243.20
[0699] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 7.35 (d,
1H), 6.90 (d, 1H), 6.75 (d, 1H), 3.80 (m, 1H), 3.40 (m, 1H), 3.20
(m, 2H), 3.10 (m, 1H), 2.80 (m, 1H), 2.70 (m, 1H), 2.40 (m, 1H),
2.15 (m, 1H), 2.00 (m, 4H), 1.85 (m, 1H), 1.70 (m, 1H), 0.80 (s,
3H).
Example 57
1-Fluoro-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline,
Trifluoroacetic Acid (Compound of the Formula I.a in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-866 of Table A)
57.1 Preparation of methyl pyrrolidine-2-carboxylate
[0700] To a solution of pyrrolidine-2-carboxylic acid (75 g, 651
mmol) in methanol (750 ml), SOCl.sub.2 (250 ml) was added dropwise
at 0.degree. C., and the reaction mixture was stirred for 16 hrs at
20.degree. C. One additional vial was set up in the same way. Both
reaction mixtures were combined and concentrated under reduced
pressure to give the title compound (90 g, 543 mmol, yield
50%).
[0701] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]: 9.83 (s,
1H), 4.32 (t, J=7.6 Hz, 1H), 3.72 (s, 3H), 3.21-3.15 (m, 2H),
2.22-2.20 (m, 1H), 1.96-1.87 (m, 3H)
57.2 Preparation of methyl
1-(2-fluoro-6-nitro-phenyl)-pyrrolidine-2-carboxylate
[0702] To a mixture of methyl pyrrolidine-2-carboxylate (17.18 g,
104 mmol) in acetonitril (500 mL), triethylamine (26.3 mL, 189
mmol) and 1,2-difluoro-3-nitrobenzene (15 g, 94 mmol) were added at
20.degree. C., and the reaction mixture was stirred for 12 h at
80.degree. C. Then the mixture was cooled to 20.degree. C.,
concentrated under reduced pressure, and the residue was purified
by column chromatography on silica gel (petrol ether:ethyl
acetate=20:1 to 10:1) to give the title compound (20 g, 74.6 mmol,
yield 79%).
[0703] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. [ppm]: 7.36 (d,
J=8 Hz, 1H), 7.15-7.11 (m, 1H), 6.99-6.96 (m, 1H), 4.35-4.31 (m,
1H), 3.55 (s, 3H), 3.52-3.49 (m, 1H), 3.06-3.04 (m, 1H), 2.29-2.26
(m, 1H), 2.06-1.89 (m, 3H)
57.3 Preparation of
9-fluoro-2,3,3a,5,5a,6-hexahydro-1H-pyrrolo[1,2-a]quinoxalin-4-one
[0704] To a solution of methyl
1-(2-fluoro-6-nitro-phenyl)-pyrrolidine-2-carboxylate (10 g, 37.3
mmol) in methanol (200 ml), Pd/C (3.97 g, 37.3 mmol) was added
under Ar protection, then the reaction mixture was stirred for 12 h
at 20.degree. C. at 15 psi under H.sub.2 atmosphere. One additional
vial was set up as described above. The two reaction mixtures were
combined, filtered, and the filtrate was concentrated under reduced
pressure to give the title compound (10 g, 48.5 mmol, yield
65%).
[0705] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. [ppm]: 9.33 (s,
1H), 6.73-6.63 (m, 2H), 6.55-6.53 (m, 1H), 3.89-3.86 (m, 1H),
3.72-3.68 (m, 1H), 3.40-3.39 (m, 1H), 2.30-2.22 (m, 2H), 1.92-1.84
(m, 2H)
57.4 Preparation of
9-fluoro-1,2,3,3a,4,5,5a,6-octahydropyrrolo[1,2-a]quinoxaline
[0706] To a solution of
9-fluoro-2,3,3a,5,5a,6-hexahydro-1H-pyrrolo[1,2-a]quinoxalin-4-one
(10 g, 48.5 mmol) in THF (200 ml), a solution of BH.sub.3.THF (12.5
g, 145 mmol) was added at 0.degree. C., then the reaction solution
was stirred 12 h at 70.degree. C. After cooling to 0.degree. C.,
methanol (100 ml) was added dropwise at 0.degree. C., and the
reaction solution was stirred for 30 minutes at 20.degree. C.,
concentrated under reduced pressure, and the residue was purified
by column chromatography on silica gel (petrol ether:ethyl
acetate=20:1 to 10:1) to give the title compound (5 g, 26 mmol,
yield 53.6%).
[0707] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. [ppm]: 6.54-6.49
(m, 1H), 6.40-6.37 (m, 1H), 6.28 (d, J=8 Hz, 1H), 3.92 (s, 1H),
3.78-3.76 (m, 1H), 3.34-3.20 (m, 1H), 3.20-3.17 (m, 1H), 2.99-2.97
(m, 1H), 2.66-2.61 (m, 1H), 2.13-2.11 (m, 1H), 1.86-1.78 (m, 2H),
1.50-1.47 (m, 1H)
57.5 Preparation of
2-(9-fluoro-2,3,3a,4,5a,6-hexahydro-1H-pyrrolo[1,2-a]quinoxalin-5-yl)acet-
amide
[0708] To a solution of
9-fluoro-1,2,3,3a,4,5,5a,6-octahydropyrrolo[1,2-a]quinoxaline (5.6
g, 29.1 mmol), diisopropylethyl amine (30.5 mL, 175 mmol) in
dimethylformamide (DMF) (100 ml), 2-bromoacetamide (16.08 g, 117
mmol) was added and the reaction solution was stirred 12 h at
100.degree. C. After cooling to 20.degree. C., water (300 ml) was
added, and the mixture was extracted with ethyl acetate
(3.times.200 ml); the organic layer was dried over anhydrous
Na.sub.2SO.sub.4, concentrated under reduced pressure, and the
residue was purified by column chromatography on silica gel
(dichloromethane: methanol=100:1 to 50:1) to give the title
compound (3 g, 12.03 mmol, yield 41.3%).
[0709] LCMS (ESI+): nm/z 250 (M+H).sup.+
57.6 Preparation of
2-(9-fluoro-2,3,3a,4,5a,6-hexahydro-1H-pyrrolo[1,2-a]quinoxalin-5-yl)etha-
namine
[0710] To a solution of
2-(9-fluoro-2,3,3a,4,5a,6-hexahydro-1H-pyrrolo[1,2-a]quinoxalin-5-yl)acet-
amide (3 g, 12.03 mmol) in THF (20 ml), a solution of BH.sub.3.THF
(3.1 g, 36.1 mmol) was added at 0.degree. C., then the reaction
solution was stirred for 12 h at 70.degree. C. After cooling to
0.degree. C., methanol (100 ml) was added at 0.degree. C., and the
reaction solution was stirred for 30 minutes at 20.degree. C. Then
the solution was concentrated under reduced pressure, and the
residue was purified by column chromatography on silica gel (petrol
ether/ethyl acetate=20:1 to 10:1) to give title compound (1.3 g,
5.52 mmol, yield 45.9%).
[0711] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. [ppm]: 6.63-6.59
(m, 1H), 6.48 (d, J=8.4 Hz, 1H), 6.34-6.29 (m, 1H), 3.73-3.70 (m,
1H), 3.34-3.25 (m, 3H), 3.11-3.08 (m, 1H), 2.84-2.79 (m, 3H),
2.64-2.61 (m, 1H), 2.13-2.09 (m, 1H), 1.80-1.76 (m, 2H), 1.55-1.51
(m, 1H)
57.7 Preparation of 1-fluoro-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
[0712] To a solution of
2-(9-fluoro-2,3,3a,4,5a,6-hexahydro-1H-pyrrolo[1,2-a]quinoxalin-5-yl)etha-
namine (1.1 g, 4.67 mmol) and formaldehyde (2.106 g, 70.1 mmol) in
ethanol (20 ml), trifluoroacetic acid (TFA) (2.88 mL, 37.4 mmol)
was added, and the reaction solution was stirred for 12 h at
90.degree. C. After cooling to 40.degree. C., the solution was
concentrated under reduced pressure, and the residue was purified
by prep-HPLC to give the title compound as TFA salt (1.087 g, yield
94%).
Prep-HPLC Method:
[0713] Instrument: Shimadzu LC-20AP preparative HPLC
Column: Luna(2) C18 250*50 mm i.d. 10 u
[0714] Mobile phase: A for H.sub.2O (0.09% TFAl) and B for
CH.sub.3CN Gradient: B from 0% to 20% in 20 min Flow rate: 80
ml/min
Wavelength: 220 &254 nm
[0715] Injection amount: 1.1 g per injection
[0716] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. [ppm]: 6.79-6.71
(m, 2H), 4.23 (s, 2H), 4.01-3.96 (m, 1H), 3.36-3.32 (m, 3H),
3.29-3.27 (m, 2H), 3.15-3.12 (m, 2H), 2.49-2.43 (m, 1H), 2.29-2.21
(m, 1H), 1.95-1.90 (m, 2H), 1.58-1.54 (m, 1H)
Example 58
1-Bromo-5,6,7,9,9a,10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1-
,2-a]quinoxaline (Compound of the Formula I.a in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-868 of Table A)
58.1 Preparation of
1-(2-bromo-6-nitro-phenyl)-pyrrolidine-2-carboxylate
[0717] A mixture of 1-bromo-2-fluoro-3-nitrobenzene (60 g, 273
mmol), methyl pyrrolidine-2-carboxylate (54.2 g, 327 mmol; see
example 57.1) and triethylamine (83 g, 818 mmol) was heated at
70.degree. C. for 16 h. Then the mixture was cooled, diluted with
ethyl acetate (1000 ml), washed with 2N HCl (500 ml), aqueous
K.sub.2CO.sub.3 (300 ml) and brine (300 ml) sequentially, and the
aqueous phase was extracted with ethyl acetate (500 ml) again. The
ethyl acetate layer was dried over Na.sub.2SO.sub.4, filtered,
concentrated, and the residue was purified by column chromatography
on silica gel (eluted with petrol ether/ethyl acetate=50:1 to 10:1)
to afford the title compound (66 g, yield 74%) as yellow solid.
[0718] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 7.80-7.78
(m, 1H), 7.64-7.62 (m, 1H), 7.19 (t, J=8.2 Hz, 1H), 4.26-4.16 (m,
1H), 3.70-3.65 (m, 1H), 3.59 (s, 3H), 3.36-3.23 (m, 1H), 2.40-2.23
(m, 2H), 2.15-2.04 (m, 2H)
58.2 Preparation of
9-bromo-2,3,3a,5,5a,6-hexahydro-1H-pyrrolo[1,2-a]quinoxalin-4-one
[0719] To a solution of
1-(2-bromo-6-nitro-phenyl)-pyrrolidine-2-carboxylate (45 g, 137
mmol) in methanol (225 ml) was added a solution of NH.sub.4Cl (65.8
g, 1230 mmol) in water (225 ml) and Fe powder (53.4 g, 957 mmol) at
23.degree. C., and the resulting mixture was heated at 85.degree.
C. for 1.5 h. Then the reaction was cooled, diluted with methanol
(1000 ml), and the resulting mixture was stirred for 10 minutes,
filtered, and the filter cake was washed with methanol (500 ml).
The filtrate was concentrated under reduced pressure, the residue
was put into water, extracted with ethyl acetate (3.times.800 ml),
the extracts were washed with brine (400 ml), dried over
Na.sub.2SO.sub.4, filtered, and concentrated to afford the title
compound (33 g, yield 90%) as a light yellow solid.
[0720] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 9.78 (s,
1H), 7.27-7.17 (m, 1H), 6.91-6.75 (m, 2H), 4.10-3.90 (m, 2H),
3.09-3.06 (m, 1H), 2.86-2.68 (m, 1H), 2.37-2.20 (m, 1H), 2.04-2.02
(m, 1H), 1.88-1.68 (m, 1H)
58.3 Preparation of
9-bromo-1,2,3,3a,4,5,5a,6-octahydropyrrolo[1,2-a]quinoxaline
[0721] To a solution of
9-bromo-2,3,3a,5,5a,6-hexahydro-1H-pyrrolo[1,2-a]quinoxalin-4-one
(24 g, 90 mmol) in THF (360 ml) was added dropwise BH.sub.3.DMS (50
ml, 500 mmol, 10 M in dimethylsulfide (DMS)) at 23.degree. C., and
the resulting solution was stirred at 70.degree. C. for 2 h. The
reaction was then cooled, and quenched with methanol. One
additional reaction was set up and quenched as described above. The
two resulting mixtures were combined, concentrated to about one
third of volume, 6N HCl (250 mL) was added, and the resulting
solution was heated at 70.degree. C. for 20 minutes. Then the
solution was cooled, adjusted to pH 9 by addition of saturated
aqueous K.sub.2CO.sub.3, extracted with ethyl acetate (3.times.400
mL), the extracts were washed with brine, dried over
Na.sub.2SO.sub.4, concentrated to give the residue, which was
purified by column chromatography on silica gel (eluted with petrol
ether/ethyl acetate=20:1 to 5:1) to afford the title compound (40
g, yield 88%) as a white solid.
[0722] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 6.93-6.91
(m, 1H), 6.66 (t, J=7.7 Hz, 1H), 6.54-6.51 (m, 1H), 4.24-4.20 (m,
1H), 4.08 (s, 1H), 3.37-3.35 (m, 1H), 3.14-.311 (m, 1H), 2.89-2.76
(m, 1H), 2.76-2.62 (m, 1H), 2.37-2.22 (m, 1H), 1.96-1.93 (m, 1H),
1.89-1.77 (m, 1H), 1.75-1.63 (m, 1H).
58.4 Preparation of
2-(9-bromo-2,3,3a,4,5a,6-hexahydro-1H-pyrrolo[1,2-a]quinoxalin-5-yl)aceta-
mide
[0723] A mixture of
9-bromo-1,2,3,3a,4,5,5a,6-octahydropyrrolo[1,2-a]quinoxaline (20 g,
79 mmol), 2-bromoacetamide (32.7 g, 237 mmol), and DIEA (51.1 g,
395 mmol) in DMF (200 mL) was stirred at 100.degree. C. for 15 h.
The reaction was cooled, diluted with water (600 ml), and extracted
with ethyl acetate (3.times.400 ml). The organic layers were washed
with brine (200 ml), dried over Na.sub.2SO.sub.4 and filtered,
concentrated to give a residue, which was recrystallized from ethyl
acetate to afford the title compound (22 g, yield 90%) as a light
yellow solid.
[0724] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 7.04 (d,
J=7.9 Hz, 1H), 6.75 (t, J=7.9 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 6.39
(s, 1H), 5.69 (s, 1H), 4.28-4.25 (m, 1H), 3.96-3.75 (m, 2H),
3.55-3.42 (m, 1H), 3.13-3.04 (m, 1H), 3.03-2.91 (m, 1H), 2.77-2.65
(m, 1H), 2.39-2.23 (m, 1H), 2.04-1.90 (m, 1H), 1.90-1.78 (m, 1H),
1.71-1.67 (m, 1H)
58.5 Preparation of
2-(9-bromo-2,3,3a,4,5a,6-hexahydro-1H-pyrrolo[1,2-a]quinoxalin-5-yl)ethan-
amine
[0725] To a solution of
2-(9-bromo-2,3,3a,4,5a,6-hexahydro-1H-pyrrolo[1,2-a]quinoxalin-5-yl)aceta-
mide (11 g, 35.5 mmol) in THF (165 ml) was added dropwise
BH.sub.3.DMS (18 ml, 180 mmol, 10 M in DMS) at 23.degree. C., and
the resulting solution was heated at 70.degree. C. for 4 h. The
reaction was then quenched with methanol. One additional reaction
was set up and quenched as described above. The two resulting
mixtures were combined, concentrated to about one third of volume,
6N HCl (200 mL) was added, and the resulting solution was heated at
70.degree. C. for 20 minutes. The solution was then cooled,
adjusted to pH 9 by addition of saturated aqueous K.sub.2CO.sub.3,
and extracted with ethyl acetate (3.times.300 m). The extracts were
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to
give a residue, which was purified by column chromatography on
silica gel (eluted with dichloromethane/methanol=60:1 to 15:1) to
afford the title compound (15 g, yield 71%) as a light yellow
oil.
[0726] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 6.94-6.87
(m, 1H), 6.78-6.67 (m, 2H), 4.25-4.21 (m, 1H), 3.51-3.40 (m, 1H),
3.39-3.28 (m, 2H), 3.07-3.05 (m, 1H), 3.02-2.84 (m, 3H), 2.67-2.57
(m, 1H), 2.29-2.27 (m, 1H), 2.00-1.87 (m, 1H), 1.87-1.74 (m, 1H),
1.71-1.60 (m, 1H), 1.26 (s, 2H)
58.6 Preparation of 1-bromo-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
[0727] To a solution of
2-(9-bromo-2,3,3a,4,5a,6-hexahydro-1H-pyrrolo[1,2-a]quinoxalin-5-yl)ethan-
amine (13 g, 43.9 mmol) in ethanol (390 ml) was added formaldehyde
(7.1 g, 88 mmol, 37% aqueous) and TFA (15 g, 132 mmol), and the
resulting solution was heated at 80.degree. C. for 2 h. Then the
reaction was concentrated, the residue was dissolved in ethyl
acetate (300 ml), and washed with saturated aqueous K.sub.2CO.sub.3
(150 ml), and brine (100 ml). The ethyl acetate layer was dried
over Na.sub.2SO.sub.4, filtered, and concentrated to afford the
title compound (13 g, crude) as a yellow solid.
[0728] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 7.17-7.08
(m, 1H), 6.69-6.60 (m, 1H), 4.40-4.27 (m, 1H), 3.96-3.78 (m, 2H),
3.24-3.14 (m, 1H), 3.13-3.02 (m, 2H), 3.01-2.88 (m, 3H), 2.79-2.70
(m, 1H), 2.66-2.58 (m, 1H), 2.36-2.28 (m, 1H), 2.23 (s, 1H),
1.99-1.88 (m, 1H), 1.83-1.71 (m, 1H), 1.71-1.61 (m, 1H)
[0729] Analytical Method: 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 acetonitril. The column
used for the chromatography was a 2.1.times.50 mm Venusil XBP-C18
column (5 m particles). Detection methods are diode array (DAD) and
evaporative light scattering (ELSD) detection as well as
positive/negative electrospray ionization.).
Example 59
1-Methyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline,
Trifluoroacetic Acid (Compound of the Formula I.a in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-869 of Table A)
59.1 Preparation of boc-protected 1-bromo-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
[0730] To a solution of 1-bromo-5,6,7,9,9a, 10,1
1,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
(13 g, 42.2 mmol) in dichloromethane (DCM) (260 ml) were added
triethylamine (6.4 g, 63.3 mmol) and a solution of Boc.sub.2O (10.1
g, 46.4 mmol) in DCM (20 ml) at 0.degree. C., then it was allowed
to warm to 23.degree. C. and stirred for 16 h. The reaction was
diluted with DCM (250 ml), washed with 2 N HCl (200 ml), saturated
aqueous K.sub.2CO.sub.3 (150 ml) and brine (150 ml), and the water
phase was extracted with DCM (200 mL) again. The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated, and the residue was purified by column chromatography
on silica gel (eluted with petrol ether/ethyl acetate=30:1 to 4:1)
to give the boc-protected compound (6 g, yield 35%, 2 steps).
[0731] LCMS (ESI+): m/z 408 (M+H).sup.+
[0732] .sup.1H NMR (400 MHz; CD.sub.3OD): .delta. [ppm]: 7.11 (d,
J=7.50 Hz, 1H), 6.73 (d, J=7.94 Hz, 1H), 4.67-4.50 (m, 1H),
4.36-4.24 (m, 1H), 4.18-4.01 (m, 1H), 3.91 (d, J=11.91 Hz, 1H),
3.27 (s, 1H), 3.20-2.90 (m, 4H), 2.76-2.55 (m, 2H), 2.27-2.25 (m,
1H), 1.97-1.66 (m, 3H), 1.46 (m, 9H)
59.2 Preparation of boc-protected 1-methyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
[0733] To a mixture of boc-protected
1-bromo-5,6,7,9,9a,10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[-
1,2-a]quinoxaline (500 mg, 1.2 mmol), tricyclohexylphosphine (34.3
mg, 0.12 mmol), and Pd(OAc).sub.2 (13.7 mg, 0.06 mmol) in toluene
(20 ml) under N.sub.2 atmosphere was added methylboronic acid (366
mg, 6.1 mmol), K.sub.3PO.sub.4 (1.04 g, 4.9 mmol) and Water (2 mL).
The reaction mixture was heated at 100.degree. C. for 16 h. After
cooling, the reaction mixture was diluted with ethyl acetate (100
ml) and washed with brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by column chromatography on silica gel (eluted with petrol
ether/ethyl acetate=25:1 to 4:1) to afford the title compound (0.35
g, yield 73%) as white solid.
[0734] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 6.95-6.49
(m, 2H), 4.81-4.48 (m, 1H), 4.20-3.68 (m, 3H), 3.52-3.17 (m, 2H),
3.11-2.81 (m, 3H), 2.78-2.51 (m, 2H), 2.32 (s, 3H), 2.01-1.86 (m,
1H), 1.86-1.71 (m, 1H), 1.71-1.60 (m, 1H), 1.44 (s, 9H)
59.3 Preparation of 1-methyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
[0735] To a solution of boc-protected 1-methyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
(350 mg, 0.9 mmol) in DCM (6 ml) was added TFA (3 ml), and the
resulting solution was stirred at 20.degree. C. for 5 h. The
reaction was then concentrated and the residue was purified by
Prep-HPLC and lyophilized to afford the title compound (242 mg,
yield 92%, TFA salt) as a light gray solid.
[0736] .sup.1H NMR (400 MHz; CD.sub.3OD): .delta. [ppm]: 7.12 (d,
J=7.5 Hz, 1H), 6.97-6.86 (m, 1H), 4.34-4.22 (m, 2H), 4.16-4.11 (m,
1H), 3.69-3.66 (m, 1H), 3.54-3.43 (m, 1H), 3.39-3.33 (m, 2H),
3.30-3.23 (m, 2H), 3.10-2.97 (m, 2H), 2.43 (s, 3H), 2.41-2.31 (m,
1H), 2.13-1.98 (m, 2H), 1.95-1.85 (m, 1H)
Example 60
1-Cyclopropyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline,
Trifluoroacetic Acid (Compound of the Formula I.a in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-873 of Table A)
[0737] The compound was prepared in analogy to example 59.
[0738] LCMS (ESI+): m/z 270 (M+H).sup.+
[0739] .sup.1H NMR (400 MHz; CD.sub.3OD): .delta. [ppm]: 7.10 (d,
J=7.9 Hz, 1H), 6.67 (d, J=7.9 Hz, 1H), 4.41-4.38 (m, 1H), 4.26 (s,
2H), 3.67-3.66 (m, 1H), 3.52-3.42 (m, 1H), 3.39-3.33 (m, 2H),
3.29-3.21 (m, 2H), 3.15-3.09 (m, 1H), 3.00-2.87 (m, 1H), 2.46-2.31
(m, 1H), 2.17-1.94 (m, 3H), 1.93-1.82 (m, 1H), 1.20-1.17 (m, 1H),
1.07-0.93 (m, 2H), 0.69-0.54 (m, 1H).
Example 61
1-Cyclobutyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
(Compound of the Formula I.a in which the Combination of R.sup.5a,
R.sup.5b, R.sup.6 and R.sup.9a is as in Row A-874 of Table A)
61.1 Preparation of boc-protected
1-(1-hydroxy-cyclobut-1-yl)-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
[0740] To a solution of boc-protected 1-bromo-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
(800 mg, 1.96 mmol) in THF (16 ml) was added dropwise n-BuLi (1.6
ml, 3.92 mmol, 2.5 M in hexane) at -70.degree. C. with stirring
under N.sub.2 atmosphere, and the resulting solution was stirred at
-70.degree. C. for 1 hour. A solution of cyclobutanone (275 mg,
3.92 mmol) in THF (0.5 ml) was added dropwise at -70.degree. C.,
and the reaction solution was stirred for 2 h at same temperature.
Then it was allowed to warm slowly to 20.degree. C. and stirred for
16 h. The reaction was quenched by saturated aqueous NH.sub.4Cl,
extracted with ethyl acetate (2.times.100 ml), the organic layers
were dried over Na.sub.2SO.sub.4, concentrated, and the residue was
purified by column chromatography on silica gel (eluted with petrol
ether/ethyl acetate=10:1 to 2:1) to afford the title compound (0.5
g, yield 64%) as white solid.
[0741] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 7.07-6.90
(m, 2H), 4.64-4.48 (m, 1H), 4.23 (d, J=14.1 Hz, 1H), 3.86 (d,
J=11.5 Hz, 1H), 3.68-3.67 (m, 1H), 3.52-3.31 (m, 1H), 3.25-3.11 (m,
2H), 3.10-2.94 (m, 2H), 2.94-2.76 (m, 2H), 2.60-2.47 (m, 2H),
2.46-2.33 (m, 2H), 2.29-2.16 (m, 1H), 2.01-1.82 (m, 3H), 1.82-1.68
(m, 1H), 1.68-1.54 (m, 1H), 1.41 (s, 9H).
61.2 Preparation of 1-cyclobutyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
[0742] To a solution of boc-protected
1-(1-hydroxy-cyclobut-1-yl)-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
(380 mg, 0.95 mmol) in DCM (3 ml) was added triethylsilane (1.66 g,
14.3 mmol), and the resulting solution was stirred for 0.5 h. Then
TFA (10 ml) was added, and the resulting solution was stirred at
60.degree. C. overnight. The solvent was removed under reduced
pressure. The residue was dissolved in 3 N HCl (50 ml), and washed
with DCM (3.times.50 ml). The aqueous phase was adjusted to pH 9 by
addition of saturated aqueous K.sub.2CO.sub.3, the resulting
mixture was extracted with DCM (2.times.100 ml), the DCM layers
were washed with brine (30 ml), dried over Na.sub.2SO.sub.4,
filtered, and concentrated to afford the title compound (160 mg,
yield 60%) as a gray solid.
[0743] LCMS (ESI+): m/z 284(M+H)
[0744] .sup.1H NMR (400 MHz; CD.sub.3OD): .delta. [ppm]: 6.91 (d,
J=7.9 Hz, 1H), 6.79 (d, J=7.5 Hz, 1H), 3.89-3.71 (m, 3H), 3.69-3.60
(m, 1H), 3.17-3.05 (m, 1H), 3.05-2.84 (m, 5H), 2.68-2.48 (m, 2H),
2.48-2.36 (m, 1H), 2.33-2.18 (m, 2H), 2.17-1.93 (m, 3H), 1.93-1.74
(m, 3H), 1.68-1.54 (m, 1H)
Example 62
1-Cyclopentyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline,
Trifluoroacetic Acid (Compound of the Formula I.a in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-875 of Table A)
62.1 Preparation of boc-protected
1-(1-hydroxy-cyclopent-1-yl)-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
[0745] To a solution of boc-protected 1-bromo-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
(100 mg, 0.25 mmol) in THF (2 ml) was added dropwise n-BuLi (0.2
ml, 0.5 mmol, 2.5 M in hexane) at -70.degree. C. with stirring
under N.sub.2 atmosphere, and the resulting solution was stirred at
-70.degree. C. for 1 hour. A solution of cyclopentanone (40 mg, 0.5
mmol) in THF (0.2 ml) was added dropwise at -70.degree. C., and the
reaction solution was stirred for 8 h at same temperature. It was
then allowed to warm slowly to 20.degree. C. and stirred for 16 h.
The reaction was quenched by saturated aqueous NH.sub.4Cl,
extracted with ethyl acetate (2.times.50 ml), the organic layers
were dried over Na.sub.2SO.sub.4, concentrated, and the residue was
purified by Prep-TLC (petrol ether/ethyl acetate=2:1) to afford the
title compound (16 mg, yield 22%) as white solid.
[0746] .sup.1H NMR (400 MHz; DMSO-d.sub.6 (T=273+80 K)): .delta.
[ppm]: 7.50 (s, 1H), 6.81-6.75 (m, 1H), 6.74-6.68 (m, 1H),
4.46-4.24 (m, 2H), 3.75-3.66 (m, 2H), 3.42-3.26 (m, 2H), 3.24-3.12
(m, 2H), 2.93 (d, J=9.7 Hz, 1H), 2.63-2.51 (m, 2H), 2.15-2.03 (m,
4H), 1.99-1.90 (m, 1H), 1.83-1.82 (m, 5H), 1.72-1.55 (m, 3H), 1.34
(s, 9H)
62.2 Preparation of boc-protected 1-cyclopent-1-enyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
[0747] A mixture of boc-protected
1-(1-hydroxy-cyclopent-1-yl)-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
(100 mg, 0.25 mmol),
2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (95
mg, 0.49 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (12 mg, 0.017 mmol) and
Cs.sub.2CO.sub.3 (160 mg, 0.49 mmol) in dioxane (2 ml) and water
(0.6 ml) was placed in a microwave tube under N.sub.2 atmosphere.
The reaction mixture was heated at 100 C for 1 hour in microwave
reactor. Six additional reactions were set up as described above.
All seven reaction mixtures were combined, was put into water,
extracted with ethyl acetate (2.times.100 ml); the extracts were
washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to
give crude product, which was purified by column chromatography on
silica gel (eleted with petrol ether/ethyl acetate=25:1 to 5:1) to
afford the title compound (400 mg, yield 58%) as light yellow
solid.
[0748] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta.[ppm]: 6.93-6.68
(m, 2H), 5.94-5.78 (m, 1H), 4.81-4.52 (m, 1H), 4.15 (d, J=13.7 Hz,
1H), 4.08-3.78 (m, 1H), 3.71-3.58 (m, 1H), 3.45-3.17 (m, 2H),
3.15-2.85 (m, 4H), 2.69-2.41 (m, 4H), 2.38-2.18 (m, 2H), 2.02-1.96
(m, 2H), 1.86-1.66 (m, 2H), 1.59-1.51 (m, 1H), 1.44 (s, 9H)
62.3 Preparation of boc-protected 1-cyclopentyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
[0749] A mixture of 1-cyclopent-1-enyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
(0.3 g, 0.76 mmol), and Pd/C (0.09 g, 5%) in methanol (20 ml) was
stirred at 20.degree. C. under a H.sub.2 balloon for 16 h. Then the
reaction was filtered, and concentrated to afford the title
compound (0.29 g, yield 96%) as light yellow solid.
[0750] LCMS (ESI+): m/z 398 (M+H).sup.+
62.4 Preparation of 1-cyclopentyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
[0751] To a solution of boc-protected 1-cyclopentyl-5,6,7,9,9a,
10,11,12-octahydro-4H-[1,4]diazepino[1,7,6-de]pyrrolo[1,2-a]quinoxaline
(0.29 g, 0.74 mmol) in DCM (6 ml) was added TFA (3 ml), and the
resulting solution was stirred for 3 h at 25.degree. C. The
reaction was concentrated and lyophilized to afford the title
compound (351 mg, yield 90%, TFA salt) as brown oil.
[0752] .sup.1H NMR (400 MHz; CD.sub.3OD): .delta.[ppm]: 7.34 (d,
J=8.4 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 4.37-4.25 (m, 2H), 4.24-4.14
(m, 1H), 3.96-3.87 (m, 1H), 3.62-3.52 (m, 1H), 3.44-3.32 (m, 4H),
3.30-3.19 (m, 3H), 2.48-2.35 (m, 1H), 2.25-2.04 (m, 4H), 2.04-1.85
(m, 3H), 1.85-1.70 (m, 2H), 1.70-1.56 (m, 2H)
Example 63
8-Methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-8-ol
(Compound of the Formula I.g, I.h or I.i in which the Combination
of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is as in Row
B-241 of Table B)
63.1 Preparation of boc-protected ethyl
3-(2,3,4,5-tetrahydro-1,4-benzodiazepin-1-yl)propanoate
[0753] To a solution of 4-boc-protected
2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (7 g, 28.2 mmol) in acetic
acid (14 ml) was added ethyl acrylate (14.1 g, 141 mmol) and the
reaction mixture was heated at 100.degree. C. for 16 hrs. Then it
was cooled, concentrated, and the residue was purified by column
chromatography on silica gel (eluted with petrol ether/ethyl
acetate=25:1 to 5:1) to give the title compound (5 g, yield 51%) as
light yellow oil.
[0754] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 7.32-7.14
(m, 2H), 7.03-6.88 (m, 2H), 4.43-4.26 (m, 2H), 4.20-4.08 (m, 2H),
3.64-3.51 (m, 4H), 3.10-2.99 (m, 2H), 2.63-2.53 (m, 2H), 1.49-1.38
(m, 9H), 1.30-1.19 (m, 3H)
63.2 Preparation of boc-protected
3-(2,3,4,5-tetrahydro-1,4-benzodiazepin-1-yl)propanoic Acid
[0755] To a solution of boc-protected ethyl
3-(2,3,4,5-tetrahydro-1,4-benzodiazepin-1-yl)propanoate (7.5 g,
21.5 mmol) in THF (70 mL), H.sub.2O (50 mL) and methanol (23 ml)
was added a solution of NaOH (2.6 g, 64.6 mmol) in H.sub.2O (20 mL)
at 5.degree. C., and the resulting solution was stirred at
25.degree. C. for 3 h. Then the solution was cooled to 5.degree.
C., adjusted to pH 3 by addition of 1N HCl, and the resulting
mixture was extracted with ethyl acetate three times. The ethyl
acetate layers were combined, dried over Na.sub.2SO.sub.4,
filtered, and concentrated to give the title compound (6.7 g, yield
97%) as yellow oil.
[0756] .sup.1H NMR (400 MHz; CD.sub.3OD): .delta. [ppm]: .delta.
7.23-7.06 (m, 2H), 6.98-6.85 (m, 2H), 4.39-4.21 (m, 2H), 3.65-3.41
(m, 4H), 3.05-2.91 (m, 2H), 2.56 (t, J=6.6 Hz, 2H), 1.40-1.31 (m,
9H).
63.3 Preparation of boc-protected
3-(2,3,4,5-tetrahydro-1,4-benzodiazepin-1-yl)propanoyl Chloride
[0757] To a solution of boc-protected
3-(2,3,4,5-tetrahydro-1,4-benzodiazepin-1-yl)propanoic acid (6.5 g,
20.3 mmol) in dichloromethane (300 ml) were added dimethylformamide
(0.15 g, 2 mmol) and dropwise a solution of (COCl).sub.2 (7.7 g,
60.9 mmol) in dichloromethane (30 ml) at 0.degree. C. The the
reaction was stirred for 1 hour at 25.degree. C., and concentrated
under reduced pressure below 30.degree. C. to give the title
compound as a residue which was used directly in the next step
without further purification.
63.4 Preparation of boc-protected
1,2,3,4,6,7-hexahydro[1,4]diazepino[6,7,1-ij]-quinolin-8-one
[0758] To a solution of boc-protected
3-(2,3,4,5-tetrahydro-1,4-benzodiazepin-1-yl)propanoyl chloride
(6.6 g, crude, .about.20 mmol) in dichloroethane (400 ml) was added
A1Cl.sub.3 (10.4 g, 78 mmol) in portions at 0-5.degree. C., then
the resulting mixture was stirred at 65.degree. C. for 7 hrs. The
reaction was quenched with water (100 ml), adjusted to pH 9 by
addition of aqueous saturated K.sub.2CO.sub.3, then Boc.sub.2O (6.4
g, 29.2 mmol) was added, and the resulting mixture was stirred for
2 hrs. The mixture was extracted with dichloromethane twice, the
organic phase was washed with brine, dried over Na.sub.2SO.sub.4,
concentrated, and the residue was purified by column chromatography
on silica gel (eluted with petrol ether/ethyl acetate=10:1 to 2:1)
to give the title compound (4.2 g, yield 71%) as yellow solid.
[0759] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. [ppm]: 7.85 (d,
J=7.5 Hz, 1H), 7.40-7.20 (m, 1H), 6.83 (t, J=7.5 Hz, 1H), 4.58-4.40
(m, 2H), 3.74 (d, J=3.5 Hz, 2H), 3.60-3.50 (m, 2H), 3.44-3.37 (m,
2H), 2.72-2.62 (m, 2H), 1.47-1.29 (m, 9H).
63.5 Preparation of
1,2,3,4,6,7-hexahydro[1,4]diazepino[6,7,1-ij]-quinolin-8-one
[0760] To a solution of boc-protected
1,2,3,4,6,7-hexahydro[1,4]diazepino[6,7,1-ij]-quinolin-8-one (500
mg, 1.7 mmol) in dichloromethane (10 ml) was added trifluoroacetic
acid (5 ml), and then the resulting mixture was stirred at
25.degree. C. for 3 hrs. This was concentrated and lyophilized to
give the title compound (500 mg, yield 100%, trifluoroacetic acid
salt) as yellow solid.
[0761] .sup.1H NMR (400 MHz; CD.sub.3OD): .delta. [ppm]: 7.92-790
(m, 1H), 7.49 (d, J=6.6 Hz, 1H), 6.97 (t, J=7.7 Hz, 1H), 4.40 (s,
2H), 3.71-3.63 (m, 4H), 3.55-3.47 (m, 2H), 2.75-2.67 (m, 2H).
63.6 Preparation of Cbz-protected
1,2,3,4,6,7-hexahydro[1,4]diazepino[6,7,1-ij]-quinolin-8-one
[0762] To a solution of
1,2,3,4,6,7-hexahydro[1,4]diazepino[6,7,1-ij]-quinolin-8-one (2 g,
6.92 mmol) (TFA salt) in DCM (30 ml) were added triethylamine (1.4
g, 13.8 mmol) and a solution of CbzCl (Cbz=benzyloxycarbonyl; 1.5
g, 9 mmol) in DCM (5 mL) at 0-5.degree. C., then the reaction
mixture was stirred at 25.degree. C. for 2 hrs. Then it was diluted
with DCM (100 ml), washed with aqueous K.sub.2CO.sub.3 (50 mL) and
brine (50 ml); the water phase was extracted with DCM again, the
DCM layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated under reduced pressure to give the title compound (1.5
g, yield 64%) as brown oil.
[0763] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 7.79 (d,
J=7.6 Hz, 1H), 7.30-7.11 (m, 6H), 6.76-6.72 (m, 1H), 5.04-5.01 (m,
2H), 4.55-4.48 (m, 2H), 3.75-3.74 (m, 2H), 3.48-3.38 (m, 4H),
2.60-2.55 (m, 2H)
63.7 Preparation of Cbz-protected
8-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-8-ol
[0764] To a solution of Cbz-protected
1,2,3,4,6,7-hexahydro[1,4]diazepino[6,7,1-ij]-quinolin-8-one (1.5
g, 4.5 mmol) in THF (45 ml) was added dropwise methyllithium (3.7
ml, 5.8 mmol, 1.6 M in ether) at -70.degree. C., and the resulting
solution was stirred at -70.degree. C. for 2 h. Then it was
quenched with aqueous NH.sub.4Cl (20 ml), extracted with ethyl
acetate (50 ml) three times, the ethyl acetate layers were washed
with brine (30 ml), dried over Na.sub.2SO.sub.4, filtered,
concentrated, and the residue was purified by column chromatography
on silica gel (eluted with DCM/methanol=150:1 to 50:1) to give the
title compound (1 g, yield 64%) as light yellow oil.
[0765] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 7.47 (d,
J=7.5 Hz, 1H), 7.39-7.25 (m, 5H), 7.25-6.99 (m, 1H), 6.93-6.80 (m,
1H), 5.18-5.02 (m, 2H), 4.62-4.35 (m, 2H), 3.79 s, 1H), 3.73-3.59
(m, 1H), 3.45-3.34 (m, 1H), 3.29-3.15 (m, 3H), 2.00-1.89 (m, 2H),
1.59 (s, 3H)
63.8 Preparation of
8-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-8-ol
[0766] A mixture of Cbz-protected
8-hydroxy-8-methyl-1,2,3,4,7,8-hexahydro-6H-[1,4]diazepino[6,7,1-ij]quino-
line (0.5 g, 1.42 mmol), NH.sub.3--H.sub.2O (1 ml) and Pd/C (168
mg, 10%) in THF (30 ml) was stirred under a H.sub.2 balloon for 2
h. Then it was filtered, concentrated, and the residue was purified
by Prep-HPC (basic method) and lyophilized to give the title
compound (214 mg, yield 69%) as white solid.
[0767] LCMS (ESI+): m/z 219 (M+H).sup.+
[0768] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 7.44 (d,
J=7.5 Hz, 1H), 7.01 (d, J=7.1 Hz, 1H), 6.83 (t, J=7.5 Hz, 1H),
3.92-3.81 (m, 2H), 3.43-3.32 (m, 1H), 3.29-3.17 (m, 1H), 3.14-3.00
(m, 4H), 1.99-1.91 (m, 2H), 1.59 (s, 3H)
Example 64
8-Methoxy-8-methyl-2,3,4,6,7,8-hexahydro-6H-[1,4]diazepino[6,7,1-ij]quinol-
ine (Compound of the Formula I.g, I.h or I.i in which the
Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and R.sup.9a is
as in Row B-201 of Table B)
64.1 Preparation of Cbz-protected
8-methoxy-8-methyl-1,2,3,4,7,8-hexahydro-6H-[1,4]diazepino[6,7,1-ij]quino-
line
[0769] To a solution of Cbz-protected
8-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-8-ol
(0.5 mg, 1.42 mmol; see example 63.2) in DMF (10 ml) was added NaH
(113 mg, 2.84 mmol) in portions at 0.about.5.degree. C., and then
the resulting mixture was stirred at 25.degree. C. for 0.5 hrs. A
solution of MeI (403 mg, 2.84 mmol) in DMF (2 ml) was added
dropwise at 0-5.degree. C., then the reaction mixture was stirred
at 25.degree. C. for 16 h. It was quenched with water (30 ml), and
extracted with ethyl acetate (60 ml) twice. The ethyl acetate layer
was washed with brine, dried over Na.sub.2SO.sub.4, and
concentrated to give a residue, which was purified by column
chromatography on silica gel (eluted with petrol ether/ethyl
acetate=15:1 to 4:1) to give the title compound (200 mg, yield 39%)
as light yellow oil.
[0770] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 7.41-7.24
(m, 6H), 7.23-7.01 (m, 1H), 6.93-6.79 (m, 1H), 5.12 (s, 2H),
4.64-4.49 (m, 1H), 4.44-4.34 (m, 1H), 3.88-3.75 (m, 1H), 3.69-3.58
(m, 1H), 3.40-3.26 (m, 2H), 3.23-3.12 (m, 2H), 3.08 (s, 3H),
2.28-2.19 (m, 1H), 1.72-1.63 (m, 1H), 1.53 (s, 3H)
64.2 Preparation of
8-methoxy-8-methyl-1,2,3,4,7,8-hexahydro-6H-[1,4]diazepino[6,7,1-ij]quino-
line
[0771] A mixture of Cbz-protected
8-methoxy-8-methyl-1,2,3,4,7,8-hexahydro-6H-[1,4]diazepino[6,7,1-ij]quino-
line (160 mg, 0.44 mmol), NH.sub.3--H.sub.2O (0.5 ml) and Pd/C (50
mg, 10%) in THF (20 ml) was stirred under a H.sub.2 balloon at
25.degree. C. for 2 hrs. Then it was filtered, concentrated, and
the residue was purified by Prep-HPC (basic method) and lyophilized
to give the title compound (55 mg, yield 54%) as yellow oil.
[0772] LCMS (ESI+): m/z 233(M+H).sup.+
[0773] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 7.30-7.27
(m, 1H), 7.02 (d, J=7.1 Hz, 1H), 6.83 (t, J=7.5 Hz, 1H), 3.94-3.84
(m, 2H), 3.38-3.24 (m, 2H), 3.16-3.01 (m, 7H), 2.27-2.22 (m, 1H),
1.69-1.63 (m, 1H), 1.54 (s, 3H)
Example 65
2,8-Dimethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-8-o-
l
[0774] A mixture of Cbz-protected
8-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-8-ol
(50 mg, 0.14 mmol; see example 63.2), formaldehyde (21 mg, 0.28
mmol, 40% in water) and Pd/C (17 mg, 10%) in methanol (5 ml) was
stirred under a H.sub.2 balloon for 6 hrs. Then it was filtered,
concentrated, and the residue was purified by Prep-HPC (basic
method) and lyophilized to give the title compound (12 mg, yield
36%) as light yellow solid.
[0775] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. [ppm]: 7.44-7.42
(m, 1H), 7.07-7.00 (m, 1H), 6.83 (t, J=7.5 Hz, 1H), 3.71-3.57 (m,
2H), 3.40-3.31 (m, 1H), 3.25-3.17 (m, 1H), 3.17-3.04 (m, 2H), 2.82
(t, J=5.1 Hz, 2H), 2.37 (s, 3H), 1.94 (t, J=6.0 Hz, 2H), 1.58 (s,
3H)
Example 66
11-Methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1-
'-cyclobutane], 2,2,2-trifluoroacetic Acid (Compound of the Formula
I.i in which the Combination of R.sup.5a, R.sup.5b, R.sup.7,
R.sup.8 and R.sup.9a is as in Row B-325 of Table B)
[0776] The title compound was prepared in analogy to example 1,
using however tert-butyl
6-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-4-carboxylate and
2-cyclobutylidene-acetic acid as starting materials.
[0777] ESI-MS [M+H.sup.+]=243.20
[0778] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) [ppm]: 7.28 (d, J=7.9
Hz, 1H), 6.71 (d, J=7.9 Hz, 1H), 3.74 (s, 2H), 3.10-3.03 (m, 2H),
2.99-2.94 (m, 2H), 2.90-2.84 (m, 2H), 2.34-2.25 (m, 2H), 2.22 (s,
3H), 2.09-1.96 (m, 1H), 1.92-1.83 (m, 5H).
Example 67
9-Methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-
-cyclobutane], Trifluoroacetic Acid (Compound of the Formula I.g in
which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and
R.sup.9a is as in Row B-325 in Table B)
[0779] The intermediate tert-butyl
9-chloro-3,4,6,7-tetrahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-c-
yclobutane]-2(1H)-carboxylate was prepared in analogy to example 1,
steps 1.1 to 1.3 using tert-butyl
8-chloro-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate
and 2-cyclobutylideneacetyl chloride as starting materials.
67.1 Preparation of tert-butyl
9-methyl-3,4,6,7-tetrahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-c-
yclobutane]-2(1H)-carboxylate
[0780] 75 mg (0.21 mmol) of tert-butyl
9-chloro-3,4,6,7-tetrahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-c-
yclobutane]-2(1H)-carboxylate were dissolved in 0.5 ml of
tetrahydrofurane, 0.5 ml toluene and 5 .mu.l water. To this
solution 35 .mu.l (0.25 mmol) trimethylboroxine, 0.2 mg (0.4
.mu.mol) of
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2yl)phosphine
and 65.8 mg (0.31 mmol) of potassium phosphate were added and the
solution was degassed with Argon. 0.1 mg (0.4 .mu.mol) of
palladium(II)acetate were added and the reaction mixture was heated
at 100.degree. C. for 10 minutes in a microwave unit. The reaction
mixture was concentrated in vacuo. The residue was purified by
column chromatography on silica (eluent: 0-30% methanol in
dichloromethane) to yield 40 mg of the title compound.
[0781] ESI-MS [M+H.sup.+]=343.20
67.2 Preparation of
9-methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]-quinoline-8,-
1'-cyclobutane], Trifluoroacetic Acid
[0782] To 40 mg (0.12 mmol) of tert-butyl
9-methyl-3,4,6,7-tetrahydrospiro[[1,4]diazepino-[6,7,1-ij]quinoline-8,1'--
cyclobutane]-2(1H)-carboxylate in 3 ml dichloromethane were added
90 .mu.l (1.2 mmol) of trifluoroacetic acid at 0.degree. C. The
solution was stirred for 2 h at room temperature. The reaction
mixture was concentrated in vacuo. The residue was purified by
preparative HPLC to yield 4.6 mg of the title compound.
[0783] ESI-MS [M+H.sup.+]=243.20
[0784] .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta. [ppm]: 9.15 (bs,
2H), 6.95 (d, 1H), 6.80 (d, 1H), 4.15 (m, 2H), 3.30 (m, 2H), 3.25
(m, 2H), 3.10 (m, 2H), 2.85 (m, 2H), 2.70 (s, 3H), 2.20 (m, 2H),
2.00 (m, 2H), 1.85 (m, 2H).
Example 68
4,5,6,7,9,9a,9b,10,10a,
11-Decahydrocyclopropa[3,4]pyrrolo[1,2-a][1,4]diazepino[1,7,6-de]quinoxal-
ine
##STR00024##
[0786] The title compound was prepared in analogy to example 44
using however 1-fluoro-2-nitrobenzene and ethyl
3-azabicyclo[3.1.0]hexane-2-carboxylate as starting materials.
[0787] ESI-MS [M+H+]=242.20
[0788] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.65 (m,
1H), 6.35 (d, 1H), 6.30 (d, 1H), 3.65 (m, 1H), 3.60 (m, 1H), 3.35
(m, 4H), 3.30 (m, 1H), 2.90 (m, 3H), 2.55 (m, 1H), 1.65 (m, 1H),
1.60 (m, 1H), 0.50 (m, 1H), 0.15 (m, 1H).
Example 69
1-Ethyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline
(Compound of the Formula I.a, I.b or I.c in which the Combination
of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in Row A-289 in
Table A)
[0789] The title compound was prepared in analogy to example 33,
using however acetaldehyde instead of cyclobutanone.
[0790] ESI-MS [M+H.sup.+]=218.20
[0791] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.70 (m,
1H), 6.60 (d, 1H), 6.40 (d, 1H), 3.65 (s, 2H), 3.35 (m, 2H), 3.15
(m, 2H), 3.10 (m, 2H), 2.90 (m, 2H), 2.80 (m, 2H), 1.05 (t,
3H).
Example 70
1-Propyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline
(Compound of the Formula I.a, I.b or I.c in which the Combination
of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in Row A-325 in
Table A)
[0792] The title compound was prepared in analogy to example 33,
using however propionaldehyde instead of cyclobutanone.
[0793] ESI-MS [M+H.sup.+]=232.20
[0794] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.70 (m,
1H), 6.60 (d, 1H), 6.40 (d, 1H), 3.65 (s, 2H), 3.25 (m, 2H), 3.15
(m, 4H), 2.90 (m, 2H), 2.80 (m, 2H), 1.50 (m, 2H), 0.90 (t,
3H).
Example 71
1-Cyclobutyl-5-methyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]qui-
noxaline (Compound of the Formula I.Gg, I.Hh or I.II in which the
Combination of R.sup.5A, R.sup.5B, R.sup.6 and R.sup.9a is as in
Row a-433 in Table a)
[0795] The title compound was prepared in analogy to example 33,
using tert-butyl
5-methyl-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline-7(8H)--
carboxylate and cyclobutanone. tert-Butyl
5-methyl-2,3,5,6-tetrahydro-1H-[1,4]diazepino[1,7,6-de]quinoxaline-7(8H)--
carboxylate was prepared in analogy to example 30 however using
2-bromopropaneamide instead of 2-chloroacetamide and in analogy to
example 32.
[0796] ESI-MS [M+H.sup.+]=258.20
[0797] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.65 (m,
1H), 6.55 (d, 1H), 6.45 (d, 1H), 3.90 (m, 1H), 3.80 (m, 1H), 3.55
(m, 1H), 3.30-3.15 (m, 3H), 3.10 (m, 1H), 2.95 (m, 1H), 2.85 (m,
1H), 2.75 (m, 1H), 2.20 (m, 1H), 2.15 (m, 1H), 2.05 (m, 2H), 1.65
(m, 2H), 0.9 (d, 3H).
Example 72
5-Methyl-1-(oxetan-3-yl)-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]-
quinoxaline (Compound of the Formula I.Gg, I.Hh or I.ii in which
the Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as
in Row A-541 in Table A)
[0798] The title compound was prepared in analogy to example 71,
using however oxetane-3-one instead of cyclobutanone.
[0799] ESI-MS [M+H.sup.+]=260.20
[0800] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.60 (m,
1H), 6.55 (d, 1H), 6.05 (d, 1H), 4.80 (m, 1H), 4.75 (m, 1H), 4.65
(m, 1H), 4.60 (m, 1H), 4.45 (m, 1H), 3.80 (d, 1H), 3.50 (d, 1H),
3.35 (m, 2H), 3.15 (m, 2H), 2.90 (m, 1H), 2.85 (m, 1H), 2.75 (m,
1H), 0.9 (d, 3H).
Example 73
1-Ethyl-5-methyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxal-
ine (Compound of the Formula I.Gg, I.Hh or I.ii in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-289 in Table A)
[0801] The title compound was prepared in analogy to example 71,
using however acetaldehyde instead of cyclobutanone.
[0802] ESI-MS [M+H.sup.+]=232.20
[0803] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.80 (m,
1H), 6.65 (d, 1H), 6.50 (d, 1H), 3.95 (d, 1H), 3.80 (d, 1H),
3.45-3.05 (m, 8H), 2.85 (m, 1H), 1.15 (t, 3H), 1.00 (d, 3H).
Example 74
5-Methyl-1-propyl-2,3,5,6,7,8-hexahydro-1H-[1,4]diazepino[1,7,6-de]quinoxa-
line (Compound of the Formula I.Gg, I.Hh or I.ii in which the
Combination of R.sup.5a, R.sup.5b, R.sup.6 and R.sup.9a is as in
Row A-325 in Table A)
[0804] The title compound was prepared in analogy to example 71,
using however propionaldehyde instead of cyclobutanone.
[0805] ESI-MS [M+H.sup.+]=246.20
[0806] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): .delta. [ppm]: 6.80 (m,
1H), 6.60 (d, 1H), 6.50 (d, 1H), 3.95 (d, 1H), 3.80 (d, 1H), 3.30
(m, 4H), 3.20 (m, 2H), 3.10 (m, 1H), 3.00 (m, 1H), 2.80 (m, 1H),
1.60 (m, 2H), 0.95 (d, 3H), 0.90 (t, 3H).
Example 75
9-Chloro-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1'-
-cyclobutane], Trifluoroacetic Acid (Compound of the Formula I.g in
which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8 and
R.sup.9a is as in Row B-323 in Table B)
[0807] The title compound was prepared in analogy to example 1
using tert-butyl
8-chloro-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate
and 2-cyclobutylideneacetyl chloride as starting materials.
[0808] ESI-MS [M+H.sup.+]=236.10
[0809] .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta. [ppm]: 9.60 (bs,
2H), 7.00 (m, 2H), 4.15 (s, 2H), 3.25 (m, 6H), 3.10 (m, 2H), 2.15
(m, 2H), 2.05 (m, 2H), 1.75 (m, 2H).
Example 76
10-Methyl-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1-
'-cyclobutane], Trifluoroacetic Acid (Compound of the Formula I.h
in which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8
and R.sup.9a is as in Row B-325 in Table B)
[0810] ESI-MS [M+H.sup.+]=243.20
[0811] .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta. [ppm]: 9.35 (bs,
2H), 7.40 (s, 1H), 6.90 (s, 1H), 4.15 (m, 2H), 3.35 (m, 2H), 3.25
(m, 2H), 3.15 (m, 2H), 2.40 (m, 2H), 2.30 (s, 3H), 2.15-1.90 (m,
6H).
Example 77
10-Chloro-1,2,3,4,6,7-hexahydrospiro[[1,4]diazepino[6,7,1-ij]quinoline-8,1-
'-cyclobutane], Trifluoroacetic Acid (Compound of the Formula I.h
in which the Combination of R.sup.5a, R.sup.5b, R.sup.7, R.sup.8
and R.sup.9a is as in Row B-323 in Table B)
[0812] ESI-MS [M+H.sup.+]=236.10
[0813] .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta. [ppm]: 9.65 (bs,
2H), 7.55 (s, 1H), 7.05 (s, 1H), 4.15 (s, 2H), 3.30 (m, 4H), 3.20
(m, 2H), 2.35 (m, 2H), 2.15-1.90 (m, 6H).
II. Biological Tests
Functional Activity
[0814] The functional activity of compounds of formula I was
assayed by incubation with U2OS_HTR.sub.2C--.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 (3-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.
[0815] 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
((LogEC50-x)*HillSlope))res=(y-fit)). Results are compiled in the
table below.
TABLE-US-00003 TABLE Potency (EC50) in # functional assay %
efficacy 1 ++ 71 6 ++ 63 8 ++ 40 9 +++ 61 16 + 55 17 ++ 84 19 ++ 25
22 ++ 69 25 ++ 90 26 +++ 107 27 + 87 28 ++ 55 33 + 78 35 ++ 112 36
+ 31 37 + 21 40 ++ 131 41 + 75 42 +++ 163 43 + 59 44 ++ 55 45 ++ 77
46 + 71 47 ++ 59 48 ++ 105 49 + 78 51 ++ 102 54 + 24 55 + 26 56 +++
124 57 + 35 59 ++ 51 66 + 53 67 +++ 116 68 ++ 76 69 + 54 70 ++ 63
76 +++ 98 Potency (EC50): + from 200 nM to <1 .mu.M ++ from 20
nM to <200 nM +++ <20 nM
* * * * *